title: The influence of CYP2D6 and CYP2C19 genetic variation on diabetes mellitus risk in people taking antidepressants and antipsychotics.

abstract:
BackgroundCYP2D6 and CYP2C19 enzymes are essential in the metabolism of antidepressants and antipsychotics. Genetic variation in these genes may increase risk of adverse drug reactions. Antidepressants and antipsychotics have previously been associated with risk of diabetes. We examined whether individual genetic differences in CYP2D6 and CYP2C19 contribute to these effects.

MethodsWe identified 31,579 individuals taking antidepressants and 2,699 taking antipsychotics within UK Biobank. Participants were classified as poor, intermediate or normal metabolisers of CYP2D6, and as poor, intermediate, normal, rapid and ultra-rapid metabolisers of CYP2C19. Risk of diabetes mellitus represented by HbA1c level was examined in relation to the metabolic phenotypes. We analysed drugs either individually (where sample size permitted) or grouped by class.

ResultsCYP2D6 poor metabolisers taking paroxetine had higher Hb1Ac than normal metabolisers (mean difference: 2.29mmol/mol; p < 0.001). Among participants with diabetes who were taking venlafaxine, CYP2D6 poor metabolisers had higher HbA1c levels compared to normal metabolisers (mean differences: 10.15 mmol/mol; p < 0.001. Among participants with diabetes who were taking fluoxetine, we observe that CYP2D6 intermediate metabolisers and decreased HbA1c, compared to normal metabolisers (mean difference - 7.74mmol/mol; p=0.017). We did not observe any relationship between CYP2D6 or CYP2C19 metabolic status and HbA1c levels in participants taking antipsychotic medication.

ConclusionOur results indicate that the impact of genetic variation in CYP2D6 differs depending on diabetes status. Although our findings support existing clinical guidelines, further research is essential to inform pharmacogenetic testing for people taking antidepressants and antipsychotics.


title: Ethnicity, migration, and weight misperception: a Born in Bradford study

abstract:
BackgroundWeight perception may differ by ethnicity but is not well-understood, particularly among migrants to the United Kingdom (UK). It is also unknown whether a figure rating scale (FRS) or perceived weight question (PWQ) is more accurate for assessing body weight perception.

MethodsAt 24-months postpartum, women in the Born in Bradford cohort (Bradford, UK) completed the 9-item Stunkard FRS and a 7-category PWQ. Both scales were condensed to weight categories representing the World Health Organisation cut-offs. Weighted kappa statistics assessed agreement between measured and perceived weight categories. {chi}2 and Fishers exact tests assessed categories of misperception by ethnicity and migration and logistic regression was used to examine odds of underestimation.

ResultsThirty percent of white British and 23% of Pakistani-origin women had obesity. Agreement between measured and perceived weight categories were similar for white British women using either a visual scale or weight question (FRS: {kappa} [95%CI]: 0.61 [0.56, 0.65]; PWQ: 0.61 [0.55, 0.68)]. Overall agreement was lower for Pakistani-origin women with the visual scale performing better (FRS (0.58 [0.52, 0.63]) vs PWQ (0.47 [0.40, 0.54]). Pakistani-origin women, particularly those born outside the UK, were more likely to underestimate their body weight compared to white British women; this was greater with the PWQ (18% vs 10%; p<0.001) than FRS (14% vs 6%; p<0.001). Pakistani-origin women were 154% more likely to underestimate their body weight compared to white British women with the FRS and 111% more likely to underestimate when using the PWQ.

ConclusionWe observed ethnic differences in weight misperception with Pakistani-origin women more likely to underestimate their weight compared to white British women. Our findings suggest visual scales, rather than perceived weight questions, are more appropriate for the self-assessment of body weight.

category: public and global health


title: Serum Oxidative Stress Markers in Women with Uterine Fibroids in Lagos, Nigeria.

abstract:
BackgroundUterine fibroid is the most common benign gynaecological tumour in women of reproductive age group, with significant impact on the quality of life, economy, morbidity and sometimes mortality of affected women. Black women of reproductive age group are more likely to develop uterine fibroids. Although available evidence suggests racial and genetic predisposition to the aetiology of uterine fibroid, oxidative stress has been implicated in the onset and progression of uterine fibroids. Epidemiological and experimental studies have suggested that oxidative stress may play an important role in the pathogenesis of gynaecological diseases including uterine fibroids.

Aim and ObjectivesThis study aims to assess the serum levels of antioxidants (catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx)) and oxidants (protein carbonyl (PC), advanced oxidation protein products (AOPP)) in women with uterine fibroids and to identify any association between the size of uterine fibroids and serum levels of the analysed antioxidants and oxidants.

MethodsForty-four women with ultrasound diagnosis of uterine fibroids and 44 women without uterine fibroids were recruited from a University Teaching Hospital. Blood samples were obtained and analysed for serum levels of selected antioxidants (CAT, SOD, GPx) and oxidants (PC, AOPP). Pelvic ultrasonography was performed on all study participants.

ResultsThe median serum levels of antioxidants: CAT (2.20 vs 4.32 ng/ml; p < 0.001); SOD (285.54 vs 380.96 ng/ml; p < 0.001) and GPx (9.67 vs 11.26 {micro}U/ml; p < 0.001) were significantly lower in women with uterine fibroids. The median serum levels of oxidants: PC (162.08 vs 142.36 ng/ml; p = 0.04); and AOPP (22.42 vs 13.94 ng/ml; p < 0.001) were significantly higher in women with uterine fibroids. There was a strong negative correlation between serum levels of AOPP and SOD (r = -0.95; p < 0.001) in women with uterine fibroids. The maximum diameter of fibroids showed a significant positive correlation with AOPP (r = 1.000; p < 0.001) and a negative correlation with SOD (r = -1.000; p < 0.001).

ConclusionWomen with uterine fibroids had lower levels of antioxidants and higher levels of oxidants. In women with uterine fibroids, AOPP negatively correlated with SOD. There was a positive correlation between fibroid size and AOPP and a negative correlation between fibroid size and SOD. The findings of this study suggests that AOPP and SOD may play an important role in uterine fibroids.

category: obstetrics and gynecology


title: Assessing neuropathic pain in sickle cell disease: How useful is quantitative sensory testing?

abstract: Quantitative sensory testing (QST) is a psychophysical test of sensory function which may assist in assessing neuropathic pain (NP). This study compares QST findings with a standardized NP questionnaire to assess their agreement among Jamaicans with sickle cell disease (SCD). A cross sectional study consecutively recruited SCD patients 14 years and older, not pregnant, and without history of clinical stroke or acute illness in Kingston, Jamaica. QST identified thresholds for cold detection, heat detection, heat pain and pressure pain at the dominant thenar eminence, opposite dorsolateral foot and the subjects most frequent pain site. The Douleur Neuropathique 4 (DN4) was interviewer-administered to diagnose NP. Subjects were divided into low and high sensitization groups if below the 5th and above the 95th percentiles, respectively on QST measures. Kappa agreement coefficients, and receiver operator characteristic (ROC) curves were performed to compare QST with the DN4. Two-hundred and fifty-seven SCD subjects were recruited (mean age 31.7 {+/-} 12.2 years, 55.7% female, 75% SS genotype). Kappa agreements were fair (0.2-0.4) to good (0.6-0.8) between DN4 individual items of itching, hypoesthesia to touch, hypoesthesia to pinprick and brush allodynia with various QST sensitization groups. However, kappa agreements between the NP overall diagnosis on the DN4 with sensitization groups were poor (<0.2). Only heat detection (0.75) and heat pain (0.75) at the leg as a pain site showed satisfactory area under the curve (>0.7). QST may assist in assessing individual components of NP but its use should be limited as a tool to augment clinical assessments.

category: pain medicine


title: Comparison of Two Genome-Wide Association Studies for Heart Rate Response to Exercise from the UK Biobank

abstract:
The short-term changes in heart rate (HR) during and after exercise are important physiologic traits mediated via the autonomic nervous system. Variations in these traits are associated with mortality from cardiovascular causes. We conducted a systematic review of genome-wide association studies for these traits (with >10,000 participants) with the aim of comparing Polygenic Risk Scores (PRS) from different studies. Additionally, we applied the STrengthening of Reporting of Genetic Association Studies (STREGA) statement for assessing the completeness of reporting of evidence. Our systematic search yielded two studies (Verweij et al. and Ramirez et al.) that met our inclusion criteria. Both were conducted on the UK Biobank. Both defined their exercise traits as the difference between resting HR and the maximum HR during exercise. Their recovery traits were defined differently. Verweij et al. defined 5 recovery traits as the differences between the peak HR during exercise and the HRs at 10-50 sec post exercise cessation. Ramirez et al. defined their recovery trait as the difference between peak HR during exercise and the minimum HR during the minute post exercise cessation. While Ramirez et al. divided their sample into discovery and replication subsets, Verweij et al. analyzed the whole sample together. In terms of results, there were several common SNPs identified between studies and traits. There was evidence for the phenomenon of winners curse operating for a SNP from the Ramirez studys HR recovery analysis. Many of the SNPs were mutually exclusive between the studies. However, there was a good agreement of PRS from the studies. The differences in the results could be attributed to the different exclusion criteria, analytic approaches, and definitions of traits used. Both studies had an under-representation of individuals of non-European ancestry compared to those of European ancestry. Further studies with proportionate representation of individuals of all ancestries would help address this gap.

Graphical Abstract

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category: genetic and genomic medicine


title: Decoding Clinical Biomarker Space of COVID-19: Exploring Matrix Factorization-based Feature Selection Methods

abstract: One of the most critical challenges in managing complex diseases like COVID-19 is to establish an intelligent triage system that can optimize the clinical decision-making at the time of a global pandemic. The clinical presentation and patients characteristics are usually utilized to identify those patients who need more critical care. However, the clinical evidence shows an unmet need to determine more accurate and optimal clinical biomarkers to triage patients under a condition like the COVID-19 crisis. Here we have presented a machine learning approach to find a group of clinical indicators from the blood tests of a set of COVID-19 patients that are predictive of poor prognosis and morbidity. Our approach consists of two interconnected schemes: Feature Selection and Prognosis Classification. The former is based on different Matrix Factorization (MF)-based methods, and the latter is performed using Random Forest algorithm. Our model reveals that Arterial Blood Gas (ABG) O2 Saturation and C-Reactive Protein (CRP) are the most important clinical biomarkers determining the poor prognosis in these patients. Our approach paves the path of building quantitative and optimized clinical management systems for COVID-19 and similar diseases.

category: infectious diseases


title: COVID-19 Serology Control Panel Using the Dried Tube Specimen Method

abstract:
We used the dried tube specimen (DTS) procedure to develop the COVID-19 Serology Control Panel (CSCP). The CSCP contains five well-characterized SARS-CoV-2 pooled plasma samples made available for labs around the world to compare test kits, use for external quality assurance, harmonize laboratory testing, and train laboratory workers.

Article Summary LineThe dried tube specimen system is a highly effective and resilient way to provide laboratories with well-characterized serology materials. The CSCP can help clinical laboratories inform their choice of diagnostic test to supplement clinical diagnoses of SARS-CoV-2 infection.


title: Myeloid-derived suppressor cells in the blood of Iranian COVID-19 patients

abstract:
BackgroundA cytokine storm and lymphopenia are reported in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection associated with coronavirus disease 2019 (COVID-19). Myeloid-derived suppressive cells (MDSCs) exist in two different forms, granulocyte (G-MDSCs) and monocytic (M-MDSCs) that both suppress T-cell function. Serum IL-6 and IL-8 levels seem to correlate with the number of blood MDSCs.

ObjectiveTo determine the frequency of MDSCs in severe COVID-19 patients from Iran and their correlations with serum IL-8 levels.

Methods37 severe (8 on ventilation, 29 without ventilation) and 13 moderate COVID-19 patients together with 8 healthy subjects were enrolled at the Masih Daneshvari Hospital, Tehran-Iran between 10th April 2020-9th March 2021. Clinical and biochemical features, serum and whole blood were obtained. CD14, CD15, CD11b and HLA-DR expression on MDSCs was measured by flow cytometry.

ResultsM-MDSCs (P[≤]0.0001) and G-MDSCs (P[≤]0.0001) frequency were higher in Iranian COVID-19 patients compared to healthy subjects. M-MDSC frequency was higher in non-ventilated compared to moderate COVID-19 subjects (P=0.004). Serum IL-8 levels were higher in patients with COVID-19 than in normal healthy subjects (P=0.03). IL8 level was significant difference in ventilated, non-ventilated and moderate patients (P=0.005). The frequency of G-MDSCs correlated negatively with INR (r=-0.39, P=0.02).

ConclusionSerum IL-8 levels did not correlate with the number of systemic MDSCs in COVID-19 patients. The highest levels of M-MDSCs were seen in the blood of severe non-ventilated patients. MDSC frequency in blood in the current study did not predict the survival and severity of COVID-19 patients.


title: Long-distance migration was associated with increased prevalence of post-traumatic stress disorder in Syrian refugees

abstract:
BackgroundRefugees are forced migrants but there is a large variation in the distance that refugees cover and there is a paucity in the evidence of how this may affect refugees health and health care needs. We investigated the association between long-distance migration and post-traumatic stress disorder (PTSD), a serious psychiatric disorder associated with deteriorating mental and somatic health.

MethodsIncluded from 2016-2019 were 712 adult Syrian refugees and asylum seekers in Lebanon and Denmark arrived up to 12 months prior. PTSD was assessed using the Harvard Trauma Questionnaire and the estimate of association was obtained by multiply imputing missing data and adjusting for confounding by propensity score-weighting with covariates age, sex, socioeconomic status, trauma experience and WHO-5-score, reporting the bootstrap 95-percentile confidence interval (95% CI). Additionally, a number of sensitivity analyses were performed.

ResultsAfter multiply imputing missing data and propensity score-weighted adjustment for confounding, migration to Denmark instead of Lebanon was associated with an increase in PTSD prevalence of 9 percentage point (95% CI [-1; 19] percentage point).

DiscussionWe found that long-distance migration was associated with an increase in the prevalence of PTSD suggesting that long-distance migration may be a factor to consider when assessing refugees and asylum seekers health. Practitioners should consider "long-distance migration" in refugee health screenings and in particular when assessing the risk of post-traumatic stress disorder. Future research should be designed to ultimately lead to studies of relevant interventions to lower the risk of post-traumatic stress disorder in refugees.


title: Genome-wide polygenic risk score method for diabetic kidney disease in patients with type 2 diabetes

abstract: Diabetic kidney disease (DKD) is considered partially hereditary, but the genetic factors underlying disease remain largely unknown. A key barrier to our understanding stems from its heterogeneity, and likely polygenic etiology. Proteinuric and non-proteinuric DKD are two sub-classes of DKD, defined by high urinary albumin-to-creatinine ratio (UACR) and low creatinine estimated glomerular filtration rate (eGFR). Prior genome-wide association studies (GWAS) have identified multiple loci associated with eGFR and UACR. We aimed to combine summary statistics from previous GWAS for eGFR and UACR in one prediction model and associate it with DKD prevalence. We then tested this using genetic data from 18,841 individuals diagnosed with type 2 diabetes in UK Biobank. We computed two genome-wide polygenic risk scores (GPS) aggregating effects of common variants associated with the two measurements, eGFR and UACR. We show that including both GPS in a single model confers significant improvement in comparison with the single GPS model generated from GWAS summary statistics for DKD. We also find in replication analysis in 5,389 individuals in the multi-ethnic BioMe Biobank, that although the combined model had consistent direction of association, the lowest performance was in individuals with recent African ancestry. In summary, we show that joint modeling of polygenic associations of eGFR and UACR is more significantly associated with DKD than individual modeling as well as a GPS comprised of only DKD summary statistics and may be used to gain insights into biology and progression. However, efforts should be made to develop and validate polygenic approaches in diverse populations.

category: nephrology


title: A case of autosomal dominant osteopetrosis type II with a severe bone phenotype but no amino acid converting mutation in the CLCN7 gene

abstract: Autosomal Dominant Osteopetrosis type II (ADOII), also known as Albers-Schonberg disease, is caused by mutation of the CLCN7 chloride channel gene and is characterized by reduced bone resorption. Here we report on an individual with the classic features of ADOII, who had a history of fractures from childhood, displayed high bone mass and characteristic "sandwich vertebrae" on x-ray. Our genetic analyses showed no amino acid converting mutation in the patients DNA but we did find evidence of haploinsufficiency of CLCN7 mRNA. An iliac crest bone sample from the patient revealed bone tissue and material abnormalities relative to normal controls based on quantitative backscattered electron imaging and histomorphometric analyses. Additionally to lamellar bone, we observed significant amounts of woven bone and mineralised cartilage, as well as an increased frequency and thickness (up to 15 microns) of cement lines. Giant osteoclasts with numerous nuclei were present. The bone mineralisation density distribution (BMDD) of the entire bone area revealed markedly increased average mineral content of the dense bone (CaMean T-score +10.1) and frequency of bone with highest mineral content (CaHigh T-score +19.6), suggesting continued mineral accumulation and lack of bone remodelling. Osteocyte lacunae sections (OLS) characteristics were unremarkable except the OLS shape which was unusually circular. Together, our findings suggest that the reduced expression of CLCN7 mRNA in osteoclasts, and possibly also osteocytes, causes poorly remodelled bone with abnormal bone matrix with high mineral content. This together with the lack of adequate bone repair mechanisms makes the material brittle and prone to fracture.

category: orthopedics


title: Proxalutamide (GT0918) Reduces the Rate of Hospitalization in mild-to-moderate COVID-19 Female Patients: A Randomized Double-Blinded Placebo-Controlled Two-Arm Parallel Trial.

abstract:
BackgroundAntiandrogens were shown to be effective in mild-tomoderate COVID-19 male patients, supported by the SARS-CoV-2 dependency on transmembrane protease, serine 2 (TMPRSS2), which is solely modulated by androgens, for cell entry. While women with hyperandrogenism experiment more symptoms in COVID-19 compared to women without hyperandrogenism, and the chronic use of an antiandrogen seemed to mitigate these symptoms, whether the benefits would be observed in overall females is unknown. The objective of this study is to evaluate the efficacy of proxalutamide as a treatment for mild-to-moderate COVID-19 in females.

MethodsThis was a randomized, double-blind, placebo-controlled, two-arm, parallel study on COVID-19 female outpatients, that compared the use of proxalutamide versus placebo. The primary outcome was hospitalization rates throughout 30 days after randomization. Patients with laboratory confirmed COVID-19 not hospitalized were recruited in two sites in Brasilia, Brazil, between January 4 and February 28, 2021, were randomized on a 2:3 ratio between proxalutamide and placebo, and were administered proxalutamide 200mg/day or placebo for seven days, in addition to usual care.

ResultsA total of 177 women were randomized, including 75 in the proxalutamide arm and 102 patients in the placebo arm. None of the patients lost follow-up or discontinued treatment. The 30-day hospitalization rate was 2.7% in the proxalutamide arm and 18.6% in the placebo arm (p<0.001), with a hospitalization risk ratio (RR) of 0.14 [95% confidence interval (CI), 0.03-0.59].

ConclusionsThese findings suggest that treatment of COVID-19 patients with proxalutamide in combination with standard of care was reduced hospitalization rate by 86% (p < 0.001), with no safety concerns. (Clinicaltrials.gov: NCT04853134)


title: Effectiveness of Rosuvastatin plus Colchicine, Emtricitabine/Tenofovir and a combination of them in Hospitalized Patients with SARS Covid-19

abstract:
BACKGROUNDThe effectiveness of rosuvastatin plus colchicine, emtricitabine/tenofovir, and of their combined use in hospitalized patients with coronavirus disease 2019 (Covid-19) pneumonia is unclear.

METHODSIn each hospital, hospitalized adults with Covid-19 pneumonia, were randomly assigned, in a 1:1 ratio, to receive: a) standard of care; or b) emtricitabine/tenofovir; or c) colchicine + rosuvastatin; or d) emtricitabine/tenofovir + colchicine + rosuvastatin. The primary outcome was all-cause mortality within the first 28 days after randomization. Severe adverse events (SAE) were those with a high probability of being treatment-related.

RESULTS633 patients were randomized in 6 hospitals in Bogota, Colombia. Overall, 98% of the patients received glucocorticoids during hospitalization. The cumulative incidence of death through day 28 was 10.7% in the emtricitabine/tenofovir + colchicine + rosuvastatin arm, 14.4% in the colchicine + rosuvastatin arm, 13.8% in the emtricitabine/tenofovir arm, and 17.4% in the standard of care arm, with adjusted risk differences (aRD) against the standard treatment of -0.07 (95% confidence interval [CI], -0.17 to 0.04), aRD -0.03 (95%CI: -0.11 to 0.05) and aRD: -0.05 (95%CI: -0.15 to 0.05), respectively. Need for invasive mechanical ventilation was lower in the emtricitabine/tenofovir + colchicine + rosuvastatin arm compared to the standard treatment arm, aRD: -0.06 (95%CI: -0.11 to -0,01), but no differences were found between the other comparisons. SAE occurred in 3 patients distributed in the 3 treatment arms.

CONCLUSIONSAmong patients hospitalized with moderate and severe SARS Covid-19, the use of the emtricitabine/tenofovir + colchicine + rosuvastatin combination emerges as a treatment alternative.

ClinicalTrials.gov number: NCT04359095


title: Advancing our understanding of genetic risk factors and potential personalized strategies in pelvic organ prolapse: largest GWAS to date reveals 19 novel associated loci

abstract:
ObjectivesTo identify the genetic determinants of pelvic organ prolapse (POP) and assess the predictive ability of polygenic risk scores (PRS) alone or in combination with clinical risk factors.

DesignMeta-analysis of genome-wide association studies (GWAS) and PRS construction and validation.

SettingGWAS summary statistics from three European datasets and individual-level data from Estonian Biobank, including phenotype questionnaire and measurement panel, together with follow-up data from linkage with national health-related registries.

ParticipantsA total of 28,086 women with POP and 546,321 controls of European ancestry. Genetic risk scores were derived from a dataset of 20,118 cases and 427,426 controls of European ancestry and validated in a target dataset of 7,896 cases and 118,895 controls. Cases were defined using ICD codes and classical risk factors were derived from questionnaire data and ICD10 codes.

ResultsThe identified novel loci reinforce the role of connective tissue abnormalities, urogenital tract development and point towards association with a range of cardiometabolic traits. A novel PRS combining 3,242,959 variants demonstrated that women in the top 5% have 1.63 (95% CI: 1.37 to 1.93) times the hazard of developing POP compared to the rest of the women. When analyzing PRS in incident POP, it showed similar predictive ability (Harrell C-statistic 0.583, sd=0.007) than five established clinical risk factors (number of children, body mass index (BMI), ever smoked, constipation and asthma) combined (Harrell C-statistic 0.588, sd=0.007) and demonstrated its incremental value in combination with these (Harrell C-statistic 0.630, sd=0.007).

ConclusionsThe largest GWAS meta-analysis in POP to date identified 26 genetic loci which establish links between POP and connective tissue abnormalities, urogenital development and cardiometabolic health. We present a PRS for POP which provides the first potential tool for preventive strategies and early detection of higher risk susceptibility to POP including genetic risk factors.


title: COVID-19 and Black Fungus: Analysis of the Public Perception through Machine Learning

abstract: While COVID-19 is ravaging the lives of millions of people across the globe, a second pandemic  black fungus has surfaced robbing people of their lives especially people who are recovering from coronavirus. Again, the public perceptions regarding such pandemics can be investigated through sentiment analysis of social media data. Thus the objective of this study is to analyze public perceptions through sentiment analysis regarding black fungus during the time of the COVID-19 pandemic. To attain the objective, first, a Support Vector Machine model, with an average AUC of 82.75%, was developed to classify user sentiments in terms of anger, fear, joy, and sad. Next, this Support Vector Machine is used to supervise the class labels of the public tweets (n = 6477) related to COVID-19 and black fungus. As outcome, this study found that public perceptions belong to sad (n = 2370, 36.59 %), followed by joy (n = 2095, 32.34%), fear (n = 1914, 29.55 %) and anger (n = 98, 1.51%) towards black fungus during COVID-19 pandemic. This study also investigated public perceptions of some critical concerns (e.g., education, lockdown, hospital, oxygen, quarantine, and vaccine) and it was found that public perceptions of these issues varied. For example, for the most part, people exhibited fear in social media about education, hospital, vaccine while some people expressed joy about education, hospital, vaccine, and oxygen.

category: health informatics


title: Endothelial dysfunction determines severe COVID-19 in combination with dysregulated lymphocyte responses and cytokine networks

abstract: The systemic processes involved in the manifestation of life-threatening COVID-19 and in disease recovery are still incompletely understood, despite investigations focusing on the dysregulation of immune responses after SARS-CoV-2 infection. To define hallmarks of severe COVID-19 and disease recovery in convalescent patients, we combined analyses of immune cells and cytokine/chemokine networks with endothelial activation and injury. ICU patients displayed an altered immune signature with prolonged lymphopenia but expansion of granulocytes and plasmablasts along with activated and terminally differentiated T and NK cells and high levels of SARS-CoV-2-specific antibodies. Core signature of seven plasma proteins revealed a highly inflammatory microenvironment in addition to endothelial injury in severe COVID-19. Changes within this signature were associated with either disease progression or recovery. In summary, our data suggest that besides a strong inflammatory response, severe COVID-19 is driven by endothelial activation and barrier disruption, whereby recovery depends on the regeneration of the endothelial integrity.


title: Aspirin Use is Associated with Decreased Mortality in Patients with COVID-19: A Systematic Review and Meta-analysis

abstract:
BackgroundNovel Corona Virus Disease 2019 (COVID-19) has resulted in more than three and half million deaths worldwide as of June 6, 2021. The role of aspirin in prevention of COVID-19 mortality has not been much studied. We aimed to study the relationship between aspirin use and covid-19 mortality.

MethodsWe searched PubMed, MEDLINE, EMBASE, and Cochrane database for studies from January 2019 till June 6, 2021 with inclusion criteria of RCT, Cohort study, studies reporting mortality, and comparison studies on aspirin versus non-aspirin. Statistical analysis was done with Review Manager 5.4 statistical software using the inverse variance method. We assessed the pooled hazard ratio (HR), and 95% confidence interval using the random effect model and I-squared test was used to determine statistical heterogeneity.

ResultsWe included five retrospective cohort studies which met our inclusion criteria with total of 14065 participants in both groups. There were 6797 participants in the aspirin group and 7268 participants in the non-aspirin group. Our results show that the use of aspirin was associated with 53% decrease in mortality compared to non-aspirin in patients with COVID-19 (adjusted HR 0.47, 95% CI 0.35-0.63, P< 0.001, I2= 47%). In the analysis restricted to patients hospitalized for COVID-19, the use of aspirin was associated with a 49% reduction in the risk for in-hospital mortality (adjusted HR 0.51, 95% CI 0.33-0.80, P = 0.004, I2= 39%).

ConclusionsOur results show that aspirin is associated with decrease in both overall mortality and in-hospital mortality in patients with COVID-19.


title: Metaphors that shape parents' perceptions of effective communication with healthcare practitioners following child death: a qualitative UK study

abstract:
ObjectivesTo offer an interpretation of bereaved parents evaluations of communication with healthcare practitioners surrounding the death of a child.

DesignInterpretative qualitative study employing thematic and linguistic analyses of metaphor embedded in interview data.

SettingEngland and Scotland.

Participants24 bereaved parents (21 women, 3 men)

MethodsParticipants were recruited through the True Colours Trust website and mailing list, similar UK charities, and word of mouth. Following interviews in person or via video-conferencing platforms (Skype/Zoom), transcripts first underwent thematic and subsequently linguistic analyses supported by Nvivo. A focused analysis of metaphors used by the parents was undertaken allow in-depth interpretation of how they conceptualised their experiences.

ResultsThe findings illuminate the ways parents experienced communication with healthcare practitioners surrounding the death of a child. They show how their evaluations of effective care relate to the experience of the bereavement itself, as expressed through metaphor. We identified three broad themes: (1) Identity (2) Emotional and Physical Response(s) and (3) Time. Successful communication from healthcare practitioners takes account of parents experiences related to these themes.

ConclusionsThis study suggests that healthcare practitioners when communicating with bereaved parents need to recognise, and seek to comprehend, the ways in which the loss impacts upon an individuals identity as a parent, the  physical nature of the emotions that can be unleashed, and the ways in which the death of a child can alter their metaphorical conceptions of time.

Strengths and limitations of the studyO_LIThis interpretative qualitative study contributes to the growing literature on the experience of parental bereavement through its focus on the use of metaphor in parents accounts of child loss.
C_LIO_LIThe metaphor analysis afforded a focus not only on the content of the interviews, but also on the language that was used to express this content, providing more depth and nuance to the interpretation of the findings.
C_LIO_LIParticipants were all UK-based and self-selecting which could limit transferability.
C_LI

category: pediatrics


title: Beyond Low-Hanging Fruit: A Systematic Approach to Assessing Quality Improvement Needs in Healthcare Practices

abstract: Quality Improvement (QI) tools abound to help clinicians improve the quality of their care. Such tools, however, assume one knows the process that needs attention. A systematic approach is thus needed for selecting the QI activities that have the greatest impact on quality. This study applies Functional Job Analysis (FJA) to systematically identify areas in preventive care most suitable for high-impact QI efforts. Seven internal medicine practice personnel served as subject matter experts (SMEs) in multiple FJA style focus groups to identify the tasks required to ensure successful execution of eight preventive-care measures. Tasks with the greatest prevalence across measures and highest human error consequence ratings were deemed most suitable for QI. SMEs generated improvement recommendations for the identified tasks via focus groups. Tasks with greatest cross-measure prevalence centered on information gathering; tasks with the greatest potential consequence of error centered on medication management, testing and test follow-up (MMTTF). SMEs reported time, space, staffing, and equipment constraints as fundamental barriers impacting all aspects of primary care. Barriers to successful information gathering included issues with front desk staff and the electronic health record. Barriers to MMTTF included lab workflow and patient-related factors. Improvement recommendations included strategic staffing, technology-based solutions, and added in-house testing capabilities. FJA successfully identified two clear, distinct clinic workflow areas that could benefit from QI initiatives. Although our work is limited by its single-site design, results are consistent with prior multi-site FJA research. Contrary to traditional, disease-specific QI approaches, our work identified a core set of processes that, if optimized, can improve care across multiple clinical conditions, and presented a novel application of a classic HR tool to make more systematic QI decisions.

category: primary care research


title: Modulation of a Stable Neurobehavioral Trait Using Repetitive Transcranial Magnetic Stimulation: A Preregistered Randomized Controlled Trial

abstract:
Hypnotizability, ones ability to experience cognitive, emotional, behavioral, and physical changes in response to suggestions in the context of hypnosis, is a highly stable trait associated with increased functional connectivity between the left dorsolateral prefrontal cortex (L-DLPFC) and dorsal anterior cingulate cortex (dACC). We conducted a preregistered, triple-blinded, randomized controlled trial to test the ability of continuous theta-burst stimulation (cTBS) over a personalized neuroimaging-based L-DLPFC target to temporarily enhance hypnotizability. We tested our hypothesis in 78 patients with fibromyalgia syndrome (FMS), a functional pain disorder for which hypnosis has consistently been shown to be beneficial as a nonpharmacological treatment option. Pre-to-post cTBS change in Hypnotic Induction Profile scores (HIP; a standardized measure of hypnotizability) was significantly greater in the Active versus Sham group. Our findings suggest a causal relationship between L-DLPFC and dACC function and hypnotizability. Dose-response optimization should be further examined to formalize guidelines for future clinical utilization.

Trial registrationClinicalTrials.gov NCT02969707

category: psychiatry and clinical psychology


title: The Lived Experience of Implementing Infection Control Measures in Care Homes during two waves of the COVID-19 Pandemic. A mixed-methods study

abstract:
ContextDuring COVID-19 care-homes had to implement strict Infection Control Measures (ICMs), impacting on care and staff morale.

ObjectivesTo explore the lived experiences of care-home staff in implementing ICMs.

MethodsMixed-methods study comprising 238 online survey responses and 15 in-depth interviews with care-home staff, November 2020-January 2021 in England.

ResultsThree themes were identified:  Integrating COVID-19 ICMs with caring,  Conveying knowledge and information,  Professional and personal impacts of care-work during the pandemic. Reported adherence to ICMs was high but fatalistic attitudes towards COVID-19 infection were present. Challenges of providing care using personal protective equipment (PPE), especially for residents with dementia, were highlighted. Interviewees reported dilemmas between strictly implementing ICMs and conflicts with providing best care to residents and preserving personal space. Nine months into COVID-19, official guidance was reported as confusing, constantly changing and poorly suited to care-homes. Care-home staff appreciated opportunities to work with other care-homes and experts to interpret and implement guidance. ICM training was undertaken using multiple techniques but with little evaluation of these or how to sustain behaviour change.

LimitationsResults may not be generalizable to other countries.

ImplicationsCOVID-19 has had a profound effect on well-being of care-home staff. Despite challenges, participants reported broadly good morale, potentially a consequence of supportive colleagues and management. Nevertheless, clear, concise and care-home focussed ICM guidance is still needed. This should include evidence-based assessments on implementing and sustaining adherence. Groups of care-home staff and ICM experts working together to co-create, interpret and implement guidance were viewed positively.


title: Confidence in government and rumors amongst international migrant workers involved in dormitory outbreaks of COVID-19: A cross-sectional survey

abstract:
BackgroundIn the coronavirus disease (COVID-19) pandemic, confidence in the government and access to accurate information have been critical to the control of outbreaks. Although outbreaks have emerged amongst communities of international migrant workers worldwide, little is known about how they perceive the governments response or their exposure to rumors.

MethodsBetween 22 June to 11 October 2020, we surveyed 1011 low-waged migrant workers involved in dormitory outbreaks within Singapore. Participants reported their confidence in the government; whether they had heard, shared, or believed widely-disseminated COVID-19 rumors; and their socio-demographics. Logistic regression models were fitted to identify factors associated with confidence and rumor exposure.

Results1 in 2 participants (54.2%, 95% CI: 51.1-57.3%) reported that they believed at least one COVID-19 rumor. This incidence was higher than that observed in the general population for the host country (Singapore). Nonetheless, most participants (90.0%, 95% CI: 87.6-91.5%) reported being confident that the government could control the spread of COVID-19. Age was significantly associated with belief in rumors, while educational level was associated with confidence in government.

ConclusionsOur findings suggest that language and cultural differences may limit the access that migrant workers have to official COVID-19 updates. Correspondingly, public health agencies should use targeted messaging strategies to promote health knowledge within migrant worker communities.


title: Self-reported word-finding complaints are associated with cerebrospinal fluid beta-amyloid and atrophy in cognitively normal older adults

abstract:
Background and ObjectivesSelf-reported language complaints, and more specifically word-finding difficulties, are among the most frequent cognitive complaints in cognitively normal older adults (CN). The clinical significance of elevated self-reported word-finding complaints in CN is still a matter of debate. The present study aims at characterizing word-finding complaints in CN, establish their sociodemographic and psychological correlates, determine if they are predictive of lower levels of cerebrospinal fluid A{beta} levels and finally, investigate if they are associated with brain atrophy in regions associated with naming impairments.

MethodsIn this observational case-control study, 239 CN from the Alzheimers Disease Neuroimaging Initiative (ADNI) database were selected. All participants completed the self-reported version of the Everyday Cognition (ECog) questionnaire, as well as a lumbar puncture for A{beta} and a MRI.

ResultsWord-finding complaints were rated equally severe as a few other memory items and significantly more severe compared to all the other cognitive complaints. Ecog-Lang1 (Forgetting the names of objects) was not related to any demographic (age, sex, years of education) or psychological variable (depression-related symptoms, anxiety-related symptoms), while Ecog-Lang3 (Finding the right words to use in a conversation) was significantly negatively associated with years of education and positively associated with depression-related symptoms. Ecog-Lang1 severity significantly predicted CSF A{beta} levels in CN, and this result remained significant even when controlling for all demographic and psychological variables as well as general level of cognitive complaint. Individuals with high Ecog-Lang1 complaints showed atrophy in the left fusiform gyrus and the left rolandic operculum in comparison to CN with no or low Ecog-Lang1 complaints.

DiscussionOverall, our results support the fact that word-finding complaints are significant in CN and should be taken seriously. They have the potential to identify CN at risk of AD and support the need to include other cognitive domains in the investigation of subjective cognitive decline.

category: neurology


title: Transient infection with SARS-CoV-2 without induction of systemic immunity

abstract: SARS-CoV-2 testing using PCR is currently used as screening test to guide isolation and contact tracing. Among 1,700 players and staff of the German Bundesliga and Bundesliga 2 who were regularly tested twice weekly, 98 individuals had a positive PCR. Among those, 11 asymptomatic cases were identified who only had a transient single positive PCR of low viral load. As only one out of 11 individuals developed SARS-CoV-2 specific cellular and humoral immunity, this indicates that transient colonization with SARS-CoV-2 may frequently occur without systemic induction of specific adaptive immunity. This knowledge may have implications for management of isolation and contact tracing, which may not be justified in these cases.


title: High prevalence of previous infection with SARS-CoV-2 and persistent symptoms at a large university

abstract:
ImportanceUniversities are unique settings with large populations, congregate housing, and frequent attendance of events in large groups. However, the prevalence of previous infection with SARS-CoV-2 in university students, including symptomatic and asymptomatic disease, is unknown.

ObjectiveTo determine the prevalence of previous infection, risk factors for infection, and the prevalence of persistent symptoms following infection among university students.

DesignThis was a cross-sectional study that surveyed students about demographics, risk factors, and symptoms, and simultaneously tested their saliva for IgA antibodies to SARS-CoV-2. To estimate the prevalence of previous infection we adjusted our intentional sample of a diverse student population for year in school and age to resemble the composition of the entire student body, and adjusted for the imperfect sensitivity and specificity of the antibody test. Univariate and multivariate analysis was used to identify independent risk factors for infection.

SettingA large public university in Athens, Georgia between January 22 and March 22, 2021.

ParticipantsUndergraduate and graduate students; 488 completed the survey, 432 had a valid antibody result. and 428 had both.

ExposurePrevious infection with SARS-CoV-2 based on measurement of IgA antibodies in saliva and adjustment for sample characteristics and test accuracy.

Main Outcomes and MeasuresThe primary outcome was the estimated prevalence of previous infection with SARS-CoV-2. Secondary outcomes were independent risk factors for infection, and the prevalence of persistent symptoms among persons reporting a previous symptomatic infection.

ResultsThe estimated prevalence of previous infection for 432 participants with valid antibody results was between 41% and 42%. Independent risk factors for infection included male sex, having a roommate with a known symptomatic infection, and having 2 or fewer roommates. More frequent attendance of parties and bars was a univariate risk factor, but not in the multivariate analysis. Of 122 students reporting a previous symptomatic infection, 14 (11.4%) reported persistent symptoms a median of 132 days later.

Conclusions and RelevancePrevious infection with SARS-CoV-2, both symptomatic and asymptomatic, was common at a large university. Measures that could prevent resurgence of the infection when students return to campus include mandatory vaccination policies, mass surveillance testing, and testing of sewage for antigen to SARS-CoV-2.

Key PointsO_ST_ABSQuestionC_ST_ABSWhat is the prevalence of previous infection with SARS-CoV-2 and the prevalence of persistent symptoms in university students?

FindingsIn this sample of 432 students who provided saliva for IgA antibodies, we estimate that 41% to 42% had evidence of previous infection. Of 122 reporting a previous symptomatic infection, 14 (11%) were still symptomatic a median of 132 days later.

MeaningSymptomatic and asymptomatic infections with SARS-CoV-2 are common among university students, and a significant percentage had persistent symptoms over a long duration.


title: Detection and Quantification of Infectious Severe Acute Respiratory Coronavirus-2 in Diverse Clinical and Environmental Samples from Infected Patients: Evidence to Support Respiratory Droplet, and Direct and Indirect Contact as Significant Modes of Transmission

abstract:
Few studies have assessed for infectious SARS-CoV-2 in multiple types of clinical and environmental samples. In almost 500 samples from 75 hospitalized and community cases, we detected infectious virus with quantitative burdens varying from 5.0 plaque-forming units/mL (PFU/mL) up to 1.0x106 PFU/mL in clinical specimens and up to 1.3x106 PFU/mL on fomites including facial tissues, nasal prongs, call bells/cell phones, dentures, and sputum deposits with confirmation by plaque morphology, PCR, immunohistochemistry, and sequencing. Expectorated sputum samples had the highest percentage of positive samples and virus titers (71%, 2.9x102 to 5.2x105 PFU/mL), followed by saliva (58%, 10 to 4.6x104 PFU/mL), and cough samples without sputum (19%, 5 to 1.9x103 PFU/mL). We also detected infectious SARS-CoV-2 from patients hands (28%, 60 to 2.3x102 PFU/mL) but no infectious virus was found in continuous speech samples despite finding high levels of infectious virus in the associated nasopharynx, throat, or saliva specimens. We demonstrated infectious virus stability in clinical samples, including those dried for prolonged periods of time. Infectious virus correlated with time since symptom onset with no detection after 7-8 days in immunocompetent hosts and with N-gene based Ct values [≤] 25 significantly predictive of yielding plaques in culture. One PFU was associated with [~]105 copies of N gene RNA across a diversity of samples and times from symptom onset. Clinical salivary isolates caused illness in a hamster model with a minimum infectious dose of [≤]14 PFU/mL. Our findings of high quantitative burdens of infectious virus, stability even with drying, and a very low minimal infectious dose suggest multiple modes of transmission are exploited by SARS-CoV-2, including direct contact, large respiratory droplet, and fomite transmission and in the context of a high binding avidity to human cellular receptors, offer an explanation of the high contagiousness of this virus.

Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSWe searched the literature for articles that reported on the presence of infectious SARS-CoV-2 in patients samples from clinical and environmental sources. We found several key primary studies and systematic reviews providing valuable background on the carriage of infectious virus and the correlation with cycle threshold (Ct) and/or RNA copies/mL on PCR testing. Clinical correlations with respect to underlying clinical conditions and details on the onset of illness were not commonly reported with respect to the timing of obtaining specimens for culture. Few studies carefully assessed the presence of infectious virus in cough samples, sputum, nasal secretions, hands, and common high touch surfaces. A few published works were found on factors which may be associated with shedding of infectious virus.

Added value of this studyWe assessed the presence of infectious virus shedding in almost 500 specimens from 75 patients with COVID-19 in both the hospital and community setting. High titers of infectious virus were detected in multiple clinical and environmental samples. The longest duration of recovery of infectious virus in a fomite sample was from a dried facial tissue found at a patients bedside table, used at least 9 hours earlier. Cough specimens revealed infectious virus in 28% of specimens with infectious virus titers as high as 5.2x105 PFU/mL. Hand samples contained infectious virus with titers ranging from 55 to 2.3x102 PFU/mL. Infectious viral loads correlated with N-gene based Ct values and showed that Ct values [≤] 25 were predictive of yielding plaques in culture. These experiments also showed that infectious virus is most often recovered during a 7 to 8-day period following illness onset in immunocompetent persons, and during that time the ratio of RNA/PFU in these clinical specimens varies relatively little, with a ratio [~]160,000:1. Infectious virus may be recovered for weeks to several months in immunosuppressed persons. We also showed that virus recovered from saliva specimens, representing a commonly encountered fomite sample, caused infection in the Syrian hamster model, hence demonstrating the infectiousness of the virus sourced from this type of specimen. A challenge dose as low as 14 PFU/mL yielded infection in this model.

Implications of all the available evidenceWe have shown that SARS-CoV-2 is relatively easy to culture when obtained early in the course of illness and there are high levels of cultivatable SARS-CoV-2 in multiple types of clinical specimens and common fomites, including high-touch surfaces and demonstrated their infectiousness in a mammalian host. Our results demonstrate the presence of high quantitative burdens of SARS-CoV-2 in sputum, saliva, and droplets from coughing, which would lend support to large respiratory droplet transmission, hands which would support direct contact transmission, and fomites which would promote indirect contact transmission. We were unable to detect any infectious virus in continuous speech samples which suggests that brief conversations, without coughing or sneezing, pose little risk of transmitting SARS-CoV-2. Our findings provide an explanation for the high contagiousness of this virus and support current public health measures and infection prevention and control guidelines including physical distancing, hand hygiene, masking, and cleaning and disinfection.


title: Direct detection of humoral marker corelates of COVID-19, glycated HSA and hyperglycosylated IgG3, by MALDI-ToF mass spectrometry.

abstract:
The prefusion Spike protein of SARS-CoV2 binds advanced glycation end product (AGE) glycated human serum albumin (HSA) and a higher mass, hyperglycosylated/glycated, IgG3, as determined by matrix assisted laser desorption mass spectrometry (MALDI-ToF MS). We set out to investigate if the total blood plasma of patients who had recovered from acute respiratory distress as a result of COVID-19, contained more glycated HSA and higher mass (glycosylated/glycated) IgG3 than those with only clinically mild or asymptomatic infections. A direct dilution and disulphide bond reduction method was development and applied to plasma samples from SARS-CoV2 seronegative (N = 30) and seropositive (N = 31) healthcare workers and 38 convalescent plasma samples from patients who had been admitted with acute respiratory distress syndrome (ARDS) associated with COVID-19.

Patients recovering from COVID-19 ARDS had significantly higher mass, AGE-glycated HSA and higher mass IgG3 levels. This would indicate that increased levels and/or ratios of hyper-glycosylation (probably terminal sialic acid) IgG3 and AGE glycated HSA may be predisposition markers for development of ARDS as a result of COVID-19 infection. Furthermore, rapid direct analysis of plasma samples by MALDI-ToF MS for such humoral immune correlates of COVID-19 presents a feasible screening technology for the most at risk; regardless of age or known health conditions.

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title: Immunogenicity of Oxford-AstraZeneca COVID-19 vaccine in Vietnamese healthcare workers

abstract: We studied the immunogenicity of Oxford-AstraZeneca vaccine in Vietnamese healthcare workers. We collected blood samples before each dose, at 14 days after each dose, and month 1 and 3 after dose 1 from each participant alongside demographics data. We measured neutralizing antibodies using a surrogate virus neutralization assay. The 554 study participants (136 males and 418 females) were aged between 22-71 years (median: 36 years). 104 and 94 out of 144 selected participants were successfully followed up at 14 days after dose 2 and 3 months after dose 1, respectively. Neutralizing antibodies increased after each dose, with the sero-conversion rate reaching 98.1% (102/104) at 14 days after dose 2. At month 3 after dose 1, neutralizing antibody levels decreased, while 94.7% (89/94) of the study participants remained seropositive. Oxford-AstraZeneca COVID-19 vaccine is immunogenic in Vietnamese healthcare workers. The requirement for a third dose warrants further research.

category: epidemiology


title: Pandemic trends in health care use: From the hospital bed to the general practitioner with COVID-19

abstract:
AimTo explore whether the acute 30-day burden of COVID-19 on health care use has changed from the beginning to the end of the pandemic.

MethodsIn all Norwegians (N=122 699) who tested positive for SARS-CoV-2 in three pandemic waves (March 1st-July 31st 2020 (1st wave), August 1st-December 31st 2020 (2nd wave), and January 1st-May 31st 2021 (3rd wave)), we studied the age- and sex-specific share of patients (by age groups 1-19, 20-67, and 68 or more) who had: 1) Relied on self-care, 2) used primary care, and 3) used specialist care.

ResultsWe find that a remarkably high and stable share (70-80%) of patients with COVID-19 exclusively had contact with primary care in the acute phase, both in the 1st, 2nd and 3rd wave. The mean number of primary care visits ranged between 2 and 4. We also show that the use of specialist care in the acute 30-day phase of COVID-19 has decreased, from 14% being hospitalized at least once during spring 2020, to 4% during spring 2021. The mean number of hospital bed-days decreased significantly for men from the 1st to the 2nd wave (from 13 days, 95% CI=11.5-14.5 to 10 days (9-11) for men aged [≥]68 years, and from 11 days (10-12) to 9 days (8-10) for men aged 20-67 years), but not for women.

ConclusionCOVID-19 places a continued high demand on the primary care services, and a decreasing demand on the specialist care services.


title: WHY SOME HESITATE MORE: CROSS-CULTURAL VARIATION IN CONSPIRACY BELIEFS, BELIEF IN SCIENCE, AND VACCINE ATTITUDES

abstract:
BackgroundCountries differ in their levels of vaccine hesitancy (a delay in acceptance or refusal of vaccines), trust in vaccines, and acceptance of new vaccines. In this paper, we examine the factors contributing to the cross-cultural variation in vaccine attitudes, measured by levels of 1) general vaccine hesitancy, 2) trust in vaccines, and 3) COVID-19 vaccine acceptance.

MethodsWe examined the relative effect of conspiracy mentality, belief in COVID-19 conspiracies, and belief in science on the above-mentioned vaccine attitudes in the UK (n= 1533), US (n= 1550), and Turkey (n= 1567) through a quota-sampled online survey to match the population for age, gender, ethnicity, and education level.

ResultsWe found that belief in COVID-19 conspiracies and conspiracy mentality were the strongest predictors of general vaccine hesitancy across all three countries. Belief in science had the largest positive effect on general vaccine trust and COVID-19 vaccine acceptance. Although participants in Turkey demonstrated the lowest level of vaccine trust, their belief in science score was significantly higher than participants in the US, suggesting that belief in science cannot explain the cross-cultural variation in vaccine trust. The mean levels of conspiracy mentality and agreement with COVID-19 conspiracies were consistent with the country-level differences in general and COVID-19 vaccine attitudes. Demographic variables did not predict vaccine attitudes as much as belief in conspiracies and science.

ConclusionsOur findings suggest that cross-cultural variation in vaccine hesitancy, vaccine trust, and COVID-19 vaccine acceptance rates are mainly driven by differences in the prevalence of conspiratorial thinking across countries.


title: Using big data analytics to explore the relationship between government stringency and preventative social behaviour during the COVID-19 pandemic in the United Kingdom

abstract: We evaluated the association between preventative social behaviour and government stringency. Additionally, we sought to evaluate the influence of additional factors including time, need to protect others (using the reported number of COVID-19 deaths as a surrogate measure) and reported confidence in government handling of the COVID-19 pandemic. We used repeated national cross-sectional surveys the UK over the course of 41 weeks from 1st April 2020 to January 28th, 2021, including a total of 38,092 participants. Preventative social behaviour and government stringency index scores were significantly associated on linear regression analyses (R2 =0.6468, p<0.001, and remained significant after controlling for the effect of reported COVID-19 deaths, confidence in government handling of the pandemic, and time (R2=0.898, p<0.001). Longitudinal data suggest that government stringency is an effective tool in promoting preventative social behaviour in the fight against COVID-19.


title: Discovery of a simple two-gene expression biomarker in whole blood predictive of the need for treatment escalation in inflammatory bowel disease

abstract:
Background and aimsThe IBD-Character consortium has recruited large internationally based inception cohorts of treatment-naive inflammatory bowel disease (IBD) patients, providing a unique resource to derive a simple transcriptome signature in the field of prognostication.

MethodsThe discovery cohort (n=160) was recruited in Norway, Sweden and Spain. The replication inception cohort from the United Kingdom (n=97) was followed-up for a mean ({+/-}SD) of 350{+/-}228 days. Treatment escalation was formally defined as the need for a biologic agent, ciclosporin and/or surgery, instituted for disease flare after initial remission, or colectomy during the index admission for ulcerative colitis. Whole blood RNA was subject to paired-end sequencing. In the discovery cohort a simple procedure was applied, which exploited differences of transcript ratios. The ten top performing ratios were tested using Cox regression models in the validation cohort.

ResultsNewly diagnosed IBD patients with high CACNA1E/LRRC42 expression ratio had an increased risk of treatment intensification (validation cohort: HR=19.3, 95%CI 2.6-143.9, p=0.000005; AUC 0.76, 95%CI 0.66-0.86). In 51 patients with CRP < 3.5 mg/L, CACNA1E/LRRC42 still predicted escalation (HR=10.4; 95%CI 1.2-86.5, p=0.007). The second best performing transcript ratio was CACNA1E/CEACAM21 yielding a HR of 10.9 (95%CI 2.5-46.7, p=0.00002) and an AUC of 0.76 (95%CI 0.65-0.86) in the validation cohort.

ConclusionTranscriptomic profiling of an IBD inception cohort identified gene expression ratios CACNA1E/LRRC42 and CACNA1E/CEACAM21 as prognostic biomarkers. These were validated in a replication cohort as strongly associated with short- and long-term risk of treatment intensification and may provide valuable information in clinical decision-making.

category: gastroenterology


title: Identifying patients at high risk of inappropriate drug dosing in periods with renal dysfunction

abstract:
IntroductionDosing of renally cleared drugs in patients with kidney failure often deviates from clinical guidelines but little is known about what is predictive of receiving inappropriate doses.

Methods and materialsWe combined data from the Danish National Patient Register and in-hospital data on drug administrations and estimated glomerular filtration rates for admissions between 1 October 2009 and 1 June 2016, from a pool of about 2.9 million persons. We trained artificial neural network and linear logistic ridge regression models to predict the risk of five outcomes (>0, [≥]1, [≥]2, [≥]3 and [≥]5 inappropriate doses daily) with index set 24 hours after admission. We used time-series validation for evaluating discrimination, calibration, clinical utility and explanations.

ResultsOf 52,451 admissions included, 42,250 (81%) were used for model development. The median age was 77 years; 50% of admissions were of women. [≥]5 drugs were used between admission start and index in 23,124 admissions (44%); the most common drug classes were analgesics, systemic antibacterials, diuretics, antithrombotics, and antacids. The neural network models had better discriminative power (all AUROCs between 0.77 and 0.81) and were better calibrated than their linear counterparts. The main prediction drivers were use of anti-inflammatory, antidiabetic and anti-Parkisons drugs as well as having a diagnosis of chronic kidney failure. Sex and age affected predictions but slightly.

ConclusionOur models can flag patients at high risk of receiving at least one inappropriate dose daily in a controlled in-silico setting. A prospective clinical study may confirm this holds in real-life settings and translates into benefits in hard endpoints.

category: pharmacology and therapeutics


title: Markers of immune activation and inflammation in individuals with post-acute sequelae of SARS-CoV-2 infection

abstract:
BACKGROUNDThe biological processes associated with post-acute sequelae of SARS-CoV-2 infection (PASC) are unknown.

METHODSWe measured soluble markers of inflammation in a SARS-CoV-2 recovery cohort at early (<90 days) and late (>90 days) timepoints. We defined PASC as the presence of one or more COVID-19-attributed symptoms beyond 90 days. We compared fold-changes in marker values between those with and without PASC using mixed effects models with terms for PASC and early and late recovery time periods.

RESULTSDuring early recovery, those who went on to develop PASC generally had higher levels of cytokine biomarkers including TNF-alpha (1.14-fold higher mean ratio, 95%CI 1.01-1.28, p=0.028) and IP-10 (1.28-fold higher mean ratio, 95%CI 1.01-1.62, p=0.038). Among those with PASC, there was a trend toward higher IL-6 levels during early recovery (1.28-fold higher mean ratio, 95%CI 0.98- 1.70, p=0.07) which became more pronounced in late recovery (1.44-fold higher mean ratio, 95%CI: 1.11-1.86, p<0.001). These differences were more pronounced among those with a greater number of PASC symptoms.

CONCLUSIONSPersistent immune activation may be associated with ongoing symptoms following COVID-19. Further characterization of these processes might identify therapeutic targets for those experiencing PASC.


title: Gender-Specific Long-Term Prognostic Values of QRS Duration, QT Interval, and QTc from Automated ECG Analysis for Mortality and Adverse Outcomes in Patients Hospitalized for Heart Failure

abstract:
BackgroundGender-specific prognostic values of electrocardiographic (ECG) measurements in patients hospitalized for heart failure (HF) are lacking, which we hence investigated in this study.

MethodsPatients admitted to a single tertiary center for HF between 1 January 2010 and 31 December 2016 without atrial fibrillation and with at least one baseline ECG were included. Automated ECG measurements were performed. The primary outcomes were all-cause and cardiovascular (CAD) mortality, and the secondary outcomes were stroke, and ventricular arrhythmia and sudden cardiac death (VA/SCD). The prognostic values of the heart rate, PR segment, QRS duration, PT interval, QT interval, and QTc were assessed. Gender-specific optimal cutoffs of the above measurements were identified with the maximally selected rank statistics approach.

ResultsIn total, 2718 patients (median age 77 years; 1302 males) were included with a median follow-up of 4.8 years; the females were significantly older (p<0.0001). Females had higher rates of all-cause (p=0.04) and CAD mortality (p=0.02), while males had higher rates of VA/SCD (p=0.02). Higher heart rate, longer PT interval, wider QRS, and longer QT interval and QTc predicted all-cause mortality in males, while only shorter PR segment, longer QRS duration and QTc predicted the same in females. Longer QRS duration, QT interval, and QTc predicted CAD mortality in males, while longer PT interval, wider QRS and longer QTc predicted the same in females. ECG measurements also predicted the secondary outcomes to different extents depending on genders.

ConclusionsSelected ECG measurements have significant gender-specific prognostic value in patients admitted for heart failure.

category: cardiovascular medicine


title: Rivaroxaban is Comparable to Warfarin in Prevention of Thromboembolism in Patients with Non-Valvular Atrial Fibrillation with Valvular Heart Disease: A Systematic Review and Meta-analysis

abstract:
ObjectivesWhile the use of novel oral anticoagulants (NOACs) has been approved in the treatment of non-valvular atrial fibrillation (NVAF), we are lacking studies on individual NOACs in NVAF with valvular heart disease (VHD) including bio-prosthetic valve and valve repair. We aimed to determine the efficacy and safety of rivaroxaban compared to warfarin in prevention of thromboembolism in patients with NVAF with VHD.

MethodsWe searched PubMed, MEDLINE, and EMBASE including only RCTs and Cohort studies from inception till April 2021. Eligible studies compared rivaroxaban with warfarin in patients with NVAF with VHD. We excluded patients with valvular AF. We used Review Manager (version 5.4, Cochrane Collaboration, Oxford, UK) applying the Mantel-Haenszel test and followed PRISMA guidelines. Risk ratio (RR) and 95% confidence intervals (CIs) were estimated using a random-effects method and heterogeneity using I squared test.

ResultsWe had total of 23136 participants in both groups. Our results showed stroke and systemic thromboembolism in 88 of 4258 (2.06%) patients in the rivaroxaban group compared to 351 of 18878 (1.85%) patients in the warfarin group (RR 0.76; 95% CI, 0.55, 1.06; heterogeneity I2 = 35%, P = 0.10), major bleeding in 247 of 4258 (5.8%) patients in the rivaroxaban group compared to 270 of 18879 (1.4%) patients in the warfarin group (HR 1.68; 95% CI, 0.59, 4.77; heterogeneity I2 = 97%) and intracranial hemorrhage in 24 out of 2583 (0.9%) patients in the rivaroxaban group compared to 35 of 2160 (1.6%) in warfarin group (HR 0.49; 95% CI, 0.16, 1.56; heterogeneity I2 = 70%).

ConclusionsOur results show that rivaroxaban is comparable to warfarin in prevention of stroke and systemic thromboembolism in patients with NVAF with VHD. Rivaroxaban is also comparable to warfarin in bleeding risks in these patients.

REGISTRATION NUMBERCRD42021222490


title: Efficacy and safety of Andrographis paniculata extract in patients with mild COVID-19: A randomized controlled trial

abstract:
ObjectivesTo assess the efficacy and safety of Andrographis paniculata extract (APE) in adults with mild COVID-19.

MethodsSixty-three adults aged 18-60 years, without co-morbidity, with laboratory-confirmed mild COVID-19, were randomized 1:1 to receive APE (60 mg andrographolide, t.i.d, for 5 days) or placebo within 24 hours after admission, plus standard supportive care. The outcomes were clinical recovery rates by Day 5 using self-assessment scores, pneumonia by chest X-rays, nasopharyngeal SARS-CoV-2 detection by rRT-PCR on Day 5, changes of serum CRP levels, and adverse drug reactions. Chest X-rays and blood tests for CRP, liver and renal function, were performed on Days 1, 3, and 5.

ResultsBaseline characteristics of patients in the APE-treatment (n=29) and placebo-control (n=28) groups were comparable. None had self-assessment scores showing complete clinical recovery by Day 5. Pneumonia occurred in 0/29 (0%) versus 3/28 (10.7%), (p=0.112). On Day 5, patients with SARS-CoV-2 detection were 10/29 (34.5%) versus 16/28 (57.1%), (p=0.086); patients with CRP >10 mg/L were 0/29 (0%) versus 5/28 (17.9%), (p=0.023), for APE-treatment and placebo-control groups, respectively. All three patients with pneumonia had substantially rising serum CRP; and high CRP levels on Day 5. None had evidence of hematologic, hepatic or renal impairment.

ConclusionEven though the study was limited by small sample size, our findings suggested promising efficacy and safety of the APE-treatment regimen in adults with mild COVID-19. Further studies, with adequate power to assure these findings, are required.


title: Human leishmaniasis vaccines: use cases, target population and potential global demand

abstract:
The development of vaccines against one or all forms of human leishmaniasis remains hampered by a paucity of investment, at least in part resulting from the lack of well-evidenced and agreed estimates of vaccine demand. Starting from the definition of 4 main use cases (prevention of visceral leishmaniasis, prevention of cutaneous leishmaniasis, prevention of post-kala-azar dermal leishmaniasis and treatment of post-kala-azar dermal leishmaniasis), we have estimated the size of each target population, focusing on those endemic countries where incidence levels are sufficiently high to justify decisions to adopt a vaccine. We assumed a dual vaccine delivery strategy, including a wide age-range catch-up campaign before the start of routine immunisation. Vaccine characteristics and delivery parameters reflective of a target product profile and the likely duration of the clinical development effort were considered in forecasting the demand for each of the four indications. Over a period of 10 years, this demand is forecasted to range from 310-830 million doses for a vaccine preventing visceral leishmaniasis and 557-1400 million doses for a vaccine preventing cutaneous leishmaniasis under the different scenarios we simulated. In a scenario with an effective prophylactic visceral leishmaniasis vaccine, demand for use to prevent or treat post-kala-azar dermal leishmaniasis would be more limited (over the 10 years [~]160,000 doses for prevention and [~]7,000 doses for treatment). Demand would rise to exceed 330,000 doses, however, in the absence of an effective vaccine for visceral leishmaniasis. Because of the sizeable demand and potential for public health impact, a single-indication prophylactic vaccine for visceral or cutaneous leishmaniasis, and even more so a cross-protective prophylactic vaccine could attract the interest of commercial developers. Continuous refinement of these first-of-their kind estimates and confirmation of country willingness and ability to pay will be paramount to inform the decisions of policy makers and developers in relation to a leishmaniasis vaccine. Positive decisions can provide a much-needed contribution towards the achievement of global leishmaniasis control.

Author SummaryThe leishmaniases are potentially vaccine-preventable diseases of global importance, yet no vaccines for human use have attained registration. This work sheds lights on the potential size of demand for a human vaccine for the prevention of visceral and cutaneous leishmaniasis as well as for the prevention and treatment of post-kala-azar dermal leishmaniasis. The analysis is grounded in the definition of vaccine use cases which, by transparently defining different applications of the vaccines in the immunisation programs, provides the basis for defining the target populations and vaccine characteristics. The output of this work, the first-of-its-kind for leishmaniasis, fills a critical information gap and will provide policy makers and vaccine developers with important insights into the public health relevance of a human leishmaniasis vaccine and the strengths of its commercial value proposition. Ultimately this research aims to inform future decisions on disease prioritization and on investments by key stakeholders, as well as to identify areas for further research.


title: COVID-19 and Herpes Simplex Virus Infection: A Cross-Sectional Study

abstract:
BackgroundDespite being variable and poorly characterized, the reported cutaneous manifestations of COVID-19 are of increasing concern.

Aim of the StudyThis study aimed to assess the prevalence and possible association between COVID-19 and herpes simplex virus (HSV) infection.

Patients and methodsA 9-item questionnaire was sent to 120 PCR-confirmed COVID-19 patients with a response rate of 66.67%. This cross-sectional observational study included 80 patients with mild to moderate COVID-19 infection who did not require hospitalization or steroid therapy.

ResultsOne or more HSV infections were observed in 28 patients (35%) with COVID-19 infection, including 10 males (35.7%) and 18 females (64.29%). Of the 28 patients, fever was reported in 17 patients (75%) during COVID-19. Most of the respondents (78%) described a single HSV reactivation, 14.29% had 2 attacks, and 7.14% experienced 3 attacks. Compared to previous non-COVID-19 related HSV reactivation, the COVID-19 related attacks were more severe in 12 patients (42.85%), equally severe in 5 patients (17.85%) and less severe in 1 patient (3.57%). Interestingly, 10 patients (35.71%) developed an initial symptomatic HSV attack during COVID-19 infection.

ConclusionsThis study demonstrated a possible association between COVID-19 infection and primary HSV infection and/or reactivation. The COVID-19 direct neuronal effect in addition to COVID-19 related psychological stress, fever and immunological dysregulation could play a potential role.

category: dermatology


title: Impact of COVID-19 pandemic on weight and BMI among UK adults: a longitudinal analysis of data from the HEBECO study

abstract:
BackgroundCOVID-19-related restrictions impacted weight and weight-related factors during the initial months of the pandemic. However, longitudinal analyses are scarce.

MethodsAn online, longitudinal study was conducted among self-selected UK adults (n=1,818), involving three surveys during 2020 (May-June, August-September, November-December), covering height, weight and sociodemographic, COVID-19-related and behavioural measures. Data were analysed using generalised estimating equations.

ResultsSelf-reported average weight and body mass index (BMI) significantly increased from May-June to August-September (74.95kg to 75.33kg, 26.22kg/m2 to 26.36kg/m2, both p<0.001), and then significantly decreased to November-December (to 75.06kg, 26.27kg/m2, both p<0.01), comparable to May-June levels (p=0.274/0.204). However, there was great interindividual variation, with 37.0%/26.7% reporting an increase and 34.5%/26.3% reporting a decrease in weight/BMI greater than 0.5kg/0.5kg/m2, respectively from May-June to November-December. The average weight/BMI increase was 3.64kg (95% confidence interval: 3.32,3.97)/1.64kg/m2 (1.49,1.79), and the average weight/BMI decrease was 3.59kg (3.34,3.85)/1.53kg/m2 (1.42,1.63). In fully adjusted models, increase in weight/BMI across surveys was significantly negatively associated with initial BMI, and positively associated with monthly high fat, salt and sugar (HFSS) snacks intake and alcohol consumption, and for BMI only, older age. However, associations were time-varying, such that lower initial BMI, higher HFSS snacks intake and high-risk alcohol consumption were associated with maintenance of increased weight/BMI from August-September to November-December.

ConclusionThe average weight/BMI of UK adults increased during the early pandemic months, before returning to baseline levels in November-December 2020. However, this masks substantial interindividual variation in weight/BMI trajectories, indicating vulnerabilities associated with changes in food and alcohol consumption throughout the pandemic.

What is currently known from previous studiesO_LISmall increases in average weight/BMI have been reported (1.57kg/0.31kg/m2) during the initial three months of the pandemic.
C_LIO_LIChanges in weight/BMI during the early months were not uniform, with significant proportions increasing (11.2-72.4%) as well as decreasing (7.2-51.4%) weight/BMI.
C_LIO_LIWeight/BMI change has been associated with several sociodemographic, lifestyle and behavioural factors.
C_LIO_LIWhether these weight/BMI changes persist over longer durations of the pandemic, and the factors associated with any long-term weight/BMI change is largely unknown.
C_LI

What this paper addsO_LIIn UK adults, average weight/BMI first increased and then decreased from May to December 2020 during the pandemic, but this masks large interindividual variability in average changes.
C_LIO_LIInitial BMI at the start of the pandemic and health behavioural factors such as alcohol consumption and high fat, salt and sugar (HFSS) snacks intake were significantly associated with a change in weight/BMI.
C_LIO_LIThe strength of the association of alcohol consumption, initial BMI and HFSS snacks intake with weight/BMI change was dependent on the stage of the pandemic, with more pronounced differences becoming apparent during the latter part of 2020.
C_LI


title: Risk of Severe COVID-19 Outcomes Among Patients with Rheumatoid Arthritis in the United States

abstract:
IntroductionCoronavirus disease 2019 (COVID-19) has infected over 22 million individuals worldwide. It remains unclear whether patients with COVID-19 and Rheumatoid Arthritis (RA) experience worse clinical outcomes compared to similar patients with COVID-19 without RA.

AimThe aim of this study is to provide insights on how COVID-19 impacted patients with RA given the nature of the disease and medication used.

MethodsRA cases were identified via International Classification of Diseases (ICD) codes and COVID-19 cases by laboratory results in the U.S. based TriNetX network. Patients with COVID-19 and RA were propensity-score matched based on demographics with patients with COVID-19 without RA at a 1:3 ratio. A hospitalized sub-population was defined by procedure codes.

ResultsWe identified 1,014 COVID-19 patients with RA and 3,042 non-RA matches selected from 137,757 patients. The odds of hospitalization (non-RA:23%, RA:24.6%, OR:1.08, 95% CI: 0.88 to 1.33) or mortality (non-RA:5.4%, RA:6%, OR:0.93, 95% CI: 0.65 to 1.34) were not significantly different.

The hospitalized sub-population included 249 patients with COVID-19 and RA and 745 non-RA matches selected from 21,435 patients. The risk of intensive care unit (ICU) admission (non-RA:18.8%, RA:18.1%, OR:0.94, 95% CI: 0.60 to 1.45), and inpatient mortality (non-RA:14.4%, RA:14.5%, OR:0.86, 95% CI: 0.53 to 1.40) were not significantly different.

ConclusionWe didnt find evidence suggesting patients with COVID-19 and RA are more likely to have severe outcomes than patients with COVID-19 without RA.

Key Messages- Patients with Rheumatoid Arthritis (RA) tend to be older, and often have co-morbidities which could put them at greater risk of severe COVID-19 outcomes.
- This study is one of the largest studies of COVID-19 infected RA populations to date. We did not find increased risk of hospitalization, ICU admission, or mortality among RA patients vs. matched non-RA patients.
- Patients previously exposed to anti-coagulants experienced higher risks of hospitalization and overall mortality. Extra attention is needed for treating such patients.


title: Predicted Norovirus Resurgence in 2021-2022 Due to the Relaxation of Nonpharmaceutical Interventions Associated with COVID-19 Restrictions in England: A Mathematical Modelling Study

abstract:
BackgroundTo reduce the coronavirus disease burden in England, along with many other countries, the Government implemented a package of non-pharmaceutical interventions (NPIs) that have also impacted other transmissible infectious diseases such as norovirus. It is unclear what future norovirus disease incidence is likely to look like upon lifting these restrictions.

MethodsHere we use a mathematical model of norovirus fitted to community incidence data in England to project forward expected incidence based on contact surveys that have been collected throughout 2020-2021.

ResultsWe report that susceptibility to norovirus infection has likely increased between March 2020 to mid-2021. Depending upon assumptions of future contact patterns incidence of norovirus that is similar to pre-pandemic levels or an increase beyond what has been previously reported is likely to occur once restrictions are lifted. Should adult contact patterns return to 80% of pre-pandemic levels the incidence of norovirus will be similar to previous years. If contact patterns return to pre-pandemic levels there is a potential for the expected annual incidence to be up to 2-fold larger than in a typical year. The age-specific incidence is similar across all ages.

ConclusionsContinued national surveillance for endemic diseases such as norovirus will be essential after NPIs are lifted to allow healthcare services to adequately prepare for a potential increase in cases and hospital pressures beyond what is typically experienced.


title: Analyzing the U.S. Post-marketing safety surveillance of COVID-19 vaccines

abstract:
BackgroundSince December 2020, three COVID-19 vaccines have been authorized in the United States (U.S.) and were proceeded by large immunization programs. The aim of this study was to characterize the U.S. post-marketing safety (PMS) profiles of these vaccines with an in-depth analysis of mortality data.

MethodsThis was a retrospective database analysis study. Details of the U.S. PMS reports (15 December 2020 to 19 March 2021) of the three vaccines (Pfizer-BioNTech, Moderna, and Janssen Ad26.COV2.S) were retrieved from the U.S. Vaccine Adverse Event Reporting System (VAERS). A descriptive analysis was conducted to characterize the reported adverse events (AEs). A comparative (Pfizer-BioNTech vs. Moderna) analysis of mortality was conducted. The mean count ratio of death between the two vaccines was estimated using a negative binomial regression model adjusting for the measured confounders.

ResultsA total of 44,451 AE reports were retrieved (corresponding to 0.05% of the U.S. population who received at least one dose). The most commonly reported AEs were injection site reactions (30.4% of the reports), pain (reported in 26.7% of the reports), and headache (18.6% of the reports). Serious AEs were reported in only 14.6% of the reports with 4,108 hospitalizations. The total number of deaths was 1,919 with a mean count ratio of Moderna (n=997) vs. Pfizer-BioNTech (n=899) of 1.07 (95% confidence interval 0.86 to 1.33).

ConclusionsThe vast majority of PMS AEs in the U.S. were non-serious, and the number of serious AEs is very low given the total number of vaccinated U.S. population.

category: public and global health


title: Speech and language impairments in behavioral variant frontotemporal dementia: A systematic review

abstract: Although behavioral variant frontotemporal dementia (bvFTD) is classically defined by behavioral and socio-emotional changes, impairments often extend to other cognitive functions. These include early speech and language deficits related to the diseases core neural disruptions. Yet, their scope and clinical relevance remains poorly understood. This systematic review characterizes such disturbances in bvFTD, considering clinically, neuroanatomically, genetically, and neuropathologically defined subgroups. We included 181 experimental studies, with at least 5 bvFTD patients diagnosed using accepted criteria, comparing speech and language outcomes between bvFTD patients and healthy controls or between bvFTD subgroups. Results reveal extensive and heterogeneous deficits across cohorts, with (a) consistent lexico-semantic, orthographic, and prosodic impairments; (b) inconsistent deficits in motor speech and grammar; and (c) relative preservation of phonological skills. Also, preliminary findings suggest that the severity of speech and language deficits might be associated with global cognitive impairment, predominantly temporal or fronto-temporal atrophy and MAPT mutations (vs C9orf72). Although under-recognized, these impairments contribute to patient characterization and phenotyping, while potentially informing diagnosis and prognosis.


title: Viral infection and Transmission in a large well-traced outbreak caused by the Delta SARS-CoV-2 variant

abstract: We report the first local transmission of the SARS-CoV-2 Delta variant in mainland China. All 167 infections could be traced back to the first index case. Daily sequential PCR testing of the quarantined subjects indicated that the viral loads of Delta infections, when they first become PCR+, were on average [~]1000 times greater compared to A/B lineage infections during initial epidemic wave in China in early 2020, suggesting potentially faster viral replication and greater infectiousness of Delta during early infection. We performed high-quality sequencing on samples from 126 individuals. Reliable epidemiological data meant that, for 111 transmission events, the donor and recipient cases were known. The estimated transmission bottleneck size was 1-3 virions with most minor intra-host single nucleotide variants (iSNVs) failing to transmit to the recipients. However, transmission heterogeneity of SARS-CoV-2 was also observed. The transmission of minor iSNVs resulted in at least 4 of the 30 substitutions identified in the outbreak, highlighting the contribution of intra-host variants to population level viral diversity during rapid spread. Disease control activities, such as the frequency of population testing, quarantine during pre-symptomatic infection, and level of virus genomic surveillance should be adjusted in order to account for the increasing prevalence of the Delta variant worldwide.


title: Daily sampling of early SARS-CoV-2 infection reveals substantial heterogeneity in infectiousness

abstract: The dynamics of SARS-CoV-2 replication and shedding in humans remain poorly understood. We captured the dynamics of infectious virus and viral RNA shedding during acute infection through daily longitudinal sampling of 60 individuals for up to 14 days. By fitting mechanistic models, we directly estimate viral reproduction and clearance rates, and overall infectiousness for each individual. Significant person-to-person variation in infectious virus shedding suggests that individual-level heterogeneity in viral dynamics contributes to superspreading. Viral genome load often peaked days earlier in saliva than in nasal swabs, indicating strong compartmentalization and suggesting that saliva may serve as a superior sampling site for early detection of infection. Viral loads and clearance kinetics of B.1.1.7 and non-B.1.1.7 viruses in nasal swabs were indistinguishable, however B.1.1.7 exhibited a significantly slower pre-peak growth rate in saliva. These results provide a high-resolution portrait of SARS-CoV-2 infection dynamics and implicate individual-level heterogeneity in infectiousness in superspreading.


title: Humoral immune response in inactivated SARS-CoV-2 vaccine: When should a booster dose be administered?

abstract:
BackgroundFor a sustained and essential protective antibody response, it is important to understand how long the humoral immune response induced by the SARS-CoV-2 inactivated vaccine persists.

AimsThis study aimed to detect the first and third-month concentrations and seroconversion rates of the antibodies induced by the inactivated vaccine.

Study DesignThis is a vaccine efficacy study.

MethodsThe study included 272 health workers who were vaccinated at days 0 and 28 by the inactivated SARS-CoV-2 vaccine (3g/0.5ml). Anti-S-RBD-IgG and total anti-spike/anti- nucleocapsid-IgG antibody concentrations and seroconversion rates were examined in vaccinated health workers at the 1st and 3rd months after the vaccination. The test method used for the qualitative detection and differentiation of IgG antibodies (indirect method) to SARS-CoV-2 is a chemiluminescence reaction (CLIA).

ResultsThe mean age of the health workers was 38.93{+/-}10.59 (min:21-max:64). A total of 45(16.5%) participants declared to have had COVID-19 before the first dose of the inactivated vaccine. The participants were found to be reactive for anti-S-RBD-IgG antibodies by 98.2% and 97.8% at the first and third months, respectively, after the administration of the second dose. The decrease in the mean plasma concentrations of anti-S-RBD IgG was observed as 56.7% in the cohort with only two doses of the vaccine (1st month:42.4AU/ml versus 3rd month: 18.2AU/ml). In the cohort with a history of COVID-19 prior to the vaccination, the decrease was observed as 25.1% (1st month:58.29 versus 3rd month:43.64 AU/ml) and at a mean of 57.4 (0-90) days prior to vaccination, the decrease was of 43.1% (1st month:55.05 AU/ml versus 3rd month:31.28 AU/ml), keeping more stable in participants infected at a mean of 183.1 (91-330) days prior to vaccination (a decrease of 5.2%; with 62.34 AU/ml at 1st and 59.08 AU/ml at 3rd months). Anti-S-RBD concentrations were observed to increase 10-fold (30.44 AU/ml at 1st and 310.64 AU/ml at 3rd months) in participants infected after the vaccination and to decrease among people aged 50 years and older.

ConclusionAntibody concentrations at the 1st and 3rd months after the vaccination with two doses of the inactivated SARS-CoV-2 vaccine were found to be decreased, but still detectable (except in one participant). As participants who had COVID-19 at a mean of 181 (90-330) days before the vaccination presented with a more stable antibody level, it can be concluded that a booster at months 6-12, resulting in a schedule of 0-1-6 months, is recommended for the inactive SARS-CoV-2 vaccination.


title: Infection fatality rate of COVID-19 in community-dwelling populations with emphasis on the elderly: An overview

abstract:
ObjectiveThis mixed design synthesis aimed to estimate the infection fatality rate (IFR) of Coronavirus Disease 2019 (COVID-19) in community-dwelling elderly populations and other age groups from seroprevalence studies. Protocol: https://osf.io/47cgb.

Methods and analysesEligible were seroprevalence studies done in 2020 and identified by any of four existing systematic reviews; with [≥]1000 participants aged [≥]70 years that presented seroprevalence in elderly people; that aimed to generate samples reflecting the general population; and whose location had available data on cumulative COVID-19 deaths in elderly (primary cutoff [≥]70 years; [≥]65 or [≥]60 also eligible). We extracted the most fully adjusted (if unavailable, unadjusted) seroprevalence estimates. We also extracted age- and residence-stratified cumulative COVID-19 deaths (until 1 week after the seroprevalence sampling midpoint) from official reports, and population statistics, to calculate IFRs corrected for unmeasured antibody types. Sample size-weighted IFRs were estimated for countries with multiple estimates. Secondary analyses examined data on younger age strata from the same studies.

ResultsTwenty-five seroprevalence surveys representing 14 countries were included. Across all countries, the median IFR in community-dwelling elderly and elderly overall was 2.9% (range 0.2%-6.9%) and 4.9% (range 0.2%-16.8%) without accounting for seroreversion (2.4% and 4.0%, respectively, accounting for 5% monthly seroreversion). Multiple sensitivity analyses yielded similar results. IFR was higher with larger proportions of people >85 years. Younger age strata had low IFR values (median 0.0013%, 0.0088%, 0.021%, 0.042%, 0.14%, and 0.65%, at 0-19, 20-29, 30-39, 40-49, 50-59, and 60-69 years even without accounting for seroreversion).

ConclusionsThe IFR of COVID-19 in community-dwelling elderly people is lower than previously reported. Very low IFRs were confirmed in the youngest populations.


title: PathML: A unified framework for whole-slide image analysis with deep learning

abstract: The inspection of stained tissue slides by pathologists is essential for the early detection, diagnosis and monitoring of disease. Recently, deep learning methods for the analysis of whole-slide images (WSIs) have shown excellent performance on these tasks, and have the potential to substantially reduce the workload of pathologists. However, successful implementation of deep learning for WSI analysis is complex and requires careful consideration of model hyperparameters, slide and image artefacts, and data augmentation. Here we introduce PathML, a Python library for performing preand post-processing of WSIs, which has been designed to interact with the most widely used deep learning libraries, PyTorch and TensorFlow, thus allowing seamless integration into deep learning workflows. We present the current best practices in deep learning for WSI analysis, and give a step-by-step guide using the PathML framework: from annotating and pre-processing of slides, to implementing neural network architectures, to training and post-processing. PathML provides a unified framework in which deep learning methods for WSI analysis can be developed and applied, thus increasing the accessibility of an important new application of deep learning.

category: pathology


title: COVID-19 vaccine uptake, predictors of vaccination, and self-reported barriers to vaccination among primary school teachers in Poland

abstract: It has been proposed that teachers, like healthcare workers, constitute a strategic target for COVID-19 vaccine programs as immunization is a key element in protecting both them and their pupils. The present study examined vaccine uptake among primary-school teachers and sought to identify factors associated with it. A sample was recruited from 553 Polish primary schools, and data were collected at two time points: December 2020 and March 2021. Associations between vaccine uptake among teachers and their attitudes toward COVID-19 vaccination were assessed through multivariate logistic regression. 6152 participants completed both baseline and follow-up surveys. Of these, 4502 (73.2%) reported their intention at baseline to receive a COVID-19 vaccination, if available; at follow-up, 3894 (86.5%) of the same 4502 reported having received the vaccination. A significant association was revealed between vaccine uptake and perceived severity, self-efficacy, and social norms. The principal driver for vaccine acceptance was the wish to avoid contracting the disease. Conversely, the principal driver for vaccine refusal was concern about side effects and safety. A strong association exists between intention to receive the COVID-19 vaccine and actual uptake. Future COVID-19 immunization programs may benefit from a stronger understanding of the factors associated with vaccine uptake among this cohort.


title: Genetic regulation of OAS1 nonsense-mediated decay underlies association with risk of severe COVID-19

abstract: Genomic regions have been associated with COVID-19 susceptibility and outcomes, including the chr12q24.13 locus encoding antiviral proteins OAS1-3. Here, we report genetic, functional, and clinical insights into genetic associations within this locus. In Europeans, the risk of hospitalized vs. non-hospitalized COVID-19 was associated with a single 19Kb-haplotype comprised of 76 OAS1 variants included in a 95% credible set within a large genomic fragment introgressed from Neandertals. The risk haplotype was also associated with impaired spontaneous but not treatment-induced SARS-CoV-2 clearance in a clinical trial with pegIFN-{lambda}1. We demonstrate that two exonic variants, rs10774671 and rs1131454, affect splicing and nonsense-mediated decay of OAS1. We suggest that genetically-regulated loss of OAS1 expression contributes to impaired spontaneous clearance of SARS-CoV-2 and elevated risk of hospitalization for COVID-19. Our results provide the rationale for further clinical studies using interferons to compensate for impaired spontaneous SARS-CoV-2 clearance, particularly in carriers of the OAS1 risk haplotypes.