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Background/Aim: This research investigated the biophysical properties, safety, and efficacy of polydioxanone (PDO) filler compared to poly-L-lactic acid (PLLA), polycaprolactone (PCL), and hyaluronic acid (HA) fillers. In both mouse and human skin models, a novel collagen stimulation was compared with hyaluronic acid filler. Materials and Methods: An electron microscope was used to capture images of the solid particle microsphere shape. Moreover, animal models named SKH1-Hrhr were used to assess the 12-week persistence of PDO, PLLA, or PCL filler. H&E and Sirus Red staining were used to compare collagen density. Five participants in the clinical trial received three injections in the dermis over an eight-month period. Skin density, wrinkles, and gloss were evaluated using DUB(®) skin scanner, Antera 3D CS, Mark-Vu, and Skin gloss meter after injection to assess the efficacy of fillers. Results: PDO microspheres had uneven surfaces and were spherical and consistent in size. In comparison to other fillers, the PDO filler demonstrated complete biodegradability in just 12 weeks and better neocollagenesis, and a lower inflammatory response than the HA filler. After three injections, the human body assay showed a significant improvement in skin gloss, wrinkles, and density. Conclusion: In comparison to PCL and PLLA, PDO filler demonstrated a comparable volume increase rate and better biodegradability. Furthermore, although its physical characteristics are similar to those of a solid, PDO has the advantage of being more organically spread. In photoaging mice, PDO fillers are thought to offer equivalent or superior anti-wrinkle and anti-aging effects to PBS, PCL, and PLLA.

INTRODUCTION: We evaluated real-world data on the patterns and outcomes of radiotherapy (RT) for brain metastases (BM) in a population-based cohort of patients with lung cancer (LC) in Victoria. METHODS: The Victorian Radiotherapy Minimum Data set (VRMDS) and the Victorian Cancer Registry (VCR) were linked to identify patients with LC who underwent RT for BM between 2013 and 2016. We determined: (i) proportion of patients treated with stereotactic radiosurgery (SRS); (ii) overall survival (OS); and (iii) 30-day mortality (30M) following RT for BM. RESULTS: Of the 1001 patients included in the study, 193 (19%) had SRS. There was no significant increase in SRS use over time - from 18% in 2013 to 21% in 2016 (P-trend = 0.8). In multivariate analyses, increased age (P = 0.03) and treatment in regional centres (P

Additional file 5: Fig. S4. Spline curves for the hazard ratio of 1-year all-cause mortality according to glucose variability. Glycemic variability was presented by (A) standard deviation (SD) of serum glucose levels and (B) coefficient of variation (CoV) of serum glucose levels.

Additional file 2: Fig. S1. Scatter plot of the blood glucose level of all subjects (at the time of admission, minimum, maximum values during hospitalization, and at discharge, respectively).

Additional file 4: Fig. S3. Scatter plots of the blood glucose level of the subjects (at the time of admission, minimum, maximum values during hospitalization, and at discharge, respectively) according to the use of insulin during hospitalization were presented. The plot on the left is a plot of patients who used insulin, and the plot on the right is a plot of patients who did not use insulin.

Additional file 1: Additional Tables.

Additional file 3: Fig. S2. Scatter plots of the blood glucose level of the subjects (at the time of admission, minimum, maximum values during hospitalization, and at discharge, respectively) according to the presence of diabetes were presented. The plot on the left is for diabetic patients, and the plot on the right is for non-diabetic patients.

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3-50, P

To identify genetic determinants of airway dysfunction, we performed a transcriptome-wide association study for asthma by combining RNA-seq data from the nasal airway epithelium of 681 children, with UK Biobank genetic association data. Our airway analysis identified 95 asthma genes, 58 of which were not identified by transcriptome-wide association analyses using other asthma-relevant tissues. Among these genes were MUC5AC, an airway mucin, and FOXA3, a transcriptional driver of mucus metaplasia. Muco-ciliary epithelial cultures from genotyped donors revealed that the MUC5AC risk variant increases MUC5AC protein secretion and mucus secretory cell frequency. Airway transcriptome-wide association analyses for mucus production and chronic cough also identified MUC5AC. These cis-expression variants were associated with trans effects on expression; the MUC5AC variant was associated with upregulation of non-inflammatory mucus secretory network genes, while the FOXA3 variant was associated with upregulation of type-2 inflammation-induced mucus-metaplasia pathway genes. Our results reveal genetic mechanisms of airway mucus pathobiology.

Hepatitis E virus (HEV) is a causative agent of acute hepatitis and jaundice. The number of human infections is approximated to be over 20 million cases per year. The transmission is mainly via the fecal-oral route and contaminated water and food are considered to be a major source of infection. As a mouse model is not available, a recent development of a cell culture-adapted HEV strain (47832c) is considered as a very important tools for molecular analysis of HEV pathogenesis in cells. Previously, we demonstrated that HEV-encoded methyltransferase (MeT) encoded by the 47832c strain inhibits MDA5- and RIG-I-mediated activation of interferon β (IFN-β) promoter. Here, we report that MeT impairs the phosphorylation and activation of interferon regulatory factor 3 and the p65 subunit of NF-κB in a dose-dependent manner. In addition, the MeT encoded by the 47832c, but not that of HEV clinical or field isolates (SAR-55, Mex-14, KC-1, and ZJ-1), displays the inhibitory effect. A deeper understanding of MeTmediated suppression of IFN-β expression would provide basis of the cell culture adaptation of HEV.

Scripts or steps used in Horowitz et al. 2021* to:(i) perform GWAS withREGENIE; (ii) analyze RNA-seq data for ACE2; and (iii) estimate continental ancestries. *Genome-wide analysis provides genetic evidence that ACE2 expression influences COVID-19 risk and yields risk scores associated with severe disease. Nature Genetics (in press)

The Toxicology Investigators Consortium (ToxIC) Registry was established by the American College of Medical Toxicology in 2010. The registry collects data from participating sites with the agreement that all bedside and telehealth medical toxicology consultation will be entered. This eleventh annual report summarizes the Registry's 2020 data and activity with its additional 6668 cases. Cases were identified for inclusion in this report by a query of the ToxIC database for any case entered from January 1 to December 31, 2020. Detailed data was collected from these cases and aggregated to provide information which included demographics, reason for medical toxicology evaluation, agent and agent class, clinical signs and symptoms, treatments and antidotes administered, mortality, and whether life support was withdrawn. Gender distribution included 50.6% cases in females, 48.4% in males, and 1.0% identifying as transgender. Non-opioid analgesics were the most commonly reported agent class, followed by opioid and antidepressant classes. Acetaminophen was once again the most common agent reported. There were 80 fatalities, comprising 1.2% of all registry cases. Major trends in demographics and exposure characteristics remained similar to past years' reports. Sub-analyses were conducted to describe race and ethnicity demographics and exposures in the registry, telemedicine encounters, and cases related to the COVID-19 pandemic.

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias.

Traditional Hardy-Weinberg equilibrium (HWE) tests (the χ2 test and the exact test) have long been used as a metric for evaluating genotype quality, as technical artifacts leading to incorrect genotype calls often can be identified as deviations from HWE. However, in data sets composed of individuals from diverse ancestries, HWE can be violated even without genotyping error, complicating the use of HWE testing to assess genotype data quality. In this manuscript, we present the Robust Unified Test for HWE (RUTH) to test for HWE while accounting for population structure and genotype uncertainty, and to evaluate the impact of population heterogeneity and genotype uncertainty on the standard HWE tests and alternative methods using simulated and real sequence data sets. Our results demonstrate that ignoring population structure or genotype uncertainty in HWE tests can inflate false-positive rates by many orders of magnitude. Our evaluations demonstrate different tradeoffs between false positives and statistical power across the methods, with RUTH consistently among the best across all evaluations. RUTH is implemented as a practical and scalable software tool to rapidly perform HWE tests across millions of markers and hundreds of thousands of individuals while supporting standard VCF/BCF formats. RUTH is publicly available at https://www.github.com/statgen/ruth.

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)1. In the first 53,831 TOPMed samples, we detected more than 400million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.

Additional file 1: Figure S1. Flow chart for study subject selection. Table S1. Composition of the oral hypoglycemic medication for the OHA-only group and both OHAs and insulin group. Table S2. Insulin treatment in KorAHF registry. Table S3. Mortality rates according to hypoglycemic therapy among the patients with diabetes and heart failure. Table S4. Association between diabetes therapy and overall mortality according to age in the pseudo-cohort. Table S5. Association between diabetes therapy and overall mortality according to sex in the pseudo-cohort. Table S6. Association between diabetes therapy and overall mortality according to ischemic etiology in the pseudo-cohort. Table S7. Association between diabetes therapy and overall mortality according to left ventricular ejection fraction in the pseudo-cohort. Table S8. Association between diabetes therapy and overall mortality according to glycated hemoglobin levels in the pseudo-cohort. Table S9. Association between diabetes therapy and overall mortality according to severity of heart failure in the pseudo-cohort. Table S10. Overall mortality according to diabetes therapy in stratified population by diabetes mellitus medication in the weighted pseudo-cohort.

Animals locomote for various reasons: to search for food, find suitable habitat, pursue prey, escape from predators, or seek a mate. The grand scale of biodiversity contributes to the great locomotory design and mode diversity. Various creatures make use of legs, wings, fins and other means to move through the world. In this report, we refer to the locomotion of general biological species as biolocomotion. We present a computational approach to detect biolocomotion in unprocessed video. Significantly, the motion exhibited by the body parts of a biological entity to navigate through an environment can be modeled by a combination of an overall positional advance with an overlaid asymmetric oscillatory pattern, a distinctive signature that tends to be absent in non-biological objects in locomotion. We exploit this key trait of positional advance with asymmetric oscillation along with differences in an object's common motion (extrinsic motion) and localized motion of its parts (intrinsic motion) to detect biolocomotion. An algorithm is developed to measure the presence of these traits in tracked objects to determine if they correspond to a biological entity in locomotion. An alternative algorithm, based on generic features combined with learning is assembled out of components from allied areas of investigation, also is presented as a basis of comparison. A novel biolocomotion dataset encompassing a wide range of moving biological and non-biological objects in natural settings is provided. Also, biolocomotion annotations to an extant camouflage animals dataset are provided. Quantitative results indicate that the proposed algorithm considerably outperforms the alternative approach, supporting the hypothesis that biolocomotion can be detected reliably based on its distinct signature of positional advance with asymmetric oscillation and extrinsic/intrinsic motion dissimilarity.

Additional file 1.

Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of the protein. This includes ZNF529:p.K405X, which is associated with decreased low-density-lipoprotein (LDL) cholesterol (P = 1.3 × 10-8) without being associated with liver enzymes or non-fasting blood glucose. Silencing of ZNF529 in human hepatoma cells results in upregulation of LDL receptor and increased LDL uptake in the cells. This suggests that inhibition of ZNF529 or its gene product should be prioritized as a novel candidate drug target for treating dyslipidemia and associated CVD.

The Toxicology Investigators Consortium (ToxIC) Registry was established by the American College of Medical Toxicology (ACMT) in 2010. The Registry collects data from participating sites with the agreement that all bedside medical toxicology consultation will be entered. This tenth annual report summarizes the Registry's 2019 data and activity with its additional 7177 cases. Cases were identified for inclusion in this report by a query of the ToxIC database for any case entered from 1 January to 31 December 2019. Detailed data was collected from these cases and aggregated to provide information which included demographics, reason for medical toxicology evaluation, agent and agent class, clinical signs and symptoms, treatments and antidotes administered, mortality, and whether life support was withdrawn. 50.7% of cases were female, 48.5% were male, and 0.8% were transgender. Non-opioid analgesics was the most commonly reported agent class, followed by opioid and antidepressant classes. Acetaminophen was once again the most common agent reported. There were 91 fatalities, comprising 1.3% of all Registry cases. Major trends in demographics and exposure characteristics remained similar to past years' reports. Sub-analyses were conducted to describe exposures in cases of self-harm, gender differences in substance use disorder, and trends in addiction medicine and pain management consultations.

High vertical resolution profiles of atmospheric state variables are required when one intends to define the evaporation duct, an atmospheric phenomenon that significantly affects surface radar propagation in the atmosphere. Results from mesoscale models have low vertical resolution and cannot resolve the evaporative ducts. Direct measurements by rawinsonde are also problematic at the lowest level, where they are affected by flow distortion and thermal effect induced by the ship. This research evaluated a physics-based blending scheme to append a reasonable surface layer M-profile to soundings profiles. The “blending” technique can be used to extend the measured or model refractivity profiles down to the surface layer to include the evaporation duct. The basic framework used COAMPS in a single column mode with high vertical resolution and thus was capable of resolving the evaporation duct. In this study, results from the single column model (SCM) are compared to profiles from tethered balloon measurements on small boats, an effort of the Coupled Air-Sea Processes and Electromagnetic Ducting Research project. Lieutenant, Taiwan Navy Approved for public release. distribution is unlimited

Purpose To describe adverse drug reactions (ADRs) to carbamazepine (CBZ) and oxcarbazepine (OXC), including severe cutaneous ADRs, at a tertiary care hospital over a 10-year period. Materials and methods The frequency and clinical features of ADRs caused by CBZ and OXC were analyzed using the pharmacovigilance database and spontaneous ADR reporting data of Yonsei University Severance Hospital & Dental Hospital (Seoul, Korea) from January 1, 2010 to January 31, 2020. Results Among 10419 cases prescribed CBZ and OXC, 204 ADR cases were reported. The incidences of ADRs were 1.8% and 2.2% for CBZ and OXC respectively, with no significant difference (p=0.169). The most common clinical presentations were skin disorders. Female patients had relatively more frequent ADRs than male patients. Although mild skin ADRs were more frequent with OXC, nervous system disorders, general disorders, and hepatobiliary disorders occurred more often with CBZ. There were six reports of severe cutaneous adverse reactions to CBZ, while OXC had none. Both CBZ and OXC caused ADRs at daily doses lower than the recommended initial dose. Conclusion Due to lower incidence of severe ADRs with OXC than CBZ, we suggest OXC as a first-line prescription.

The Toxicology Investigators Consortium (ToxIC) Registry was established by the American College of Medical Toxicology (ACMT) in 2010. The Registry collects data from participating sites with the agreement that all bedside medical toxicology consultation will be entered. The objective of this ninth annual report is to summarize the Registry's 2018 data and activity with its additional 7043 cases. Cases were identified for inclusion in this report by a query of the ToxIC database for any case entered from 1 January to 31 December 2018. Detailed data was collected from these cases and aggregated to provide information which included demographics, reason for medical toxicology evaluation, agent and agent class, clinical signs and symptoms, treatments and antidotes administered, mortality, and whether life support was withdrawn. A total of 51.5% of cases were female, 48% were male, and 0.6% transgender. Non-opioid analgesics were the most commonly reported agent class, followed by antidepressants and opioids. Acetaminophen was once again the most common agent reported. There were 106 fatalities, comprising 1.5% of all registry cases. Major trends in demographics and exposure characteristics remained similar to past years' reports. Sub-analyses were conducted to describe exposures in elderly patients, addiction consultation practices, and risk factors for bupropion-induced seizures. The launch of the ToxIC Qualified Clinical Data Registry (TQCDR) is also described.

Heritability is a fundamental parameter in genetics. Traditional estimates based on family or twin studies can be biased due to shared environmental or non-additive genetic variance. Alternatively, those based on genotyped or imputed variants typically underestimate narrow-sense heritability contributed by rare or otherwise poorly tagged causal variants. Identical-by-descent (IBD) segments of the genome share all variants between pairs of chromosomes except new mutations that have arisen since the last common ancestor. Therefore, relating phenotypic similarity to degree of IBD sharing among classically unrelated individuals is an appealing approach to estimating the near full additive genetic variance while possibly avoiding biases that can occur when modeling close relatives. We applied an IBD-based approach (GREML-IBD) to estimate heritability in unrelated individuals using phenotypic simulation with thousands of whole-genome sequences across a range of stratification, polygenicity levels, and the minor allele frequencies of causal variants (CVs). In simulations, the IBD-based approach produced unbiased heritability estimates, even when CVs were extremely rare, although precision was low. However, population stratification and non-genetic familial environmental effects shared across generations led to strong biases in IBD-based heritability. We used data on two traits in ~120,000 people from the UK Biobank to demonstrate that, depending on the trait and possible confounding environmental effects, GREML-IBD can be applied to very large genetic datasets to infer the contribution of very rare variants lost using other methods. However, we observed apparent biases in these real data, suggesting that more work may be required to understand and mitigate factors that influence IBD-based heritability estimates.

이 연구는 초등학교에서 여자 축구부를 담당하는 초임 여교사가 축구부를 지도하는 과정에서의 경험과 그 의미를 자문화기술지를 통해 드러내고자 하였다. 이를 위해 2016년 3월부터 동년 12월까지 여자 축구부를 지도하면서 작성한 회상 자료, 지도 일지, 심층 면담 자료, 문서 자료 등을 수집하였고 자료 분석은 Spradley(1979)가 제안한 영역분석과 분류분석 방법을 실시하였다. 연구결과, 연구자는 경력을 중시하고 남성 위주로 조성되는 운동부 지도자 문화 속에서 자신의 운동부 지도 전문성 부족과 학생들의 패배의식 극복에 대한 강박관념 등으로 자존감 하락과 심리적 소진을 경험하였다. 또한 일방적인 지시와 지나치게 안전을 강요하는 학교행정가의 태도, 주먹구구식 역할 부여, 여자코치의 잦은 교체로 인해 지도에 어려움을 겪는 등 비체계적이며 모순된 운동부 운영 구조를 경험하였다. 축구부 지도 경험의 의미는 다음과 같다. 원활한 운동부 지도를 위해서는 해당 운동 종목에 대한 지식과 소양이 요구됨을 알 수 있었다. 동료교사들의 지지와 응원은 운동부 운영 지속의 동력이 되고 있었다. 운동부 운영의 문제점 해결을 위해서는 적극적인 자세로 개선을 요구하는 용기가 필요하나 침묵하는 자신의 모습을 발견하였다. 마지막으로 운동부 지도교사와 학급 담임 업무의 병행 과정에서의 갈등 극복은 연구자 자신의 업무 유능감을 키울 수 있는 좋은 기회가 되었다.