title: Polygenic Risk Scores for Prediction of Breast Cancer Risk in Women of African Ancestry: a Cross-Ancestry Approach

abstract:
Polygenic risk scores (PRSs) are useful to predict breast cancer risk, but the prediction accuracy of existing PRSs in women of African ancestry (AA) remain relatively low. We aim to develop optimal PRSs for prediction of overall and estrogen receptor (ER) subtype-specific breast cancer risk in women of African ancestry. The AA dataset comprised 9,235 cases and 10,184 controls from four genome-wide association study (GWAS) consortia and a GWAS study in Ghana. We randomly divided samples into training and validation sets. Genetic variants were selected by forward stepwise logistic regression or lasso penalized regression in the training set and the corresponding PRSs were evaluated in the validation set. To improve accuracy, we also developed joint PRSs that combined 1) the best PRSs built in the AA training dataset, 2) a previously-developed 313-variant PRS in women of European ancestry, and 3) PRSs using variants that were discovered in previous GWASs in women of European and African ancestry and were nominally significant the training set. For overall breast cancer, the odd ratio (OR) per standard deviation of the joint PRS in the validation set was 1.39 (95%CI: 1.31-1.46) with area under receiver operating characteristic curve (AUC) of 0.590. Compared to women with average risk (40th-60th PRS percentile), women in the top decile of the PRS had a 2.03-fold increased risk (95%CI: 1.68-2.44). For PRSs of ER-positive and ER-negative breast cancer, the AUCs were 0.609 and 0.597, respectively. The proposed PRS can improve prediction of breast cancer risk in women of African ancestry.

Author SummaryPolygenic risk scores have been developed to predict breast cancer risk in non-Hispanic white American women, where polygenic risk score combines the effects of multiple single nucleotide polymorphisms. However, reliable polygenic risk scores do not exist for women of African ancestry, including African Americans, African Barbadians, and indigenous Africans. Due to distinct allele frequencies and linkage disequilibrium structures across populations, polygenic risk scores developed in European ancestry populations have an attenuated predictive value when applied to African ancestry populations. In this study, we constructed polygenic risk scores for African ancestry women by using African ancestry datasets. Since the sample sizes of existing African ancestry datasets are much smaller than those from European-ancestry studies, these polygenic risk scores using only African ancestry datasets may have limited accuracy. To increase the prediction accuracy, we constructed joint polygenic risk scores by combining polygenic risk scores trained in African ancestry datasets with polygenic risk scores that were previously developed using a large European ancestry dataset. Results showed that the joint polygenic risk scores could improve prediction of breast cancer risk in women of African ancestry.


title: Genome-wide association meta-analysis identifies novel ancestry-specific primary open-angle glaucoma loci and shared biology with vascular mechanisms and cell proliferation

abstract: Primary open-angle glaucoma (POAG) is a leading cause of irreversible blindness globally. There is disparity in POAG prevalence and manifestations across ancestries. We identify novel and unique genetics that underlie POAG risk in different ancestries by performing meta-analysis across 15 biobanks (of the Global Biobank Meta-analysis Initiative) with previously multi-ancestry studies. 18 novel significant loci, three of which were ancestry-specific, and five sex-specific were identified. We performed gene-enrichment and transcriptome-wide association studies (TWAS), implicating vascular and cancer genes. A fifth of these genes are primary ciliary genes. Extensive statistical analysis of genes in the SIX6 and CDKN2B-AS1 loci (implicated in POAG, cardiovascular diseases and cancers) found interaction between SIX6 and causal variants in chr9p21.3, with expression effect on CDKN2A/B. We infer that some POAG risk variants may be ancestry-specific, sex-specific, or both. Our results further support the contribution of vascular, cancer, and primary cilia genes in POAG pathogenesis.

category: genetic and genomic medicine


title: Human blood DNA methylation patterns reflect individual lifestyle

abstract: Obesity is driven by modifiable lifestyle factors whose effects may be mediated by epigenetics. Therefore, we investigated lifestyle effects (diet, physical activity, smoking and alcohol) on blood DNA methylation in participants of the LIFE-Adult study, a well-characterized population-based cohort from Germany. Fifty subjects with an extremely healthy and 50 with an extremely unhealthy lifestyle were selected for genome-wide DNA methylation analysis in blood samples. Whereas obesity was only marginally related to variability in DNA methylation pattern, comparisons between lifestyle categories resulted in 145 Differentially Methylated Positions (DMPs) and 4682 Differentially Methylated Regions (DMRs) annotated to 4426 unique genes. Intersection analysis showed that diet, physical activity, smoking and alcohol intake are equally contributing to the observed differences, which particularly affects pathways related to glutamatergic synapse and axon guidance. DNA methylation patterns help discriminate individuals with a healthy vs. unhealthy lifestyle, which may mask subtle methylation differences derived from obesity.


title: A reliable and valid measure of COVID-19 patient-reported symptoms in outpatients: the Symptoms Evolution of COVID-19 (SE-C19) instrument

abstract:
BackgroundThere is no valid and reliable patient self-reported measure assessing symptomology among outpatients with COVID-19. The Symptoms Evolution of COVID-19 (SE-C19) is a self-administered new instrument that includes 23 symptoms, each rated for severity at their worst moment within the last 24 hours. We studied the psychometric properties of SE-C19.

MethodsReliability, validity, and sensitivity to change of the SE-C19 were assessed in 657 outpatients with confirmed COVID-19 enrolled in NCT04425629. SE-C19 and Patient Global Impression of Severity (PGIS) were administered daily from baseline (predose at Day 1) to end of study (Day 29).

FindingsMost patients (70{middle dot}0%) were aged [≤]50 years and white (85{middle dot}5%). At baseline, patients reported an average (SD) of 6{middle dot}6 (3{middle dot}9) symptoms (ie, rated as at least Mild) with 3{middle dot}8 (3{middle dot}3) of these symptoms being rated as Moderate or Severe. By Day 29, most symptoms had resolved; 74{middle dot}4% of patients reported no symptoms and on average, only 0{middle dot}6 (SD 1{middle dot}5) symptoms were reported as at least Mild.

Stable patients according to the PGIS showed scores with intraclass correlation values indicating moderate-to-good test-retest reliability (ie, 0{middle dot}50-0{middle dot}90). At baseline, 20 item scores (87%) varied significantly across PGIS defined groups supporting the validity of SE-C19.

A symptom-resolution endpoint was defined after excluding the item "Sneezing", due to its low ability to discriminate severity levels, and "Confusion", "Rash", and "Vomiting", due to their low prevalence in this population. Symptoms resolution required complete absence of all remaining items, except "Cough", "Fatigue", and "Headache", which could be Mild or Moderate in severity.

InterpretationWe identified 19 items that are valid and reliable to measure disease-related symptoms in COVID-19 outpatients and propose a definition of symptom resolution that could be used in future clinical trials and potentially, also in clinical practice.

FundingThis research was funded by Regeneron Pharmaceuticals, Inc.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSThe majority of COVID-19-infected patients (>80%) have mild-to-moderate symptoms and are managed at an outpatient setting. Although clinical research has primarily focused on prevention of the disease and the treatment of hospitalised patients, close monitoring of the COVID-19 symptoms and their severity in outpatients is equally important and needed to prevent community transmission. Patient-reported outcome (PRO) instruments are a key method to assess COVID-19 related symptoms and associated burden as these symptoms are best known by the patient and are best measured from the patient perspective. However, a valid and reliable instrument to assess symptom severity and progression among outpatients with COVID-19 is not yet available. This study focuses on the psychometric properties (reliability, validity, and sensitivity to change) of a new recently developed self-administered PRO symptom measure (SE-C19) for COVID-19-positive outpatients.

Added value of this studyThis is the first study to systematically examine the psychometric properties of a PRO symptom measure designed for COVID-19 outpatients and it provides a method for identifying symptom resolution among outpatients, which may be useful in clinical research and clinical practice contexts. The SE-C19 instrument is a self-administered questionnaire that assesses the severity of 23 COVID-19-related symptoms. The recall period is 24 hours and the response options include None, Mild, Moderate and Severe. The analyses reported here demonstrate that the SE-C19 is a valid and reliable measure to capture daily COVID-19 symptom severity from the outpatients perspective. These psychometric analyses also provide empirical evidence for a method to determine symptoms resolution based on the score of 19 of the SE-19 items; this may be useful not only in clinical trials but also in real-world studies and clinical practice. The 4 items not included in the symptoms resolution endpoint may be useful to clinicians to monitor severe disease.

The SE-C19 instrument is relevant for the clinical management of outpatients, as it measures a large number of symptoms that are relevant in the outpatient setting and reflect the heterogeneity of symptom experience, and it is sensitive to the longitudinal changes in the severity of these symptoms.

Implications of all the available evidenceThe SE-C19 can be used to monitor COVID-19-related symptoms over time in outpatients. The definition of symptoms resolution established here can be used to inform clinical trial endpoints and may also be useful in clinical practice to aid discussions between healthcare professionals and patients, and inform treatment decisions. Symptoms resolution is based on 19 of the 23 items included in the SE-C19 instrument.

category: infectious diseases


title: Commercially-available heart rate monitor repurposed into a 9-gram standalone device for automatic arrhythmia detection with snapshot electrocardiographic capability: a pilot validation.

abstract:
BackgroundThe usefulness of opportunistic arrhythmia screening strategies, using an electrocardiogram (ECG) or other methods for random "snapshot" assessments is limited by the unexpected and occasional nature of arrhythmias, leading to a high rate of missed-diagnosis.

We have previously validated a cardiac monitoring system for AF detection pairing simple consumer-grade Bluetooth low-energy (BLE) heart rate (HR) sensors with a smartphone application (RITMIAtm, Heart Sentinel srl, Italy). In the current study we test a significant upgrade to the abovementioned system, thanks to the technical capability of new HR sensors to run algorithms on the sensor itself and to acquire (and store on-board) single-lead ECG strips, if asked to do so.

Methods and ResultWe have reprogrammed a HR monitor intended for sports use (Movensense HR+) to run our proprietary RITMIA algorithm code in real-time, based on RR analysis, so that if any type of arrhythmia is detected it triggers a brief retrospective recording of a single-lead ECG, providing tracings of the specific arrhythmia for later consultation.

We report the initial data on the behavior, feasibility and high diagnostic accuracy of this ultra-low weight customized device for standalone automatic arrhythmia detection and ECG recording, when several types of arrhythmias were simulated, under different baseline conditions.

ConclusionsThe customized device was capable to detect all types of simulated arrhythmias and correctly triggered an visually interpretable ECG tracing. Future human studies are needed to address real-life accuracy of this device.

category: cardiovascular medicine


title: Social mixing patterns relevant to infectious diseases spread by close contact in urban Blantyre, Malawi.

abstract:
IntroductionUnderstanding human mixing patterns relevant to infectious diseases spread through close contact is vital for modelling transmission dynamics and optimisation of disease control strategies. Mixing patterns in low-income countries like Malawi are not well understood.

MethodologyWe conducted a social mixing survey in urban Blantyre, Malawi between April and July 2021 (between the 2nd and 3rd wave of COVID-19 infections). Participants living in densely-populated neighbourhoods were randomly sampled and, if they consented, reported their physical and non-physical contacts within and outside homes lasting at least 5 minutes during the previous day. Age-specific mixing rates were calculated, and a negative binomial mixed effects model was used to estimate determinants of contact behaviour.

ResultsOf 1,201 individuals enrolled, 702 (58.5%) were female, the median age was 15 years (interquartile range [IQR] 5-32) and 127 (10.6%) were HIV-positive. On average, participants reported 10.3 contacts per day (range: 1-25). Mixing patterns were highly age-assortative, particularly those within the community and with skin-to-skin contact. Adults aged 20-49y reported the most contacts (median:11, IQR: 8-15) of all age groups; 38% (95%CI: 16-63) more than infants (median: 8, IQR: 5-10), who had the least contacts. Household contact frequency increased by 3% (95%CI 2-5) per additional household member. Unemployed participants had 15% (95%CI: 9-21) fewer contacts than other adults. Among long range (>30 meters away from home) contacts, secondary school children had the largest median contact distance from home (257m, IQR 78-761). HIV-positive status in adults >18 years-old was not associated with increased contact patterns (1%, 95%CI -9-12). During this period of relatively low COVID-19 incidence in Malawi, 301 (25.1%) individuals stated that they had limited their contact with others due to COVID-19 precautions; however, their reported contacts were not fewer (8%, 95%CI 1-13).

ConclusionIn urban Malawi, contact rates, are high and age-assortative, with little behavioural change due to either HIV-status or COVID-19 circulation. This highlights the limits of contact-restriction-based mitigation strategies in such settings and the need for pandemic preparedness to better understand how contact reductions can be enabled and motivated.

category: epidemiology


title: The tryptophan catabolite or kynurenine pathway in schizophrenia: meta-analysis reveals dissociations between central, serum and plasma compartments.

abstract: The tryptophan catabolite (TRYCAT) pathway is implicated in the pathophysiology of schizophrenia (SCZ) since the rate-limiting enzyme indoleamine-dioxygenase (IDO) may be induced by inflammatory and oxidative stress mediators. This systematic review searched PubMed, Web of Science, and Google Scholar for papers published from inception until August 2021 and meta-analyzed the association between SCZ and TRYCATs in the central nervous system (CNS) and peripheral blood. We included 61 studies comprising 2813 patients and 2948 healthy controls. In the CNS we found a significant (p<0.001) increase in the kynurenine/tryptophan (KYN/TRP) (standardized mean difference, SMD=0.769, 95% confidence interval, CI: 0.456; 1.082) and kynurenic acid (KA)/KYN+TRP (SMD=0.697, CI:0.478-0.917) ratios, KA (SMD=0.646, CI: 0.422; 0.909) and KYN (SMD=1.238; CI: 0.590; 1.886), while the 3OH-kynurenine (3HK) + KYN-3-monooxygenase (KMO)/KYN ratio was significantly reduced (SMD=-1.089, CI: -1.682; -0.496). There were significant differences between KYN/TRP, (KYN+KA)/TRP, (3HK+KMO)/KYN, KA, and KYN levels among the CNS and peripheral blood, and among serum and plasma KYN. The only useful peripheral marker of CNS TRYCATs findings was the increased KYN/TRP ratio in serum (SMD=0.211, CI: 0.056; 0.366, p=0.007), but not in plasma. There was no significant increase in a neurotoxic composite score based on KYN, 3HK, and picolinic, xanthurenic, and quinolinic acid. SCZ is accompanied by increased IDO activity in the CNS and serum, and reduced KMO activity and a shift towards KA production in the CNS. This CNS TRYCATs profile indicates neuroprotective, negative immunoregulatory and anti-inflammatory effects. Peripheral blood levels of TRYCATs are dissociated from CNS findings except for a modest increase in serum IDO activity.

category: psychiatry and clinical psychology


title: Lower infant mortality and access to contraception reduce fertility in low- and middle-income nations

abstract:
Although average contraceptive use has increased globally in recent decades, an estimated 222 million (26%) of women of child-bearing age worldwide face an unmet need for family planning -- defined as a discrepancy between fertility preferences and contraception practice, or failing to translate desires to avoid pregnancy into preventative behaviours and practices.

While many studies have reported relationships between availability of contraception, infant mortality, and fertility, these relationships have not been evaluated quantitatively across a broad range of low- and middle-income countries. Using publicly available data from 46 low- and middle-income countries, we collated test and control variables in six themes: (i) availability of family planning, (ii) quality of family planning, (iii) maternal education, (iv) religion, (v) mortality, and (vi) socio-economic conditions. We predicted that higher nation-level availability/quality of family-planning services, maternal education, and wealth reduce average fertility, whereas higher infant mortality and religious adherence increase it. Given the sample size, we first constructed general linear models to test for relationships between fertility and the variables from each theme, from which we retained those with the highest explanatory power within a final general linear model set to determine the partial correlation of dominant test variables. We also applied boosted regression trees, generalised least-squares models, and a generalised linear mixed-effects models to account for non-linearity and spatial autocorrelation. On average among all countries, we found an association between all main variables and fertility, with reduced infant mortality having the strongest relationship with reduced fertility. Access to contraception was the next-highest correlate with reduced fertility, with female secondary education, home health visitations, and adherence to Catholicism having weak, if any, explanatory power. Our models suggest that decreasing infant mortality and increasing access to contraception will have the greatest effect on decreasing global fertility. We thus provide new evidence that progressing the United Nations Sustainable Development Goals for reducing infant mortality can be accelerated by increasing access to any form of family planning.

category: public and global health


title: Aerosol decontamination and spatial separation using a free-space LED-based UV-C light curtain

abstract:
BackgroundThe SARS-CoV-2 pandemic demonstrated the vulnerability of our societies to aerosol transmitted pathogens. With no less than 260mio known cases and > 5mio deaths, SARS-CoV-2 is a global catastrophe leading to human and economic losses unprecedented in recent history. Thus, effective methods to limit the spread of aerosol transmitted pathogens are needed. Universal masking and curfew laws are effective but no permanent solution.

MethodsA mass producible LED light source emitting homogeneous parallel UV-C light was used as a "light-barrier" to block the spread of infectious aerosols. In an aerosol test channel, Gram-negative and Gram-positive bacteria as well as coronavirus were nebulized and inactivation rates were determined.

FindingsWith air speeds of 0.1 m s-1 an exposure time of 1 s in the UV-C light is obtained. Reduction in CFU for E. coli was >3log10 and for S. aureus [~]2.8log10. Plug-forming-units of the murine coronavirus (Mouse Hepatitis Virus, MHV) were reduced by about 3log10.

InterpretationThe concept of a UV-C light barrier to ward off infectious aerosols if feasible and possible with a light element as described here. Coupled with sensor based activation/deactivation, such a technology could greatly reduce the transmission rates of aerosol transmitted pathogens while not disturbing natural human behaviour. This is an interesting technology allowing a "new normal" in societies after/with SARS-CoV-2.

category: occupational and environmental health


title: Poor prognosis of stage I lung adenocarcinoma patients determined by elevated expression over pre/minimally invasive status of COL11A1 and THBS2 in the focal adhesion pathway

abstract: Around 20% of stage I lung adenocarcinoma (LUAD) patients die within five years after surgery, and efforts for developing gene-expression based models for risk-tailored post-surgery treatment are largely unsatisfactory due to overfitting-related lack of validation and extrapolation. Because patients with adenocarcinomas in situ (AIS) and minimally invasive (MIA) LUAD are completely curable by surgical resection, we hypothesize that poor-prognosis stage I patients may exhibit key molecular characteristics deviating from AIS/MIA. We first found focal adhesion (FA) as the only pathway significantly perturbed at both genomic and transcriptomic levels by comparing 98 AIS/MIA and 99 invasive LUAD patients. Then, we identified two FA pathway genes (COL11A1 and THBS2) strongly upregulated from AIS/MIA to stage I while expressed steadily from normal to AIS/MIA. Furthermore, unsupervised clustering separated stage I patients into two molecularly and prognostically distinct subtypes (S1 and S2) based solely on the expression levels of COL11A1 and THBS2 (FA2). Subtype S1 looked like AIS/MIA, whereas S2 exhibited more somatic alterations, elevated expression of COL11A1 and THBS2, and more activated cancer-associated fibroblast (CAF). The prognostic performance of the knowledge-driven and overfitting-resistant FA2 model was validated with 12 external data sets and may help reliably identify high-risk stage I patients for more intensive post-surgery treatment.

category: oncology


title: A Machine Learning Ensemble Based on Radiomics to Predict BI-RADS Category and Reduce the Biopsy Rate of Ultra-sound-Detected Suspicious Breast Masses

abstract: We developed a machine learning model based on radiomics to predict the BI-RADS category of ultrasound-detected suspicious breast lesions and support medical decision making towards short-interval follow-up versus tissue sampling. From a retrospective 2015-2019 series of ultrasound-guided core needle biopsies performed by four board-cer-tified breast radiologists using six ultrasound systems from three vendors, we collected 821 images of 834 suspicious breast masses from 819 patients, 404 malignant and 430 benign according to histopathology. A balanced image set of biopsy-proven benign (n = 299) and malignant (n = 299) lesions were used for training and cross-validation of ensembles of ma-chine learning algorithms supervised during learning by histopathological diagnosis as a reference standard. Based on a majority vote (over 80% of the votes to have a valid prediction of benign lesion), an ensemble of support vector machines showed an ability to reduce the biopsy rate of benign lesions by 15% to 18%, always keeping a sensitivity over 94%, when externally tested on 236 images from two image sets: 1) 123 lesions (51 malignant and 72 benign) obtained from the same four ultrasound systems used for training, resulting into a positive predictive value (PPV) of 45.9% (95% confidence inter-val 36.3-55.7%) versus a radiologists PPV of 41.5% (p < 0.005), combined with a 98.0% sensitivity (89.6-99.9%); 2) 113 lesions (54 malignant and 59 benign) obtained from two ultrasound systems from vendors different from those used for training, resulting into a 50.5% PPV (40.4-60.6%) versus a radiologists PPV of 47.8% (p < 0.005), combined with a 94.4% sensitivity (84.6-98.8%). Errors in BI-RADS 3 category (i.e., assigned by the model as BI-RADS 4) were 0.8% and 2.7% in the Testing set I and II, respectively. The board-certified breast radiologist accepted the BI-RADS classes assigned by the model in 114 masses (92.7%) and modified the BI-RADS classes of 9 breast masses (7.3%). In 6 of 9 cases the model performed better than the radiologist, since it assigned a BI-RADS 3 classification to histopathology-confirmed benign masses that were classified as BI-RADS 4 by the radiologist.


title: Partial recovery of amblyopia following fellow eye ischemic optic neuropathy

abstract:
BackgroundRecovery from amblyopia in adulthood following fellow eye (FE) vision loss is a well-known phenomenon. Incidence of recovery varies widely following different FE pathologies and rate of recovery following FE ischemic optic neuropathy (ION) has not been examined. We aimed to determine frequency and degree of improvement in amblyopic eye (AE) visual function following ION in the FE.

MethodsWe performed a retrospective chart review of patients between 2007-2021 confirmed to have amblyopia and ischemic optic neuropathy in different eyes. Patients with unstable ocular pathology potentially limiting vision were excluded. We compared best-corrected visual acuity (VA) in each eye before and after FE ION over time. For patients with available data, we examined change in perimetric performance over time.

ResultsAmong the 12 patients who met inclusion criteria (mean age 67{+/-}8 years), 9 (75%) improved [≥]1 line and 2 (17%) improved [≥]3 lines. Median time from ION symptom onset to maximal improvement was 6 months (range: 2-101 months). Reliable perimetric data were available for 6 patients. Mean sensitivity improved in the amblyopic eye for all patients, with a mean improvement of 1.9{+/-}1.1 dB. There was no correspondence between foci of ION-related field loss and gains in field sensitivity in the AE.

ConclusionA high proportion of patients with amblyopia and contralateral ION experience improvement in their amblyopic eye. Modest gains in perimetric sensitivity in the AE may accompany FE ION. These findings support the view that residual plasticity in the adult visual cortex can be tapped to support functional improvement in amblyopia.

category: ophthalmology


title: Individualised exercise in chronic non-specific low back pain: a systematic review with meta-analysis on the effects of exercise alone or in combination with psychological interventions on pain and disability

abstract:
ObjectiveTo investigate the effects of individualised exercise interventions consisting with or without combined psychological intervention on pain intensity and disability in patients with chronic non-specific low back pain.

DesignSystematic review with meta-analysis and meta-regression.

Data sourcesFive databases (PubMed, Cochrane Central, EMBASE, Clarivate Web of Science, and Google Scholar) were searched up to 31 March 2021.

Selection criteriaRandomised controlled trials were eligible if they included participants with chronic non-specific low back pain, compared at least one individualised/personalised/stratified exercise intervention with or without psychological treatment to any control / comparator group, and if they assessed at least pain intensity or disability as outcome measure.

ResultsFifty-eight studies (n = 9099 patients, 44.3 years, 56% female) compared individualised to other types of exercise (n = 44; 62%), usual care (n = 16; 23%), advice to stay active, or true controls. The remaining studies had passive controls.

At short-term follow-up, low-certainty evidence for pain intensity (SMD -0.33 [95%CI -0.47 to -0.18]) and very low-certainty evidence for disability (-0.16 [-0.30 to -0.02]) indicates effects of individualised exercise compared to other exercises. Very low-certainty evidence for pain intensity (-0.35; [-0.53 to - 0.17])) and low-certainty evidence for disability (-0.12; [-0.22 to -0.02]) indicates effects compared to passive controls.

At long-term follow-up, moderate-certainty evidence for pain intensity (-0.14 [-0.23 to -0.06]) and disability (-0.23 [-0.33 to -0.12]) indicates effects compared to passive controls exercises.

All findings stayed below the threshold for minimal clinically important difference (MCID). Certainty of evidence was downgraded mainly due to evidence of risk of bias, publication bias and inconsistency that could not be explained. Sensitivity analyses indicated that the effects on pain, but not on disability (always short-term and versus active treatments) were robust. Sub-group analysis of pain outcomes suggested that individualised exercise treatment is probably more effective in combination with psychological interventions (-0.32 [-0.51 to -0.14]), a clinically important difference

ConclusionWe found very low to moderate-certainty evidence that individualised exercise is effective for treatment of chronic non-specific low back pain. Individualised exercise seems superior to other active treatments and sub-group analysis suggests that some forms of individualised exercise (especially motor-control based treatments) combined with behavioural therapy interventions enhances the treatment effect. Certainty of evidence was higher for long-term follow-up. In summary, individualised exercise can be recommended from a clinical point of view.

category: pain medicine


title: HLA-B27 and not variation in MICA is responsible for genotype by sex interaction in risk of Ankylosing Spondylitis

abstract: Ankylosing Spondylitis (AS) is a highly heritable inflammatory arthritis which occurs more frequently in men than women. In their recent publication examining sex differences in the genetic aetiology of common complex traits and diseases, Bernabeu et al. (2021) observe differences in heritability of AS between sexes, and a genome-wide significant genotype by sex interaction in risk of AS at the major histocompatability (MHC) locus1. The authors then present evidence suggesting that this genotype by sex interaction arises primarily as a result of differential expression of the gene MICA across the sexes in skeletal muscle tissue. Through a series of conditional association analyses in the UK Biobank, reanalysis of the GTEx gene expression resource and RNASeq experiments on peripheral blood cells from AS cases and controls, we show that the genotype by sex interaction the authors report is unlikely to be a result of variation in MICA, but probably reflects a known interaction between the HLA-B gene, sex and risk of AS. We demonstrate that the diagnostic accuracy of AS in the UK Biobank is low, particularly amongst women, likely explaining some of the observed differences in heritability across the sexes and the difficulty in precisely locating association signals in the cohort.


title: The Omicron variant mutation at position 28,311 in the SARS-CoV-2 N gene does not perturb CDC N1 target detection

abstract: The emergence of new SARS-CoV-2 variants necessitates the reevaluation of current COVID-19 tests to ensure continued accuracy and reliability. The new SARS-CoV-2 variant, Omicron, is heavily mutated, with over 50 mutations within its RNA genome. Any of these mutations could adversely affect the ability of diagnostic assays to detect the virus in patient samples, potentially leading to inconclusive or false negative results. In fact, the U.S. Food and Drug Administration (FDA) has identified over two dozen diagnostic tests that contain a gene target that is expected to have "significantly reduced sensitivity due to a mutation in the SAS-CoV-2 Omicron variant"1. Additionally, one of the U.S. Centers for Disease Control and Prevention (CDC) Emergency Use Authorization (EUA) targets for COVID-19 tests, 2019-nCoV_N1, overlaps an Omicron mutation within the sequence targeted by the fluorescent probe. This target from the CDC has been used in many other EUA assays. Using in vitro transcribed (IVT) N gene RNA representing the wild-type (GenBank/GISAID ID MN908947.3) and Omicron variant (BA.1, GISAID ID EPI_ISL_6752027), we evaluated the performance of two different amplification protocols, both of which include the CDC 2019-nCoV_N1 primer-probe set. Both assays were able to detect the mutant N1 sequence as efficiently as the wild-type sequence. Consequently, these data suggest that diagnostic assays that use the 2019-nCoV-N1 primer-probe set are unlikely to be impacted by currently circulating Omicron lineage viruses.


title: Randomized controlled trial of gut decontamination in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation

abstract:
BackgroundGut decontamination (GD) can decrease the incidence and severity of acute graft- versus-host-disease (aGVHD) in murine models of allogeneic hematopoietic cell transplantation (HCT). Several HCT centers standardly practice GD with different antibiotic regimens. In this pilot study, we examined the impact of GD on the gut microbiome composition and incidence of aGVHD in HCT patients.

MethodsWe randomized 20 pediatric patients undergoing allogeneic HCT to receive (GD) or not receive (no-GD) oral vancomycin-polymyxin B from day -5 through neutrophil engraftment. We evaluated shotgun metagenomic sequencing of serial stool samples to compare the composition and diversity of the gut microbiome between study arms. We assessed clinical outcomes in the 2 arms and performed strain-specific analyses of pathogens that caused bloodstream infections (BSI).

ResultsThe two arms did not differ in Shannon diversity of the gut microbiota at two weeks post- HCT (Genus, p=0.8; Species, p=0.44) or aGVHD incidence (p=0.58). Immune reconstitution of T- cell subsets was similar, but absolute CD19+ B-cell counts were higher in the GD arm at 12 months post-HCT (p=0.02). Five patients in the no-GD arm had eight BSI episodes vs one episode in the GD arm (p=0.09). The BSI-causing pathogens were traceable to the gut in seven of eight BSI episodes in the no-GD arm, including the genus Staphylococcus.

ConclusionsWhile GD did not differentially impact Shannon diversity or clinical outcomes, our findings suggest that GD may protect against gut-derived BSI in HCT patients by decreasing the prevalence or abundance of gut microbial pathogens.

Key points- In this phase 2 randomized study of gut decontamination (GD) in 20 pediatric HCT patients, neither two-week post-HCT Shannon diversity of the gut microbiome nor incidence of aGVHD differ between the GD and no-GD arms.
- All bloodstream infections (BSIs) caused by pathogens traceable to the gut either temporally or via strain-specific analysis (concomitant gut colonization) occurred in patients in the no-GD arm; this suggests that GD with vancomycin-polymyxin B may decrease the incidence of gut-derived BSI in allo-HCT patients.
- In contrast to prior studies, we find that non-mucosal barrier injury (MBI) pathogens, such as Staphylococcus aureus, can be found in the gut microbiome of HCT patients.

category: hematology


title: Cash Transfer Programs and HIV-Related Outcomes: an Analysis of 42 Countries from 1996 to 2019

abstract:
BackgroundMany low- and middle-income countries have introduced cash transfer programs as part of their poverty reduction and social protection strategies. These programs have the potential to overcome various drivers of HIV risk behaviors and usage of HIV services, but their overall effects on a broad range of HIV-related outcomes remains unknown.

MethodsWe used publicly reported data to determine whether low- and middle-income countries with HIV prevalence >1% and baseline annual incidence >1/1000 had conditional or unconditional cash transfer programs that covered >5% of the impoverished population, and the year in which those programs began and ended. We obtained country- and individual-level data on HIV-related outcomes from UNAIDS and population-representative household surveys, focusing on the period between 1996 and 2019. We conducted difference-in-differences analyses with country and year fixed effects to evaluate the effects of cash transfer programs on country- and individual-level HIV-related outcomes.

FindingsForty-two countries across three continents were included. Among these, 21 were in the intervention group, having implemented cash program(s) with impoverished population coverage greater than 5% during the study period. Cash transfer programs were associated with lower probability of reporting sexually transmitted infection within the last 12 months among females (odds ratio [OR] 0.67, 95% confidence interval [CI] 0.50-0.91) and higher probability of an HIV test within the last 12 months among females (OR 2.61, 95% CI 1.15-5.88) and males (OR 3.19, 95% CI 2.45-4.15). For country-level outcomes, cash transfer programs were associated with a reduction in new HIV infections (incidence rate ratio [IRR] 0.94, 95% CI 0.89-0.99), but not with the proportion of people with HIV receiving antiretroviral therapy (5.0%, 95% CI -0.2-10.1) or AIDS-related deaths (IRR 0.99, 95% CI 0.95-1.03), though temporal analyses showed delayed improvements in both antiretroviral coverage and deaths.

InterpretationsCash transfer programs, which are being expanded in the context of the COVID-19 pandemic, have the potential to promote ongoing efforts to end HIV as a public health threat. Alongside the already existing focus on expanding biomedical services, these anti-poverty programs can play a greater role in achieving global targets for HIV prevention and treatment.

FundingNone

category: hiv aids


title: Evaluation of a phenotypic, point-of-care solution for the detection and quantitative antibiotic susceptibility testing for lower Urinary Tract Infection

abstract:
BackgroundUrinary tract infections (UTIs) are one of the most common bacterial infections seen in primary care. The current standard for diagnosis is microbiological culture and antibiotic sensitivity testing of a mid-stream urine sample; however, this technique is costly, labour intensive and typically takes 2-3 days to yield a result.

Study design and ObjectiveThis is a nonexperimental cross-sectional study. The aim of this study was to evaluate the efficacy of U-treat, a bioluminescent approach for rapid detection of bacteriuria and quantitative determination of the antimicrobial susceptibility profiles of uropathogens in clinical urine specimens - in under an hour.

MethodThe evaluation was carried out in two UK-based Medical Centres using urine samples from patients presenting with symptoms of a UTI (n=249). The U-treat technology is a two test, two reagent process. Test 1 detects the presence of a bacterial UTI > 104 bacteria/mL (5-10 minutes). Test 2 produces quantitative antibiotic susceptibility (<50 minutes). Only urine samples testing positive for bacteria in Test 1 underwent Test 2 (n=82). U-treat results were compared retrospectively against reference laboratory culture and sensitivity findings. The influence of the technology on patient treatment outcomes was also analysed.

ResultsRelative to reference laboratory analysis, Test 1 showed a sensitivity of 97.1% and specificity of 92.0%. (PPV: 89.3%; NPV: 97.8%). Test 2 produced an overall sensitivity (measurement of true susceptibility) of 94.1% (Predictive value: 96%) and an overall specificity (measurement of true resistance) of 90.5% (Predictive value 86.4%). Analysis of treatment data demonstrated that had the physicians had access to U-treat results at the point of care, the percentage of patients treated successfully would have risen from 68.3% to 92.7%.

ConclusionU-treat represents the first technology, world-wide, capable of providing UTI treatment data to physicians at the point of care, in less than 60 minutes.


title: Predictors of SARS-CoV-2 infection in a multi-ethnic cohort of United Kingdom healthcare workers: a prospective nationwide cohort study (UK-REACH)

abstract:
IntroductionHealthcare workers (HCWs), particularly those from ethnic minority groups, have been shown to be at disproportionately higher risk of infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) compared to the general population. However, there is insufficient evidence on how demographic and occupational factors influence infection risk among ethnic minority HCWs.

MethodsWe conducted a cross-sectional analysis using data from the United Kingdom Research study into Ethnicity And COVID-19 Outcomes in Healthcare workers (UK-REACH) cohort study. We used logistic regression to examine associations of demographic, household and occupational predictor variables with SARS-CoV-2 infection (defined by PCR, serology or suspected COVID-19) in a diverse group of HCWs.

Results2,496 of the 10,772 HCWs (23.2%) who worked during the first UK national lockdown in March 2020 reported previous SARS-CoV-2 infection. In an adjusted model, demographic and household factors associated with increased odds of infection included younger age, living with other key workers and higher religiosity. Important occupational risk factors associated with increased odds of infection included attending to a higher number of COVID-19 positive patients (aOR 2.49, 95%CI 2.03-3.05 for [≥]21 patients per week vs none), working in a nursing or midwifery role (1.35, 1.15- 1.58, compared to doctors), reporting a lack of access to personal protective equipment (1.27, 1.15 - 1.41) and working in an ambulance (1.95, 1.52-2.50) or hospital inpatient setting (1.54, 1.37 - 1.74). Those who worked in Intensive Care Units were less likely to have been infected (0.76, 0.63-0.90) than those who did not. Black HCWs were more likely to have been infected than their White colleagues, an effect which attenuated after adjustment for other known predictors.

ConclusionsWe identified key sociodemographic and occupational risk factors associated with SARS-CoV-2 infection amongst UK HCWs, and have determined factors that might contribute to a disproportionate odds of infection in HCWs from Black ethnic groups. These findings demonstrate the importance of social and occupational factors in driving ethnic disparities in COVID-19 outcomes, and should inform policies, including targeted vaccination strategies and risk assessments aimed at protecting HCWs in future waves of the COVID-19 pandemic.

Trial registrationISRCTN 11811602


title: Bacterial shedding and serologic responses following an outbreak of Salmonella Typhi in an endemic cohort

abstract:
BackgroundSalmonella enterica serovar Typhi (S. Typhi), the causative agent of Typhoid fever, is transmitted faecal-orally. Some typhoid sufferers shed S. Typhi beyond convalescence, but culturing stool following every case is impractical. Here we hypothesised that serology might direct testing and identify shedding after a typhoid outbreak.

Methodology/Principle FindingsIn 2016 there was a typhoid outbreak in a Nursing School in Malosa, Malawi. We collected serum three and six-months post-outbreak. We measured IgG antibody titres against Vi capsular polysaccharide (anti-Vi IgG) and IgM / IgG antibodies against H:d flagellin (anti-H:d). We screened faecal samples from participants with high and low anti-Vi IgG (measured at visit one) by culture and PCR. Participants reported whether they had persistent fever for [≥] three days (in keeping with World Health Organization definitions for typhoid) during the outbreak. We tested for environmental S. Typhi.

368 people provided serum at 3-months, of whom 320 provided serum at 6-months; 49 participants provided a faecal sample (25 from the highest and 24 from the lowest deciles for anti-Vi IgG titre). We did not grow S. Typhi from faeces, but one sample produced a positive PCR amplification for S. Typhi. Median anti-Vi IgG titre fell amongst participants with persistent fever (8.08 to 3.7 EU/ml, <0.000001, Wilcoxon signed rank). Median anti-H:d IgG titres fell in those with and without persistent fever (87.8 to 77.4 EU/, p = <0.000001 and 82.4 to 79.2 EU/ml, p = 0.0002, Wilcoxon signed rank, respectively). Anti-H:d IgM titres did not change significantly. Non-Typhoidal Salmonellae were identified in water sampled at source and a kitchen tap.

Conclusions / SignificanceWe did not identify culture-confirmed shedding through sero-surveillance. Serologic trends signify a fall from an outbreak-associated peak. Despite effective vaccines, identifying ways to detect and treat shedding remain vital to break transmission and eliminate typhoid.

Author SummaryTyphoid fever spreads by the faecal-oral route. Some people continue to shed the bacterium that causes typhoid (Salmonella enterica serovar Typhi, or S. Typhi) after recovering from the illness. To stop onward spread it is important that these people are identified and treated.

Shedders are detected when S. Typhi grows from faeces, but it is not practical to obtain stool samples from large populations. Following a typhoid outbreak we tested whether a subset of participants with high antibodies to S. Typhi proteins contained more shedders than a subset with low antibody responses. We tested whether antibody levels changed in the months after the outbreak, to inform whether they are useful markers of exposure in a population.

We did not grow S. Typhi. This may be because our population had few risk factors for S. Typhi carriage, or because exposure to other endemic bacteria influence antibody levels. We saw a decline in antibody levels over time, most marked in those who reported fever during the outbreak. We think that this reflects a response to recent infection. It is important to continue to evaluate ways of finding carriers so that, combined with vaccines and improved sanitation, we can one day eliminate typhoid.


title: Identifying weather variables as important clinical predictors of bacterial diarrhea among international travelers to Nepal and Thailand

abstract:
BackgroundClinicians and travelers often have limited tools to differentiate bacterial from non-bacterial causes of travelers diarrhea (TD). Development of a clinical prediction rule assessing the etiology of TD may help identify episodes of bacterial diarrhea and limit inappropriate antibiotic use. We aimed to identify predictors of bacterial diarrhea among clinical, demographic, and weather variables, as well as to develop and cross-validate a parsimonious predictive model.

MethodsWe collected de-identified clinical data from 457 international travelers with acute diarrhea presenting to two healthcare centers in Nepal and Thailand. We used conventional microbiologic and multiplex molecular methods to identify diarrheal etiology from stool samples. We used random forest and logistic regression to determine predictors of bacterial diarrhea.

ResultsWe identified 195 cases of bacterial etiology, 63 viral, 125 mixed pathogens, 6 protozoal/parasite, and 68 cases without a detected pathogen. Random forest regression indicated that the strongest predictors of bacterial over viral or non-detected etiologies were average location-specific environmental temperature and RBC on stool microscopy. In 5-fold cross-validation, the parsimonious model with the highest discriminative performance had an AUC of 0.73 using 3 variables with calibration intercept -0.01 (SD 0.31) and slope 0.95 (SD 0.36).

ConclusionsWe identified environmental temperature, a location-specific parameter, as an important predictor of bacterial TD, among traditional patient-specific parameters predictive of etiology. Future work includes further validation and the development of a clinical decision-support tool to inform appropriate use of antibiotics in TD.


title: Prolonged Detection of SARS CoV2 RNA in Extracellular Vesicles in Nasal Swab RT-PCR Negative Patients

abstract:
BackgroundThere is a prolonged RT-PCR positivity seen in COVID-19 infected patients up to 2-3 months. We aim to investigate the presence of viral particles inside Extracellular vesicles (EV) and its role in underlying liver disease patients.

MethodsSARS CoV2 nasal RT-PCR positive n=78 {n=24(66.6%) chronic liver disease (CLD); n=52 (81.3%) non-liver disease} were studied. SARS CoV2 patients were also followed up for day (d) 7, 14 and 28. Extracellular vesicles were isolated using differential ultracentrifugation. SARS CoV2 RNA was measured using qRT-PCR by Altona Real Star kit.

ResultsIn baseline RT-PCR positive patients, SARS-CoV2 RNA inside the EV was present in 64/74 (82%) patients with comparable viral load between VTM and EV (mean 1CT - 0.033{+/-}0.005 vs. 1CT - 0.029{+/-}0.014, p=ns). On follow-up at day 7, of the 24 patients negative for COVID19, 10 (41%) had persistence of virus in the EV (1CT - 0.028{+/-}0.004) and on day 14, 14 of 40 (35%) negative RT-PCR had EVs with SARS CoV2 RNA (1CT - 0.028{+/-}0.06). The mean viral load decreased at day7 and day14 in nasal swab from baseline (p=0.001) but not in EV. SARS-CoV2 RNA otherwise undetectable in plasma, was found to be positive in EV in 12.5% of COVID19 positive patients. Interestingly, significantly prolonged and high viral load was found in EV at day 14 in CLD-COVID19 patients compared to COVID19 alone (p=0.002). The high cellular injury was seen in CLD-COVID19 infected patients with significant high levels of EV associated with endothelial cells and hepatocytes than COVID19 alone (p=0.004; 0.001).

ConclusionIdentification of SARS-CoV2 RNA in EV, in RT-PCR negative patients indicates persistence of infection for and likely recurrence of the infection. EV associated RNA may determine the clinical course of subjects with undetectable SARS-CoV2 virus and this may also have relevance in management of chronic liver disease patients.


title: Persistence of immune response in health care workers after two doses BNT162b2 in a longitudinal observational study

abstract:
BackgroundThe mRNA-based vaccine BNT162b2 of BioNTech/Pfizer has shown high efficacy against SARS-CoV-2 infection and a severe course of the COVID-19 disease. However, little is known about the long-term durability of the induced immune response resulting from the vaccination.

MethodsIn a longitudinal observational study in employees at a German hospital we compared the humoral and cellular immune response in 184 participants after two doses of the BioNTech/Pfizer vaccine (BNT162b2) with a mid-term follow-up after 9 months. Anti-SARS-CoV-2 binding antibodies were determined using both a quantitative and a semi-quantitative assay. For a qualitative assessment of the humoral immune response, we additionally measured neutralizing antibodies. Cellular immune response was evaluated by measuring Interferon-gamma release after stimulating blood-cells with SARS-CoV-2 specific peptides using a commercial assay.

ResultsIn the first analysis, a 100% humoral response rate was described after two doses of BNT162b2 vaccine with a mean antibody ratio of 8.01 {+/-} 1.00. 9 months after the second dose of BNT162b2, serological testing showed a significant decreased mean antibody ratio of 3.84 {+/-} 1.69 (p < 0.001). Neutralizing antibodies were still detectable in 96% of all participants, showing an average binding inhibition value of 68.20% {+/-} 18.87%. Older age, (p < 0.001) and obesity (p = 0.01) had a negative effect on the antibody persistence. SARS-CoV-2 specific cellular immune response was proven in 75% of individuals (mean IFN-gamma release: 579.68 mlU/ml {+/-} 705.56 mlU/ml).

ConclusionOur data shows a declining immune response 9 months after the second dose of BNT162b2, supporting the potentially beneficial effect of booster vaccinations, the negative effect of obesity and age stresses the need of booster doses especially in these groups.


title: SAFETY PROFILE OF COVID-19 VACCINES IN PREGNANT AND POSTPARTUM WOMEN IN BRAZIL

abstract:
BackgroundAlthough COVID-19 vaccines are currently under use in pregnant and postpartum women, there is still lack of evidence regarding safety and effectiveness in these populations. This study aims to describe the safety profile of COVID-19 vaccines in pregnant and postpartum women in the early stage of vaccination campaign in Brazil.

MethodsThis is an observational cross-sectional study using data from the Brazilian surveillance information system for adverse events (SI-EAPV) to characterize the safety of COVID-19 vaccines available (Sinovac/Butantan, Pfizer/BioNTech, AstraZeneca and Janssen) in Brazilian pregnant and postpartum women after receiving it from April to August 2021. A descriptive analysis was performed to assess the frequency and incidence rate of the adverse events (AE) for COVID-19 vaccines.

ResultsA total of 3,333 adverse events following COVID-19 immunization were reported for the study population in the SIEAPV. The incidence of AE found was 309.4/100,000 doses (95% CI 297.23, 321.51). Regarding the four vaccines available in the country, Sinovac/Butantan had the lowest incidence (74.08/100,000 doses; 95% CI 63.47, 84.69). Systemic events were the most frequent notified for the group (82.07%), followed by local (11.93%) and maternal (4.74%), being most of them classified as non-severe (90.65%).

ConclusionA similar pattern of AE as stated in other studies was found, with even better results for non-viral vector vaccines, corroborating to the recommendation of vaccination for these groups. Even though, further studies appraising a longer observation time are still needed to provide a broader safety aspect for the vaccines currently under use for this population.


title: Comparative evaluation of rapid isothermal amplification and antigen assays for screening testing of SARS-CoV-2

abstract: Human transmission of SARS-CoV-2 and emergent variants of concern has continued to occur globally, despite mass vaccination campaigns. Public health strategies to reduce virus spread should therefore rely, in part, on frequent screening with rapid, inexpensive, and sensitive tests. We evaluated two digitally integrated rapid tests and assessed their performance using stored nasal swab specimens collected from individuals with or without COVID-19. An isothermal amplification assay combined with a lateral flow test had a limit of detection of 10 RNA copies per reaction, and a positive percent agreement (PPA)/negative percent agreement (NPA) during the asymptomatic and symptomatic phases of 100%/100% and 95.83/100%, respectively. Comparatively, an antigen-based lateral flow test, had a limit of detection of 30,000 copies, and a PPA/NPA during the asymptomatic and symptomatic phases of 82.86%/98.68% and 91.67/100%, respectively. Both the isothermal amplification and antigen-based lateral flow tests had optimized detection of SARS-CoV-2 during the peak period of transmission; however, the antigen-based test had reduced sensitivity in clinical samples with qPCR Ct values greater than 29.8. Low-cost, high-throughput screening enabled by isothermal amplification or antigen-based techniques have value for outbreak control.


title: Matrix metalloproteinase 2 and 9 enzymatic activities are selectively increased in the myocardium of Chronic Chagas Disease cardiomyopathy patients: role of TIMPs

abstract: Chronic Chagas disease (CCC) is an inflammatory dilated cardiomyopathy with a worse prognosis compared to other cardiomyopathies. We show the expression and activity of Matrix Metalloproteinases (MMP) and of their inhibitors TIMP (tissue inhibitor of metalloproteinases) in myocardial samples of end stage CCC, idiopathic dilated cardiomyopathy (DCM) patients, and from organ donors. Our results showed significantly increased mRNA expression of several MMPs, several TIMPs and EMMPRIN in CCC and DCM samples. MMP-2 and TIMP-2 protein levels were significantly elevated in both sample groups, while MMP-9 protein level was exclusively increased in CCC. MMPs 2 and 9 activities were also exclusively increased in CCC. Results suggest that the balance between proteins that inhibit the MMP-2 and 9 is shifted toward their activation. Inflammation-induced increases in MMP-2 and 9 activity and expression associated with imbalanced TIMP regulation could be related to a more extensive heart remodeling and poorer prognosis in CCC patients.


title: Vaccines provide disproportional protection to the increased hospitalisation risk posed by the Delta variant of SARS-CoV2: a meta-analysis

abstract: Variants of SARS-CoV2 that achieved global dominance (Alpha and Delta) have been associated with increased hospitalisation risk. A quantification of this risk across studies is currently lacking for Delta. Furthermore, how risk for severe disease changes in both vaccinated and unvaccinated individuals is important as the underlying risks determine public health impact. The surplus risk of Delta versus Alpha on hospitalisation was determined using random-effects meta-analysis. Infection with the Delta compared to the Alpha variant increased hospitalisation risk (unvaccinated: log HR 0.62, CI: 0.41 - 0.84, P < 0.0001; linear HR 1.87). This finding should inform our response to future variants of concern, currently Omicron. SARS-CoV2 variants that achieve dominance, have achieved this through a higher rate of infection and this evolutionary trajectory has also come with a correlated higher risk of severe disease. The surplus risk posed by Delta was significantly lower however in the vaccinated (model estimate -0.40, CI: -0.73 - -0.07, P = 0.017). Vaccination thus provided a disproportionate level of protection to hospitalisation with the Delta variant and provides further rationale for vaccination for SARS-CoV2 as a durable public health measure.


title: Prevalence and time trend of congenital heart defects: a registry-based study in Iran

abstract:
IntroductionCongenital Heart Defects (CHD) are one of the most common types of congenital anomalies affecting nearly one percent of births every year. The aim of this study was to report the prevalence and time trend of CHD in the northwest of Iran between 2000 and 2019.

MethodsSince 2000, infants born with birth defects have been registered in Tabriz Registry of Congenital Anomalies (TRoCA). For this study, the information and data of newborns with CHD (n=1084) were collected using the TRoCA registry system.

ResultsOver the two decades, the prevalence rate of CHD in the northwest of Iran was 3.7 per 1000 live births (95 percent CI: 34.9 to 39.4). The prevalence rate of CHD during the first decade (2000-09) and the second (2010-19) were estimated 2.8 (95 percent CI: 2.5 to 2.9) and 5.9 (95 percent CI: 5.4 to 6.4) per 1000 live births, respectively.

ConclusionThe prevalence rate of CHD in the TRoCA registry area showed an increasing trend indicating methodological improvement in the facilities and diagnosis techniques. It would therefore seem essential to concentrate on the primary prevention activities to reduce the burden of these defects.


title: How effective is vaccination protection?

abstract: This short note provides a simple static model to assess the effect of vaccination against hospitalization.


title: Triangulating evidence for the causal impact of single-dose zinc supplement on glycemic control for type-2 diabetes

abstract:
BackgroundAlthough previous studies suggested the protective effect of zinc for type-2 diabetes, the unitary causal effect remains inconclusive.

ObjectiveWe investigated the causal effect of zinc as a single intervention on glycemic control in type-2 diabetes patients, using a systematic review of RCTs and two-sample Mendelian randomization (MR).

MethodsFour outcomes were identified: fasting blood glucose/fasting glucose, hemoglobin A1c (HbA1c), homeostasis model assessment of insulin resistance (HOMA-IR), and serum insulin/fasting insulin level. In the systematic review, four databases were searched up to June 2021. Results were synthesized through the random-effects meta-analysis. Single nucleotide polymorphisms (SNPs) that are independent and are strongly related to zinc supplements were selected from MR-base to perform the two-sample MR with inverse-variance weighted (IVW) coefficient.

ResultsIn the systematic review, 14 trials were included. The zinc supplement led to a significant reduction in the post-trial mean of fasting blood glucose (mean difference (MD): - 26.52, 95%CI: -35.13, -17.91), HbA1C (MD: -0.52, 95%CI: -0.90, -0.13), and HOMA-IR (MD: -1.65, 95%CI: -2.62, -0.68), compared to the control group. In the two-sample MR, zinc supplement with 2 SNPs associated with lower fasting glucose (IVW coefficient: -2.04, 95%CI: -3.26, -0.83), but not specified type-2 diabetes.

ConclusionAlthough the study was limited by the few trials (review) and SNPs (two-sample MR), we demonstrated that the single zinc supplementary improved glycemic control among type-2 diabetes patients with causal evidence to a certain extent.


title: Deficits in hospital care among clinically vulnerable children aged 0 to 4 years during the COVID-19 pandemic

abstract:
ObjectiveTo quantify deficits in hospital care for clinically vulnerable children during the COVID-19 pandemic.

DesignBirth cohort in Hospital Episode Statistics (HES).

SettingNHS hospitals in England.

Study populationAll children aged <5 years with a birth recorded in hospital administrative data (January 2010 to March 2021).

Main exposureClinical vulnerability defined by a chronic health condition, preterm birth (<37 weeks gestation) or low birthweight (<2500g).

Main outcomesDeficits in care defined by predicted rates for 2020, estimated from 2015- 2019, minus observed rates per 1000 child years during the pandemic (March 2020-2021).

ResultsOf 3,813,465 children, 17.7% (1 in 6) were clinically vulnerable (9.5% born preterm or low birthweight, 10.3% had a chronic condition). Deficits in hospital care during the pandemic were much higher for clinically vulnerable children than peers: respectively, outpatient attendances (314 versus 73 per 1000 child years), planned admissions (55 versus 10), and unplanned admissions (105 versus 79). Clinically vulnerable children accounted for 50.1% of the deficit in outpatient attendances, 55.0% in planned admissions, and 32.8% in unplanned hospital admissions. During the pandemic, weekly rates of planned care returned to pre-pandemic levels for infants with chronic conditions but not older children. Deficits in care differed by ethnic group and level of deprivation. Virtual outpatient attendances increased from 3.2% to 24.8% during the pandemic.

Conclusion1 in 6 clinically vulnerable children accounted for one-third to one half of the deficit in hospital care during the pandemic.

category: pediatrics


title: Modeling Prenatal Adversity/Advantage: Effects on Birth Weight

abstract:
ImportanceHow maternal experiences of adversity/advantage during pregnancy impact the developing fetus remains unclear.

ObjectiveUsing prospective data about experiences of adversity/advantage and other factors known to impact fetal developmental, we explored how these risk and protective factors relate to each other and impact infant birth weight by gestational age.

DesignA prospective study that collected data on of forms of social advantage/disadvantage, and psychological factors from pregnant women during each trimester of pregnancy that accounted for maternal medical and nutritional status. We aimed to determine the differential impact of social advantage/disadvantage and adversity and psychological factors on infant birthweight accounting for gestational age. Structural Equation Modeling (SEM) was used to investigate the relationship of these forms of adversity as latent constructs on infant outcome. The follow-up of children is ongoing as a part of the Early Life Adversity Biological Embedding and Risk for Developmental Precursors of Mental Disorders (eLABE). Data collection was conducted from 2017-2020.

SettingAn academic medical center.

ParticipantsPregnant women who were participants in a study of preterm birth within the Prematurity Research Center at Washington University in St. Louis with negative drug screens (other than cannabis) and without known pregnancy complications or known fetal congenital problems, were invited for participation. N=395 mothers were included in the analysis and N=268 eligible subjects declined participation. N=399 singleton offspring were included.

Main Outcome(s) and Measure(s)Birthweight accounting for gestational age.

ResultsThe study included N=395 pregnant women and their N=399 singleton offspring. The Social Advantage latent factor significantly predicted the residual birthweight after accounting for gestational age (p=.006) representing a 2.57% increase in residual gestational age-adjusted birthweight for each one standard deviation increase in the Social Advantage. The only other significant predictor was pre-pregnancy BMI (p=.019) which was associated with increased birthweight by gestational age while the Psychosocial Stress factor was no longer significant when other factors were accounted for.

Conclusions and RelevanceFindings elucidate the significant effects of social adversity on the developing fetus and underscore the need to protect pregnant women in this risk group.

Key PointsO_LIQuestion: What are the differential effects of social adversity/advantage and psychosocial stress during pregnancy on fetal development evidenced by birthweight?
C_LIO_LIFindings: Psychosocial adversity/advantage significantly impacted birthweight after accounting for other salient risk factors including maternal physical health.
C_LIO_LIMeaning: Resources and interventions for pregnant women experiencing social adversity should become a public health priority for the protection of the developing fetus.
C_LI


title: The impact of shielding during the COVID-19 pandemic on mental health: Evidence from the English Longitudinal Study of Ageing

abstract:
BackgroundDuring the COVID-19 pandemic, older and clinically vulnerable people were instructed to shield or stay at home to save lives. Policies restricting social contact and human interaction pose a risk to mental health, but we know very little about the impact of shielding and stay at home orders on the mental health of older people.

AimsUnderstand the extent to which shielding contributes to poorer mental health.

MethodExploiting longitudinal data from Wave 9 (2018/19) and two COVID-19 sub-studies (June/July 2020; November/December 2020) of the English Longitudinal Study of Ageing we use logistic and linear regression models to investigate associations between patterns of shielding during the pandemic and mental health, controlling for socio-demographic characteristics, pre-pandemic physical and mental health, and social isolation measures.

ResultsBy December 2020, 70% of older people were still shielding or staying at home, with 5% shielding throughout the first 9 months of the pandemic. Respondents who shielded experienced worse mental health. Although prior characteristics and lack of social interactions explain some of this association, even controlling for all covariates, those shielding throughout had higher odds of reporting elevated depressive symptoms (OR=1.87, 95%CI=1.22;2.87) and reported lower quality of life (B=-1.28, 95%CI=-2.04;-0.52) than those who neither shielded nor stayed at home. Shielding was also associated with increased anxiety.

ConclusionsShielding itself seems associated with worse mental health among older people, highlighting the need for policymakers to address the mental health needs of those who shielded, both in emerging from the current pandemic and for the future.


title: Predictors of uncertainty and unwillingness to receive the COVID-19 booster vaccine in a sample of 22,139 fully vaccinated adults in the UK

abstract:
BackgroundThe continued success of the COVID-19 vaccination programme in the UK will depend on widespread uptake of booster vaccines. However, there is evidence of hesitancy and unwillingness to receive the booster vaccine, even in fully vaccinated adults. Identifying factors associated with COVID-19 booster vaccine intentions specifically in this population is therefore critical.

MethodsWe used data from 22,139 fully vaccinated adults who took part in the UCL COVID-19 Social Study. Multinomial logistic regression examined predictors of uncertainty and unwillingness (versus willingness) to receive a COVID-19 booster vaccine (measured 22 November 2021 to 6 December 2021), including (i) socio-demographic factors, (ii) COVID-19 related factors (e.g., having been infected with COVID-19), and (iii) initial intent to receive a COVID-19 vaccine in the four months following the announcement in the UK that the vaccines had been approved (2 December 2020 to 31 March 2021).

Findings4% of the sample reported that they were uncertain about receiving a COVID-19 booster vaccine, and a further 4% unwilling. Initial uncertainty and unwillingness to accept the first COVID-19 vaccine in 2020-21 were each associated with over five times the risk of being uncertain about and unwilling to accept a booster vaccine. Healthy adults (those without a pre-existing physical health condition) were also more likely to be uncertain or unwilling to receive a booster vaccine. In addition, low levels of current stress about catching or becoming seriously ill from COVID-19, consistently low compliance with COVID-19 government guidelines during periods of strict restrictions (e.g., lockdowns), lower levels of educational qualification, lower socio-economic position, and age below 45 years were all associated with uncertainty and unwillingness.

InterpretationOur findings highlight that there are a range of factors that predict booster intentions, with the strongest predictor being previous uncertainty and unwillingness. Two other concerning patterns also emerged from our results. First, administration of booster vaccinations may increase social inequalities in experiences of COVID-19 as adults from lower socio-economic backgrounds are also most likely to be uncertain or unwilling to accept a booster vaccine as well as most likely to be seriously affected by the virus. Second, some of those most likely to spread COVID-19 (i.e., those with poor compliance with guidelines) are most likely to be uncertain and unwilling. Public health messaging should be tailored specifically to these groups.

FundingThe Nuffield Foundation [WEL/FR-000022583], the MARCH Mental Health Network funded by the Cross-Disciplinary Mental Health Network Plus initiative supported by UK Research and Innovation [ES/S002588/1], and the Wellcome Trust [221400/Z/20/Z and 205407/Z/16/Z].


title: Predictors of uncertainty and unwillingness to receive the COVID-19 booster vaccine: an observational study of 22,139 fully vaccinated adults in the UK


title: NFL COVID-19 Return to Sport Injury Prevalence Comparison

abstract:
1. PurposeDuring the COVID 19 Pandemic, the NFL teams have been reported to have limited training sections in preparation for their games. This study compares the prevalence of injury during the 2018, 2019, and 2020 NFL seasons, with the aim to determine the potential causes of the differences in prevalence.

2. MethodOfficial injury reports from each team were counted during the 17-week regular season of each year (2018, 2019, and 2020). The data was analyzed using an unpaired t-test to compare the injury prevalence between each of the three seasons.

3. ResultsThe 2018 season produced a total of 1,561 injuries and a mean of 48.78 injuries per team. The 2019 season produced a total of 1,897 injuries and mean of 59.28 injuries per team, while the 2020 season produced a total of 2, 484 injuries and mean of 77.63 injuries per team. An unpaired t-test was performed using the data to compare the mean number of injuries per team of each of the seasons. Comparison of the 2020 season against the 2019 season showed a statistically significant difference (P=.0003). Comparison of the 2020 season to the 2018 season found a statistically significant difference (P=.0001). Comparison between the 2019 and the 2018 seasons found a statistically significant difference (P=.0314).

ConclusionAlthough the 2019 and 2018 season showed a statistically significant difference (P=0.0314), this difference is not as astronomical when we compare the 2020 seasons vs 2019 and 2018 seasons (P=0.0003 and P=0.0001, respectively) (Figure 2). The astronomical increase in injury prevalence in the 2020 season over the previous years does raise the possibility that there was reduced physiological adaption to stress, due to the limited amount of training embarked on. The limited amount of training was the result of closure of practice facilities during the COVID-19 pandemic. More physiological investigation involving players must be done at the professional and amateur levels to determine if there is a lack of physiological adaptation due to limited use of practice and training facilities during the COVID-19 pandemic.

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category: sports medicine


title: White Matter Beta-Amyloid Precursor Protein Immunoreactivity in Autopsied Subjects With and Without COVID-19

abstract: The coronavirus SARS-CoV-2 causes COVID-19, a predominantly respiratory disease that has been reported to be associated with numerous neurological signs, symptoms and syndromes. More than 20 published studies have used RT-PCR methods to determine viral SARS-CoV-2 genomic presence in postmortem brain tissue and the overall impression is that viral brain invasion is relatively uncommon and occurs in low copy numbers, supporting indirect mechanisms as the cause of most neurological phenomena. Hypoxic-ischemic brain injury and stroke are one such possible indirect mechanism, as acute ischemia or stroke concurrence with COVID-19 has been reported as being 0.5% to 20%. Immunohistochemical stains for {beta}-amyloid precursor protein (APP) have been suggested to be a "signature" change of hypoxic leukoencephalopathy or COVID-19 brain disease, although prior reports have not had a non-COVID-19 control group. We therefore compared the prevalence and intensity of white matter APP staining in the brains of subjects dying with and without COVID-19. Clinical and neuropathological results, including semi-quantitative assessment of the density of white matter APP staining, were compared between 20 COVID-19 cases and 20 pre-COVID-19 autopsy cases, including 10 cases with autopsy-proven non-COVID-19 pneumonia and 10 cases without pneumonia. Positive APP white matter staining in at least one of the two brain regions (precentral gyrus and cingulate gyrus) studied was not significantly more common in COVID-19 vs controls (14/20 vs 12/20). Comparing density scores from both brain regions combined, the mean scores for COVID-19 cases were higher than those for controls of both types together but not significantly different when restricting to controls with pneumonia. Among control cases, cases with pneumonia had significantly higher scores. The presence or absence of a major neuropathologically-defined neurodegenerative disorder did not significantly affect the APP scores. The major finding is that while APP white matter staining cannot be regarded as a specific marker of COVID-19, as it does not occur with significantly greater probability in in COVID-19 brains as compared to non-COVID-19 brains, it is possible that white matter APP staining, representing acute or subacute axonal damage, may be a common occurrence in the perimortem period, and that it may be more intense in subjects dying with pneumonia, regardless of cause.

category: neurology


title: MIRS: an AI scoring system for predicting the prognosis and therapy of breast cancer

abstract: Current scoring systems for prognosis of breast cancer are available but usually consider only one prognostic feature. We aim to develop a novel prognostic scoring system based on both immune-infiltration and metastatic features to not only assess the patient prognoses more accurately but also guide therapy for patients with breast cancer. Computational immune-infiltration and gene profiling analysis identified a 12-gene panel firstly characterizing immune-infiltrating and metastatic features. Neural network model yielded a precise prognostic scoring system called metastatic and immunogenomic risk score (MIRS). The influence of MIRS on the prognosis and therapy of breast cancer was then comprehensively investigated. MIRS significantly stratifies patients into high risk-group (MIRShigh) and low risk-group (MIRSlow) in both training and test cohorts. The MIRSlow patients exhibit significantly improved survival rate compared with MIRShigh patients. A series of analyses demonstrates that MIRS can well characterize the metastatic and immune landscape of breast cancer. Further analysis on the usage of MIRS in chemotherapy suggests that MIRShigh patients may benefit from three chemotherapeutic drugs (Cisplatin, Tamoxifen and Vincristine). Higher immune infiltration and significantly prolonged survival are observed in MIRSlow patients, indicating a better response in immune checkpoint inhibitor therapy. Our analysis demonstrates that MIRS could effectively improve the accuracy of prognosis for patients with breast cancer. Also, MIRS is a useful webtool, which is deposited at https://lva85.github.io/MIRS/, to help clinicians in designing personalized therapies for patients with breast cancer.


title: Participatory Research: A Priority Setting Partnership for Chronic Musculoskeletal Pain in Denmark

abstract:
BackgroundPatient and stakeholder engagements in research have increasingly gained attention in healthcare and healthcare-related research. A common and rigorous approach to establish research priorities based on input from people and stakeholders is the James Lind Alliance Priority Setting Partnership (JLA-PSP). The aim of this study was to establish research priorities for chronic musculoskeletal (MSK) pain by engaging with humans living with chronic MSK pain, relatives to humans living with chronic MSK pain, healthcare professionals (HCP), and researchers working with chronic MSK pain.

MethodsThis JLA-PSP included a nation-wide survey in Denmark, an interim prioritisation, and an online consensus building workshop. The information gained from this was the basis for developing the final list of specific research priorities within chronic MSK pain.

ResultsIn the initial survey, 1010 respondents (91% people living with chronic MSK pain/relatives, 9% HCPs/researchers) submitted 3121 potential questions. These were summarised into 19 main themes and 36 sub-themes. In the interim prioritisation exercise, 51% people living with pain/relatives and 49% HCPs/researchers reduced the list to 33 research questions prior to the final priority setting workshop. 23 participants attended the online workshop (12 people/relatives, 10 HCPs, and 1 researcher) who reached consensus for the most important research priorities after two rounds of discussion of each question.

ConclusionThis study identified several specific research questions generated by people living with chronic MSK pain, relatives, HCPs, and researchers. The stakeholders proposed prioritization of the healthcare systems ability to support patients, focus on developing coherent pathways between sectors and education for both patients and HCP. These research questions can form the basis for future studies, funders, and be used to align research with end-users priorities


title: Clinical genetics laboratories use divergent demographic frameworks across countries: comparing data structures for race, ethnicity, and ancestry on test requisition forms

abstract:
PurposeThe goal of this study is to investigate how population groups are represented on requisition forms for clinical genetic testing in different laboratories.

MethodsClinical laboratory test requisition forms (RFs) were obtained from 70 laboratories in the US, Canada, Europe, and Australia. Details about the laboratories and how RFs represent patient demographics were extracted and analyzed for trends between forms in the U.S. (N=213) and other countries (N=203).

ResultsClinical genetics laboratories included in the analysis vary widely regarding the format of demographic data collected on test requisition forms. US-based laboratory RFs are more likely than those from other countries to include  race or  ethnicity. These are most often represented as categorical data, with multiple-choice options. RFs from laboratories in other countries do not include  race, and those that include  ethnicity most often provide a blank space for open-ended responses.

ConclusionsThese results are consistent with existing research on heterogeneity in the nomenclature and number of categories used to describe patient populations across clinical genetics laboratories in the US. It also suggests systemic differences in the way measures of diversity are conceptualized in the US compared to other countries.


title: Mendelian randomization analyses reveal mediating factors of the causal effect of height on coronary artery disease

abstract: An inverse correlation between stature and risk of coronary artery disease (CAD) has been observed in several epidemiologic studies, and recent Mendelian randomization (MR) experiments have suggested evidence that this association may be causal. However, the extent to which the effect estimated by MR can be explained by established cardiovascular risk factors is unclear, with a recent report suggesting that lung function traits could fully explain the height-CAD effect. To clarify this relationship, we utilized the largest set of genetic instruments for human stature to date, comprising >2,000 genetic variants for height and CAD. In univariable analysis, we confirmed that a one standard deviation decrease in height ([~]6.5 cm) was associated with a 12.0% increase in the risk of CAD, consistent with previous reports. In multivariable analysis accounting for effects from up to 12 established risk factors, we observed a >3-fold attenuation in the causal effect of height on CAD susceptibility (3.7%, p = 2.1x10-2). We observed minimal effects of lung function traits on CAD risk in our analyses, indicating that these traits are unlikely to explain the residual association between height and CAD risk. In sum, these results suggest that height does not add meaningful clinical impact on CAD risk prediction beyond established risk factors.


title: A machine learning-based approach to determine infection status in recipients of BBV152 whole virion inactivated SARS-CoV-2 vaccine for serological surveys

abstract: Data science has been an invaluable part of the COVID-19 pandemic response with multiple applications, ranging from tracking viral evolution to understanding the effectiveness of interventions. Asymptomatic breakthrough infections have been a major problem during the ongoing surge of Delta variant globally. Serological discrimination of vaccine response from infection has so far been limited to Spike protein vaccines used in the higher-income regions. Here, we show for the first time how statistical and machine learning (ML) approaches can discriminate SARS-CoV-2 infection from immune response to an inactivated whole virion vaccine (BBV152, Covaxin, India), thereby permitting real-world vaccine effectiveness assessments from cohort-based serosurveys in Asia and Africa where such vaccines are commonly used. Briefly, we accessed serial data on Anti-S and Anti-NC antibody concentration values, along with age, sex, number of doses, and number of days since the last vaccine dose for 1823 Covaxin recipients. An ensemble ML model, incorporating a consensus clustering approach alongside the support vector machine (SVM) model, was built on 1063 samples where reliable qualifying data existed, and then applied to the entire dataset. Of 1448 self-reported negative subjects, 724 were classified as infected. Since the vaccine contains wild-type virus and the antibodies induced will neutralize wild type much better than Delta variant, we determined the relative ability of a random subset of such samples to neutralize Delta versus wild type strain. In 100 of 156 samples, where ML prediction differed from self-reported uninfected status, Delta variant, was neutralized more effectively than the wild type, which cannot happen without infection. The fraction rose to 71.8% (28 of 39) in subjects predicted to be infected during the surge, which is concordant with the percentage of sequences classified as Delta (75.6%-80.2%) over the same period.

category: health informatics


title: Real-world response of COVID-19 patients in Mexico

abstract: Currently in Mexico, the available clinical guidelines published for COVID-19 treatment recommend symptom treatment and home isolation for mild forms; and other medications for severe and acute forms. The effectiveness of how real-world treatment patterns impact mortality and recovery is still unknown. In this retrospective observational study, we investigated 5,575 medicated patients with COVID-19 treated at two Mexican states seen in the largest healthcare system in Mexico. A survival analysis was performed using death and discharge as primary and secondary outcomes (respectively). Machine learning models were built to predict mortality and discharge. The higher prevalence of obesity, diabetes, and heart disease comorbidities is consistent with Mexicos epidemiological profile. Mortality occurs around 15-20 days from the start of symptoms. Antivirals in combination with antibiotics present lower survival rates, with patients undertaking neuraminidase inhibitors (NAIs) being the most affected. Our findings recommend against using specific treatment combinations with NAIs, and should help improve the countrys clinical guidelines.


title: Patients' and carers' experiences of, and engagement with remote home monitoring services for COVID-19 patients: a rapid mixed-methods study

abstract:
IntroductionRemote home monitoring models were implemented during the COVID-19 pandemic to shorten hospital length of stay, reduce unnecessary hospital admission, readmission and infection, and appropriately escalate care. Within these models, patients are asked to take and record readings and escalate care if advised. There is limited evidence on how patients and carers experience these services. This study aimed to evaluate patient experiences of, and engagement with, remote home monitoring models for COVID-19.

MethodsA rapid mixed-methods study in England. We conducted a cross-sectional survey and interviews with patients and carers. Interview findings were summarised using rapid assessment procedures sheets and grouping data into themes (using thematic analysis). Survey data were analysed using descriptive statistics.

ResultsWe received 1069 surveys (18% response rate) and conducted interviews with patients (n=59) and carers (n=3).  Care relied on support from staff members, and family/friends. Patients and carers reported positive experiences and felt that the service and human contact reassured them and was easy to engage with. Yet, some patients and carers identified problems with engagement. Engagement was influenced by: patient factors such as health and knowledge, support from family/friends and staff, availability and ease-of-use of informational and material resources (e.g. equipment), and service factors.

ConclusionRemote home monitoring models place responsibility on patients to self-manage symptoms in partnership with staff; yet many patients required support and preferred human contact (especially for identifying problems). Caring burden and experiences of those living alone, and barriers to engagement should be considered when designing and implementing remote home monitoring services.

Patient or public contributionFor this evaluation, members of the study team met with service user and public members of the BRACE PPI group and Health and Care Panel and patient representatives from RSET in a series of workshops. These workshops informed study design, data collection tools, data interpretation and to discuss study dissemination for Phase 2. For example, patient facing documents, such as the consent form, topic guides, patient survey and patient information sheet were reviewed by this group. Additionally, PPI members helped to pilot patient surveys and interview guides with the research team. We also asked some members of the public to pilot the patient survey. Members of the PPI group were given the opportunity to comment on the manuscript. One PPI member commented on the manuscript and the manuscript was amended accordingly.

category: health systems and quality improvement


title: The quorum sensing com system regulates pneumococcal colonisation and invasive disease in a pseudo-stratified airway tissue model

abstract:
Streptococcus pneumoniae (Spn) colonises respiratory epithelia but can also invade lung cells causing pneumonia. We developed an ex vivo model with human airway epithelial (HAE) cells harvested from lung biopsies to study Spn colonisation and translocation. Flow-cytometry, confocal imaging and electron microscopy studies identified the epithelial lineage with signs of differentiation (beating cilia, mucus, and tight junctions). HAE cells were challenged with Spn wild-type TIGR4 (wtSpn) or its isogenic {Delta}comC quorum sensing-deficient mutant. {Delta}comC mutant colonised significantly less than wtSpn at 6 h post-inoculation but at significantly higher levels at 19 h and 30 h. Translocation correlated inversely with colonisation density. Transepithelial electric resistance (TEER) decreased after pneumococcal infection and correlated with increased translocation for both strains.

Confocal imaging illustrated colocalisation of intracellular Spn with both cilia and zonulin-1 and prominent microcolony formation with wtSpn but disintegration of microcolony structures over time with {Delta}comC mutant. {Delta}comC caused a more pronounced release of both zonulin-1 and lactate dehydrogenase into the supernatant at later time points than wtSpn, suggesting that cytotoxicity is likely not the mechanism leading to translocation. There was a density- and time-dependent increase of inflammatory cytokines from human HAE cells infected with {Delta}comC compared with wtSpn, including increased levels of the NLRP3 inflammasome-related IL-18.

In conclusion, our experiments indicate that ComC system allows a higher organisational level of population structure resulting in microcolony formation, increased early colonisation and subsequent translocation. We propose that ComC inactivation unleashes a very different and possibly more virulent phenotype that merits further investigation.


title: Pathogenic CD8 T cells defined by longitudinal liver sampling in chronic hepatitis B patients starting antiviral therapy

abstract: Accumulation of activated immune cells results in non-specific hepatocyte killing in chronic hepatitis B (CHB), leading to fibrosis and cirrhosis. We enrolled 15 CHB patients with active liver damage to receive antiviral therapy, and performed longitudinal liver sampling using fine-needle aspiration to investigate mechanisms of CHB pathogenesis in the human liver. Single-cell sequencing of total liver cells revealed a distinct liver-resident, polyclonal CD8 T cell population that was enriched at baseline and displayed a highly activated immune signature during liver damage. Cytokine combinations, identified by in silico prediction of ligand-receptor interaction, induced the activated phenotype in healthy liver CD8 T cells, resulting in non-specific Fas ligand-mediated killing of target cells. These results define a CD8 T cell population in the human liver that can drive pathogenesis, and a key pathway involved in their function in CHB patients.


title: A one health approach to investigating an outbreak of alimentary tick-borne encephalitis in a non-endemic area in France (Ain, Eastern France): a longitudinal serological study in livestock, detection in ticks, and the first TBE virus isolation and molecular characterization

abstract: Tick borne encephalitis virus geographic range and human incidence is increasing throughout Europe, putting a number of non-endemic regions and countries at risk of outbreaks. In spring 2020, there was an outbreak of TBE in Ain, Eastern France, where the virus had never been detected before. All patients but one had consumed traditional unpasteurized raw goat cheese from a local producer. We conducted an investigation in the suspected farm using an integrative One Health approach. Our methodology included (i) the detection of virus in cheese and milk products, (ii) serological testing of all animals in the suspected farm and surrounding farms, (iii) an analysis of the landscape and localisation of wooded area, (iv) the capture of questing ticks and small mammals for virus detection and estimating enzootic hazard, and (v) virus isolation and genome sequencing. This approach allowed us to confirm the alimentary origin of the TBE outbreak and to witness in real time the seroconversion of recently exposed individuals and the excretion of virus in goat milk. In addition, we identified a wooded focus area where and around which there is a risk of TBEV exposure. We provide the first TBEV isolate responsible for as a source of dietary contamination in France, obtained its full-length genome sequence, and found that it does not cluster very closely neither with the isolate circulating in Alsace nor with any other isolate within the European lineage. TBEV is now a notifiable human disease in France, which should facilitate surveillance of TBEV incidence and distribution throughout France.


title: A Single Dose of COVID-19 mRNA Vaccine Induces Airway Immunity in COVID-19 Convalescent Patients

abstract:
BackgroundMucosal antibodies can prevent virus entry and replication in mucosal epithelial cells and hence virus shedding. Preclinical and clinical studies have shown that a parenteral booster injection of a vaccine against a mucosal pathogen promotes stronger mucosal immune responses following prior infection compared to two injections of a parenteral vaccine. We investigated whether this was also the case for a COVID-19 mRNA vaccine.

MethodsTwenty-three COVID-19 convalescent patients and 20 SARS-CoV-2-naive subjects were vaccinated with respectively one and two doses of the Pfizer-BioNTech COVID-19 RNA vaccine. Nasal Epithelial Lining Fluid (NELF) and plasma were collected before and after vaccination and assessed for Immunoglobulin (Ig)G and IgA to Spike and for their ability to inhibit the binding of Spike to its ACE-2 receptor. Blood was analyzed one week after vaccination for the number of Spike-specific Antibody Secreting Cells (ASCs) with a mucosal tropism.

ResultsIn COVID-19 convalescent patients, a single dose of vaccine amplified pre-existing Spike-specific IgG and IgA antibody responses in both NELF and blood against both vaccine homologous and variant strains, including delta. These responses were associated with Spike-specific IgG and IgA ASCs with a mucosal tropism in blood. Nasal IgA and IgG antibody responses were lower in magnitude in SARS-CoV-2-naive subjects after two vaccine doses

ConclusionThis study showed that a parenteral booster injection of a COVID-19 RNA vaccine promoted stronger mucosal immune responses in COVID-19 convalescent patients compared to SARS-CoV-2 naive subjects who had received a first vaccine dose.


title: SARS-CoV-2 lineage dynamics in England from September to November 2021: high diversity of Delta sub-lineages and increased transmissibility of AY.4.2

abstract: Since the emergence of SARS-CoV-2, evolutionary pressure has driven large increases in the transmissibility of the virus. However, with increasing levels of immunity through vaccination and natural infection the evolutionary pressure will switch towards immune escape. Here we present phylogenetic relationships and lineage dynamics within England (a country with high levels of immunity), as inferred from a random community sample of individuals who provided a self-administered throat and nose swab for rt-PCR testing as part of the REal-time Assessment of Community Transmission-1 (REACT-1) study. From 9 to 27 September 2021 (round 14) and 19 October to 5 November 2021 (round 15), all lineages sequenced within REACT-1 were Delta or a Delta sub-lineage with 44 unique lineages identified. The proportion of the original Delta variant (B.1.617.2) was found to be increasing between September and November 2021, which may reflect an increasing number of sub-lineages which have yet to be identified. The proportion of B.1.617.2 was greatest in London, which was further identified as a region with an increased level of genetic diversity. The Delta sub-lineage AY.4.2 was found to be robustly increasing in proportion, with a reproduction number 15% (8%, 23%) greater than its parent and most prevalent lineage, AY.4. Both AY.4.2 and AY.4 were found to be geographically clustered in September but this was no longer the case by late October/early November, with only the lineage AY.6 exhibiting clustering towards the South of England. Though no difference in the viral load based on cycle threshold (Ct) values was identified, a lower proportion of those infected with AY.4.2 had symptoms for which testing is usually recommend (loss or change of sense of taste, loss or change of sense of smell, new persistent cough, fever), compared to AY.4 (p = 0.026). The evolutionary rate of SARS-CoV-2, as measured by the mutation rate, was found to be slowing down during the study period, with AY.4.2 further found to have a reduced mutation rate relative to AY.4. As SARS-CoV-2 moves towards endemicity and new variants emerge, genomic data obtained from random community samples can augment routine surveillance data without the potential biases introduced due to higher sampling rates of symptomatic individuals.