title: Combination therapy of infliximab and thiopurines, but not monotherapy with infliximab or vedolizumab, is associated with attenuated IgA and neutralisation responses to SARS-CoV-2 in inflammatory bowel disease.

abstract: There is substantial interest regarding the perceived risk that immunomodulator and biologic therapy could have on COVID-19 disease severity among patients with inflammatory bowel disease (IBD) and clinicians. In this study, we show that infliximab/thiopurine combination therapy is associated with significantly lower IgA, a range of lower IgG responses as well as impaired neutralising antibody responses, compared to responses observed in healthy individuals. We also demonstrate that whilst IgG responses were significantly reduced in individuals with IBD treated with infliximab or vedolizumab monotherapy compared to healthy controls, there was no significant reduction in IgA and neutralising antibody responses. As neutralising antibody responses correlate with protection, this observation may provide the mechanistic explanation for the observation reported by the SECURE-IBD study that individuals on infliximab/thiopurine combination therapy were at greater risk of severe COVID-19 outcomes than patients on monotherapy.

category: gastroenterology


title: Causality of Abdominal Obesity on Cognition: a Trans-ethnic Mendelian Randomization study

abstract: Obesity has been associated with cognition in observational studies; however, whether its effect is confounding, reverse causality, or causal remains inconclusive. Using two-sample Mendelian randomization (MR) analyses, we investigated the causality of overall obesity, measured by BMI, and abdominal adiposity, measured by waist-hip ratio adjusted for BMI (WHRadjBMI), on cognition. Using summary data from the GIANT consortium, COGENT consortium, and UK Biobank of European ancestry, there was no causal effect of BMI on cognition performance (beta[95% CI]=-0.04[-0.12,0.04], p-value=0.35); however, a 1-SD increase in WHRadjBMI was associated with 0.07 standardized decrease in cognition performance (beta[95% CI]=-0.07[-0.12,-0.02], p=0.006). Using raw data from the Taiwan Biobank of Asian ancestry, there was no causal effect of BMI on cognitive aging (beta[95% CI]=0.00[-0.09,0.09], p-value=0.95); however, a 1-SD increase in WHRadjBMI was associated with a 0.17 standardized decrease in cognitive aging (beta[95% CI]=-0.17[-0.30,-0.03], p=0.02). This trans-ethnic MR study reveals that abdominal adiposity impairs cognition.

category: public and global health


title: SARS-CoV-2 Pandemic Preventive Methods Efficacy - A Simulation Case Study

abstract:
The world has been facing the SARS-CoV-2, a.k.a. COVID-19, pandemic with different preventive methods including social distancing, face masking, screening tests (a.k.a. active surveillance), and vaccination. There are many publications and studies on the efficacy of each of these preventive methods for the last couple of years. Not all methods are readily available in each country and not all methods are accepted by all people in each society.

In this study, we explore the interaction of the three preventive methods: face masking, vaccinations, and screening tests. We study a confined space to represent schools, businesses, or healthcare facilities and we model the spread of the COVID-19 virus for a 60-day period among a sample population while varying the percentage of people adopting one or more of the three preventive methods.

To interpret the simulation results, we define a (Health Goal) target, for example achieving <5% infection rate, i.e., protecting 95% or more of the sample population. We then construct a (Decision Tree) that depicts all valid combinations that achieve this goal. Multiple scenarios are derived from the decision tree to guide decision makers in drawing effective policies to contain the virus spread. We demonstrate a ramping vaccination rate scenario, a removal of the face-masking mandate scenario, and a cost-minimizing goal scenario.

The study highlights the efficacy of combining the three prevention methods to constrain the virus spread among the sample population. For example, results show that a combination of 0% vaccination rate, 6% daily screening test rate, and 80% face masking rate will achieve the target [≥]95 protection rate, which can represent a scenario in which vaccination is not yet readily available. As the vaccination rate ramps up to 80% among the sample population, the screening test rate can be 0%, while the face masking rate can be as low as 5% to still achieve the health target. Many other scenarios are derived from this study to meet the defined health target, which represents the flexibility afforded to policy and decision makers when trying to adopt a combination of these preventive methods to contain virus spread.

The study also reveals the higher efficiency of either the vaccination or screening test over face masking under the assumed virus transmissibility rates in the study.


title: Second-generation optoacoustic imaging of breast cancer patients

abstract: Since the initial breast transillumination almost a century ago, breast cancer imaging using light has been considered in different implementations aiming to improve diagnostics, minimize the number of available biopsies, or monitor treatment. However, due to strong photon scattering, conventional optical imaging yields low resolution images, challenging quantification and interpretation. Optoacoustic imaging addresses the scattering limitation and yields high-resolution visualization of optical contrast, offering great potential value for breast cancer imaging. Nevertheless, the image quality of experimental systems remains limited due to a number of factors, including signal attenuation with depth and partial view angle and motion effects, particularly in multi-wavelength measurements. We developed data analytics methods to improve the accuracy of handheld optoacoustic breast cancer imaging, yielding second-generation optoacoustic imaging performance operating in tandem with ultrasonography. We produced the best images yet with handheld optoacoustic examinations of the human breast and breast cancer, in terms of resolution and contrast. Using these advances, we examined optoacoustic markers of malignancy, including vasculature abnormalities, hypoxia, and inflammation, on images obtained from breast cancer patients. We achieved the best optoacoustic images of the human breast ever obtained using handheld examination, advancing the diagnostic and theranostic potential of the hybrid optoacoustic-ultrasound (OPUS) examination over routine ultrasonography.

category: radiology and imaging


title: Construction and Validation of a Nomogram Based on the Log Odds of Positive Lymph Nodes to Predict the Prognosis of Lung Neuroendocrine Tumors

abstract:
ObjectivesThis study aimed to investigate the prognostic value of Log odds of positive lymph nodes (LODDS) for predicting the long-term prognosis of patients with node-positive lung neuroendocrine tumors (LNETs).

Materials and MethodsWe collected 506 eligible patients with resected N1/N2 classification LNETs from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015. First, we applied the Cox proportional-hazards regression model to evaluate the relationship between LODDS and study endpoints (cancer-specific survival [CSS] and overall survival [OS]) based on the entire cohort. Second, the study cohort was divided into derivation cohort (n=300) and external validation cohort (n=206) based on different geographic regions. Nomograms were constructed and validated based on these two cohorts to predict the 1-, 3- and 5-year survival of patients with LNETs. The accuracy and clinical practicability of nomograms were tested and compared by Harrells concordance index (C-index), integrated discrimination improvement (IDI), net reclassification improvement (NRI), calibration plots, and decision curve analyses.

ResultsThe Cox proportional-hazards model showed the high LODDS group (-0.33[≤]LODDS[≤]1.14) had significantly higher mortality compared to those in the low LODDS group (-1.44 [≤]LODDS<-0.33) for both CSS and OS. In addition, besides LODDS, age at diagnosis, histotype, type of surgery, radiotherapy, and chemotherapy were shown as independent predictors in Cox regression analyses and included in the nomograms. The values of c-index, NRI, and IDI indicated that the established nomogram performed significantly better than the conventional eighth edition of the TNM staging system alone. The calibration plots for predictions of the 1-, 3-, and 5-year OS were in excellent agreement. Decision curve analyses showed that the nomogram had value in terms of clinical application.

ConclusionsWe created visualized nomograms for CSS and OS of LNET patients, facilitating clinicians to provide highly individualized risk assessment and therapy.

category: oncology


title: Epithelial-to-mesenchymal transition lowers the cholesterol pathway, wich influences colon tumors differentiation.

abstract:
Colorectal cancer (CRC) is the second cause of death worldwide. Up to 70% of CRC patients will metastasize. Identify new biomarkers of progression to prevent/delay disease evolution is urgent. Epithelial-to-mesenchymal transition (EMT) is a major program engaged during metastasis. We aim at identifying a combination of new genes that further identify signs of EMT in cancer tissues. We treated HT-29 cells grown in 3D with an EMT Inducing cocktail, and collect them before during and after treatment. For each condition, pan-transcriptomic analyses were done. Genes that were both induced upon EMT induction and inhibited upon EMT release (mesenchymal-to-epithelial transition or MET) were selected. We identified new genes for EMT-MET programs. These genes were used to build a metagene that, when applied to a database of transcriptomic data from primary colorectal tumors (n= 2,239), had an independent prognosis value. Finally, we submitted this metagene to CMap and identified drugs that might affect EMT-MET programs. Statins, well-known inhibitors of cholesterol synthesis, were among them and effectively delayed MET. These data show that cholesterol and EMT pathways are opposite regulators and impact differently tumor differentiation and outcome.

TRANSLATIONAL RELEVANCEMetastases are the main cause of death of colorectal cancer (CRC) and the major issue in CRC management. Understanding the chain of events that lead to metastasis occurrence is urgent to identify new biomarkers of progression and/or new potential targets. Epithelial to mesenchymal transition (EMT) is a major player in cancer dissemination that remains non-targetable due to its broad involvement in tissue homeostasis. Here, we used a relevant in vitro dynamic model to identify the pathways triggered during EMT in CRC and how this might improve tumors classification, prognosis and open therapeutic avenue for this deadly disease. The cholesterol pathway surprisingly popped-out from this model and turned out to be a good prognosis factor of disease-free survival for CRC. Altogether, our results showed that an active EMT program lowers the cholesterol pathway, which further influence the differentiation of colon tumor toward the most aggressive subtypes.


title: Epithelial-to-mesenchymal transition lowers the cholesterol pathway, which influences colon tumors differentiation.


title: A Randomized Clinical Trial of Bioimpedance Spectroscopy or Tape Measure Triggered Compression Intervention in Chronic Breast Cancer Lymphedema Prevention

abstract:
BackgroundThis study compared rates of progression to chronic breast cancer-related lymphedema (defined as a [≥] 10% arm volume change from baseline requiring complex decongestive physiotherapy (CDP)) following an intervention for subclinical lymphedema (S-BCRL) triggered by bioimpedance spectroscopy (BIS) or by tape measurement (TM).

Methods and ResultsThis stratified, randomized, international trial enrolled new breast cancer patients undergoing: mastectomy/partial mastectomy, axillary treatment (dissection, sentinel lymph node biopsy >6 nodes or radiation), radiation therapy (chest wall/ breast, supraclavicular fossa), or taxane-based chemotherapy. Following post-surgery eligibility reassessment, centralized, 1:1 randomization to prospective surveillance by BIS or TM occurred. S-BCRL detection triggered a 4-week, 12-hour per day, compression sleeve and gauntlet intervention. The primary outcome (n=209), rates of post-intervention progression to CDP, were assessed over three years. Between June 24, 2014 and September 11, 2018, 1,200 patients were enrolled, 963 randomized (BIS n=482;TM n=481) and 879 analyzed (BIS n=442;TM n=437). Median follow-up was 32.9 months (IQR=22,35). BIS patients triggered an intervention at a lower rate than TM patients (20.1%, n=89 vs 27.5%, n=120, p = 0.011). Median months to trigger was longer with BIS than TM (9.7; 95%CI,8.2-12.6 vs 3.9; 95%CI,2.8-4.5, p = 0.001). Overall, 14.4%(n=30) progressed post-intervention, with reduced likelihood for BIS patients than TM patients (7.9%, n=7 vs 19.2%, n=23; RR=0.41; 95%CI,0.13-0.81; absolute reduction 11.3%; 95%CI,2.3%-20.3%; p = 0.016).

ConclusionsAs compared to TM, BIS provides a more precise identification of patients likely to benefit from an early compression intervention.

Condensed AbstractThis stratified, multi-site, international trial enrolled newly diagnosed breast cancer patients, randomized them to prospective surveillance by bioimpedance spectroscopy (BIS) or tape measurement (TM), and screened them for lymphedema development at frequent intervals for three years after surgery. When subclinical lymphedema was detected a 4-week, 12-hour per day, compression sleeve and gauntlet intervention was implemented. Overall, 14.4% (n=30) progressed post-intervention to chronic lymphedema, with reduced likelihood for BIS patients than TM patients (7.9%, n=7 vs 19.2%, n=23; RR=0.41; 95%-CI,0.13-0.81; absolute reduction 11.3%; 95%-CI,2.3%-20.3%; p = 0.016). BIS best supported intervention success for prevention of chronic lymphedema compared to TM.


title: Molecular evidence of coinfection with acute respiratory viruses and high prevalence of SARS-CoV-2 among patients presenting flu-like illness in Bukavu city, Democratic Republic of Congo

abstract: The coronavirus 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with clinical manifestation cases are almost similar to those of common respiratory viral infections. This study determined the prevalence of SARS-CoV-2 and other acute respiratory viruses among patients with flu-like symptoms in Bukavu city Democratic republic of Congo. We screened 1352 individuals with flu-like illnesses seeking treatment in 10 health facilities. Nasopharyngeal swabs specimens were collected to detect SARS-CoV-2 using real-time reverse transcription-polymerase chain reaction (RT-PCR) and 10 common respiratory viruses were detected by multiplex reverse transcription polymerase chain reaction assay. Overall, 13.9% (188/1352) patients were confirmed positive for SARS-CoV-2. Influenza A 5.6% (56/1352), and Influenza B 0.9% (12/1352) were the most common respiratory viruses detected. Overall more than two cases of the other acute respiratory viruses were detected. Frequently observed symptoms associated with SARS-CoV-2 positivity were shivering (47.8%; OR= 1.8; CI: 0.88-1.35), cough (89.6%; OR=6.5, CI: 2.16-28.2), myalgia and dizziness (59.7%; OR=2.7; CI: 1.36-5.85). Moreover, coinfection was observed in 12 (11.5%) specimens. SARS-CoV-2, and Influenza A were the most co-occurring infections, accounting for 33.3% of all positive cases. This study demonstrates cases of COVID-19 infections co-occurring with other acute respiratory infections in Bukavu city during the ongoing outbreak of COVID-19. These data emphasize the need for routine testing of multiple viral pathogens for better prevention and treatment plans.

category: genetic and genomic medicine


title: Medical genetics workforce in Brazil: practitioners, services, and disease distribution

abstract:
PurposeIn anticipation of the implementation of personalized medicine (PM) in Brazil we assessed the demographic characteristics of its medical genetics workforce together with the distribution of rare genetic diseases (RGD) and hereditary cancer syndromes (HCS) across municipalities in the country.

MethodsWe used demographic data from an earlier report on medical specialties, and open databases providing summarized data on the public and private healthcare systems, for the years 2019 and 2020. In the public system we considered RGD live births and hospitalizations, and HCS mortality. In the private system we obtained data on RGD, HCS and genetic counselling appointments.

ResultsThe 332 registered medical geneticists (MGs) were mostly female, attended a public medical school, and were predominantly registered in the Southeast. The distribution of MGs overlapped the country-wise distribution of all types of genetic disease and service examined, indicating that [~]30% of the patient population has access to a MG specialist.

ConclusionThe Brazilian MG workforce is concentrated in the richest and most populated areas and while it covers a significant proportion of the population there are vast regions with very limited services. The public health system should address these inequalities for a successful transition to PM.


title: Genetics of the human microglia regulome refines Alzheimer's disease risk loci

abstract:
Microglia are brain resident myeloid cells that play a critical role in neuroimmunity and the etiology of Alzheimers Disease (AD). Yet our understanding of how the genetic regulatory landscape controls microglial function and contributes to disease is limited. Here, we performed transcriptome and chromatin accessibility profiling in primary human microglia from 150 donors to identify genetically-driven variation and cell-specific enhancer-promoter interactions. Integrative fine-mapping analysis identified putative regulatory mechanisms for 21 AD risk loci, of which 18 were refined to a single gene, including 3 novel genes (KCNN4, FIBP and LRRC25). Transcription factor regulatory networks captured AD risk variation and identified SPI1 as a key regulator of microglia expression and AD risk. This comprehensive resource capturing variation in the human microglia regulome provides novel insights into the etiology of neurodegenerative disease.

One-Sentence SummaryCharacterizing the genetic regulation of chromatin accessibility and gene expression in human microglia refines molecular mechanisms of Alzheimers disease risk loci.


title: Temperature and Low-stakes Cognitive Performance

abstract:
In this paper we offer among the first evidence in a developing country context that transitory exposure to heat waves may disrupt low-stakes cognitive activities across a wide range of age cohorts. Matching cognitive test scores from a nationally representative longitudinal survey in China with weather data according to the exact time and geographic location of assessment, we find that exposure to a temperature above 32 {degrees}C on the test date, relative to a day within 22-24 {degrees}C, leads to a sizable decline in math scores by 0.088 SDs (equivalent to 0.30 years of education). The negative effect is more pronounced for less educated older adults taking math tests. Test takers living in hotter regions or having air conditioning installed on site are less vulnerable to extreme high temperatures, indicating the role of adaptation.

JEL CodesI24, Q54, Q51

category: health economics


title: A high content microscopy-based platform for detecting antibodies to the nucleocapsid, spike and membrane proteins of SARS-CoV-2

abstract: The strong humoral immune response produced against the SARS-CoV-2 nucleocapsid (N) and spike (S) proteins has underpinned serological testing but the prevalence of antibody responses to other SARS-CoV-2 proteins, which may be of use as further serological markers, is still unclear. Cell-based serological screening platforms can fulfil a crucial niche in the identification of antibodies which recognise more complex folded epitopes or those incorporating post-translation modifications which may be undetectable by other methods used to investigate the antigenicity of the SARS-CoV-2 proteome. Here, we employed automated high content immunofluorescence microscopy (AHCIM) to assess the viability of such an approach as a method capable of assaying humoral immune responses against full length SARS-CoV-2 proteins in their native cellular state. We first demonstrate that AHCIM provides high sensitivity and specificity in the detection of SARS-CoV-2 N and S IgG. Assessing the prevalence of antibody responses to the SARS-CoV-2 structural membrane protein (M), we further find that 85% of COVID-19 patients within our sample set developed detectable M IgG responses (M sensitivity 85%, N sensitivity 93%, combined N + M sensitivity 95%). The identification of M as a serological marker of high prevalence may be of value in detecting additional COVID-19 cases during the era of mass SARS-CoV-2 vaccinations, where serological screening for SARS CoV-2 infections in vaccinated individuals is dependent on detection of antibodies against N. These findings highlight the advantages of using cell-based systems as serological screening platforms and raise the possibility of using M as a widespread serological marker alongside N and S.

category: infectious diseases


title: A Thermostable Cas12b from Brevibacillus Leverages One-pot Detection of SARS-CoV-2 Variants of Concern

abstract: Current SARS-CoV-2 detection platforms lack the ability to differentiate among variants of concern (VOCs) in an efficient manner. CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) has the potential to transform diagnostics due to its programmability. However, many of the CRISPR-based detection methods are reliant on either a multi-step process involving amplification or elaborate guide RNA designs. A complete one-pot detection reaction using alternative Cas effector endonucleases has been proposed to overcome these challenges. Yet, current approaches using Alicyclobacillus acidiphilus Cas12b (AapCas12b) are limited by its thermal instability at optimum reverse transcription loop-mediated isothermal amplification (RT-LAMP) reaction temperatures. Herein, we demonstrate that a novel Cas12b from Brevibacillus sp. SYP-B805 (referred to as BrCas12b) has robust trans-cleavage activity at ideal RT-LAMP conditions. A competitive profiling study of BrCas12b against Cas12b homologs from other bacteria genera underscores the potential of BrCas12b in the development of new diagnostics. As a proof-of-concept, we incorporated BrCas12b into an RT-LAMP-mediated one-pot reaction system, coined CRISPR-SPADE (CRISPR Single Pot Assay for Detecting Emerging VOCs) to enable rapid, differential detection of SARS-CoV-2 VOCs, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), and Delta (B.1.617.2) in 205 clinical samples. Notably, a BrCas12b detection signal was observed within 1-3 minutes of amplification, achieving an overall 98.1% specificity, 91.2% accuracy, and 88.1% sensitivity within 30 minutes. Significantly, for samples with high viral load (Ct value [≤] 30), 100% accuracy and sensitivity were attained. To facilitate dissemination and global implementation of the assay, we combined the lyophilized one-pot reagents with a portable multiplexing device capable of interpreting fluorescence signals at a fraction of the cost of a qPCR system. With relaxed design requirements, one-pot detection, and simple instrumentation, this assay has the capability to advance future diagnostics.


title: Assessment of knowledge about human papillomavirus vaccination among primary school girls in Arba Minch town, South Ethiopia, 2020. An institution-based cross-sectional study

abstract:
IntroductionCervical cancer is the second leading cause of cancer-related mortality among females in Ethiopia. The knowledge regarding human papillomavirus vaccination and its acceptability among adolescent girls affects the human papillomavirus vaccine uptake, however, the status of knowledge of the human papillomavirus vaccination among adolescent girls in Ethiopia, particularly in this study area is not well known. Therefore, this study aimed to determine the knowledge of human papillomavirus vaccination and associated factors among primary school girls in Arba Minch town, South Ethiopia, 2020.

MethodsA school-based cross-sectional study in which 516 school girls participated was conducted on January 24, 2020. The study participants were selected by a simple random sampling technique. A pre-tested and self-administered questionnaire was used to collect the data. Data was entered to Epi_data version 4.6 and exported to SPSS Version 23 for analysis. The logistic regression model was used to identify the statistically significant variables for knowledge of the human papillomavirus vaccination.

ResultsThe overall knowledge level of the study participants in this study was 71.7%. Their main information source was social media 41.74% followed by health care workers 29.69%.

ConclusionsNearly three-fourths of the study participants were knowledgeable about human papillomavirus vaccination. The knowledge about the human papillomavirus vaccination shows a positive association with age, education level, and access to information sources, and parents educational status.


title: Agile design and development of a high throughput cobas(R) SARS-CoV-2 RT-PCR diagnostic test

abstract: Diagnostic testing is essential for management of the COVID-19 pandemic. An agile assay design methodology, optimized for the cobas(R) 6800/8800 system, was used to develop a dual-target, qualitative SARS-CoV-2 RT-PCR test using commercially available reagents and existing sample processing and thermocycling profiles. The limit of detection was 0.004 to 0.007 TCID50/mL for USA-WA1/2020. Assay sensitivity was confirmed for SARS-CoV-2 variants Alpha, Beta, Gamma, Delta and Kappa. The coefficients of variation of the cycle threshold number (Ct) were between 1.1 and 2.2%. There was no difference in Ct using nasopharyngeal compared to oropharyngeal swabs in universal transport medium (UTM). A small increase in Ct was observed with specimens collected in cobas(R) PCR medium compared to UTM. In silico analysis indicated that the dual-target test is capable of detecting all >1,800,000 SARS-CoV-2 sequences in the GISAID database. Our agile assay design approach facilitated rapid development and deployment of this SARS-CoV-2 RT-PCR test.


title: How frequent are acute reactions to COVID-19 vaccination and who is at risk?

abstract:
IntroductionOur objective was to describe and compare self-reported side effects of COVID-19 vaccines in the USA.

MethodsA web-based registry enrolled volunteers who received a COVID-19 vaccine between March 19 -July 15, 2021. We collected self-reported short-term side effects, medical consultation, hospitalization, and quality of life impact following completed vaccination regimens (Pfizer, Moderna, J&J).

ResultsWe recruited 6,966 volunteers who completed their full course of vaccination (median age 48 years, IQR 35.0-62.0; 83.6% female): Pfizer 3,486; Moderna 2,857; J&J 623. Few (3.1%) sought medical care for post-vaccination side effects. Hospitalization (n=17; 0.3%) and severe allergic reactions (n=39; 0.6%) also were rare. Those with autoimmune disease or lung disease were approximately twice as likely to seek medical care (adjusted odds ratio (aOR) 2.01 [95% CI: 1.39;2.92] and 1.70 [95% CI: 1.12;2.58] respectively). 92.4% of participants reported [≥]1 side effect (median 3), with injection site reactions (78.9%), fatigue (70.3%), headache (49.0%) reported most frequently. More side effects were reported after the second dose of two-dose vaccines (medians: 1 vs. 2 for Pfizer and 1 vs. 3 for Moderna for first and second doses respectively) versus 3 for J&Js single-dose vaccine. For the employed, the median number of workdays missed was one. Diabetics and those vaccinated against influenza were substantially less likely to report [≥]3 symptoms (aOR 0.68, 95% CI 0.56,0.82 and aOR 0.82, 95% CI 0.73,0.93, respectively.)

DiscussionThe total side effect burden was, not unexpectedly, greater with two-dose regimens but all three vaccines appear relatively safe. Very few subjects reported side effects serious enough to warrant medical care or reported post-vaccination hospitalization. While these findings do not address possible long-term effects, they do inform on their short-term safety and tolerability and will hopefully provide some reassurance and positively inform the benefit-risk and pharmacoeconomic assessment for all three vaccines.

Clinicaltrials.gov NCT04368065


title: COVID-19 Likelihood Meter: a machine learning approach to COVID-19 screening for Indonesian health workers

abstract: The COVID-19 pandemic poses a heightened risk to health workers, especially in low- and middle-income countries such as Indonesia. Due to the limitations to implementing mass RT-PCR testing for health workers, high-performing and cost-effective methodologies must be developed to help identify COVID-19 positive health workers and protect the spearhead of the battle against the pandemic. This study aimed to investigate the application of machine learning classifiers to predict the risk of COVID-19 positivity (by RT-PCR) using data obtained from a survey specific to health workers. Machine learning tools can enhance COVID-19 screening capacity in high-risk populations such as health workers in environments where cost is a barrier to accessibility of adequate testing and screening supplies. We built two sets of COVID-19 Likelihood Meter (CLM) models: one trained on data from a broad population of health workers in Jakarta and Semarang (full model) and tested on the same, and one trained on health workers from Jakarta only (Jakarta model) and tested on an independent population of Semarang health workers. The area under the receiver-operating-characteristic curve (AUC), average precision (AP), and the Brier score (BS) were used to assess model performance. Shapley additive explanations (SHAP) were used to analyze feature importance. The final dataset for the study included 3979 health workers. For the full model, the random forest was selected as the algorithm of choice. It achieved cross-validation mean AUC of 0.818 {+/-} 0.022 and AP of 0.449 {+/-} 0.028 and was high performing during testing with AUC and AP of 0.831 and 0.428 respectively. The random forest model was well-calibrated with a low mean brier score of 0.122 {+/-} 0.004. A random forest classifier was the best performing model during cross-validation for the Jakarta dataset, with AUC of 0.824 {+/-} 0.008, AP of 0.397 {+/-} 0.019, and BS of 0.102 {+/-} 0.007, but the extra trees classifier was selected as the model of choice due to better generalizability to the test set. The performance of the extra trees model, when tested on the independent set of Semarang health workers, was AUC of 0.672 and AP of 0.508. Our models yielded high predictive performance and may have the potential to be utilized as both a COVID-19 screening tool and a method to identify health workers at greatest risk of COVID-19 positivity, and therefore most in need of testing.


title: Predicting COVID-19 Vaccine Efficacy from Neutralizing Antibody Levels

abstract: Recent studies using data accrued from global SARS-CoV-2 vaccination efforts have demonstrated that breakthrough infections are correlated with levels of neutralizing antibodies. The decrease in neutralizing antibody titers of vaccinated individuals over time, combined with the emergence of more infectious variants of concern has resulted in waning vaccine efficacy against infection and a rise in breakthrough infections. Here we use a combination of neutralizing antibody measurements determined by a high throughput surrogate viral neutralization test (sVNT) together with published data from vaccine clinical trials and comparative plaque reduction neutralization test (PRNT) between SARS-CoV-2 variants to develop a model for vaccine efficacy (VE) against symptomatic infection. Vaccine efficacy estimates using this model show good concordance with real world data from the US and Israel. Our work demonstrates that appropriately calibrated neutralizing antibody measurements determined by high throughput sVNT can be used to provide a semi-quantitative estimate of protection against infection. Given the highly variable antibody levels among the vaccinated population, this model may be of use in identification of individuals with an elevated risk of breakthrough infections.


title: Clinical observation of high-flow nasal cannula (HFNC) with non-rebreather mask (NRM) use on severe or critically ill COVID-19 diabetic patients

abstract:
Background and aimsPrevalence of diabetes is a vital factor in COVID-19s clinical prognosis. This study aimed to investigate and compare the efficacy of High-flow Nasal Cannula (HFNC) with/without non-rebreather mask (NRM) use on critical COVID-19 patients with/without diabetes.

MethodsFor analysis and comparison, epidemiological, biochemical, and clinical data were collected from 240 HFNC ({+/-}NRM) treated severe and critical COVID-19 patients (diabetic = 136; non-diabetic = 104) admitted into ICUs of five hospitals in Chattogram, Bangladesh.

Results59.1% of patients with fever had diabetes (p=0.012). ICU stay was longer for diabetic patients (9.06{+/-}5.70) than non-diabetic patients (7.41{+/-}5.11) (p=0.020). Majority of the hypertensive patients were diabetic (68.3%; p<0.001). Majority of diabetic patients (70.4%; p<0.005) had elevated creatinine levels. Partial pressure of oxygen (mmHg) after HFNC (only) administration was significantly (p=0.031) higher in non-diabetic patients (69.30{+/-}23.56) than in diabetic patients (61.50{+/-}14.49). Diabetic (62.64{+/-}13.05) and non-diabetic patients (59.40{+/-}13.22) had almost similar partial pressure of oxygen (mmHg) from HFNC with NRM. Patients with elevated RBS required NRM with HFNC five times (AOR=5.1, 1.2-20.8) higher than others. Besides age, and hypertension were significantly associated with the HFNC+NRM treated diabetic patients. Factors those affected the HFNC only treated patients were fever and impaired glucose tolerance.

ConclusionsThe results of this study imply that oxygen supply with HFNC and NRM may be beneficial for the elderly/hypertensive diabetic patients with COVID-19 associated AHRF; and that increased blood glucose level could be a determinant for the need of HFNC + NRM treatment.

HighlightsO_LIElderly diabetic patients required both HFNC and NRM to increase oxygen saturation.
C_LIO_LIHypertension may be a factor for diabetic patients with COVID-19 requiring HFNC and NRM together.
C_LIO_LI HFNC + NRM-combination therapy might be needed when blood glucose levels rise.
C_LI

category: intensive care and critical care medicine


title: Clinical observation of high-flow nasal cannula with non-rebreather mask use on severe or critically ill COVID-19 diabetic patients


title: Differentiating COVID-19 and dengue from other febrile illnesses in co-epidemics: Development and internal validation of COVIDENGUE scores

abstract:
BackgroundFrom a cohort study, we developed two scores to discriminate coronavirus 2019 (COVID-19) from dengue and other febrile illnesses (OFIs).

MethodsAll subjects suspected of COVID-19 who attended the SARS-CoV-2 testing center of Saint-Pierre hospital, Reunion, between March 23 and May 10, 2020, were assessed for identifying predictors of both infectious diseases from a multinomial logistic regression model. Two scores were developed after weighting the odd ratios then validated by bootstrapping.

ResultsOver 49 days, 80 COVID-19, 60 non-severe dengue and 872 OFIs were diagnosed. The translation of the best fit model yielded two scores composed of 11 criteria: contact with a COVID-19 positive case (+3 points for COVID-19; 0 point for dengue), return from travel abroad within 15 days (+3/-1), previous individual episode of dengue (+1/+3), active smoking (-3/0), body ache (0/+5), cough (0/-2), upper respiratory tract infection symptoms (-1/-1), anosmia (+7/-1), headache (0/+5), retro-orbital pain (-1/+5), and delayed presentation (>3 days) to hospital (+1/0). The area under the receiver operating characteristic curve was 0.79 (95%CI 0.76-0.82) for COVID-19 score and 0.88 (95%CI 0.85-0.90) for dengue score. Calibration was satisfactory for COVID-19 score and excellent for dengue score. For predicting COVID-19, sensitivity was 97% at the 0-point cut-off and specificity 99% at the 10-point cut-off. For predicting dengue, sensitivity was 97% at the 3-point cut-off and specificity 98% at the 11-point cut-off.

ConclusionsThe COVIDENGUE scores proved discriminant to differentiate COVID-19 and dengue from OFIs in the context of SARS-CoV-2 testing center during a co-epidemic.

category: epidemiology


title: Re-emergence of Invasive Pneumococcal Disease in Germany during the Spring and Summer of 2021

abstract:
BackgroundThe incidence of invasive pneumococcal disease (IPD) decreased worldwide in 2020 and the first quarter of 2021, concurrent with non-pharmaceutical interventions (NPIs) intended to stymie transmission of SARS-CoV-2. In 2021, stringency of these NPI strategies has varied. We investigated age- and serotype-specific variations in IPD case counts in Germany in 2020-2021.

MethodsIPD cases through July 31, 2021 were stratified by age group, serotype, or geographic location. IPD surveillance data in 2020-2021 were compared with: 1) IPD surveillance data from 2015-2019, 2) mobility data during 2020 and 2021, and 3) NPI stringency data in 2020 and 2021.

ResultsIPD began to return towards baseline values among children 0 to 4 years old in April 2021 and exceeded baseline levels by June 2021 (a 9% increase over the average monthly values for 2015-2019). Children 5 to 14, adults aged 15-34 and adults 80 years and older showed increases in IPD cases which went over baseline values starting in July 2021, with increases also starting in Spring 2021. The age distribution and proportion of vaccine serotype IPD remained comparable to previous years despite lower overall case counts in 2020 and 2021. The percent change in IPD incidence compared to the previous five years correlated with changes in mobility and with NPI stringency.

ConclusionsIPD levels began to return to and exceed seasonal levels in Spring/Summer 2021 in Germany following sharp declines in 2020 that coincided with NPIs related to the COVID-19 pandemic. Proportions of vaccine serotypes remained largely consistent throughout 2020-2021.


title: The SARS-CoV-2 infection among students in the University of Porto: a cross-sectional study

abstract:
IntroductionIncidence based on notified cases of SARS-CoV-2 infection underestimates the real extension of the infection. We aimed to quantify SARS-CoV-2 specific antibodies seroprevalence among University students in Porto.

MethodsA rapid point of care testing for SARS-CoV-2 specific immunoglobulin (Ig) M and IgG antibodies was performed, and a questionnaire was applied to the 6512 voluntary students from September to December 2020. We computed the apparent IgM, IgG and IgM or IgG prevalence, and the true prevalence and 95% credible intervals (95% CI) using Bayesian inference.

ResultsWe found an apparent prevalence (IgM or IgG) of 9.7%, the true prevalence being 7.9% (95% CI 4.9-11.1). Prevalence was significantly higher among males (10.9% vs 9.2%), international students (18.1% vs 10.4% local vs 8.8% nationally displaced) and increased with age. Those with a known risk contact, that experienced quarantine, had symptoms, or a previous negative molecular test had a higher seroprevalence. Of the 91 (1.4%) students who reported a molecular diagnosis, 86.7% were reactive for IgM or IgG.

ConclusionBased on immunological evidence infection was 5.6 times more frequent than if based on a molecular diagnosis. The higher seroprevalence among male, older, and international students emphasizes the importance of identifying particular groups.


title: Prenatal alcohol consumption and child IQ and cognition: a Mendelian randomization study

abstract:
BackgroundPrevious studies using Mendelian randomization have found that fetal alcohol exposure may be associated with lower IQ and test scores in childhood.

ObjectivesWe aim to replicate and extend these findings in Generation R Study, a birth cohort based in Rotterdam, the Netherlands.

MethodsWe used data from Generation R which recruited pregnant women between 2002 and 2006. Alcohol use was assessed via questionnaire during each trimester. IQ was measured in the children between ages 5 and 8 using the Snijders-Oomen Non-Verbal Intelligence Test. Scores from a national standardized test administered around age 12 were used as a measure of cognition. We estimated the associations between ten genetic variants in the mothers previously found to be related to alcohol consumption and metabolism and each of the outcomes. In the children, we also estimated the association between the same genetic variants as well as two polygenic scores for alcohol consumption and the outcomes.

ResultsMaternal genetic variants were not found to be related to either outcome but wide confidence intervals did not preclude important effects. A few genetic variants in the children were suggestive of a decrease in IQ. Likewise, one genetic variant and the genetic score had estimates and confidence intervals consistent with increases in standardized test scores.

ConclusionsOur results provide slight support for associations between genetic variants in children related to maternal prenatal alcohol consumption and IQ and cognition outcomes. These findings are in line with two previous studies on this topic.


title: Variation at Spike position 142 in SARS-CoV-2 Delta genomes is a technical artifact caused by dropout of a sequencing amplicon

abstract: Public SARS-CoV-2 genomes from the Delta lineage show complex and confusing patterns of mutations at Spike codon 142, and at another nearby position, Spike codon 95. It has been hypothesised that these represent recurrent mutations with interesting evolutionary dynamics, and that these mutations may affect viral load. Here we show that these patterns, and the relationship with viral load, are artifacts of sequencing difficulties in this region of the Delta genome caused by a deletion in the binding site for the 72_RIGHT primer of the ARTIC V3 schema. Spike G142D should be considered a lineage-defining mutation of Delta.


title: Modeling the influence of vaccine administration on COVID-19 testing strategies

abstract: Vaccination is considered the best strategy for limiting and eliminating the COVID-19 pandemic. The success of this strategy relies on the rate of vaccine deployment and acceptance across the globe. As these efforts are being conducted, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus is continuously mutating, which leads to the emergence of variants with increased transmissibility, virulence, and lower response the vaccines. One important question is whether surveillance testing is still needed in order to limit SARS-CoV-2 transmission in an increasingly vaccinated population. In this study, we developed a multi-scale mathematical model of SARS-CoV-2 transmission in a vaccinated population and used it to predict the role of testing in an outbreak with alpha and delta variants. We found that, when the alpha variant is dominant, testing is effective when vaccination levels are low to moderate and its impact is diminished when vaccination levels are high. When the delta variant is dominant, widespread vaccination is necessary in order to prevent significant outbreaks. When only moderate vaccination can be achieved, frequent testing can significantly reduce the cumulative size of delta variant outbreak, with the impact of testing having maximum effects when focused on the non-vaccinated population.


title: Vaccine effectiveness of Ad26.COV2.S against symptomatic COVID-19 and clinical outcomes in Brazil: a test-negative study design

abstract: We used a test-negative design to estimate the vaccine effectiveness of Ad26.COV2.S (Janssen) against symptomatic COVID-19 and clinical outcomes in Mato-Grosso do Sul, Brazil. We analyzed 11,817 RT-PCR tests. The mean age was 37 (SD=17) years, 2,308 (20%) of individuals more or equal than 50 years and almost two-thirds of the population was Brown/Pardo. Adjusted effectiveness against symptomatic COVID-19 after 28 days of the single dose was 50.9% (95% CI, 35.5-63.0). Adjusted effectiveness against clinical outcomes was 72.9% (95% CI, 35.1-91.1) for hospitalization, 92.5% (95% CI, 54.9-99.6) for ICU admission, 88.7% (95% CI, 17.9-99.5) for mechanical ventilation and 90.5% (95% CI, 31.5-99.6) for death. Despite lacking precision on some estimates, a single dose of Ad26.COV2.S vaccine continues to protect specially for severe forms of COVID-19 in the context of new variants.


title: CoWWAn: Model-based assessment of COVID-19 epidemic dynamics by wastewater analysis

abstract: We present COVID-19 Wastewater Analyser (CoWWAn) to reconstruct the epidemic dynamics from SARS-CoV-2 viral load in wastewater. As demonstrated for various regions and sampling protocols, this mechanistic model-based approach quantifies the case numbers, provides epidemic indicators and accurately infers future epidemic trends. In situations of reduced testing capacity, analysing wastewater data with CoWWAn is a robust and cost-effective alternative for real-time surveillance of local COVID-19 dynamics.


title: Sex steroid hormones and risk of breast cancer incidence and survival: A two-sample Mendelian randomization study

abstract:
BackgroundBreast cancer (BC) is the cancer with the highest incidence and mortality in women worldwide. Observational epidemiological studies suggest a positive association between testosterone, estradiol, dehydroepiandrosterone sulphate (DHEAS) and both pre- and post-menopausal BC. Since previous studies may be prone to bias and confounding, we used a two-sample Mendelian randomization (MR) analysis to investigate this association.

MethodsGenetic instruments for nine sex steroid hormones and sex hormone binding globulin (SHBG) were obtained from genome-wide association studies (GWAS) conducted in the UK Biobank (total testosterone (TT) N:230,454, bioavailable testosterone (BT) N: 188,507 and SHBG N: 189,473), The United Kingdom Household Longitudinal Study (DHEAS N: 9,722), the LIFE-Adult and LIFE-Heart cohorts (estradiol N: 2,607), the LIFE-Heart cohort only (androstenedione N: 711, aldosterone N: 685, progesterone N: 1,259 and 17-hydroxyprogesterone N: 711) and the CORtisol NETwork (CORNET) consortium (cortisol N: 25,314). GWAS summary statistics were also obtained from the Breast Cancer Association Consortium (BCAC) for overall BC risk (N: 122,977 cases and 105,974 controls) and BC mortality (96,661 BC cases and 7,697 BC-specific deaths). Subtype specific analysis were carried out for incidence of estrogen receptor (ER)+ BC, ER- BC, luminal A-like BC, luminal B-like BC, luminal B/HER2-negative-like BC, HER2-enriched-like BC, triple negative BC (TNBC) and BRCA1 mutated TNBC.

ResultsUsing an inverse-variance weighted (IVW) approach, we found that a standard deviation (SD) increase in TT, BT and estradiol increased the risk of overall BC (OR: 1.14, 95% CI: 1.09-1.21, OR: 1.19, 95% CI: 1.07-1.33 and OR: 1.03, 95% CI: 1.01-1.06, respectively) and ER+ BC (OR: 1.19, 95% CI: 1.12-1.27, OR: 1.25, 95% CI: 1.11-1.40 and OR: 1.06, 95% CI: 1.03-1.09, respectively). A SD increase in DHEAS also increased ER+ BC risk (OR: 1.09, 95% CI: 1.03-1.09). Subtype specific analyses showed similar associations with ER+ expressing subtypes: luminal A-like BC, luminal B-like BC and luminal B/HER2-negative-like BC. A SD increase in cortisol was associated with poor survival after a diagnosis of ER-BC (HR: 2.35, 95% CI: 1.00-5.49).

Discussion/ConclusionTT, BT, DHEAS and estradiol increase the risk of ER+ type BCs similar to observational studies, but none of these hormone measures are associated with BC survival. We found some evidence that cortisol reduced ER- BC survival. Stronger genetic instruments are required before definitive conclusions can be made about the role of other sex-steroid hormones in breast cancer. Understanding the role of sex steroid hormones in BC risk, particularly subtype-specific risks, highlights the potential importance of attempts to modify and/or monitor hormone levels in order to prevent BC.


title: Incidence of SARS-CoV-2 infection in a cohort of workers from the University of Porto

abstract:
BackgroundRepeated serosurveys in the same population provide more accurate estimates of the frequency of SARS-CoV-2 infection and more comparable data than notified cases. We aimed to estimate the incidence of SARS-CoV-2 infection, identify associated risk factors, and assess time trends in the ratio of serological/molecular diagnosis in a cohort of university workers.

MethodsParticipants had a serological rapid test for SARS-CoV-2 Immunoglobulins M and G, and completed a questionnaire, in May-July 2020 (n=3628) and November 2020-January 2021 (n=2661); 1960 participated in both evaluations and provided data to compute the incidence proportion and the incident rate. Crude and adjusted incidence rate ratios (aIRR) and 95% confidence intervals (CI) were computed using generalised linear models with Poisson regression.

ResultsThe incidence rate was 1.8/100 person-month (95%CI 1.6-2.1), and the 6 months cumulative incidence was 10.7%. The serological/molecular diagnosis ratio was 10:1 in the first evaluation and 3:1 in the second. Considering newly identified seropositive cases at the first (n=69) and second evaluation (n=202), 29.0% and 9.4% never reported symptoms, respectively, 14.5% and 33.3% reported contact with a confirmed case and 82.6%, and 46.0% never had a molecular test. Males (aIRR: 0.59; 95%CI: 0.42-0.83) and "high-skilled white-collar" workers (aIRR: 0.73, 95%CI: 0.52-1.02) had lower incidence of infection.

ConclusionUniversity workers presented a high SARS-CoV-2 incidence while restrictive measures were in place. The time decrease in the proportion of undiagnosed cases reflected the increased access to testing, but opportunities continued to be missed, even in the presence of COVID-19 like symptoms.

What is already known on this subjectO_LIThe median ratio of seroprevalence to the corresponding cumulative incidence is 18, however, there is great variability between studies.
C_LIO_LISeroprevalence studies are essential to estimate the true burden of the infection.
C_LIO_LIFew cohort studies focused on essential non-healthcare workers, such as university workers.
C_LI

What this study addsO_LIThis longitudinal seroprevalence study among university workers found a SARS-CoV-2-specific IgM or IgG incidence rate of 1.8/100 person-month, and a 6 months cumulative incidence of 10.7%.
C_LIO_LIThe undiagnosed fraction was 3:1 in the second evaluation, representing a decrease from a 10:1 in the first evaluation in the same population showing that a gap to test-trace-isolate remained in this highly educated working population.
C_LIO_LISeropositive participants were mostly pauci- or symptomatic with no known contact with a COVID-19 confirmed case; "high-skilled white-collar" workers were at lower risk of being an incident seropositive case.
C_LI


title: Updated Model for the USA Summer 2021 CoVID-19 Resurgence

abstract:
Over the course of the CoVID-19 pandemic, we utilized widely-available real-time data to create models for predicting its spread, and to estimate the time evolution for each of the USA CoVID-19 waves. Our recent medrxiv.org preprint (10.1101_2021.08.16.21262150) examined the USA Summer 2021 resurgence, from [~]6/7/2021 up through [~]8/15/2021 (Stage 1). Our preprint covering this period showed that CoVID-19 could infect virtually all susceptible non-vaccinated persons, who were practicing minimal Social Distancing and NO Mask-Wearing.

The most recent USA Summer 2021 resurgence data, from [~]8/13/2021 up through 10/7/2021 (Stage 2), shows a significant "flattening of the curve". Since no new government mandates were involved, our interpretation is that some vaccine-hesitant people have now elected to become vaccinated. The Social Distancing parameter in our model showed a [~]6.67X increase between Stage 1 and Stage 2, indicating that this parameter also can serve as an indicator of vaccination rates. The other parameter in our model, which is associated with Mask-Wearing, increased from zero to a finite but relatively small value. Using the 10/7/2021 USA CoVID-19 overall mortality rate of [~]1.60942 % gives these updated predictions for the total number of USA CoVID-19 cases and deaths:

NTOTAL(3/21/2022) {approx} 52, 188, 000 ; NDeaths(3/21/2022) {approx} 839, 900, NTOTAL(3/21/2024) {approx} [52, 787, 000 ; NDeaths(3/21/2024) {approx} 849, 600, assuming no new 2021 Winter Resurgence occurs (with 3 Figures).


title: Predicting sensitivity and resilience to modifiable risk factors for cardiometabolic morbidity and mortality

abstract:
BackgroundLifestyle exposures play a major role in the development of disease, yet people vary in their susceptibility. A critical step towards precision medicine is identifying individuals who are resilient or sensitive to the environment, and, assess whether the allocation to these predicted groups are more or less likely to develop cardiometabolic disease.

MethodsWe have used repeated data from the VHU study (n=35440) to identify sensitive and resilient individuals using prediction intervals at the 5th and 95th quantile. Three exposure susceptibility groups were derived per cardiometabolic score using quantile regression forests in the training dataset; next, in the validation dataset, we assessed the different risks of the groups using Cox proportional hazard models for CVD and diabetes.

ResultsThe results of our study suggest that, after [~]10 y of follow-up, individuals with sensitivity to the environmental exposures associated with systolic and diastolic blood pressure, blood lipids, and glucose were at higher risk of developing cardiometabolic disease. Moreover, when hazards were pooled with the replication cohort, for those individuals sensitive to the exposures associated with blood pressure traits, the hazards remained significant.

ConclusionsIdentifying individuals who are predicted to be sensitive are at higher risk of developing disease, this population may be a clinical target for prevention or early intervention and public health strategies.


title: Prediction of severe COVID-19 infection at the time of testing: A machine learning approach

abstract: Early and effective detection of severe infection cases during a pandemic can significantly help patient prognosis and resource allocation. We develop a machine learning framework for detecting severe COVID-19 cases at the time of RT-PCR testing. We retrospectively studied 988 patients from a small Canadian province that tested positive for SARS-CoV-2 where 42 (4%) cases were at-risk (i.e., resulted in hospitalization, admission to ICU, or death), and 8 (< 1%) cases resulted in death. The limited information available at the time of RT-PCR testing included age, comorbidities, and patients reported symptoms, totaling 27 features. Vaccination status was unavailable. Due to the severe class imbalance and small dataset size, we formulated the problem of detecting severe COVID as anomaly detection and applied three models: one-class support vector machine (OCSVM), weight-adjusted XGBoost, and weight-adjusted Ad-aBoost. The OCSVM was the best performing model for detecting the deceased cases with an average 95% true positive rate (TPR) and 27.2% false positive rate (FPR). Meanwhile, the XGBoost provided the best performance for detecting the at-risk cases with an average 96.2% TPR and 19% FPR. In addition, we developed a novel extension to SHAP interpretability to explain the outputs from the models. In agreement with conventional knowledge, we found that comorbidities were influential in predicting severity, however, we also found that symptoms were generally more influential, noting that machine learning combines all available data and is not a single-variate statistical analysis.


title: Context Matters! Depression following childbirth or a chronic disease diagnosis shows specific risk factor profiles.

abstract:
Progress towards understanding the etiology of major depression (MD) is compromised by its clinical heterogeneity. The variety of contexts underlying the development of a major depressive episode may contribute to such heterogeneity. Here, we aimed to compare risk factor profiles of three subgroups of MD according to episode context.

Using self-report questionnaires and administrative records from the UK Biobank, we characterised three contextual subgroups of MD: postpartum depression (3,581 cases), depression following diagnosis of a chronic disease (409 cases) and a more typical (named heterogeneous) MD phenotype excluding the two prior contexts (34,699 cases). Controls with the same exposure were also defined. We tested each subgroup for association with MD polygenic risk scores (PRS) and other risk factors previously associated with MD (bipolar disorder PRS, neuroticism, reported trauma in childhood and adulthood, socioeconomic status, family history of depression, education).

MD polygenic risk scores were associated with all subgroups, however, postpartum depression cases had higher PRS than heterogeneous MD cases (OR = 1.06, 95% CI: 1.02 - 1.10). Relative to heterogeneous depression, postpartum depression was more weakly associated with adulthood trauma and neuroticism. Relative to heterogeneous depression, depression following diagnosis of a chronic disease did not have higher MD polygenic risk scores but had weaker associations with neuroticism and reported trauma in adulthood and childhood.

The observed differences in risk factor profiles according to the context of a major depressive episode help provide insight into the heterogeneity of depression. Future studies dissecting such heterogeneity could help reveal more refined etiological insights.

category: psychiatry and clinical psychology


title: Reward Dysfunction in General and Specific Psychopathology in Children and Adults

abstract:
BackgroundReward dysfunction has been implicated in many psychiatric disorders such as attention-deficit/hyperactivity disorders, depression, and substance use disorders. However, psychiatric comorbidities are common, and the specificity of reward dysfunction to individual psychopathologies is unknown. The objective of this study was to evaluate the association between reward functioning and specific or general psychopathologies.

Methods1044 adults and their 1215 children (ages 6-12) completed various measures of the Positive Valence System domain from the Research Domain Criteria (RDoC), which included the Delayed and Probability Discounting Tasks, Energy Expenditure for Reward Task, and Iowa Gambling Task. Children also completed the Experienced Pleasure Scale for children, while adults completed the Temporal Experience of Pleasure Scale and the Behavioral Activation System tasks. Psychopathology was assessed using the Child Behavior Checklist (CBCL) for children and the Adult Self Report (ASR) for parents.

ResultsOne general factor identified via principal factors factor analysis explained the majority of variance in psychopathology in both groups. Reward measures in both adults and children were significantly associated with general psychopathology as well as most specific psychopathologies. Some associations between reward and psychopathology did not hold following removal of general psychopathology; nonetheless, certain reward constructs were uniquely associated with specific disorder problems but not general psychopathology.

ConclusionDisorder problem specific associations with reward functioning can be identified after removal of comorbidity. General propensity toward psychopathology is significantly but not uniquely correlated with reward dysfunction. Altogether, this may have broader implications for future study of the role of reward in disease pathogenesis.


title: Refining the Analysis of Multidimensional Psychometric Data: A Geometric Distance Approach

abstract:
Validated instruments such as questionnaires, patient-reported outcome measures and clinician-rated psychopathology scales, are indispensable for measuring symptom burden and mental state, and for defining outcomes in both psychiatric practice and clinical trials. Most often, the values on the instruments multiple items (dimensions) are added to derive a single, univariate (scalar) sum-score. Although this approach simplifies interpretation, there are always many possible combinations of individual items that can yield the same sum-score. Two patients can therefore obtain identical scores on a given instrument, despite having very different combinations of underlying item scores corresponding to different patterns of clinical symptoms. The same is also true when a single patient is measured at two different time points, where the resulting sum-scores can obscure changes that may be clinically meaningful.

We present an alternative analytic framework, which leverages geometric concepts to represent measurements as points in a vector space. Using this framework, we show why sum-scores obscure information present in measurements of clinical state, and also provide a straightforward algorithm to mitigate against this problem. Clinically-relevant outcomes, such as remission or patient-centered treatment goals, can be represented intuitively, as reference points or  anchors within this space. Using real-world data, we then demonstrate how measuring the relative distance between points and anchors preserves more information, allowing outcomes such as proximity to remission, to be defined and measured.


title: Fetal brain growth and infant autistic traits

abstract:
BackgroundResearch indicates that structural differences exist in the brains of individuals who later display developmental conditions (e.g., autism). To date only a handful of studies have explored the relationship between fetal brain growth and later infant outcomes, with a particular focus on fetal head circumference (HC) as a proxy for brain development. These findings have been inconsistent. We investigate whether fetal brain measurements correlate with the emergence of autistic traits in toddlers.

Method219 singleton pregnancies (104 males and 115 females) were recruited at the Rosie Hospital, Cambridge, UK. A 2D ultrasound was performed at 12-, 20- and between 26-30-weeks of pregnancy, measuring head circumference (HC), ventricular atrium (VA) and transcerebellar diameter (TCD). 178 infants were subsequently followed up at 18-20 months of age and completed the Quantitative Checklist for Autism in Toddlers (Q-CHAT) to observe early autistic traits.

ResultsHC was larger in males than in females in both the second and third trimester. There was a significant positive association between TCD size at 20 weeks and Q-CHAT scores at 18-20 months of age, found in both univariate and multivariate analyses, and this remained significant after controlling for sex.

ConclusionThere is a positive relationship between cerebellar (TCD) development at 20 weeks gestation and the later emergence of autistic traits (at 18-20 months of age). Atypical neurodevelopment may start prenatally. If replicated these findings could facilities early diagnosis and improved outcomes.


title: Estimating COVID-19 Hospitalizations in the United States with surveillance data using a Bayesian Hierarchical model

abstract:
IntroductionIn the United States, COVID-19 is a nationally notifiable disease, cases and hospitalizations are reported to the CDC by states. Identifying and reporting every case from every facility in the United States may not be feasible in the long term. Creating sustainable methods for estimating burden of COVID-19 from established sentinel surveillance systems is becoming more important. We aimed to provide a method leveraging surveillance data to create a long-term solution to estimate monthly rates of hospitalizations for COVID-19.

MethodsWe estimated monthly hospitalization rates for COVID-19 from May 2020 through April 2021 for the 50 states using surveillance data from COVID-19-Associated Hospitalization Surveillance Network (COVID-NET) and a Bayesian hierarchical model for extrapolation. We created a model for six age groups (0-17, 18-49, 50-64, 65-74, 75-84, and [≥]85 years), separately. We identified covariates from multiple data sources that varied by age, state, and/or month, and performed covariate selection for each age group based on two methods, Least Absolute Shrinkage and Selection Operator (LASSO) and Spike and Slab selection methods. We validated our method by checking sensitivity of model estimates to covariate selection and model extrapolation as well as comparing our results to external data.

ResultsWe estimated 3,569,500 (90% Credible Interval:3,238,000 - 3,934,700) hospitalizations for a cumulative incidence of 1,089.8 (988.6 - 1,201.3) hospitalizations per 100,000 population with COVID-19 in the United States from May 2020 through April 2021. Cumulative incidence varied from 352 - 1,821per 100,000 between states. The age group with the highest cumulative incidence was aged [≥]85 years (5,583.1; 5,061.0 - 6,157.5). The monthly hospitalization rate was highest in December (183.8; 154.5 - 218.0). Our monthly estimates by state showed variations in magnitudes of peak rates, number of peaks and timing of peaks between states.

ConclusionsOur novel approach to estimate COVID-19 hospitalizations has potential to provide sustainable estimates for monitoring COVID-19 burden, as well as a flexible framework leveraging surveillance data.


title: Combining Tumor Segmentation Masks with PET/CT Images and Clinical Data in a Deep Learning Framework for Improved Prognostic Prediction in Head and Neck Squamous Cell Carcinoma

abstract: PET/CT images provide a rich data source for clinical prediction models in head and neck squamous cell carcinoma (HNSCC). Deep learning models often use images in an end-to-end fashion with clinical data or no additional input for predictions. However, in the context of HNSCC, the tumor region of interest may be an informative prior in the generation of improved prediction performance. In this study, we utilize a deep learning framework based on a DenseNet architecture to combine PET images, CT images, primary tumor segmentation masks, and clinical data as separate channels to predict progression-free survival (PFS) in days for HNSCC patients. Through internal validation (10-fold cross-validation) based on a large set of training data provided by the 2021 HECKTOR Challenge, we achieve a mean C-index of 0.855 {+/-} 0.060 and 0.650 {+/-} 0.074 when observed events are and are not included in the C-index calculation, respectively. Ensemble approaches applied to cross-validation folds yield C-index values up to 0.698 in the independent test set (external validation). Importantly, the value of the added segmentation mask is underscored in both internal and external validation by an improvement of the C-index when compared to models that do not utilize the segmentation mask. These promising results highlight the utility of including segmentation masks as additional input channels in deep learning pipelines for clinical outcome prediction in HNSCC.


title: Head and Neck Cancer Primary Tumor Auto Segmentation using Model Ensembling of Deep Learning in PET-CT Images

abstract: Auto-segmentation of primary tumors in oropharyngeal cancer using PET/CT images is an unmet need that has the potential to improve radiation oncology workflows. In this study, we develop a series of deep learning models based on a 3D Residual Unet (ResUnet) architecture that can segment oropharyngeal tumors with high performance as demonstrated through internal and external validation of large-scale datasets (training size = 224 patients, testing size = 101 patients) as part of the 2021 HECKTOR Challenge. Specifically, we leverage ResUNet models with either 256 or 512 bottleneck layer channels that are able to demonstrate internal validation (10-fold cross-validation) mean Dice similarity coefficient (DSC) up to 0.771 and median 95% Hausdorff distance (95% HD) as low as 2.919 mm. We employ label fusion ensemble approaches, including Simultaneous Truth and Performance Level Estimation (STAPLE) and a voxel-level threshold approach based on majority voting (AVERAGE), to generate consensus segmentations on the test data by combining the segmentations produced through different trained cross-validation models. We demonstrate that our best performing ensembling approach (256 channels AVERAGE) achieves a mean DSC of 0.770 and median 95% HD of 3.143 mm through independent external validation on the test set. Concordance of internal and external validation results suggests our models are robust and can generalize well to unseen PET/CT data. We advocate that ResUNet models coupled to label fusion ensembling approaches are promising candidates for PET/CT oropharyngeal primary tumors auto-segmentation, with future investigations targeting the ideal combination of channel combinations and label fusion strategies to maximize segmentation performance.


title: Back to the medical classes-Part I- Strategy for return to the presential practices during COVID-19 pandemics in a Brazilian Medical School

abstract:
IntroductionIn Brazil, practices of medical students have been interrupted due to COVID-19 to meet emergency demands.

AimTo describe a strategy for a controlled return to the presential practices for medical students.

MethodsWe developed a standardized protocol to be applied before and during the return of the practical classes in medical students of Universidade Federal Fluminense, in the follow months after COVID-19 pandemic beginning. The protocol was comprised in three parts: Remote training on COVID-19 prevention; Face-to-face training focused in COVID-19 prevention, handwashing and personal protective equipment use; Investigation of students COVID-19 status before starting practical activities and weekly monitoring for COVID-19 during seven weeks. The training was done by medical teachers in small groups for medical students of the last lective semester.

ResultsThe classes were interrupted on March 12, 2020 and returned in August 10, 2020. Seventy-one students were trained and followed. The mean age was 26.6 years (26.7 {+/-}0.835) and 54% were female. Forty-nine (69%) students over 71 had a private health insurance, 60 (84.5%) shared a house/apartment with one or more person and 12(16.9%) reported a previous comorbidity. Eighteen (25.4%) over 71 reported previous symptoms of COVID-19, being positive in two students. During the follow-up, fourteen (19.7%) over 71 students were placed in quarantine due to signals/symptoms compatible with COVID-19 or contact with symptomatic case. Only two cases (2.8%) were confirmed and occurred in Brazilian epidemiological week 37.

ConclusionThe protocol was successful in minimizing COVID-19 acquisition during practical classes of medical students.

category: medical education


title: Efficacy and safety of a third SARS-CoV-2 vaccination in multiple sclerosis vaccine non-responders

abstract:
ImportanceVaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to protect against coronavirus disease of 2019 (COVID-19) is recommended for patients with multiple sclerosis (pwMS). However, approximately 80% of all pwMS treated with anti-CD20 therapy (rituximab, ocrelizumab) or fingolimod have low or absent humoral immunity after vaccination with two doses of SARS-CoV-2 mRNA vaccines. The efficacy and safety of a third vaccine dose in this group is largely unknown.

ObjectiveTo characterize the humoral immunogenicity and the safety of a third dose of mRNA-COVID-19 vaccine in anti-CD20-or fingolimod-treated pwMS with low or absent humoral immunity (i.e., anti-SARS-CoV-2 IgG <70 arbitrary units (AU) and <5 AU, respectively) after two vaccinations.

Design, setting and participants130 anti-CD20- or fingolimod-treated pwMS with low or absent humoral immunity despite full vaccination against SARS-CoV-2, received a third dose of SARS-CoV-2 mRNA vaccine. Humoral immunity (i.e., antibody response against SARS-CoV-2) and the frequency and characteristics of side-effects were analyzed in all participants.

ExposuresA third vaccine dose against SARS-CoV-2 with BNT162b2- or mRNA-1273-COVID-19 vaccine.

Main outcomes and measuresPatient- and treatment-specific variables were acquired using a digital questionnaire, the Norwegian Immunization Registry and hospital journals. Humoral immunity was assessed by measuring SARS-CoV-2 SPIKE receptor-binding domain (RBD) IgG response. Low/absent humoral immunity was assumed in cases of AU<70 after anti-SPIKE protein-based serology 3-5 weeks after revaccination.

ResultsA third dose of SARS-CoV-2 mRNA vaccine increased anti-SARS-CoV-2 SPIKE RBD IgG levels significantly. The proportion of patients with assumed protective humoral immunity (anti-SARS-CoV-2 SPIKE RBD IgG > 70 AU) were 25% among patients using anti-CD20 therapy and 7% among those treated with fingolimod. No adverse events were registered during the study period.

Conclusion and relevanceA third dose of mRNA-COVID-19 vaccine was associated with significantly increased levels of anti-SARS-CoV-2 SPIKE RBD IgG, - and hence assumed protective humoral immunity - in anti-CD20- or fingolimod-treated pwMS with low or absent humoral immunity despite full vaccination. The effect of a third vaccine dose was limited and more prominent among those treated with anti-CD20 therapy.

category: neurology


title: A deep learning based graph-transformer for whole slide image classification

abstract: Deep learning is a powerful tool for assessing pathology data obtained from digitized biopsy slides. In the context of supervised learning, most methods typically divide a whole slide image (WSI) into patches, aggregate convolutional neural network outcomes on them and estimate overall disease grade. However, patch-based methods introduce label noise in training by assuming that each patch is independent with the same label as the WSI and neglect the important contextual information that is significant in disease grading. Here we present a Graph-Transformer (GT) based framework for processing pathology data, called GTP, that interprets morphological and spatial information at the WSI-level to predict disease grade. To demonstrate the applicability of our approach, we selected 3,024 hematoxylin and eosin WSIs of lung tumors and with normal histology from the Clinical Proteomic Tumor Analysis Consortium, the National Lung Screening Trial, and The Cancer Genome Atlas, and used GTP to distinguish adenocarcinoma (LUAD) and squamous cell carcinoma (LSCC) from those that have normal histology. Our model achieved consistently high performance on binary (tumor versus normal: mean overall accuracy = 0.975 {+/-} 0.013) as well as three-label (normal versus LUAD versus LSCC: mean accuracy = 0.932 {+/-} 0.019) classification on held-out test data, underscoring the power of GT-based deep learning for WSI-level classification. We also introduced a graphbased saliency mapping technique, called GraphCAM, that captures regional as well as contextual information and allows our model to highlight WSI regions that are highly associated with the class label. Taken together, our findings demonstrate GTP as a novel interpretable and effective deep learning framework for WSI-level classification.


title: Rare Variant Aggregation in 148,508 Exomes Identifies Genes Associated with Proxy Alzheimer's Disease

abstract: We generated a proxy Alzheimers disease phenotype for 148,508 individuals in the UK biobank in order to perform exome-wide rare variant aggregation analyses to identify genes associated with proxy Alzheimers disease. We identified four genes significantly associated with the proxy phenotype, three of which have been previously associated with clinically diagnosed Alzheimers disease (SORL1, TREM2, and TOMM40). We identified one gene (HEXA) which has not been previously associated with Alzheimers disease but is known to contribute to neurodegenerative disease. Here we show that proxy Alzheimers disease can capture some of the rare variant association signal for Alzheimers disease and can be used to highlight genes and variants of interest. The proxy phenotype allows for the utilisation of large genetic databases without clinically diagnosed Alzheimers disease patients to uncover variants and genes that contribute to Alzheimers disease.


title: Establishment and preliminary evaluation of a teaching hospital-based dementia consultation service for rurally-based regional district general hospitals

abstract: The treatment of patients with dementia poses a considerable challenge to regional district general hospitals, particularly in rural areas. Here we report the establishment and initial evaluation of a dementia-specific consultation service provided by a teaching hospital-based Psychiatry Department to regional district general hospitals in smaller surrounding towns. The service was provided to patients both with pre-existing and newly diagnosed or suspected dementia, who were in acute hospital care for concurrent conditions. An initial evaluation of 61 consultations - 49 on-site and 12 via telemedicine - was performed to assess the needs of the participating hospitals and the specific nature of the referrals to the consultation service. Suspected dementia or cognitive dysfunction was the primary reason for consultation requests (>50% of cases). Other common requests concerned suspected delirium, behavioral disturbances, and therapeutic recommendations. During the consultations, a diagnosis of dementia was reached in 52.5% of cases, with other common diagnoses including delirium and depression. Recommendations related to pharmacotherapy were given in 54.1% of consultations. Other recommendations included referral for outpatient neurological or psychiatric follow-up, further diagnostic assessment, or assessment in a memory clinic. Geriatric psychiatric inpatient treatment was recommended in only seven cases (11.5 %). Our initial evaluation demonstrates the feasibility of providing a dementia-specific consultation service in a rural area. The service has the potential to reduce acute transfers to inpatient geriatric psychiatry and enables older patients with dementia or delirium to be treated locally by helping and empowering rurally-based regional hospitals to manage these problems and associated complications.

category: geriatric medicine


title: Factors affecting use of speech testing in adult audiology

abstract:
ObjectiveTo investigate the factors affecting the use speech testing in adult audiology services

DesignA mixed-methods cross-sectional questionnaire study

Study SampleA UK sample (n=306) of hearing healthcare professionals (HHPs) from the public (64%) and private sector (36%) completed the survey

ResultsIn the UK, speech testing practice varied significantly between health sector. Speech testing was carried out during the audiology assessment by 68% of private sector HHPs and 5% of those from the public sector. During the hearing aid intervention stage speech testing was carried out by 40% and 8% of HHPs from the private and public sector, respectively. Recognised benefits of speech testing included: 1) providing patients with relatable assessment information, 2) guiding hearing aid fitting, 3) supporting a diagnostic test battery. A lack of clinical time was a key barrier to uptake.

ConclusionUse of speech testing varies in adult audiology. Results from the present study found the percentage of UK HHPs making use of speech tests was low compared to other countries. HHPs recognised different benefits of speech testing in audiology practice but the barriers limiting uptake were often driven by factors derived from decision makers rather than clinical rationale. Privately funded HHPs used speech tests more frequently than those working in the public sector where time and resources are under greater pressure and governed by guidance that does not include a recommendation for speech testing. Therefore, the inclusion of speech testing in national clinical guidelines could increase the consistency of use.

category: health systems and quality improvement


title: Persistence of antibody and T cell responses to the Sinopharm/BBIBP-CorV vaccine in Sri Lankan individuals

abstract:
BackgroundTo determine the kinetics and persistence of immune responses following the Sinopharm/BBIBP-CorV, we investigated immune responses in a cohort of Sri Lankan individuals.

MethodsSARS-CoV-2 specific total antibodies were measured in 20-to-39 year (n=61), 40-to-59-year and those >60 years of age (n=22) by ELISA, 12 weeks after the second dose of the vaccine. ACE2 receptor blocking antibodies (ACE2R-Ab), antibodies to the receptor binding domain (RBD) of the ancestral virus (WT) and variants of concern, were measured in a sub cohort. T cell responses and memory B cell responses were assessed by ELISpot assays.

Results193/203 (95.07%) of individuals had detectable SARS-CoV-2 specific total antibodies, while 67/110 (60.9%) had ACE2R-Ab. 14.3% to 16.7% individuals in the 20 to 39 age groups had detectable antibodies to the RBD of the WT and VOC, while the positivity rates of those >60 years of age was <10%. 14/49 (28.6%) had IFN{gamma} ELISpot responses to overlapping peptides of the spike protein, while memory B cell responses were detected in 9/20 to the S1 recombinant protein. The total antibody levels and ACE2R-Ab declined after 2 to 12 weeks from the second dose, while ex vivo T cell responses remained unchanged. The decline in ACE2R-Ab levels was significant among the 40 to 59 (p=0.0007) and [≥]60 (p=0.005) age groups.

ConclusionsAntibody responses declined in all age groups, especially in those >60 years, while T cell responses persisted. The effect of waning of immunity on hospitalization and severe disease should be assessed by long term efficacy studies.

category: allergy and immunology


title: Simulation and predictions of a new COVID-19 pandemic wave in Ukraine with the use of generalized SIR model

abstract: A new wave of the COVID-19 pandemic in Ukraine, which began in the summer of 2021, was characterized by almost exponential growth of smoothed daily numbers of new cases. This is a matter of great concern and the need to immediately predict the dynamics of the epidemic in order to assess the possible maximum values of new cases, the risk of infection and the number of deaths. The generalized SIR-model and corresponding parameter identification procedure was used to simulate and predict the dynamics of this epidemic wave. The new COVID-19 epidemic wave in Ukraine will begin to subside in mid-October 2021, but its duration will be quite long. Unfortunately, new cases may appear by the summer of 2022.


title: SEIRDQ: A COVID-19 case projection modeling framework using ANN to model quarantine

abstract: We propose and implement a novel approach to model the evolution of COVID-19 pandemic and predict the daily COVID-19 cases (infected, recovered and dead). Our model builds on the classical SEIR-based framework by adding additional compartments to capture recovered, dead and quarantined cases. Quarantine impacts are modeled using an Artificial Neural Network (ANN), leveraging alternative data sources such as the Google mobility reports. Since our model captures the impact of lockdown policies through the quarantine functions we designed, it is able to model and predict future waves of COVID-19 cases. We also benchmark out-of-sample predictions from our model versus those from other popular COVID-19 case projection models.


title: Investigating the transparency of reporting in two-sample summary data Mendelian randomization studies

abstract:
BackgroundTwo-sample Mendelian randomization (2SMR) is an increasingly popular epidemiological method that uses genetic variants as instruments for making causal inferences. Clear reporting of methods employed in such studies is important for evaluating their underlying quality. However, the quality of methodological reporting of 2SMR studies is currently unclear.

ObjectivesWe aimed to assess the reporting quality of studies that used MR-Base, one of the most popular platforms for implementing 2SMR analysis.

MethodsWe created a bespoke reporting checklist to evaluate reporting quality of 2SMR studies. We then searched Web of Science Core Collection, PsycInfo, MEDLINE, EMBASE and Google Scholar citations of the MR-Base descriptor paper to identify published MR studies that used MR-Base for any component of the MR analysis. Study screening and data extraction were performed by at least two independent reviewers.

Results87 studies were included in the primary analysis. Reporting quality was generally poor across studies with a mean of 53% (SD = 14%) of items reported in each study. Many items required for evaluating the validity of key assumptions made in MR were poorly reported: only 44% of studies provided sufficient details for assessing if the genetic variant associates with the exposure ( relevance assumption), 31% for assessing if there are any variant-outcome confounders ( independence assumption), 89% for the assessing if the variant causes the outcome independently of the exposure ( exclusion restriction assumption), and 32% for assumptions of falsification tests. We did not find evidence of a change in reporting quality over time or a difference in reporting quality between studies that used MR-Base and a random sample of MR studies that did not use this platform.

DiscussionThe quality of reporting of two-sample Mendelian randomization studies in our sample was generally poor. Journals and researchers should implement the STROBE-MR guidelines to improve reporting quality.

Other: FundingESRC, CRUK, MRC, John Climax Benevolent Fund, University of Bristol, and the Wellcome Trust. Registration: This study pre-registered on the OSF, and the protocol can be found at DOI 10.17605/OSF.IO/NFM27


title: Excess risk and clusters of symptoms after COVID-19 in a large Norwegian cohort

abstract: Physical, psychological and cognitive symptoms have been reported as post-acute sequelae for COVID-19 patients but are also common in the general, uninfected population. We aimed to calculate the excess risk and identify patterns of 22 symptoms up to 12 months after COVID-19 infection. We followed more than 70,000 participants in an ongoing cohort study, the Norwegian Mother, Father and Child Cohort Study (MoBa) during the COVID-19 pandemic. Infected and non-infected cohort participants registered presence of 22 different symptoms in March 2021. One year after the initial infection, 13 of 22 symptoms were associated with SARS-CoV-2 infection, based on relative risks between infected and uninfected subjects. For instance, 17.4% of SARS-CoV-2 infected cohort participants reported fatigue that persist 12 months after infection, compared to new occurrence of fatigue that had lasted less than 12 months in 3.8% of non-infected subjects (excess risk 13.6%). The adjusted relative risk for fatigue was 4.8 (95 % CI 3.5 to 6.7). Two main underlying factors explained 50% of the variance in the 13 symptoms. Brain fog, poor memory, dizziness, heart palpitations, and fatigue had high loadings on the first factor, while shortness-of breath and cough had high loadings on the second factor. Lack of taste and smell showed low to moderate correlation to other symptoms. Anxiety, depression and mood swings were not strongly related to COVID-19. Our results suggest that there are clusters of symptoms after COVID-19 due to different mechanisms and question whether it is meaningful to describe long COVID as one syndrome.


title: Maternal postnatal depression and offspring emotional and behavioural development at age 7 years in a UK-birth cohort: the role of paternal involvement

abstract:
BackgroundThere is considerable variability in emotional and behavioural outcomes of children whose mothers experience depression. Few longitudinal studies have examined potential contributions of dimensions of paternal involvement in the association between maternal postnatal depression (PND) and offspring development.

MethodsWe examined pathways from maternal PND at 8 weeks postnatally (assessed using the Edinburgh Postnatal Depression Scale) to offspring emotional and behavioural development at 7 years (assessed using the Strengths and Difficulties Questionnaire) through behavioural, affective and cognitive child-focused and mother-influenced dimensions of paternal involvement in 3,434 members of the UK-based birth cohort, the Avon Longitudinal Study of Parents and Children. Analyses were adjusted for a range of baseline confounders and paternal postnatal depression (PND) as an intermediate confounder.

ResultsMaternal PND was associated with higher levels of some aspects of child-focused and mother-influenced paternal involvement in models accounting for paternal PND, however these pathways were not associated with offspring emotional and behavioural development at age 7 years. There was strong evidence of direct effect from maternal PND to offspring development, but no evidence of mediation through the combination of all indirect pathways through child-focused and mother-influenced paternal involvement. However, higher levels of father-child conflict were associated with increased risk of offspring emotional and behavioural difficulties, and this pathway mediated a proportion of the maternal PND to offspring risk. Additionally, maternal PND was associated with paternal PND, which, in turn, was associated with lower levels of child-focused and mother-influenced paternal involvement.

ConclusionsThe positive associations between maternal PND and some aspects of paternal involvement suggest that non-depressed fathers may engage in  compensatory parenting strategies in response to maternal PND, which although important may not be sufficient in reducing the adverse impact of maternal PND on offspring emotional and behavioural development. Conflictual father-child relationships emerged as a risk factor for adverse offspring development and as an explanatory mechanism in the association between maternal PND and offspring development. These results suggest that interventions that reduce father-child conflict may reduce the risk of emotional and behavioural difficulties in offspring of depressed mothers.


title: Evaluation of viral loads in patients with SARS-CoV-2 Delta variant infection: Higher loads do not translate into different testing scenarios

abstract: The Delta SARS-CoV-2 variant is very infectious, and it is spreading quickly during this pandemic. In the study, we compared viral loads in surging cases infected with the SARS-CoV-2 Delta variant in the fourth wave of COVID-19 with the three prior waves. The data comprised viral loads from positive cases detected within the UPMC health care system in Allegheny County, Pennsylvania. A total of 2,059 upper airway samples were collected and tested for SARS-CoV-2 positive by RT-PCR during March 2020-September 2021. We did not observe significant difference in viral load difference between the third (December 2020 - January 2021) and fourth (June 2021 - September 2021) waves; however, they had the higher viral load than the first (March 2020 - June 2020) and second waves (June 2020 - August 2020). We did find an age-related effect with the elderly presenting with lower viral loads, which was also seen in the earlier waves. However, the level of viral load in the fourth wave was not sufficient higher to qualitatively change our expected detected rates using various testing modalities.

category: pathology


title: Understanding the contexts and mechanisms of bluespace prescription programmes implemented in health and social care settings: a realist review

abstract:
BackgroundNature-based social prescribing programmes such as  bluespace prescription may promote public health and health improvement of individuals with long-term conditions. However, there is limited systematically synthesised evidence that investigates the contexts and mechanisms of Bluespace Prescription Programmes (BPPs) that could inform programme theories for policy and practice.

MethodsWe conducted a realist review by searching six databases for articles published between January 2000 and February 2020, in English, about health and social care professionals providing referral to or prescription of blue space activities with health-related outcomes. We developed themes of contextual factors by analysing the contexts of BPPs. We used these contextual factors to develop programme theories describing the mechanisms of BPP implementation. Our study was registered with PROSPERO (CRD42020170660).

ResultsFifteen studies with adequate to strong quality were included from 6,736 records. Service users had improvements on their physical, mental, social health, and environmental knowledge after participating in BPPs referred to or prescribed by health and social care professionals. Patient-related contextual factors were referral information, free equipment and transportation, social support, blue space environments, and skills of service providers. Programme-related contextual factors were communication, multi-stakeholder collaboration, financing, and adequate service providers. Programme theories on patient enrolment, engagement, adherence, communication protocols, and long-term programme sustainability described the mechanisms of BPP implementation.

ConclusionBPPs could support health and social care services if contextual factors and mechanisms of programme theories associated with patients and programme delivery are considered for implementation. Our findings have implications in planning, development, and implementation of similar nature-based social prescribing programmes in health and social care settings.

category: primary care research


title: Disrupted reward processing in Parkinson's Disease and its relationship with dopamine state and neuropsychiatric syndromes: a systematic review and meta-analysis

abstract:
BackgroundNeuropsychiatric symptoms are common in Parkinsons disease (PD) and predict poorer outcomes. Reward processing dysfunction is a candidate mechanism for the development of psychiatric symptoms including depression and impulse control disorders (ICD). We aimed to determine whether reward processing is impaired in PD and its relationship with neuropsychiatric syndromes and dopamine replacement therapy.

MethodsThe Ovid MEDLINE/PubMed, Embase and PsycInfo databases were searched for articles published up to November 5th, 2020. Studies reporting reward processing task performance by PD patients and healthy controls were included. Summary statistics comparing reward processing between groups were converted to standardized mean difference (SMD) scores and meta-analysed using a random effects model.

ResultsWe identified 55 studies containing 2578 participants (1,638 PD and 940 healthy controls). Studies assessing three subcomponent categories of reward processing tasks were included: Option Valuation (n=12), Reinforcement Learning (n=37) and Reward Response Vigour (n=6). Across all studies, PD patients on medication exhibited a small-to-medium impairment versus healthy controls (SMD=0.34; 95%CI 0.14-0.53), with greater impairments observed off dopaminergic medication in within-subjects designs (SMD=0.43, 95%CI 0.29-0.57). Within-subjects subcomponent analysis revealed impaired processing off medication on Option Valuation (SMD=0.57, 95%CI 0.39-0.75) and Reward Response Vigour (SMD=0.36, 95%CI 0.13-0.59) tasks. However, the opposite applied for Reinforcement Learning, which relative to healthy controls was impaired on-medication (SMD=0.45, 95%CI 0.25-0.65) but not off-medication (SMD=0.28, 95%CI -0.03-0.59). ICD was the only neuropsychiatric syndrome with sufficient studies (n=13) for meta-analysis, but no significant impairment was identified compared to non-ICD patients (SMD=-0.02, 95%CI -0.43-0.39).

ConclusionReward processing disruption in PD differs according to subcomponent and dopamine medication state and warrants further study as a potential treatment target and mechanism underlying associated neuropsychiatric syndromes.


title: Psychometric Properties of the ASEBA Child Behaviour Checklist and Youth Self-Report in Sub-Saharan Africa: A Systematic Review

abstract:
ObjectiveBehavioural screening tools may be used to identify at-risk children in resource-limited settings in sub-Saharan Africa. The ASEBA forms (Child Behaviour Checklist and Youth Self-Report) are frequently translated and adapted for use in sub-Saharan African populations, but little is known about their measurement properties in these contexts.

MethodsWe conducted a systematic review of all published journal articles that used the ASEBA forms with sub-Saharan African samples. We evaluated the reported psychometric properties, as well as the methodological quality of the psychometric evaluations, using COSMIN (COnsensus-based Standards for the selection of health Measurement INstruments) guidelines.

ResultsFifty-eight studies reported measurement properties of the ASEBA forms. Most studies came from Southern (n = 29, 50%) or East African (n = 25, 43%) countries. Forty-nine studies (84%) used translated versions of the tool, but details regarding the translation process, if available, were often sparse. Most studies (n = 47, 81%) only reported internal consistency (using coefficient alpha) for one or more subscales. The methodological quality of the psychometric evaluations ranged from  very good to  inadequate across all measurement properties, except for internal consistency.

ConclusionThere is limited good quality psychometric evidence available for the ASEBA forms in sub-Saharan Africa. We recommend (i) implementing a standardised procedure for conducting and reporting translation processes, and (ii) conducting more comprehensive psychometric evaluations of the translated versions of the tools.