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Instruct:
Identify the main category of Medrxiv papers based on the titles
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After the Haiti 2021 Earthquake: Triage and treatment data for a cohort of patients transported for higher level of care
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public and global health
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Predicting Oncogene Mutations of Lung Cancer Using Deep Learning and Histopathologic Features on Whole-Slide Images
Lung cancer is a leading cause of death in both men and women globally. The recent development of tumor molecular profiling has opened opportunities for targeted therapies for lung adenocarcinoma (LUAD) patients. However, the lack of access to molecular profiling or cost and turnaround time associated with it could hinder oncologists willingness to order frequent molecular tests, limiting potential benefits from precision medicine. In this study, we developed a weakly supervised deep learning model for predicting somatic mutations of LUAD patients based on formalin-fixed paraffin-embedded (FFPE) whole-slide images (WSIs) using LUAD subtypes-related histological features and recent advances in computer vision. Our study was performed on a total of 747 hematoxylin and eosin (H&E) stained FFPE LUAD WSIs and the genetic mutation data of 232 patients who were treated at Dartmouth-Hitchcock Medical Center (DHMC). We developed our convolutional neural network-based models on 172 training cases and tested on 60 independent cases to analyze whole slides and predict five major genetic mutations, i.e., BRAF, EGFR, KRAS, STK11, and TP53. We additionally used 111 cases from the LUAD dataset of the CPTAC-3 study for external validation. Our model achieved an AUROC of 0.799 (95% CI: 0.686-0.904) and 0.686 (95% CI: 0.620-0.752) for predicting EGFR genetic mutations on the DHMC and CPTAC-3 test sets, respectively. Predicting TP53 genetic mutations also showed promising outcomes. Our results demonstrated that H&E stained FFPE LUAD whole slides could be utilized to predict oncogene mutations, such as EGFR, indicating that somatic mutations could present subtle morphological characteristics in histology slides, where deep learning-based feature extractors can learn such latent information.
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pathology
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Effects of testing and vaccination levels on the dynamics of the COVID-19 pandemic and the prospects for its termination
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epidemiology
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Infant Vaccination Does Not Predict Increased Infant Mortality Rate: Correcting Past Misinformation
Despite extensive scientific research supporting the safety and effectiveness of approved vaccines, debates about their use continue in the public sphere. A paper prominently circulated on social media concluded that countries requiring more infant vaccinations have higher infant mortality rates (IMR), which has serious public health implications. However, inappropriate data exclusion and other statistical flaws in that paper merit a closer examination of this correlation. We re-analyzed the original data used in Miller and Goldmans study to investigate the relationship between vaccine doses and IMR. We show that the sub-sample of 30 countries used in the original paper was not a random sample from the entire dataset, as the correlation coefficient of 0.49 reported in that study would only arise about 1 in 100,000 times from random sampling. Next, we show IMR as a function of countries actual vaccination rates, rather than vaccination schedule, and show a strong negative correlation between vaccination rates and IMR. Finally, we analyze United States IMR data as a function of Hepatitis B vaccination rate to show an example of increased vaccination rates corresponding with reduced infant death over time. From our analyses, it is clear that vaccination does not predict higher IMR as previously reported.
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public and global health
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Understanding the cultural environment of the outpatient care setting for patients with dementia receiving cancer treatment: a qualitative study
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oncology
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Characterization of the Second Wave of COVID-19 in India
AO_SCPLOWBSTRACTC_SCPLOWThe second wave of COVID-19, which began around 11 February 2021, has hit India very hard with the daily cases reaching nearly triple the first peak value as on April 19, 2021. The epidemic evolution in India is quite complex due to regional inhomogeneities and the spread of several coronavirus mutants. In this paper, we characterize the virus spread in the ongoing second wave in India and its states until April 19, 2021, and also study the dynamical evolution of the epidemic from the beginning of the outbreak. Variations in the effective reproduction number (Rt) are taken as quantifiable measures of the virus transmissibility. Rt value for every state, including those with large rural populations, has value greater than the self-sustaining threshold of 1. An exponential fit on recent data also shows that the infection rate is much higher than the first wave. Subsequently, characteristics of the COVID-19 spread are analyzed regionwise, by estimating test positivity rates (TPRs) and case fatality rates (CFRs). Very high TPR values for several states present an alarming situation. CFR values are lower than those in the first wave but recently showing signs of increase as healthcare systems become over-stretched with the surge in infections. Preliminary estimates with a classical epidemiological model suggest that the peak for the second wave could occur around mid-May 2021 with daily count exceeding 0.4 million. The study strongly suggests that an effective administrative intervention is needed to arrest the rapid growth of the epidemic.
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epidemiology
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Development and validation of the MMCD score to predict kidney replacement therapy in COVID-19 patients
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infectious diseases
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Improving Machine Learning Prediction of ADHD Using Gene Set Polygenic Risk Scores and Risk Scores from Genetically Correlated Phenotypes
BackgroundPolygenic risk scores (PRSs), which sum the effects of SNPs throughout the genome to measure risk afforded by common genetic variants, have improved our ability to estimate disorder risk for Attention-Deficit/Hyperactivity Disorder (ADHD) but the accuracy of risk prediction is rarely investigated.
MethodsWith the goal of improving risk prediction, we performed gene set analysis of GWAS data to select gene sets associated with ADHD within a training subset. For each selected gene set, we generated gene set polygenic risk scores (gsPRSs), which sum the effects of SNPs for each selected gene set. We created gsPRS for ADHD and for phenotypes having a high genetic correlation with ADHD. These gsPRS were added to the standard PRS as input to machine learning models predicting ADHD. We used feature importance scores to select gsPRS for a final model and to generate a ranking of the most consistently predictive gsPRS.
ResultsFor a test subset that had not been used for training or validation, a random forest (RF) model using PRSs from ADHD and genetically correlated phenotypes and an optimized group of 20 gsPRS had an area under the receiving operating characteristic curve (AUC) of 0.72 (95% CI: 0.70 - 0.74). This AUC was a statistically significant improvement over logistic regression models and RF models using only PRS from ADHD and genetically correlated phenotypes.
ConclusionsSumming risk at the gene set level and incorporating genetic risk from disorders with high genetic correlations with ADHD improved the accuracy of predicting ADHD. Learning curves suggest that additional improvements would be expected with larger study sizes. Our study suggests that better accounting of genetic risk and the genetic context of allelic differences results in more predictive models.
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genetic and genomic medicine
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The Milano Sforza Registers
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epidemiology
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The impact of policy timing on the spread of COVID-19
We model COVID-19 data for 89 nations and US states with a recently developed formalism that describes mathematically any pattern of growth with the minimum number of parameters. The results show that the disease has a typical duration of 18 days, with a significant increase in fatality when it lasts longer than about 4 months. Searching for correlations between "flattening of the curve" and preventive public policies, we find strong statistical evidence for the impact of the first implemented policy on decreasing the pandemic growth rate; a delay of one week in implementation nearly triples the size of the infected population, on average. Without any government action, the initial outburst still slows down after 36 days, possibly thanks to changes in public behavior in response to the pandemic toll. Stay-at-home (lockdown) was not the first policy of any sample member and we do not find statistically meaningful evidence for its added impact, similar to a recent study that employed an entirely different approach. However, lockdown was mostly imposed only shortly before the exponential rise was arrested. The possibility remains that lockdown might have shortened significantly the initial exponential rise had it been employed as first, rather than last resort.
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epidemiology
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Digital technologies for monitoring and improving treatment adherence in children and adolescents with asthma: A scoping review of randomised controlled trials
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health informatics
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Assessment of Pharmacokinetic Interaction Potential Between Caffeine and Methylliberine
Methylliberine and theacrine are methylurates found in the leaves of various Coffea species and Camellia assamica var. kucha, respectively. We previously demonstrated that the methylxanthine caffeine increased theacrines oral bioavailability in humans. Consequently, we conducted a double-blind, placebo-controlled study pharmacokinetic study in humans administered methylliberine, theacrine, and caffeine to determine methylliberines pharmacokinetic interaction potential with either caffeine or theacrine. Subjects (n = 12) received an oral dose of either methylliberine (25 or 100 mg), caffeine (150 mg), methylliberine (100 mg) plus caffeine (150 mg), or methylliberine (100 mg) plus theacrine (50 mg) using a randomized, double-blind, crossover design. Blood samples were collected over 24 hours and analyzed for methylliberine, theacrine, and caffeine using UPLC-MS/MS. Methylliberine exhibited linear pharmacokinetics that were unaffected by co-administration of either caffeine or theacrine. However, methylliberine co-administration resulted in decreased oral clearance (41.9 {+/-} 19.5 vs. 17.1 {+/-} 7.80 L/hr) and increased half-life (7.2 {+/-} 5.6 versus 15 {+/-} 5.8 hrs) of caffeine. Methylliberine had no impact on caffeines maximum concentration (440 {+/-} 140 vs. 458 {+/-} 93.5 ng/mL) or oral volume of distribution (351 {+/-} 148 vs. 316 {+/-} 76.4 L). We previously demonstrated theacrine bioavailability was enhanced by caffeine, however, caffeine pharmacokinetics were unaffected by theacrine. Herein, we found that methylliberine altered caffeine pharmacokinetics without a reciprocal interaction, which suggests caffeine may interact uniquely with different methylurates. Understanding the mechanism(s) of interaction between methylxanthines and methylurates is of critical importance in light of the recent advent of dietary supplements containing both purine alkaloid classes.
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pharmacology and therapeutics
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Examining the experiences of Indigenous families seeking health information for their sick or injured child: a scoping review protocol
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pediatrics
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Performances of community pharmacists and community pharmacies during COVID-19 outbreak: a cross-sectional study
BackgroundCommunity pharmacists can play an important role in the management of coronavirus disease-19 (COVID-19) outbreak by providing pharmaceutical care and education services. In addition to providing drug-related services, community pharmacies must take measures to reduce the risk of COVID-19 transmission to customers and technicians in pharmacy. Therefore, a study was designed to assess community pharmacists performance and community pharmacies preparedness during COVID-19 outbreak.
Materials & MethodsA cross-sectional study was conducted in Kerman, Iran. A 20-item checklist consisting of nine items assessing the practice of pharmacists regarding use of personal protective equipment (PPE) and education of people about routes of transmission, prophylaxis and treatment of COVID-19 and eleven items evaluating the adherence of pharmacies to principles of reducing the risk of COVID-19 transmission in public places was used.
ResultsOf 95 enrolled pharmacists, 55 (57.9%) were female and 78.9% had work experience [≤] 10 years. More than 90% of pharmacists used appropriate PPE and provided information about medications for prevention and treatment of COVID-19 and routs of its transmission to the pharmacy customers. Phone consultation was done by 71.6% of pharmacists. Concerning the preparedness of pharmacies, 92% of personnel used PPE, and hand sanitizers were available in 89.5% of pharmacies. However, a clear sheet was not placed at counters in the majority of pharmacies, and home delivery services were not provided by most pharmacies.
ConclusionsThe practice of most community pharmacists was acceptable. However, stricter measures should be taken to diminish the probability of COVID-19 transmission in community pharmacies.
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health systems and quality improvement
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Understanding Convergence Between Non-Hispanic Black and White COVID-19 Mortality: A County-Level Approach
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health policy
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Systematic review and meta-analysis of the prevalence of coronavirus in the world: One health approach is urgent
Coronaviruses have been responsible for major epidemic crises in 2003 with SARS-CoV-1, in 2012 with MERS-CoV and in 2019 with SARS-CoV-2 (COVID-19), causing serious atypical pneumonia in humans. We intend, with this systematic analysis and meta-analysis, to clarify the prevalence of the various strains of coronavirus in different animal species. For this purpose, we carried out an electronic survey using Pubmeds Veterinary Science search tool to conduct a systematic assessment of published studies reporting the prevalence of different strains of coronavirus in different animal species between 2015 and 2020. We conducted different analysis to assess sensitivity, publication bias, and heterogeneity, using random and fixed effects. The final meta-analysis included 42 studies for systematic review and 29 in the meta-analysis. For the geographic regions with a prevalence greater than or equal to 0.20 (Forest plot overall; prevalence = 0.20, p < 0.01, Q = 10476.22 and I2 = 100%), the most commonly detected viruses were: enteric coronavirus (ECoV), pigeon-dominant coronavirus, (PdCoV), Avian coronavirus M41, Avian coronavirus C46, Avian coronavirus A99, Avian coronavirus JMK, MERS-CoV, Bovine coronavirus, Ro-BatCoV GCCDC1, Alphacoronavirus, Betacoronavirus, Deltacoronavirus, Gamacoronavirus and human coronaviruses (HCoVs). The wide presence of different strains of coronavirus in different animal species on all continents demonstrates the great biodiversity and ubiquity of these viruses.
The most recent epidemiological crises caused by coronavirus demonstrates our unpreparedness to anticipate and mitigate emerging risks, as well as the need to implement new epidemiological surveillance programs for viruses. Combined with the need to create advanced training courses in One Health, this is paramount in order to ensure greater effectiveness in fighting the next pandemics.
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public and global health
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Data Resource Profile: thousands of circulating RNA profiles of pre-clinical samples from the Janus Serum Bank Cohort
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epidemiology
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Plitidepsin has a positive therapeutic index in adult patients with COVID-19 requiring hospitalization.
Plitidepsin is a marine-derived cyclic-peptide that inhibits SARS-CoV-2 replication at low nanomolar concentrations by the targeting of host protein eEF1A (eukaryotic translation-elongation-factor-1A). We evaluated a model of intervention with plitidepsin in hospitalized COVID-19 adult patients where three doses were assessed (1.5, 2 and 2.5 mg/day for 3 days, as a 90-minute intravenous infusion) in 45 patients (15 per dose-cohort). Treatment was well tolerated, with only two Grade 3 treatment-related adverse events observed (hypersensitivity and diarrhea). The discharge rates by Days 8 and 15 were 56.8% and 81.8%, respectively, with data sustaining dose-effect. A mean 4.2 log10 viral load reduction was attained by Day 15. Improvement in inflammation markers was also noted in a seemingly dose-dependent manner. These results suggest that plitidepsin impacts the outcome of patients with COVID-19.
One-Sentence SummaryPlitidepsin, an inhibitor of SARS-Cov-2 in vitro, is safe and positively influences the outcome of patients hospitalized with COVID-19.
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infectious diseases
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Prevalence and source analysis of COVID-19 misinformation of 138 countries
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public and global health
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Predictors for participation in DNA self-sampling of childhood cancer survivors in Switzerland
Research on germline genetic variants relies on a sufficient number of eligible participants which is difficult to achieve for rare diseases such as childhood cancer. With self-collection kits using saliva or buccal swabs, participants can contribute genetic samples conveniently from their home. We identified determinants of participation in DNA self-collection in this cross-sectional study.
We invited 928 childhood cancer survivors in Switzerland with a median age of 26.5 years (interquartile range 18.8-36.5), of which 463 (50%) participated. Foreign nationality (odds ratio [OR] 0.5, 95%-confidence interval [CI] 0.4-0.7), survivors aged 30-39 years at study versus other age groups (OR 0.5, CI 0.4-0.8), and those with a known cancer predisposition syndrome (OR 0.5, CI 0.3-1.0) participated less. Survivors with a second primary neoplasm (OR 1.9, CI 1.0-3.8) or those living in a French or Italian speaking region (OR 1.3, 1.0-1.8) tended to participate more.
We showed that half of survivors participate in germline DNA self-sampling relying completely on mailing of sample kits. Foreign nationality, age 30-39 years, and cancer predisposition syndromes were associated with less participation. More targeted recruitment strategies may be advocated for these subgroups. To increase participation in DNA self-sampling, understanding and perceptions of survivors need to be better understood.
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genetic and genomic medicine
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Logistic Formula in Biology and Its Application to COVID-19 in Japan
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epidemiology
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Molecular network analyses implicate death-associated protein kinase 3 (DAPK3) as a key factor in colitis-associated dysplasia progression
Ulcerative colitis (UC) is a progressive disorder that elevates the risk of cancer development through a colitis-dysplasia-carcinoma sequence. Differential gene expression (DEGs) profiles of three UC clinical subtypes and healthy controls were developed for the GSE47908 microarray dataset [n = 15 (healthy controls), n = 20 (left-sided colitis), n = 19 (pancolitis), and n = 6 (colitis-associated dysplasia, CAD)] using limma R. Gene ontology (GO) enrichment analysis of DEGs revealed a shift in transcriptome landscape as UC progressed from left-sided colitis to pancolitis to CAD, from being immune-centric to being cytoskeleton-dependent. Hippo signaling (via Yes-associated protein, YAP) and Ephrin receptor signaling were the top canonical pathways progressively altered in concert with the pathogenic progression of UC. Molecular interaction network analysis of DEGs in left-sided colitis, pancolitis, and CAD revealed one pairwise line or edge that was topologically important to the network structure. This edge was found to be highly enriched in actin-based processes, and death-associated protein kinase 3 (DAPK3) was a critical member and sole protein kinase associated with this edge. DAPK3 is a regulator of actin-cytoskeleton reorganization that controls proliferation and apoptosis. Differential correlation analyses revealed a negative correlation for DAPK3-YAP in healthy controls which flipped to positive in left-sided colitis. With UC progression to CAD, the DAPK3-YAP correlation grew progressively more positive. In summary, DAPK3 was identified as a candidate gene involved in UC progression to dysplasia.
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gastroenterology
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A Randomized Trial of Wearable UV dosimeter for Skin Cancer Prevention
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dermatology
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Clinical and Virologic Factors associated with Outcomes of COVID-19 before and after Vaccination among Veterans: Retrospective Analysis from Six New England States
BackgroundA region-wide analysis of COVID-19 outcomes in New England has not been done. We aimed to characterize clinical, demographic, and vaccination status affecting COVID-19 clinical outcomes and describe viral epidemiology.
MethodsClinical variables of Veterans with COVID-19 in Veterans Administration healthcare systems in six New England states from April 8, 2020, to September 2, 2021 were correlated with outcomes of 30-day mortality, non-psychiatric hospitalization, intensive care unit admission (ICU-care), and post-vaccination infection. We sequenced 754 whole viral genomes and 197 partial genomes.
ResultsOf 4,170 Veterans with COVID-19, 81% were White, 8% women, mean age was 60.1 {+/-}17.7 years, and 2,399 became fully vaccinated. Overall, 19% Veterans needed hospitalization, 2.8% required ICU-care, and 3.7% died. Veterans with post-vaccination COVID-19 were older, with higher rates of tobacco/drug use, CKD, and malignancy, and 0.38% died. Among the unvaccinated, ICU-care and mortality correlated with age, while hospitalization correlated with age, male sex, black race, drug use, chronic heart disease, COPD, CKD, and chronic liver disease. Age, CKD, and alcohol use correlated with hospitalization in vaccinated patients.
Most New England Veterans (>97%) were infected with B.1 sub-lineages with the D614G mutation in 2020 and early 2021. B.1.617.2 lineage (71%) predominated after July 2021, including the post-vaccination infections.
ConclusionIn New England Veterans with mean age of 60 years, age and CKD significantly correlated with hospitalization regardless of vaccination-status. Age correlated with mortality and ICU-care among the unvaccinated. The Delta variant of SARS-CoV-2 (B.1.617.2) dominated post-vaccination infections.
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infectious diseases
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Insecticide resistance outpaces behavioural adaptation, as a response to Long-Lasting Insecticidal Net distribution, in malaria vectors in Burkina Faso
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infectious diseases
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Salzburg Visual Field Trainer (SVFT): A virtual reality device for (the evaluation of) neuropsychological rehabilitation
ObjectiveSo-called "Visual Restitution Therapies" (VRT) claim to ameliorate visual field defects of neurological patients by repeated visual light stimulation, leading to training-related neuroplasticity and resulting in reconnection of lesioned neurons in early cortical areas. Because existing systems are stationary, uncomfortable and unreliable, we developed a training instrument based on virtual reality goggles. The goal of the "Salzburg Visual Field Trainer" (SVFT) is twofold: (1) The device facilitates the clinical evaluation of established neuropsychological rehabilitation approaches, such as VRT. (2) The device enables patients to independently perform VRT based (or other) neuropsychological training methodologies flexibly, comfortably and reliably.
Methods and AnalysisThe SVFT was developed on the principles of VRT. Individual configuration of the SVFT is based on perimetric data of the respective patients visual field. To validate the utmost important procedure in neuropsychological rehabilitation methodologies - that is displaying stimuli precisely in desired locations in the users visual field - two steps were conducted in this proof-of-concept study: First, we assessed the individual "blind spots" location and extent of 40 healthy, normal sighted participants. This was done with the help of our recently developed and validated perimetric methodology "Eye Tracking Based Visual Field Analysis" (EFA). Second, depending on the individual characteristics of every participants blind spots, we displayed - with the help of the SVFT - 15 stimuli in the respective locations of every participants blind spots and 85 stimuli in the surrounding, fully intact visual area. The ratio between visible and non-visible stimuli, which reflects in the documented behavioral response (clicks on a remote control) of the 40 participants, provides insight into the accuracy of the SVFT to display training stimuli in areas desired by the investigator. As the blind spot is a naturally occurring, absolute scotoma in human vision, we utilized this blind area as an objective criterion and a "simulated" visual field defect to evaluate the (technical) methodology of SVFT.
ResultsOutcomes indicate that the SVFT and its methodology is highly accurate in displaying training stimuli in desired areas of the users visual field with an accuracy of 99.0%. Data analysis further shows a sensitivity of .980, specificity of .992, positive predictive value of .955, negative predictive value of .996, hit rate of .990, random hit rate of .742 and RATZ-Index of .976. This translates to 14.7% correct non-reactions, 0.7% false non-reactions, 0.3% false reactions and 84.3% correct reactions to displayed test stimuli during the evaluation study with the SVFT. Reports from participants further indicate that the SVFT is comfortable to wear and intuitive to use.
ConclusionsThe SVFT can help to investigate the true effects of VRT based methodologies (or other neuropsychological approaches) and the underlying mechanisms of training-related neuroplasticity in early regions of the visual cortex in neurological patients suffering from visual field defects.
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neurology
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Modelled Optimization of SARS-Cov-2 Vaccine Distribution: an Evaluation of Second Dose Deferral Spacing of 6, 12, and 24 weeks
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public and global health
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Preliminary Efficacy of the NVX-CoV2373 Covid-19 Vaccine Against the B.1.351 Variant
BackgroundThe emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants threatens progress toward control of the Covid-19 pandemic. Evaluation of Covid-19 vaccine efficacy against SARS-CoV-2 variants is urgently needed to inform vaccine development and use.
MethodsIn this phase 2a/b, multicenter, randomized, observer-blinded, placebo-controlled trial in South Africa, healthy human immunodeficiency virus (HIV)-negative adults (18 to 84 years) or medically stable people living with HIV (PLWH) (18 to 84 years) were randomized in a 1:1 ratio to receive two doses, administered 21 days apart, of either NVX-CoV2373 nanoparticle vaccine (5 {micro}g recombinant spike protein with 50 {micro}g Matrix-M1 adjuvant) or placebo. The primary endpoints were safety and vaccine efficacy [≥]7 days following the second dose against laboratory-confirmed symptomatic Covid-19 in previously SARS-CoV-2 uninfected participants.
ResultsA total of 4387 participants were randomized and dosed at least once, 2199 with NVX-CoV2373 and 2188 with placebo. Approximately 30% of participants were seropositive at baseline. Among 2684 baseline seronegative participants (94% HIV-negative; 6% PLWH), there were 15 and 29 predominantly mild to moderate Covid-19 cases in NVX-CoV2373 and placebo recipients, respectively; vaccine efficacy was 49.4% (95% confidence interval [CI]: 6.1 to 72.8). Efficacy in HIV-negative participants was 60.1% (95% CI: 19.9 to 80.1), and did not differ by baseline serostatus. Of the primary endpoint cases with available whole genome sequencing, 38 (92.7%) of 41 were the B.1.351 variant. Post-hoc vaccine efficacy against B.1.351 was 51.0% (95% CI: - 0.6 to 76.2) in HIV-negative participants. Among placebo recipients, the incidence of symptomatic Covid-19 was similar in baseline seronegative vs baseline seropositive participants during the first 2 months of follow-up (5.3% vs 5.2%). Preliminary local and systemic reactogenicity were primarily mild to moderate and transient, and higher with NVX-CoV2373; serious adverse events were rare in both groups.
ConclusionsThe NVX-CoV2373 vaccine was efficacious in preventing Covid-19, which was predominantly mild to moderate and due to the B.1.351 variant, while evidence of prior infection with the presumptive original SARS-CoV-2 did not confer protection against probable B.1.351 disease. (Funded by Novavax, The Bill and Melinda Gates Foundation, and the Coalition for Epidemic Preparedness Innovations; ClinicalTrials.gov number, NCT04533399)
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infectious diseases
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Time-Varying Death Risk After SARS-CoV-2-Infection in Swedish Long-Term Care Facilities
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infectious diseases
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Genetic support of a causal relationship between Iron status and atrial fibrillation: a Mendelian randomization study
BackgroundAtrial fibrillation is the most common arrhythmia disease.Animal and observational studies have found a link between iron status and atrial fibrillation. However, the causal relationship between iron status and the risk of atrial fibrillation may be biased by confounding and reverse causality.The purpose of this investigation was to use Mendelian randomization (MR) analysis, which has been widely appied to estimate the causal effect,to reveal whether systemic iron status was causally related to atrial fibrillation.
MethodsSingle nucleotide polymorphisms (SNPs) strongly associated (P < 5x10-8) with four biomarkers of systemic iron status were obtained from a genome-wide association study involving 48,972 subjects conducted by the Genetics of Iron Status consortium.
Summary-level data for the genetic associations with atrial fibrillation were acquired from AFGen (Atrial Fibrillation Genetics) consortium study(including 65,446 atrial fibrillation cases and 522,744 controls). We used a two-sample MR analysis to obtain a causal estimate, and further verified credibility through sensitivity analysis.
ResultsGenetically instrumented serum iron [OR:1.09;95%; confidence interval (CI)1.02-1.16; p=0.01], ferritin [OR:1.16;95%CI:1.02-1.33; p=0.02], and transferrin saturation [OR:1.05;95%CI:1.01-1.11; p=0.01] had positive effects on atrial fibrillation. Genetically instrumented transferrin levels [OR:0.90;95%CI:0.86-0.97; p=0.006] was an inverse correlation with atrial fibrillation.
ConclusionIn conclusion,our results strongly elucidated a causal link between genetically determined higher iron status and increased the risk of atrial fibrillation.This provided new ideas for clinical prevention and treatment of atrial fibrillation.
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cardiovascular medicine
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Early detection of acute kidney injury in critically ill children: Predictive value of renal arterial Doppler assessment
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pediatrics
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The Missing Link: A Closed Form Solution to the Kermack and McKendrick Model Equations
Susceptible-infectious-recovered (SIR) models are widely used for estimating the dynamics of epidemics. Such models project that containment measures "flatten the curve", i.e., reduce but delay the peak in daily infections, cause a longer epidemic, and increase the death toll. These projections have entered common understanding; individuals and governments often advocate lifting containment measures such as social distancing to shift the peak forward, limit societal and economic disruption, and reduce mortality. It was, then, an extraordinary surprise to discover that COVID-19 pandemic data exhibit phenomenology opposite to the projections of SIR models. With the knowledge that the commonly used SIR equations only approximate the original equations developed to describe epidemics, we identified a closed form solution to the original epidemic equations. Unlike the commonly used approximations, the closed form solution replicates the observed phenomenology and quantitates pandemic dynamics with simple analytical tools for policy makers. The complete solution is validated using independently measured mobility data and accurately predicts COVID-19 case numbers in multiple countries.
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epidemiology
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Antibody and memory B-cell immunity in a heterogeneously SARS-CoV-2 infected and vaccinated population
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infectious diseases
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RPE65-related retinal dystrophy: mutational and phenotypic spectrum in 44 affected patients.
BackgroundBiallelic pathogenic RPE65 variants are related to a spectrum of clinically overlapping inherited retinal dystrophies (IRD). Most affected individuals show a severe progression, with 50% of patients legally blind by 20 years of age. A better knowledge of the mutational spectrum and the phenotype-genotype correlation in RPE65-related IRD is needed.
MethodsForty-five affected subjects from 27 unrelated families with a clinical diagnosis of RPE65-related IRD were included. Clinical evaluation consisted on self-reported ophthalmological history and objective ophthalmological examination. Patients genotype was classified accordingly to variant class (truncating or missense) or to variant location at different protein domains. Main phenotypic outcome was age at onset (AAO) of the symptomatic disease and a Kaplan-Meier analysis of disease symptom event-free survival was performed.
ResultsTwenty-nine different RPE65 variants were identified in our cohort, 7 of them novel. Most frequent variants were p.(Ile98Hisfs*26), p.(Pro111Ser) and p.(Gly187Glu) accounting for the 24% of the detected alleles. Patients carrying two missense alleles showed a later disease onset than those with 1 or 2 truncating variants (Log Rank test p<0.05). While the 60% of patients carrying a missense/missense genotype presented symptoms before or at the first year of life, almost all patients with at least 1 truncating allele (91%) had an AAO [≤]1 year (p<0.05).
ConclusionOur findings suggest an association between the type of the RPE65 carried variant and the AAO. Thus, our results provide useful data on RPE65-associated IRD phenotypes which may help to improve clinical and therapeutic management of these patients.
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genetic and genomic medicine
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Analysis of COVID-19 infection amongst healthcare workers in Rivers State, Nigeria
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public and global health
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Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England
A novel SARS-CoV-2 variant, VOC 202012/01 (lineage B.1.1.7), emerged in southeast England in November 2020 and is rapidly spreading towards fixation. Using a variety of statistical and dynamic modelling approaches, we estimate that this variant has a 43-90% (range of 95% credible intervals 38-130%) higher reproduction number than preexisting variants. A fitted two-strain dynamic transmission model shows that VOC 202012/01 will lead to large resurgences of COVID-19 cases. Without stringent control measures, including limited closure of educational institutions and a greatly accelerated vaccine roll-out, COVID-19 hospitalisations and deaths across England in 2021 will exceed those in 2020. Concerningly, VOC 202012/01 has spread globally and exhibits a similar transmission increase (59-74%) in Denmark, Switzerland, and the United States.
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epidemiology
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IgG N-glycans are associated with prevalent and incident complications of type 2 diabetes
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cardiovascular medicine
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Monitoring the propagation of SARS CoV2 variants by tracking identified mutation in wastewater using specific RT-qPCR
Since the end of 2020, the COVID-19 pandemic has experienced a major turning point with the appearance and rapid spread of new variants, causing a significant increase in the number of new cases requiring hospitalization. These so-called UK, South African or Brazilian variants are characterized by combinations of mutations which allow them to be distinguished from the variants which have circulated since the start of the epidemic. The impact of these variants on the functioning of healthcare systems requires monitoring the spread of these variants, which are more contagious, more lethal and may reinfect people who are already immune to a natural infection or to a vaccination. Monitoring the viral genome in wastewater has shown great value in early detection of the dynamics of virus spreading in populations.
The sequencing of viral genomes is used in humans, but its application and interpretation on wastewater matrices are much more complex due to the diversity of circulating strains. Also this study demonstrates the possibility of following certain mutations found in these new variants by targeted RT-qPCR. This study is the first carried out in France demonstrating the spreading dynamics of the 69-70 deletion in the Spike protein of SARS-CoV-2.
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infectious diseases
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"At that moment, understanding the donation is crucial to make a decision": A qualitative study exploring the process of postmortem brain tissue donation after suicide
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psychiatry and clinical psychology
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Immunity to COVID-19 in India through vaccination and natural infection
In India, Corona Virus-2 Disease-2019 (COVID-19) continues to this day, although with subdued intensity, following two major waves of viral infection. Despite ongoing vaccination drives to curb the spread of COVID-19, the potential of the administered vaccines to render immune protection to the general population, and how this compares with the immune potential of natural infection remain unclear. In this study we examined correlates of immune protection (humoral and cell mediated) induced by the two vaccines Covishield and Covaxin, in individuals living in and around Kolkata, India. Additionally, we compared the vaccination induced immune response profile with that of natural infection, evaluating thereby if individuals infected during the first wave retained virus specific immunity. Our results indicate that while Covaxin generates better cell-mediated immunity toward the Delta variant of SARS-CoV-2 than Covishield, Covishield is more effective than Covaxin in inducing humoral immunity. Both Covishield and Covaxin, however, are more effective toward the wild type virus than the Delta variant. Moreover, the overall immune response resulting from natural infection in and around Kolkata is not only to a certain degree better than that generated by vaccination, especially in the case of the Delta variant, but cell mediated immunity to SARS-CoV-2 also lasts for at least ten months after the viral infection.
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epidemiology
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Are fast test results preferable to high test sensitivity in contact-tracing strategies?
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infectious diseases
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Spatial frequency discrimination in patients with schizophrenia spectrum and bipolar disorders: Evidence of early visual processing deficits and associations with intellectual abilities
ObjectiveLow-level sensory disruption is hypothesized as a precursor to clinical and cognitive symptoms in severe mental disorders. We compared visual discrimination performance in patients with schizophrenia spectrum disorder or bipolar disorder with healthy controls, and investigated associations with clinical symptoms and IQ.
MethodsPatients with schizophrenia spectrum disorder (n=32), bipolar disorder (n=55) and healthy controls (n=152) completed a computerized visual discrimination task. Participants responded whether the latter of two consecutive grids had higher or lower spatial frequency, and discrimination thresholds were estimated using an adaptive maximum likelihood procedure. Case-control differences in threshold were assessed using linear regression, F-test and post-hoc pair-wise comparisons. Linear models were used to test for associations between visual discrimination threshold and psychotic symptoms derived from the PANSS and IQ assessed using the Matrix Reasoning and Vocabulary subtests from the Wechsler Abbreviated Scale of Intelligence (WASI).
ResultsRobust regression revealed a significant main effect of diagnosis on discrimination threshold (robust F=6.76, p=.001). Post-hoc comparisons revealed that patients with a schizophrenia spectrum disorder (mean=14%, SD=0.08) had higher thresholds compared to healthy controls (mean=10.8%, SD = 0.07, {beta} = 0.35, t=3.4, p=0.002), as did patients with bipolar disorder (12.23%, SD=0.07, {beta}= 0.21, t=2.42, p=0.04). There was no significant difference between bipolar disorder and schizophrenia ({beta}=-0.14, t=-1.2, p=0.45). Linear models revealed negative associations between IQ and threshold across all participants when controlling for diagnostic group ({beta} = -0.3, t=-3.43, p=0.0007). This association was found within healthy controls (t=-3.72, p=.0003) and patients with bipolar disorder (t=-2.53, p=.015), and no significant group by IQ interaction on threshold (F=0.044, p=.97). There were no significant associations between PANSS domain scores and discrimination threshold.
ConclusionPatients with schizophrenia spectrum or bipolar disorders exhibited higher visual discrimination thresholds than healthy controls, supporting early visual deficits among patients with severe mental illness. Discrimination threshold was negatively associated with IQ among healthy controls and bipolar disorder patients. These findings elucidate perception-related disease mechanisms in severe mental illness, which warrants replication in independent samples.
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psychiatry and clinical psychology
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HbA1c measurements from UK Biobank are different to those in linked primary care records: implications for combining biochemistry data from research studies and routine clinical care
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epidemiology
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Humoral response to Pfizer mRNA vaccine against SARS CoV2, in patients with autoimmune inflammatory rheumatic diseases and the impact on the rheumatic disease activity
BackgroundThe registration trials of mRNA vaccines against SARS CoV2 did not address patients with autoimmune inflammatory rheumatoid diseases (AIRD).
AimsTo assess the humoral response to mRNA vaccine against SARS CoV2, in AIRD patients treated with immunomodulating drugs and the impact on AIRD activity.
MethodsConsecutive patients treated at the rheumatology institute who received their first SARS-CoV-2 (Pfizer) vaccine were recruited to the study, at their routine visit. The patients were invited for serology test 4-6 weeks after receiving the second dose of vaccine. IgG Antibodies (Ab) against SARS COV2 virus were detected using the SARS-Cov-2 IgG II Quant (Abbott) assay
ResultsOne hundred fifty-six consecutive patients (76% females) treated at a single rheumatology center (mean age (range) 59.1 (21-83) years), mean (range) disease duration 10.8 (1-55) years), were recruited to the study. Thirty-five percents of patients received conventional synthetic (cs)DMARDs only, 64% biological/targeted synthetic (b/ts) DMARDs, 34% received combined treatment with csDMARDs and b/tsDMARDs and 32% corticosteroids (mean dose(range) 5.8mg(2.5-20mg) prednisone). One hundred thirty-seven patients (88%) were seropositive for IgG Ab against SARS CoV2 virus (median 2832.5 AU/ml, range 58-29499). Nineteen (12%) patients had negative tests, 11/19 were treated with B cell depleting agents. The reported side effects of the vaccine were minor (muscle sore, headache, low grade fever). The rheumatic disease remained stable in all patients.
ConclusionsThe vast majority of AIRD patients developed a significant humoral response following the administration of the second dose of the Pfeizer mRNA vaccine against SARS CoV2 virus. Only minor side effects were reported and no apparent impact on AIRD activity was noted.
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rheumatology
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SARS-CoV-2 antibodies rapid tests: a valuable epidemiological tool in challenging settings
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infectious diseases
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Was R<1 before the English lockdowns? On modelling mechanistic detail, causality and inference about Covid-19
Detail is a double edged sword in epidemiological modelling. The inclusion of mechanistic detail in models of highly complex systems has the potential to increase realism, but it also increases the number of modelling assumptions, which become harder to check as their possible interactions multiply. In a major study of the Covid-19 epidemic in England, Knock et al. (2020) fit an age structured SEIR model with added health service compartments to data on deaths, hospitalization and test results from Covid-19 in seven English regions for the period March to December 2020. The simplest version of the model has 684 states per region. One main conclusion is that only full lockdowns brought the pathogen reproduction number, R, below one, with R >> 1 in all regions on the eve of March 2020 lockdown. We critically evaluate the Knock et al. epidemiological model, and the semi-causal conclusions made using it, based on an independent reimplementation of the model designed to allow relaxation of some of its strong assumptions. In particular, Knock et al. model the effect on transmission of both non-pharmaceutical interventions and other effects, such as weather, using a piecewise linear function, b(t), with 12 breakpoints at selected government announcement or intervention dates. We replace this representation by a smoothing spline with time varying smoothness, thereby allowing the form of b(t) to be substantially more data driven, and we check that the corresponding smoothness assumption is not driving our results. We also reset the mean incubation time and time from first symptoms to hospitalisation, used in the model, to values implied by the papers cited by Knock et al. as the source of these quantities. We conclude that there is no sound basis for using the Knock et al. model and their analysis to make counterfactual statements about the number of deaths that would have occurred with different lockdown timings. However, if fits of this epidemiological model structure are viewed as a reasonable basis for inference about the time course of incidence and R, then without very strong modelling assumptions, the pathogen reproduction number was probably below one, and incidence in substantial decline, some days before either of the first two English national lockdowns. This result coincides with that obtained by more direct attempts to reconstruct incidence. Of course it does not imply that lockdowns had no effect, but it does suggest that other non-pharmaceutical interventions (NPIs) may have been more effective than Knock et al. imply, and that full lockdowns were probably not the cause of R dropping below one.
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epidemiology
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Predictive power of SARS-CoV-2 wastewater surveillance for diverse populations across a large geographical range
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epidemiology
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PCR Testing in the UK During the SARS-CoV-2 Pandemic - Evidence from FOI Requests
Polymerase Chain Reaction ("PCR") tests have been used to identify cases of COVID-19 during the course of the pandemic. Notably, PCR alone cannot differentiate between the presence of whole viruses (which can be transmitted and infect individuals) and small fragments of genetic material that are not infectious. A feature of PCR known as the cycle threshold (Ct) can be used to discriminate between these states, but the relationship between Ct and infectiousness is still poorly understood.
This well-known limitation of the test compromises the identification of cases and their trends, and consequently those measures to interrupt transmission (such as isolation) that are undertaken on the basis of reliably identifying infectious individuals.
Here, we interrogate the public authorities understanding of PCR testing for SARS-CoV-2 in the UK by accessing Freedom of Information requests submitted in 2020-21.We searched WhatDoTheyKnow and found 300 FOI requests, from over 150 individuals. We grouped their questions into four themes addressing the number of tests in use, the reporting of cycle thresholds ( Ct), the Ct values themselves, and the accuracy of tests.
The number of validated tests in use in the UK is currently not clear: In FOI responses, Public Health England (PHE) report it may be "80" or "85". However, European regulations suggest there could be over 400 different CE marked tests available on the market and available for use. Laboratories have a statutory duty to report positive cases to PHE, but they do not have to advise which tests they are using nor submit Ct values. Only two FOI responses provided answers on Ct values, indicating that in a set time span, 24-38% of the Ct values were over 30. The most common FOI asked if there was a cycle threshold for positivity. In those that responded, the Ct for a positive result varied from 30 to 45. We found limited information on the technical accuracy of the tests. Several responses stated there is no static, specific or standard cycle threshold.
The current system requires significant changes to ensure it offers accurate diagnostic data to enable effective clinical management of SARS-CoV-2. PCR is an important and powerful tool, but its systematic misuse and misreporting risk undermining its usefulness and credibility.
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public and global health
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The role of alternative splicing in CEP290-related disease pathogenesis
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genetic and genomic medicine
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Altered immunity to microbiota, B cell activation and depleted γδ / resident memory T cells in colorectal cancer
We sought methods of rectifying microbiota:immune dysregulation as a route to prophylaxis and improved immunotherapy of colorectal cancer (CRC). CRC develops in gut epithelium, accompanied by low level inflammatory signaling, intestinal microbial dysbiosis and immune dysfunction. We examined populations of intraepithelial lymphocytes in non-affected colonic mucosa of CRC and healthy donors and circulating immune memory to commensal bacterial species and yeasts. Colonic tissue in CRC was significantly depleted of {gamma}{delta} T cells and resident memory T cells, populations with a regulatory CD39-expressing phenotype. T cell memory responses to a panel of commensals were distinct in CRC, while B cell memory responses to several bacteria/yeast were significantly increased, accompanied by increased proportions of effector memory B cells, transitional B cells and plasmablasts in blood. IgA responses to mucosal microbes were unchanged. Our data describe a novel immune signature with similarities to and differences from that of inflammatory bowel disease. They implicate B cell dysregulation as a potential contributor to parainflammation and identify pathways of weakened barrier function and tumor surveillance in CRC-susceptible individuals.
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gastroenterology
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Salicylic acid and risk of colorectal cancer: a two sample Mendelian randomization study
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epidemiology
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Three-dimensional cranio-facial landmark detection in CT slices from a publicly available database, using multi-phased regression networks on a personal computer.
AimGeometrical assessments to comprehend the shape of an object are done based on characteristic landmarks. Computer assisted tomography (CT) images, horizontal slices as two-dimensional pictures, can be digitally restructured into virtual three-dimensional objects. Automatic detection of the landmarks, if developed, will be a great help not only medically, but also for anthropologically. The aim of this study is to develop an automated system to predict three-dimensional coordinate values of cranio-facial landmarks in sequences of CT slices.
MethodsCT images were obtained from a publicly available database. Digital reconstruction was done to obtain three dimensional models. Sixteen landmarks were plotted on the models and coordinate values of them were recorded. Multi-phased deep learning system was constructed. For the first phase, 512 x 512 pixels images were resized to 96 x 96 pixels. A regression deep learning network was trained with 90 training data. For the second phase, for each landmark, 100 x 100 pixels images were cropped from the original images. Sixteen models were trained. For the third phase, 50 x 50 pixels images were cropped, and models were trained.
ResultsThree-dimensional error for the first phase, testing 30 data, was 11.60 pixels in average. (1 pixel = 500 / 512 mm) For the second phase, it was significantly improved to 4.66 pixels. For the third phase, it was significantly progressed to 2.89. This was comparable to the gaps between the landmarks, plotted by two experienced practitioners.
DiscussionThe calculation volume required to process three-dimensional pile of images is tremendous. One solution may be to compress the images, but detailed information may be lost during the process. Our proposing method of multi-phased prediction, coarse detection first and narrowing down the detection area, may be a possible solution, within the physical limitation of memory and computation.
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radiology and imaging
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Genetic analysis of lung cancer reveals novel susceptibility loci and germline impact on somatic mutation burden
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genetic and genomic medicine
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Genetic variation of IFNL4 is associated with COVID-19
COVID-19 currently represents a major public health problem. The causes that underlying susceptibility to infection in have not yet been determined. Interferons (IFNs) are intensively being investigated because of their antiviral properties. Among them, Interferon lambda 4 (IFNL4) has been reported to have antiviral activity against viral infections of the upper respiratory tract, Hepatitis virus C (HCV), and coronaviruses. The importance of this cytokine was shown by the fact that genetic variants of IFNL4 have been associated with viral clearance and response to IFNs-based therapies in HCV and other infections by RNA virus. In this study, we have investigated whether the rs12979860 polymorphism within the IFNL4 was also associated with COVID-19. Our findings show that the presence of the CC allele of rs12979860 was significantly lower in SARS-CoV-2 infected patients with regard to non-COVID-19 controls (38% vs 55%, p<0001). These results were not affected by sex, age, and severity of disease. These findings suggest that the CC allele may also confer protection against COVID-19. They may contribute to understanding the mechanisms of disease, the response to IFN-based treatments, and the racial differences observed in the disease.
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infectious diseases
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Nanomechanical and molecular characterization of aging in dentinal collagen
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dentistry and oral medicine
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Cardiovascular disease and all-cause mortality risk prediction from abdominal CT using deep learning
Cardiovascular disease is the number one cause of mortality worldwide. Risk prediction can help incentivize lifestyle changes and inform targeted preventative treatment. In this work we explore utilizing a convolutional neural network (CNN) to predict cardiovascular disease risk from abdominal CT scans taken for routine CT colonography in otherwise healthy patients aged 50-65. We find that adding a variational autoencoder (VAE) to the CNN classifier improves its accuracy for five year survival prediction (AUC 0.787 vs. 0.768). In four-fold cross validation we obtain an average AUC of 0.787 for predicting five year survival and an AUC of 0.767 for predicting cardiovascular disease. For five year survival prediction our model is significantly better than the Framingham Risk Score (AUC 0.688) and of nearly equivalent performance to method demonstrated in Pickhardt et al. (AUC 0.789) which utilized a combination of five CT derived biomarkers.
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radiology and imaging
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Function is more reliable than quantity to follow up the humoral response to the Receptor Binding Domain of SARS- CoV-2 Spike Protein after Natural Infection or COVID-19 vaccination
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infectious diseases
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Towards definitions of critical illness and critical care using concept analysis
ObjectiveAs "critical illness" and "critical care" lack consensus definitions, this study aims to explore how the concepts are used, describe their defining attributes and propose potential definitions.
DesignWe used the Walker and Avant stepwise approach to concept analysis. The uses and definitions of the concepts were identified through a scoping review of the literature and an online survey of 114 global clinical experts. Through content analysis of the data we extracted codes, categories and themes to determine the concepts defining attributes and we proposed potential definitions. To assist understanding, we present model, related and contrary cases concerning the concepts, we identified antecedents and consequences to the concepts, and defined empirical referents.
ResultsThe defining attributes of critical illness were a high risk of imminent death; vital organ dysfunction; requirement for care to avoid death; and potential reversibility. The defining attributes of critical care were the identification, monitoring and treatment of critical illness; vital organ support; initial and sustained care; any care of critical illness; and specialized human and physical resources. Our proposed definition of critical illness is, "a state of ill health with vital organ dysfunction, a high risk of imminent death if care is not provided and the potential for reversibility". Our proposed definition of critical care is, "the identification, monitoring and treatment of patients with critical illness through the initial and sustained support of vital organ functions."
ConclusionThe concepts critical illness and critical care lack consensus definitions and have varied uses. Through concept analysis of uses and definitions in the literature and among experts we have identified the defining attributes of the concepts and propose definitions that could aid clinical practice, research, and policy making.
Strengths and Limitations of the StudyO_LIThis concept analysis is the first study to systematically describe the uses and definitions of the concepts critical illness and critical care
C_LIO_LIThe study uses a scoping review of the literature and input from over one hundred clinical experts from diverse settings globally to identify the defining attributes and provide proposed definitions of the concepts
C_LIO_LISome uses and definitions of the concepts in languages other than English, in unpublished grey literature and from clinical experts not included in the study may have been missed
C_LIO_LIAs current usage of the concepts is diverse, the proposed definitions may not be universally accepted and are aimed to stimulate further discussion
C_LI
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intensive care and critical care medicine
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SARS-CoV-2 reinfections with BA.1 (Omicron) variant among fully vaccinated individuals in the northeast of Brazil
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infectious diseases
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Identifying Bipolar patients from controls, using post- mortem cerebellum gene expression data and fully Automated Machine Learning
ObjectiveComplex machine learning classification algorithms using transcriptome data from post-mortem cerebellar tissue of bipolar patients and unaffected controls, have been recently included in pipelines for patient - control classification and identification of characteristic biomarkers. Transcriptomic profile differences between patients and controls, can provide useful information about the role of the cerebellum in the pathogenesis of bipolar disorder and mood deregulation and in normal mood regulation and physiology. User-friendly, fully automated machine learning algorithms, using data extracted from established repositories, could achieve extremely high classification scores and disease-related predictive biomarker identification, in very short time frames and scaled down to small datasets, thus facilitating research on mood disorders.
MethodAn application of a fully automated machine learning platform, based on the most suitable algorithm selection and relevant set of hyper-parameter values, for classification between patients and controls and the production of models for biosignature selection, is presented. Transcriptome data used for the analysis were downloaded from the BioDataome preprocessed datasets database. The Dataome dataset, derived from the parent Gene Expression Omnibus GSE35974 (2013) and GSE35978 datasets, which have been originally produced from the cerebellar and parietal lobe tissue of deceased bipolar patients and unaffected controls, (from the Stanley Medical Research Institutes Neuropathology Consortium and Array collections), using Affymetrix Human Gene 1.0 ST Array. Patient and control groups were closely matched for age and sex.
ResultsBipolar patients have been identified from controls based on the cerebellar transcriptomic profile with AUC 0.929 and Average Precision 0.955. Patients and Controls have been classified in two separated groups with no close-to-the-boundary cases. Using 6 of the characteristic features discovered during the selection process, 99,6% classification accuracy was achieved. The three biomarkers contributing most to the predictive power of the model (92,7%), are also deregulated in temporal lobe epilepsy.
ConclusionThe cerebellar transcriptome of bipolar patients has a discrete profile and can be used for further exploration of the role of this area in health and disease.
93% AUC and 96% Precision were achieved during classification between unaffected controls and patients with Bipolar Disorder.
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psychiatry and clinical psychology
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Presence of SARS-CoV-2 in food surfaces and public space surfaces in 3 districts of Lima, Peru.
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public and global health
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Strength and durability of antibody responses to BNT162b2 and CoronaVac
We studied 2780 adults in Hong Kong who received CoronaVac inactivated virus vaccine (Sinovac) and BNT162b2 mRNA vaccine ("Comirnaty", BioNTech/Fosun Pharma). We found stronger and more durable antibody responses to two doses of the mRNA vaccine, and slightly stronger initial antibody responses to each vaccine in younger adults and women.
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infectious diseases
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Interventions designed to improve vaccination uptake: Scoping review of systematic reviews and meta-analyses - (version 1)
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infectious diseases
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Association of Sleep Behaviors with Risk of Esophageal Cancer
IMPORTANCEEsophageal cancer is among the most lethal type of cancers worldwide. However, risk factors contributing to more than tenfold increase in esophageal cancer in the last 50 years remain underexplored.
OBJECTIVEThis study aimed to examine the associations between sleep behaviors and esophageal cancer overall, by histology, and according to genetic predispositions.
DESIGNA prospective cohort study.
SETTINGA population-based study.
PARTICIPANTSA total of 410,428 participants aged 37-73 years at enrollment between 2006 and 2010 in the UK Biobank were followed up until March 31st, 2016 for England and Wales and October 31st, 2015 for Scotland.
MAIN OUTCOME AND MEASUREThe risk of incident esophageal cancer.
RESULTSDuring 2,799,342 person-years of follow-up, 410 incident esophageal cancer cases (294 adenocarcinomas) were diagnosed. Evening chronotype, sleep <6 or >9 h/day, daytime napping, and daytime sleepiness were significantly associated with increased risk of esophageal cancer in age-adjusted models and had a Plikelihood ratio test [≤]0.20 after multivariable adjustment. Compared with the group without these high-risk behaviors, participants with one high-risk behavior had a 41% (HR=1.41, 95%CI: 1.13, 1.77) increased risk of esophageal cancer, and those with two or more behaviors showed a 79% higher risk (HR=1.79, 95%CI: 1.32, 2.42) (Ptrend<0.001). These associations were largely driven by esophageal adenocarcinoma (Ptrend<0.001) but not squamous cell carcinoma (Ptrend=0.340). The elevated risks for esophageal adenocarcinoma were similar within strata of PRS quintiles (Pinteraction=0.791).
CONCLUSION AND RELEVANCEUnhealthy sleep behaviors were associated with an increased risk of esophageal cancer, primarily adenocarcinoma, independent of genetic risk. Sleep behaviors may serve as modifiable factors for the prevention of esophageal cancer, particularly esophageal adenocarcinomas.
Key PointsO_ST_ABSQuestionC_ST_ABSAre sleep behaviors associated with the risk of esophageal cancer?
FindingsIn this prospective cohort study that included 410,428 participants in the UK Biobank, evening chronotype, sleep <6 or >9 h/day, daytime napping, and sleepiness were associated with increased risk of esophageal cancer. A greater number of these unhealthy sleep behaviors was associated with a higher risk of esophageal cancer. The elevated risks were primarily observed for esophageal adenocarcinoma and were independent of genetic risk.
MeaningSleep behaviors may serve as modifiable factors for the esophageal cancer prevention, particularly esophageal adenocarcinoma, independent of genetic risk.
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epidemiology
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Single-dose mRNA vaccine effectiveness against SARS-CoV-2, including P.1 and B.1.1.7 variants: a test-negative design in adults 70 years and older in British Columbia, Canada
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infectious diseases
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Impact of Vaccine Prioritization Strategies on Mitigating COVID-19: An Agent-Based Simulation Study using an Urban Region in the United States
BackgroundApproval of novel vaccines for COVID-19 had brought hope and expectations, but not without additional challenges. One central challenge was understanding how to appropriately prioritize the use of limited supply of vaccines. This study examined the efficacy of the various vaccine prioritization strategies using the vaccination campaign underway in the U.S.
MethodsThe study developed a granular agent-based simulation model for mimicking community spread of COVID-19 under various social interventions including full and partial closures, isolation and quarantine, use of face mask and contact tracing, and vaccination. The model was populated with parameters of disease natural history, as well as demographic and societal data for an urban community in the U.S. with 2.8 million residents. The model tracks daily numbers of infected, hospitalized, and deaths for all census age-groups. The model was calibrated using parameters for viral transmission and level of community circulation of individuals. Published data from the Florida COVID-19 dashboard was used to validate the model. Vaccination strategies were compared using a hypothesis test for pairwise comparisons.
ResultsThree prioritization strategies were examined: a minor variant of CDCs recommendation, an age-stratified strategy, and a random strategy. The impact of vaccination was also contrasted with a no vaccination scenario. The study showed that the campaign against COVID-19 in the U.S. using vaccines developed by Pfizer/BioNTech and Moderna 1) reduced the cumulative number of infections by 10% and 2) helped the pandemic to subside below a small threshold of 100 daily new reported cases sooner by approximately a month when compared to no vaccination. A comparison of the prioritization strategies showed no significant difference in their impacts on pandemic mitigation.
ConclusionsEven though vaccines for COVID-19 were developed and approved much quicker than ever before, their impact on pandemic mitigation was small as the explosive spread of the virus had already infected a significant portion of the population, thus reducing the susceptible pool. A notable observation from the study is that instead of adhering strictly to a sequential prioritizing strategy, focus should perhaps be on distributing the vaccines among all eligible as quickly as possible, after providing for the most vulnerable. As much of the population worldwide is yet to be vaccinated, results from this study should aid public health decision makers in effectively allocating their limited vaccine supplies.
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epidemiology
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Enrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders
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neurology
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Quantifying representativeness in randomized clinical trials using machine learning fairness metrics
ObjectiveWe formulate population representativeness of randomized clinical trials (RCTs) as a machine learning (ML) fairness problem, derive new representation metrics, and deploy them in visualization tools which help users identify subpopulations that are underrepresented in RCT cohorts with respect to national, community-based or health system target populations.
Materials and MethodsWe represent RCT cohort enrollment as random binary classification fairness problems, and then show how ML fairness metrics based on enrollment fraction can be efficiently calculated using easily computed rates of subpopulations in RCT cohorts and target populations. We propose standardized versions of these metrics and deploy them in an interactive tool to analyze three RCTs with respect to type-2 diabetes and hypertension target populations in the National Health and Nutrition Examination Survey (NHANES).
ResultsWe demonstrate how the proposed metrics and associated statistics enable users to rapidly examine representativeness of all subpopulations in the RCT defined by a set of categorical traits (e.g., sex, race, ethnicity, smoker status, and blood pressure) with respect to target populations.
DiscussionThe normalized metrics provide an intuitive standardized scale for evaluating representation across subgroups, which may have vastly different enrollment fractions and rates in RCT study cohorts. The metrics are beneficial complements to other approaches (e.g., enrollment fractions and GIST) used to identify generalizability and health equity of RCTs.
ConclusionBy quantifying the gaps between RCT and target populations, the proposed methods can support generalizability evaluation of existing RCT cohorts, enrollment target decisions for new RCTs, and monitoring of RCT recruitment, ultimately contributing to more equitable public health outcomes.
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health informatics
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Genetic overlap between major depression, bipolar disorder and Alzheimer's Disease
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genetic and genomic medicine
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Surgical activity in England and Wales during the COVID-19 pandemic: a nationwide observational cohort study
ObjectivesTo report the volume of surgical activity and the number of cancelled surgical procedures during the COVID-19 pandemic.
Design and settingAnalysis of electronic health record data from the National Health Service (NHS) in England and Wales.
MethodsWe used hospital episode statistics for all adult patients undergoing surgery between 1st January 2020 and 31st December 2020. We identified surgical procedures using a previously published list of procedure codes. Procedures were stratified by urgency of surgery as defined by NHS England. We calculated the deficit of surgical activity by comparing the expected number of procedures from the years 2016-2019 with the actual number of procedures in 2020. We estimated the cumulative number of cancelled procedures by 31st December 2021 according patterns of activity in 2020.
ResultsThe total number of surgical procedures carried out in England and Wales in 2020 was 3,102,674 compared to the predicted number of 4,671,338. This represents a 33.6% reduction in the national volume of surgical activity. There were 763,730 emergency surgical procedures (13.4% reduction), compared to 2,338,944 elective surgical procedures (38.6% reduction). The cumulative number of cancelled or postponed procedures was 1,568,664. We estimate that this will increase to 2,358,420 by 31st December 2021.
ConclusionsThe volume of surgical activity in England and Wales was reduced by 33.6% in 2020, resulting in over 1,568,664 cancelled operations. This deficit will continue to grow in 2021.
Summary boxesO_ST_ABSWhat is already known on this topicC_ST_ABSO_LIThe COVID-19 pandemic necessitated a rapid change in the provision of care, including the suspension of a large proportion of surgical activity
C_LIO_LISurgical activity has yet to return to normal and has been further impacted by subsequent waves of the pandemic
C_LIO_LIThis will lead to a large backlog of cases
C_LI
What this study addsO_LI3,102,674 surgical procedures were performed in England and Wales during 2020, a 33.6% reduction on the expected yearly surgical activity
C_LIO_LIOver 1.5 million procedures were not performed, with this deficit likely to continue to grow to 2.3 million by the end of 2021
C_LIO_LIThis deficit is the equivalent of more than 6 months of pre-pandemic surgical activity, requiring a monumental financial and logistic challenge to manage
C_LI
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surgery
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Seizure likelihood varies with day-to-day variations in sleep duration in patients with refractory focal epilepsy: A longitudinal EEG investigation.
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neurology
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To mask, or not to mask, Alice and Bob's dating dilemma
AO_SCPLOWBSTRACTC_SCPLOWFace masking in current COVID-19 pandemic seems to be a deceivingly simple decision-making problem due to its multifaceted nature. Questions arising from masking span biomedicine, epidemiology, physics, and human behaviors. While science has shown masks work generally, human behaviors (particularly under influences of politics) complicate the problem significantly given science generally assumes rationality and our minds are not always rational and/or honest. Minding minds, a legitimate concern, can also make masking legitimately confusing. To disentangle the potential confusions, particularly, the ramifications of irrationality and dishonesty, here we resort to evolutionary game theory. Specifically, we formulate and analyze the masking problem with a fictitious pair of young lovers, Alice and Bob, as a Sir Philip Sydney (SPS) evolutionary game, inspired by the handicap principle in evolutionary biology and cryptography figures in computer science. With the proposed ABD (Alice and Bobs dating dilemma) as an asymmetric four-by-four strategic-form game, 16 strategic interactions were identified, and six of which may reach equilibriums with different characteristics such as separating, pooling, and polymorphic hybrid, being Nash, evolutionarily stable or neutrally stable. The six equilibrium types seem to mirror the diverse behaviors of mask believers, skeptics, converted, universal masking, voluntarily masking, coexisted and/or divided world of believers and skeptics. We suggest that the apparently simple ABD game is sufficiently general not only for studying masking policies for populations (via replicator dynamics), but also for investigating other complex decision-making problems with COVID-19 pandemic including lockdown vs. reopening, herd immunity vs. quarantines, and aggressive tracing vs. privacy protection.
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public and global health
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Barriers to early initiation of breastfeeding in healthy neonates in an urban hospital setting.
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nutrition
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Short-term functional outcome in psychotic patients. Results of the Turku Early Psychosis Study (TEPS).
BackgroundFunctional recovery of patients with clinical and sub-clinical psychosis is associated with clinical, neuropsychological and developmental factors. Less is known how these factors predict functional outcome in same models.
AimWe investigated functional outcome and its predictors in patients with first-episode psychosis (FEP) or confirmed vs. non-confirmed clinical high risk to psychosis (CHR-P vs. CHR-N).
MethodsAltogether, 130 FEP, 60 CHR-P and 47 CHR-N patients were recruited and extensively examined at baseline (T0) and at 9 (T1) and 18 (T2) months after baseline. Global Assessment of Functioning (GAF) at T0, T1 and T2, and psychotic, depression and anxiety symptoms at T1 and T2 were assessed. Functional outcome was predicted in multivariate repeated ANOVA.
ResultsDuring follow-up, GAF improved significantly in FEP and CHR-P but not in CHR-N patients. In FEP, single marital status, low basic education, poor work situation, disorganised symptoms, perceptual deficits and poor premorbid adjustment, in CHR-P, disorganised symptoms and poor premorbid adjustment and in CHR-N, low basic education, poor work situation and general symptoms predicted poor functional outcome. In FEP, psychotic symptoms at T1 and in CHR-P, psychotic and depression symptoms at T1 and anxiety symptoms at T2 associated with poor functioning.
DiscussionIn FEP and CHR-P patients, poor premorbid adjustment and disorganised symptomatology are common predictors for functional outcome, while poor education and work situation predict poor functional outcome in FEP and CHR-N patients. Interventions aimed to improve studying and ability to work are most important in improving functioning of patients with clinical or subclinical psychosis.
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psychiatry and clinical psychology
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Non-intuitive trends of fetal fraction development related to gestational age and fetal gender, and their practical implications for non-invasive prenatal testing
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obstetrics and gynecology
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General Framework for Evaluating Outbreak Prediction, Detection, and Annotation Algorithms
The COVID-19 pandemic has highlighted and accelerated the use of algorithmic-decision support for public health. The latters potential impact and risk of bias and harm urgently call for scrutiny and evaluation standards. One example is the early detection of local infectious disease outbreaks. Whereas many statistical models have been proposed and disparate systems are routinely used, each tai-lored to specific data streams and use, no systematic evaluation strategy of their performance in a real-world context exists.
One difficulty in evaluating outbreak prediction, detection, or annotation lies in the scales of different approaches: How to compare slow but fine-grained genetic clustering of individual samples with rapid but coarse anomaly detection based on aggregated syndromic reports? Or alarms generated for different, overlapping geographical regions or demographics?
We propose a general, data-driven, user-centric framework for evaluating hetero-geneous outbreak algorithms. Discrete outbreak labels and case counts are defined on a custom data grid, associated target probabilities are then computed and compared with algorithm output. The latter is defined as discrete "signals" are generated for a number of grid cells (the finest available in the benchmarking data set) with different weights and prior outbreak information from which then estimated outbreak label probabilities are derived. The prediction performance is quantified through a series of metrics, including confusion matrix, regression scores, and mutual information. The dimensions of the data grid can be weighted by the user to reflect epidemiological criteria.
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epidemiology
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Relationship between temperature and relative humidity on the initial spread of COVID-19 cases and deaths in Brazil
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infectious diseases
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Tilted 3D visual scenes - A new therapy approach for pusher syndrome
Hemiparetic stroke patients with pusher syndrome use their non-paretic extremities to push towards their paralyzed side and actively resist external posture correction. The disorder is associated with a distorted perception of postural vertical combined with a maintained, or little deviating perception of visual upright. With the aim of reducing this mismatch, and thus reducing pushing behavior, we manipulated the orientation of visual input in a virtual reality setup. We presented healthy subjects and an acute stroke patient with severe pusher syndrome a 3D visual scene that was either upright or tilted in roll plane by 20{degrees}. By moving the sitting participants in roll plane to the left and right, we assessed the occurrence of active pushing behavior, namely the active resistance to external posture manipulation. With the 3D visual scene oriented upright, the patient with pusher syndrome showed the typical active resistance against tilts towards the ipsilesional side. He used his non-paretic arm to block the examiners attempt to move the body axis towards that side. With the visual scene tilted to the ipsiversive left, his pathological resistance was significantly reduced. Statistically, the tolerated body tilt angles no longer differed from those of healthy controls. We conclude that even short presentations of tilted 3D visual input can reduce pusher symptoms. The technique provides potential for a new treatment method of pusher syndrome and offers a simple, straightforward approach that can be effortlessly integrated in clinical practice.
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neurology
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Evaluation of the Access Bio CareStartTM rapid SARS-CoV-2 antigen test in asymptomatic individuals tested at a community mass-testing program in Western Massachusetts
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infectious diseases
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A Quick Displacement of the SARS-CoV-2 variant Delta with Omicron: Unprecedented Spike in COVID-19 Cases Associated with Fewer Admissions and Comparable Upper Respiratory Viral Loads
BackgroundThe increase in SARS-CoV-2 infections in December 2021 in the United States was driven primarily by the Omicron variant which largely displaced the Delta over a three week span. Outcomes from infection with the Omicron remain uncertain. We evaluate whether clinical outcomes and viral loads differ between Delta and Omicron infections during the period when both variants were co-circulating.
MethodsRemnant clinical specimens from patients that tested positive for SARS-CoV-2 after standard of care testing between the last week of November and the end of December 2021were used for whole viral genome sequencing. Cycle threshold values (Ct) for viral RNA, the presence of infectious virus, and levels of respiratory IgG were measured, and clinical outcomes were obtained. Differences in each measure were compared between variants stratified by vaccination status.
ResultsThe Omicron variant displaced the Delta during the study period and constituted 95% of the circulating lineages by the end of December 2021. Patients with Omicron infections (N= 1121) were more likely to be vaccinated compared to patients with Delta (N = 910), but were less likely to be admitted, require ICU level care, or succumb to infection regardless of vaccination status. There was no significant difference in Ct values based on the lineage regardless of the vaccination status. Recovery of infectious virus in cell culture was reduced in boosted patients compared to fully vaccinated without a booster and unvaccinated when infected with the Delta lineage. However, in patients with Omicron infections, recovery of infectious virus was not affected by vaccination.
ConclusionsOmicron infections of vaccinated individuals are expected, yet admissions are less frequent. Admitted patients might develop severe disease comparable to Delta. Efforts for reducing the Omicron transmission are required as even though the admission risk is lower, the numbers of infections continue to be high.
Research in context Evidence before this studyThe unprecedented increase in COVID-19 cases in the month of December 2021, associated with the displacement of the Delta variant with the Omicron, triggered a lot of concerns. An understanding of the disease severity associated with infections with Omicron is essential as well as the virological determinants that contributed to its widespread predominance. We searched PubMed for articles published up to January 23, 2022, using the search terms ("Omicron") AND ("Disease severity") as well as ("Omicron") AND ("Viral load") And/ or ("Cell culture"). Our search yielded 3 main studies that directly assessed the omicrons clinical severity in South Africa, its infectious viral load compared to Delta, and the dynamics of viral RNA shedding. In South Africa, compared to Delta, Omicron infected patients showed a significant reduction in severe disease. In this study, Omicron and non-Omicron variants were characterized based on S gene target failure using the TaqPath COVID-19 PCR (Thermo Fisher Scientific). In the study from Switzerland that assessed the infectious viral load in Omicron versus Delta, the authors analyzed only 18 Omicron samples that were all from vaccinated individuals to show that compared to Delta, Omicron had equivalent infectious viral titers. The third study that assessed the Omicron viral dynamics showed that the peak viral RNA in Omicron infections is lower than Delta. No published studies assessed the clinical discrepancies of Omicron and Delta infected patients from the US, nor comprehensively assessed, by viral load and cell culture studies, the characteristics of both variants stratified by vaccination status.
Added value of this studyTo the best of our knowledge, this is the only study to date to compare the clinical characteristics and outcomes after infection with the Omicron variant compared to Delta in the US using variants characterized by whole genome sequencing and a selective time frame when both variant co-circulated. It is also the first study to stratify the analysis based on the vaccination status and to compare fully vaccinated patients who didnt receive a booster vaccination to patients who received a booster vaccination. In addition, we provide a unique viral RNA and infectious virus load analyses to compare Delta and Omicron samples from unvaccinated, fully vaccinated, and patients with booster vaccination.
Implications of all the available evidenceOmicron associated with a significant increase in infections in fully and booster vaccinated individuals but with less admissions and ICU level care. Admitted patients showed similar requirements for supplemental oxygen and ICU level care when compared to Delta admitted patients. Viral loads were similar in samples from Omicron and Delta infected patients regardless of the vaccination status. The recovery of infectious virus on cell culture was reduced in samples from patients infected with Delta who received a booster dose, but this was not the case with Omicron. The recovery of infectious virus was equivalent in Omicron infected unvaccinated, fully vaccinated, and samples from patients who received booster vaccination.
FundingNIH/NIAID Center of Excellence in Influenza Research and Surveillance contract HHS N2772201400007C, Johns Hopkins University, Maryland department of health, Centers for Disease Control and Prevention contract 75D30121C11061.
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infectious diseases
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A Cross Sectional Study to Assess Perception and Behavior towards COVID-19 Vaccine Among Students and Faculties of Nursing Colleges at Anand and Kheda Districts, Gujarat
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nursing
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Virtual Recruitment is Here to Stay: 2020 ID Fellowship Program and Matched Applicant Recruitment Experiences
BackgroundGraduate Medical Education training programs transitioned to all-virtual recruitment in 2020. Few data have been published regarding the consequences of this transition. We desired to understand (1) infectious diseases (ID) fellowship programs recruitment efforts and the effect of virtual recruitment on application and interview numbers, and (2) the number of programs to which matched applicants applied and interviewed, and their perspectives on virtual recruitment.
MethodsIn 2020-21 we surveyed all United States ID fellowship program directors (PDs) and matched applicants. Descriptive data analysis was performed on quantitative survey items. Free-text responses were analyzed through a quantitative content analysis approach.
ResultsPD response rate was 68/158 (43%); applicant response rate was at least 23% (85/365). PDs reported a 27% increase in mean number of applications received and a 45% increase in mean number of applicants interviewed. Applicants especially valued online program structure information, PD program overview videos, fellow testimonials, didactic and curriculum content, and current fellow profiles. Most applicants preferred interviews lasting no more than 40 minutes and interview days lasting no more than 5 hours. Nearly all (60/64, 94%) PDs adequately learned about candidates; most (48/64, 75%) felt unable to showcase their program as well as when in-person. Most PDs (54/64, 84%) and applicants (56/73, 77%) want at least an option for virtual recruitment moving forward.
ConclusionsVirtual recruitment enabled programs to accommodate more applicants and highlighted applicants preferences for programs augmented online presences and time-limited interview days. Most programs and applicants want the option for virtual interviews.
Main PointsVirtual recruitment enables programs to accommodate more applicants. Applicants value programs augmented online presences and favor time-limited interview days. Most programs and applicants prefer in-person interviews and want at least an option for virtual interviews.
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medical education
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Thromboembolic risk in hospitalised and non-hospitalised Covid-19 patients: A self-controlled case series analysis of a nation-wide cohort
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cardiovascular medicine
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CHANGES IN LIFE EXPECTANCY BETWEEN 2019 AND 2021: UNITED STATES AND 19 PEER COUNTRIES
BACKGROUNDPrior studies reported large decreases in US life expectancy during 2020 as a result of the COVID-19 pandemic, disproportionately affecting Hispanic and non-Hispanic Black populations and vastly exceeding the average change in life expectancy in other high-income countries. Life expectancy estimates for 2021 have not been reported. This study estimated changes in life expectancy during 2019-2021 in the US population, in three US racial/ethnic groups, and in 19 peer countries.
METHODSUS and peer country death data for 2019-2021 were obtained from the National Center for Health Statistics, the Human Mortality Database, and overseas statistical agencies. The 19 peer countries included Austria, Belgium, Denmark, England and Wales, Finland, France, Germany, Israel, Italy, Netherlands, New Zealand, Northern Ireland, Norway, Portugal, Scotland, South Korea, Spain, Sweden, and Switzerland. Life expectancy was calculated for 2019 and 2020 and estimated for 2021 using a previously validated modeling method.
RESULTSUS life expectancy decreased from 78.86 years in 2019 to 76.99 years in 2020 and 76.47 years in 2021, a net loss of 2.39 years. In contrast, peer countries averaged a smaller decrease in life expectancy between 2019 and 2020 (0.57 years) and a 0.27-year increase between 2020 and 2021, widening the gap in life expectancy between the United States and peer countries to more than five years. The decrease in US life expectancy was highly racialized: whereas the largest decreases in 2020 occurred among Hispanic and non-Hispanic Black populations, in 2021 only the non-Hispanic White population experienced a decrease in life expectancy.
DISCUSSIONThe US mortality experience during 2020 and 2021 was more severe than in peer countries, deepening a US disadvantage in health and survival that has been building for decades. Over the two-year period between 2019 and 2021, US Hispanic and non-Hispanic Black populations experienced the largest losses in life expectancy, reflecting the legacy of systemic racism and inadequacies in the US handling of the pandemic. Reasons for the crossover in racialized outcomes between 2020 and 2021, in which life expectancy decreased only in the non-Hispanic White population, could have multiple explanations.
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public and global health
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Design and implementation of an international, multi-arm, multi-stage platform master protocol for trials of novel SARS-CoV-2 antiviral agents: Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3)
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infectious diseases
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Gene and metabolite expression dependence on body mass index in human myocardium.
We hypothesized that body mass index (BMI) dependent changes in myocardial gene expression and energy-related metabolites underlie the biphasic association between BMI and mortality (the obesity paradox) in cardiac surgery. We performed transcriptome profiling and measured a panel of 144 metabolites in 53 and 55, respectively, myocardial biopsies from a cohort of sixty-seven adult patients undergoing coronary artery bypass grafting (registration: NCT02908009). The initial analysis identified 239 transcripts with biphasic BMI dependence. 120 displayed u-shape and 119 n-shape expression patterns. The identified local minima or maxima peaked at BMI 28-29. Based on these results and to best fit the WHO classification, we grouped the patients into three groups: BMI<25, 25[≤]BMI[≤]32, and BMI>32. The group analysis indicated that protein translation-related pathways were downregulated in 25[≤]BMI[≥]32 compared with BMI<25 patients. Muscle contraction transcripts were upregulated in 25[≤]BMI[≥]32 patients, and cholesterol synthesis and innate immunity transcripts were upregulated in the BMI>32 group. Transcripts involved in translation, muscle contraction and lipid metabolism also formed distinct correlation networks with biphasic dependence on BMI. Metabolite analysis identified acylcarnitines and ribose-5-phosphate increasing in the BMI>32 group and -ketoglutarate increasing in the BMI<25 group. Molecular differences in the myocardium mirror the biphasic relationship between BMI and mortality.
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cardiovascular medicine
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Instruct:
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Machine learning algorithm to perform ASA Physical Status Classification
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anesthesia
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The social experience of participation in a COVID-19 vaccine trial: Subjects' motivations, others' concerns, and insights for vaccine promotion
BackgroundVaccine hesitancy could undermine the effectiveness of COVID-19 vaccination programs. Knowledge about peoples lived experiences regarding COVID-19 vaccination can enhance vaccine promotion and increase uptake.
AimTo use COVID-19 vaccine trial participants experiences to identify key themes in the lived experience of vaccination early in the vaccine approval and distribution process.
MethodsWe interviewed 31 participants in the Iowa City, Iowa US site of the Pfizer/BioNTech COVID-19 vaccine phase 3 clinical trial. While trial participation differs from clinical receipt of an approved vaccine in key ways, it offers the first view of peoples lived experiences of potentially receiving a COVID-19 vaccine. The trial context is also useful since decision-making about vaccination and medical research participation often involve similar hopes and concerns, and because the public appears to view even approved COVID-19 vaccines as experimental given their novelty. Semi-structured interviews addressed subjects experiences, including decision-making and telling others about their trial participation. We analyzed verbatim transcripts of these interviews thematically and identified common themes relevant for vaccination decision-making.
ResultsParticipants across demographic groups, including age, sex/gender, race/ethnicity, and political affiliation, described largely similar experiences. Key motivations for participation included ending the pandemic/restoring normalcy, protecting oneself and others, doing ones duty, promoting/modeling vaccination, and expressing aspects of identity like being a helper, career-related motivations, and support of science/vaccines. Participants often felt uniquely qualified to help via trial participation due to personal attributes like health, sex/gender or race/ethnicity. They reported hearing concerns about side effects and the speed and politicization of vaccine development. Participants responded by normalizing and contextualizing side effects, de-politicizing vaccine development, and explaining how the rapid development process was nevertheless safe.
ConclusionThese findings regarding participants reported motivations for trial participation and interactions with concerned others can be incorporated into COVID-19 vaccine promotion messaging aimed at similar populations.
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infectious diseases
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COVID-19 Clinical Characteristics and Outcomes in Children and Adolescents Hospitalized at the University Hospital of the West Indies, Jamaica in 2020-2021
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infectious diseases
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Instruct:
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A Qualitative Expert Interview Study: Mobility Health in Indonesia
BackgroundIndonesia has an ageing population that can develop mobility health-related problems in the future, including osteoporosis, arthritis, sarcopenia, low back pain, neck pain, and peripheral neuropathy. However, there are limited references and research that look upon mobility health and problems surrounding it in Indonesia.
AimsTo improve understanding on issues surrounding mobility health in Indonesia through a semi-structured interview with relevant experts.
MethodSemi-structured qualitative interviews via phone calls were conducted with eight different experts. Data were analysed using reflexive thematic analysis. Experts with experience dealing with mobility (bone, muscle, joint, movement) related issues for more than ten years, working in Indonesia, and communicating in English or Bahasa Indonesia were included.
ResultsFour themes were then identified across the experts on issues surrounding mobility health in Indonesia; this includes [1] screening and assessment of mobility health, [2] treatment for mobility health problems, [3] awareness campaign, [4] supplement for mobility health.
ConclusionsDiagnostic modalities for mobility health are abundant but still expensive. Treatment of mobility health with herbal medicine (jamu) might be beneficial. Social media can be a promising tool to increase awareness regarding mobility health. In general, there needs to be a change in mindset from curative to prevention in both health care providers and the general population.
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geriatric medicine
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High Seroprevalence of anti-SARS-CoV-2 antibodies among Ethiopian healthcare workers
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infectious diseases
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Fixed dosing of tocilizumab in ICU admitted COVID-19 patients is a superior choice compared to bodyweight based dosing; an observational population pharmacokinetic and pharmacodynamic study
BackgroundTocilizumab improves outcome, including survival, in intensive care unit (ICU) admitted COVID-19 patients. The currently applied dosage of 8 mg/kg is based on use of this drug for other indications, however is has not formally been investigated for COVID-19. In this study pharmacokinetics and dynamics of tocilizumab were investigated in ICU admitted COVID-19 patients.
MethodsThis was an open-label, single-center observational pharmacokinetic and -dynamic evaluation study. Enrolled patients, with polymerase chain reaction confirmed Covid-19 were admitted to the ICU for mechanical ventilation or high flow nasal canula oxygen support. All patients were 18 years of age or older and received tocilizumab within 24 hours after admission to the ICU and received 6 mg dexamethasone daily as concomitant therapy.
Results29 patients were enrolled between 15 December 2020 and 15 March 2021. A total of 139 tocilizumab plasma samples were obtained covering the pharmacokinetic curve of day 0 up to day 20 after tocilizumab initiation. A population pharmacokinetic model with parallel linear and non-linear clearance was developed and validated. Average AUC0-inf 1stDOSE was 938 [{+/-}190] ug/mL*days. Tocilizumab half-life was estimated to be 4{middle dot}15 [{+/-}0{middle dot}24] days. All patients had tocilizumab exposure above 1 ug/ml for at least 15 days.
ConclusionThis study provides evidence to support a fixed dose of 600 mg tocilizumab in COVID-19 patients. Furthermore our findings suggest that alternative cost saving regimens with even lower doses are likely to be as effective as the current 8 mg/kg recommendation.
FundingNo external funding was received for this work
BackgroundIn the randomized controlled trial REMAP-CAP, the IL-6 receptor antagonist tocilizumab was shown to improve outcome, including survival in ICU admitted COVID-19 patients. Because obesity is a risk factor for development of severe COVID-19, concerns have been raised about overtreatment as well as undertreatment through weight-based dosing of tocilizumab. Furthermore pharmacokinetic and pharmacodynamic parameters of medications are often found to be different in severely ill patients when compared to mild or moderately ill patients. However, the effects of different dosing schedules were only investigated to a very limited extent in non-randomized observational studies. Hence, evaluation of the PK/PD parameters of tocilizumab in severely ill patients - is warranted.
Added value of this studyThis study provides valuable information about the population pharmacokinetics and dynamics of tocilizumab in dexamethasone cotreated ICU admitted COVID-19 patients. This research shows that there is no rationale for the 8 mg/kg dosing recommendation in ICU patients. Fixed dosing of 600 mg tocilizumab is a cost saving, logistically attractive and safe alternative without losing efficacy.
Implications of all the evidenceDue to the ongoing pandemic, shortages of tocilizumab and other IL-6 receptor antagonists may be anticipated. A fixed tocilizumab dose regimen has many practical and safety advantages, e.g. it will reduce dosing errors and avoid unnecessary wastage of medication. More importantly, according to the data presented in this study, relative underdosing of patients with low, or low-normal bodyweight compared to patients with high bodyweight will be avoided. Last but not least, in view of the large number of patients currently being treated with these agents, a significant cost saving can also be expected.
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pharmacology and therapeutics
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Cost-effectiveness analysis of Intravascular Temperature Management after cardiac arrest in England
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health economics
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Cohort Profile Update: The HUNT Study, Norway
In the HUNT Study, all residents aged [≥]20 years in the Nord-Trondelag region, Norway have been invited to repeated surveys since 1984-86. The study data may be linked to local and national health registries. The HUNT4 survey in 2017-19 included 56 042 participants in Nord-Trondelag and 107 711 participants in the neighboring Sor-Trondelag region. The HUNT4 data enable more long-term follow-up, studies of life-course health trajectories, and within-family studies. New measures include body composition analysis using bioelectrical impedance; a one-week accelerometer recording; physical and cognitive testing in older adults; measurements of hemoglobin and blood cell counts, HbA1c and phosphatidylethanol; and genotyping. Researchers can apply for HUNT data access from HUNT Research Centre if they have obtained project approval from the Regional Committee for Medical and Health Research Ethics, see www.ntnu.edu/hunt/data.
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epidemiology
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Epidemiological and evolutionary considerations of SARS-CoV-2 vaccine dosing regimes
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epidemiology
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Instruct:
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Prediction of Subsequent Need for Intensive Oxygen Supplementation in Galveston, Texas: A Retrospective Cohort Study and Multivariable Regression Model of Unvaccinated COVID-19 Patients
ObjectiveThe severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2) has caused a pandemic claiming more than 4 million lives worldwide. Overwhelming Coronavirus-Disease-2019 (COVID-19) respiratory failure placed tremendous demands on healthcare systems increasing the death toll. Cost-effective prognostic tools to characterize COVID-19 patients likely to progress to severe hypoxemic respiratory failure are still needed.
DesignWe conducted a retrospective cohort study to develop a model utilizing demographic and clinical data collected in the first 12-hours admission to explore associations with severe hypoxemic respiratory failure in unvaccinated and hospitalized COVID-19 patients.
SettingUniversity based healthcare system including 6 hospitals located in the Galveston, Brazoria and Harris counties of Texas.
ParticipantsAdult patients diagnosed with COVID-19 and admitted to one of six hospitals between March 19th and June 31st, 2020.
Primary outcomeThe primary outcome was defined as reaching a WHO ordinal scale between 6-9 at any time during admission, which corresponded to severe hypoxemic respiratory failure requiring high-flow oxygen supplementation or mechanical ventilation.
ResultsWe included 329 participants in the model cohort and 62 (18.8%) met the primary outcome. Our multivariable regression model found that lactate dehydrogenase (OR 2.36), qSOFA score (OR: 2.26), and neutrophil to lymphocyte ratio (OR:1.15) were significant predictors of severe disease. The final model showed an area under curve (AUC) of 0.84. The sensitivity analysis and point of influence analysis did not reveal inconsistencies.
ConclusionsOur study suggests that a combination of accessible demographic and clinical information collected on admission may predict the progression to severe COVID-19 among adult patients with mild and moderate disease. This model requires external validation prior to its use.
STRENGTHS AND LIMITATIONS OF THIS STUDY Our study utilized objective and measurable demographic and clinical information regularly available in healthcare settings even among patients unable to communicate.
Our primary outcome corresponds to WHO ordinal score which would allow compare our results to other studies and in other settings.
Our model could serve as an effective point of service tool during early admission to assist in clinical management and allocation of resources to unvaccinated patients.
Our study is a retrospective study of unvaccinated COVID19 patients, and validation of our prediction model in the rest of our study population is still needed.
In addition, testing our model in a more recent cohort after emergence of new SARS-CoV-2 variants will be needed to assess its robustness.
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infectious diseases
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Instruct:
Identify the main category of Medrxiv papers based on the titles
Query:
Rescaling and Small Area Estimation of Health Survey Data as applied to Smoking Rates in Allegheny County, Pennsylvania
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epidemiology
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Instruct:
Identify the main category of Medrxiv papers based on the titles and abstracts
Query:
Genetic, structural and clinical analysis of spastic paraplegia 4
IntroductionSpastic paraplegia type 4 (SPG4), resulting from heterozygous mutations in the SPAST gene, is the most common form among the heterogeneous group of hereditary spastic paraplegias (HSPs). We aimed to study genetic and clinical characteristics of SPG4 across Canada.
MethodsThe SPAST gene was analyzed in a total of 696 HSP patients from 431 families by either HSP-gene panel sequencing or whole exome sequencing (WES). We used Multiplex ligation-dependent probe amplification to analyze copy number variations (CNVs), and performed in silico structural analysis of selected mutations. Clinical characteristics of patients were assessed, and long-term follow-up was done to study genotype-phenotype correlations.
ResultsWe identified 157 SPG4 patients from 65 families who carried 41 different SPAST mutations, six of which are novel and six are CNVs. We report novel aspects of mutations occurring in Arg499, a case with homozygous mutation, a family with probable compound heterozygous mutations, three patients with de novo mutations, three cases with pathogenic synonymous mutation, co-occurrence of SPG4 and clinically isolated syndrome, and novel or rarely reported signs and symptoms seen in SPG4 patients.
ConclusionOur study demonstrates that SPG4 is a heterogeneous type of HSP, with diverse genetic features and clinical manifestations. In rare cases, biallelic inheritance, de novo mutation, pathogenic synonymous mutations and CNVs should be considered.
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neurology
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Instruct:
Identify the main category of Medrxiv papers based on the titles
Query:
Rapid displacement of SARS-CoV-2 variants within Japan correlates with cycle threshold values on routine RT-PCR testing
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infectious diseases
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Instruct:
Identify the main category of Medrxiv papers based on the titles and abstracts
Query:
Association between Fat-Infiltrated Axillary Lymph Nodes on Screening Mammography and Cardiometabolic Disease
ObjectiveEctopic fat deposition within and around organs is a stronger predictor of cardiometabolic disease status than body mass index. Fat deposition within the lymphatic system is poorly understood. This study examined the association between the prevalence of cardiometabolic disease and ectopic fat deposition within axillary lymph nodes (LNs) visualized on screening mammograms.
MethodsA cross-sectional study was conducted on 834 women presenting for full-field digital screening mammography. The status of fat-infiltrated LNs was assessed based on the size and morphology of axillary LNs from screening mammograms. The prevalence of cardiometabolic disease was retrieved from the electronic medical records, including type 2 diabetes mellitus (T2DM), hypertension, dyslipidemia, high blood glucose, cardiovascular disease, stroke, and non-alcoholic fatty liver disease.
ResultsFat-infiltrated axillary LNs were associated with a high prevalence of T2DM among all women (adjusted odds ratio: 3.92, 95% CI: [2.40, 6.60], p-value < 0.001) and in subgroups of women with and without obesity. Utilizing the status of fatty LNs improved the classification of T2DM status in addition to age and BMI (1.4% improvement in the area under the receiver operating characteristic curve).
ConclusionFat-infiltrated axillary LNs visualized on screening mammograms were associated with the prevalence of T2DM. If further validated, fat-infiltrated axillary LNs may represent a novel imaging biomarker of T2DM in women undergoing screening mammography.
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epidemiology
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