title: COVID-19 is associated with higher risk of venous thrombosis, but not arterial thrombosis, compared with influenza: Insights from a large US cohort

abstract:
IntroductionInfection with SARS-CoV-2 is typically compared with influenza to contextualize its health risks. SARS-CoV-2 has been linked with coagulation disturbances including arterial thrombosis, leading to considerable interest in antithrombotic therapy for Coronavirus Disease 2019 (COVID-19). However, the independent thromboembolic risk of SARS-CoV-2 infection compared with influenza remains incompletely understood. We evaluated the adjusted risks of thromboembolic events after a diagnosis of COVID-19 compared with influenza in a large retrospective cohort.

MethodsWe used a US-based electronic health record (EHR) dataset linked with insurance claims to identify adults diagnosed with COVID-19 between April 1, 2020 and October 31, 2020. We identified influenza patients diagnosed between October 1, 2018 and April 31, 2019. Primary outcomes [venous composite of pulmonary embolism (PE) and acute deep vein thrombosis (DVT); arterial composite of ischemic stroke and myocardial infarction (MI)] and secondary outcomes were assessed 90 days post-diagnosis. Propensity scores (PS) were calculated using demographic, clinical, and medication variables. PS-adjusted hazard ratios (HRs) were calculated using Cox proportional hazards regression.

ResultsThere were 417,975 COVID-19 patients (median age 57y, 61% women), and 345,934 influenza patients (median age 47y, 66% women). Compared with influenza, patients with COVID-19 had higher venous thromboembolic risk (HR 1.53, 95% CI 1.38-1.70), but not arterial thromboembolic risk (HR 1.02, 95% CI 0.95-1.10). Secondary analyses demonstrated similar risk for ischemic stroke (HR 1.11, 95% CI 0.98-1.25) and MI (HR 0.93, 95% CI 0.85-1.03) and higher risk for DVT (HR 1.36, 95% CI 1.19-1.56) and PE (HR 1.82, 95% CI 1.57-2.10) in patients with COVID-19.

ConclusionIn a large retrospective US cohort, COVID-19 was independently associated with higher 90-day risk for venous thrombosis, but not arterial thrombosis, as compared with influenza. These findings may inform crucial knowledge gaps regarding the specific thromboembolic risks of COVID-19.


title: BREAst screening Tailored for HEr (BREATHE) - A Study Protocol On Personalised Risk-based Breast Cancer Screening Programme

abstract:
BackgroundRoutine mammography screening is currently the standard tool for finding cancers at an early stage, when treatment is most successful. Current breast screening programmes are one-size-fits-all which all women above a certain age threshold are encouraged to participate. However, breast cancer risk varies by individual. The BREAst screening Tailored for HEr (BREATHE) study aims to assess acceptability of a comprehensive risk-based personalised breast screening in Singapore.

Methods/DesignAdvancing beyond the current age-based screening paradigm, BREATHE integrates both genetic and non-genetic breast cancer risk prediction tools to personalise screening recommendations. BREATHE is a cohort study targeting to recruit [~]3,500 women. The first recruitment visit will include questionnaires and a buccal cheek swab. After receiving a tailored breast cancer risk report, participants will attend an in-person risk review, followed by a final session assessing the acceptability of our risk stratification programme. Risk prediction is based on: a) Gail model (non-genetic), b) mammographic density and recall, c) BOADICEA predictions (breast cancer predisposition genes), and d) breast cancer polygenic risk score.

DiscussionFor national implementation of personalised risk-based breast screening, exploration of the acceptability within the target populace is critical, in addition to validated predication tools. To our knowledge, this is the first study to implement a comprehensive risk-based mammography screening programme in Asia. The BREATHE study will provide essential data for policy implementation which will transform the health system to deliver a better health and healthcare outcomes.

Trial registrationNot applicable.

category: public and global health


title: Systematic review and meta-analyses on the prevalence of dementia in Latin America and Caribbean countries: Exploring sex, rurality, age, and education as possible determinants

abstract:
BackgroundStudies have shown that the prevalence of dementia in Latin America and the Caribbean (LAC) may be higher than in high-income countries. Thus, we sought to systematically analyse the prevalence of dementia and explore possible drivers that lead to this disparity in LAC countries.

MethodWe searched Pubmed, Web of Knowledge, Scopus, Lilacs, and SciELO for studies on dementia in LAC countries in English, Spanish, and Portuguese languages. Random-effects model was applied.

ResultsTwenty-nine studies from 12 LAC countries were included. Pooled prevalence of all-cause dementia was 11%. Further analyses with studies providing raw prevalence by sex, area, and educational level showed a higher prevalence for women (9%) than for men (5%). Also, dementia prevalence was higher for rural than urban residents (12% vs 8%, respectively). Participants without formal education presented more than double the prevalence of dementia (22%) compared to those with at least one year of formal education (10%). Studies with more recent data collection showed higher dementia prevalence.

ConclusionOur findings suggest a high global dementia prevalence in LAC countries and an unequal burden of dementia for women, lower-educated, and rural residents. Secular raises in dementia prevalence call for increased public health efforts for preventative action.

HighlightsO_LIRigorous and most comprehensive review of dementia prevalence in Latin America and the Caribbean (LAC) to date.
C_LIO_LIPooled dementia prevalence estimates are higher in LAC countries compared to high-income countries.
C_LIO_LIHigher prevalence of dementia among women and lower-educated adults.
C_LIO_LIHigher prevalence among older adults living in rural compared to urban areas.
C_LIO_LIQualitative analyses suggest a modest increase in dementia prevalence in LAC countries over time.
C_LI


title: Brain predictors of fatigue in Rheumatoid Arthritis: a machine learning study

abstract:
BackgroundFatigue is a common and burdensome symptom in Rheumatoid Arthritis (RA), yet is poorly understood. Currently, clinicians rely solely on fatigue questionnaires, which are inherently subjective measures. For the effective development of future therapies and stratification, it is of vital importance to identify biomarkers of fatigue. In this study, we identify brain differences between RA patients who improved and did not improve their levels of fatigue, and we compared the performance of different classifiers to distinguish between these samples at baseline.

MethodsFifty-four fatigued RA patients underwent a magnetic resonance (MR) scan at baseline and 6 months later. At 6 months we identified those whose fatigue levels improved and those for whom it did not. More than 900 brain features across three data sets were assessed as potential predictors of fatigue improvement. These data sets included clinical, structural MRI (sMRI) and diffusion tensor imaging (DTI) data. A genetic algorithm was used for feature selection. Three classifiers were employed in the discrimination of improvers and non-improvers of fatigue: a Least Square Linear Discriminant (LSLD), a linear Support Vector Machine (SVM) and a SVM with Radial Basis Function kernel. Results: The highest accuracy (67.9%) was achieved with the sMRI set, followed by the DTI set (63.8%), whereas classification performance using clinical features was at the chance level. The mean curvature of the left superior temporal sulcus was most strongly selected during the feature selection step, followed by the surface are of the right frontal pole and the surface area of the left banks of the superior temporal sulcus. Conclusions: The results presented in this study evidence a superiority of brain metrics over clinical metrics in predicting fatigue changes. Further exploration of these methods may enable clinicians to triage patients towards the most appropriate fatigue alleviating therapies.

category: radiology and imaging


title: A scoping review of the research integrity architecture and how it is addressed in legal frameworks, institutional policies, and the scholarly literature: Research protocol.

abstract:
BackgroundResearch integrity is a dynamic area within the ethical research ecosystem. Several efforts have been made to incorporate this topic in scientific governance frameworks. However, the efforts generally result in non-binding declarations and policies. Due to differences in legal systems, research cultures, and institutional approaches worldwide, there is a need to identify and map existent strategies on sound scientific practices.

ObjectiveThis scoping review aims to systematically search, map, and evaluate the best available evidence on strategies and recommendations regarding research integrity. The goal is to identify international, national, regional, and local legal frameworks, institutional policies and guidelines, research integrity policies, interventions, strategies, and recommendations for:

O_LIThe design and conduct of research projects,
C_LIO_LIThe publication of research results,
C_LIO_LIThe monitoring of scientific practices,
C_LIO_LIThe implementation of corrective actions, and
C_LIO_LIMentoring and education on research integrity.
C_LI

MethodsThe search will follow the PRISMA Extension for Scoping Reviews (PRISMA-ScR) and the methodological approach designed by Arksey and OMalley. It will include legal frameworks, national and international governmental and non-governmental documentation, and scholarly articles published in peer-reviewed journals on research integrity. The search will be conducted in PubMed/MEDLINE, Web of Science, JSTOR, Latin American & Caribbean Health Sciences Literature (Lilacs), Scopus, OECD Library. It will be complemented with hand searching and scanning, covering other databases and grey literature sources. We will extract and synthesize the data using two macro-genres: legal documents (soft law and hard law) and non-legal documents.

category: medical ethics


title: Metabolic network changes that are strongly associated with Dementia with Lewy Bodies as determined through signed distance and partial correlation analysis

abstract:
INTRODUCTIONDetermining significant metabolic changes in Dementia with Lewy Bodies (DLB), a complex and multifactorial neurodegenerative disease, requires, in addition to the analysis of concentration changes, a deep understanding of functional modifications in the context of metabolic networks.

METHODSBrain metabolomics data from DLB patients and healthy controls was explored using novel correlation analysis approaches to identify metabolites with the largest changes in their network in the disease state.

RESULTSNovel clustering and correlation network analysis shows major change in the metabolic network in DLB brain relative to age and sex-matched controls with the largest interaction network alterations for fructose, propylene-glycol, pantothenate and O-acetylcarnitine, although there were no statistically significant changes in their concentrations.

DISCUSSIONNetwork and correlation analyses indicate major changes in the purine degradation pathway, propanoate and {beta}-alanine metabolism as well as an increased role of fructose and reduced significance of glucose in the brains of DLB patients.

category: neurology


title: Applications of fluorescence-guided surgery across multiple tumor types using a near-infrared labeled EGFR antibody

abstract:
BackgroundAs receptor-ligand based strategies emerge for surgical imaging, the relative importance of receptor expression in different tumor types is unknown. Near-infrared (NIR) labeled epidermal growth factor receptor (EGFR) antibody, panitumumab-IRDye800, was evaluated across three cancers to demonstrate its clinical utilities and a holistic analysis framework.

MethodsThirty-one patients diagnosed with high-grade glioma (HGG, n=5, NCT03510208), head and neck squamous cell carcinoma (HNSCC, n=23, NCT02415881) or lung adenocarcinoma (LAC, n=3, NCT03582124) received systemic administration of 50 mg panitumumab-IRDye800 days prior to surgery. Intraoperative NIR laparoscopic or open-field images of the surgical field were acquired and tissue mimicking phantoms were constructed to identify optimal imaging conditions. Margin distance was correlated to fluorescence on resected specimen surface. Panitumumab-IRDye800 distribution was registered to histology in fixed tissue sections. Immunohistochemistry characterized EGFR expression.

ResultsIntraoperative NIR imaging enhanced tumor contrast against surrounding healthy tissue by 5.2-fold, 3.4-fold and 1.4-fold in HGG, HNSCC and LAC, respectively. Imaging quality was optimal at the lowest gain possible under ambient light. Ex vivo NIR fluorescence identified 78 - 97% of at-risk resection margins, with 72 - 92% sensitivity and 67 - 96% specificity for tumor in fixed tissue sections. Intratumoral panitumumab-IRDye800 concentration correlated with total tumoral EGFR expression (HGG > HNSCC > LAC) and delivery barrier. Cellular EGFR expression (80%) and tumor cell density (3000 cells/mm2) was highest in HGG.

ConclusionsIn multiple tumor types, EGFR-targeting in fluorescence-guided surgery translated to enhanced macroscopic tumor contrast and successful margin assessment despite disparate tumor cell density and heterogeneous delivery of pantimumab-IRDye800.

Translational relevanceAs receptor-ligand based strategies emerge for surgical imaging, the relative importance of receptor expression in different tumor types remains unexamined. Near-infrared labeled epidermal growth factor receptor (EGFR) antibody was evaluated across three cancers to demonstrate its clinical utilities and a holistic analysis framework. Targeted fluorescence imaging was performed in patients infused with a consistent dose of panitumumab-IRDye800 using the same fluorescence imaging devices. In high-grade glioma, head and neck squamous cell carcinoma and lung adenocarcinoma, EGFR-targeting in fluorescence-guided surgery translated to enhanced macroscopic tumor contrast and successful margin assessment. While total EGFR expression and delivery barrier corresponded to overall panitumumab-IRDye800 distribution in tissue, tumor depth and operating room lighting can have greater influence over the intraoperative fluorescence contrast at specific tissue surface locations of a certain patient. These factors can facilitate selecting appropriate molecular target and tumor qualities to streamline translation across institutions and regulatory approval of new imaging probes.

category: oncology


title: SVRare: discovering disease-causing structural variants in the 100K Genomes Project

abstract:
Discovery of disease-causing structural variants (dcSV) from whole genome sequencing data is difficult due to high number of false positives and a lack of efficient way to estimate allele frequency. Here we introduce SVRare, an application that aggregates structural variants (SV) called by other tools, and efficiently annotates rare SVs to aid dcSVs discovery.

Applied in the Genomics England (GEL) research environment to data from the 100K Genomes Project, SVRare aggregated 554,060,126 SVs called by Manta and Canvas in all the 71,408 participants in the rare-disease arm. From a pilot study of 4313 families, SVRare identified 36 novel protein-coding disrupting SVs on diagnostic grade genes that may explain probands phenotype. It is estimated that SVRare can increase SV-based diagnosis yield by at least 4-fold. We also performed a genome-wide association study, and uncovered clusters of dcSVs in genes with known pathogenicity, such as PKD1/2 - cystic kidney diseases and LDLR - familial hypercholesterolaemia.

category: genetic and genomic medicine


title: Effects of a multimedia campaign on HIV self-testing and PrEP outcomes among young people in South Africa: A mixed-methods impact evaluation of MTV Shuga Down South

abstract:
IntroductionInnovative HIV technologies can help to reduce HIV incidence, yet uptake of such tools is relatively low among young people. To create awareness and demand among adolescents and young adults, a new campaign of the pan-African MTV Shuga series ("Down South 2"; DS2), featured storylines and messages about HIV self-testing (HIVST) and pre-exposure prophylaxis (PrEP) through television, radio and accompanying multimedia activities in 2019-2020.

MethodsWe conducted a mixed-methods evaluation of the new MTV Shuga series among 15-24 year-olds in Eastern Cape, South Africa, in 2020. A web-based survey, promoted via social media platforms of schools, universities, and communities, assessed exposure to MTV Shuga and knowledge of HIV status; secondary outcomes included awareness and uptake of HIVST and PrEP. An embedded qualitative evaluation explored mechanisms of MTV Shugas impact through in-depth individual and group interviews.

ResultsAmong 3,431 online survey participants, 43% had engaged with MTV Shuga and 24% with DS2 specifically. Knowledge of HIV status was higher among those exposed to DS2 (58%) versus those who were not (35%; adjusted OR=2.06 [95% CI:1.64-2.58]). Exposure was also associated with increased awareness of HIVST (60% vs 28%; aOR=1.99[1.61-2.47]) and use of HIVST (29% vs 10%; aOR=2.49[1.95-3.19]). One-third of respondents were aware of PrEP, with higher proportions among those exposed versus non-exposed to DS2 (52% vs 27%; aOR=1.90[1.53-2.35]). Qualitative insights identified mechanisms by which DS2 increased awareness, confidence and motivation to use HIVST and PrEP, but had less influence on service access.

ConclusionsWe found evidence consistent with a positive causal impact of the MTV Shuga DS2 campaign on HIV prevention outcomes among young people in a high-prevalence setting. As diverse testing and PrEP technologies become accessible, an immersive edutainment campaign can help to expand HIV prevention choices and close age and gender gaps in HIV testing and prevention goals.

category: hiv aids


title: Factors associated with severity of COVID-19 disease in a multicenter cohort of people with HIV in the United States, March-December 2020

abstract:
BackgroundUnderstanding the spectrum of SARS-CoV-2 infection and COVID-19 disease in people with HIV (PWH) is critical to provide clinical guidance and implement risk-reduction strategies.

ObjectiveTo characterize COVID-19 in PWH in the United States and identify predictors of disease severity.

DesignObservational cohort study.

SettingGeographically diverse clinical sites in the CFAR Network of Integrated Clinical Systems (CNICS)

ParticipantsAdults receiving HIV care through December 31, 2020.

MeasurementsCOVID-19 cases and severity (hospitalization, intensive care, death).

ResultsOf 16,056 PWH in care, 649 were diagnosed with COVID-19 between March-December 2020. Case fatality was 2%; 106 (16.3%) were hospitalized and 12 died. PWH with current CD4 count <350 cells/mm3 (aRR 2.68; 95%CI 1.93-3.71; P<.001) or lowest recorded CD4 count <200 (aRR 1.67; 95%CI 1.18-2.36; P<.005) had greater risk of hospitalization. HIV viral load suppression and antiretroviral therapy (ART) status were not associated with hospitalization, although the majority of PWH were suppressed (86%). Black PWH were 51% more likely to be hospitalized with COVID-19 compared to other racial/ethnic groups (aRR 1.51; 95%CI 1.04-2.19, P=.03). Chronic kidney disease (CKD), chronic obstructive pulmonary disease, diabetes, hypertension, obesity, and increased cardiovascular and hepatic fibrosis risk scores were associated with higher risk of hospitalization. PWH who were older, not on ART, with current CD4 <350, diabetes, and CKD were overrepresented amongst PWH who required intubation or died.

LimitationsUnable to compare directly to persons without HIV; underestimate of total COVID-19 cases.

ConclusionsPWH with CD4 <350 cells/mm3, low CD4/CD8 ratio, and history of CD4 <200, have a clear excess risk of severe COVID-19, after accounting for comorbidities also associated with severe outcomes. PWH with these risk factors should be prioritized for COVID-19 vaccination, early treatment, and monitored closely for worsening illness.


title: Durability of antibody responses and frequency of clinical and subclinical SARS-CoV-2 infection six months after BNT162b2 COVID-19 vaccination in healthcare workers

abstract: Antibodies against SARS-CoV-2 decay but persist six months post-vaccination, with lower levels of neutralizing titers against Delta than wild-type. Only 2 of 227 vaccinated healthcare workers experienced outpatient symptomatic breakthrough infections despite 59 of 227 exhibiting serological evidence of exposure to SARS-CoV-2 as defined by development of anti-nucleocapsid protein antibodies.

category: infectious diseases


title: Hierarchical Representation of Complex Intervention Sequences for Automated Subgroup Analysis in Critical Care Settings

abstract: Our understanding of the impact of interventions in critical care is limited by the lack of techniques that represent and analyze complex intervention spaces applied across heterogeneous patient populations. Existing work has mainly focused on selecting a few interventions and representing them as binary variables, resulting in oversimplification of intervention representation. The goal of this study is to find effective representations of sequential interventions to support intervention effect analysis. To this end, we have developed Hi-RISE (Hierarchical Representation of Intervention Sequences), an approach that transforms and clusters sequential interventions into a latent space, with the resulting clusters used for heterogenous treatment effect analysis. We apply this approach to the MIMIC III dataset and identified intervention clusters and corresponding subpopulations with peculiar odds of 28-day mortality. Our approach may lead to a better understanding of the subgrouplevel effects of sequential interventions and improve targeted intervention planning in critical care settings.

category: intensive care and critical care medicine


title: Long-term predictions of humoral immunity after two doses of BNT162b2 and mRNA-1273 vaccines based on dosage, age and sex

abstract:
SummaryO_ST_ABSBackgroundC_ST_ABSThe lipid nanoparticle (LNP)-formulated mRNA vaccines are a widely adopted two-dose vaccination public health strategy to manage the COVID-19 pandemic. Clinical trial data has described the immunogeneicity of the vaccine, albeit within a limited study time frame. Our aims were to use a within-host mathematical model for LNP-formulated mRNA vaccines, informed by available clinical trial data, to project a longer term understanding of humoral immunity as a function of vaccine type, dosage amount, age, and sex.

MethodsWe developed a mathematical model describing the immunization process of LNP-formulated mRNA vaccines, and fit our model to twenty-two clinical humoral and cytokine BNT162b2 or mRNA-1273 human two-dose vaccination data sets. We incorporated multi-dose effects in our model to specify whether the dosage is standard or low-dose. We further specify the age groups 18-55, 56-70, and 70+ in our fits for two-standard doses of mRNA-1273, and sex in our fits for two-standard doses of BNT162b2. We used non-linear mixed effect models to fit to all similar data types (e.g. standard two-dose BNT162b2 or mRNA-1273, or two low-dose mRNA-1273). Therefore, in our fits all estimated parameters are statistically correlated, which allowed us to determine the underlying  population-dynamics structure common to a data type. We therefore made accurate long-term predictions informed by all clinical data used in this study.

FindingsWe estimate that two standard doses of either mRNA-1273 or BNT162b2, with dosage times separated by the company-mandated intervals, results in individuals loosing more than 99% humoral immunity relative to peak immunity by eight months following the second dose. We predict that within an eight month period following dose two (corresponding to the CDC time-frame for administration of a third dose), there exists a period of time longer than one month where an individual has less then 99% humoral immunity relative to peak immunity, regardless of which vaccine was administered. We further find that age has a strong influence in maintaining humoral immunity; by eight months following dose two we predict that individuals aged 18-55 have a four-fold humoral advantage compared to aged 56-70 and 70+ individuals. We find that sex has little effect on the vaccine uptake and long-term IgG counts. Finally, we find that humoral immunity generated from two low doses of mRNA-1273 decays substantially slower relative to peak immunity gained than compared to two standard doses of either mRNA-1273 or BNT162b2.

InterpretationFor the two dose mRNA vaccines, our predictions highlight the importance of the recommended third booster dose in order to maintain elevated levels of antibodies. We further show that age plays a critical role in determining the antibody levels. Hence, a third booster dose may confer an immuno-protective advantage in older individuals.

FundingThis research is supported by NSERC Discovery Grant (RGPIN-2018-04546), NSERC COVID-19 Alliance Grant ALLRP 554923-20, CIHR-Fields COVID Immunity Task Force, NRC Pandemic Response Challenge Program Grant No. PR016-1.


title: Co-administration of treatment for rifampicin-resistant tuberculosis and chronic hepatitis C virus infection: a TBnet and ESGMYC study

abstract: Concomitant treatment for chronic hepatitis C virus infection and multidrug-resistant tuberculosis is safe and effective.


title: Public Perception of COVID-19 Vaccines on Twitter in the United States

abstract:
BackgroundCOVID-19 vaccines play a vital role in combating the COVID-19 pandemic. Social media provides a rich data source to study public perception of COVID-19 vaccines.

ObjectiveIn this study, we aimed to examine public perception and discussion of COVID-19 vaccines on Twitter in the US, as well as geographic and demographic characteristics of Twitter users who discussed about COVID-19 vaccines.

MethodsThrough Twitter streaming Application Programming Interface (API), COVID-19-related tweets were collected from March 5th, 2020 to January 25th, 2021 using relevant keywords (such as "corona", "covid19", and "covid"). Based on geolocation information provided in tweets and vaccine-related keywords (such as "vaccine" and "vaccination"), we identified COVID-19 vaccine-related tweets from the US. Topic modeling and sentiment analysis were performed to examine public perception and discussion of COVID-19 vaccines. Demographic inference using computer vision algorithm (DeepFace) was performed to infer the demographic characteristics (age, gender and race/ethnicity) of Twitter users who tweeted about COVID-19 vaccines.

ResultsOur longitudinal analysis showed that the discussion of COVID-19 vaccines on Twitter in the US reached a peak at the end of 2020. Average sentiment score for COVID-19 vaccine-related tweets remained relatively stable during our study period except for two big peaks, the positive peak corresponds to the optimism about the development of COVID-19 vaccines and the negative peak corresponds to worrying about the availability of COVID-19 vaccines. COVID-19 vaccine-related tweets from east coast states showed relatively high sentiment score. Twitter users from east, west and southern states of the US, as well as male users and users in age group 30-49 years, were more likely to discuss about COVID-19 vaccines on Twitter.

ConclusionsPublic discussion and perception of COVID-19 vaccines on Twitter were influenced by the vaccine development and the pandemic, which varied depending on the geographics and demographics of Twitter users.


title: Safety and efficacy of a prehospital initiated protocol of nitrates plus non-invasive ventilation on prehospital and Emergency Department outcomes for acute cardiogenic pulmonary oedema

abstract:
BackgroundAcute heart failure is a common presentation to Emergency Departments (ED) the world over. Amongst the most common presenting signs and symptoms is dyspnoea due to acute pulmonary oedema, a life-threatening emergency that if left untreated or poorly managed. There is increasing evidence demonstrating improved outcomes following the use of vasodilators or non-invasive ventilation for these patients in the emergency setting. Consequently, the potential exists that initiating these therapies in the prehospital setting will similarly improve outcomes.

MethodsA historical cohort study was conducted to assess the effect of a prehospital initiated treatment protocol of nitrates plus non-invasive ventilation (NIV) versus regular therapy for severe cardiogenic APO on all-cause in-hospital mortality at 7 days, 30 days, and in total. Secondary outcomes included changes in EMS respiratory and haemodynamic parameters; admission status; length of stay; and emergency endotracheal intubation.

ResultsThe intervention led to an approximate 85% reduction in adjusted odds of mortality at 7 days compared to the regular therapy (AOR 0.15, 95% CI: 0.05 - 0.46, p = 0.001); approximate 80% reduction in odds of mortality at 30 days (AOR 0.19, 95% CI: 0.07 - 48, p < 0.0001); and Approximate 60% reduction in odds of total mortality (AOR 0.25, 95% CI: 0.12 - 0.56, p = 0.001).

ConclusionThe results of this analysis provide strong evidence of the potential synergistic benefits that can be achieved with the early implementation of a simple treatment protocol of prehospital administered nitrates and initiation of NIV for cardiogenic APO.

category: emergency medicine


title: Waist circumference thresholds predicting incident dysglycemia and type 2 diabetes in Black African men and women

abstract:
ObjectiveTo determine the waist circumference (WC) thresholds for the prediction of incident dysglycemia and type 2 diabetes in Black South African (SA) men and women and compare these to advocated International Diabetes Federation (IDF) Europid thresholds.

Research design and methodIn this prospective study, Black SA men (n=502) and women (n=527) from the Middle Aged Sowetan Cohort (MASC) study who had normal or impaired fasting glucose at baseline (2011-2015) were followed up through 2017-2018. Baseline measurements included anthropometry, blood pressure and fasting glucose, HDL-cholesterol and triglyceride concentrations. At follow-up, glucose tolerance was assessed using an oral glucose tolerance test. The Youden index was used to determine the optimal threshold of WC to predict incident dysglycemia and type 2 diabetes.

ResultsIn men, the optimal WC threshold was 96.8 cm for both dysglycemia and type 2 diabetes (sensitivity 56 and 70%, specificity 74 and 70%, respectively), which performed similarly to the IDF threshold of 94 cm. In women, the optimal WC threshold for incident dysglycemia was 91.8 cm (sensitivity 86%, specificity 37%) and for type 2 diabetes was 95.8 cm (sensitivity 85%, specificity 45%). In comparison, the IDF threshold of 80 cm in women had higher sensitivity (97 and 100%), but lower specificity (12 and 11%) to predict incident dysglycemia and type 2 diabetes, respectively.

ConclusionsIn this first prospective study of incident type 2 diabetes in Africa, we show that African-specific WC thresholds perform better than the IDF WC thresholds to predict incident dysglycemia and type 2 diabetes.

category: endocrinology


title: Computer skills of health workers in rural Ghana and their use of social media: Implications for increased use of information technology in service delivery

abstract:
BackgroundInformation and Communication Technologies (ICTs) have improved the delivery of healthcare worldwide especially in disease control, patient management, and health data analysis. However, access to infrastructure like computers and knowledge of ICT is a major problem to various digital health initiatives among health professionals.

ObjectiveThe aim of the present study was, to assess healthcare workers basic computer skills and use of social media and identify specific deficiencies that require training to help them function effectively.

MethodsWe conducted a cross-sectional study among 51 healthcare workers in seven health centers in a region in Ghana over three months using a self-administered pre-tested questionnaire.

ResultsHalf of the participants had adequate basic computer skills, of which 60.87% were women (P=0.0205). Only 15.69%, who were all males, of participants used computer software at least once a month. Most participants also used Facebook and WhatsApp.

ConclusionHealth professionals in the health centers need to be trained on basic computer skills and, information technology should be incorporated into the health systems for efficient health delivery.

category: epidemiology


title: Extent of cord pathology in the lumbosacral enlargement in non-traumatic versus traumatic spinal cord injury

abstract:
ObjectivesThis study compares remote neurodegenerative changes caudal to a cervical injury in degenerative cervical myelopathy (DCM) (i.e. non-traumatic) and incomplete traumatic spinal cord injury (tSCI) patients, using MRI-based tissue area measurements and diffusion tensor imaging (DTI).

MethodsEighteen mild to moderate DCM patients with sensory impairments (mean mJOA score: 16.2), 14 incomplete tetraplegic tSCI patients (AIS C&D), and 20 healthy controls were recruited. All participants received DTI and T2*-weighted scans in the lumbosacral enlargement (caudal to injury) and at C2/C3 (rostral to injury). MRI readouts included DTI metrics in the white matter (WM) columns and cross-sectional WM and gray matter area. One-way ANOVA with Tukey post-hoc comparison (p<0.05) was used to assess group differences.

ResultsIn the lumbosacral enlargement, compared to DCM, tSCI patients exhibited decreased fractional anisotropy in the lateral (tSCI vs. DCM, -11.9%, p=0.007) and ventral WM column (-8.0%, p=0.021), and showed trend toward lower values in the dorsal column (-8.9%, p=0.068). At C2/C3, no differences in DTI metrics were observed between DCM and tSCI, but compared to controls, fractional anisotropy was lower in both groups in the dorsal (DCM vs. controls, -7.9%, p=0.024; tSCI vs. controls, -10.0%, p=0.007) and in the lateral column (DCM: -6.2%, p=0.039; tSCI: -13.3%, p<0.001). WM areas were not different between patient groups, but were significantly lower compared to healthy controls both in the lumbosacral enlargement (DCM: -16.9%, p<0.001; tSCI, -10.5%, p=0.043) and at C2/C3 (DCM: -16.0%, p<0.001; tSCI: -18.1%, p<0.001).

ConclusionIn conclusion, mild to moderate DCM and incomplete tSCI lead to similar degree of degeneration of the dorsal and lateral columns at C2/C3, but tSCI results in more widespread white matter damage in the lumbosacral enlargement. These remote changes are likely to contribute to the impairment and recovery of the patients. Diffusion MRI is a sensitive tool to assess remote pathological changes in DCM and tSCI patients.


title: Radical versus partial nephrectomy and survival from stage T1 renal cell carcinoma in three prospective cohorts

abstract:
BackgroundWhether or not a survival difference exists between radical and partial nephrectomy for stage T1 renal cell carcinoma (RCC) is controversial. We therefore aimed to evaluate cancer-specific, other cause, and overall survival among patients undergoing radical or partial nephrectomy for stage pT1 RCC.

Materials and methodsWe identified 330 participants with pT1a-b RCC diagnosed between 2000-2015 in three prospective cohort studies and compared treatment with radical nephrectomy (N=196) versus partial nephrectomy (N=134). The primary outcome was overall survival. Secondary outcomes were other-cause and cancer-specific mortality. Kaplan-Meier plots were used to visualize overall survival for the two treatment groups. Cox proportional hazards regression was utilized to compare outcomes between groups, and Fine and Gray competing risks regression was used to compare cancer-specific and other cause mortality between groups. Multivariable models adjusted for age, tumor size, sex, year of diagnosis, body mass index, history of smoking, history of hypertension, surgical technique, and pathological differentiation.

ResultsDuring a median follow-up of eight years, overall survival was 84%. We did not detect a statistically significant difference in overall survival between partial and radical nephrectomy (Hazard Ratio (HR) = 0.84, 95% Confidence Interval: 0.40-1.78). There was no significant difference in cause-specific or other cause mortality between groups. This study had 80% power to detect an HR [≥]2.20.

ConclusionsThese results did not suggest a difference in long-term survival outcomes between radical and partial nephrectomy.

category: urology


title: Characterizing Potential Conflicts of Interest Among UpToDate and DynaMed Content Contributors

abstract:
BACKGROUNDFinancial conflicts of interest among physicians have the potential to negatively impact patient care. Physicians contribute content to two popular, evidence-based websites, UpToDate and DynaMed; while other physicians use these websites to influence their clinical decision making. Each website maintains a conflict-of-interest policy, and contributors are required to self-report a disclosure status. This research investigated the occurrence for potential conflicts of interest among the self-reported statuses of UpToDate and DynaMed content contributors.

METHODSAn initial list of contributors for each website was compiled using the Centers for Disease Control and Preventions 2017 Leading Causes of Death. The top 50 causes were used to determine a relevant article with clinical implications from each database. All named authors and editors of those articles comprised our list of investigated contributors. Contributor disclosure status was then compared with public records of financial remuneration as reported in the Open Payments database maintained by the Centers for Medicare and Medicaid Services and ProPublicas Dollar for Docs website from 2013 to 2018. Descriptive analysis and Fishers exact tests were performed on the data.

RESULTSOf 76 UpToDate contributors, 57.9% reported nothing to disclose but had a record of receiving a financial payment on Open Payments, which was found to be statistically significant (p = 0.0002). Of DynaMeds 42 contributors who reported nothing to disclose, 83.3% had an entry on Open Payments. However, this was not statistically significant. The sum total of industry payments between 2013-2018 made to UpToDate contributors was $68.1 million. The top ten UpToDate contributors who received the most financial remuneration earned approximately $56.1 million (82.4% of all UpToDate renumeration), were all male, and only one had a nothing-to-disclose status. The sum total of compensation reported for the discordant UpToDate contributors between 2013-2018 was approximately $4.81 million (or 7.07% of the total monies reported to UpToDate contributors.) In that same time frame, DynaMed contributors received a sum total of $9.58 million from industry, while the top ten DynaMed contributors earned $8.88 million (or 92.8%) of that. The top ten DynaMed contributors were 80% male and 20% female, and six individuals reported nothing to disclose, yet had an Open Payments entry. The sum total of money reported for all discordant DynaMed contributors between 2013-2018 was approximately $2.79 million (or 29.2% of the total monies reported to DynaMed contributors).

CONCLUSIONSWhile this research does not ascertain that a conflict of interest or anything untoward, it does provide evidence that there was a significant difference between having an Open Payment entry among those who did versus those who did not disclose a conflict of interest. Websites such as UpToDate and DynaMed should consider implementing a more stringent conflict of interest policy and employ an unbiased team to verify self-reported disclosure statuses among its content contributors. Similarly, physicians who use such informational websites to inform their clinical decision making should look beyond a contributors self-reported disclosure status and verify relevant financial remuneration from the healthcare industry via Open Payments or Dollars for Docs.


title: Self-reported safety of the BBIBP-CorV (Sinopharm) COVID-19 vaccine among Iranian people with multiple sclerosis

abstract: To affirm the short-term safety of the BBIBP-CorV (Sinopharm) COVID-19 vaccine among people with multiple sclerosis (pwMS), 517 vaccinated and 174 unvaccinated pwMS were interviewed. 16.2% of the vaccinated pwMS reported at least one neurological symptom in their respective at-risk periods (ARP) - a period from the first until two weeks after the second vaccine dose. In a multivariable logistic regression model, presence of comorbidities (P = 0.01), being on natalizumab (P = 0.03), and experiencing post-vaccination myalgia (P < 0.01) predicted the development of post-vaccination neurological symptoms. One MS relapse, one COVID-19 contraction, and one ulcerative colitis flare after the first, and four MS relapses after the second dose, were the only reported serious adverse events during the ARPs. A multivariable Poisson regression model accounting for possible confounders failed to show any statistically-significant increase in relapse rates during the ARPs of vaccinated, compared to the prior year of unvaccinated pwMS (P = 0.78). Hence, the BBIBP-CorV vaccine does not seem to affect short-term MS activity. Furthermore, as 83.33% of the unvaccinated pwMS reported fear of possible adverse events to be the reason of their vaccination hesitancy, provision of misinformed pwMS with evidence-based consultations in this regard is encouraged.


title: Can infrared camera images be used for screening in Adolescent Idiopathic Scoliosis?

abstract:
Introduction/Background contextAdolescent idiopathic scoliosis (AIS) is the most common type of scoliosis, and affects up to 4% of adolescents in early stages1. The deformity can develop during any of the rapid periods of growth in children2, and the time of pubertal growth spurt also plays a role in spinal curve progression3. Hence it is crucial to detect the disease early, to provide timely intervention.

Detection of scoliosis when it is mild or before the growth spurt can be conducted via various screening methods. Adams forward bend test (FBT) and scoliometer measurement of the angle of trunk rotation (ATR) are commonly used4, to observe lateral bending and rotation of the spine, causing a visible rib hump. Moire topography can also be used, but is reserved for second tier due to some degree of ambiguity5. X-rays (XR) remain the best way to diagnose scoliosis, as it provides a clear image of the spine and allows measurement of Cobb angle; however it has risks associated including requirement of the use of ionising radiation6.

Infrared (IR) thermography can be used to measure surface temperature and is performed with an IR camera. The temperature distribution and data matrix can be visualised into a thermal map, which has previously been studied and associated with the thermal asymmetry in paraspinal muscles7, as well as significant temperature differences between the convex and concave side of the spinal curvature for idiopathic scoliotic patients8. We hypothesize that such asymmetry and temperature differences may produce a detectable pattern on IR thermography, which would prompt further confirmatory investigations to reach a fast and non-radiation screening of AIS.

Aims and ObjectivesFor the purposes of this study, the hypothesised thermal pattern detected by IR thermography will be compared to the spinal deformities observed on XR, the ground truth as labelled by specialists. This will allow us to establish a paired dataset comparing spine visualisation between the two imaging modalities. Thus, the compared dataset would enable the generation of a machine learning model capable of automated classification of the deformity severities. The predictive accuracy of the model will be evaluated by the specialists assessment results. The aim of the project is to use IR to predict the severity of the scoliotic curve, opening up the possibility of using IR thermography with no radiation exposure and fully automated analytical pipeline for the screening of AIS.

category: orthopedics


title: Long-term manifestations and modifiers of prevalence estimates of the post-COVID-19 syndrome: A systematic review and meta-analysis.

abstract:
BackgroundPost-acute COVID-19 syndrome (PACS) is a multi-system disease comprising persistent symptomatology after the acute phase of infection. Long-term PACS effects significantly impact patient outcomes, but their incidence remains uncharacterized due to high heterogeneity between studies. Therefore, we aimed to summarize published data on PACS, characterizing the clinical presentation, prevalence, and modifiers of prevalence estimates.

MethodIn this systematic review and meta-analysis, we research MEDLINE for original studies published from January 1st, 2020, to January 31st, 2021, that reported proportions of PACS manifestations. Studies were eligible for inclusion if they included patients aged [≥]18 years with confirmed COVID-19 by RT-PCR or antigen testing and a minimum follow-up of 21 days. The prevalence of individual manifestations across studies was pooled using random-effects meta-analysis. For evaluating determinants of heterogeneity, meta-regression analysis was performed. This study was registered in PROSPERO (CRD42019125025).

ResultsAfter screening 1,235 studies, we included 29 reports for analysis. Twenty-seven meta-analyses were performed, and 61 long-term manifestations were described. The pooled prevalence of PACS was 56% (95%CI 45-66%), with the most common manifestations being diminished health status, fatigue, asthenia, dyspnea, myalgias, hyposmia and dysgeusia. Most of the included studies presented high heterogeneity. After conducting the meta-regression analysis, we identified that age, gender, number of comorbidities, and reported symptoms significantly modify the prevalence estimation of PACS long-term manifestations.

ConclusionPACS is inconsistently reported between studies, and population characteristics influence the prevalence estimates due to high heterogeneity. A systematized approach for the study of PACS is needed to characterize its impact adequately.

Fundingnone


title: Meta-analysis of coagulation disbalances in COVID-19: 41 studies and 17601 patients

abstract:
IntroductionCoagulation parameters are important determinants for COVID-19 infection. We conducted meta-analysis to assess the early hemostatic parameters in retrospective studies in association with severity of infection.

MethodsOvid, PubMed, Web of Sciences, and Google Scholar were searched for research articles that addressed clinical characteristics of COVID-19 patients and disease severity. Results were filtered using exclusion and inclusion criteria and then pooled into a meta-analysis to estimate the standardized mean difference with 95% CI for each of five coagulation parameters (D-dimers, fibrinogen, prothrombin time, platelets count, activated partial thromboplastin time). Two authors independently extracted data and assessed study quality. To explore the heterogeneity and robustness of our fundings, sensitivity and subgroup analyses were conducted. Publication bias was assessed with contour-enhanced funnel plots and Egger test by linear regression.

ResultsOverall, 41 original studies (17601 patients) on SARS-CoV2 were included. For the two groups of patients, stratified by severity, we identified that D-dimers, fibrinogen, activated partial thromboplastin time, and prothrombin time were significantly higher in the severe group (SMD 0.6985 with 95%CI [0.5155; 0.8815]); SMD 0.661with 95%CI [0.3387; 0.9833]; SMD 0.2683 with 95%CI [0.1357; 0.4009]; SMD 0.284 with 95%CI [0.1472; 0.4208]). In contrast, PLT was significantly lower in patients with more severe cases of COVID-19 (SMD -0.1684 with 95%CI [-0.2826; -0.0542]). Neither the analysis by the leave-one-out method nor the influence diagnostic have identified studies that solely cause significant change in the effect size estimates. Subgroup analysis showed no significant difference between articles originated from different countries but revealed that severity assessment criteria might have influence over estimated effect sizes for platelets and D-dimers. Contour-enhanced funnel plots and the Egger test for D-dimers and fibrinogen revealed significant asymmetry that might be a sign of publication bias.

ConclusionsThe standard coagulation laboratory parameters with exception of platelets counts are significantly elevated in patients with severe COVID-19. However, fibrinolysis shutdown requires evaluation outside conventional coagulation tests and analysis of additional specific markers related to clotting formation and PLT characteristics. We hypothesize that a proportion and parameters of immature reticulated platelets may serve as additional biomarkers for prediction of adverse events.


title: Reduced seroconversion in children compared to adults with mild COVID-19

abstract:
ImportanceThe immune response in children with SARS-CoV-2 infection is not well understood.

ObjectiveTo compare seroconversion in children and adults with non-hospitalized (mild) SARS-CoV-2 infection and to understand the factors that influence this.

DesignParticipants were part of a household cohort study of SARS-CoV-2 infection. Weekly nasopharyngeal/throat swabs and blood samples were collected during the acute and convalescent period following PCR diagnosis for analysis.

SettingParticipants were recruited at the Royal Childrens Hospital, Melbourne, Australia between May and October 2020.

ParticipantsThose who had a SARS-CoV-2 PCR-positive nasal/throat swab.

Main outcomes and measuresSARS-CoV-2 antibody and cellular responses in children and adults. Seroconversion was defined by seropositivity in all three serological assays.

ResultsAmong 108 SARS-CoV-2 PCR-positive participants, 57 were children (median age: 4, IQR 2-10) and 51 were adults (median age: 37, IQR 34-45). Using three established serological assays, a lower proportion of children seroconverted compared with adults [20/54 (37.0%) vs 32/42 (76.2%); (p<0.001)]. This was not related to viral load, which was similar in children and adults [mean Ct 28.58 (SD: 6.83) vs 24.14 (SD: 8.47)]. Age and sex also did not influence seroconversion or the magnitude of antibody response within children or adults. Notably, in adults (but not children) symptomatic adults had three-fold higher antibody levels than asymptomatic adults (median 227.5 IU/mL, IQR 133.7-521.6 vs median 75.3 IU/mL, IQR 36.9-113.6). Evidence of cellular immunity was observed in adults who seroconverted but not in children who seroconverted.

Conclusion and RelevanceIn this non-hospitalized cohort with mild COVID-19, children were less likely to seroconvert than adults despite similar viral loads. This has implications for future protection following COVID-19 infection in children and for interpretation of serosurveys that involve children. Further research to understand why children are less likely to seroconvert and develop symptoms following SARS-CoV-2 infection, and comparison with vaccine responses may be of clinical and scientific importance.

Key pointsO_ST_ABSQuestionC_ST_ABSWhat proportion of children with non-hospitalized (mild) SARS-CoV-2 infection seroconvert compared to adults?

FindingsIn this cohort study conducted in 2020, we found the proportion of children who seroconverted to SARS-CoV-2 was half that in adults despite similar viral load.

MeaningSerology is a less reliable marker of prior SARS-CoV-2 infection in children. SARS-CoV-2-infected children who do not seroconvert may be susceptible to reinfection. Our findings support strategies to protect children against COVID-19 including vaccination.


title: The usefulness of antigen testing in predicting contagiousness in COVID-19

abstract: Increasing the diagnostic capacity of COVID-19 (SARS-CoV-2 infection) is required to improve case detection, reduce COVID-19 expansion, and boost the world economy. Rapid antigen detection tests are cheaper and easier to implement, but their diagnostic performance has been questioned compared to RT-PCR. Here, we evaluate the performance of the Standard Q COVID-19 antigen test for diagnosing SARS-CoV-2 infection and predicting contagiousness compared to RT-PCR and viral culture, respectively. The antigen test was 100.0% specific but only 40.9% sensitive for diagnosing infection compared to RT-PCR. Interestingly, SARS-CoV-2 contagiousness is highly unlikely with a negative antigen test since it exhibited a negative predictive value of 99.9% than viral culture. Furthermore, a cycle threshold (Ct) value of 18.1 in RT-PCR was shown to be the one that best predicts contagiousness (AUC 97.6%). Thus, screening people with antigen testing is a good approach to prevent SARS-CoV-2 contagion and allow returning to daily activities.


title: Intravenous corticosteroid treatment in adult patients with sepsis defined by the Sepsis-3 criteria: a systematic review and meta-analysis

abstract:
ObjectivesTo summarize the effects of intravenous corticosteroid treatment for sepsis defined by the Sepsis-3 criteria in adult patients.

DesignSystematic review and meta-analysis.

MethodsWe searched RCTs from PubMed, Embase, ClinicalTrials.gov, Cochrane Central Register of Controlled Trials, Web of Science, and International Clinical Trials Registry Platform from inception to July 12th, 2019 and updated on June 28th, 2020. Conference proceedings from relevant societies and the reference lists of previous reviews were manually screened. Abstract or full-text articles were screened by two independent investigators. We included RCTs where (1) the participants had infections and the baseline Sequential Organ Failure Assessment (SOFA) score [≥] 2 (the Sepsis-3 definitions) (2) the intervention involved any intravenous corticosteroids; (3) the control group received placebo or standard of care (4) the outcomes of interest included mortality or clinical recovery. We chose the 28-day mortality as the pre-specified primary outcome and risk ratio (RR) as the effect measure. We followed PRISMA guidelines and chose random-effects models for the pooled analyses.

ResultsThis study included 24 RCTs and 19 of them (7,115 participants) reported the 28-day mortality. Pooled analyses showed that intravenous corticosteroid treatment compared to placebo or standard of care was not associated with a lower risk of 28-day mortality (RR, 0.88; 95%CI, 0.73 to 1.05), but with a higher risk of hyperglycemia (RR, 1.16; 95%CI, 1.06 to 1.27). Sensitivity analysis of high-quality studies revealed a similar result for the 28-day mortality (RR, 0.95; 95%CI, 0.86 to 1.05).

ConclusionsOur findings suggested that intravenous corticosteroids compared to placebo or standard of care may not reduce the 28-day mortality in adult patients with sepsis defined by the Sepsis-3 criteria. Further studies are warranted to clarify the roles of disease severity and treatment timing in the effects of corticosteroid treatment in this population.

PROSPERO registration numberCRD42019143083

Strengths and limitations of this studyO_LIThis is the first systematic review and meta-analysis that summarized the effects of intravenous corticosteroid treatments in patients with sepsis defined by the Sepsis-3 criteria.
C_LIO_LIWe provide the quality of evidence to support the development of treatment guidelines specific to the Sepsis-3 cohort.
C_LIO_LIWe only include randomized controlled trials in this systematic review and meta-analysis, which exclude less controlled evidences from clinical settings closer to our daily practice.
C_LIO_LIThe Sepsis-3 definitions will be retrospectively applied to the included studies, so clinical trials without enough reported baseline data available may be excluded.
C_LI


title: Time-varying effectiveness of the mRNA-1273, BNT162b2 and Ad26.COV2.S vaccines against SARS-CoV-2 infections and COVID-19 hospitalizations and deaths: an analysis based on observational data from Puerto Rico

abstract:
BackgroundAs of October 1, 2021 2,217,547 individuals were fully vaccinated against COVID-19 in Puerto Rico. Since the vaccination process commenced on December 15, 2020 111,052 laboratory-confirmed SARS-CoV-2 infections have been reported. These data permitted us to quantify the benefits of the immunization campaign and to compare effectiveness of the mRNA-1273 (Moderna), BNT162b2 (Pfizer), and Ad26.COV2.S (J&J) vaccines.

MethodsDepartment of Health databases holding vaccination status, SARS-CoV-2 test results, and COVID-19 hospitalizations and deaths were integrated. We fit a statistical model that adjusted for time-varying incidence rates and age to estimate vaccine effectiveness and hospitalization and death relative risks. Code and data are provided here: https://github.com/rafalab/vax-eff-pr.

ResultsAt the peak of their protection, mRNA-1273, BNT162b2, and Ad26.COV2.S had an effectiveness of 90% (88%-91%), 87% (85%-89%), and 58% (51%-65%), respectively. After four months, effectiveness waned to about 70%, 60%, and 30%. We found no evidence that effectiveness was different after the Delta variant became dominant. For those infected, the vaccines provided further protection against hospitalization and deaths across all age groups. All vaccines had a lower effectiveness for those over 85 years, with a larger decrease for the Ad26.COV2.S vaccine. Overall, thousands of hospitalizations and deaths were avoided thanks to the vaccines.

ConclusionsThe mRNA-1273 and BNT162b2 vaccines were highly effective across all age groups. They were still effective after four months although the protection waned. The Ad26.COV2.S vaccine was effective but to a lesser degree, especially for older age groups.


title: Time-Varying Effectiveness of Three Covid-19 Vaccines in Puerto Rico


title: The premature mortality to incidence ratio (PREMIER): a person-centred measure of cancer burden

abstract:
BackgroundCancer control initiatives are informed by quantifying the capacity to reduce cancer burden through effective interventions. Burden measures using health administrative data are a sustainable way to support monitoring and evaluating of outcomes among patients and populations. The PREmature Mortality to IncidencE Ratio (PREMIER) is one such burden measure. We use data on Aboriginal and non-Aboriginal South Australians from 1990 to 2010 to show how PREMIER quantifies disparities in cancer burden: between populations; between sub-population cohorts where stage at diagnosis is available; and when follow-up is constrained to 24-months after diagnosis.

MethodPREMIERcancer is the ratio of years of life expectancy lost due to cancer (YLLcancer) to life expectancy years at risk at time of cancer diagnosis (LYAR) for each person. The Global Burden of Disease standard life table provides referent life expectancies. PREMIERcancer was estimated for the population of cancer cases diagnosed in South Australia from 1990 to 2010. Cancer stage at diagnosis was also available for cancers diagnosed in Aboriginal people and a cohort of non-Aboriginal people matched by sex, year of birth, primary cancer site and year of diagnosis.

ResultsCancers diagnoses (N=144,891) included 777 among Aboriginal people. Cancer burden described by PREMIERcancer was higher among Aboriginal than non-Aboriginal (0.55, 95%CIs 0.52-0.59 versus 0.39, 95%CIs 0.39-0.40). Diagnoses at younger ages among Aboriginal people, 7 year higher LYAR (31.0, 95%CIs 30.0-32.0 versus 24.1, 95%CIs 24.1-24.2) and higher premature cancer mortality (YLLcancer=16.3, 95%CIs 15.1-17.5 versus YLLcancer=8.2, 95%CIs 8.2-8.3) influenced this. Disparities in cancer burden between the matched Aboriginal and non-Aboriginal cohorts manifested 24-months after diagnosis with PREMIERcancer 0.44, 95%CIs 0.40-0.47 and 0.28, 95%CIs 0.25-0.31 respectively.

ConclusionPREMIER described disproportionately higher cancer burden among Aboriginal people in comparisons involving: all people diagnosed with cancer; the matched cohorts; and, within groups diagnosed with same staged disease. The extent of disparities were evident 24-months after diagnosis. This is evidence of Aboriginal peoples substantial capacity to benefit from cancer control initiatives, particularly those leading to earlier detection and treatment of cancers. PREMIERs use of readily available, person-level administrative records can help evaluate health care initiatives addressing this need.


title: Comparative assessment of methods for short-term forecasts of COVID-19 admissions in England at the local level

abstract:
BackgroundForecasting healthcare demand is essential in epidemic settings, both to inform situational awareness and facilitate resource planning. Ideally, forecasts should be robust across time and locations. During the COVID-19 pandemic in England, it is an ongoing concern that demand for hospital care for COVID-19 patients in England will exceed available resources.

MethodsWe made weekly forecasts of daily COVID-19 hospital admissions for National Health Service (NHS) Trusts in England between August 2020 and April 2021 using three disease-agnostic forecasting models: a mean ensemble of autoregressive time series models, a linear regression model with 7-day-lagged local cases as a predictor, and a scaled convolution of local cases and a delay distribution. We compared their point and probabilistic accuracy to a mean-ensemble of them all, and to a simple baseline model of no change from the last day of admissions. We measured predictive performance using the Weighted Interval Score (WIS) and considered how this changed in different scenarios (the length of the predictive horizon, the date on which the forecast was made, and by location), as well as how much admissions forecasts improved when future cases were known.

ResultsAll models outperformed the baseline in the majority of scenarios. Forecasting accuracy varied by forecast date and location, depending on the trajectory of the outbreak, and all individual models had instances where they were the top- or bottom-ranked model. Forecasts produced by the mean-ensemble were both the most accurate and most consistently accurate forecasts amongst all the models considered. Forecasting accuracy was improved when using future observed, rather than forecast, cases, especially at longer forecast horizons.

ConclusionsAssuming no change in current admissions is rarely better than including at least a trend. Using confirmed COVID-19 cases as a predictor can improve admissions forecasts in some scenarios, but this is variable and depends on the ability to make consistently good case forecasts. However, ensemble forecasts can make forecasts that make consistently more accurate forecasts across time and locations. Given minimal requirements on data and computation, our admissions forecasting ensemble could be used to anticipate healthcare needs in future epidemic or pandemic settings.


title: Comparative assessment of methods for short-term forecasts of COVID-19 hospital admissions in England at the local level


title: Reductions in US life expectancy from COVID-19 by Race and Ethnicity: Is 2021 a repetition of 2020?

abstract: COVID-19 had a huge mortality impact in the US in 2020 and accounted for most of the overall reduction in 2020 life expectancy at birth. There were also extensive racial/ethnic disparities in the mortality impact of COVID-19 in 2020, with the Black and Latino populations experiencing reductions in life expectancy at birth due to COVID-19 approximately two to three times that of the White population. Despite continued vulnerability of these populations, the hope was that widespread distribution of effective vaccines would mitigate the overall impact and reduce racial/ethnic disparities in 2021. In this study, we use cause-deleted life table methods to quantify the impact of COVID-19 mortality on 2021 US period life expectancy by race and ethnicity and compare these impacts to those estimated for 2020. Our estimates, based on provisional COVID-19 deaths for 2021, indicate that racial/ethnic disparities have persisted and that COVID-19 deaths resulted in a decline in life expectancy at birth in 2021 of 1.8 years from 2019, 0.5 years more than estimated for 2020. The corresponding reductions estimated for the Black and Latino populations are 1.3-1.9 times that for Whites, suggesting smaller disparities than those in 2020. However, this narrowing is almost entirely the result of a large increase in COVID-19 mortality among Whites in 2021, in contrast to relatively constant reductions for the Black and Latino populations in the two years. Estimated declines in life expectancy at age 65 due to COVID-19 mortality increased slightly for Whites between 2020 and 2021 but decreased for both the Black and Latino populations, resulting in the same overall reduction (1.1 years) estimated for 2020 and 2021.


title: A new fMRI localizer for preoperative language mapping using a sentence completion task: Validity, choice of baseline condition, and test-retest reliability

abstract:
To avoid post-neurosurgical language deficits, intraoperative mapping of the language function in the brain can be complemented with preoperative mapping with fMRI. The validity of an fMRI  language localizer paradigm crucially depends on the choice of an optimal language task and baseline condition. This study presents a new fMRI  language localizer in Russian using overt sentence completion, a task that comprehensively engages the language function by involving both production and comprehension at the word and sentence level. The paradigm was validated in 18 neurologically healthy volunteers who participated in two scanning sessions, for estimating test-retest reliability. For the first time, two baseline conditions for the sentence completion task were compared.

At the group level, the paradigm significantly activated both anterior and posterior language-related regions. Individual-level analysis showed that activation was elicited most consistently in the inferior frontal regions, followed by posterior temporal regions and the angular gyrus. Test-retest reliability of activation location, as measured by Dice coefficients, was moderate and thus comparable to previous studies. Test-retest reliability was higher in the frontal than temporo-parietal region and with the most liberal statistical thresholding compared to two more conservative thresholding methods. Lateralization indices were expectedly left-hemispheric, with greater lateralization in the frontal than temporo-parietal region, and showed moderate test-retest reliability. Finally, the pseudoword baseline elicited more extensive and more reliable activation, although the syllable baseline appears more feasible for future clinical use.

Overall, the study demonstrated the validity and reliability of the sentence completion task for mapping the language function in the brain. The paradigm needs further validation in a clinical sample of neurosurgical patients. Additionally, the study contributes to general evidence on test-retest reliability of fMRI


title: Applying Behavioral Nudges in a Dietary Comparator for Surgical Trials: Developing the MediDiet

abstract:
IntroductionThe Mediterranean diet is being studied as an alternative to surgery for common gastrointestinal conditions. However, dietary change can be challenging. "Nudges" - behavioral science strategies seeking to influence cognitive processes to promote good behaviors - may help. We conducted a pilot study evaluating the acceptability of the MediDiet, a behaviorally designed dietary intervention incorporating nudges and recommendations based on the Mediterranean Diet.

MethodsWe conducted a three-phase pilot study involving parallel randomized surveys of U.S. adults. After completing a validated questionnaire assessing dietary consistency with a Mediterranean diet, participants were randomized to feedback containing no nudge versus nudge: peer comparison; peer comparison + positive affect induction; or default. Participants then rated their positive and negative emotions, motivation for dietary change, and interest in recipes. Responses were analyzed using baseline covariate-adjusted regression.

ResultsAmong 1,709 participants, 56% were men, 73% were White, and the mean age was 38. In response to dietary feedback, participants reported low negative emotions, high positive emotions, moderate motivation for dietary change and high interest in recipes. Nudges did not affect the extent of negative (p=0.104) or positive (p=0.34) emotions, motivation (p=0.139), or interest (p=0.86). In exploratory analyses, those with moderate and high consistency with the Mediterranean diet, with or without nudges, reported lower negative affect, greater positive affect, greater motivation, and greater interest in recipes, than the minimally consistent, no nudge group.

ConclusionDelivering dietary feedback based on the Mediterranean diet using behavioral nudges was acceptable among U.S. adults, rousing positive reactions without triggering negative ones. As early evidence, this pilot study provides the basis for testing nudge-based dietary guidance among individuals with symptomatic gallstones, diverticulitis, and other gastrointestinal diseases.

HighlightsO_LIThe MediDiet is being developed as a novel, behaviorally designed dietary intervention for the non-operative management of common gastrointestinal conditions including symptomatic gallstones and diverticulitis, classically managed with surgery.
C_LIO_LIIn this exploratory pilot study, delivering dietary feedback based on the Mediterranean diet using behavioral nudges was acceptable among U.S. adults.
C_LIO_LIThis foundational work will help serve as the basis for testing nudge-based dietary guidance among individuals with symptomatic gallstones, diverticulitis, and other gastrointestinal diseases, and ultimately conducting clinical trials to compare dietary interventions to surgical management for these conditions.
C_LI

category: surgery


title: Guiding caregivers through disclosure: a qualitative investigation into caregivers responses to a disclosure intervention for HIV-infected children in Soweto, South Africa

abstract: Awareness of Human Immunodeficiency Virus (HIV) status improves health outcomes in HIV infected children, yet disclosure is often delayed by hesitant caregivers. This qualitative investigation explored how 30 caregivers responded to a HIV Disclosure study conducted between 2017 and 2020 at Chris Hani Baragwanath Academic Hospital, Soweto, South Africa. Caregivers were assisted in disclosing to their children, aged 7-13 years; followed by a sub-sample of caregivers interviewed to elaborate on findings.1) Barriers to disclosure included caregivers being ill-equipped, fear of negative consequences and children considered lacking emotional or cognitive readiness. 2) Deflecting diagnosis and the need for medication motivated caregivers to disclosure. 3) Apprehension was evident during disclosure, however, overall disclosure was a positive experience with the support of the healthcare providers. These results highlight the significant role healthcare providers play in supporting caregivers through the disclosure process and how, in turn, this has a positive impact on the community as a whole.


title: A cohort of 222 anti-CD20 treated patients with multiple sclerosis followed through the COVID-19 pandemic: Attenuated humoral but robust cellular immune responses after vaccination and infection

abstract:
ObjectiveTo analyze humoral and cellular immune responses to SARS-CoV-2 vaccinations and infections in anti-CD20 treated patients with multiple sclerosis (pwMS).

Methods181 pwMS on anti-CD20 therapy and 41 pwMS who began anti-CD20 therapy were included in a prospective, observational, single-center cohort study between March 2020 and August 2021. 51 pwMS under anti-CD20 treatment, 14 anti-CD20 therapy-naive pwMS and 19 healthy controls (HC) were vaccinated twice against SARS-CoV-2. We measured SARS-CoV-2 spike protein (full-length, S1 domain and receptor binding domain) immunoglobulin (Ig)G and S1 IgA and virus neutralizing capacity and avidity of SARS-CoV-2 antibodies. SARS-CoV-2 specific T cells were determined by interferon-{gamma} release assays.

ResultsFollowing two SARS-CoV-2 vaccinations, levels of IgG and IgA antibodies to SARS-CoV-2 spike protein as well as neutralizing capacity and avidity of SARS-CoV-2 IgG were lower in anti-CD20 treated pwMS than in anti-CD20 therapy-naive pwMS and in HC (p<0.003 for all pairwise comparisons). However, in all anti-CD20 treated pwMS vaccinated twice (n=26) or infected with SARS-CoV-2 (n=2), in whom SARS-CoV-2 specific T cells could be measured, SARS-CoV-2 specific T cells were detectable, at levels similar to those of twice-vaccinated anti-CD20 therapy-naive pwMS (n=7) and HC (n=19). SARS-CoV-2 S1 IgG levels (r=0.42, p=0.002), antibody avidity (r=0.7, p<0.001) and neutralizing capacity (r=0.44, p=0.03) increased with time between anti-CD20 infusion and second vaccination. Based on detection of SARS-CoV-2 antibodies, SARS-CoV-2 infections occurred in 4/175 (2.3%) anti-CD20 treated pwMS, all of whom recovered fully.

InterpretationThese findings should inform treatment decisions and SARS-CoV-2 vaccination management in pwMS.


title: Preserved T cell responses to SARS-CoV-2 in anti-CD20 treated multiple sclerosis.


title: The Diagnostic Value of Genetic Mutation Analysis and Mutation Profiling of cfDNA in Intraocular Fluid for VRL

abstract:
ObjectiveVitreoretinal lymphoma (VRL) is a rare but aggressive masquerade syndrome, with challenging diagnosis. Since the tumor-related genetic mutation analysis based on cell-free DNA (cfDNA) are underutilized in ocular oncology, we aimed to test the VRL diagnostic value of cfDNA genetic mutation analysis using intraocular fluid (IOF) samples and to identify its mutation profile.

SubjectsSeventeen VRL and 6 uveitis patients from Zhongshan Ophthalmic Centre were selected as training group, and 5 VRL and 5 uveitis patients from Beijing Chaoyang Hospital were selected as validation group.

MethodsThe medical records and genetic mutation analysis using a panel containing 446 tumor-related genes of included patients were retrospectively reviewed. We analyzed the mutation profile, and identified the molecular subtypes and subdivisions of B-cell differentiation pathways of our VRL patients.

Main outcomesThe cfDNA genetic mutations detected in IOF.

ResultsThe VRL patients from the training group exhibited abundant cfDNA mutations in IOF (sensitivity 100%), while only 2 out of 6 uveitis patients were positive (specificity 67%). However, the number of cfDNA mutations observed in VRL patients was higher than that of uveitis patients. The mutation-positive patients from the validation group were diagnosed with VRL while the mutation-negative patients were diagnosed with uveitis (sensitivity and specificity 100%). VRL patients were characterized by the high mutation frequencies of PIM1, MYD88, CD79B, ETV6, and IRF4.

ConclusionsThe genetic mutation analysis of IOF samples represents a feasible diagnosis method for VRL with 100% sensitivity; it could track genetic profiles; thus, revealing genetic heterogeneity of VRL.

Statement of translational relevanceThe anterior chamber paracentesis and diagnostic vitrectomy have been widely used in ophthalmic clinics, as they are less invasive sampling techniques for liquid biopsies. Genetic mutation analysis of cell-free DNA (cfDNA) of intraocular fluid using a panel containing 446 targeted genes represents a feasible method with 100% sensitivity for vitreoretinal lymphoma (VRL) diagnosis. Furthermore, it can address cytological diagnostic issues including limited cellular yield, cell lysis associated with the fragile nature of lymphoma cells, and high risks associated with retinal tissue biopsies. Furthermore, it allows for genetic profile tracking, having the potential to reveal genetic heterogeneity and molecular characteristics of VRL in the future


title: Diagnostic Value of Genetic Mutation Analysis and Mutation Profiling of cfDNA in Intraocular Fluid for Vitreoretinal Lymphoma


title: VIKING II, a Worldwide Observational Cohort of Volunteers with Northern Isles Ancestry

abstract:
IntroductionThe purpose of VIKING II is to create an observational cohort of volunteers with ancestry from the Northern Isles of Scotland, primarily for identifying genetic variants influencing disease. The new online protocol is separate to, but follows on from, earlier genetic epidemiological clinic-based studies in the isolated populations of Orkney and Shetland. These populations are favourable for the study of rarer genetic variants due to genetic drift, the large number of relatives, and availability of pedigree information.

Methods and AnalysisOnline methods are being used to recruit [~]4,000 people who have Northern Isles ancestry, living anywhere in the world. The option for participants to have actionable genetic results returned is offered. Broad consent will be taken electronically. Data will be collected at baseline through an online questionnaire and longitudinally through linkage to NHS data in the electronic health record. The questionnaire collects a variety of phenotypes including personal and family health. DNA will be extracted from saliva samples then genome-wide genotyped and exome sequenced. VIKING II aims to capitalise on the special features of the Northern Isles populations to create a research cohort that will facilitate the analysis of genetic variants associated with a broad range of traits and disease endpoints.

Ethics and DisseminationThe South East Scotland Research Ethics Committee gave the study a favourable opinion. VIKING II is sponsored by the University of Edinburgh and NHS Lothian. Summary research findings will be disseminated to participants and funding bodies, presented at conferences and reported in peer-reviewed publications.

Article SummaryStrengths and limitations of this study

O_LIDetailed data and biological sample collection of research volunteers with unique ancestry.
C_LIO_LIConsent for access to routinely collected clinical EHR data and for future re-contact, providing a longitudinal component.
C_LIO_LIOptional consent for return of actionable genetic results.
C_LIO_LI4,000 participants is a relatively small number for certain types of genetic analyses, so the cohort is underpowered on its own, in some study designs.
C_LIO_LIResources to maintain the cohort, and to store data and DNA samples, are significant, with sustainability dependent on infrastructure support and continued funding.
C_LI


title: Lack of Trust, Insufficient knowledge and Risk denial; an in-depth Understanding of Health worker Barriers to uptake of the Covid-19 vaccine at Iganga Hospital Eastern Uganda, and Mengo Hospital Kampala Uganda

abstract:
Covid 19 Vaccine hesitancy among health workers remains a major hindrance to the governments vaccine roll out plan among health workers and other target populations in Uganda.

We conducted 12 focus group discussions and 20 in-depth interviews with health workers (vaccinated and unvaccinated) to understand barriers to vaccine acceptance in their own perspective and context in central and eastern Uganda. Reported barriers to vaccine acceptance included: gross lack of trust, fear of side effects, risk denial and insufficient information about the vaccine amidst negative publicity about the vaccine from the internet and social media platforms. Others were health system inhibition factors and religious beliefs against the vaccine.

We recommend a health work context specific information, education and dissemination strategy to create awareness, information and more knowledge about the vaccine to health workers.

We also recommend a sustained government media campaign to give more information about the vaccine and also dispel the negative publicity and misinformation about the vaccine.

Dialogue with health workers at all levels of care, positive peer influence, use of religious and opinion leaders as well as government ensuring accessibly to various Covid 19 vaccines and putting vaccine posts outside hospital settings to limit exposure to Covid patients could also increase uptake of the vaccine among health workers.

category: health systems and quality improvement


title: Adapting cleft care protocols in low- and middle-income countries during and after COVID-19: a process-driven review with recommendations

abstract:
ObjectiveA consortium of global cleft professionals, predominantly from low- and middle-income countries, identified adaptions to cleft care protocols during and after COVID as a priority learning area of need.

DesignA multidisciplinary international working group met on a videoconferencing platform in a multi-staged process to make consensus recommendations for adaptions to cleft protocols within resource-constrained settings. Feedback was sought from a roundtable discussion forum and global organisations involved in comprehensive cleft care.

ResultsFoundational principles were agreed to enable recommendations to be globally relevant and two areas of focus within the specified topic were identified. First the safety aspects of cleft surgery protocols were scrutinised and COVID adaptions, specifically in the pre and peri-operative periods, were highlighted. Second, surgical operations and access to services were prioritized according to their relationship to functional outcomes and time-sensitivity. The operations assigned the highest priority were emergent interventions for breathing and nutritional requirements and primary palatoplasty. The cleft services assigned the highest priority were new-born assessments, paediatric support for children with syndromes, management of acute dental or auditory infections and speech pathology intervention.

ConclusionsA collaborative, interdisciplinary and international working group delivered consensus recommendations to assist with the provision of cleft care in low- and middle-income countries. At a time of global cleft care delays due to COVID-19, a united approach amongst global cleft care providers will be advantageous to advocate for children born with cleft lip and palate in resource-constrained settings.

category: health policy


title: Deep learning-based detection and segmentation of diffusion abnormalities in acute ischemic stroke

abstract:
BackgroundAccessible tools to efficiently detect and segment diffusion abnormalities in acute strokes are highly anticipated by the clinical and research communities.

MethodsWe developed a tool with deep learning networks trained and tested on a large dataset of 2,348 clinical diffusion weighted MRIs of patients with acute and sub-acute ischemic strokes, and further tested for generalization on 280 MRIs of an external dataset (STIR).

ResultsOur proposed model outperforms generic networks and DeepMedic, particularly in small lesions, with lower false positive rate, balanced precision and sensitivity, and robustness to data perturbs (e.g., artefacts, low resolution, technical heterogeneity). The agreement with human delineation rivals the inter-evaluator agreement; the automated lesion quantification of volume and contrast has virtually total agreement with human quantification.

ConclusionOur tool is fast, public, accessible to non-experts, with minimal computational requirements, to detect and segment lesions via a single command line. Therefore, it fulfills the conditions to perform large scale, reliable and reproducible clinical and translational research.

Plain Language SummaryQuantifying the volume and location of lesions caused by acute ischemic strokes is crucial for therapeutics and prognostic assessment. Research wise, it can be a window to observe relationships between anatomy and function. The definition of such lesions, mostly made by humans, is time- and work-consuming and uses subjective criteria. We used artificial intelligence in a large database of MRIs of patients with ischemic stroke to create an automated tool to detect and segment lesions derived from acute stroke. It outputs the lesion volumes and 3D segmentation maps. Our tool is fast, public, accessible to non-experts, run in local computers, with minimal computational requirements, fulfilling the conditions to perform large scale, reliable and reproducible clinical and translational research.


title: Slower Learning Rates from Negative Outcomes in Substance Use Disorder over a 1-Year Period and their Potential Predictive Utility

abstract: Computational modelling is a promising approach to parse dysfunctional cognitive processes in substance use disorders (SUDs), but it is unclear how much these processes change during the recovery period. We assessed 1-year follow-up data on a sample of treatment-seeking individuals with one or more SUDs (alcohol, cannabis, sedatives, stimulants, hallucinogens, and/or opioids; N = 83) that were previously assessed at baseline within a prior computational modelling study. Relative to healthy controls (HCs; N = 48), these participants were found at baseline to show altered learning rates and less precise action selection while completing an explore-exploit decision-making task. Here we replicate these analyses when these individuals returned and re-performed the task 1 year later to assess the stability of these baseline differences. We also examine whether baseline modelling measures can predict symptoms at follow-up. Bayesian analyses indicate that: (a) group differences in learning rates were stable over time (posterior probability = 1); (b) intra-class correlations (ICCs) between model parameters at baseline and follow-up were significant and ranged from small to moderate (.25 [≤] ICCs [≤] .54); and (c) learning rates and/or information-seeking values at baseline were associated with substance use severity at 1-year follow-up in stimulant and opioid users (.36 [≤] rs [≤] .43, .002 [≤] ps [≤] .02). These findings suggest that learning dysfunctions are moderately stable during recovery and could correspond to trait-like vulnerability factors. In addition, computational measures at baseline had some predictive value for changes in substance use severity over time and could be clinically informative.

category: addiction medicine


title: Long-term Complications of Unintentional Dural Puncture During Labor Epidural Analgesia: A Case-Control Study.

abstract:
IntroductionEpidural analgesia is the preferred method to manage pain during labor and delivery. The insertion of the epidural catheter can be complicated by unintentional dural puncture that may result in postdural puncture headache. There is limited evidence on the long term implications of this complication. We sought to investigate if women who sustained a dural puncture have a higher risk of developing chronic headache, low back pain and visual or auditory impairment.

MethodsWe conducted a 1:1 case-control study with women who delivered at our institution from January 2015 to December 2019. Cases were women who received epidural analgesia and sustained an unintentional dural puncture and controls were women who received epidural analgesia but did not sustain such complication. We matched cases and controls for date of delivery, age, and BMI. All women completed an online survey with validated questionnaires for diagnosis of chronic headache and chronic back pain. We used dichotomic (yes/no) questions to look for the presence of chronic visual and auditory impairment.

ResultsSixty-three case-control pairs were studied. Women who sustained a dural puncture during their epidural catheter insertion had a higher risk of developing chronic headache [14.3%, versus 4.8%, p=0.049, AOR: 3.36 (1.05, 12.82)] and chronic back pain [39.7% versus 19.1%, p=0.009, AOR: 2.67 (1.25, 5.72)] than women who did not sustain a dural puncture. The incidence of chronic auditory impairment was also higher in the dural puncture group [14.3% versus 1.6%, p=0.007, AOR: 9.98 (1.21, 82.62)].

ConclusionsAn unintentional dural puncture during epidural catheter insertion in parturients is associated with increased risk of chronic headache, back pain and auditory impairment.

category: anesthesia


title: Accuracy of emergency medical service telephone triage of need for an ambulance response in suspected COVID-19: An observational cohort study

abstract:
BackgroundEmergency Medical Services (EMS) have experienced surges in demand as the COVID-19 pandemic has progressed with ambulances services in the UK declaring major incidents due to the risk of care being compromised. COVID-19 specific EMS telephone triage tools have been introduced to help manage demand. There has been no previous evaluation of the accuracy of EMS telephone triage in identifying patients with suspected COVID-19 at risk of serious adverse outcome.

We aimed to assess accuracy of EMS telephone triage in identifying patients who need an EMS response and identify factors which affect triage accuracy.

MethodPatients who made an emergency call to Yorkshire Ambulance Service between 2nd April and 29th June 2020 and were assessed using an AMPDS pandemic pathway for suspected COVID-19 were linked to Office for National Statistics death registration data, hospital and general practice electronic health care data collected by NHS Digital.

Accuracy of decision to dispatch an ambulance was assessed in terms of death or need for organ support at 30 days from the first 999 call. Multivariable logistic regression was used to identify factors associated with false negative and false positive triage.

ResultsOf 12, 653 callers included in the study population, 11.1% experienced the primary composite adverse outcome. Using the triage pathway, 16% of callers did not receive an emergency response and they had a lower risk (3.5%) of the primary outcome. Ambulances were dispatched to 4, 230 callers (33.4%) who were not subsequently conveyed to hospital and did not experience the primary outcome (false positive triage). Multivariable modelling found older age and presence of pre-existing respiratory disease were significant predictors of false positive triage.

ConclusionEMS telephone triage avoided 16% of calls receiving an emergency ambulance, of whom 3.5% died or needed organ support by 30 days. Telephone triage can therefore reduce the burden of EMS responses but with the cost of a small proportion of patients who do not receive an initial emergency response deteriorating. Research is needed to identify the appropriate balance between over- and under-triage


title: Cohort Profile Update: The HUNT Study, Norway

abstract: In the HUNT Study, all residents aged [≥]20 years in the Nord-Trondelag region, Norway have been invited to repeated surveys since 1984-86. The study data may be linked to local and national health registries. The HUNT4 survey in 2017-19 included 56 042 participants in Nord-Trondelag and 107 711 participants in the neighboring Sor-Trondelag region. The HUNT4 data enable more long-term follow-up, studies of life-course health trajectories, and within-family studies. New measures include body composition analysis using bioelectrical impedance; a one-week accelerometer recording; physical and cognitive testing in older adults; measurements of hemoglobin and blood cell counts, HbA1c and phosphatidylethanol; and genotyping. Researchers can apply for HUNT data access from HUNT Research Centre if they have obtained project approval from the Regional Committee for Medical and Health Research Ethics, see www.ntnu.edu/hunt/data.


title: Genomics-based identification of a potential causal role for acylcarnitine metabolism in depression

abstract:
BackgroundAltered metabolism of acylcarnitines - transporting fatty acids to mitochondria - may link cellular energy dysfunction to depression. We examined the potential causal role of acylcarnitine metabolism in depression by leveraging genomics and Mendelian randomization.

MethodsSummary statistics were obtained from large GWAS: the Fenland Study (N= 9,363), and the Psychiatric Genomics Consortium (246,363 depression cases and 561,190 controls). Two-sample Mendelian randomization analyses tested the potential causal link of 15 endogenous acylcarnitines with depression.

ResultsIn univariable analyses, genetically-predicted lower levels of short-chain acylcarnitines C2 (Odds Ratio [OR] 0.97, 95% Confidence Intervals [CIs] 0.95-1.00) and C3 (OR 0.97, 95%CIs 0.96-0.99) and higher levels of medium-chain acylcarnitines C8 (OR 1.04, 95%CIs 1.01-1.06) and C10 (OR 1.04, 95%CIs 1.02-1.06) were associated with increased depression risk. No reverse potential causal role of depression genetic liability on acylcarnitines levels was found. Multivariable analyses showed that the association with depression was driven by the medium-chain acylcarnitines C8 (OR 1.04, 95%CIs 1.02-1.06) and C10 (OR 1.04, 95%CIs 1.02-1.06), suggesting a potential causal role in the risk of depression. Causal estimates for C8 (OR=1.05, 95%CIs=1.02-1.07) and C10 (OR=1.05, 95%CIs=1.02-1.08) were confirmed in follow-up analyses using genetic instruments derived from a GWAS meta-analysis including up to 16,841 samples.

DiscussionAccumulation of medium-chain acylcarnitines is a signature of inborn errors of fatty acid metabolism and age-related metabolic conditions. Our findings point to a link between altered mitochondrial energy production and depression pathogenesis. Acylcarnitine metabolism represents a promising access point for the development of novel therapeutic approaches for depression.

category: psychiatry and clinical psychology


title: Quantifying Cause-Effect Relations Between Walking Speed, Propulsive Force, and Metabolic Cost

abstract: Walking speed is a useful surrogate for health status across the population. Walking speed appears to be governed in part by propulsive force (FP) generated during push-off and simultaneously optimized to minimize metabolic cost. However, no study to our knowledge has established empirical cause-effect relations between FP, walking speed, and metabolic cost, even in young adults. To overcome the potential linkage between these factors, we used a self-paced treadmill controller and real-time biofeedback to independently prescribe walking speed or FP across a range of condition intensities. Walking with larger and smaller FP led to instinctively faster and slower walking speeds, respectively, with about 80% of variance explained between those outcomes. We also found that comparable changes in either FP or walking speed elicited predictable and relatively uniform changes in metabolic cost, each explaining about [~]53% of the variance in net metabolic power and [~]15% of the variance in cost of transport, respectively. These findings build confidence that interventions designed to increase FP will translate to improved walking speed. Repeating this protocol in other populations may identify additional cause-effect relations that could inform the time course of gait decline due to age and disease.

category: rehabilitation medicine and physical therapy


title: Proteomic and clinical biomarkers for acute mountain sickness diagnosis, prognosis, protection, and pathogenesis in a longitudinal cohort

abstract: Acute mountain sickness (AMS) is frequently experienced by non-high-altitude natives at high altitudes, which affects the quality of health and productivity of humans. The diagnosis of the disease mainly depends on a self-questionnaire, which reveals our insufficient understanding of AMS and the necessity of developing reliable biomarkers for AMS. In addition to 65 clinical indexes and 22 AMS symptom phenotypes, we profiled the plasma proteomic profiles of AMS via a combination of proximity extension assay with multiple reaction monitoring for a longitudinal cohort of 53 individuals divided into discovery and validation stages. Through differential analysis, machine learning models with high accuracy and protein-symptom-clinical index functional network analysis, we identified proteomic and clinical biomarkers for AMS diagnosis, prognosis, protection, and pathogenesis. RET, a top-weighted protein in the pathogenesis model, showed opposite regulations between individuals with AMS and those without AMS ascending to a high altitude. The downregulation of ADAM15 may play a protective role at high altitude in individuals without AMS. These results suggest that RET and ADAM15 could be promising therapeutic targets for AMS. Moreover, PHGDH and TRAF2 could be candidate predictive and diagnostic biomarkers for AMS, respectively. Additionally, C-peptide was found to be actively involved in the pathogenesis and could aid the assistant diagnosis of AMS. Notably, individuals with AMS showed higher gluconeogenesis activity at the plain than those without AMS. Our findings shed light on the proteomic and clinical biomarkers of AMS, provide a wealth of biological insights into AMS, and thereby promote precision medicine for AMS.

category: occupational and environmental health


title: Leveraging interindividual variability of regulatory activity refines genetic regulation of gene expression in schizophrenia

abstract: Schizophrenia is a polygenic psychiatric disorder with limited understanding about the mechanistic changes in gene expression regulation. To elucidate on this, we integrate interindividual variability of regulatory activity with gene expression and genotype data captured from the prefrontal cortex of 272 cases and controls. We show that regulatory element activity is structured into 10,936 and 10,376 cis-regulatory domains in cases and controls, respectively, which display distinct regulatory element coordination structures in both states. By studying the interplay among genetic variants, gene expression and cis-regulatory domains, we ascertain that changes in coordinated regulatory activity tag alterations in gene expression levels (p=8.62e-06, OR=1.60), unveil case-specific QTL effects, and identify regulatory machinery changes for genes affecting synaptic function and dendritic spine morphology in schizophrenia. Altogether, we show that accounting for coordinated regulatory activity provides a novel mechanistic approach to reduce the search space for unveiling genetically perturbed regulation of gene expression in schizophrenia.

category: genetic and genomic medicine