bluuebunny/crossref_metadata_2025 huggingface dataset:
Natural history of serum creatine kinase levels and motor, pulmonary, and cardiac functions in 337 patients with Duchenne muscular dystrophy: a retrospective study at a single referral center in Japan
Authors: Awano Hiroyuki , Nambu Yoshinori , Ito Chieko , Kida Akihiro , Yamamoto Tetsushi , Lee Tomoko , Takeshima Yasuhiro , Nozu Kandai , Matsuo Masafumi
Published: October 2022

Introduction/Aims

Duchenne muscular dystrophy (DMD) presents with skeletal muscle weakness, followed by respiratory and cardiac muscle involvement. Recently, with the development of treatments, the need for a natural history to serve as a control for determining treatment efficacy in clinical trials has increased dramatically, however, few large-scale studies have investigated changes in these symptoms. The present study examined the natural history of Japanese DMD patients as a whole and individual patient with genetic mutations eligible for exon skipping therapy.

Methods

Medical records of 337 patients with DMD who visited Kobe University Hospital over a period of 30 years from their first visit until 20 years of age were examined.

Results

Serum creatine kinase levels showed a stair-step pattern of decline, with extremely high values until 6 and a rapid decline from 7 to 12 years of age. Both the median 10-meter run/walk velocity and rise-from-floor velocity peaked at the age of 4 years and declined with age. The values for respiratory function declined from the age of 11 years. The median left ventricular ejection fraction was >60% until the age of 12 years and rapidly declined from 13 to 15 years of age. Examination of the relationship between gene mutations eligible for exon-skipping therapy and natural history revealed no characteristic findings.

Discussion

We found that creatine kinase levels and motor, respiratory, and cardiac functions each exhibited unique changes over time. These findings will be useful in developing new therapeutic agents for DMD and in determining their efficacy in clinical trials.
Dynamics of non-household contacts during the COVID-19 pandemic in 2020 and 2021 in the Netherlands
Authors: Backer Jantien A. , Bogaardt Laurens , Beutels Philippe , Coletti Pietro , Edmunds W. John , Gimma Amy , van Hagen Cheyenne C. E. , Hens Niel , Jarvis Christopher I. , Vos Eric R. A. , Wambua James , Wong Denise , van Zandvoort Kevin , Wallinga Jacco
Published: October 2022

The COVID-19 pandemic was in 2020 and 2021 for a large part mitigated by reducing contacts in the general population. To monitor how these contacts changed over the course of the pandemic in the Netherlands, a longitudinal survey was conducted where participants reported on their at-risk contacts every two weeks, as part of the European CoMix survey. The survey included 1659 participants from April to August 2020 and 2514 participants from December 2020 to September 2021. We categorized the number of unique contacted persons excluding household members, reported per participant per day into six activity levels, defined as 0, 1, 2, 3-4, 5-9 and 10 or more reported contacts. After correcting for age, vaccination status, risk status for severe outcome of infection, and frequency of participation, activity levels increased over time, coinciding with relaxation of COVID-19 control measures.
Preserved electrophysiological markers of confidence in schizophrenia spectrum disorder
Authors: Rouy Martin , Roger Matthieu , Goueytes Dorian , Pereira Michael , Roux Paul , Faivre Nathan
Published: October 2022

A large number of behavioral studies suggest that confidence judgments are impaired in schizophrenia, motivating the search for neural correlates of an underlying metacognitive impairment. Electrophysiological studies suggested that a specific evoked response potential reflecting performance monitoring, namely the error-related negativity (ERN), was blunted in schizophrenia compared to healthy controls. However, attention has recently been drawn to a potential confound in the study of metacognition, namely that lower first-order performance in schizophrenia compared to healthy controls could lead to a spurious decrease in metacognitive performance among patients. Here, we assessed how this confound might also apply to ERN-blunting in schizophrenia. We used an adaptive staircase procedure to titrate first-order performance on a motion discrimination task in which participants (N = 14 patients and 19 controls) had to report their confidence after each trial while we recorded high density EEG. Interestingly, not only metaperceptual abilities were preserved among patients at the behavioral level, but we also found no electrophysiological evidence for altered EEG markers of performance monitoring. These results bring additional evidence suggesting an unaltered ability to monitor perceptual performance on a trial by trial basis in schizophrenia.
Socioeconomic inequalities of Long COVID: findings from a population-based survey in the United Kingdom
Authors: Shabnam Sharmin , Razieh Cameron , Dambha-Miller Hajira , Yates Tom , Gillies Clare , Chudasama Yogini V , Pareek Manish , Banerjee Amitava , Kawachi Ichiro , Lacey Ben , Morris Eva JA , White Martin , Zaccardi Francesco , Khunti Kamlesh , Islam Nazrul
Published: October 2022

Objective

To estimate the risk of Long COVID by socioeconomic deprivation and to further examine the socioeconomic inequalities in Long COVID by sex and occupational groups.

Design

We analysed data from the COVID-19 Infection Survey conducted by the Office for National Statistics between 26/04/2020 and 31/01/2022. This is the largest and nationally representative survey of COVID-19 in the UK and provides uniquely rich, contemporaneous, and longitudinal data on occupation, health status, COVID-19 exposure, and Long COVID symptoms.

Setting

Community-based longitudinal survey of COVID-19 in the UK.

Participants

We included 201,799 participants in our analysis who were aged between 16 and 64 years and had a confirmed SARS-CoV-2 infection.

Main outcome measures

We used multivariable logistic regression models to estimate the risk of Long COVID at least 4 weeks after acute SARS-CoV-2 infection by deciles of index of multiple deprivation (IMD) and adjusted for a range of demographic and spatiotemporal factors. We further examined the modifying effects of socioeconomic deprivation by sex and occupational groups.

Results

A total of 19,315 (9.6%) participants reported having Long COVID symptoms. Compared to the least deprived IMD decile, participants in the most deprived decile had a higher adjusted risk of Long COVID (11.4% vs 8.2%; adjusted OR: 1.45; 95% confidence interval [CI]: 1.33, 1.57). There were particularly significantly higher inequalities (most vs least deprived decile) of Long COVID in healthcare and patient facing roles (aOR: 1.76; 1.27, 2.44), and in the education sector (aOR: 1.62; 1.26, 2.08). The inequality of Long COVID was higher in females (aOR: 1.54; 1.38, 1.71) than males (OR: 1.32; 1.15, 1.51).

Conclusions

Participants living in the most socioeconomically deprived areas had a higher risk of Long COVID. The inequality gap was wider in females and certain public facing occupations (e.g., healthcare and education). These findings will help inform public health policies and interventions in adopting a social justice and health inequality lens.
PCNA thermosensitivity underlies an Ataxia Telangiectasia-like disorder
Authors: Magrino Joseph , Munford Veridiana , Martins Davi Jardim , Homma Thais K , Page Brendan , Gaubitz Christl , Freire Bruna L , Lerario Antonio M , Vilar Juliana Brandstetter , Amorin Antonio , Leão Emília K E , Kok Fernando , Menck Carlos F M , Jorge Alexander A L , Kelch Brian A
Published: October 2022

Proliferating Cell Nuclear Antigen (PCNA) is a sliding clamp protein that coordinates DNA replication with various DNA maintenance events that are critical for human health. Recently, a hypomorphic homozygous serine to isoleucine (S228I) substitution in PCNA was described to underlie a DNA repair disorder known as PCNA-Associated DNA Repair Disorder (PARD). PARD symptoms range from UV sensitivity, neurodegeneration, telangiectasia, and premature aging. We, and others, previously showed that the S228I variant changes the protein binding pocket of PCNA to a conformation that impairs interactions with specific partners. Here, we report a second PCNA substitution (C148S) that also causes PARD. Unlike PCNA-S228I, PCNA-C148S has WT-like structure and affinity towards partners. In contrast, both disease-associated variants possess a thermo-stability defect. Furthermore, patient-derived cells homozygous for theC148Sallele exhibit low levels of chromatin-bound PCNA and display temperature-dependent phenotypes. The stability defect of both PARD variants indicates that PCNA levels are likely an important driver of PARD disease. These results significantly advance our understanding of PARD and will likely stimulate additional work focused on clinical, diagnostic, and therapeutic aspects of this severe disease.
Performance on the Balloon Analogue Risk Task and Anticipatory Response Inhibition Task is Associated with Severity of Impulse Control Behaviours in People with Parkinson’s Disease
Authors: Hall Alison , Weightman Matthew , Jenkinson Ned , MacDonald Hayley J
Published: October 2022

Introduction

Dopamine agonist medication is one of the largest risk factors for development of problematic impulse control behaviours (ICBs) in people with Parkinson’s disease. The present study investigated the potential of dopamine gene profiling and individual performance on impulse control tasks to explain ICB severity.

Methods

Clinical, genetic and task performance data were entered into a mixed-effects linear regression model for people with Parkinson’s disease taking (n = 50) or not taking (n = 25) dopamine agonist medication. Severity of ICBs was captured via the Questionnaire for Impulsive-compulsive disorders in Parkinson’s disease Rating Scale. A cumulative dopamine genetic risk score (DGRS) was calculated for each participant from variance in five dopamine-regulating genes. Objective measures of impulsive action and impulsive choice were measured on the Anticipatory Response Inhibition Task and Balloon Analogue Risk Task, respectively.

Results

For participants on dopamine agonist medication, task performance reflecting greater impulsive choice (p = .014), and to a trend level greater impulsive action (p = .056), as well as a longer history of DA medication (p < .001) all predicted increased ICB severity. DGRS however, did not predict ICB severity (p = .708). No variables could explain ICB severity in the non-agonist group.

Conclusions

Our task-derived measures of impulse control have the potential to predict ICB severity in people with Parkinson’s and warrant further investigation to determine whether they can be used to monitor ICB changes over time. The DGRS appears better suited to predicting the incidence, rather than severity, of ICBs on agonist medication.
The COVID-19 burnout scale: Development and initial validation
Authors: Galanis Petros , Katsiroumpa Aglaia , Sourtzi Panayota , Siskou Olga , Konstantakopoulou Olympia , Kaitelidou Daphne
Published: October 2022

We developed and validated a self-assessment instrument to measure COVID-19 pandemic-related burnout in the general population. We assessed the psychometric properties of the COVID-19 burnout scale (COVID-19-BS). Exploratory and confirmatory factor analysis identified three factors for the COVID-19-BS; emotional exhaustion, physical exhaustion, and exhaustion due to measures against the COVID-19. Cronbach’ s alpha coefficients for the three factors and the COVID-19-BS ranged from 0.860 to 0.921. Kaiser-Meyer-Olkin value was 0.945 and p-value for Bartlett test was <0.001 indicating highly acceptable values. Convergent validity results indicated a significant positive correlation between COVID-19-BS and anxiety and depression. Known-groups analysis identified the ability of COVID-19-BS to discriminate groups according to gender, chronic condition, and health status. Our findings indicate that the final 13-item model of COVID-19-BS is a brief, easy to administer, valid and reliable scale for assessing COVID-19-related burnout in the general public.
Prediction of COVID-19 Diagnosis from Healthy and Pneumonia CT scans using Convolutional Neural Networks
Authors: Srirambhatla Rushil , Karim Helmet T.
Published: October 2022

Background

Current methods of COVID-19 detection from other respiratory illnesses using computed tomography (CT) scans are highly inaccurate. However, understanding pathogen-specific immune responses can help reduce inconsistencies and improve the accuracy of COVID-19 and Pneumonia detection. A deep learning model using Relief-based feature selection (RBAs) was developed to detect COVID-19 and Pneumonia. Patient-specific Class Activation Maps (CAMs) were produced to highlight immunopathogenic differences and identify differences between COVID-19 and Pneumonia on CT scans.

Methods

To examine the effect on lung lesions, a COVIDx CT-2 dataset, containing CT scans from 3,745 patients, was examined. We developed an algorithm to convert the 3-D CT scan of each patient into multiple 2-D slices. Altogether, there were 194,344 2-D slices retrieved from 3,745 CT Scans. The distribution of slices was 67%-20%-17% consisting of COVID-19, Pneumonia, and normal CT scan, respectively. An AlexNet architecture was implemented with additional feature extraction layers (containing RBA) and classification layers to perform deep learning. The 2-D slices were divided into 3 groups: Training, Test, and Validation. The training set consisted of 70% of the data, the test set consisted of 20% of the data, and the validation consisted of 10% of the data. After training, unique CAMs were generated on patient CT scans using the immunopathogenic differences to highlight COVID-19 and Pneumonia related abnormalities.

Results

The model accurately distinguished hyperinflammation in COVID-19 patients from Pneumonia patients and achieved a validation accuracy of 95.60% and a false-positive rate of 4.65%. Additionally, the segmented lung, shown by the patient-specific CAMs, identified higher levels of inflammation in the lung of COVID scans compared to the other two groups.

Discussion

The use of deep learning in disease diagnosis and prevention has provided many avenues to advance current techniques. Likewise, in this analysis, deep learning was shown to successfully predict COVID-19 via CT scan. By providing patient-specific CAMs, the model can be used to not just aid in diagnosis but potentially also to evaluate serial chest CT scans for treatment.
Signs and symptoms associated with a need for supervision in patients with Alzheimer’s disease
Authors: Huey Celia C. , Kociolek Anton , Fernandez Kayri K. , Hernandez Michelle , Gottesman Reena T. , Barker Megan , Cosentino Stephanie , Stern Yaakov
Published: October 2022

Caregivers identify the need for continuous supervision of Alzheimer’s disease patients while awake as a “milestone” functional change that has a profound impact on the lives of the caregiver and patient. The specific predictors of this important functional change are not known. We determined specific cognitive, neuropsychiatric, and motor symptoms associated with Alzheimer’s disease patients needing supervision while awake in a longitudinal, ethnically diverse cohort of Alzheimer’s disease patients in Northern Manhattan. At the initial visit, neuropsychiatric and behavioral symptoms, including more hallucinations (OR=3.12) and lower elation (OR=0.13) were associated with the need for supervision while awake, as were poor memory (OR=0.89) and higher letter fluency (OR=1.33) abilities. The findings presented in the current study can aid clinicians and caregivers in prognosis and planning, suggest symptoms to target with non-pharmacological and pharmacological treatments to forestall this important functional “milestone”, and suggest priorities for future research.

Significance Statement

Need for supervision while awake is identified by caregivers of AD patients as a “milestone” symptom that greatly changes caregiving needs and quality of life

Specific neuropsychiatric and cognitive symptoms, including hallucinations, elation, and memory and executive dysfunction, are associated with a significantly increased or decreased need for supervision while awake

These patient-centered findings aid prognosis and planning, and indicate symptoms to prioritize for treatment and future research to improve AD patient functioning
Multiple hypervirulent methicillin-sensitiveStaphylococcus aureuslineages contribute towards poor patient outcomes in orthopedic device-related infections
Authors: Post Virginia , Pascoe Ben , Mourkas Evangelos , Calland Jessica K. , Hitchings Matthew D. , Erichsen Christoph , Fischer Julian , Morgenstern Mario , Richards R. Geoff , Sheppard Samuel K. , Moriarty T. Fintan
Published: October 2022

Staphylococci are the most common cause of orthopedic device-related infections (ODRIs), withStaphylococcus aureusresponsible for a third or more of cases. This prospective clinical and laboratory study investigated the association of genomic and phenotypic variation with treatment outcomes in ODRI isolates. Eighty-six invasiveS. aureusisolates were collected from patients with ODRI, and clinical outcome was assessed after a follow-up examination of 24 months. Each patient was then considered to have been “cured” or “not cured” based on predefined clinical criteria. Whole genome sequencing and molecular characterization identified isolates belonging to globally circulating community- and hospital-acquired pandemic lineages. Most isolates were phenotypically susceptible to methicillin and lacked the SCCmeccassette (MSSA), but contained several (hyper) virulence genes, including toxins and biofilm genes. While recognizing the role of the host immune response, we identify characteristics of isolate genomes that, with larger datasets, could help contribute to infection severity or clinical outcome predictions. While this and several other studies reinforce the role antibiotic resistance (e.g., MRSA infection) has on treatment failure, it is important not to overlook MSSA that can cause equally destructive infections and lead to poor patient outcomes.

Importance

Staphylococcus aureusis a prominent cause of orthopedic device-associated infections, yet little is known about how the infecting pathogen, and specifically the repertoire of genome-encoded virulence factors can impact treatment outcome. Past studies have focused on distinguishing commensal from invasiveS. aureusisolates but in this study, we aim to investigate traits in infecting isolates that influence patient outcomes. InvasiveS. aureusisolates were collected from orthopedic-device related infection patients and categorized according to the success of subsequent treatment (“cured” /”not cured”), as determined following hospital discharge two years after initial presentation. Several MSSA hypervirulent clones were associated with a “not cured” clinical outcome. Improved understanding of the bacterial traits associated with treatment failure in ODRI will inform the risk assessment, prognosis, and therapy of these infections.
Robust Machine Learning predicts COVID-19 Disease Severity based on Single-cell RNA-seq from multiple hospitals
Authors: Lemsara Amina , Chan Adrian , Wolff Dominik , Marschollek Michael , Li Yang , Dieterich Christoph
Published: October 2022

Coronavirus disease 2019 (COVID-19) has a highly variable disease severity. Possible associations between peripheral blood signatures and disease severity have been investigated since the emergence of the pandemic. Although several signatures were identified based on exploratory analyses of single-cell omics data, there are no state-of-the-art validated models to predict COVID-19 severity from comprehensive transcriptome profiling of Peripheral Blood Mononuclear Cells (PBMCs). In this paper, we present a computational workflow based on a Multilayer perceptron network that predicts the necessity of mechanical ventilation from PBMCs single-cell RNA-seq data. The study includes patient cohorts from Bonn, Berlin, Stanford, and three Korean medical centers. Training and model validation are performed using Berlin and Bonn samples, while testing is performed on completely unseen samples from the Stanford and Korean datasets. Our model shows a high area under the receiver operating characteristic (AUROC) curve (Korea: 1 (CI:1-1), Stanford: 0.86 (CI:0.81-0.9)), proving our model’s robustness. Moreover, we explain our model’s performance by identifying gene loci and cell types, which are most critical for the classification task. In summary, we could show that the expression of 15 genes and the cell type proportion of 29 PBMC classes distinguish between COVID-19 disease states.

Graphical Abstract
Meta-analysis of genotype-phenotype associations in Alström syndrome
Authors: Bea-Mascato Brais , Valverde Diana
Published: October 2022

Introduction

Alström syndrome (ALMS, #203800) is an ultra-rare monogenic recessive disease. This the syndrome is associated with mutations in theALMS1gene, which codes for a centrosome structural protein responsible for centrosome cohesion. The type of mutation associated with ALMS is mostly cLOF (97%) and they are mainly located in exons 8, 10 and 16 of the gene. Other studies in the literature have tried to establish a genotype-phenotype correlation in this syndrome with little success. The difficulty in recruiting a large cohort in rare diseases is the main barrier to conducting this type of study.

Methods

In this study we have collected all cases published to date for ALMS. We have created a database with those patients who had a genetic diagnosis and an individualised clinical history. Finally, we have attempted to establish a genotype-phenotype correlation using the truncation site of the patient’s longest allele as a grouping criterion.

Results

We collected a total of 357 patients of which 227 had complete clinical information, complete genetic diagnosis and meta information regarding sex and age. We have seen that there are 5 variants in high frequency with p.(Arg2722Ter) being the most common variant with 28 alleles. There are no gender differences in disease progression. Finally, truncating mutations in exon 10 seem to be correlated with a higher prevalence of liver disorders in patients with ALMS.

Conclusion

The location of the mutation in theALMS1gene does not have a major impact on the phenotype developed by the patient. Only mutations in exon 10 of theALMS1gene were associated with a higher prevalence of liver disease.
Retina-arrestin is not a CD8+ T-cell autoantigen in HLA-A29-positive birdshot chorioretinitis
Authors: Venema W.J. , Hiddingh S. , Janssen G.M.C. , Ossewaarde J. , van Loon N. Dam , de Boer J.H. , van Veelen P.A. , Kuiper J.J.W.
Published: October 2022

Background

HLA-A29-positivebirdshot chorioretinitis(BCR) is an inflammatory eye disorder that is generally assumed to be caused by an autoimmune response to HLA-A29-presented peptides from retinal arrestin (SAG), yet the epitopes recognized by CD8+ T cells from patients remain to be identified.

Objectives

The identification of natural ligands of SAG presented by HLA-A29. To quantify CD8+ T cells reactive to antigenic SAG peptides presented by HLA-A29 in patients and controls.

Methods

We performed mass-spectrometry based immunopeptidomics of HLA-A29 of antigen-presenting cell lines from patients engineered to express SAG. MHC-I Dextramer technology was utilised to identify antigen-specific CD8+ T cells reactive to SAG peptides in complex with HLA-A29 in a cohort of BCR patients, HLA-A29-positive controls, and HLA-A29-negative controls.

Results

We report on the naturally presented antigenic SAG peptides identified by sequencing the HLA-A29 immunopeptidome of antigen-presenting cells of patients. We show that the N-terminally extended SAG peptide precursors can be trimmedin vitroby the antigen-processing aminopeptidases ERAP1 and ERAP2. Unexpectedly, no antigen engagement by CD8+ T cells upon stimulation with SAG peptides was observed in patients or HLA-A29-positive controls. Multiplexed HLA-A29-peptide dextramer profiling of a case-control cohort revealed that CD8+ T cells specific for these SAG peptides were neither detectable in peripheral blood nor in eye biopsies of patients.

Conclusions

Collectively, these findings demonstrate that SAG is not a CD8+ T cell autoantigen and sharply contrast the paradigm in the pathogenesis of BCR. Therefore, the mechanism by which HLA-A29 is associated with BCR does not involve SAG.
Receipt of COVID-19 and seasonal influenza vaccines in California (USA) during the 2021-2022 influenza season
Authors: Andrejko Kristin L. , Myers Jennifer F. , Openshaw John , Fukui Nozomi , Li Sophia , Watt James P. , Murray Erin L. , Hoover Cora , Lewnard Joseph A. , Jain Seema , Pry Jake M.
Published: October 2022

Background

Despite lower circulation of influenza virus throughout 2020–2022 during the COVID-19 pandemic, seasonal influenza vaccination has remained a primary tool to reduce influenza-associated illness and death. The relationship between the decision to receive a COVID-19 vaccine and/or an influenza vaccine is not well understood.

Methods

We assessed predictors of receipt of 2021–2022 influenza vaccine in a secondary analysis of data from a case-control study enrolling individuals who received SARS-CoV-2 testing. We used mixed effects logistic regression to estimate factors associated with receipt of seasonal influenza vaccine. We also constructed multinomial adjusted marginal probability models of being vaccinated for COVID-19 only, seasonal influenza only, or both as compared with receipt of neither vaccination.

Results

Among 1261 eligible participants recruited between 22 October 2021 – 22 June 2022, 43% (545) were vaccinated with both seasonal influenza vaccine and ≥1 dose of a COVID-19 vaccine, 34% (426) received ≥1 dose of a COVID-19 vaccine only, 4% (49) received seasonal influenza vaccine only, and 19% (241) received neither vaccine. Receipt of ≥1 COVID-19 vaccine dose was associated with seasonal influenza vaccination (adjusted odds ratio [aOR]: 3.72; 95% confidence interval [CI]: 2.15–6.43); this association was stronger among participants receiving ≥1 COVID-19 booster dose (aOR=16.50 [10.10– 26.97]). Compared with participants testing negative for SARS-CoV-2 infection, participants testing positive had lower odds of receipt of 2021-2022 seasonal influenza vaccine (aOR=0.64 [0.50–0.82]).

Conclusions

Recipients of a COVID-19 vaccine were more likely to receive seasonal influenza vaccine during the 2021–2022 season. Factors associated with individuals’ likelihood of receiving COVID-19 and seasonal influenza vaccines will be important to account for in future studies of vaccine effectiveness against both conditions. Participants who tested positive for SARS-CoV-2 in our sample were less likely to have received seasonal influenza vaccine, suggesting an opportunity to offer influenza vaccination before or after a COVID-19 diagnosis.
Applying Machine Learning to Blood Count Data Predicts Sepsis with ICU Admission
Authors: Ahrens Paul C. , Steinbach Daniel , Schmidt Maria , Federbusch Martin , Heuft Lara , Lübbert Christoph , Nauck Matthias , Gründling Matthias , Isermann Berend , Gibb Sebastian , Kaiser Thorsten
Published: October 2022

Background

Delay in diagnosing sepsis results in potentially preventable deaths. Mainly due to their complexity or limited applicability, machine learning (ML) models to predict sepsis have not yet become part of clinical routines. For this reason, we created a ML model that only requires complete blood count (CBC) diagnostics.

Methods

Non-intensive care unit (non-ICU) data from a German tertiary care centre were collected from January 2014 to December 2021. Patient age, sex, and CBC parameters (haemoglobin, platelets, mean corpuscular volume, white and red blood cells) were utilised to train a boosted random forest, which predicts sepsis with ICU admission. Two external validations were conducted using data from another German tertiary care centre and the Medical Information Mart for Intensive Care IV database (MIMIC-IV). Using the subset of laboratory orders also including procalcitonin (PCT), an analogous model was trained with PCT as an additional feature.

Findings

After exclusion, 1,381,358 laboratory requests (2016 from sepsis cases) were available. The derived CBC model shows an area under the receiver operating characteristic (AUROC) of 0.872 (95% CI, 0.857–0.887) for predicting sepsis. External validations show AUROCs of 0.805 (95% CI, 0.787–0.824) and 0.845 (95% CI, 0.837–0.852) for MIMIC-IV. The model including PCT revealed a significantly higher performance (AUROC: 0.857; 95% CI, 0.836–0.877) than PCT alone (AUROC: 0.790; 95% CI, 0.759–0.821; p<0.001).

Interpretation

Our results demonstrate that routine CBC results could significantly improve diagnosis of sepsis when combined with ML. The CBC model can facilitate early sepsis prediction in non-ICU patients with high robustness in external validations. Its implementation in clinical decision support systems has strong potential to provide an essential time advantage and increase patient safety.

Funding

The study was part of the AMPEL project (www.ampel.care), which is co-financed through public funds according to the budget decided by the Saxon State Parliament under the RL eHealthSax 2017/18 grant number 100331796.
Possible harms ofMomordica charantia L. in humans; a systematic review
Authors: Demmers Armelle , Mes Jurriaan J. , Elbers Roy G. , Pieters Raymond HH
Published: October 2022

Introduction

A few cases of serious side effects have been reported of Momordica charantia L. (MC). No comprehensive safety assessment has yet been performed based on human intake.This systematic review aims to evaluate the potential harm of Momordica charantia L. derived products using data from randomized controlled trials.

Methods

Databases Cochrane Library, Pubmed and EMBASE were searched until December 2020. The PRISMA harms checklist was followed. Data extraction was on aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine, adverse effects (AE), reasons for drop out related to the intervention and interaction with other treatment. Two authors independently extracted data and bias was evaluated based on the latest version of the Cochrane risk of Bias Tool (RoB 2). Additional safety data were requested from Health Regulatory Agencies, Herbal Medicine Associations and manufacturers.

Results

Seventeen trials met the inclusion criteria. The IRR was calculated for each study ranging from 0.30 (95% CI = 0.12 to 0.75) to 13.00 (95% CI = 0.73 to 230.76) of any adverse events.

Conclusions

Under a daily dosage of 6g of MC-derived products no evidence was seen of harms in humans. In case reports that showed serious harm, MC was used in a liquid form. The safety of traditional MC-based supplements appears more guaranteed when produced under strict quality standards.
Clinical criteria for genetic testing in pediatric oncology show a low specificity and miss every 4thchild carrying a cancer predisposition
Authors: Friedrich Ulrike Anne , Bienias Marc , Zinke Claudia , Prazenicova Maria , Lohse Judith , Jahn Arne , Menzel Maria , Langanke Jonas , Walter Carolin , Wagener Rabea , Brozou Triantafyllia , Varghese Julian , Dugas Martin , Schröck Evelin , Suttorp Meinolf , Borkhardt Arndt , Hauer Julia , Auer Franziska
Published: October 2022

Clinical checklists are the current gold standard to determine whether a child with cancer shows indications for genetic testing. Nevertheless, the efficacy of these tests to reliably detect genetic cancer predisposition in children with cancer is still insufficiently investigated. Here, we assessed the validity of clinically recognizable signs to identify cancer predisposition by correlating a state-of-the-art clinical checklist to the corresponding whole exome sequencing analysis in an unselected single-center cohort of 139 child-parent datasets. We applied a strict testing to only include autosomal dominant or compound heterozygous cancer-related variants.

Our study reflects a high consent rate for genetic testing (>90%). In total, 1/3rdof patients had a clinical indication for genetic testing according to current recommendations and 10.8% (n=15/139) of children harbored a proven cancer predisposition based on exome sequencing. Out of these only 73.3% (n=11/15) were identified through the clinical checklist. In addition, >2 clinical findings in the applied checklist increased the likelihood to identifying genetic predisposition from 15% to 50%. While our data revealed a high rate of genetic predisposition (50%, n=5/10) in Myelodysplastic Syndrome (MDS) cases, no cancer predisposition variants were identified in the sarcoma and lymphoma group.

In summary, our data showed a low checklist specificity of 68.5%, and missed every 4thchild with genetic predisposition. This highlights the drawbacks of sole clinical evaluation to accurately identify all children at risk and underlines the need for routine germline sequencing of pediatric cancers.
An Adjudication Protocol for Severe Bacterial and Viral Pneumonia
Authors: Pickens Chiagozie I. , Gao Catherine A. , Walter James M. , Kruser Jacqueline M. , Donnelly Helen K. , Donayre Alvaro , Clepp Katie , Borkowski Nicole , Wunderink Richard G. , Singer Benjamin D. ,   The NU SCRIPT Study Investigators
Published: October 2022

Rationale

Clinical endpoints that constitute successful treatment in severe pneumonia are difficult to ascertain and vulnerable to bias. Utility of a protocolized adjudication procedure to determine meaningful endpoints in severe pneumonia is not well described.

Objectives

To develop and validate a protocol for classification and adjudication of clinical endpoints in severe bacterial and viral pneumonia in a prospective cohort of critically ill, mechanically ventilated patients.

Methods

Each episode of pneumonia was independently reviewed by two of six pulmonary and critical care physician adjudicators. If a discrepancy in at least one critical answer occurred between the two adjudicators, a third adjudicator reviewed the case and answered the specific question(s) for which there was a lack of agreement. If discrepancy remained after all three adjudications, consensus was achieved through committee review.

Results

Evaluation of 784 pneumonia episodes during 593 hospitalizations achieved a 79% crude rate of interobserver agreement defined as agreement between 2 of 3 reviewers. Culture-negative pneumonia was associated with increased interobserver agreement. Multiple episodes of pneumonia and bacterial and viral co-infection in the initial episode of pneumonia were associated with decreased interobserver agreement. For bacterial pneumonia, patients with an adjudicated day 7-8 clinical impression of cure for the initial episode of pneumonia were more likely to be discharged alive compared to patients with a day 7-8 clinical impression of indeterminate (p < 0.01), superinfection (p = 0.03), or a combined impression of persistence and superinfection (p = 0.04). In viral pneumonia, patients with an adjudicated clinical impression of cure for an initial episode of viral pneumonia were more likely to be discharged alive compared to patients with an adjudicated clinical impression of persistence (p < 0.01), indeterminate (p < 0.01), or bacterial superinfection (p < 0.01).

Conclusions

We developed and validated a protocol for classification and adjudication of clinical endpoints in severe pneumonia. This protocol can be applied to cohorts of patients with severe pneumonia to provide uniform assessment of patient-centered endpoints.
T-Rex: sTandalone Recorder of EXperiments; An easy and versatile neural recording platform
Authors: Amigó-Vega Joaquín , Ottenhoff Maarten C. , Verwoert Maxime , Kubben Pieter , Herff Christian
Published: October 2022

Abstract

Recording time in invasive neuroscientific empirical research is short and must be used as efficiently as possible. Time is often lost due to long setup times and errors by the researcher. Minimizing the number of manual actions reduces both and can be achieved by automating as much as possible. Importantly, automation should not reduce the flexibility of the system. Currently, recording setups are either custom-made by the researchers or provided as a module in comprehensive neuroscientific toolboxes, and no platforms exist focused explicitly on recording. Therefore, we developed a lightweight, flexible, platform- and measurement-independent recording system that can start and record experiments with a single press of a button. Data synchronization and recording are based on Lab Streaming Layer to ensure that all major programming languages and toolboxes can be used to develop and execute experiments. We have minimized the user restrictions as much as possible and imposed only two requirements on the experiment: The experiment should include a Lab Streaming Layer stream, and it should be able to run from a command line call. Further, we provided an easy-to-use interface that can be adjusted to specific measurement modalities, amplifiers, and participants. The presented system provides a new way of setting up and recording experiments for researchers and participants. Because of the automation and easy-to-use interface, the participant could even start and stop experiments by themselves, thus potentially providing data without the experimenter’s presence.
DLPFC-PPC-cTBS Effects on Metacognitive Awareness
Authors: Martin Antonio , Lane Timothy J. , Hsu Tzu-Yu
Published: October 2022

Background

Neuroimaging and lesion studies suggested that the dorsolateral prefrontal and posterior parietal cortices mediate visual metacognitive awareness. The causal evidence provided by non-invasive brain stimulation, however, is inconsistent.

Objective/Hypothesis

Here we revisit a major figure discrimination experiment adding a new Kanizsa figure task trying to resolve whether bilateral continuous theta-burst transcranial magnetic stimulation (cTBS) over these regions affects perceptual metacognition. Specifically, we tested whether subjective visibility ratings and/or metacognitive efficiency are lower when cTBS is applied to these two regions in comparison to an active control region.

Methods

A within-subjects design including three sessions spaced by one-week intervals was implemented. In each session, every participant was administered bilateral cTBS to either prefrontal, control or parietal cortices. Two concurrent tasks were performed, a real and an illusory figure task, stabilising objective performance with use of an adaptive staircase procedure.

Results

When performing the replicated task, cTBS was found insufficient to disrupt neither visibility ratings nor metacognitive efficiency. However, with use of Kanizsa style illusory figures, cTBS over the dorsolateral prefrontal, but not over the posterior parietal cortex, was observed to significantly diminish metacognitive efficiency.

Conclusion(s)

Real and illusory figure tasks demonstrated different cTBS effects. A possible explanation is the involvement of the prefrontal cortex in the creation of expectations, which is necessary for efficient metacognition. Failure to replicate previous findings for the real figure task, however, cannot be said to support, conclusively, the notion that these brain regions have a causal role in metacognitive awareness. This inconsistent finding may result from certain limitations of our study, thereby suggesting the need for yet further investigation.
Propofol Reverses Surgery-Induced Neuroinflammation and Cognitive Impairment in Aged Mice via α5-GABAAReceptors
Authors: Nagarajan Rajasekar , Lyu Jinrui , Kambali Maltesh , Wang Muxiao , Pearce Robert A. , Rudolph Uwe
Published: October 2022

Surgery may lead to long-lasting cognitive deficits that are referred to as perioperative neurocognitive disorder (NCD), particularly in elderly patients. Currently, no interventions are routinely employed in clinical practice to prevent perioperative NCD. Here we show that perioperative chronic intermittent administration of propofol to aged mice undergoing laparotomy under isoflurane anesthesia effectively blocks the surgery-induced increase in nitrosative stress, increased expression of proapoptotic proteins, microglial activation, and cognitive deficits. By contrast, in the absence of surgery and anesthesia, propofol had little effect on biochemical parameters and led to cognitive improvement only in a subset of behavioral paradigms. The actions of propofol were largely absent in mice lacking the GABAAreceptor α5-subunit, indicating that they are mediated by α5-containing GABAAreceptors. These results demonstrate that propofol – via α5-containing GABAAreceptors that are redistributed to the cell surface membranes in a sustained manner – can attenuate surgery-induced neuroinflammation and postsurgical cognitive deficits.
KDM6A/UTX promotes spermatogenic gene expression across generations but is dispensable for male fertility
Authors: Walters Benjamin William , Rainsford Shannon R , Dias Nicolas , Huang Xiaofang , de Rooij Dirk G , Lesch Bluma J
Published: October 2022

Paternal chromatin undergoes extensive structural and epigenetic changes during mammalian spermatogenesis, producing sperm that contain an epigenome optimal for the transition to embryogenesis. Histone modifiers play an important role in this process by encoding specialized regulatory information in the sperm epigenome. Lysine demethylase 6a (KDM6A) promotes gene activation via demethylation of H3K27me3, a developmentally important repressive modification abundant throughout the epigenome of sperm and embryonic stem cells. Despite its developmental importance in pluripotent cells and germ cell progenitors, the function of KDM6A during spermatogenesis has not been described. Here, we show thatKdm6ais transiently expressed in the male germline in late spermatogonia and during the early stages of meiotic entry. Deletion ofKdm6ain the male mouse germline (Kdm6acKO) yielded a modest increase in sperm head defects but did not affect fertility or the overall progression of spermatogenesis. However, hundreds of genes were deregulated upon loss ofKdm6ain spermatogenic cells and in an immortalized spermatogonia cell line (GC-1 spg) with a strong bias towards downregulation. Single cell RNA-seq revealed that most of these genes were deregulated in spermatogenic cells at the same stage whenKdm6ais expressed and encode epigenetic factors involved in chromatin organization and modification. A subset of these genes was persistently deregulated in the male germ line across two generations of offspring ofKdm6acKO males. Our findings highlight KDM6A as a transcriptional activator in the mammalian male germline that is dispensable for spermatogenesis but important for safeguarding gene regulatory state intergenerationally.

Author summary

Offspring viability and fitness relies upon the development of functional sperm and the integrity of information that they carry. Chromatin is modified and remodeled extensively throughout spermatogenesis to facilitate meiosis, DNA compaction, and to encode gene regulatory information for the next generation. In mice, a paternal germline lacking KDM6A, a histone modifier, yields offspring with reduced lifespans and increased cancer risk. How KDM6A functions in the paternal germline to support offspring health is unknown. Here, we show thatKdm6aexpression is limited to a distinct developmental interval when differentiated spermatogonia transition from mitosis to meiosis. During this timepoint, KDM6A acts as a transcriptional activator for hundreds of genes, many of which encode meiotic factors and epigenetic modifiers. Nevertheless, this activity is dispensable for overall spermatogenesis and fertility. Surprisingly, we find a significant overlap in germline transcriptomes ofKdm6acKO mice and wildtype offspring. We propose that KDM6A encodes gene regulatory information in the male germline that is retained across generations.
Characterization of undocumented CO2hydrothermal vent’s system in the Mediterranean Sea: implications for ocean acidification forecasting
Authors: D’Alessandro Michela , Gambi Maria Cristina , Caruso Cinzia , Di Bella Marcella , Esposito Valentina , Gattuso Alessandro , Giacobbe Salvatore , Kralj Martina , Italiano Francesco , Lazzaro Gianluca , Sabatino Giuseppe , Bazzarro Matteo , Urbini Lidia , De Vittor Cinzia
Published: October 2022

A previously undocumented shallow water hydrothermal field from Sicily (Southern Tyrrhenian Sea, Italy), is here described based on a multidisciplinary investigation. The field, covering an area of nearly 8000 m2and ranging in depth from surface to −5 m, was explored in June 2021, to characterise the main physico-chemical features of the water column, describe bottom topography and features, and identify the main megabenthic and nektonic species. Twenty sites were investigated to characterize the carbonate system. Values of pH ranged between 7.84 and 8.04, ΩCa between 3.68 and 5.24 and ΩAr from 2.41 to 3.44. Geochemical analyses of hydrothermal fluids gases revealed a dominance of CO2(98.1%) along with minor amounts of oxygen and reactive gases. Helium isotope ratios (R/Ra =2.51) and δ13CCO2(3) support an inorganic origin of hydrothermal degassing of CO2and the ascent of heat and deep-seated magmatic fluids to the surface. Visual census of fishes and megabenthos (mainly sessile organisms) allowed identification of 62 species, of which four are protected by the SPA/BIO Protocol and two by the International Union for Conservation of Nature. The macroalgaeHalopteris scopariaandJania rubensand the spongeSarcotragussp. were the dominant taxa in the area, while among fishesCoris julisandChromis chromiswere predominant. The preliminary description of this venting field indicates this site as an area of considerable interest and suitable for future experimental studies on ocean acidification.
A new class of polymorphic T6SS effectors and tethers
Authors: Kanarek Katarzyna , Fridman Chaya Mushka , Bosis Eran , Salomon Dor
Published: October 2022

Bacteria use the type VI secretion system (T6SS) to deliver toxic effectors into bacterial or eukaryotic cells during interbacterial competition, host colonization, or when resisting predation. The identity of many effectors remains unknown. Here, we identify RIX, a new domain that defines a class of polymorphic T6SS cargo effectors. RIX, which is widespread in theVibrionaceaefamily, is located at N-termini of proteins containing diverse antibacterial and anti-eukaryotic toxin domains. We demonstrate that RIX-containing proteins are delivered via T6SS into neighboring cells, and that RIX is necessary and sufficient for secretion. We show that RIX-containing proteins can also act as tethers, enabling the T6SS-mediated delivery of other cargo effectors by a previously undescribed mechanism. RIX-containing proteins significantly enlarge the repertoire of known T6SS effectors, especially those with anti-eukaryotic activities. Our findings also suggest that T6SSs may play a major, currently underappreciated, role in interactions between vibrios and eukaryotes.