Whole-exome sequencing in familial type 2 diabetes identifies an atypical missense variant in the RyR2 gene.

Genome-wide association studies have identified several hundred loci associated with type 2 diabetes mellitus (T2DM). Additionally, pathogenic variants in several genes are known to cause monogenic diabetes that overlaps clinically with T2DM. Whole-exome sequencing of related individuals with T2DM is a powerful approach to identify novel high-penetrance disease variants in coding regions of the genome. We performed whole-exome sequencing on four related individuals with T2DM - including one individual diagnosed at the age of 33 years. The individuals were negative for mutations in monogenic diabetes genes, had a strong family history of T2DM, and presented with several characteristics of metabolic syndrome. A missense variant (p.N2291D) in the type 2 ryanodine receptor (RyR2) gene was one of eight rare coding variants shared by all individuals. The variant was absent in large population databases and affects a highly conserved amino acid located in a mutational hotspot for pathogenic variants in Catecholaminergic polymorphic ventricular tachycardia (CPVT). Electrocardiogram data did not reveal any cardiac abnormalities except a lower-than-normal resting heart rate (< 60 bpm) in two individuals - a phenotype observed in CPVT individuals with RyR2 mutations. RyR2-mediated Ca2+ release contributes to glucose-mediated insulin secretion and pathogenic RyR2 mutations cause glucose intolerance in humans and mice. Analysis of glucose tolerance testing data revealed that missense mutations in a CPVT mutation hotspot region - overlapping the p.N2291D variant - are associated with complete penetrance for glucose intolerance. In conclusion, we have identified an atypical missense variant in the RyR2 gene that co-segregates with diabetes in the absence of overt CPVT.

The prevalence and impact of psychiatric comorbidities on hospitalized inflammatory bowel disease patients in the United States: insights from the National Inpatient Sample from 2009-2018.

Background: Patients with inflammatory bowel disease (IBD) are at increased risk of anxiety and mood disorders. This study examines the temporal trends and clinical impact of anxiety and mood disorder diagnoses in hospitalized IBD patients in the United States during a 10-year period. Methods: Using the National Inpatient Sample from 2009-2018, all IBD-related discharges in adults were analyzed. Primary outcomes were the prevalence and temporal trends of mood disorder and anxiety diagnoses for IBD-related admissions. The impact of the psychiatric comorbidities on clinical outcomes was also evaluated. Results: A total of 1,718,736 IBD-related discharged were identified. A diagnosis of anxiety or a mood disorder was found to have a prevalence of 16.44% and 18.97%, respectively, amongst IBD-related admissions. The prevalence of anxiety disorders amongst hospitalized IBD patients increased significantly (from 12.13% to 20.26%), whereas the prevalence of mood disorders did not (17.46% and 18.9%). IBD admissions with psychiatric comorbidities had lower rates of IBD-related complications or mortality during hospitalization compared to IBD admissions without comorbid psychiatric diagnoses. This population, however, was more likely to experience certain comorbidities such as Clostridioides difficile, pneumonia, and venous thromboembolism, as well as a longer hospitalization. Conclusions: The prevalence of comorbid anxiety among hospitalized IBD patients in the United States matches or exceeds the prevalence of anxiety in the general hospitalized population. Given its association with more in-hospital complications and a longer hospital stay, it is important to further understand how psychological screening and mental health services can improve the management of hospitalized IBD patients.

Role of continuous pulse oximetry and capnography monitoring in the prevention of postoperative respiratory failure, postoperative opioid-induced respiratory depression and adverse outcomes on hospital wards: A systematic review and meta-analysis.

OBJECTIVE: The current standards of postoperative respiratory monitoring on medical-surgical floors involve spot-pulse oximetry checks every 4-8 h, which can miss the opportunity to detect prolonged hypoxia and acute hypercapnia. Continuous respiratory monitoring can recognize acute respiratory depression episodes; however, the existing evidence is limited. We sought to review the current evidence on the effectiveness of continuous pulse oximetry (CPOX) with and without capnography versus routine monitoring and their effectiveness for detecting postoperative respiratory failure, opioid-induced respiratory depression, and preventing downstream adverse events. METHODS: We performed a systematic literature search on Ovid Medline, Embase, and Cochrane Library databases for articles published between 1990 and April 2023. The study protocol was registered in Prospero (ID: 439467), and PRISMA guidelines were followed. The NIH quality assessment tool was used to assess the quality of the studies. Pooled analysis was conducted using the software R version 4.1.1 and the package meta. The stability of the results was assessed using sensitivity analysis. DESIGN: Systematic Review and Meta-Analysis. SETTING: Postoperative recovery area. PATIENTS: 56,538 patients, ASA class II to IV, non-invasive respiratory monitoring, and post-operative respiratory depression. INTERVENTIONS: Continuous pulse oximetry with or without capnography versus routine monitoring. MEASUREMENTS: Respiratory rate, oxygen saturation, adverse events, and rescue events. RESULTS: 23 studies (17 examined CPOX without capnography and 5 examined CPOX with capnography) were included in this systematic review. CPOX was better at recognizing desaturation (SpO2 < 90%) OR: 11.94 (95% CI: 6.85, 20.82; p < 0.01) compared to standard monitoring. No significant differences were reported for ICU transfer, reintubation, and non-invasive ventilation between the two groups. CONCLUSIONS: Oxygen desaturation was the only outcome better detected with CPOX in postoperative patients in hospital wards. These comparisons were limited by the small number of studies that could be pooled for each outcome and the heterogeneity between the studies.

Effect of breathing exercises on blood pressure and heart rate: A systematic review and meta-analysis.

Background: Breathing exercises have been reported to have positive physiological effects on the body. The incidence of hypertension has become a major risk factor for cardiac complications leading to higher morbidity and mortality. Our aim was to conduct a systematic review and meta-analysis to study the effect of breathing exercises on blood pressure (BP) and heart rate (HR). Methods: A systematic review and meta-analysis analyzing randomized clinical trials (RCTs) about the effect of breathing exercises on blood pressure was conducted (PROSPERO Registration ID: CRD42022316413). PubMed, ScienceDirect, WebofScience, and Cochrane Library databases were screened for RCTs from January 2017 to September 2022. The main search terms included "breathing exercise", "Pranayam", "Bhramari", "alternate nostril breathing", "deep breathing", "slow breathing", "hypertension", and "high blood pressure". The primary outcome was the value of the systolic blood pressure and diastolic blood pressure after the intervention. The effect on heart rate was also analyzed as a secondary outcome. Results: A total of 15 studies were included in the meta-analysis. Breathing exercises have a modest but significant effect on decreasing systolic blood pressure (-7.06 [-10.20, -3.92], P = <0.01) and diastolic blood pressure (-3.43 [-4.89, -1.97], P = <0.01) mm Hg. Additionally, breathing exercises were also observed to cause a significant decrease in the heart rate (-2.41 [-4.53, -0.30], P = 0.03) beats/minute. Conclusion: In a comprehensive systematic review and meta-analysis of breathing exercises and its effect on BP and HR, there is a moderate but significant positive effect. The studies are not deprived of bias.

Validation of automated data abstraction for SCCM discovery VIRUS COVID-19 registry: practical EHR export pathways (VIRUS-PEEP).

Background: The gold standard for gathering data from electronic health records (EHR) has been manual data extraction; however, this requires vast resources and personnel. Automation of this process reduces resource burdens and expands research opportunities. Objective: This study aimed to determine the feasibility and reliability of automated data extraction in a large registry of adult COVID-19 patients. Materials and methods: This observational study included data from sites participating in the SCCM Discovery VIRUS COVID-19 registry. Important demographic, comorbidity, and outcome variables were chosen for manual and automated extraction for the feasibility dataset. We quantified the degree of agreement with Cohen's kappa statistics for categorical variables. The sensitivity and specificity were also assessed. Correlations for continuous variables were assessed with Pearson's correlation coefficient and Bland-Altman plots. The strength of agreement was defined as almost perfect (0.81-1.00), substantial (0.61-0.80), and moderate (0.41-0.60) based on kappa statistics. Pearson correlations were classified as trivial (0.00-0.30), low (0.30-0.50), moderate (0.50-0.70), high (0.70-0.90), and extremely high (0.90-1.00). Measurements and main results: The cohort included 652 patients from 11 sites. The agreement between manual and automated extraction for categorical variables was almost perfect in 13 (72.2%) variables (Race, Ethnicity, Sex, Coronary Artery Disease, Hypertension, Congestive Heart Failure, Asthma, Diabetes Mellitus, ICU admission rate, IMV rate, HFNC rate, ICU and Hospital Discharge Status), and substantial in five (27.8%) (COPD, CKD, Dyslipidemia/Hyperlipidemia, NIMV, and ECMO rate). The correlations were extremely high in three (42.9%) variables (age, weight, and hospital LOS) and high in four (57.1%) of the continuous variables (Height, Days to ICU admission, ICU LOS, and IMV days). The average sensitivity and specificity for the categorical data were 90.7 and 96.9%. Conclusion and relevance: Our study confirms the feasibility and validity of an automated process to gather data from the EHR.

Clinical Research With Large Language Models Generated Writing-Clinical Research with AI-assisted Writing (CRAW) Study.

IMPORTANCE: The scientific community debates Generative Pre-trained Transformer (GPT)-3.5's article quality, authorship merit, originality, and ethical use in scientific writing. OBJECTIVES: Assess GPT-3.5's ability to craft the background section of critical care clinical research questions compared to medical researchers with H-indices of 22 and 13. DESIGN: Observational cross-sectional study. SETTING: Researchers from 20 countries from six continents evaluated the backgrounds. PARTICIPANTS: Researchers with a Scopus index greater than 1 were included. MAIN OUTCOMES AND MEASURES: In this study, we generated a background section of a critical care clinical research question on "acute kidney injury in sepsis" using three different methods: researcher with H-index greater than 20, researcher with H-index greater than 10, and GPT-3.5. The three background sections were presented in a blinded survey to researchers with an H-index range between 1 and 96. First, the researchers evaluated the main components of the background using a 5-point Likert scale. Second, they were asked to identify which background was written by humans only or with large language model-generated tools. RESULTS: A total of 80 researchers completed the survey. The median H-index was 3 (interquartile range, 1-7.25) and most (36%) researchers were from the Critical Care specialty. When compared with researchers with an H-index of 22 and 13, GPT-3.5 was marked high on the Likert scale ranking on main background components (median 4.5 vs. 3.82 vs. 3.6 vs. 4.5, respectively; p < 0.001). The sensitivity and specificity to detect researchers writing versus GPT-3.5 writing were poor, 22.4% and 57.6%, respectively. CONCLUSIONS AND RELEVANCE: GPT-3.5 could create background research content indistinguishable from the writing of a medical researcher. It was marked higher compared with medical researchers with an H-index of 22 and 13 in writing the background section of a critical care clinical research question.

Pneumothorax, pneumomediastinum, and subcutaneous emphysema in hospitalized COVID-19 patients: incidence, clinical characteristics, and outcomes.

BACKGROUND: Limited data is available on the incidence and outcomes of pneumothorax (PTX), pneumomediastinum (PNM), and subcutaneous emphysema (SCE) in COVID-19 patients. This study aimed to investigate the characteristics of these complications in hospitalized COVID-19 patients. RESEARCH DESIGN AND METHODS: A retrospective study was conducted, involving adult COVID-19 patients admitted to Mayo Clinic Florida from 03/2020-06/2022. Patients were divided into two groups based on the presence or absence of PTX/PNM/SCE. RESULTS: 1926 hospitalized patients with COVID-19 were included, of which 518 were admitted to the ICU. The incidence of PTX/PNM/SCE was 6.3%. Patients with these complications were more likely to be male, Asian, and unvaccinated. Conversely, they were less likely to have chronic obstructive pulmonary disease. Patients who developed PTX/PNM/SCE after 72 hours of admission were more likely to receive high-dose corticosteroids and for an extended duration. The affected group had an adjusted odds ratio for in-hospital mortality of 13.32 (95%CI, 8.19-21.59) and ICU admission of 9.14 (95%CI, 5.3-12.78) compared to the unaffected group. CONCLUSION: Although the occurrence of PTX/PNM/SCE in hospitalized COVID-19 patients was rare, it was associated with worse outcomes. Corticosteroids may contribute to the pathogenesis of these complications; however, further studies are needed to investigate this relationship in more detail.

SARS-CoV-2 infection induces epigenetic changes in the LTR69 subfamily of endogenous retroviruses.

Accumulating evidence suggests that endogenous retroviruses (ERVs) play an important role in the host response to infection and the development of disease. By analyzing ChIP-sequencing data sets, we show that SARS-CoV-2 infection induces H3K27 acetylation of several loci within the LTR69 subfamily of ERVs. Using functional assays, we identified one SARS-CoV-2-activated LTR69 locus, termed Dup69, which exhibits regulatory activity and is responsive to the transcription factors IRF3 and p65/RELA. LTR69_Dup69 is located about 500 bp upstream of a long non-coding RNA gene (ENSG00000289418) and within the PTPRN2 gene encoding a diabetes-associated autoantigen. Both ENSG00000289418 and PTPRN2 showed a significant increase in expression upon SARS-CoV-2 infection. Thus, our study sheds light on the interplay of exogenous with endogenous viruses and helps to understand how ERVs regulate gene expression during infection.

ViSHWaS: Violence Study of Healthcare Workers and Systems-a global survey.

OBJECTIVE: To provide insights into the nature, risk factors, impact and existing measures for reporting and preventing violence in the healthcare system. The under-reporting of violence against healthcare workers (HCWs) globally highlights the need for increased public awareness and education. METHODS: The Violence Study of Healthcare Workers and Systems study used a survey questionnaire created using Research Electronic Data Capture (REDCap) forms and distributed from 6 June to 9 August 2022. Logistic regression analysis evaluated violence predictors, including gender, age, years of experience, institution type, respondent profession and night shift frequency. A χ2 test was performed to determine the association between gender and different violence forms. RESULTS: A total of 5405 responses from 79 countries were analysed. India, the USA and Venezuela were the top three contributors. Female respondents comprised 53%. The majority (45%) fell within the 26-35 age group. Medical students (21%), consultants (20%), residents/fellows (15%) and nurses (10%) constituted highest responders. Nearly 55% HCWs reported firsthand violence experience, and 16% reported violence against their colleagues. Perpetrators were identified as patients or family members in over 50% of cases, while supervisor-incited violence accounted for 16%. Around 80% stated that violence incidence either remained constant or increased during the COVID-19 pandemic. Among HCWs who experienced violence, 55% felt less motivated or more dissatisfied with their jobs afterward, and 25% expressed willingness to quit. Univariate analysis revealed that HCWs aged 26-65 years, nurses, physicians, ancillary staff, those working in public settings, with >1 year of experience, and frequent night shift workers were at significantly higher risk of experiencing violence. These results remained significant in multivariate analysis, except for the 55-65 age group, which lost statistical significance. CONCLUSION: This global cross-sectional study highlights that a majority of HCWs have experienced violence, and the incidence either increased or remained the same during the COVID-19 pandemic. This has resulted in decreased job satisfaction.

Implementation of a Virtual Interprofessional ICU Learning Collaborative: Successes, Challenges, and Initial Reactions From the Structured Team-Based Optimal Patient-Centered Care for Virus COVID-19 Collaborators.

Initial Society of Critical Care Medicine Discovery Viral Infection and Respiratory illness Universal Study (VIRUS) Registry analysis suggested that improvements in critical care processes offered the greatest modifiable opportunity to improve critically ill COVID-19 patient outcomes. OBJECTIVES: The Structured Team-based Optimal Patient-Centered Care for Virus COVID-19 ICU Collaborative was created to identify and speed implementation of best evidence based COVID-19 practices. DESIGN SETTING AND PARTICIPANTS: This 6-month project included volunteer interprofessional teams from VIRUS Registry sites, who received online training on the Checklist for Early Recognition and Treatment of Acute Illness and iNjury approach, a structured and systematic method for delivering evidence based critical care. Collaborators participated in weekly 1-hour videoconference sessions on high impact topics, monthly quality improvement (QI) coaching sessions, and received extensive additional resources for asynchronous learning. MAIN OUTCOMES AND MEASURES: Outcomes included learner engagement, satisfaction, and number of QI projects initiated by participating teams. RESULTS: Eleven of 13 initial sites participated in the Collaborative from March 2, 2021, to September 29, 2021. A total of 67 learners participated in the Collaborative, including 23 nurses, 22 physicians, 10 pharmacists, nine respiratory therapists, and three nonclinicians. Site attendance among the 11 sites in the 25 videoconference sessions ranged between 82% and 100%, with three sites providing at least one team member for 100% of sessions. The majority reported that topics matched their scope of practice (69%) and would highly recommend the program to colleagues (77%). A total of nine QI projects were initiated across three clinical domains and focused on improving adherence to established critical care practice bundles, reducing nosocomial complications, and strengthening patient- and family-centered care in the ICU. Major factors impacting successful Collaborative engagement included an engaged interprofessional team; an established culture of engagement; opportunities to benchmark performance and accelerate institutional innovation, networking, and acclaim; and ready access to data that could be leveraged for QI purposes. CONCLUSIONS AND RELEVANCE: Use of a virtual platform to establish a learning collaborative to accelerate the identification, dissemination, and implementation of critical care best practices for COVID-19 is feasible. Our experience offers important lessons for future collaborative efforts focused on improving ICU processes of care.

Association of plasma volume status with outcomes in hospitalized Covid-19 ARDS patients: A retrospective multicenter observational study.

PURPOSE: To evaluate the association of estimated plasma volume (ePV) and plasma volume status (PVS) on admission with the outcomes in COVID-19-related acute respiratory distress syndrome (ARDS) patients. MATERIALS AND METHODS: We performed a retrospective multi-center study on COVID-19-related ARDS patients who were admitted to the Mayo Clinic Enterprise health system. Plasma volume was calculated using the formulae for ePV and PVS, and these variables were analyzed for correlation with patient outcomes. RESULTS: Our analysis included 1298 patients with sequential organ failure assessment (SOFA) respiratory score ≥ 2 (PaO2/FIO2 ≤300 mmHg) and a mortality rate of 25.96%. A Cox proportional multivariate analysis showed PVS but not ePV as an independent correlation with 90-day mortality after adjusting for the covariates (HR: 1.015, 95% CI: 1.005-1.025, p = 0.002 and HR 1.054, 95% CI 0.958-1.159, p = 0.278 respectively). CONCLUSION: A lower PVS on admission correlated with a greater chance of survival in COVID-19-related ARDS patients. The role of PVS in guiding fluid management should be investigated in future prospective studies.

Association of Non-Alcoholic Fatty Liver Disease and Metabolic-Associated Fatty Liver Disease with COVID-19-Related Intensive Care Unit Outcomes: A Systematic Review and Meta-Analysis.

Background and Objective: The association of non-alcoholic fatty liver disease (NAFLD) and metabolic-associated fatty liver disease (MAFLD) with intensive care unit (ICU) admissions and the need for mechanical ventilation and disease severity in COVID-19 patients. Material and Methods: A systematic literature review was conducted on the databases: Cochrane, Embase, PubMed, ScienceDirect, and the Web of Science from January 2019 to June 2022. Studies evaluating MAFLD using laboratory methods, non-invasive imaging, or liver biopsy were included. The study protocol was registered in PROSPERO (ID CRD42022313259), and PRISMA guidelines were followed. The NIH quality assessment tool was used for quality assessment. RevMan version 5.3 software was used for pooled analysis. A sensitivity analysis was performed to assess the result's stability. Results: A total of 37,974 patients from 17 studies were assessed for the association between MAFLD and ICU admission. A total of 3396 COVID-19 patients required ICU admission: 1236 (20.41%) in the MAFLD group and 2160 (6.77%) in the non-MAFLD group. The odds ratio was 1.86 for ICU admission, p = 0.007, and a (95% CI) of [1.18-2.91]. A total of 37,166 patients from 13 studies were included in the need for invasive mechanical ventilation analysis. A total of 1676 patients required mechanical ventilation: 805 in the MAFLD group (14.20% of all MAFLD patients) and 871 patients in the non-MAFLD group (2.76% of all non-MAFLD patients). The odds ratio was 2.05, p = 0.02, and a (95% CI) of [1.12-3.74]. A total of 5286 patients from 14 studies were included in the COVID-19 disease severity analysis. Severe COVID-19 was seen in 1623 patients, with 33.17% (901/2716) of MAFLD patients and 28.09% (722/2570) of non-MAFLD patients having severe disease. The odds ratio was 1.59 for disease severity, p = 0.010, and a (95% CI) of [1.12-2.26]. Conclusions: Our meta-analysis suggests that there are significantly increased odds of ICU admissions, a need for invasive mechanical ventilation, and disease severity in MAFLD patients who acquire COVID-19.

Transcriptomic changes in oligodendrocytes and precursor cells predicts clinical outcomes of Parkinson's disease.

Several prior studies have proposed the involvement of various brain regions and cell types in Parkinson's disease (PD) pathology. Here, we performed snRNA-seq on the prefrontal cortex and anterior cingulate regions from post-mortem control and PD brain tissue. We found a significant association of oligodendrocytes (ODCs) and oligodendrocyte precursor cells (OPCs) with PD-linked risk loci and report several dysregulated genes and pathways, including regulation of tau-protein kinase activity, regulation of inclusion body assembly and protein processing involved in protein targeting to mitochondria. In an independent PD cohort with clinical measures (681 cases and 549 controls), polygenic risk scores derived from the dysregulated genes significantly predicted Montreal Cognitive Assessment (MoCA)-, and Beck Depression Inventory-II (BDI-II)-scores but not motor impairment (UPDRS-III). We extended our analysis of clinical outcome prediction by incorporating three separate datasets that were previously published by different laboratories. In the first dataset from the anterior cingulate cortex, we identified a correlation between ODCs and BDI-II. In the second dataset obtained from the substantia nigra (SN), OPCs displayed notable predictive ability for UPDRS-III. In the third dataset from the SN region, a distinct subtype of OPCs, labeled OPC_ADM, exhibited predictive ability for UPDRS-III. Intriguingly, the OPC_ADM cluster also demonstrated a significant increase in PD samples. These results suggest that by expanding our focus to glial cells, we can uncover region-specific molecular pathways associated with PD symptoms.

Association of non-alcoholic fatty liver and metabolic-associated fatty liver with COVID-19 outcomes: A systematic review and meta-analysis.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) and metabolic-associated fatty liver disease (MAFLD) are on the rise like any other liver disease, and tend to affect 25% of the United States population. The impact of NAFLD and MAFLD on patients with coronavirus disease 2019 (COVID-19) remains unclear. AIM: To identify the association of NAFLD and MAFLD with mortality, hospitalization, hospital length of stay, and supplemental oxygen utilization in COVID-19 patients. METHODS: A systematic review of literature on Cochrane, Embase, PubMed, ScienceDirect, and Web of Science databases was conducted from January 2019 to July 2022. Studies that evaluated NAFLD/MAFLD using laboratory methods, noninvasive imaging, or liver biopsy were included. The study protocol was registered in PROSPERO (ID CRD42022313259) and PRISMA guidelines were followed. The National Institutes of Health quality assessment tool was used to assess the quality of the studies. Pooled analysis was conducted using software Rev Man version 5.3. The stability of the results was assessed using sensitivity analysis. RESULTS: Thirty-two studies with 43388 patients were included in the meta-analysis of whom 8538 (20%) patients were observed to have NAFLD. There were 42254 patients from 28 studies included in the mortality analysis. A total of 2008 patients died from COVID-19; 837 (10.52%) in the NAFLD group and 1171 (3.41%) in the non-NAFLD group. The odds ratio (OR) was 1.38 for mortality with a 95% confidence interval (95%CI) = 0.97-1.95 and P = 0.07. A total of 5043 patients from eight studies were included in the hospital length of stay analysis. There were 1318 patients in the NAFLD group and 3725 patients in the non-NAFLD group. A qualitative synthesis showed that the mean difference in hospital length of stay was about 2 d between the NAFLD and non-NAFLD groups with a 95%CI = 0.71-3.27 and P = 0.002. For hospitalization rates, the OR was 3.25 with a 95%CI of 1.73-6.10 and P = 0.0002. For supplemental oxygen utilization, the OR was 2.04 with a 95%CI of 1.17-3.53 and P = 0.01. CONCLUSION: Our meta-analysis suggests that there are increased odds of hospitalization, longer hospital length of stay, and increased use of supplemental oxygen in NAFLD/MAFLD patients.

A multilocus approach for accurate variant calling in low-copy repeats using whole-genome sequencing.

MOTIVATION: Low-copy repeats (LCRs) or segmental duplications are long segments of duplicated DNA that cover > 5% of the human genome. Existing tools for variant calling using short reads exhibit low accuracy in LCRs due to ambiguity in read mapping and extensive copy number variation. Variants in more than 150 genes overlapping LCRs are associated with risk for human diseases. METHODS: We describe a short-read variant calling method, ParascopyVC, that performs variant calling jointly across all repeat copies and utilizes reads independent of mapping quality in LCRs. To identify candidate variants, ParascopyVC aggregates reads mapped to different repeat copies and performs polyploid variant calling. Subsequently, paralogous sequence variants that can differentiate repeat copies are identified using population data and used for estimating the genotype of variants for each repeat copy. RESULTS: On simulated whole-genome sequence data, ParascopyVC achieved higher precision (0.997) and recall (0.807) than three state-of-the-art variant callers (best precision = 0.956 for DeepVariant and best recall = 0.738 for GATK) in 167 LCR regions. Benchmarking of ParascopyVC using the genome-in-a-bottle high-confidence variant calls for HG002 genome showed that it achieved a very high precision of 0.991 and a high recall of 0.909 across LCR regions, significantly better than FreeBayes (precision = 0.954 and recall = 0.822), GATK (precision = 0.888 and recall = 0.873) and DeepVariant (precision = 0.983 and recall = 0.861). ParascopyVC demonstrated a consistently higher accuracy (mean F1 = 0.947) than other callers (best F1 = 0.908) across seven human genomes. AVAILABILITY AND IMPLEMENTATION: ParascopyVC is implemented in Python and is freely available at https://github.com/tprodanov/ParascopyVC.

Loss of TDP-43 causes ectopic endothelial sprouting and migration defects through increased fibronectin, vcam 1 and integrin α4/ß1.

Aggregation of the Tar DNA-binding protein of 43 kDa (TDP-43) is a pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia and likely contributes to disease by loss of nuclear function. Analysis of TDP-43 function in knockout zebrafish identified an endothelial directional migration and hypersprouting phenotype during development prior lethality. In human umbilical vein cells (HUVEC) the loss of TDP-43 leads to hyperbranching. We identified elevated expression of FIBRONECTIN 1 (FN1), the VASCULAR CELL ADHESION MOLECULE 1 (VCAM1), as well as their receptor INTEGRIN α4ß1 (ITGA4B1) in HUVEC cells. Importantly, reducing the levels of ITGA4, FN1, and VCAM1 homologues in the TDP-43 loss-of-function zebrafish rescues the angiogenic defects indicating the conservation of human and zebrafish TDP-43 function during angiogenesis. Our study identifies a novel pathway regulated by TDP-43 important for angiogenesis during development.

A new human embryonic cell type associated with activity of young transposable elements allows definition of the inner cell mass.

There remains much that we do not understand about the earliest stages of human development. On a gross level, there is evidence for apoptosis, but the nature of the affected cell types is unknown. Perhaps most importantly, the inner cell mass (ICM), from which the foetus is derived and hence of interest in reproductive health and regenerative medicine, has proven hard to define. Here, we provide a multi-method analysis of the early human embryo to resolve these issues. Single-cell analysis (on multiple independent datasets), supported by embryo visualisation, uncovers a common previously uncharacterised class of cells lacking commitment markers that segregates after embryonic gene activation (EGA) and shortly after undergo apoptosis. The discovery of this cell type allows us to clearly define their viable ontogenetic sisters, these being the cells of the ICM. While ICM is characterised by the activity of an Old non-transposing endogenous retrovirus (HERVH) that acts to suppress Young transposable elements, the new cell type, by contrast, expresses transpositionally competent Young elements and DNA-damage response genes. As the Young elements are RetroElements and the cells are excluded from the developmental process, we dub these REject cells. With these and ICM being characterised by differential mobile element activities, the human embryo may be a "selection arena" in which one group of cells selectively die, while other less damaged cells persist.

Discharge Disposition and Loss of Independence Among Survivors of COVID-19 Admitted to Intensive Care: Results From the SCCM Discovery Viral Infection and Respiratory Illness Universal Study (VIRUS).

OBJECTIVES: To describe incidence and risk factors of loss of previous independent living through nonhome discharge or discharge home with health assistance in survivors of intensive care unit (ICU) admission for coronavirus disease 2019 (COVID-19). DESIGN: Multicenter observational study including patients admitted to the ICU from January 2020 till June 30, 2021. HYPOTHESIS: We hypothesized that there is a high risk of nonhome discharge in patients surviving ICU admission due to COVID-19. SETTING: Data were included from 306 hospitals in 28 countries participating in the SCCM Discovery Viral Infection and Respiratory Illness Universal Study COVID-19 registry. PATIENTS: Previously independently living adult ICU survivors of COVID-19. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was nonhome discharge. Secondary outcome was the requirement of health assistance among patients who were discharged home. Out of 10 820 patients, 7101 (66%) were discharged alive; 3791 (53%) of these survivors lost their previous independent living status, out of those 2071 (29%) through nonhome discharge, and 1720 (24%) through discharge home requiring health assistance. In adjusted analyses, loss of independence on discharge among survivors was predicted by patient age ≥ 65 years (adjusted odds ratio [aOR] 2.78, 95% confidence interval [CI] 2.47-3.14, P < .0001), former and current smoking status (aOR 1.25, 95% CI 1.08-1.46, P = .003 and 1.60 (95% CI 1.18-2.16), P = .003, respectively), substance use disorder (aOR 1.52, 95% CI 1.12-2.06, P = .007), requirement for mechanical ventilation (aOR 4.17, 95% CI 3.69-4.71, P < .0001), prone positioning (aOR 1.19, 95% CI 1.03-1.38, P = .02), and requirement for extracorporeal membrane oxygenation (aOR 2.28, 95% CI 1.55-3.34, P < .0001). CONCLUSIONS: More than half of ICU survivors hospitalized for COVID-19 are unable to return to independent living status, thereby imposing a significant secondary strain on health care systems worldwide.

Temperament and character in an Australian sample: examining cross-sectional associations of personality with age, sex, and satisfaction with life.

Objective: Personality can influence how we interpret and react to our day-to-day life circumstances. Temperament and character are the primary dimensions of personality, and both are influenced genetically. Temperament represents our emotional core, while character reflects our goals and values as we develop through life. Research shows that where people live, their social, economic, and physical environment can influence attitudes and behaviors, and these have links to variations in personality traits. There are few studies that focus on Australian personality as temperament and character. Using an Australian general population sample, we examined the psychometric properties of the Temperament and Character Inventory (TCIR140) and investigated the associations between TCIR140 traits with both sociodemographic variables and measures of well-being. In addition, we investigated differences in temperament and character between our Australian general population sample and published results of similar studies from other countries. Methods: Australians (N = 1,510) completed the Temperament and Character Inventory (TCIR-140), the Positive and Negative Affect Scale and the Satisfaction with Life Scale. Cronbach's alpha and confirmatory factor analysis (CFA) examined the TCIR-140 psychometrics. Correlation analyzes, independent sample t-tests and ANOVA with post-hoc comparisons analyzed the sample. Results: Cronbach's alphas were high, ranging from α = 0.78-0.92, and the CFA confirmed two constructs of temperament and character. Females were higher in Harm Avoidance (p < 0.001), Reward Dependence (p < 0.001), and Cooperativeness (p < 0.001) compared to males, who were higher in Self-Directedness (p < 0.001). Age groups showed significant differences among all temperament and character traits (p < 0.001) except for Reward Dependence (p = 0.690). Young adults had the least resilient personality profile and poorest measures of well-being. Correlations with measures of temperament and character, well-being and affect were all in the expected direction. Conclusions: Temperament and character are related to indicators of wellbeing and differs by age and sex. This Australian sample demonstrate a temperament that is high in Persistence and a character high in Self-Directedness and Cooperativeness with an overall postive affect and a general satisfaction with life. In comparison to other countries, Australians in this sample differ in levels of several traits, demonstrating a cautious and independent temperament with a character that is cooperative, industrious, and self-reliant. Young-adults in comparison to older groups have a temperament and character profile that is prone to negative emotions and a lower satisfaction with life.

Development and Validation of an Acute Respiratory Distress Syndrome Prediction Model in Coronavirus Disease 2019: Updated Lung Injury Prediction Score.

OBJECTIVE: To develop and validate an updated lung injury prediction score for coronavirus disease 2019 (COVID-19) (c-LIPS) tailored for predicting acute respiratory distress syndrome (ARDS) in COVID-19. PATIENTS AND METHODS: This was a registry-based cohort study using the Viral Infection and Respiratory Illness Universal Study. Hospitalized adult patients between January 2020 and January 2022 were screened. Patients who qualified for ARDS within the first day of admission were excluded. Development cohort consisted of patients enrolled from participating Mayo Clinic sites. The validation analyses were performed on remaining patients enrolled from more than 120 hospitals in 15 countries. The original lung injury prediction score (LIPS) was calculated and enhanced using reported COVID-19-specific laboratory risk factors, constituting c-LIPS. The main outcome was ARDS development and secondary outcomes included hospital mortality, invasive mechanical ventilation, and progression in WHO ordinal scale. RESULTS: The derivation cohort consisted of 3710 patients, of whom 1041 (28.1%) developed ARDS. The c-LIPS discriminated COVID-19 patients who developed ARDS with an area under the curve (AUC) of 0.79 compared with original LIPS (AUC, 0.74; P<.001) with good calibration accuracy (Hosmer-Lemeshow P=.50). Despite different characteristics of the two cohorts, the c-LIPS's performance was comparable in the validation cohort of 5426 patients (15.9% ARDS), with an AUC of 0.74; and its discriminatory performance was significantly higher than the LIPS (AUC, 0.68; P<.001). The c-LIPS's performance in predicting the requirement for invasive mechanical ventilation in derivation and validation cohorts had an AUC of 0.74 and 0.72, respectively. CONCLUSION: In this large patient sample c-LIPS was successfully tailored to predict ARDS in COVID-19 patients.