Detection of Somatic Copy Number Deletion of CDKN2A Gene for Clinical Practices Based on Discovery of A Base-Resolution Common Deletion Region BackgroundCDKN2A is most frequently inactivated by somatic copy number deletion (SCND) in human cancers. An accurate method to detect CDKN2A SCND is absent.

MethodsTo look for the pattern of CDKN2A SCND in cancer cells, interstitial base-resolution deletion/fusion coordinates for CDKN2A were extracted from published articles and our whole genome sequencing (WGS) datasets. A multiplex PCR assay was setup to quantify CDKN2A copy number and confirmed with WGS and loss of heterozygosity (LOH) assays using gastric carcinoma (GC) samples from two sets of patients (n=156 and 140), respectively.

ResultsWe characterized a 5.1-kb common deletion region (CDR) from the CDKN2A/P16INK4A promoter to intron-2 in >90% (83/92) of cancer cell lines and 100% (18/18) of GC samples by WGS. The CDR includes exon-2 that is shared by P16INK4A and P14ARF genes. Then, a highly reproducible and quantitative assay, P16-Light, targeted to the CDR was setup with a lower limit of detection at 20%. P16-Light was further compared with WGS (gold standard) and LOH assay by denaturing high performance liquid chromatography. The positive rate of CDKN2A SCND by P16-Light was more than two times of that by WGS in GCs from a patients cohort (25.6% vs. 10.9%), and was significantly correlated with each other (p<0.028). While CDKN2A SCND was significantly associated with GC distant metastasis (p=0.023), such association was not observed for CDKN2A LOH.

ConclusionBased on our finding that there is a 5.1-kb CDR within the CDKN2A gene, a vary convenient P16-Light assay was setup to detect CDKN2A SCND for routine clinical applications.
Efficacy and Safety of FLOT regimen vs DCF, FOLFOX, and ECF regimens as Perioperative Chemotherapy Treatments for Resectable Gastric Cancer Patients PurposeThis study aimed to compare the efficacy and toxicity of perioperative chemotherapy regimens including ECF, DCF, FOLFOX, and FLOT to identify the most effective chemotherapy regimen with less toxicity.

MethodThis retrospective cohort study(2014-2021) was based on 152 eligible resectable gastric cancer patients who had received one of the perioperative chemotherapy regimens including ECF, DCF, FOLFOX, or FLOT, and followed for at least two years. The primary endpoint of this study was Overall Survival (OS), Progression-Free Survival (PFS), Overall Response Rate (ORR), and R0 resection. We also considered toxicity according to CTCAE (v.4.0) criteria as a secondary endpoint.

ResultsOf included patients, 32(21%), 51(33.7%), 37(24.3%), and 32(21%) had received ECF, DCF, FOLFOX and FLOT, respectively. After the median 30 months follow-up, overall survival was higher with the FLOT regimen in comparison with other regimens (hazard ratio [HR] = 0. 276). The median OS of the FLOT regimen was 39 months. Besides, the median OS was 28, 25, and 21 months for DCF, FOLOFX, and ECF regimens, respectively. Moreover, a median PFS of 24, 18, 17, and 14 months was observed for FLOT, DCF, FOLFOX, and ECF regimens, respectively (Log-rank <0.001). FLOT regimen showed 84. 4% ORR, was notably higher than other groups (p-value<0. 01).

ConclusionsFor resectable gastric cancer patients, the perioperative FLOT regimen led to a significant improvement in patients OS and PFS in comparison with ECF, DCF, and FOLFOX regimens. As such, the FLOT regimen could be considered the optimal option for managing resectable gastric cancer patients.
A Cross-Sectional Examination of Conflict-of-Interest Disclosures of Physician-Authors Publishing in High-Impact US Medical Journals ObjectiveTo assess the accuracy of self-reported financial conflict-of-interest (COI) disclosures in the New England Journal of Medicine (NEJM) and Journal of the American Medical Association (JAMA) within the requisite disclosure period prior to article submission.

DesignCross-sectional investigation.

Data SourcesOriginal clinical-trial research articles published in NEJM (n = 206) or JAMA (n = 188) from January 1 to December 31, 2017; self-reported COI disclosure forms submitted to NEJM or JAMA with the authors published articles; Open Payments website (from database inception; latest search: August 2019).

Main outcome measuresFinancial data reported to Open Payments from 2014 to 2016 (time period that included all subjects requisite disclosure windows) were compared to self-reported disclosure forms submitted to the journals. Payments were defined as those not associated with a research study or formal research funding. Payment types were categorized as "disclosed," "undisclosed," "indeterminate," or "unrelated."

ResultsThirty-one articles from NEJM and 31 articles from JAMA met inclusion criteria. The physician-authors (n = 118) received a combined total of $7.48 million. Of the 106 authors (89.8%) who received payments, 86 (81.1%) received undisclosed payments. The top 23 most highly compensated received $6.32 million, of which $3.00 million (47.6%) was undisclosed. Disclosure rates were the equivalent between the top 23 and the entire sample.

ConclusionsHigh payment amounts, as well as high proportions of undisclosed financial compensation, regardless of amount received, comprised potential COIs for two influential US medical journals. Further research is needed to explain why such high proportions of general payments were undisclosed and whether journals that rely on self-reported COI disclosure need to reconsider their policies. Prognostication for prelabor rupture of membranes and the time of delivery in nationwide insured women: development, validation, and deployment ImportancePrognostic predictions of prelabor rupture of membranes lack proper sample sizes and external validation.

ObjectiveTo develop, validate, and deploy statistical and/or machine learning prediction models using medical histories for prelabor rupture of membranes and the time of delivery.

DesignA retrospective cohort design within 2-year period (2015 to 2016) of a single-payer, government-owned health insurance database covering 75.8% individuals in a country

SettingNationwide healthcare providers (n=22,024) at primary, secondary, and tertiary levels

Participants12-to-55-year-old women that visit healthcare providers using the insurance from [~]1% random sample of insurance holders stratified by healthcare provider and category of family: (1) never visit; (2) visit only primary care; and (3) visit all levels of care

PredictorsMedical histories of diagnosis and procedure (International Classification of Disease version 10) before the latest visit of outcome within the database period

Main Outcomes and MeasuresPrelabor rupture of membranes prognostication (area under curve, with sensitivity, specificity, and likelihood ratio), the time of delivery estimation (root mean square error), and inference time (minutes), with 95% confidence interval

ResultsWe selected 219,272 women aged 33 {+/-} 12 years. The best prognostication achieved area under curve 0.73 (0.72 to 0.75), sensitivity 0.494 (0.489 to 0.500), specificity 0.816 (0.814 to 0.818), and likelihood ratio being positive 2.68 (2.63 to 2.75) and negative 0.62 (0.61 to 0.63). This outperformed models from previous studies according to area under curve of an external validation set, including one using a biomarker (area under curve 0.641; sensitivity 0.419; sensitivity 0.863; positive likelihood ratio 3.06; negative likelihood ratio 0.67; n=1177). Meanwhile, the best estimation achieved {+/-} 2.2 and 2.6 weeks respectively for predicted events and non-events. Our web application only took 5.14 minutes (5.11 to 5.18) per prediction.

Conclusions and RelevancePrelabor rupture of membranes and the time of delivery were predicted by medical histories; but, an impact study is required before clinical application.

Key PointsO_ST_ABSQuestionC_ST_ABSCan we use medical histories of diagnosis and procedure in electronic health records to predict prelabor rupture of membranes and the time of delivery before the day in nationwide insured women?

FindingsIn this prognostic study applying retrospective cohort paradigm, a significant predictive performance was achieved and validated. The area under receiver operating characteristics curve was 0.73 with the estimation errors of {+/-} 2.2 and 2.6 weeks for the time of delivery.

MeaningPreliminary prediction can be conducted in a wide population of insured women to predict prelabor rupture of membranes and estimate the time of delivery. Association of preference and frequency of teleworking with work functioning impairment: a nationwide cross-sectional study of Japanese full-time employees ObjectiveWe examined whether teleworking preference and frequency were associated with work functioning impairment.

MethodsThis online cross-sectional study was conducted using a self-administered questionnaire among 27,036 full-time Japanese workers. The Work Functioning Impairment Scale was used to measure work functioning impairment, and we performed multilevel logistic regression analysis.

ResultsHigher odds ratios for work functioning impairment were observed among employees who preferred to telework compared with those who preferred working in the workplace. A similar trend was observed among employees who teleworked 4 or more days a week compared with those who almost never teleworked. When teleworking preference and frequency were adjusted, only teleworking preference was associated with work functioning impairment.

ConclusionsA preference for teleworking was associated with work functioning impairment and one factor that increased the teleworking frequency. A Randomised Trial of a Wearable UV dosimeter for Skin Cancer Prevention BackgroundNon-melanoma skin cancer (NMSC) is the most prevalent cancer in the United States, affecting 5 million people and costing $8.1 billion per year. Despite well-defined guidelines on ultraviolet radiation (UVR) avoidance, it remains difficult for people to assess their individual exposure, as UVR is invisible and the onset of symptoms due to UVR damage are delayed.

MethodsIn a prospective, randomized-controlled trial, 97 patients with a history of actinic keratoses were enrolled from March 2018 to July 2018 and followed over 6 months. 50 patients were given a wearable device that measured UV exposure and a smartphone application that provided both real-time and cumulative UV exposure information, and 47 patients were provided with UV protection counseling by a dermatologist.

ResultsWe observed a significant decrease in the incidence rate of NMSC in the intervention group compared to the control group over 3 months (p = 0.02). We did not observe a significant decrease in the incidence rate of actinic keratoses (AK) in the intervention group compared to the control group. The observed clinical benefit was not accompanied by psychological side effects such as anxiety and depression.

ConclusionsThis study suggests that providing real-time UV exposure data using a wearable UV dosimeter is a safe and effective behavioral change strategy to prevent NMSC. (Funded by the National Cancer Institute, contract HHSN261201700005C; ClinicalTrials.gov number NCT03315286.) Virtual reality intervention alleviates dyspnea in patients recovering from COVID pneumonia BackgroundImmersive virtual reality (iVR)-based digital therapeutics (DTx) are gaining clinical attention in the field of pain management. Based on known analogies between pain and dyspnea, we investigated the effects of visual-respiratory feedback, on persistent dyspnea in patients recovering from COVID-19 pneumonia.

MethodsWe performed a controlled, randomized, single-blind, cross-over clinical study to evaluate an iVR-based intervention to alleviate dyspnea in patients recovering from COVID-19 pneumonia. Included patients reported persistent dyspnea ([&ge;]5 on a 10-point scale) and preserved cognitive function (MoCA>24). Assignment was random and concealed. Patients received synchronous (intervention) or asynchronous (control) feedback of their breathing, embodied via a gender-matched virtual body. Outcomes were assessed using questionnaires and breathing recordings. COVVR is registered with ClinicalTrials.gov (NCT04844567).

FindingsStudy enrollment was open between November 2020 and April 2021. Twenty-six patients were enrolled (27% women; age: median=55, interquartile range (IQR)=18). Data were available for 24 of 26 patients. The median (IQR) rating on a 7-point Likert-scale of breathing comfort improved from 1(2) at baseline, to 2(1) for synchronous feedback, but remained unchanged at 1(1.5) for asynchronous feedback (p<0.05) between iVR conditions). Moreover, 91.2% of all patients were satisfied with the intervention (p<0.0001) and 66.7% perceived it as beneficial for their breathing (p<0.05). No adverse events were reported.

InterpretationBased on these findings, our iVR-based DTx presents a feasible and safe respiratory rehabilitation tool that improves breathing comfort in patients recovering from COVID-19 infection presenting with persistent dyspnea. Future research should investigate the DTxs generalizability to persistent dyspnea with other etiologies and its potential for preventing chronification.

FundingMarie Sklodowska-Curie Individual Fellowship (H2020-MSCA-IF-2019 894111/ RESPVR), Bertarelli Foundation Reflex single-gene non-invasive prenatal testing significantly increases the cost-effectiveness of carrier screening ObjectiveTo evaluate the clinical and cost savings benefits of adoption of a carrier screen with reflex single-gene non-invasive prenatal test (sgNIPT) in prenatal care.

MethodA decision-analytic model was developed to compare carrier screen with reflex sgNIPT (maternal carrier status and fetal risk reported together) as first-line carrier screening to the traditional carrier screening workflow (positive maternal carrier screen followed by paternal screening to evaluate fetal risk). The model compared the clinical outcomes and cost effectiveness between the two screening methods. These results were used to simulate appropriate pricing for reflex sgNIPT.

ResultsReflex sgNIPT carrier screening detected 108 of 110 affected pregnancies per 100,000 births (98.5% sensitivity), whereas traditional carrier screening detected 46 of 110 affected pregnancies (41.5% sensitivity). The cost to identify one affected pregnancy was reduced by 62% in the reflex sgNIPT scenario compared to the traditional scenario. Adding together the testing cost savings and the savings from earlier clinical intervention made possible by reflex sgNIPT, the total cost savings was $37.6 million per 100,000 pregnancies. Based on these cost savings, we simulated appropriate reflex sgNIPT pricing range: if the cost to identify one affected pregnancy is the unit cost, carrier screening with reflex sgNIPT can be priced up to $1,859 per test (or $7,233 if sgNIPT is billed separately); if the cost per 100,000 pregnancies is the unit cost, carrier screening with sgNIPT can be priced up to $1,070 per test (or $2,336 if sgNIPT is billed separately).

ConclusionUsing the carrier screen with reflex sgNIPT as first-line screening improves the detection of affected fetuses by 2.4-fold and can save costs for the healthcare system. A real-life experience will be needed to assess the clinical utility and exact cost savings of carrier screen with reflex sgNIPT. COMPARISON OF sPLA2-IIA PERFORMANCE WITH HIGH-SENSITIVE CRP, NEUTROPHIL PERCENTAGE, PCT AND LACTATE TO IDENTIFY BACTERIAL INFECTION: A PROSPECTIVE STUDY Early bacterial infection (BI) identification in resource-limiting Emergency Departments (ED) is challenging especially in low- and middle-income counties (LMIC). Misdiagnosis predisposes to antibiotic overuse and propagates antimicrobial resistance. This study evaluates new emerging biomarkers, secretory phospholipase A2 group IIA (sPLA2-IIA), and compares with other biomarkers on their performance characteristic of BI detection in Malaysia, an LMIC. A prospective cohort study was conducted involving 151 consecutive patients admitted to the ED. A single measurement was taken upon patient arrival in ED and was analysed for serum levels of sPLA2-IIA, high-sensitive C-reactive protein (CRP), procalcitonin (PCT), neutrophil percentage (N%), and lactate. All biomarkers performance was compared for the outcomes using area under the receiver operating characteristic curve (AUROC), sensitivity, and specificity. The performance of sPLA2-IIA (AUROC 0.93 [95% CI: 0.89-0.97]; Sn 80% [95% CI: 72-87] Sp 94% [95% CI: 81-89]) was the highest among all. It was comparable with high-sensitive CRP (AUROC 0.93 [95% CI: 0.88-0.97]; Sn 75% [95% CI: 66-83]; Sp 91 [95% CI: 77-98]) but had a higher Sn and Sp. The sPLA2-IIA was also found superior to N%, PCT, and lactate. This finding suggested sPLA2-IIA was recommended biomarkers for BI detection in LMIC. Machine Learning Approaches for Binary Classification to Discover Liver Diseases using Clinical Data For a medical diagnosis, health professionals use different kinds of pathological ways to make a decision for medical reports in terms of patients medical condition. In the modern era, because of the advantage of computers and technologies, one can collect data and visualize many hidden outcomes from them. Statistical machine learning algorithms based on specific problems can assist one to make decisions. Machine learning data driven algorithms can be used to validate existing methods and help researchers to suggest potential new decisions. In this paper, Multiple Imputation by Chained Equations was applied to deal with missing data, and Principal Component Analysis to reduce the dimensionality. To reveal significant findings, data visualizations were implemented. We presented and compared many binary classifier machine learning algorithms (Artificial Neural Network, Random Forest, Support Vector Machine) which were used to classify blood donors and non-blood donors with hepatitis, fibrosis and cirrhosis diseases. From the data published in UCI-MLR, all mentioned techniques were applied to find one better method to classify blood donors and non-blood donors (hepatitis, fibrosis, and cirrhosis) that can help health professionals in a laboratory to make better decisions. Our proposed ML-method showed a better accuracy score (e.g. 98.23% for SVM). Thus, it improved the quality of classification. A protocol for a multicentre observational study across an integrated care system to understand the effect of living with frailty on access to video consultations Risks for digital exclusion include older age, disability, and deprivation. No literature exists examining frailty as an additional possible risk factor. Many studies have shown frailty to be a more accurate predictor of adverse outcome in healthcare than age alone. Understanding risk factors for digital exclusion may help healthcare services appropriately tailor interventions. The Healthier Together integrated care system (HTICS) in Bristol is developing video consultations for clinics. The aim of this prospective observational cross-sectional study is to identify whether living with frailty is a risk factor of digital exclusion from video consultation. Data will be collected using a structured survey including patients from three sites across the Heal secondary care services at North Bristol Trust, and then two subsequent sites will be included across HTICS. Data will be collected on known risk factors for digital exclusion, frailty using the Clinical Frailty Scale, and will cover four domains for digital exclusion as defined by NHS Digital: access, skill, motivation, and confidence. Data will be presented with descriptive statistics. The association between frailty and outcomes will be analysed with a multivariable logistic regression.

Key Study Contacts

O_TBL View this table:
org.highwire.dtl.DTLVardef@134f5d7org.highwire.dtl.DTLVardef@1f8149forg.highwire.dtl.DTLVardef@11dbf0org.highwire.dtl.DTLVardef@7e854borg.highwire.dtl.DTLVardef@61272f_HPS_FORMAT_FIGEXP  M_TBL C_TBL Study Summary

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org.highwire.dtl.DTLVardef@53a9f0org.highwire.dtl.DTLVardef@b9e76dorg.highwire.dtl.DTLVardef@108bd12org.highwire.dtl.DTLVardef@b500ddorg.highwire.dtl.DTLVardef@14be1d8_HPS_FORMAT_FIGEXP  M_TBL C_TBL Funding and Support in Kind

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org.highwire.dtl.DTLVardef@d86811org.highwire.dtl.DTLVardef@1985973org.highwire.dtl.DTLVardef@118ca5corg.highwire.dtl.DTLVardef@8d7839org.highwire.dtl.DTLVardef@1cff6e1_HPS_FORMAT_FIGEXP  M_TBL C_TBL Role of Study Sponsor and FunderThe pilot at North Bristol Trust (NBT) is overseen by Neuromusculoskeletal (NMSK) Division governance. NBT NMSK Division takes responsibility for ensuring that the design of the study meets appropriate standards and that arrangements are in place to ensure appropriate conduct and reporting. Governance oversight for Hospital at Home was registered with NBT NMSK, and for primary care with Horfield Health Centre.

Roles and Responsibilities

Study Flow Chart

O_TBL View this table:
org.highwire.dtl.DTLVardef@594232org.highwire.dtl.DTLVardef@904b3org.highwire.dtl.DTLVardef@138af7org.highwire.dtl.DTLVardef@10898a3org.highwire.dtl.DTLVardef@15d2719_HPS_FORMAT_FIGEXP  M_TBL C_TBL Subjective impact of the COVID-19 pandemic on schizotypy and general mental health in Germany and the UK, for independent samples in May and in October 2020 Studies reported a strong impact on mental health during the first wave of the COVID-19 pandemic in March-June, 2020. In this study, we assessed the impact of the pandemic on mental health in general and on schizoptypal traits in two independent general population samples of the UK (May sample N: 239, October sample N: 126; participation at both timepoints: 21) and in two independent general population samples of Germany (May sample N: 543, October sample N: 401; participation at both timepoints: 100) using online surveys. Whereas general psychological symptoms (global symptom index, GSI) and percentage of responders above clinical cut-off for further psychological investigation were higher in the May sample compared to the October sample, schizotypy scores (Schizotypal Personality Questionnaire) were higher in the October sample. We investigated potential associations, using general linear regression models (GLM). For schizotypy scores, we found that loneliness, use of drugs, and financial burden were more strongly corrected with schizotypy in the October compared to the May sample. We identified similar associations for GSI, as for schizotypy scores, in the May and October samples. We furthermore found that living in the UK was related to higher schizotypal scores or GSI. However, individual estimates of the GLM are highly comparable between the two countries. In conclusion, this study shows that while the general psychological impact is lower in the October than the May sample, potentially showing a normative response to an exceptional situation; schizotypy scores are higher at the second timepoint, which may be due to a stronger impact of estimates of loneliness, drug use, and financial burden. The ongoing, exceptional circumstances within this pandemic might increase the risk for developing psychosis in some individuals. The development of general psychological symptoms and schizotypy scores over time requires further attention and investigation. The Preventive Treatment of Migraine with Low-Dose naltrexone and acetaminophen Combination: Findings of a Small, Randomized, Double-Blind, and Placebo-Controlled Clinical Trial with an Open-Label Extension for None-Responders We tested a low-dose naltrexone and acetaminophen combination for episodic migraine prevention. We randomly assigned patients to naltrexone and acetaminophen combination (n=6) or placebo (n=6) for a 12-week double-blind treatment. Non-responders continued into open-label treatment with naltrexone and acetaminophen combination (n=5) for additional 12 weeks. Patients were adults who experienced 5 to 17 (average 9.7) migraine days at baseline. The primary endpoint was the mean change in the monthly migraine days during the last 4 weeks of the double-blind treatment period. The key secondary endpoint was the mean change in the monthly migraine days from the 4-week double-blind follow-up (2nd baseline) to the last 4 weeks of the open-label treatment period.

The magnitude of the treatment effect for the naltrexone and acetaminophen combination observed in the double-blind period was 2.2 fewer monthly migraine days than placebo (p=0.43). Four out of 6 (66.7%) naltrexone and acetaminophen-treated patients experienced 75% reduction in migraine days compared to 1 out of 6 (16.7%) placebo-treated patients (p=0.09).

In the open-label phase, treatment with the naltrexone and acetaminophen combination (n=5) led to 8.2 fewer mean monthly migraine days (from 11.8 to 3.6), representing 69.5% improvement (p=0.03), and 100% of the patients experienced a 50% reduction in monthly migraine days. Adverse events were mild to moderate and transient, included dry mouth, fatigue, sedation, nausea, and feeling jittery.

We postulate that naltrexones toll-like receptor (TLR4) antagonism properties prevent pro-inflammatory cytokines production in the trigeminal ganglion averting "overactive nerves" (laymans term) and migraine. Although this trial used low-dose naltrexone (defined as 1 - 5 mg/day), in future phase 3 studies we will test a range of naltrexone and acetaminophen combination doses. In situ transcriptional profile of a germinal center plasmablastic burst hints at MYD88/CD79B mutants-enriched Diffuse Large B-cell Lymphomas. The germinal center (GC) reaction results in the selection of B-cells acquiring effector Ig secreting ability by progressing towards plasmablastic differentiation. This transition is associated with exclusion from the GC microenvironment. The aberrant expansion of plasmablastic elements within the GC fringes configures an atypical condition, the biological characteristics of which have not been defined yet. We investigated the in situ immunophenotypical and transcriptional characteristics of a non-clonal germinotropic expansion of plasmablastic elements (GEx) occurring in the tonsil of a young patient. Compared to neighboring GC and peri-follicular regions, the GEx showed a distinctive signature featuring key regulators of plasmacytic differentiation, cytokine signaling, and cell metabolism. The GEx signature was tested in the setting of diffuse large B-cell lymphoma (DLBCL) as a prototypical model of lymphomagenesis encompassing transformation at different stages of GC and post-GC functional differentiation. The signature outlined DLBCL clusters with different immune microenvironment composition and enrichment in genetic subtypes.

SignificanceThis report represents the first insight into the transcriptional features of a germinotropic plasmablastic burst, shedding light into the molecular hallmarks of B cells undergoing plasmablastic differentiation and aberrant expansion within the non-canonical setting of the GC microenvironment. Characteristic and Sex Differences in Auditory Function and Cochlear Pathophysiology in a Noise-exposed Cohort: A Cross-sectional Study BackgroundTo determine the characteristics and sex differences of auditory perception and cochlear function in individuals with long-term occupational noise exposure.

MethodsYoung workers with long-term occupational noise exposure from a shipyard were recruited in the current study as the hidden hearing loss (HHL) risk group. Age-matched office workers in the same shipyard who had no occupational noise-exposure history were enrolled in the control group. The auditory processing ability of speech-in-noise (SIN) score and gap detection threshold (GDT) were further examined by sex. The cochlear function of action potential (AP) and summating potential (SP)/AP values were tested and compared by sex and side. The correlation between the SIN score and cochlear function was studied by sex. The correlation between either auditory processing ability or cochlear function and occupational-noise working length (OWL) was also analysed in the HHL risk group.

ResultsSignificantly decreased SIN scores and a higher GDT of the 4 kHz gap marker were only found in men in the HHL risk group. Although the hearing thresholds of the women in the HHL risk group were slightly but significantly worse than those of the women in the control group, no significant defects in auditory processing or temporal resolution were found between the two groups. Significantly decreased cochlear function and increased SP/AP values in the left ear were only found in men in the HHL risk group. Neither the AP amplitude nor the AP latency differed significantly between the two groups by sex. A correlation study indicated that only the correlation between the SIN score and the AP amplitude of the right ear in men was significant. No significant difference was found between the SIN score and cochlear function in women. The AP latency of the right ear was only significantly correlated with OWL in men.

ConclusionIn long-term occupational working exposure individuals with normal hearing, defects in auditory processing, temporal resolution and cochlear function showed sex differences, none of which were significant in women. In men, a weak correlation between the SIN score and the AP amplitude of the right ear was found. There was only a weak correlation between OWL and the AP latency of the right ear in men. Our findings indicate men are more vulnerable to occupational noise than women. Considering the noise-exposure dose differences between the control and HHL risk groups, our measures are insensitive to cochlear synaptopathy in humans. Deceased donor kidney degradomics indicates cytoskeletal proteolytic alterations impacting post-transplant function. BackgroundIn brain death, cerebral injury contributes to systemic biological dysregulation, causing significant cellular stress in donor kidneys that adversely impacts the quality of grafts. Here, we hypothesized that DBD kidneys may undergo proteolytic processes that renders grafts susceptible to post-transplant dysfunction.

Material & MethodsUsing mass spectrometry and immunoblotting analyses, we profiled degradation patterns of cytoskeletal proteins in deceased (n=55) and living (n=10) donor kidneys.

ResultsWe found that in DBD kidneys, key podocyte cytoskeletal proteins had been proteolytically cleaved. Generated degradation profiles were not associated to donor related demographic and clinical factors but were associated to suboptimal post-transplant function. Strikingly, -actinin -4 and Talin-1 degradation profiles were not observed in circulatory-death or living-donor kidneys. As Talin-1 is a specific proteolytic target of Calpain-1, we investigated a potential trigger of Calpain activation and Talin-1 degradation using ex-vivo precision-cut human kidney slices and in-vitro immortalised human podocytes. Notably, we found that Transforming-Growth Factor-{beta} (TGF-{beta}) activated Calpain-1 and proteolytically cleaved Talin-1 to generate distinct peptide fragments. These peptide fragments were of similar size and matched the degradation patterns observed in DBD kidneys. Talin-1 degradation was prevented in vitro by Calpain-1 inhibition.

ConclusionsHere, we provide initial evidence that DBD kidneys are susceptible to cytoskeletal protein degradation that impacts posttransplant kidney function. Subsequent studies should aim to further investigate the link between brain death and activation of proteolytic pathways exploring new therapeutic opportunities. Dental biofilm microbiota dysbiosis is associated with the risk of acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation Acute graft-versus-host disease (aGVHD) is one of the major causes of death after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recently, aGVHD onset was linked to intestinal microbiota (IM) dysbiosis. However, other bacterial-rich gastrointestinal sites, such as the mouth, which hosts several distinctive microbiotas, may also impact the risk of GVHD. The dental biofilm microbiota (DBM) is highly diverse and, like the IM, interacts with host cells and modulates immune homeostasis. We characterized changes in the DBM of patients during allo-HSCT and evaluated whether the DBM could be associated with the risk of aGVHD. DBM dysbiosis during allo-HSCT was marked by a gradual loss of bacterial diversity and changes in DBM genera composition, with commensal genera reductions and potentially pathogenic bacteria overgrowths. High Streptococcus and high Corynebacterium relative abundance at preconditioning were associated with a higher risk of aGVHD (67% vs. 33%; HR = 2.89, P = 0.04 and 73% vs. 37%; HR = 2.74, P = 0.04, respectively), while high Veillonella relative abundance was associated with a lower risk of aGVHD (27% vs. 73%; HR = 0.24, P < 0.01). Enterococcus faecalis bloom during allo-HSCT was observed in 20% of allo-HSCT recipients and was associated with a higher risk of aGVHD (100% vs. 40%; HR = 4.07, P < 0.001) and severe aGVHD (60% vs. 12%; HR = 6.82, P = 0.01). To the best of our knowledge, this is the first study demonstrating that DBM dysbiosis is associated with the aGVHD risk after allo-HSCT. Development and validation of a multimodal neuroimaging biomarker for electroconvulsive therapy outcome in depression: a multicenter machine learning analysis BackgroundElectroconvulsive therapy (ECT) is the most effective intervention for patients with treatment resistant depression. A clinical decision support tool could guide patient selection to improve the overall response rate and avoid ineffective treatments with adverse effects. Initial small-scale, mono-center studies indicate that both structural magnetic resonance imaging (sMRI) and functional MRI (fMRI) biomarkers may predict ECT outcome, but it is not known whether those results can generalize to data from other centers.

ObjectiveTo develop and validate neuroimaging biomarkers for ECT outcome in a multi-center setting.

MethodsMultimodal data (i.e., clinical, sMRI and resting-state fMRI) was collected from seven centers of the Global ECT-MRI Research Collaboration (GEMRIC). We used data from 189 depressed patients to evaluated which data modalities or combinations thereof could provide the best predictions for treatment response ([&ge;]50% symptom reduction) or remission (HAM-D score [&le;]7) using a support vector machine classifier.

ResultsRemission classification using a combination of gray matter volume and functional connectivity led to good performing models with average 0.82-0.83 area under the curve (AUC) when trained and tested on samples coming from the three largest centers, and remained acceptable when validated using leave-one-site-out cross-validation (0.70-0.73 AUC).

ConclusionsThese results show that multimodal neuroimaging data is able to provide good prediction of remission with ECT for individual patients across different treatment centers, despite significant variability in clinical characteristics across centers. This suggests that these biomarkers are robust, indicating that future development of a clinical decision support tool applying these biomarkers may be feasible. Epicardial adipose tissue thickness is associated with increased COVID-19 severity and mortality BACKGROUNDIncreased adiposity and visceral obesity have been linked to adverse COVID-19 outcomes. The amount of epicardial adipose tissue (EAT) may have relevant implications given its proximity to the heart and lungs. Here, we explored the role of EAT in increasing the risk for COVID-19 adverse outcomes.

METHODSWe included 748 patients with COVID-19 attending a reference center in Mexico City. EAT thickness, sub-thoracic and extra-pericardial fat were measured using thoracic CT scans. We explored the association of each thoracic adipose tissue compartment with COVID-19 mortality and severe COVID-19 (defined as mortality and need for invasive mechanical ventilation), according to the presence or absence of obesity. Mediation analyses evaluated the role of EAT in facilitating the effect of age, body mass index and cardiac troponin levels with COVID-19 outcomes.

RESULTSEAT thickness was associated with increased risk of COVID-19 mortality (HR 1.18, 95%CI 1.01-1.39) independent of age, gender, comorbid conditions and BMI. Increased EAT was associated with lower SpO2 and PaFi index and higher levels of cardiac troponins, D-dimer, fibrinogen, C-reactive protein, and 4C severity score, independent of obesity. EAT mediated 13.1% (95%CI 3.67-28.0%) and 5.1% (95%CI 0.19-14.0%) of the effect of age and 19.4% (95%CI 4.67-63.0%) and 12.8% (95%CI 0.03-46.0%) of the effect of BMI on requirement for intubation and mortality, respectively. EAT also mediated the effect of increased cardiac troponins on myocardial infarction during COVID-19.

CONCLUSIONEAT is an independent risk factor for severe COVID-19 and mortality independent of obesity. EAT partly mediates the effect of age and BMI and increased cardiac troponins on adverse COVID-19 outcomes. Delayed bystander CD8 T cell activation, early immune pathology and persistent dysregulation characterise severe COVID-19 In a study of 207 SARS-CoV2-infected individuals with a range of severities followed over 12 weeks from symptom onset, we demonstrate that an early robust bystander CD8 T cell immune response, without systemic inflammation, is characteristic of asymptomatic or mild disease. Those presenting to hospital had delayed bystander responses and systemic inflammation already evident at around symptom onset. Such early evidence of inflammation suggests immunopathology may be inevitable in some individuals, or that preventative intervention might be needed before symptom onset. Viral load does not correlate with the development of this pathological response, but does with its subsequent severity. Immune recovery is complex, with profound persistent cellular abnormalities correlating with a change in the nature of the inflammatory response, where signatures characteristic of increased oxidative phosphorylation and reactive-oxygen species-associated inflammation replace those driven by TNF and IL-6. These late immunometabolic inflammatory changes and unresolved immune defects may have clinical implications. Factors affecting first return to work following arthroscopic rotator cuff repair: A retrospective observational study in an occupational medicine clinic and single-surgeon practice BackgroundReturn to work (RTW) following arthroscopic rotator cuff repair (aRCR) within New South Wales (NSW), Australia, under compensable schemes has not been reported.

AimsDetermine factors affecting RTW status and time in patients treated with aRCR under state-based compensation schemes, compared to those outside such schemes.

MethodsPatients undergoing aRCR by one surgeon with minimum 1-year follow-up were grouped into those under (CP) or outside (non-CP) workers or vehicle accident compensation schemes, matched by age and gender. RTW status and time were assessed using chi-square analysis and multivariable linear regression.

ResultsOf 1054 available patients, 90 CP patients were identified with 29 consented and matched to non-CP (N=29). A higher proportion of CP patients (17.2 vs 0%, P<0.001) never returned to work and a lower proportion resumed pre-injury duties at first RTW (3 vs 52%, P<0.01). Median time to first RTW did not differ between CP and non-CP groups (5.1 vs 4.4, P=0.86). Smoking (P=0.007) and post-injury activity level (P=0.004) were significantly associated with longer time to first RTW, whereas compensation status was not.

ConclusionsCP patients undergoing aRCR in NSW are at risk of not returning to work. For those that return, there is no significant difference compared to non-CP in time to first RTW. Particularly, patient and management factors associated with extended time to first RTW have been identified. Interventions aimed at modifiable factors such as smoking cessation and increasing preoperative activity may improve future outcomes.

What is already known about this subjectO_LIWork-related injury and disease present a significant financial burden to the Australian economy ($AUD61.8billion per annum), with shoulder conditions due to body stressing accounting for 7% of this total cost (>$AUD4.2billion)
C_LIO_LIPatients receiving compensation appear to have poorer outcomes and take longer to return to work than their non-compensated counterparts, but the degree to which this occurs is variably reported in the literature
C_LIO_LIThe effect of modifiable factors on return to work status and time remain unclear, and have not previously been reported for the Australian population under the New South Wales workers compensation scheme
C_LI

What this study addsO_LIPatients receiving arthroscopic rotator cuff repair under a compensable scheme in New South Wales are at increased risk of not returning to work compared to patients presenting outside of a compensable scheme and patients in equivalent schemes internationally
C_LIO_LIPatients reporting a longer duration of symptoms and smokers are at increased risk of extended time to first return to work
C_LI

What impact this may have on practice or policyO_LIThe study has identified smoking and pre-surgery activity levels as key targets for intervention in patients receiving arthroscopic rotator cuff repair under a workers compensation scheme in New South Wales
C_LIO_LIBy further investigating whether interventions designed to modify these factors are able to favourably affect patient outcomes, there is potential to return patients to their preoperative level of work sooner
C_LI Hyperreflective foci, OCT progression indicators in age-related macular degeneration, include transdifferentiated retinal pigment epithelium PurposeBy optical coherence tomography (OCT) imaging, hyperreflective foci (HRF) indicate progression risk for advanced age-related macular degeneration (AMD) and are in part attributable to ectopic retinal pigment epithelium (RPE). We hypothesized that ectopic RPE are molecularly distinct from in-layer cells and that their cross-retinal course follows Muller glia.

MethodIn clinical OCT (61 eyes, 44 AMD patients, 79.4 {+/-} 7.7 years; 29 female; follow-up = 4.7 {+/-} 0.9 years) one HRF type, RPE plume, was reviewed. Twenty eyes of 20 donors characterized by ex vivo OCT were analyzed by histology (normal, 4; early/intermediate AMD, 7; geographic atrophy (GA), 6; 3 neovascular AMD (nvAMD). Cryosections were stained with antibodies to retinoid (RPE65, CRALPB) and immune (CD68, CD163) markers. In published RPE cellular phenotypes, red immunoreactivity was assessed semi-quantitatively by one observer (none, some cells, all cells).

ResultsTrajectories of RPE plume and cellular debris paralleled Muller glia, whether ordered or subsident, near atrophy borders. RPE corresponding to HRF lost immunoreactivity for retinoid markers and gained immunoreactivity for immune markers. Aberrant immunoreactivity appeared in individual in-layer RPE cells and extended to all abnormal phenotypes. Muller glia remained CRALBP-positive. Plume cells approached and contacted retinal capillaries.

ConclusionGain- and loss-of-function starts with individual in-layer RPE cells and extends to all abnormal phenotypes. Down-regulated RPE retinoid handling may impair rod vision while Muller glia sustain cone vision. Evidence for RPE transdifferentiation, possibly due to ischemia, supports a proposed process of epithelial-mesenchyme transition. Data can propel new biomarkers and therapeutic strategies for AMD.

PrecisHyperreflective foci (HRF) are OCT progression risk indicators in age-related macular degeneration. Abnormal RPE cells including some that correspond to HRF lose immunoreactivity for retinoid markers and gain immunoreactivity for immune markers, indicating molecular transdifferentiation. Health-related quality of life of female sex workers living with HIV in South Africa: a cross-sectional study IntroductionHealth-related quality of life (HRQoL) is an important HIV outcome beyond viral suppression. However, there are limited data characterizing HRQoL of key populations including female sex workers (FSW) living with HIV.

MethodsWe used baseline data (June 22, 2018-March 23, 2020) of FSW who were diagnosed with HIV and enrolled into a randomized trial in Durban, South Africa. HRQoL information was collected by a generic preference-accompanied tool with five domains (EQ-5D), and summarized into a single score (range 0-1) which represents health utility. We employed multivariable beta regression models to identify determinants of HRQoL and to estimate subgroup-specific HRQoL score. Using external estimates of life expectancy and population size, we estimated the number of quality adjusted life years reduced among FSW living with HIV in South Africa associated with violence and drug use.

ResultsOf 1363 individuals (mean age: 32.4 years; mean HRQoL score: 0.857) in our analysis, 62.6% used drugs, 61.3% experienced physical or sexual violence, and 64.6% self-reported taking antiretroviral treatment (ART). The following were associated with a reduction in the average marginal HRQoL score: older age (per decade: 0.018 [95% confidence interval (CI): 0.008, 0.027]), drug use (0.022 [0.007, 0.036]), experience of violence (0.024 [0.010, 0.038]), and moderate (vs. no) level of internalized stigma (0.023 [0.004, 0.041]). Current ART use was associated with a 0.015-point (-0.001, 0.031) increase in the HRQoL score. The estimated mean (95%CI) HRQoL scores ranged from 0.838 (0.816, 0.860) for FSW who used drugs, experienced violence, and were not on ART; to 0.899 (0.883, 0.916) for FSW who did not use drugs nor experience violence and were on ART. Our results can be translated into a reduction in 37,184 and 39,722 quality adjusted life years related to drug use and experience of violence, respectively in South Africa.

ConclusionsThese results demonstrate the association of ART with higher HRQoL among FSW and the need to further address structural risks including drug use, violence, and stigma. Population-specific estimates of HRQoL score can be further used to calculate quality-adjusted life years in economic evaluations of individual and structural interventions addressing the needs of FSW living with HIV.

Clinical Trial RegistrationNCT03500172 (April 17, 2018) Genetic control of fetal placental genomics contributes to development of health and disease As the master regulator in utero, the placenta is core to the Developmental Origins of Health and Disease (DOHaD) hypothesis but is historically understudied. To identify placental gene-trait associations (GTAs) across the life course, we performed distal mediator-enriched transcriptome-wide association studies (TWAS) for 40 traits, integrating placental multi-omics from the Extremely Low Gestational Age Newborn Study. At P < 2.5 x 10-6, we detected 248 GTAs, mostly for neonatal and metabolic traits, across 176 genes, enriched for cell growth and immunological pathways. In aggregate, genetic effects mediated by placental expression significantly explained 4 early-life traits but no later-in-life traits. 89 GTAs showed significant mediation through distal genetic variants, identifying hypotheses for distal regulation of GTAs. Investigation of one hypothesis in human placenta-derived choriocarcinoma cells showed that knockdown of mediator gene EPS15 upregulated predicted targets SPATA13 and FAM214A, both associated with waist-hip ratio in TWAS, and multiple genes involved in metabolic pathways. These results suggest profound health impacts of placental genomic regulation in developmental programming across the life course. Evaluating a first fully automated interview grounded in Multiple Mini Interview (MMI) methodology: results from a feasibility study ObjectivesGlobal, Covid-driven restrictions around face-to-face interviews for healthcare student selection have forced admissions staff to rapidly adopt adapted online systems before supporting evidence is available. We have developed, what we believe is, the first fully automated interview grounded in Multiple Mini-Interview (MMI) methodology. This study aimed to explore test re-test reliability, acceptability and usability of the system.

Design, setting and participantsmixed-methods feasibility study in Physician Associate (PA) programmes from two UK and one US university during 2019 - 2020.

Primary, secondary outcomesFeasibility measures (test retest reliability acceptability and usability) were assessed using intra-class correlation (ICC), descriptive statistics, thematic and content analysis.

MethodsVolunteers took (T1), then repeated (T2), the automated MMI, with a seven-day interval (+/- 2) then completed an evaluation questionnaire. Admissions staff participated in focus group discussions.

ResultsSixty-two students and seven admission staff participated; 34 students and four staff from UK and 28 students and three staff from US universities.

Good-excellent test-retest reliability was observed with T1 and T2 ICC between 0.62-0.81 (p<0.001) when assessed by individual total scores (range 80.6-119), station total scores 0.6-0.91, p<0.005, individual site (all ICC[&ge;] 0.76 p<0.001) and mean test retest across sites 0.82 p<0.001 (95% CI 0.7-0.9).

Admissions staff reported potential to reduce resource costs and bias through a more objective screening tool for pre-selection or to replace some MMI stations in a  hybrid model. Maintaining human interaction through  touch points was considered essential.

Users positively evaluated the system, stating it was intuitive with an accessible interface. Concepts chosen for dynamic probing needed to be appropriately tailored.

ConclusionThese preliminary findings suggest that the system is reliable, generating consistent scores for candidates and is acceptable to end-users provided human touchpoints are maintained. Thus, there is evidence for the potential of such an automated system to augment healthcare student selection processes. Normative cognitive scores in western India, stratified by age, rurality, cognitive domains, and psychiatric comorbidity. Background and objectivesIndian ethnic and educational diversities necessitate obtaining normative cognitive data in different populations. We aimed to evaluate cognitive scores using a Marathi translation of the Kolkata Cognitive Battery (KCB), and to study the association of KCB components with depression and socio-demographic variables.

MethodologyWe studied 2651 individuals aged [&ge;]40 years, without pre-existing neuropsychiatric conditions, from urban (Mumbai) and rural districts of Maharashtra. For each component of KCB, the lowest 10th percentile score was used to define cognitive impairment.

ResultsWe studied 1435 (54%) rural and 1216 (46%) urban residents equally divided by gender (1316 women, 1335 men), average age 54 years. KCB scores were significantly lower with female sex, older age, illiteracy and depression. The largest effect sizes attributable to these factors were in the domains of calculation (gender), visuo-constructional ability (VCA; rurality) and verbal fluency (VF; depression). Scores remained significantly lower in rural residents after controlling for age, sex and education, particularly for VCA, immediate recall and calculation.

ConclusionThis Marathi KCB having been validated on large urban as well as rural samples, may be used to study cognition in Marathi speaking populations with appropriate cut-offs tailored to the degree of urbanization of the population.