title: Autoantibodies Detected in MIS-C Patients due to Administration of Intravenous Immunoglobulin

abstract: The autoantibody profile associated with known autoimmune diseases in patients with COVID-19 or multisystem inflammatory syndrome in children (MIS-C) remains poorly defined. Here we show that adults with COVID-19 had a moderate prevalence of autoantibodies against the lung antigen KCNRG, and SLE-associated Smith autoantigen. Children with COVID-19 rarely had autoantibodies; one of 59 children had GAD65 autoantibodies associated with acute insulin-dependent diabetes. While autoantibodies associated with SLE/Sjogrens syndrome (Ro52, Ro60, and La) and/or autoimmune gastritis (gastric ATPase) were detected in 74% (40/54) of MIS-C patients, further analysis of these patients and of children with Kawasaki disease (KD), showed that the administration of intravenous immunoglobulin (IVIG) was largely responsible for detection of these autoantibodies in both groups of patients. Monitoring in vivo decay of the autoantibodies in MIS-C children showed that the IVIG-derived Ro52, Ro60, and La autoantibodies declined to undetectable levels by 45-60 days, but gastric ATPase autoantibodies declined more slowly requiring >100 days until undetectable. Together these findings demonstrate that administration of high-dose IVIG is responsible for the detection of several autoantibodies in MIS-C and KD. Further studies are needed to investigate autoantibody production in MIS-C patients, independently from IVIG administration.


title: Cohort study of Covid-19 vaccine effectiveness among healthcare workers in Finland, December 2020 - October 2021

abstract: Recently, Covid-19 vaccine effectiveness has decreased especially against mild disease due to emergence of the Delta variant and waning protection. In this register-based study among healthcare workers in Finland, the vaccine effectiveness of two-dose mRNA vaccine series against SARS-CoV-2 infection decreased from 82% (95% CI 79-85%) 14-90 days after vaccination to 53% (43-62%) after 6 months. Similar trend was observed for other series. Waning was not observed against Covid-19 hospitalization. These results facilitate decision-making of booster doses for healthcare workers.

category: infectious diseases


title: The United States COVID-19 Forecast Hub dataset

abstract: Academic researchers, government agencies, industry groups, and individuals have produced forecasts at an unprecedented scale during the COVID-19 pandemic. To leverage these forecasts, the United States Centers for Disease Control and Prevention (CDC) partnered with an academic research lab at the University of Massachusetts Amherst to create the US COVID-19 Forecast Hub. Launched in April 2020, the Forecast Hub is a dataset with point and probabilistic forecasts of incident hospitalizations, incident cases, incident deaths, and cumulative deaths due to COVID-19 at national, state, and county levels in the United States. Included forecasts represent a variety of modeling approaches, data sources, and assumptions regarding the spread of COVID-19. The goal of this dataset is to establish a standardized and comparable set of short-term forecasts from modeling teams. These data can be used to develop ensemble models, communicate forecasts to the public, create visualizations, compare models, and inform policies regarding COVID-19 mitigation. These open-source data are available via download from GitHub, through an online API, and through R packages.

category: epidemiology


title: Cohort profile: the Swiss Cerebral Palsy Registry (Swiss-CP-Reg) cohort study

abstract:
BACKGROUNDCerebral Palsy (CP) is a group of permanent disorders of movement and posture that follows injuries to the developing brain. It results in motor dysfunction and a wide variety of comorbidities like epilepsy, pain, speech, hearing and vision disorders, cognitive dysfunction, and eating and digestive difficulties. Central data collection is essential to study the epidemiology, clinical presentations, care, and quality of life of patients affected by CP. CP specialists founded the Swiss Cerebral Palsy Registry (Swiss-CP-Reg) in 2017. This paper describes the design, structure, aims and achievements of the Swiss-CP-Reg and presents first results.

METHODSSwiss-CP-Reg records patients of any age suffering from CP who are born, treated, or live in Switzerland. It collects data from medical records and reports, from questionnaires answered by patients and their families, and from data linkage with routine statistics and other registries. The registry contains information on diagnosis, clinical presentation, comorbidities, therapies, personal information, family history, and quality of life.

ResultsFrom August 2017 to August 2021, 546 participants (55% males, mean age at registration 8 years (interquartile range [IQR]: 5-12) were enrolled in Swiss-CP-Reg. Most had been born at term (56%), were less than 2 years old at diagnosis (73%, median 9 months, IQR: 18-25), and were diagnosed with spastic CP (76%). Most (59%) live with a mild motor impairment (Gross Motor Function Classification System [GMFCS] level I or II), 12% with a moderate motor impairment (GMFCS level III), and 29% with a severe motor impairment (GMFCS level IV or V). In a subset of 170 participants, we measured intelligence quotient (IQ) and saw a reduced IQ by GMFCS scale increase. The Swiss-CP-Reg has a strong interest in research with currently 5 nested projects running, and many more planned.

CONCLUSIONSSwiss-CP-Reg collects and exchanges national data on people living with CP to answer clinically relevant questions. Its structure enables retrospective and prospective data collection and knowledge exchange between experts to optimise and standardise treatment and improve the health and quality of life of those diagnosed with CP in Switzerland.

ClinicalTrials.gov identifierNCT04992871


title: Influence of heterogeneous age-group contact patterns on critical vaccination rates for herd immunity to SARS-CoV-2

abstract: Currently, several western countries have more than half of their population fully vaccinated against COVID-19. At the same time, some of them are experiencing a fourth or even a fifth wave of cases, most of them concentrated in sectors of the populations whose vaccination coverage is lower than the average. So, the initial scenario of vaccine prioritization has given way to a new one where achieving herd immunity is the primary concern. Using an age-structured vaccination model with waning immunity, we show that, under a limited supply of vaccines, a vaccination strategy based on minimizing the basic reproduction number allows for the deployment of a number of vaccine doses lower than the one required for maximizing the vaccination coverage. Such minimization is achieved by giving greater protection to those age groups that, for a given social contact pattern, have smaller fractions of susceptible individuals at the endemic equilibrium without vaccination, that is, to those groups that are more vulnerable to infection.


title: Primary Care Diagnosis and Treatment of Attention-Deficit/Hyperactivity Disorder in School-aged Children: Trends and Disparities During the COVID-19 Pandemic

abstract:
ImportanceLittle is known about changes in health care in the first year of the pandemic for the large population of school-aged children with attention-deficit/hyperactivity disorder (ADHD), who were especially impacted by lockdowns, school closures, and remote learning.

ObjectiveTo assess temporal trends in rates of primary care provider (PCP) diagnosis and treatment of school-aged children with ADHD in the first year of the COVID-19 pandemic as compared to pre-pandemic years, and to investigate disparities in care.

MethodWe retrospectively analyzed electronic health records from all primary care visits (in-person and telehealth) of children ages 6-17 years seen between 01/2016 and 03/2021 in a community-based primary healthcare network in California (n=77,298 patients). Study Outcomes: (1) # of primary care visits, (2) # of visits with ADHD diagnosis (ADHD-related visits), (3) # of first ADHD diagnoses, (4) # of PCP prescriptions for ADHD medications (stimulants, alpha-2 agonists, atomoxetine), (5) # of first PCP prescriptions of ADHD medications. Interrupted time-series analysis evaluated changes in rates of study outcomes during 4 quarters of the pandemic year (3/15/2020-3/15/2021) compared to pre-pandemic years. Patient demographic characteristics were compared pre-pandemic to pandemic year.

ResultsIn the first quarter (Q1) of the pandemic year, all primary care visits dropped by 62% (CI 54.9-67.2%); ADHD-related visits dropped by 33% (95% CI 22.2-43.6%). In Q2-4, while all primary care visits remained significantly below pre-pandemic rates, ADHD-related visits returned to pre-pandemic rates. Conversely, rates of first ADHD diagnoses remained at half of pre-pandemic rates throughout the year (Q1-4). ADHD medication prescription rates remained stable throughout the pandemic year. The proportion of patients living in low-income neighborhoods who received ADHD-related care (ADHD-related visits and first ADHD diagnoses) were lower during the pandemic year compared to pre-pandemic years. Females comprised a higher proportion of first ADHD diagnoses compared to pre-pandemic years (34% vs. 28%, absolute standardized difference=0.13, p=0.03).

ConclusionOngoing treatment for school-aged children with ADHD was maintained during the pandemic, especially in children from high-income families. Socioeconomic differences in ADHD-related care emphasize the need to improve access to care for all children with ADHD in the ongoing pandemic and beyond.

category: pediatrics


title: Reappraising Treatment Effect Heterogeneity in Schizophrenia: A Meta-analysis

abstract:
ObjectiveDetermining whether individual patients differ in response to treatment ( treatment effect heterogeneity) is important as it is a prerequisite to developing personalised treatment approaches. Previous variability meta-analyses of response to antipsychotics in schizophrenia found no evidence for treatment effect heterogeneity. Conversely, individual patient data meta-analyses suggest treatment effect heterogeneity does exist. In the current paper we combine individual patient data with study level data to resolve this apparent contradiction and quantitively characterise antipsychotic treatment effect heterogeneity in schizophrenia.

MethodIndividual patient data (IPD) was obtained from the Yale University Open Data Access (YODA) project. Clinical trials were identified in EMBASE, PsycInfo, and PubMed. Treatment effect heterogeneity was estimated from variability ratios derived from study-level data from 66 RCTs of antipsychotics in schizophrenia (N=17,202). This estimation required a correlation coefficient ({rho}) between placebo response and treatment effects to be estimated. We estimated this from both study level estimates of the 66 trials, and individual patient data (N=560).

ResultsBoth individual patient ({rho}=-0.32, p=0.002) and study level ({rho}=-0.38, p<0.001) analyses yielded a negative correlation between placebo response and treatment effect. Using these estimates we found evidence of clinically significant treatment effect heterogeneity for total symptoms (our most conservative estimate was SD = 13.5 Positive and Negative Syndrome Scale (PANSS) points). Mean treatment effects were 8.6 points which, given the estimated SD, suggests the top quartile of patients experienced beneficial treatment effects of at least 17.7 PANSS points, while the bottom quartile received no benefit as compared to placebo.

ConclusionsWe found evidence of clinically meaningful treatment effect heterogeneity for antipsychotic treatment of schizophrenia. This suggests efforts to personalise treatment have potential for success, and demonstrates that variability meta-analyses of RCTs need to account for relationships between placebo response and treatment effects.

category: psychiatry and clinical psychology


title: Life after mild traumatic brain injury: Widespread structural brain changes associated with psychological distress revealed with multimodal magnetic resonance imaging

abstract:
BackgroundTraumatic brain injury (TBI) can alter brain structure and lead to onset of persistent neuropsychological symptoms. This study investigates the relationship between brain damage and psychological distress after mild TBI (mTBI) using multimodal magnetic resonance imaging (MRI).

MethodsEighty-nine mTBI patients from the TRACK-TBI (Transforming Research and Clinical Knowledge in Traumatic Brain Injury) pilot study were included. Subscales of the Brief Symptoms Inventory 18 for depression, anxiety, and somatization were used as outcome measures of psychological distress [~]6 months after the traumatic event. Glasgow Coma Scale scores were used to evaluate recovery. MRIs were acquired within 2 weeks post-injury. Perivascular spaces (PVS) were segmented using an enhanced PVS segmentation method, and the volume fraction was calculated for the whole brain and white matter regions. Cortical thickness and gray matter structures volumes were calculated in Freesurfer; diffusion imaging indices and multi-fiber tracts were extracted using the Quantitative Imaging Toolkit. The analysis was performed considering age, sex, intracranial volume, educational attainment, and improvement level upon discharge as covariates.

ResultsPerivascular space fractions in the posterior cingulate, fusiform, and postcentral areas were found to be associated with somatization symptoms. Depression, anxiety, and somatization symptoms were associated with the cortical thickness of the frontal- opercularis and occipital pole, putamen and amygdala volumes, and corticospinal tract and superior thalamic radiation. Analyses were also performed on the two hemispheres separately to explore lateralization.

ConclusionsThis study shows how PVS, cortical, and microstructural damages can predict the onset of depression, anxiety, and somatization symptoms in mTBI patients.

category: radiology and imaging


title: Candidate gene modifiers of dystrophinopathy identified by the uniform application of genome-wide datasets to novel GWAS-identified loci

abstract: Although the major determinant of disease severity in patients with severe Duchenne muscular dystrophy (DMD) or milder Becker muscular dystrophy (BMD) is whether their dystrophin gene (DMD) mutation disrupts the mRNA reading frame or allows expression of a partially functional protein, other genes have been proposed or demonstrated to modify the severity of disease progression. In a companion paper to this one, we describe our novel approaches to genome-wide association study (GWAS) of loss of ambulation (LOA) in the largest genome-wide search to date for loci influencing disease severity in DMD patients. Candidate regulatory SNPs that modify disease progression were identified using an evidential statistical paradigm and here we present a uniform application of recent functional genomic datasets to explore the potential functional impact of the top six candidate regions with PPLD scores of [≥]0.4. The results of this analysis of the largest DMD GWAS survey to date elucidate recurrent and potentially new pathways for intervention in the dystrophinopathies.

category: genetic and genomic medicine


title: Genetic Insight into Birt-Hogg-Dube syndrome in Indian patients reveals novel mutations in FLCN

abstract:
BackgroundBirt-Hogg-Dube syndrome (BHDS) is a rare monogenic condition mostly associated with germline mutations at FLCN. It is characterized by either one or more manifestations of primary spontaneous pneumothorax (PSP), skin fibrofolliculomas and renal carcinoma. Here, we comprehensively studied germline mutations in BHDS patients and asymptomatic members from 15 Indian families.

MethodsTargeted amplicon NGS and Sanger sequencing was performed to detect germline mutations at FLCN in 31 clinically diagnosed patients and 74 asymptomatic family members. Functional effects and protein-protein interaction of FLCN variants were evaluated in-silico and molecular docking method. Family-based association study between pathogenic mutations and BHDS was also performed. Germline mutations at genes associated with phenotypically similar diseases were also addressed in few families.

ResultsSix different types of pathogenic FLCN mutations were observed in the patients. Two of them: 11-nucleotide deletion (c.1150_1160delGTCCAGTCAGC) and splice acceptor mutation (c.1301-1G>A), were novel mutations. Two unreported Clinvar pathogenic mutations: stop-gain (c.634C>T) and 4-nucleotide duplication (c.1329_1332dupAGCC), and known mutations: hotspot mutation (c.1285delC) and splice donor mutations (c.1300+1G>A) were also detected. All these mutations greatly affected the protein stability and FLCN-FNIP2 protein interaction. Family-based association studies suggested pathogenic FLCN mutations are significantly associated with BHDS. Two pathogenic SNPs, rs1801133 and rs138189536, at MTHFR, associated with Homocystinuria, were found in one family.

ConclusionPathogenic mutations at FLCN may play key roles in deregulating metabolic pathways leading to disease pathogenesis. Instead of FLCN mutations, MTHFR pathogenic SNPs were also detected in clinically diagnosed BHDS patients, therefore, genetic evaluation is necessary to avoid confounding diagnosis.


title: Lightweight Mobile Automated Assistant-to-physician for Global Lower-resource Areas

abstract:
ImportanceLower-resource areas in Africa and Asia face a unique set of healthcare challenges: the dual high burden of communicable and non-communicable diseases; a paucity of highly trained primary healthcare providers in both rural and densely populated urban areas; and a lack of reliable, inexpensive internet connections.

ObjectiveTo address these challenges, we designed an artificial intelligence assistant to help primary healthcare providers in lower-resource areas document demographic and medical sign/symptom data and to record and share diagnostic data in real-time with a centralized database.

DesignWe trained our system using multiple data sets, including US-based electronic medical records (EMRs) and open-source medical literature and developed an adaptive, general medical assistant system based on machine learning algorithms.

Main outcomes and MeasureThe application collects basic information from patients and provides primary care providers with diagnoses and prescriptions suggestions. The application is unique from existing systems in that it covers a wide range of common diseases, signs, and medication typical in lower-resource countries; the application works with or without an active internet connection.

ResultsWe have built and implemented an adaptive learning system that assists trained primary care professionals by means of an Android smartphone application, which interacts with a central database and collects real-time data. The application has been tested by dozens of primary care providers.

Conclusions and RelevanceOur application would provide primary healthcare providers in lower-resource areas with a tool that enables faster and more accurate documentation of medical encounters. This application could be leveraged to automatically populate local or national EMR systems.

Key pointsO_ST_ABSQuestionC_ST_ABSLower-resource areas like many countries in Africa are suffering from severe disease burdens, how can we utilize the modern health system in developed countries to help ease it?

FindingsUtilizing AI technology with large data sets from US, we developed a smart diagnosis assistance help primary healthcare providers in lower-resource areas document demographic and medical sign/symptom data and to record and share diagnostic data in real-time with a centralized database. The assistance system has been tested in Pakistan and proven to be effective.

MeaningOur application would provide primary healthcare providers in lower-resource areas with a tool that enables faster and more accurate documentation of medical encounters.

category: health informatics


title: Somatic activating BRAF variants cause isolated lymphatic malformations

abstract: Somatic activating variants in PIK3CA, the gene that encodes the p110 catalytic subunit of PI3K, have been previously detected in [~]80% of lymphatic malformations (LM).1; 2 We report the presence of somatic activating variants in BRAF in individuals with PIK3CA-negative LM. The BRAF substitution p.Val600Glu (c.1799T>A), one of the most common driver mutations in cancer, was detected in multiple individuals with LM. Histology revealed abnormal lymphatic channels with immunopositivity for BRAFV600E in endothelial cells that was otherwise indistinguishable from PIK3CA positive LM. The finding that BRAF variants contribute to low-flow LMs increases the complexity of prior models associating low flow vascular malformations (LM and venous malformations) with mutations in the PI3K-AKT-MTOR and high flow vascular malformations (arteriovenous malformations) with mutations in the RAS-MAPK pathway.3 Additionally, this work highlights the importance of genetic diagnosis prior to initiating medical therapy as more studies examine therapeutics for individuals with vascular malformations.


title: A clustering of missense variants in the crucial chromatin modifier WDR5 defines a new neurodevelopmental disorder

abstract: WDR5 is a broadly studied, highly conserved protein involved in a wide array of biological functions. Among these functions, WDR5 is a part of several protein complexes that affect gene regulation via post-translational modification of histones. Here, we present data from ten unrelated individuals with six different rare de novo missense variants in WDR5; one identical variant was found in four individuals, and another variant in two individuals. All ten individuals had neurodevelopmental disorders including speech/language delays (N=10), intellectual disability (N=8), epilepsy (N=6) and autism spectrum disorder (N=4). Additional phenotypic features included abnormal growth parameters (N=6), heart anomalies (N=2) and hearing loss (N=2). All six missense variants occurred in regions of the WDR5 locus that are known to be extremely intolerant for variation. Three-dimensional structures indicate that all the residues affected by these variants are located at the surface of one side of the WDR5 protein. It is predicted that five out of the six amino-acid substitutions disrupt interactions of WDR5 with RbBP5 and/or KMT2A/C, as part of the COMPASS family complexes. Thus, we define a new neurodevelopmental disorder associated with missense variants in WDR5 and a broad range of associated features including intellectual disability, speech/language impairments, epilepsy and autism spectrum disorders. This finding highlights the important role of COMPASS family proteins in neurodevelopmental disorders.


title: Predicting Clinical Course from Subcortical Shape in Provisional Tic Disorder

abstract: The ongoing NewTics study examines children who have had tics for less than 9 months (NT group) -a population on which little research exists. Here, we further investigate relationships between subcortical shape and tic symptom outcomes. 138 children were assessed at baseline and a 12-month follow-up: 79 with NT, 27 tic-free healthy controls (HC), and 32 with chronic tic disorder or Tourette syndrome (TS), using T1-weighted MRI and total tic scores (TTS) from the Yale Global Tic Severity Scale to evaluate symptom change. Subcortical surface maps were generated using FreeSurfer-initialized large deformation diffeomorphic metric mapping, and linear regression models were constructed to correlate structural shapes with TTS while accounting for covariates, with relationships mapped onto structure surfaces. When compared to healthy controls, smaller mean volumes were found in the TS group for the caudate, nucleus accumbens, pallidum, and thalamus. NT had smaller mean volumes than controls in the caudate, pallidum, and thalamus. Surface maps illustrate distinct patterns of inward deformation (localized volume loss) in the TS group compared to NT children. In the NT group, a larger hippocampus at baseline significantly correlated with the worsening of tic symptoms at 12 months. Outward deformation in the hippocampus and inward deformation in the accumbens at baseline are also related to worsening tic symptoms at follow-up. Since the NT group has had tics only for a few months, we can rule out the possibility that these subcortical volume differences are caused by living with tics for years; they are more likely related to the cause of tics. These observations constitute some of the first prognostic biomarkers for tic disorders and suggest localized circuitry that may be associated with outcome of tic disorders.

category: neurology


title: Multiplexed micronutrient, inflammation, and malarial antigenemia assessment using a plasma fractionation device

abstract: Collecting, processing, and storing blood samples for future analysis of biomarkers can be challenging when performed in resource limited environments. The preparation of dried blood spots (DBS) from heel or finger stick collection of whole blood is a widely used and established method. DBS pose less risk of infection from blood borne pathogens, do not require immediate specimen processing and tolerate a wider range of storage temperatures, and are easier to ship. As such, DBS are commonly used in large-scale surveys to assess infectious disease status and/or micronutrient status in vulnerable populations. Recently, we reported that DBS can be used with a multiplexed immunoassay, the Q-plex Human Micronutrient 7-plex Array (MN 7-plex). This tool can simultaneously quantify seven protein biomarkers related to micronutrient deficiencies (iodine, iron and vitamin A), inflammation and malarial antigenemia using plasma or serum. Serum ferritin, a key iron biomarker, cannot be measured from DBS due to red blood cell (RBC) ferritin confounding the results. In this study, we demonstrate the performance of a simple and rapid blood fractionation tool that passively separates serum from cellular components via diffusion through a membrane into a plasma collection disc (PCD) to produce plasma spots. We evaluated the concordance of MN 7-plex analyte concentrations from matched panels of eighty-eight samples of PCD, DBS, and wet plasma prepared from anticoagulated venous whole blood. The results show high correlation between eluates from PCD and DBS and wet plasma for each analyte. Serum ferritin measures from the PCD eluates were highly correlated to wet plasma samples. This suggests that surveillance for iron deficiency may be improved over the current methods restricted to only measuring sTfR in DBS as when used in combination with the MN 7-plex, all seven biomarkers can be simultaneously measured using PCDs.

category: nutrition


title: Whole Exome Sequencing in dense families suggests genetic pleiotropy amongst Mendelian and complex neuropsychiatric syndromes

abstract:
IntroductionWhole Exome Sequencing (WES) studies have provided important insights into the genetic architecture of neuropsychiatric syndromes identifying rare and novel variants in the protein-coding sequence of the genome that impact function. Variants and genes that are central to the shared biology of these clinical syndromes may be identified by WES in families with multiple affected individuals with serious mental illnesses (F-SMI).

MethodsWe performed WES in 250 individuals (affected = 186, family-control = 64) from 100 families, each with [≥]2 members with SMI, and 60 unrelated population-controls. Within pedigree prioritization employed criteria of 1. rarity (Minor Allele Frequency <0.1%, GnomAD South-Asian sample, 15308 exomes); 2. functional consequence ( Loss of Function or  missense deleterious in 4/5 in silico predictions). 3. sharing by [≥]3 affected members within a family. Across the sample, gene-set-wide case-control association analysis was performed with Sequence Kernel Association Test, accounting for kinship.

ResultsIn 17 families with [≥]3 exome samples, we identified 79 rare predicted deleterious variants in 79 unique genes shared by [≥]3 affected members and absent in 60 unrelated controls. Twenty (25.32%) genes were implicated in monogenic neurodevelopmental syndromes in Online Mendelian Inheritance in Man representing a statistically significant overrepresentation (Fishers Exact test OR = 2.47, p = 0.001). In gene-set wise SKAT, statistically significant association was noted for genes related to synaptic function (SKAT-p = 0.017).

DiscussionIn F-SMI based WES study, we identify private, rare, protein altering variants in genes previously implicated in monogenic Mendelian neuropsychiatric syndromes; suggesting pleotropic influences in neurodevelopment between complex and monogenic syndromes.


title: Metabolomic and lipidomic signatures in autosomal dominant and late-onset Alzheimer disease brains

abstract: The identification of multiple genetic risk factors for Alzheimer Disease (AD) provides evidence to support that many pathways contribute to AD onset and progression. However, the metabolomic and lipidomic profiles in carriers of distinct genetic risk factors are not fully understood. The metabolome can provide a direct image of dysregulated pathways in the brain, including information on treatment targets. In this study, we interrogate the metabolomic and lipidomic signatures in the AD brain, including carriers of pathogenic variants in APP, PSEN1, and PSEN2 (autosomal dominant AD; ADAD), APOE {varepsilon}4 and TREM2 risk variant carriers, and non-carrier sporadic AD (sAD). We generated metabolomic and lipidomic data from parietal cortical tissue from 366 participants with AD pathology and 26 cognitively unimpaired controls using the Metabolon global metabolomics platform. We identified 133 metabolites associated with disease status (FDR q-value<0.05). In sAD brains these include tryptophan betaine (b=-0.57) and N-acetylputrescine (b=-0.14). Metabolites associated with sAD and ADAD include ergothioneine (b=-0.21 and -0.26 respectively) and serotonin (b=-0.34 and -0.58, respectively). TREM2 and ADAD showed association with -tocopherol (b=-0.12 and -0.12) and CDP-ethanolamine (b=-0.13 and -0.10). {beta}-citrylglutamate levels are associated with sAD, ADAD, and TREM2 compared to controls (b=-0.15; -0.22; and -0.29, respectively). Additionally, we identified a signature of 16 metabolites that is significantly altered between genetic groups (sAD vs. control p = 1.05x10-7, ADAD vs. sAD p = 3.21x10-5) and is associated with Braak tau stage and disease duration. These data are available to the scientific community through a public web browser (http://ngi.pub/Metabolomics). Our findings were replicated in an independent cohort of 327 individuals.


title: Creation and evaluation of full-text literature-derived, feature-weighted disease models of genetically determined developmental disorders

abstract:
There are >2500 different genetically-determined developmental disorders (DD), which, as a group, show very high levels of both locus and allelic heterogeneity. This has led to the wide-spread use of evidence-based filtering of genome-wide sequence data as a diagnostic tool in DD. Determining whether the association of a filtered variant at a specific locus is a plausible explanation of the phenotype in the proband is crucial and commonly requires extensive manual literature review by both clinical scientists and clinicians. Access to a database of weighted clinical features extracted from rigorously curated literature would increase the efficiency of this process and facilitate the development of robust phenotypic similarity metrics. However, given the large and rapidly increasing volume of published information, conventional biocuration approaches are becoming impractical.

Here, we present a scalable, automated method for extraction of categorical phenotypic descriptors from full-text literature. Papers identified through literature review were downloaded and parsed using the Cadmus custom retrieval package. Human Phenotype Ontology terms were extracted using MetaMap, with 76-83% precision and 72-81% recall. Mean terms per paper increased from 9 in title + abstract, to 69 using full text. We demonstrate that these literature-derived disease models plausibly reflect true disease expressivity more accurately than gold standard manually-curated models, through comparison with prospectively gathered data from the Deciphering Developmental Disorders study. AUC for ROC curves increased by 5-10% through use of literature-derived models. This work shows that scalable automated literature curation increases performance and adds weight to the need for this strategy to be integrated into informatic variant analysis pipelines.


title: Can I Afford To Be On Campus?: Do College Students with Disabilities Understand COVID-19 Vaccination Costs?

abstract: Institutions of higher education have mandated COVID-19 vaccinations for students wishing to return to an on-campus, in-person learning experience. However, college students with disabilities (SWDs) may be hesitant to take a COVID-19 vaccine for a variety of reasons, possibly delaying or denying these students access to higher education. Yet, an under-researched aspect of COVID-19 vaccinations and related communication is whether college students with disabilities understand that the COVID-19 vaccine is free and whether that understanding varies by intersectional identities. As a result, this studys research team surveyed 245 college students with disabilities to explore these students knowledge of vaccine costs and whether differences exist between groups. Data suggests many college students with disabilities do not know that COVID-19 vaccinations are free: White/Caucasian SWDs were most aware of COVID-19 vaccines being free (23.6%), while Latinx students were least aware (1.3%). Moreover, women were more aware of free COVID-19 vaccines (14.8%) than men (11.4%), first generation college students were more aware (15.6%) than non-first generation college students (12.2%), and full-time students (19%) were more aware than part-time students (8.9%). Overall, less than 25% of SWDs understood that COVID-19 vaccines are free. Implications for health communication, vaccine awareness, and higher education policy are addressed.

category: health policy


title: Cellular and humoral Immune response to mRNA COVID-19 vaccination in subjects with chronic lymphocytic leukemia

abstract: Chronic Lymphocytic Leukemia (CLL) is predominantly a B-lymphocyte leukemia associated with immune defects that are often exacerbated by CLL directed therapies. SARS-CoV-2 infection poses a significant risk of illness or mortality to CLL patients, and while SARS-CoV-2 vaccines are highly effective in immunocompetent individuals, efficacy varies substantially in immunocompromised patients, including those with CLL. To date, studies of COVID-19 vaccine immune responses in immunocompromised hosts have largely relied on semi-quantitative antibody titers that only partially characterize vaccine-elicited immune responses and do not measure B or T-cell specific responses that may also play a protective role in vaccinees. Here, we report RBD-specific antibody as well as B-cell and T-cell responses in an observational cohort of sixteen CLL subjects who received mRNA vaccination against SARS-CoV-2, finding a strong association between CLL treatment and vaccine immunogenicity, with important implications for vaccination timing in the context of CLL treatment or recovery from prior treatment.

category: hematology


title: A SARS-CoV-2 variant of concern triggers Fc effector function with increased cross-reactivity

abstract: SARS-CoV-2 variants of concern (VOCs) exhibit escape from neutralizing antibodies, causing concern about vaccine effectiveness. However, while non-neutralizing cytotoxic functions of antibodies are associated with decreased disease severity and vaccine protection, Fc effector function escape from VOCs is poorly defined. Furthermore, whether VOCs trigger Fc functions with altered specificity, as has been reported for neutralization, is unknown. Here, we demonstrate that the Beta VOC partially evades Fc effector activity in individuals infected with the original (D614G) variant. However, not all functions are equivalently affected, suggesting differential targeting by antibodies mediating distinct Fc functions. Furthermore, Beta infection triggered responses with significantly improved Fc cross-reactivity against global VOCs compared to either D614G infected or Ad26.COV2.S vaccinated individuals. This suggests that, as for neutralization, the infecting spike sequence impacts Fc effector function. These data have important implications for vaccine strategies that incorporate VOCs, suggesting these may induce broader Fc effector responses.


title: The COVID19 pandemic has changed women's experiences of pregnancy in the UK

abstract:
IntroductionDuring the SARS-CoV-2 pandemic, maternity care has been substantially altered to reduce transmission of the SARS-CoV-2 virus. Many antenatal services are now restricted or delivered online, and visiting has been restricted during labour and in the postnatal period.

MethodsWe conducted an online survey from 1st August to 31st December 2020 to investigate the experiences of women who were pregnant or breastfeeding in the UK during the SARS-CoV-2 pandemic. The survey included 55 open and closed questions and required 5 minutes to complete. We publicised the survey using social media.

ResultsWe received 96 responses, including 66 currently pregnant women and 22 women who were pregnant during the pandemic. The response rate was 70.1% of survey views. We found mixed experiences of the impact of the pandemic on antenatal and perinatal care, notably with some women feeling visiting restrictions were insufficient and others feeling they were too strict. Twenty-nine women received no information about COVID-19, and 6 women found it very difficult to find information. Thirty-nine women would have liked to have more information about breastfeeding after a pregnancy affected by COVID-19, and 37 women wanted more information about antibody persistence and transfer.

DiscussionAdditional support is required for pregnant and lactating women during the current pandemic. Provision of information and support, including via social media, may improve womens experiences of pregnancy in the current environment.

SignificanceMaternity services in the UK have been significantly restructured to prevent transmission of the SARS-CoV-2 virus, including restrictions to in-person antenatal care, and perinatal visiting. It is not fully known how these changes are perceived by pregnant and breastfeeding women.

Reactions to changes in antenatal care are mixed, including whether restrictions were too lenient or too strict. Most women underwent online antenatal care in addition in-person visits. Some received no information about COVID-19, and a significant proportion of women would have liked more information, particularly regarding antibody transfer and benefits of breastfeeding during the pandemic.

Ethical statementThis study was approved by North East - Newcastle & North Tyneside 1 Research Ethics Committee


title: Risk of HCV infection associated with hospital-based invasive procedures: a systematic review and meta-analysis

abstract:
BackgroundHealthcare settings, where invasive procedures are frequently performed, may play an important role in the transmission dynamics of blood-borne pathogens when compliance with infection control precautions remains suboptimal. This study aims at better understanding and quantifying the role of hospital-based invasive procedures on hepatitis C virus (HCV) transmission.

MethodsWe conducted a systematic review and meta-analysis to identify recent studies reporting association measures of HCV infection risk that are linked to iatrogenic procedures performed in hospital settings. Based on expert opinion, invasive procedures were categorized into 10 groups for which pooled measures were calculated. Finally, the relationship between pooled measures and the country-level HCV prevalence or the Healthcare Access and Quality (HAQ) index was assessed in meta-regressions.

FindingsA total of 71 studies were included in the analysis. The most frequently evaluated procedures were blood transfusion and surgery (60 and 37 studies, respectively). The pooled odds ratio (OR) of HCV infection varied widely, ranging from 1{middle dot}46 (95%CI: 1{middle dot}14-1{middle dot}88) for dental procedures to 3{middle dot}84 (2{middle dot}07-7{middle dot}12) for wound care. The OR for blood transfusion was higher for transfusions performed before 1998 (3{middle dot}77, 2{middle dot}42-5{middle dot}88) than for those without a specified date (2{middle dot}26, 1{middle dot}81-2{middle dot}81). Finally, the country-level overall risk for all procedures was significantly associated with HCV prevalence, but not with the HAQ index. In procedure-specific analyses, the HCV infection risk was significantly negatively associated with the HAQ for endoscopy and positively associated with HCV prevalence for endoscopy and surgery.

InterpretationVarious invasive procedures were documented to be significantly associated with HCV infection. Our results provide a ranking of procedures in terms of HCV risk that may be used for prioritization of infection control measures, especially in high HCV prevalence settings.

FundingINSERM-ANRS (France Recherche Nord and Sud Sida-HIV Hepatites)

O_TEXTBOXResearch in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed for systematic review or meta-analyses articles published between Jan 1, 2000 and Oct 31, 2021, and focused on iatrogenic risk factors associated with HCV infection in hospitalized patients, using "hepatitis C", "risk" and "hospital" as keywords. We found a single comprehensive meta-analysis assessing HCV risk factors and reporting pooled risks estimates for hospital-based procedures. However, this meta-analysis was not specific to in-hospital procedures, based on articles published between 1989 and 2013, and did not strictly follow the PRISMA guidelines.

Added value of this studyOur study presents an up-to-date assessment of the risks of HCV infection associated with different hospital-based procedures. Results suggest that iatrogenic HCV infection risk remains important, in studies that were recently conducted. We underline the importance of this risk in high prevalence settings and provide a potential prioritization of procedures associated with HCV infection that may help implementing infection control measures efficiently.

Implications of all the available evidenceThis study shows that iatrogenic procedures remain at risk of transmitting blood-borne pathogens, in particular HCV. Despite the availability of highly efficacious direct acting antivirals to treat chronic HCV infection, the prevention of iatrogenic HCV infection, through strictly complying with the established standard precautions, remains essential. These results could be used in modelling studies to help find optimal and efficient control measures to reduce in-hospital HCV transmission.

C_TEXTBOX


title: Inhaled Corticosteroids for Outpatients with Covid-19: A Meta-Analysis

abstract: The role of inhaled corticosteroids for outpatient COVID-19 is evolving. We meta-analyzed reported clinical trials and estimated probability of any effect and number needed to treat of 50 or 20 for symptom resolution by day 14 [100%, 99.8%, 93.1%] and hospitalization [89.3%, 72.9%, 26.7%] respectively.


title: Evaluation of a Machine Learning Approach Utilizing Wearable Data for Prediction of SARS-CoV-2 Infection in Healthcare Workers

abstract:
ImportancePassive and non-invasive identification of SARS-CoV-2 infection remains a challenge. Widespread use of wearable devices represents an opportunity to leverage physiological metrics and fill this knowledge gap.

ObjectiveTo determine whether a machine learning model can detect SARS-CoV-2 infection from physiological metrics collected from wearable devices.

DesignA multicenter observational study enrolling health care workers with remote follow-up.

SettingSeven hospitals from the Mount Sinai Health System in New York City

ParticipantsEligibility criteria included health care workers who were [≥]18 years, employees of one of the participating hospitals, with at least an iPhone series 6, and willing to wear an Apple Watch Series 4 or higher. We excluded participants with underlying autoimmune/inflammatory diseases, and medications known to interfere with autonomic function. We enrolled participants between April 29th, 2020, and March 2nd, 2021, and followed them for a median of 73 days (range, 3-253 days). Participants provided patient-reported outcome measures through a custom smartphone application and wore an Apple Watch, collecting heart rate variability and heart rate data, throughout the follow-up period.

ExposureParticipants were exposed to SARS-CoV-2 infection over time due to ongoing community spread.

Main Outcome and MeasureThe primary outcome was SARS-CoV-2 infection, defined as {+/-}7 days from a self-reported positive SARS-CoV-2 nasal PCR test.

ResultsWe enrolled 407 participants with 49 (12%) having a positive SARS-CoV-2 test during follow-up. We examined five machine-learning approaches and found that gradient-boosting machines (GBM) had the most favorable 10-CV performance. Across all testing sets, our GBM model predicted SARS-CoV-2 infection with an average area under the receiver operating characteristic (auROC)=85% (Confidence Interval 83-88%). The model was calibrated to improve sensitivity over specificity, achieving an average sensitivity of 76% (CI {+/-}[~]4%) and specificity of 84% (CI {+/-}[~]0.4%). The most important predictors included parameters describing the circadian HRV mean (MESOR) and peak-timing (acrophase), and age.

Conclusions and RelevanceWe show that a tree-based ML algorithm applied to physiological metrics passively collected from a wearable device can identify and predict SARS-CoV2 infection. Utilizing physiological metrics from wearable devices may improve screening methods and infection tracking.


title: A more compact photoacoustic imaging system to detect periodontitis

abstract: Photoacoustic imaging has shown value in periodontal disease, but the large size of conventional photoacoustic transducers prevents imaging of more posterior teeth, i.e., molars. Here, we report a clinical "hockey stick"-style transducer repurposed for photoacoustic (PA) via an integrated fiber bundle. The shape of the hockey stick transducer facilitates imaging of the 1st pre-molars in contrast to conventional photoacoustic transducer designs. This tool was then deployed for photoacoustic imaging of periodontal disease and the periodontal pocket via a food-grade contrast agent (cuttlefish ink). We characterized the resolution and imaging range and then validated the system with a swine model and human subjects. We could image four additional teeth per quadrant with the smaller design versus a commercial photoacoustic transducer. Three raters evaluated the performance of the hockey stick transducer. The measurements between the probing and the PA methods were blinded, but the outcomes were highly correlated. We showed a bias of [~]0.3 mm for the imaging-based technique versus conventional probing. In addition, the inter-reliability was over 0.60 for three different raters of varying experience suggesting that this approach to evaluating dental health is teachable and reproducible. Finally, we demonstrated the utility in a human subject and can image teeth much more posterior in the mouth than with conventional photoacoustic transducers.

category: dentistry and oral medicine


title: Longitudinal Changes of Cardiac and Aortic Imaging Phenotypes Following COVID-19 in the UK Biobank Cohort

abstract: Case studies conducted after recovery from acute infection with SARS-CoV-2 have frequently identified abnormalities on CMR imaging, suggesting the possibility that SARS-CoV-2 infection commonly leads to cardiac pathology. However, these observations have not been able to distinguish between associations that reflect pre-existing cardiac abnormalities (that might confer a greater likelihood of more severe infection) from those that arise as consequences of infection. To address this question, UK Biobank volunteers (n=1285; 54.5% women; mean age at baseline, 59.8 years old; 96.3% white) who attended an imaging assessment including cardiac magnetic resonance (CMR) before the start of the COVID-19 pandemic were invited to attend a second imaging assessment in 2021. Cases with evidence of previous SARS-CoV-2 infection were identified through linkage to PCR-testing or other medical records, or a positive antibody lateral flow test; n=640 in data available on 22 Sep 2021) and were matched to controls with no evidence of previous infection (n=645). The majority of these infections were milder and did not involve hospitalisation. Measures of cardiac and aortic structure and function were derived from the CMR images obtained on the cases before and after SARS-CoV-2 infection from images for the controls obtained over the same time interval using a previously validated, automated algorithm. Cases and controls had similar cardiac and aortic imaging phenotypes at their first imaging assessment. Changes between CMR imaging measures in cases before and after infection were not significantly different from those in the matched control group. Additional adjustment for comorbidities made no material difference to the results. While these results are preliminary and limited to imaging metrics derived from automated analyses, they do not suggest clinically significant persistent cardiac pathology in the UK Biobank population after generally milder (non-hospitalised) SARS-CoV-2 infection.


title: Exposure contrasts of pregnant women during the Household Air Pollution Intervention Network randomized controlled trial

abstract:
BackgroundExposure to PM2.5 arising from solid fuel combustion is estimated to result in approximately 2.3 million premature deaths and 90 million lost disability-adjusted life years annually.  Clean cooking interventions attempting to mitigate this burden have had limited success in reducing exposures to levels that may yield improved health outcomes.

ObjectivesThis paper reports exposure reductions achieved by a liquified petroleum gas (LPG) stove and fuel intervention for pregnant mothers in the Household Air Pollution Intervention Network (HAPIN) randomized controlled trial.

MethodsThe HAPIN trial included 3,195 households primarily using biomass for cooking in Guatemala, India, Peru, and Rwanda. 24-hour exposures to PM2.5, carbon monoxide (CO), and black carbon (BC) were measured for pregnant women once before randomization into control (n=1605) and LPG arms (n=1590) and twice thereafter (aligned with trimester). Changes in exposure were estimated by directly comparing exposures between intervention and control arms and by using linear mixed-effect models to estimate the impact of the intervention on exposure levels.

ResultsMedian exposures of PM2.5, BC, and CO post-randomization in the intervention arm were lower by 66% (70.7 versus 24.0 g/m3), 71% (9.6 versus 2.8 g/m3), and 83% (1.2 versus ppm), respectively, compared to the control arm. Exposure reductions were similar across research locations. Post-intervention PM2.5 exposures in the intervention arm were at the lower end of what has been reported for LPG and other clean fuel interventions, with 69% of PM2.5 samples falling below the WHO Annual Interim Target 1 of 35 g/m3.

DiscussionThis study indicates that an LPG intervention with high displacement of traditional cooking can reduce exposures to levels thought to be associated with health benefits. Success in reducing exposures was likely due to strong performance of, and high adherence to the intervention.

category: occupational and environmental health


title: Association between teleworking frequency and work functioning impairment: a nationwide cross-sectional study of Japanese full-time employees

abstract:
ObjectiveWe examined whether teleworking preference and frequency were associated with work functioning impairment.

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

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

ConclusionsA preference for teleworking was associated with work functioning impairment and one factor that increased the teleworking frequency.


title: Association of preference and frequency of teleworking with work functioning impairment: a nationwide cross-sectional study of Japanese full-time employees


title: Immediate and mid-term effect of a natural topical product in patients with musculoskeletal pain: randomized, double-blinded, and placebo-controlled clinical trial.

abstract:
IntroductionMusculoskeletal pain is a common affection due to ageing, sedentarism and injuries. The objective of this trial is to prove efficacy of a natural topical composition containing Arnica montana, Hypericum perforatum, Calendula officinalis, Melaleuca sp. and menthol in pain management in adults with acute or chronic pain.

MethodsThis randomized, double-blinded and placebo-controlled trial included 200 patients with musculoskeletal pain, 100 in the intervention group receiving the topical formula and 100 in the placebo group, receiving a similar formula without active ingredients. The products were applied topically twice daily for 14 days in affected areas. Immediate pain alleviation and stiffness perception were monitored for two hours at days 0, 7 at 14. Pain reduction and recovery perception upon sustained application were assessed after 7 and 14 days.

ResultsIntervention immediately reduced pain and stiffness at rest and in motion 30 minutes after application and kept being superior to placebo in all short-term timepoints (p < 0.05). Immediate pain reduction was maintained even at late stages of recovery. A two-week sustained intervention resulted in significant pain reduction and improvement in recovery perception. Even if both groups reached statistical significance with respect to baseline due to spontaneous lesion recovery, a significantly improved recovery was reported in the intervention group with respect to placebo.

ConclusionsIntervention was found to reduce pain and stiffness upon minutes of its application and to improve pain and mobility over the 14 days of treatment, showing benefits both for immediate alleviation and for longer term recovery.

Level of EvidenceTherapeutic Level I

category: pain medicine


title: Machine Learning in the analysis of lethality and evolution of infection by the SARS-CoV-2 virus (COVID-19) in workers of the Mexico City Metro

abstract: In terms of the number of fatalities, Mexico has been one of the countries most affected worldwide by the pandemic. Using different Machine Learning techniques, some of the first cases of the infection registered in Mexico City (CDMX), the geographical and political center of the country, are analyzed in order to determine the causes of lethality and evolution of infection by the SARS-CoV-2 virus, from April 1 to September 27, 2020 in workers of the Capital Metro.


title: Predicting Melanoma Staging using Targeted RNA Sequencing data using Machine Learning.

abstract: The aim of this study is to use machine learning to predict tumor staging and metastasis in melanoma with differentially expressed genes. Machine has been used in different clinical setting to predict different outcomes. However, it has not been used to look at predicting the diagnostic aspect of tumor staging. We used the TCGA RNA-Sequencing data on melanomas to predict tumor staging nodal and/or metastasis using deep neural networks (DNN) and random forest classifier (RF). Results: We were able to predict tumor staging (lower vs higher stage, i.e. Tis / T1 / T2 vs T3 and higher), nodal metastasis and combined nodal or distant metastasis in patients with melanomas with high accuracies. However, we need to further validate these results.

category: oncology


title: Mutations in CSRP3/MLP, a Z-disc associated gene are functionally associated with dilated cardiomyopathy in Indian population

abstract: CSRP3 is a LIM domain containing protein, known to play an important role in cardiomyocyte development, differentiation and pathology. Mutations in CSRP3 gene are reported in both dilated and hypertrophic cardiomyopathy (DCM and HCM), however, the genotype-phenotype correlation still remains elusive. To investigate the pathogenic potential of CSRP3 variants in our DCM cohort, we have screened 100 DCM cases and 100 controls and identified 3 non-synonymous variations, of which two are missense variants viz., c.233 GGC>GTC, p.G78V; c.420 TGG>TGC, p.W140C, and the third one is a single nucleotide polymorphism (SNP) c.46 ACC>TCC, p.T16S. These variants were absent from 100 control individuals (200 chromosomes). In vitro functional analysis has revealed reduction of CSRP3 protein level in stably-transfected C2C12 cells with p.G78V or p.W140C variants. Immunostaining demonstrates both cytoplasmic and nuclear localization of the wild-type protein, however variants p.G78V and p.W140C cause obvious reduction in the cytoplasmic expression of CSRP3 protein which is more pronounced in case of p.W140C. Disarrayed actin cytoskeleton was also observed in mutants. Besides, the expression of target genes namely Ldb3, Myoz2, Tcap, Tnni3 and Ttn are also downregulated in response to these variants. GST-pulldown assay has also showed a diminished binding of CSRP3 protein with -Actinin due to both variants p.G78V and p.W140C. Both 2D, 3D-modeling have shown confirmational changes. Most in silico tools predict these variants as deleterious. Taken together, all these results suggest the impaired gene function due to these deleterious variants in CSRP3, implicating its possible disease causing role in DCM.


title: Evaluation of patients treated by telemedicine in the COVID-19 pandemic by a private clinic in Sao Paulo, Brazil: A non-randomized clinical trial preliminary study

abstract:
IntroductionAs a result of the coronavirus disease 2019 (COVID-19) pandemic the year 2020 brought major changes on the delivery of health care and face to face physician patient communication was significantly reduced and the practice of remote telehealth care using computer technology is assuming a standard of care, particularly, with COVID-19 patients with attempts to reduce viral spread.

ObjectiveTo describe the clinical practice experience using telemedicine towards COVID-19 and the respective clinical outcomes.

MethodsWe performed a pilot open-label non-randomized, controlled clinical trial. The patients were divided into four groups, according severity of symptoms: (1) asymptomatic, (2) mild symptoms, (3) moderate symptoms and (4) severe symptoms, and were followed up for five days, counted from the beginning of the symptoms. A drug intervention was performed in group 3, for which the protocol followed as suggested by the International Pulmonology Societys consensus for adults with moderate symptoms: first day (attack phase) hydroxychloroquine sulfate 400 mg 12/12h; second to fifth day (maintenance phase) 200 mg (half pill) 12/12h. The medication was associated with azithromycin 500mg once a day for five days. For children with moderate symptoms were used: hydroxychloroquine sulfate 6.5 mg/kg/dose every 12 hours in the first day and 3.25 mg/kg/dose every 12 hours from day 2 to 5. The therapeutic response was telemonitored. Group 4 patients were directly oriented to seek hospital care. During the use of the drugs, the patients were telemonitored daily.

ResultsOne hundred eighty-seven patients were seen with mean age of 37,6 years ({+/-}15,6). The most frequent symptom was cough (57,6%), followed by malaise (60,3%), fever (41,1%), headache (56,0%), muscle pain (51,1%). Of all the patients that sought telemedicine service in our center, 23% were asymptomatic despite contact with people with probable diagnostic of COVID-19; 29,4% reported mild symptoms, 43,9% moderate symptoms, and 3,7% severe symptoms. It was possible to observe in patients treated their symptoms of COVID-19 (group 3) with hydroxychloroquine and azithromycin for five days, presented statistically better improvement of the symptoms when compared to those that did not follow the protocol (p = 0.039). Three patients were hospitalized and discharged after recovery.

ConclusionsOur study showed that patients with COVID-19 who had delivery of health care through telemedicine initiated in early stages of the disease presented satisfactory clinical response, reducing the need of face-to-face consultations and hospitalizations. Our results indicate that the use of telemedicine with diagnosis and drug treatment protocols is a safe and effective strategy to reduce overload of health services and the exposure of healthcare providers and the general population to infected patients in a pandemic situation.

Trial registrationRBR-658khm

Human Research Ethics Committee number: 30246520.0.0000.0069


title: Optimising the quarantining and response sequence towards SARS-CoV-2 outbreaks on board cargo vessels

abstract: The Coronavirus Disease (COVID-19) pandemic has brought significant impact onto the maritime activities worldwide, including disruption to global trade and supply chains. The ability to predict the evolution and duration of a COVID-19 outbreak on cargo vessels would inform a more nuanced response to the event and provide a more precise return-to-trade date. A SEIQ(H)R (Susceptibility-Exposed- Infected-Quarantine-(Hospitalisation)-Removed/Recovered) model is developed and fit-tested to simulate the transmission dynamics of COVID-19 on board cargo vessels of up to 60 crew. Due to specific living and working circumstances on board cargo vessels, instead of utilising the reproduction number, we consider the crew members from the same country to quantify the transmission of the disease. The performance of the model is verified using case studies based on data collected during COVID-19 outbreaks on three cargo vessels in Western Australia during 2020. The convergence between simulation results and the data verifies the performance of the model. The simulations show that the model can forecast the time taken for the transmission dynamics on each vessel to reach their equilibriums, providing informed predictions on the evolution of the outbreak, including hospitalisation rates and duration. The ability to model the evolution of an outbreak, both in duration and severity, is essential to predict outcomes and to plan for the best response strategy. At the same time, if offers a higher degree of certainty regarding the return to trade, which in turn is of significant importance to multiple stakeholders.


title: EPIDEMIOLOGY EVALUATION OF ATHLETIC INJURY IN UNIVERSITY CENTER

abstract:
IntroductionAthletics is a sport with varied modalities, which are based on patterns and activities that are natural to human beings. As a sport, it has several benefits, such as improved physical condition and interpersonal interactions, but it is not free from risks, especially injuries related to competitions or training.

ObjectivesCharacterize injuries presented by the university athletics group of the medical course and identify possible risk factors.

MethodsParticipants, enrolled in the athletics group of the medicine course, of both sexes, had anthropometric measurements evaluated and answered an injury screening questionnaire modified from the "Injury Surveillance System".

Results31 participants responded to the questionnaire where 65% of them had at least one injury. A total of 23 injuries were reported, 20 of which were serious, with no significant difference between both sexes. The total practice time was almost 2 times longer in injured practitioners than in non-injured ones.

ConclusionThe practice of university athletics is associated with a high occurrence of serious injuries.

SUMMARY BOXO_LICollege athletics appears to have a high incidence of injury.
C_LIO_LIThere is an unusually high number of serious injuries in college athletic athletes participating in the study.
C_LIO_LIMost college athletic sports injuries do not appear to be diagnosed or properly treated.
C_LIO_LIMost injuries are concentrated in the lower body.
C_LI

category: sports medicine


title: Immunogenicity and safety of the homogenous booster shot of a recombinant fusion protein vaccine (V-01) against COVID-19 in healthy adult participants primed with a two-dose regimen

abstract:
BackgroundRising concerns over waning immunity and reduction in neutralizing activity against variants of concern (VOCs) have contributed to deploying booster doses by different strategies to tackle the COVID-19 pandemic. Preliminary findings from Phase I and II have shown that V-01, a recombinant fusion protein vaccine against COVID-19, exhibited favorable safety and immunogenicity profiles in 1060 adult participants of both younger and senior age. Herein, we aimed to assess the immunogenicity and safety for a booster dose in participants previously primed with a two-dose 10g V-01 regimen (day 0, 21) from phase I trial, providing reassuring data for necessity and feasibility of a homogenous booster dose.

MethodsWe conducted a single-arm, open-label trial at the Guangdong Provincial Center for Disease Control and Prevention (Gaozhou, China). Forty-three eligible participants who were previously primed 4-5 months earlier with two-dose 10g V-01 regimen from phase I trial received booster vaccination. We primarily assessed the immunogenicity post-booster vaccination, measured by RBD-binding antibodies using ELISA and neutralizing activity against wild-type SARS-CoV-2 and emerging variants of concern (VOCs) using neutralization assays. We secondarily assessed the safety and reactogenicity of the booster vaccination.

ResultsThe third dose of V-01 exhibited significant boosting effects of humoral immune response in participants primed with two-dose 10g V-01 regimen regarding both wild-type SARS-CoV-2 and VOCs. We observed a 60.4-folds increase in neutralizing titres against SARS-CoV-2 of younger adults, with GMTs of 17 (95%CI: 12-23) prior to booster vaccination in comparison to 1017 (95%CI: 732-1413) at day 14 post booster vaccination; and a 53.6-folds increase in that of older adults, with GMTs of 14 (95%CI: 9-20) before booster vaccination in comparison to 729(95%CI: 397-1339) at day 14 post-booster vaccination. The neutralizing titres against SARS-CoV-2 Delta strain also demonstrated a sharp increase from the day of pre booster vaccination to day 14 post booster vaccination, with GMTs of 11 (95%CI:8-15) versus 383 (95%CI:277-531) in younger adults (35.4-folds increase), and 6.5(95%CI: 5-8) versus 300(95%CI:142-631) in older adults (46.0-folds increase), respectively. We also observed a considerable and consistent increase of pseudovirus neutralizing titres against emerging VOCs from day 28 post second vaccination to day 14 post booster vaccination, with GMTs of 206 (95%CI:163-259) versus 607 (95%CI: 478-771) for Alpha strain, 54 (95%CI:38-77) versus 329 (95%CI: 255-425) for Beta strain, 219 (95%CI:157-306) versus 647 (95%CI: 484-865) for Delta strain. Our preliminary findings indicate a homogenous booster dose of V-01 was safe and well-tolerated, with overall adverse reactions being absent or mild-to-moderate in severity, and no grade 3 or worse AEs were related to booster vaccination.

ConclusionsA homogenous booster immunization in participants receiving a primary series of two-dose V-01 elicited a substantial humoral immune response against wild-type SARS-CoV-2 and emerging VOCs, along with a favorable safety and reactogenicity profile. Our study provided promising data for a homogenous prime-boost strategy using recombinant protein vaccine to tackle the ongoing pandemic, potentially providing broad protection against emerging VOCs and overcoming waning immunity.

category: allergy and immunology


title: Determinants and Magnitude of Neonatal Sepsis at Hiwot Fana Comprehensive Specialized University Hospital, Harar, Ethiopia: A Cross-Sectional Study

abstract:
IntroductionNeonatal sepsis is a serious blood bacterial infection in neonates at the age of equal to or less than 28 days of life, and its still the major significant cause of death and long-term morbidity in developing countries. Therefore, this study has assessed the prevalence and related factors with neonatal sepsis among new born admitted to the neonatal intensive care unit at Hiwot Fana Comprehensive Specialized University Hospital, Harar, Ethiopia.

MethodsAn institutional based retrospective cross-sectional study design was conducted among 386 neonates admitted to NICU from September 2017 to August 2019 G.C. A systematic random sampling method was used. Data was analyzed using SPSS V.26. Descriptive summary statistics was done. Bivariate analysis was computed to identify association between dependent and independent variables. Multivariate analysis was used to control possible confounder variables and variables with p-value <0.05 were declared as having statistically significant association.

ResultThe prevalence of neonatal sepsis was 53.1% and 59.5% were males. Among the total neonates who had sepsis, 67.8% had early neonatal sepsis. Among neonatal factors, preterm neonates (AOR: 8.1, 95%CI: 2.1, 31.2), birth asphyxia (AOR: 4.7, 95%CI: 1.6, 13.6); and among maternal factors, urban residence (AOR: 0.26, 95%CI: 0.1, 0.5), ANC attendance (AOR: 0.32, 95%CI: 0.2, 0.6), SVD (AOR: 0.047, 95%CI: 0.01, 0.2), Maternal antibiotic use (AOR: 0.39; 95%CI: 0.2, 0.8), duration of rupture of membrane < 12 hours (AOR: 0.11; 95%CI: 0.05, 0.2) were found to have significant association with neonatal sepsis.

ConclusionOverall, the magnitude of neonatal sepsis was high. Being preterm, low birth weight and having birth asphyxia were found to significantly increase the odds of neonatal sepsis. Urban residence, having ANC follow up, giving birth by SVD and CS, history of antibiotic use and having rupture of membrane < 18 hours were found to significantly decrease the odds of neonatal sepsis.


title: Corpus callosum structural characteristics in very preterm children and adolescents: developmental trajectory and relationship to cognitive functioning

abstract:
Previous studies suggest that structural alteration of the corpus callosum, i.e., the largest white matter commissural pathway, occurs after a preterm birth in the neonatal period and lasts across development. The present study aims to unravel corpus callosum structural characteristics across childhood and adolescence in very preterm (VPT) individuals, and their associations with general intellectual, executive and socio-emotional functioning. Neuropsychological assessments, T1-weighted and multi-shell diffusion MRI were collected in 79 VPT and 46 full term controls aged 6 to 14 years. Volumetric, diffusion tensor and neurite orientation dispersion and density imaging (NODDI) measures were extracted on 7 callosal portions using TractSeg. A multivariate data-driven approach (partial least squares correlation) and an age normative modelling approach were used to explore associations between callosal characteristics and neuropsychological outcomes. The VPT and a full-term control groups showed similar trends of white-matter maturation over time, i.e., increase FA and reduced ODI, in all callosal segments, that was associated with increase in general intellectual functioning. However, using age-related normative modelling, findings show atypical pattern of callosal development in the VPT group, with reduced callosal maturation over time that was associated with poorer general intellectual and working memory functioning, as well as with lower gestational age.

HighlightsO_LICallosal development was explored in full-term and very preterm (VPT) aged 6 to 15 years
C_LIO_LINeuropsychological, callosal volumetric, tensor and NODDI measures were used
C_LIO_LIAge-related normative modelling revealed atypical callosal development in VPT
C_LIO_LIIn VPT, atypical callosal maturation was associated with poorer cognitive functioning
C_LIO_LIIn VPT, greater prematurity was associated with increased atypical callosal maturation
C_LI

CRediT rolesVanessa Siffredi: Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Project administration; Software; Visualization; Writing - original draft; Writing - review & editing.

Maria Chiara Liverani: Data curation; Investigation; Methodology; Project administration; Writing - review & editing.

Dimitri Van De Ville: Methodology; Resources; Software; Supervision; Writing - review & editing.

Lorena G. A. Freitas: Data curation; Writing - review & editing.

Cristina Borradori Tolsa: Investigation; Project administration; Resources; Supervision; Validation; Writing - review & editing.

Petra Susan Huppi: Conceptualization; Funding acquisition; Methodology; Project administration; Resources; Supervision; Validation; Writing - review & editing.

Russia Ha-Vinh Leuchter: Conceptualization; Investigation; Methodology; Project administration; Resources; Supervision; Validation; Writing - review & editing.


title: The efficacy of transcranial magnetic stimulation (TMS) for negative symptoms in schizophrenia: A systematic review and meta-analysis

abstract: Several trials have shown preliminary evidence for the efficacy of Transcranial Magnetic Stimulation (TMS) as a treatment for negative symptoms in schizophrenia. Here, we synthesize this literature in a systematic review and quantitative meta-analysis of double-blind randomized controlled trials of TMS in patients with schizophrenia. Specifically, MEDLINE, EMBASE, Web of Science, and PsycINFO were searched for sham-controlled, randomized trials of TMS among patients with schizophrenia. The standardized mean difference (SMD, Cohens d) with 95% confidence intervals (CI) was calculated for each study (TMS vs. sham) and pooled across studies using an inverse variance random effects model. We identified 56 studies with a total of 2550 participants that were included in the meta-analysis. The pooled analysis showed statistically significant superiority of TMS (SMD=0.37, 95%CI: 0.23; 0.52, p-value <0.00001), corresponding to a number needed to treat of 5. Furthermore, stratified analyses suggested that TMS targeting the left dorsolateral prefrontal cortex, using a stimulation frequency >1 Hz, and a stimulation intensity at or above the motor threshold, was most efficacious. There was, however, substantial heterogeneity and high risk of bias among the included studies. In conclusion, TMS appears to be an efficacious treatment option for patients with schizophrenia suffering from negative symptoms, but the optimal TMS parameters have yet to be resolved.


title: Causes, characteristics, and patterns of prolonged unplanned school closures prior to the COVID-19 pandemic - United States, 2011 - 2019

abstract:
IntroductionOutside of pandemics, there is little information about occurrence of prolonged unplanned K-12 school closures (PUSC). We describe here the reasons, characteristics, and patterns of PUSC in the United States during 8 consecutive inter-pandemic academic years, 2011-2019.

MethodsFrom August 1, 2011 through June 30, 2019, daily systematic online searches were conducted to collect data on publicly announced unplanned school closures lasting [≥]1 school days in the United States. Closures were categorized as prolonged when schools were closed for [≥]5 unplanned days (approximating one full workweek), excluding weekends and scheduled days off per school calendars.

ResultsDuring the eight academic years, a total of 22,112 PUSCs were identified, affecting over 800,000 teachers and 13 million students that resulted in 91.5 million student-days lost. A median of 62.9% of students in PUSC-affected schools were eligible for subsidized school meals. Most affected schools were in cities (35%) and suburban areas (33%). Natural disasters (47%), adverse weather conditions (35%), and budget/teacher strikes (15%) were the most frequently cited reasons for PUSC; illness accounted for 1%, and building/facility issues, environmental issues and violence together accounted for the remaining 2%. The highest number of PUSCs occurred in Health and Human Services Regions 2, 3, 4, and 6 encompassing areas that are frequently in the path of hurricanes and tropical storms. The majority of PUSCs in these regions were attributed to a handful of hurricanes during the fall season, including hurricanes Sandy, Irma, Harvey, Florence, and Matthew.

ConclusionsPUSCs occur annually in the United States due to a variety of causes and are associated with a substantive loss of student-days for in-school learning. Both these prior experiences with PUSCs and those during the current COVID-19 pandemic illustrate a need for creating sustainable solutions for high-quality distance learning and innovative supplemental feeding programs nationwide, especially in disaster-prone areas.

category: public and global health


title: The impact of heating, ventilation and air conditioning (HVAC) design features on the transmission of viruses, including the 2019 novel coronavirus (COVID-19): a systematic review of humidity

abstract:
The aerosol route has been a pathway for transmission of many viruses. Similarly, recent evidence has determined aerosol transmission for SARS-CoV-2 to be significant. Consequently, public health officials and professionals have sought data regarding the role of Heating, Ventilation, and Air Conditioning (HVAC) features as a means to mitigate transmission of viruses, particularly coronaviruses. Using international standards, a systematic review was conducted to comprehensively identify and synthesize research examining the effect of humidity on transmission of coronaviruses and influenza. The results from 24 relevant studies showed that: increasing from mid (40-60%) to high (>60%) relative humidity (RH) for SARS-CoV-2 was associated with decreased virus survival; although SARS-CoV-2 results appear consistent, coronaviruses do not all behave the same; increasing from low (<40%) to mid RH for influenza was associated with decreased persistence, infectivity, viability, and survival, however effects of increased humidity from mid to high for influenza were not consistent; and medium, temperature, and exposure time were associated with inconsistency in results for both coronaviruses and influenza. Adapting HVAC humidity to mitigate virus transmission is a complex approach due to difficulties of humidity control; humidity is a feature to be considered in conjunction with other HVAC features.

Practical ImplicationsWhile increasing relative humidity from mid (40-60%RH) to high (>60%RH) was associated with decreased SARS-CoV-2 survival, coronaviruses did not all behave the same way. As a result, blanket prescriptive humidity levels for coronavirus mitigation are difficult to ascertain. While influenza survival varied from mid to high RH, increased humidity from low (<40%RH) to mid (40-60%RH) RH was associated with decreased virus survival with maximum survival at low RH. When controlling humidity as an HVAC feature, practitioners should take into account virus type and temperature. Future research should also consider the impact of exposure time, temperature, and medium when designing experiments, while also working towards more standardized testing procedures.


title: Title: Effect of Maximum Repetition of Pelvic Floor Stabilization Exercise in Stress Urinary Incontinence.

abstract:
BackgroundStress urinary incontinence (SUI) in females is a common gynecological issue that impedes lifestyle. Exercise had a significant effect; however, studies did not determine the exercise frequency and intensity for pelvic floor stabilization in stress urinary incontinence.

AimThe aim of the study is to determine if maximum repetition of pelvic stabilization exercise impacts the management of stress urinary incontinence in females.

MethodologyOne arm quasi-experimental study design was used. 40 patients having SUI and associated musculoskeletal complaints were recruited from the outpatient unit of Physiotherapy department of the Centre for the Rehabilitation of the Paralysed (CRP), Bangladesh. The study was conducted over 4weeks. Outcome measurement was included pelvic floor and abdominal muscle strength, endurance, and incontinence measurement.

ResultPelvic floor muscle and abdominal strength, and endurance had a positive and significant result in maximum repetition (P .001). Pelvic floor strength has been significantly improvement in week 2 (P .001), and week 3 (P .01). Interference in activities (P .003), and ICIQ total (P .001) had improvement but majority of the improvement was noted in weeks 2-3. There was a significant improvement in the frequency of urine leakage in the first week (P .001), and week 3 (P .005) and week 4 (P .001).

ConclusionPelvic floor exercise with increasing repetition is an effective approach to improve stress urinary incontinence in females. The study had a significant impact on incontinence frequency, amount, and associated quality of life for women with stress urinary incontinence with pelvic floor exercise with maximum repetition.

category: rehabilitation medicine and physical therapy


title: Cognitive enhancement: Effects of methylphenidate, modafinil and caffeine on latent memory and resting state functional connectivity in healthy adults

abstract: Stimulants like methylphenidate, modafinil and caffeine have repeatedly shown to enhance cognitive processes such as attention and memory. However, brain-functional mechanisms underlying such cognitive enhancing effects of stimulants are still poorly characterized. Here, we utilized behavioral and resting-state fMRI data from a double-blind randomized placebo-controlled study of methylphenidate, modafinil and caffeine in 48 healthy male adults. The results show that performance in different memory tasks is enhanced, and functional connectivity (FC) specifically between the fronto-parietal (FPN) and default mode (DMN) network is modulated by the stimulants in comparison to placebo. Decreased negative connectivity between right prefrontal and medial parietal but also between medial temporal lobe and visual brain regions predicted stimulant-induced latent memory enhancement. We discuss dopamines role in attention and memory as well as its ability to modulate FC between large-scale neural networks (e.g. FPN and DMN) as a potential cognitive enhancement mechanism.


title: A Genetic Model for Central Chondrosarcoma Evolution Correlates with Patient Outcome

abstract: The treatment options for central chondrosarcoma are limited, and prognoses are generally unreliable. The presence and absence of mutations in IDH1, and IDH2 are defining events, and TERT mutations have been recently been associated with poor outcome. Despite this, molecular biomarkers are lacking. Here, analysing data from 356 patients, comprising results from whole genome sequencing (n=68), digital droplet PCR (n=346), and methylation arrays (n=57), we present a comprehensive genetic analysis of chondrosarcoma and suggest its clinical utility. Methylation profiles, TERT promoter mutations, genome doubling with prior haploidisation, and age at diagnosis of high grade, distinguish IDH1-mutant, IDH2-mutant and IDH wildtype tumours. The majority of IDH2-mutant tumours harbour TERT mutations, though a significant reduction in survival is only found in the less common mutational combination of IDH1 and TERT. We suggest that diagnostic testing for IDH1, IDH2 and TERT mutations could guide clinical monitoring and prognostication.


title: Protocol for a mixed methods exploratory study of success factors to escalation of care: the SUFFICE study

abstract:
BackgroundIn the United Kingdom, hospital patients suffer preventable deaths (failure to rescue) and delayed admission to the Intensive Care Unit because of poor illness recognition. This problem has consistently been identified in care reviews. Strategies to improve deteriorating ward patient care, such as early warning systems and specialist care teams (Critical Care Outreach or Rapid Response), have not reliably demonstrated reductions to patient deaths. Current research focuses on failure to rescue, but further reductions to patient deaths are possible, by examining care of unwell hospital patients who are rescued (successfully treated). Our primary objective is to develop a framework of care escalation success factors that can be developed into a complex intervention to reduce patient mortality and unnecessary admissions to the Intensive Care Unit (ICU).

Methods and AnalysisSUFFICE is a multicentre mixed-methods, exploratory sequential study examining rescue events in the acutely unwell ward patient in two National Health Service Trusts with Teaching Hospital status. The study will constitute four key phases. Firstly, we will observe ward care escalation events to generate a theoretical understanding of the process of rescue. Secondly, we will review care records from unwell ward patients in whom an ICU admission was avoided to identify care success factors. Thirdly, we will conduct staff interviews with expert doctors, nurses, and Allied Health Professionals to identify how rescue is achieved and further explore care escalation success factors identified in the first two study phases. The final phase involves integrating the study data to generate the theoretical basis for the framework of care escalation success factors.

Ethics and DisseminationEthical approval has been obtained through the Queen Square London Research and Ethics committee (REC Ref 20/HRA/3828; CAG-20CAG0106). Study results will be of interest to critical care, nursing and medical professions and results will be disseminated at national and international conferences.

Trial Registration NumberISRCTN 38850

category: health systems and quality improvement


title: Healthcare professionals knowledge and practices towards hospital infections in surgical clinics

abstract:
BackgroundHospital-acquired infections are a major public health problem, as they increase hospitalization, cost, morbidity, mortality and antibiotic resistance.

AimTo assess the level of knowledge and practices of health professionals about hospital infections in surgical clinics and investigate possible determinants that affects their compliance with international protocols for prevention and control of hospital infections.

MethodsA cross-sectional study with a convenience sample was conducted. Study population included 106 health professionals from medical and nursing staff in surgical clinics of a general hospital in Attica. Data collection was conducted during October and December 2019. We used the Healthcare-Associated Infections questionnaire to measure knowledge and practices of health professionals about hospital infections.

ResultsThe mean overall knowledge score for hospital infections was 59.4, indicating a moderate level of knowledge. The highest level of knowledge was about the safety of healthcare professionals, while the lowest level was about the source of hospital infections. The results of the multivariate linear regression showed that participants who were aware of the infection control program at their hospital and knew they had to wash their hands following the six steps of the hand hygiene protocol had a higher level of knowledge score regarding hospital infections. In contrast, participants who felt that their hospital was following a good infection control and prevention strategy had a lower level of knowledge. In addition, healthcare professionals who washed their hands before and after examining patients, after using medical equipment for patient care, throughout and after the end of the shift, and after removing disposable gloves had a higher level of knowledge for hospital infections.

ConclusionsThe findings of the present study are consistent with the international literature on the existence of a moderate level of knowledge regarding international prevention guidelines. Compliance of healthcare professionals is essential to achieve universal, quality and safe healthcare and a safe working environment.

category: infectious diseases


title: Immunogenicity of COVID-19 vaccines in patients with haematological malignancy: A systematic review and meta-analysis

abstract:
The objectives of this study were to assess the immunogenicity and safety of COVID-19 vaccines in patients with haematological malignancy. A systematic review and meta-analysis of clinical studies of immune responses to COVID-19 vaccination stratified by underlying malignancy and published from 1 January 2021 to 31 August 2021 was conducted using MEDLINE, EMBASE and CENTRAL. Primary outcome was the rate of seropositivity following 2 doses of COVID-19 vaccine with rates of seropositivity following 1 dose, rates of positive neutralising antibody (nAb), cellular responses and adverse events as secondary outcomes. Rates were pooled from single arm studies while rates of seropositivity were compared against the rate in healthy controls for comparator studies using a random effects model and expressed as a pooled odds ratio with 95% confidence intervals.

Forty-four studies (16 mixed group, 28 disease specific) with 7064 patients were included in the analysis (2331 following first dose, 4733 following second dose). Overall seropositivity rates were 61-67% following 2 doses and 37-51% following 1 dose of COVID-19 vaccine. The lowest seropositivity rate was 51% in CLL patients and was highest in patients with acute leukaemia (93%). Following 1 dose, nAb and cellular response rates were 18-63% and 33-86% respectively. Active treatment, ongoing or recent treatment with targeted and CD-20 monoclonal antibody therapies within 12 months was associated with poor COVID-19 vaccine immune responses. New approaches to prevention are urgently required to reduce COVID-19 infection morbidity and mortality in high-risk patient groups that respond poorly to COVID-19 vaccination.


title: Prone positioning of patients with moderate hypoxia due to COVID-19: A multicenter pragmatic randomized trial

abstract:
ObjectivesTo assess the effectiveness of prone positioning to reduce the risk of death or respiratory failure in non-critically ill patients hospitalized with COVID-19

DesignPragmatic randomized clinical trial of prone positioning of patients hospitalized with COVID-19 across 15 hospitals in Canada and the United States from May 2020 until May 2021.

SettingsPatients were eligible is they had a laboratory-confirmed or a clinically highly suspected diagnosis of COVID-19, required supplemental oxygen (up to 50% fraction of inspired oxygen [FiO2]), and were able to independently prone with verbal instruction. (NCT04383613).

Main Outcome MeasuresThe primary outcome was a composite of in-hospital death, mechanical ventilation, or worsening respiratory failure defined as requiring at least 60% FiO2 for at least 24 hours. Secondary outcomes included the change in the ratio of oxygen saturation to FiO2 (S/F ratio).

ResultsA total of 248 patients were included. The trial was stopped early on the basis of futility for the pre-specified primary outcome. The median time from hospital admission until randomization was 1 day, the median age of patients was 56 years (interquartile range [IQR] 45,65), 36% were female, and 90% of patients were receiving oxygen via nasal prongs at the time of randomization. The median time spent prone in the first 72 hours was 6 hours total (IQR 1.5,12.8) for the prone arm compared to 0 hours (0,2) in the control arm. The risk of the primary outcome was similar between the prone group (18 [14.3%] events) and the standard care group (17 [13.9%] events), odds ratio 0.92 (95% CI 0.44 to 1.92). The change in the S/F ratio after 72 hours was similar for patients randomized to prone compared to standard of care.

ConclusionAmong hypoxic but not critically patients with COVID-19 in hospital, a multifaceted intervention to increase prone positioning did not improve outcomes. Adherence to prone positioning was poor, despite multiple efforts. Subsequent trials of prone positioning should aim to develop strategies to improve adherence to awake prone positioning.

What is already known on this topicProne positioning is considered standard of care for mechanically ventilated patients who have severe acute respiratory distress syndrome. Recent data suggest prone positioning is beneficial for patients with COVID-19 who are requiring high flow oxygen. It is unknown of prone positioning is beneficial for patients not on high flow oxygen.

What this study addsProne positioning is generally not well tolerated and innovative approaches are needed to improve adherence. Clinical and physiologic outcomes were not improved with prone positioning among hypoxic but not critically ill patients hospitalized with COVID-19.

category: intensive care and critical care medicine


title: Epidemiological Analysis of Lower Limb Revascularization for Peripheral Arterial Disease over 12 years in the Public Health System in Brazil

abstract:
ObjectivesWorldwide, peripheral arterial disease (PAD) is a disorder with high morbidity, affecting more than 200 million people. Our objective was to analyse the surgical treatment for PAD performed in the Unified Health System of Brazil over 12 years based on publicly available data.

MethodsThe study was conducted with data analysis available on the DATASUS platform of the Brazilian Health Ministry, assessing procedure technique distribution throughout the years, mortality and cost.

ResultsA total of 129,424 procedures were analysed (either for claudicants or critical ischemia, proportion unknown). The vast majority of procedures were Endovascular (65.49%), with a tendency for increase in this disproportion (p<0.001). There were 3,306 in-hospital deaths (mortality of 2.55%), with lower mortality in the Endovascular group (1.2% vs. 5.0%, p=0.008). The overall governmental investment for these procedures was U$ 238,010,096.51, and Endovascular Procedures were on average significantly more expensive than Open Surgery (U$ 1,932.27 v. U$ 1,517.32; p=0.016).

ConclusionsIn the Brazilian Public Health System, lower limb revascularizations occurred with gradual growing frequency between 2008 and 2019. Endovascular procedures were vastly more common, and related to lower in-hospital mortality rates, but higher procedural costs.

category: cardiovascular medicine


title: Predictions of arrhythmic, heart failure and mortality outcomes in pericarditis using automatic electrocardiogram analysis

abstract:
BackgroundPericarditis is a relatively rare disease with a global burden. Despite its strong association with adverse cardiovascular outcomes, identification of patients at risk of future heart failure or arrhythmic events is difficult. In the following study, automated electrocardiogram (ECG) were used to predict new onset ventricular tachycardia/fibrillation (VT/VF), atrial fibrillation (AF) and heart failure with reduced ejection fraction (HF) in an Asian cohort of pericarditis patients.

MethodsConsecutive patients admitted to a single tertiary center in Hong Kong, China, for a diagnosis of pericarditis between 1st January 2005 and 31st December 2019 with baseline ECG measurements were included. Patients with existing AF or HF were excluded. The follow-up period was until the 31st December 2020, or death. Cox regression was applied to identify significant predictors of the primary outcomes (incident VT/VF, AF or HF).

ResultsA total of 874 patients were included. The cohort was 57% male and had a median age of 59 (IQR: 50-70) years old. During follow-up, 57 patients (6.5%), 156 (17.8%) and 168 (19.2%) suffered from VT/VF, AF and HF, respectively. Cox regression identified baseline VT/VF, terminal angle of the QRS vector in the transverse plane, mean QRS duration and mean QTc intervals as significant predictors of incident VT/VF events, with only the former most maintaining significance in multivariate analysis. In contrast, baseline age, prior diagnoses of hypertension, initial angle and magnitude of the QRS vector in the transverse plane, P-wave and QRS axis in the frontal plane, ST segment axis in the frontal and horizontal planes, mean PT interval, mean PR segment duration and QTc intervals were all univariate predictors of incident AF, albeit only baseline age and initial angel of the QRS vector in the transverse plane retained significance after multivariate adjustment. As it pertains to new-onset HF, several clinical and electrocardiographic parameters demonstrated an association with HF in univariate analysis, with prior diagnosis of HT or DM, initial QRS angle in transverse plane, I 40 in horizontal axis, ST-segment axis in the horizontal plane, T-wave frontal axis and atrial rate, of which, except for prior diagnosis of DM, I40 in horizontal axis and T-wave frontal axis, all variables showcased significant relationships in multivariate analysis

InterpretationAF and HF are relatively common complications VT/VF occurs less frequently in the context of pericarditis. Different clinical and ECG predictors of these outcomes were identified. Future studies are still needed to evaluate their use for risk stratification in the clinical setting.