title: Distinct promoter regions of the oxytocin receptor gene are hypomethylated in Prader-Willi syndrome and in Prader-Willi syndrome associated psychosis

abstract:
BackgroundPrader-Willi syndrome (PWS) is a rare neurodevelopmental disorder caused by a loss of usually paternally expressed, maternally imprinted genes located on chromosome 15q11-q13. Individuals with PWS display a specific behavioral phenotype and have a higher susceptibility than the general population for certain psychiatric conditions, especially psychosis. An impairment of the oxytocin system has been described in Prader-Willi syndrome, but has not yet been investigated on the epigenetic level. Recent studies have pointed out altered methylation patterns of the oxytocin receptor gene (OXTR) in various psychiatric disorders, including psychosis.

MethodsIn this study, we investigated methylation rates of CpG dinucleotides in the promoter region of the oxytocin receptor gene via bisulfite-sequencing using DNA extracted from peripheral blood samples of 31 individuals with PWS and 14 controls matched for age, sex and BMI.

ResultsIndividuals with PWS show significantly lower methylation in the intron 1 region of the OXTR than neurotypical controls (p=0.012). Furthermore, male PWS subjects with psychosis show significantly lower methylation of the OXTR exon 1 region than those without psychosis (p=0.002). Transcription factor binding site analysis revealed E2F1 as a transcription factor potentially binding to the exon 1 region. E2F1 is physiologically regulated by Necdin, an anti-apoptotic protein whose corresponding gene is located within the PWS locus.

ConclusionThis study provides evidence of a disruption of the Oxytocin system on an epigenetic level in PWS in general and in individuals with PWS and psychosis.


title: Hypoxaemia prevalence and management among children and adults presenting to primary care facilities in Uganda: a prospective cohort study.

abstract:
IntroductionHypoxaemia (low blood oxygen) is common among hospitalised patients, increasing risk of death five-fold and requiring prompt detection and treatment. However, we know little about hypoxaemia prevalence in primary care and the role for pulse oximetry and oxygen therapy. This study assessed the prevalence and management of hypoxaemia at primary care facilities in Uganda.

MethodsProspective cohort study in 30 primary care facilities in Uganda, Feb-Apr 2021. Clinical data collectors assessed blood oxygen level (SpO2) of all acutely unwell children, adolescents, and adults, and followed up children aged under 15 years with SpO2<93% to determine subsequent care and outcome. Primary outcome: proportion of children under 5 years of age with severe hypoxaemia (SpO2<90%). Secondary outcomes: severe/moderate hypoxaemia (SpO2 90-93%) by age/sex/complaint.

ResultsAmong children U5, the prevalence of severe hypoxaemia was 1.3% (95% CI 0.9 to 2.1); an additional 4.9% (3.9 to 6.1) had moderate hypoxaemia. Performing pulse oximetry according to World Health Organization guidelines exclusively on children with respiratory complaints would have missed 14% (3/21) of severe hypoxaemia and 11% (6/55) of moderate hypoxaemia. Hypoxaemia prevalence was low among children 5-14 years (0.3% severe, 1.1% moderate) and adolescents/adults 15+ years (0.1% severe, 0.5% moderate). A minority (12/27, 44%) of severely hypoxaemic patients were referred; 3 (12%) received oxygen.

ConclusionHypoxaemia is common among acutely unwell children under five years of age presenting to Ugandan primary care facilities. Routine pulse oximetry has potential to improve referral, management and clinical outcomes. Effectiveness, acceptability, and feasibility of pulse oximetry and oxygen therapy for primary care should be investigated in implementation trials.

KEY QUESTIONS SUMMARY BOXO_ST_ABSWhat is already known?C_ST_ABSO_LIHypoxaemia (low blood oxygen levels) is common among children and adults admitted to hospital with severe respiratory illness, increasing their risk of death at least 5-fold and requiring prompt detection and treatment.
C_LIO_LIWe know little about the prevalence of hypoxaemia in primary care, or whether pulse oximetry would improve decision-making or care for hypoxaemic patients.
C_LI

What are the new findings?O_LIIn a Ugandan primary care context, hypoxaemia was common among acutely unwell children under five years of age and most were not referred to hospital for treatment.
C_LIO_LIHypoxaemia was uncommon among older children and adults presenting to Ugandan primary care facilities but prevalence increased with age into older adulthood.
C_LI

What do the new findings imply?O_LIRoutine pulse oximetry screening may be warranted for acutely unwell children under five years of age, with a potential to improve referral, management and clinical outcomes.
C_LIO_LIEffectiveness, acceptability, and feasibility of pulse oximetry and oxygen therapy for primary care should be investigated in further implementation trials.
C_LI

category: public and global health


title: Proposing Response Evaluation Criteria in Solid Tumors Based on Genomic Profiling or Genomic RECIST: A Retrospective Study on the Liquid Biopsy Results of 29 Cancer Patients

abstract: Tumor response and disease progression are assessed using imaging technologies. However, these technologies fail to detect tumor responses at the molecular level and clonal evolution. A potential surrogate for such parameters is using circulating tumor DNA (ctDNA). This study aimed to examine the quantity and composition of the ctDNA results of 29 cancer patients before and after dendritic cell (DC) immunotherapy and develop criteria to evaluate the molecular response to treatment based on these results. We categorized the patients into four categories based on percent changes in the total ctDNA compared with the baseline ctDNA titers, and this response assessment was termed genomic response evaluation criteria in solid tumors or gRECIST. Even those who are clinically evaluated as having a good response might harbor unfavorable tumor responses at the molecular level. Newly formed ctDNA levels can be the most prognostic parameter in tumor progression or the treatment response, while ctDNA clearance and the decline or rise in existing ctDNA did not change significantly in genomic response categories (gRECIST). More research is needed to support the clinical use of ctDNA in precision oncology and personalized cancer treatment.

category: oncology


title: Cross-ancestry meta-analysis of opioid use disorder uncovers novel loci with predominant effects on brain

abstract: Despite an estimated twin heritability of [~]50%, genome-wide association studies (GWAS) of opioid use disorder (OUD) have revealed few genome-wide significant (GWS) loci, with replicated findings only in European-ancestry individuals. To identify novel loci, including those in non-European ancestries, and improve our understanding of the biology of OUD, we conducted a cross-ancestry meta-analysis using the Million Veteran Program (MVP). OUD cases in MVP had at least 1 International Classification of Diseases (ICD)-9 or ICD-10 code for opioid abuse or dependence (N=31,473). Opioid-exposed controls (N=394,471) had one or more outpatient opioid prescription fills. We conducted GWAS for each major ancestral group in MVP: African Americans (AAs; N=88,498), European Americans (EAs; N=302,585), and Hispanic Americans (HAs; N=34,861), followed by a cross-ancestry meta-analysis. Ten loci were GWS in the cross-ancestry meta-analysis, 8 of them novel. In addition to the known coding variant rs1799971 in OPRM1, which was the lead SNP genome-wide (p=6.78x10-10), and a recently reported exonic variant in FURIN, we identified intronic variants in RABEPK, FBXW4, NCAM1, and KCNN1. Ancestry-specific analyses identified an additional novel locus for each of the 3 ancestry groups. A supplementary meta-analysis within EAs that included MVP and other samples identified a locus in TSNARE1, which was also GWS in the cross-ancestry meta-analysis of all datasets. Gene-based association analyses identified 1 gene in AAs (CHRM2) and 3 in EAs (OPRM1, DRD2, and FTO). Significant genetic correlations (rgs) were identified for 127 traits, including positive correlations with schizophrenia, problematic alcohol use, and major depressive disorder. The most significantly enriched cell type group was the central nervous system with gene-expression enrichment identified in brain regions previously associated with substance use disorders. With a case sample 50% larger than that of the previous largest GWAS, we identified 14 loci for OUD, including 12 novel loci, some of which were ancestry-specific. These findings increase our understanding of the biological pathways involved in OUD, which can inform preventive, diagnostic, and therapeutic efforts and thereby help to address the opioid epidemic.

category: genetic and genomic medicine


title: Clinical characteristics with inflammation profiling of Long-COVID and association with one-year recovery following hospitalisation in the UK: a prospective observational study

abstract:
BackgroundThere are currently no effective pharmacological or non-pharmacological interventions for Long-COVID. To identify potential therapeutic targets, we focussed on previously described four recovery clusters five months after hospital discharge, their underlying inflammatory profiles and relationship with clinical outcomes at one year.

MethodsPHOSP-COVID is a prospective longitudinal cohort study, recruiting adults hospitalised with COVID-19 across the UK. Recovery was assessed using patient reported outcomes measures (PROMs), physical performance, and organ function at five-months and one-year after hospital discharge. Hierarchical logistic regression modelling was performed for patient-perceived recovery at one-year. Cluster analysis was performed using clustering large applications (CLARA) k-medoids approach using clinical outcomes at five-months. Inflammatory protein profiling from plasma at the five-month visit was performed.

Findings2320 participants have been assessed at five months after discharge and 807 participants have completed both five-month and one-year visits. Of these, 35{middle dot}6% were female, mean age 58{middle dot}7 (SD 12{middle dot}5) years, and 27{middle dot}8% received invasive mechanical ventilation (IMV). The proportion of patients reporting full recovery was unchanged between five months 501/1965 (25{middle dot}5%) and one year 232/804 (28{middle dot}9%). Factors associated with being less likely to report full recovery at one year were: female sex OR 0{middle dot}68 (95% CI 0{middle dot}46-0{middle dot}99), obesity OR 0{middle dot}50 (95%CI 0{middle dot}34-0{middle dot}74) and IMV OR 0{middle dot}42 (95%CI 0{middle dot}23-0{middle dot}76).

Cluster analysis (n=1636) corroborated the previously reported four clusters:  very severe,  severe,  moderate/cognitive,  mild relating to the severity of physical, mental health and cognitive impairments at five months in a larger sample. There was elevation of inflammatory mediators of tissue damage and repair in both the very severe and the moderate/cognitive clusters compared to the mild cluster including interleukin-6 which was elevated in both comparisons. Overall, there was a substantial deficit in median (IQR) EQ5D-5L utility index from pre-COVID (retrospective assessment) 0{middle dot}88 (0{middle dot}74-1{middle dot}00), five months 0{middle dot}74 (0{middle dot}60-0{middle dot}88) to one year: 0{middle dot}74 (0{middle dot}59-0{middle dot}88), with minimal improvements across all outcome measures at one-year after discharge in the whole cohort and within each of the four clusters.

InterpretationThe sequelae of a hospital admission with COVID-19 remain substantial one year after discharge across a range of health domains with the minority in our cohort feeling fully recovered. Patient perceived health-related quality of life remains reduced at one year compared to pre-hospital admission. Systematic inflammation and obesity are potential treatable traits that warrant further investigation in clinical trials.

FundingUKRI & NIHR

Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSWe systematically searched PubMed and Embase databases for large studies reporting one-year follow-up data for hospitalised COVID-19 patients published between January 1, 2021 and November 7, 2021, without language restrictions. Search terms related to COVID-19, hospitalisation and long-term follow-up were used. A large prospective cohort study from Wuhan, China (n = 1276) showed that 49% of patients reported at least one persistent symptom during a follow-up clinic visit at 12 months post COVID-19; no significant improvement in exercise capacity was observed between six- and 12-month visits. Another two large cohort studies in China (n = 2433) and Spain (n = 1950) with one-year follow-up data from telephone interviews showed that 45% and 81% of patients reported at least one residual COVID-19 symptom, respectively. However, no previous studies have compared the trajectories of COVID-19 recovery in patients classified by different clinical phenotypes, and there are no large studies investigating the relationship between systemic inflammation and ongoing health impairments post COVID-19.

Added value of this studyIn a diverse population of adults post-hospital admission with COVID-19, our large UK prospective multi-centre study reports several novel findings: the minority felt fully recovered at one year with minimal recovery from five months across any health domain; female sex and obesity are associated with being less likely to feel fully recovered at one year; several inflammatory mediators were increased in individuals with the most severe physical, mental health, and cognitive impairments compared to individuals with milder ongoing impairments.

Implications of all the available evidenceBoth pharmacological and non-pharmacological interventions are urgently needed to improve the ongoing burden following hospitalisation for COVID-19 both for individuals and healthcare systems; our findings support the use of a precision medicine approach with potential treatable traits of systemic inflammation and obesity.

category: infectious diseases


title: SARS-CoV-2 Omicron: reduction of potent humoral responses and resistance to clinical immunotherapeutics relative to viral variants of concern

abstract: Genetically distinct viral variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been recorded since January 2020. Over this time global vaccine programs have been introduced, contributing to lowered COVID-19 hospitalisation and mortality rates, particularly in the first world. In late 2021, the Omicron (B.1.1.529) virus variant emerged, with significant genetic differences and clinical effects from other variants of concern (VOC). This variant demonstrated higher numbers of polymorphisms in the gene encoding the Spike (S) protein, and there has been displacement of the dominant Delta variant. We assessed the impact of Omicron infection on the ability of: serum from vaccinated and / or previously infected individuals; concentrated human IgG from plasma donors, and licensed monoclonal antibody therapies to neutralise virus in vitro. There was a 17 to 22-fold reduction in neutralisation titres across all donors who had a detectable neutralising antibody titre to the Omicron variant. Concentrated pooled human IgG from convalescent and vaccinated donors had greater breadth of neutralisation, although the potency was still reduced 16-fold. Of all therapeutic antibodies tested, significant neutralisation of the Omicron variant was only observed for Sotrovimab, with other monoclonal antibodies unable to neutralise Omicron in vitro. These results have implications for ongoing therapy of individuals infected with the Omicron variant.


title: Booster of mRNA-1273 Vaccine Reduces SARS-CoV-2 Omicron Escape from Neutralizing Antibodies

abstract: The Omicron variant of SARS-CoV-2 is raising concerns because of its increased transmissibility and potential for reduced susceptibility to antibody neutralization. To assess the potential risk of this variant to existing vaccines, serum samples from mRNA-1273 vaccine recipients were tested for neutralizing activity against Omicron and compared to neutralization titers against D614G and Beta in live virus and pseudovirus assays. Omicron was 41-84-fold less sensitive to neutralization than D614G and 5.3-7.4-fold less sensitive than Beta when assayed with serum samples obtained 4 weeks after 2 standard inoculations with 100 {micro}g mRNA-1273. A 50 {micro}g boost increased Omicron neutralization titers and may substantially reduce the risk of symptomatic vaccine breakthrough infections.


title: Booster of mRNA-1273 Strengthens SARS-CoV-2 Omicron Neutralization


title: Comparison of the Immunogenicity of five COVID-19 vaccines in Sri Lanka

abstract: We assessed antibody responses 3 months post-vaccination in those who received mRNA-1273 (n=225), Sputnik V (n=128) or the first dose of Gam-COVID-Vac (n=184) and compared the results with previously reported data of Sinopharm and AZD1222 vaccinees. 99.5% of Moderna >94% of AZD1222 or Sputnik V, 72% to 76% of Gam-COVID-Vac (first dose) and 38.1% to 68.3% of Sinopharm vaccinees had ACE2 blocking antibodies above the positive threshold. The ACE2 blocking antibody levels were highest to lowest was Moderna > Sputnik V/ AZD1222 (had equal levels)> first dose of Gam-COVID-Vac > Sinopharm. All Moderna recipients had antibodies above the positive threshold to the ancestral (WT), B.1.1.7, B.1.351.1 and 80% positivity rate for B.1.617.2. Positivity rates of Sputnik V vaccinees for WT and variants, were higher than AZD1222 vaccinees, while Sinopharm vaccinees had the lowest positivity rates (<16.7%). These findings highlight the need for further studies to understand the effects on clinical outcomes.

category: allergy and immunology


title: Home monitoring of HbA1c in diabetes mellitus: A protocol for systematic review and narrative synthesis on reliability, accuracy, and patient acceptability

abstract:
IntroductionWorldwide there are an estimated 463 million people with diabetes. [1] In the UK people with diabetes are offered an annual review including monitoring of Haemoglobin A1c (HbA1c). [2] [3] This can identify people with diabetes who are not meeting their glycaemic targets, enabling early intervention. Those who do not attend these reviews often have higher HbA1c levels and poorer health outcomes. [4] During the Coronavirus disease of 2019 (COVID-19) pandemic, there was a 77% reduction in monitoring of HbA1c in the UK. [5] We hypothesise that people with diabetes could take finger-prick samples at home for the measurement of HbA1c.

Method and AnalysisWe will perform a systematic review of current evidence for capillary blood collected at home for the measurement of HbA1c. We will examine the validity, reliability, safety, and patient acceptability of the use of capillary blood compared with the usual standard of care of venous blood. We will explore variables which affect validity of results. Using core terms of  Diabetes,  HbA1c and  Capillary sampling we will search MEDLINE, Embase, CINAHL, Web of Science Core Collection, Google Scholar, Open Grey and other grey literature from database inception until 2021. Risk of bias will be assessed using the  COSMIN risk of bias tool to assess the quality of studies on reliability and measurement error. Database searches and data extraction for primary outcomes will be conducted in duplicate. We will produce a narrative synthesis exploring how variables of capillary blood collection impact on validity, as well as exploring the safety and acceptability of patient self-collection.

Ethics and DisseminationThis review will be submitted for publication in a peer-reviewed open-access journal. We will present our results at both national and international conferences. As a systematic review with no primary participant data or involvement, ethical approval is not applicable.

PROSPERO registration numberCRD42021225606

Strengths and limitations of this studyO_LITo our knowledge this is the first systematic review to explore all postal methods of capillary blood collection for the measurement of HbA1c.
C_LIO_LIThis review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, which offers transparency and enhances reproducibility.
C_LIO_LIDue to anticipated heterogeneity in statistical approaches, summary analyses, sample storage, transportation, extraction, and assay, meta-analysis is unlikely to be appropriate and therefore narrative synthesis will be used.
C_LIO_LIDue to the exclusion criteria, our findings may not be generalisable to a wider population including children, and those with haemoglobinopathies, high erythrocyte turnover or other conditions likely to affect HbA1c result.
C_LI

category: endocrinology


title: Antibody-mediated Immunogenicity against SARS-CoV-2 following priming, boosting and hybrid immunity: insights from 11 months of follow-up of a healthcare worker cohort in Israel, December 2020-October 2021

abstract:
BackgroundWe determined circulating anti-S SARS-CoV-2 IgG antibody titres in a vaccinated healthcare workers (HCWs) cohort from Northern Israel in the 11 months following primary vaccination according to age, ethnicity, boosting timing and previous infection status.

MethodsAll consenting HCWs were invited to have their circulating IgG levels measured before vaccination and at 6 subsequent timepoints. All HCWs with suspected COVID-19 were PCR tested. We described trends in circulating IgG geometric mean concentration by age, ethnicity, timing of boosting and previous infection status and compared strata using Kruskall-Wallis tests.

ResultsAmong 985 vaccinated HCWs. IgG titres gradually decreased in all groups over the study duration. Younger or previously infected individuals had higher initial IgG levels (p<0.001 in both cases); differences substantially decreased or disappeared at 7-9 months, before boosting. Pre-infection IgG levels in infected participants were similar to levels measured at the same timepoint in HCWs who remained uninfected (p>0.3). IgG GMC in those boosted 6-7 months after dose 2 was lower compared with those boosted 8-9 months after (1999-vs 2736, p=0.02).

ConclusionsImmunity waned 6 months post-priming in all age groups and in previously infected individuals, reversed by boosting. IgG titres decrease among previously infected individuals and the proportion of reinfected individuals in this group, comparable to the proportion of breakthrough infection in previously uninfected individuals suggests individuals with hybrid immunity (infection+vaccination) may also require further doses. Our study also highlights the difficulty in determining protective IgG levels and the need to clarify the optimal timing in 3 dose regimens

category: epidemiology


title: Alteration of serum leptin and LEP/LEPR promoter methylation in Prader-Willi syndrome

abstract:
Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder based on a loss of paternally expressed but maternally imprinted genes in chromosome region 15q11-13. During child development, PWS usually results in insatiable appetite with subsequent obesity representing the major mortality factor. The neurobiological basis of PWS-typical hyperphagia has remained poorly understood. Many PWS-typical abnormalities are based on hypothalamic dysregulation, the region in which hunger and satiety are hormonally regulated, with the hormone leptin being a main long-term regulator of satiety. Previous studies in PWS have inconsistently shown leptin alterations solely in early childhood, without investigating the leptin system on an epigenetic level.

The present study investigates serum leptin levels (S-leptin) and methylation of the leptin (LEP) and leptin receptor gene (LEPR) promoter in 24 individuals with PWS compared to 13 healthy controls matched for sex, age, and body mass index (BMI) and relates the results to the extent of hyperphagia in PWS.

S-Leptin levels were obtained by Enzyme-linked Immunosorbent Assay. LEP/LEPR-promoter methylation was assessed by DNA-bisulfite-sequencing, hyperphagia by Hyperphagia Questionnaire for Clinical Trials (HQ-CT). PWS and control groups differed significantly in S-leptin levels with higher S-leptin in PWS. Methylation analysis showed significant differences in mean promoter methylation rate both for LEP and LEPR with a lower methylation rate in PWS. LEPR, but not LEP methylation correlated with S-leptin levels. S-leptin and both LEP and LEPR methylation did not correlate with HQ-CT scores in PWS.

The present study is the first to show significantly elevated S-leptin levels in an adult PWS cohort combined with an altered, downregulated LEP and LEPR promoter methylation status compared to BMI-matched controls. Analogous to previous studies, no link to the behavioral dimension could be drawn. Overall, the results suggest an increased leptin dysregulation in PWS, whereby the findings partly mirror leptin resistance seen in non-syndromic obesity.

category: psychiatry and clinical psychology


title: Acute COVID-19 severity and 16-month mental morbidity trajectories in patient populations of six nations

abstract:
BACKGROUNDThe aim of this multinational study was to assess the development of adverse mental health symptoms among individuals diagnosed with COVID-19 in the general population by acute infection severity up to 16 months after diagnosis.

METHODSParticipants consisted of 247 249 individuals from seven cohorts across six countries (Denmark, Estonia, Iceland, Norway, Scotland, and Sweden) recruited from April 2020 through August 2021. We used multivariable Poisson regression to contrast symptom-prevalence of depression, anxiety, COVID-19 related distress, and poor sleep quality among individuals with and without a diagnosis of COVID-19 at entry to respective cohorts by time (0-16 months) from diagnosis. We also applied generalised estimating equations (GEE) analysis to test differences in repeated measures of mental health symptoms before and after COVID-19 diagnosis among individuals ever diagnosed with COVID-19 over time.

FINDINGSA total of 9979 individuals (4%) were diagnosed with COVID-19 during the study period and presented overall with a higher symptom burden of depression (prevalence ratio [PR] 1{middle dot}18, 95% confidence interval [95% CI] 1{middle dot}03-1{middle dot}36) and poorer sleep quality (1{middle dot}13, 1{middle dot}03-1{middle dot}24) but not with higher levels of symptoms of anxiety or COVID-19 related distress compared with individuals without a COVID-19 diagnosis. While the prevalence of depression and COVID-19 related distress attenuated with time, the trajectories varied significantly by COVID-19 acute infection severity. Individuals diagnosed with COVID-19 but never bedridden due to their illness were consistently at lower risks of depression and anxiety (PR 0{middle dot}83, 95% CI 0{middle dot}75-0{middle dot}91 and 0{middle dot}77, 0{middle dot}63-0{middle dot}94, respectively), while patients bedridden for more than 7 days were persistently at higher risks of symptoms of depression and anxiety (PR 1{middle dot}61, 95% CI 1{middle dot}27-2{middle dot}05 and 1{middle dot}43, 1{middle dot}26-1{middle dot}63, respectively) throughout the 16-month study period.

CONCLUSIONAcute infection severity is a key determinant of long-term mental morbidity among COVID-19 patients.


title: COVID-19 vaccination and Guillain-Barre syndrome: analyses using the National Immunoglobulin Database

abstract:
Vaccination against viruses has rarely been associated with Guillain-Barre syndrome (GBS). An association with the COVID-19 vaccine is unknown. We performed a population-based study of National Health Service data in England and a multicentre surveillance study from UK hospitals, to investigate the relationship between COVID-19 vaccination and GBS.

Firstly, case dates of GBS identified retrospectively in the National Immunoglobulin Database from 8 December 2021 to 8 July 2021 were linked to receipt dates of a COVID-19 vaccines using data from the National Immunisation Management System in England. For the linked dataset, GBS cases temporally associated with vaccination within a 6-week risk window of any COVID-19 vaccine were identified. Secondly, we prospectively collected incident UK-wide (four nations) GBS cases from 1 January 2021 to 7 November 2021 in a separate UK multicentre surveillance database. For this multicentre UK-wide surveillance dataset, we explored phenotypes of reported GBS cases to identify features of COVID-19 vaccine-associated GBS.

996 GBS cases were recorded in the National Immunoglobulin Database from January to October 2021. A spike of GBS cases above the 2016-2020 average occurred in March-April 2021. 198 GBS cases occurred within 6 weeks of the first-dose COVID-19 vaccination in England (0.618 cases per 100,000 vaccinations, 176 ChAdOx1 nCoV-19 (AstraZeneca), 21 tozinameran (Pfizer), 1 mRNA-1273 (Moderna)). The 6-week excess of GBS (compared to the baseline rate of GBS cases 6-12 weeks after vaccination) occurs with a peak at 24 days post-vaccination; first-doses of ChAdOx1 nCoV-19 accounted for the excess. No excess was seen for second-dose vaccination. The absolute number of excess GBS cases from January-July 2021 was between 98-140 cases for first-dose ChAdOx1 nCoV-19 vaccination. First-dose tozinameran and second-dose of any vaccination showed no excess GBS risk. Detailed clinical data from 121 GBS patients were reported in the separate multicentre surveillance dataset during this timeframe. No phenotypic or demographic differences identified between vaccine-associated and non-vaccinated GBS cases occurring in the same timeframe.

Analysis of the linked NID/NIMS dataset suggests that first-dose ChAdOx1 nCoV-19 vaccination is associated with an excess GBS risk of 0.576 (95%CI 0.481-0.691) cases per 100,000 doses. However, examination of a multicentre surveillance dataset suggests that no specific clinical features, including facial weakness, are associated with vaccination-related GBS compared to non-vaccinated cases. The pathogenic cause of the ChAdOx1 nCoV-19 specific first dose link warrants further study.

category: neurology


title: A prospective validation of nomograms based on BC-116 and BC-106 urine peptide biomarker panels for bladder cancer diagnostics and monitoring

abstract:
PurposeNon-invasive urine-based biomarkers for bladder cancer (BC) diagnosis and surveillance can potentially improve current diagnostic and monitoring protocols by guiding cystoscopy. Here, we aim to access the diagnostic performance of nomograms based on published biomarker panels for BC detection (BC-116) and monitoring of recurrence (BC-106) in combination with cytology, in two prospectively collected patient cohorts.

Experimental Design602 recruited patients were screened for presence of BC, out of which 551 were found eligible for further analysis. For the primary setting, urine samples from 73 eligible patients were analyzed from those diagnosed with primary BC (n=27) and benign urological disorders (n=46). For the surveillance setting, 478 eligible patients were considered (83 BC recurrences; 395 negative for recurrence). Urine samples were analyzed with capillary electrophoresis coupled to mass spectrometry and the biomarker score was estimated via a support vector machine-based software.

ResultsValidation of the BC-116 biomarker panel resulted in 89% sensitivity and 67% specificity (AUCBC-116=0.82), similar to the published estimates. The nomogram based on cytology and BC-116 resulted in good (AUCNom116=0.85) but not significantly better performance than the BC-116 alone (P=0.5672). BC-106 biomarker panel showed 89% sensitivity and 32% specificity for surveillance, while improved performance was achieved when a nomogram including BC-106 and cytology was evaluated (AUCNom106=0.82), significantly outperforming both cytology (AUCcyt=0.72;P=0.0022) and BC-106 alone (AUCBC-106=0.67;P=0.0012).

ConclusionsBC-116 biomarker panel is a useful test for detecting primary BC. BC-106 classifier integrated with cytology and showing >95% negative predictive value, might be useful for decreasing the number of cystoscopies during surveillance.


title: COVID-19 vaccine hesitancy in diverse groups in the UK - is the driver economic or cultural in student populations?

abstract: Studies have identified a greater reluctance for members of the Black, Asian, and minority ethnic communities to be vaccinated against COVID-19 despite a higher probability of greater harm from COVID-19. We conducted an anonymised questionnaire-based study of students (recruiting primarily before first reports of embolic events) at two London universities to identify whether economic or educational levels were primarily responsible for this reluctance: a postgraduate core group (PGCC) n=860 and a pilot study of undergraduate medical and nursing students (n=103). Asian and Black students were 2.0 and 3.2 times (PGCC) less likely to accept the COVID vaccine than White British students. Similar findings were noted in the pilot study students. As students were studying for Masters or PhD degrees and voluntarily paying high fees, educational and economic reasons were unlikely to be the underlying cause, and wider cultural reservations were more likely. Politicians exerted a strong negative influence, suggesting that campaigns should omit politicians.

category: health policy


title: Emerging from the COVID-19 pandemic: impacts of variants, vaccines, and duration of immunity

abstract: The advent of vaccines against SARS-CoV-2 and the roll out of mass vaccination programs are thought to present the most effective means to control and even end the ongoing pandemic. However, uncertainties connected with the partial effectiveness of present vaccines, duration of immunity against SARS-CoV-2, and potential impact of variant dynamics, mean that it is still possible that the contagion could follow different future paths in different communities. Here, we use an extended SEIR for SARS-COV-2 transmission sequentially calibrated to data on cases and interventions implemented in the state of Florida to explore how these factors may interact to govern potential pandemic futures. Our data-driven forecasts indicate while the introduction of vaccinations could lead to the permanent, albeit drawn-out, ending of the pandemic if the immunity generated through vaccinations and natural infections acts over the long-term, additional futures could become possible if this immunity wanes over time. These futures will be marked by repeated waves of infection, the amplitude and periodicity of which will depend on the duration over which the immunity generated in a population will operate. We conclude that the possibility of these complex futures will require continual vigilance and perhaps fundamental changes in societal responses if we are to effectively control SARS-CoV-2.


title: Multiplexed CRISPR-based microfluidic platform for clinical testing of respiratory viruses and SARS-CoV-2 variants

abstract: The COVID-19 pandemic has demonstrated a clear need for high-throughput, multiplexed, and sensitive assays for detecting SARS-CoV-2 and other respiratory viruses as well as their emerging variants. Here, we present microfluidic CARMEN (mCARMEN), a cost-effective virus and variant detection platform that combines CRISPR-based diagnostics and microfluidics with a streamlined workflow for clinical use. We developed the mCARMEN respiratory virus panel (RVP) and demonstrated its diagnostic-grade performance on 533 patient specimens in an academic setting and then 166 specimens in a clinical setting. We further developed a panel to distinguish 6 SARS-CoV-2 variant lineages, including Delta and Omicron, and evaluated it on 106 patient specimens, with near-perfect concordance to sequencing-based variant classification. Lastly, we implemented a combined Cas13 and Cas12 approach that enables quantitative measurement of viral copies in samples. mCARMEN enables high-throughput surveillance of multiple viruses and variants simultaneously.


title: Hepatitis C subtyping assay failure in UK patients born in Sub-Saharan Africa: implications for global treatment and elimination

abstract:
The newly developed direct-acting antivirals (DAAs) have revolutionised the treatment of chronic hepatitis C virus (HCV), where cohort studies have shown that cure rates as high as 98% can be achieved. Whilst genome sequencing has demonstrated that some subtypes of HCV naturally harbour drug resistance associated substitutions (RAS), these have not been considered important as previous molecular epidemiological studies have suggested that such difficult-to-treat subtypes are rare. Therefore, to optimise and streamline molecular detection and sequence-based typing of diverse RAS-containing subtypes, a novel panel of single round PCR assays was applied to HCV derived from 146 individuals, whose likely source of infection was from regions of sub-Saharan Africa (SSA). Partial NS5A and NS5B sequences were obtained from 135 HCV-positive patients born in 19 different countries from SSA but attending clinics in the UK.

Virus subtype assignments were determined by pairwise-distance analysis and compared to both diagnostic laboratory assignments and free-to-use online typing tools. We determined that routine clinical diagnostic methods incorrectly subtyped 59.0% of samples, with a further 6.8% incorrectly genotyped. Of five commonly used online tools, Geno2Pheno performed most effectively in determining a subtype in agreement with pairwise distance analysis. Considering the estimated number of HCV infections to have occurred in across Africa, this study provides a simple low-cost pathway to guide regional therapeutic choice and assist global eradication programmes.


title: Dynamics of anti-Spike IgG antibody level after full BNT162b2 COVID-19 vaccination in health care workers

abstract:
IntroductionThe administration of a third vaccine is ongoing in many countries, but the evaluation of vaccine-induced immunity is still insufficient. This study evaluated anti-spike IgG levels in 373 health care workers six months after the BNT162b2 vaccination.

MethodsDynamics of anti-spike IgG levels six months after the 2nd vaccination were assessed in 49 participants (Analysis-1). A cross-sectional assessment of anti-spike IgG level was performed in 373 participants (Analysis-2). Participants positive for anti-nucleocapsid IgG or IgM and receiving immunosuppressants were excluded from Analysis-2.

ResultsIn Analysis 1, the median anti-spike IgG level was lower in the older age group and decreased consistently after the second vaccination regardless of age. In Analysis-2, the anti-spike IgG level was significantly negatively associated with age (r = -0.35, p < 0.01). This correlation remained statistically significant (r = -0.28, p < 0.01) even after adjusting for sex, BMI, smoking habits, alcohol drinking habits, allergies, and the presence of fever or other adverse reactions at the time of the vaccination. Alcohol drinking habit was also associated with the anti-spike IgG level; daily alcohol drinkers had significantly lower anti-spike IgG levels than never alcohol drinkers. Sex, smoking habit, allergy, and fever and other side effects after the vaccination were not associated with anti-spike IgG levels six months after the 2nd vaccination.

ConclusionsSix months after the vaccination, the anti-spike IgG level was substantially low among older persons and daily alcohol drinkers.


title: COVID-19 vaccination, from first dose to booster: New insights into the frequency of most common systemic adverse events and possible booster nocebo effects based on a systematic review

abstract:
BackgroundBased on placebo data, it has been recently demonstrated that the frequencies of most common adverse events (AEs) of COVID-19 vaccination are overestimated due to negative expectation bias of vaccine recipients (nocebo effect). Since booster studies lack comparators, estimating the extent of the nocebo effect is difficult. We aimed to overcome this obstacle through a systematic comparison of most common AE frequencies across vaccine doses (first, second, booster), age groups, and vaccine vs. placebo arms.

MethodsWe systematically assessed systemic AEs in approved COVID-19 vaccines according to the PRISMA guidelines. All documents regarding COVID-19 vaccines with a booster dose authorized by the FDA (cutoff date 19 November 2021) were systematically searched on PubMed and the FDA website. Solicited systemic AEs from all documents supporting approval/authorization were collected. After standardization of doses and age groups, AE frequencies were compared between vaccine and placebo.

FindingsTwo trials were identified for BNT162b2 (n=21,785 participants), two for mRNA-1273 (n=22,324), and one for Ad26.COV2.S (n=4,085). Fever cases dropped to about half with the booster dose in all vaccines, whereas all other systemic AE frequencies were similar to the preceding dose. Almost no fever cases occurred with placebo (first/second dose); all other systemic AEs occurred at high frequencies. After subtracting placebo arm values from vaccine values, the frequencies for the various AEs were roughly comparable within each dose for each vaccine.

InterpretationFever is the only solicited systemic AE that can be assessed objectively. It occurs about 50% less often with the booster than with the preceding dose. This may indirectly indicate a considerable overestimation of systemic AEs in the case of booster vaccinations and a pronounced nocebo effect. The nocebo effect appears to substantially contribute to the differences in the frequencies of the various systemic AEs.

FundingNo funding received.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSA high nocebo effect has recently been shown for the most common solicited adverse events (AEs) based on the randomized controlled trials of several vaccines approved for COVID-19. To date, there has been no systematic review of systemic AEs in COVID-19 vaccines with a booster dose approved by the FDA. Normally, assessing the extent of the nocebo effect requires the implementation of randomized, placebo-controlled studies. However, for ethical reasons, studies underlying the authorization of COVID-19 booster vaccines are not controlled. Therefore, reported AEs lack any reference parameter.

We searched PubMed and medRxiv for nocebo effects regarding the objectively measurable AE fever using the terms "(COVID) AND (nocebo) AND (fever)" with no language restrictions; no hits were found on PubMed and six were found on medRxiv. The search without any indication, using only the search terms "(nocebo) AND (fever)", resulted in two hits on PubMed and six hits on medRxiv. An additional search was performed for "(vaccine or COVID) AND nocebo"; 21 hits were found on PubMed and 12 on medRxiv. None of the hits obtained with the three searches showed evidence of relevance for the present topic of a direct association of fever with the nocebo effect.

Added value of this studyInstead of placebo AE data as reference parameter, we suggest fever as an objectively measurable value to estimate the extent of the nocebo effect in uncontrolled vaccination studies. To our knowledge, this is a new concept with which evidence for the extent of a possible nocebo effect in COVID-19 booster vaccination can be provided. With this approach we directly supplement information on the most recently reported nocebo effects in first, second and booster vaccine doses.

To the best of our knowledge, this is the first study to indirectly compare the solicited systemic AE frequencies of approved COVID-19 vaccines across all doses, with easy-to-understand graphs and based on all approval-relevant trials. This is astonishing, as in the context of a pandemic it is essential to communicate scientific data in a generally understandable manner and according to the highest scientific standards. The graphs provided in this work could serve as an example for such clear communication.

Implications of all the available evidenceUsing the example of systemic AEs, we were able to show that the frequency of AEs in COVID-19 booster vaccination may be overestimated. Fever as an objective measure to estimate the nocebo effect could help to optimize public awareness campaigns in the future. The graphic presentation of results facilitates a deeper understanding of complex scientific data and provides new insights. It is therefore ideal for a highly dynamic scientific field and may also be applied to other challenges in the COVID-19 pandemic and beyond.


title: Impact Of an Immune Modulator Mycobacterium-w On Adaptive Natural Killer Cells and Protection Against COVID-19

abstract: The kinetics of NKG2C+ adaptive natural killer (ANK) cells and NKG2A+inhibitory NK (iNK) cells with respect to the incidence of SARS-CoV-2 infection were studied for 6 months in a cohort of health-care workers following administration of heat killed Mycobacterium w (Mw group) in comparison to a control group. In both groups, COVID-19 correlated with a lower NKG2C+ANK cells at baseline. There was a significant upregulation of NKG2C expression and IFN-{gamma} release in Mw group (p=0.0009), particularly in those with lower baseline NKG2C expression, along with downregulation of iNK cells (p<0.0001). This translated to a significant reduction in incidence and severity of COVID-19 in the Mw group (IRR-0.15, p=0.0004). RNA-seq analysis at 6 months showed an upregulation of ANK pathway genes and an enhanced ANK mediated ADCC signature. Thus, Mw was observed to have a salutary impact on the ANK cell profile and a long-term upregulation of ANK-ADCC pathways, which could have provided protection against COVID-19 in a non-immune high-risk population.


title: COVID-19 and Indian population: a comparative genetic analysis

abstract:
BackgroundMajor risk factors of COVID-19 include older age, male gender, and comorbidities. In addition, host genetic makeup is also known to play a major role in COVID-19 susceptibility and severity. To assess the genetic predisposition of the Indian population to COVID-19, a comparative analysis of the frequencies of polymorphisms directly or potentially associated with COVID-19 susceptibility, severity, immune response, and fatal outcomes was done between the Indian population and other major populations (European, African, East Asian, South Asian, and American).

Materials and methodsPolymorphisms directly or potentially associated with COVID-19 susceptibility, severity, immune response, and mortality were mined from genetic association studies, comparative genetic studies, expression quantitative trait loci studies among others. Genotype data of these polymorphisms were either sourced from the GenomegaDB database of Mapmygenome India Ltd. (sample size = 3054; Indian origin) or were imputed. Polymorphisms with minor allele frequency >= 0.05 and that are in Hardy-Weinberg equilibrium in the Indian population were considered for allele frequency comparison between the Indian population and 1000 Genome population groups.

ResultsAllele frequencies of 421 polymorphisms were found to be significantly different in the Indian population compared to European, African, East Asian, South Asian, and American populations. 128 polymorphisms were shortlisted based on linkage disequilibrium and were analyzed in detail. Apart from well-studied genes, like ACE2, TMPRSS2, ADAM17, and FURIN, variants from AHSG, IFITM3, PTPN2, CD209, CCL5, HEATR9, SELENBP9, AGO1, HLA-G, MX1, ICAM3, MUC5B, CRP, C1GALT1, and other genes were also found to be significantly different in Indian population. These variants might be implicated in COVID-19 susceptibility and progression.

ConclusionOur comparative study unraveled multiple genetic variants whose allele frequencies were significantly different in the Indian population and might have a potential role in COVID-19 susceptibility, its severity, and fatal outcomes. This study can be very useful for selecting candidate genes/variants for future COVID-19 related genetic association studies.


title: Anti-SARS-CoV-2 cellular immunity in 571 vaccinees assessed using an interferon-γ release assay

abstract: Generation of antigen-specific memory T cells has been analyzed only for few coronavirus disease 2019 (COVID-19) vaccinees, whereas antibody titers have been serologically measured for a large number of individuals. Here, we assessed the anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular immune response in a large cohort using interferon (IFN)-{gamma} release assays (IGRAs) based on short-term whole blood culture. The study included 571 individuals who received the viral spike (S) protein-expressing BNT162b2 mRNA SARS-CoV-2 vaccine. Serum IgG titers against the receptor-binding domain (RBD) of S protein were measured. Samples of 28 vaccinees were subjected to flow cytometry analysis of T cells derived from short-term whole blood culture. IFN-{gamma} production triggered by S antigens was observed in most individuals 8 weeks after receiving the second dose of the vaccine, indicating acquisition of T cell memory responses. The frequencies of activated T cell subsets were strongly correlated with IFN-{gamma} levels, supporting the usability of our approach. S antigen-stimulated IFN-{gamma} levels were weakly correlated with anti-RBD IgG titers and associated with pre-vaccination infection and adverse reactions after the second dose. Our approach revealed cellular immunity acquired after COVID-19 vaccination, providing insights regarding the effects and adverse reactions of vaccination.


title: Differential Risk of SARS-CoV-2 Infection by Occupation: Evidence from the Virus Watch prospective cohort study in England and Wales

abstract:
BackgroundWorkers differ in their risk of SARS-CoV-2 infection according to their occupation, but the direct contribution of occupation to this relationship is unclear. This study aimed to investigate how infection risk differed across occupational groups in England and Wales up to October 2021, after adjustment for potential confounding and stratification by pandemic phase.

MethodsData from 12,182 employed/self-employed participants in the Virus Watch prospective cohort study were used to generate risk ratios for virologically- or serologically-confirmed SARS-CoV-2 infection using robust Poisson regression, adjusting for socio-demographic and health-related factors and non-work public activities. We calculated attributable fractions (AF) amongst the exposed for each occupational group based on adjusted risk ratios (aRR).

FindingsIncreased risk was seen in nurses (aRR=1.90 [1.40-2.40], AF=47%); doctors (1.74 [1.26-2.40], 42%); carers (2.18 [1.63-2.92], 54%); teachers (primary = 1.94 [1.44-2.61], 48%; secondary =1.64, [1.23-2.17], 39%), and warehouse and process/plant workers (1.58 [1.20-2.09], 37%) compared to both office-based professional occupations (reported above) and all other occupations. Differential risk was apparent in the earlier phases (Feb 2020 - May 2021) and attenuated later (June - October 2021) for most groups, although teachers demonstrated persistently elevated risk.

InterpretationOccupational differentials in SARS-CoV-2 infection risk are robust to adjustment for socio-demographic, health-related, and activity-related potential confounders. Patterns of differential infection risk varied over time, and ongoing excess risk was observed in education professionals. Direct investigation into workplace factors underlying elevated risk and how these change over time is needed to inform occupational health interventions.


title: Final sizes and durations of new COVID-19 pandemic waves in Poland and Germany predicted by generalized SIR model

abstract: New waves of the COVID-19 pandemic in Europe, which began in the autumn of 2021, are a matter of great concern and the need to immediately predict the epidemic dynamics in order to assess the possible maximum values of new cases, the risk of infection and the number of deaths. The generalized SIR-model and corresponding parameter identification procedure was used to simulate and predict the dynamics of new epidemic waves in Poland and Germany. Results of calculations show that new cases in these countries will not stop to appear in 2022.


title: Global epidemiology of SARS-CoV-2 infection: a systematic review and meta-analysis of standardized population-based seroprevalence studies, Jan 2020-Oct 2021

abstract:
BackgroundOur understanding of the global scale of SARS-CoV-2 infection remains incomplete: routine surveillance data underestimates infection, cannot infer on population immunity, there is a predominance of asymptomatic infections, and uneven access to diagnostics. We meta-analyzed standardized SARS-CoV-2 seroprevalence studies after two years in the pandemic to estimate the extent of population infection and remaining susceptibility.

Objectives/MethodsWe conducted a systematic review and meta-analysis, searching MEDLINE, Embase, Web of Science, preprints, and grey literature for SARS-CoV-2 seroprevalence published between 2020-01-01 and 2021-12-30. Eligible studies - those aligned with the WHO UNITY protocol - were extracted and critically appraised in duplicate. We meta-analyzed seroprevalence by country and month, pooling to estimate regional and global seroprevalence over time; compared seroprevalence from infection to confirmed cases to estimate under-ascertainment; meta-analyzed differences in seroprevalence between demographic subgroups; and identified national factors associated with seroprevalence using meta-regression. PROSPERO: CRD42020183634.

ResultsWe identified 431 full texts reporting 803 distinct seroprevalence studies (43% LMIC), including 398 low/moderate risk of bias studies with national/sub-national scope in further analysis. By July 2021, global SARS-CoV-2 seroprevalence was 45.2%, 95% CI [40.7-49.8%]. Seroprevalence rose steeply in the first half of 2021 due to infection in some regions (e.g., 29.9% to 70.1% in Africa) and vaccination and infection in others (e.g., 5.6% to 94.9% in the Americas high-income countries), but remained low in others (e.g., 2.5% in the Western Pacific). In 2021 Q2, median seroprevalence to cumulative incidence ratios were 2.9:1 in HICs and 45.3:1 in LMICs. Children 0-9 years and adults 60+ were at lower risk of seropositivity than adults 20-29. In a multivariate model using pre-vaccination data, stringent public health and social measures were associated with lower seroprevalence.

ConclusionsGlobal seroprevalence has risen considerably over time and with regional variation, however much of the global population remains susceptible to SARS-CoV-2 infection. Our estimates of infections based on seroprevalence far exceed reported COVID-19 cases. Quality and standardized seroprevalence studies are essential to inform COVID-19 response, particularly in resource-limited regions.


title: Global epidemiology of SARS-CoV-2 infection: a systematic review and meta-analysis of standardized population-based seroprevalence studies, Jan 2020-Dec 2021


title: Protocol for a cluster randomised trial to evaluate a community level complementary food safety and hygiene and nutrition intervention in Mali: The MaaCiwara study

abstract:
BackgroundDiarrheal disease remains a significant cause of morbidity and mortality among the under-fives in many low- and middle-income countries. Changes to food safety practices and feeding methods around the weaning period, alongside improved nutrition, may significantly reduce the risk of disease and improve development for infants. This article describes a protocol for a cluster randomized trial to evaluate the effectiveness of a multi-faceted community-based educational intervention that aims to improve food safety and hygiene behaviours and enhance child nutrition.

MethodsWe will conduct a mixed-methods, parallel cluster randomised controlled trial with baseline measures. 120 clusters comprising small urban and rural communities will be recruited in equal numbers and randomly allocated in a 1:1 ratio to either treatment or control arms. Participants will be mother-child dyads (27 per cluster period) with children aged 6 to 24 months. Data collection will comprise a day of observation and interviews with each participating mother-child pair and will take place at baseline and four and 15 months post-intervention. The primary analysis will estimate the effectiveness of the intervention on changes to complementary food safety and preparation behaviours, food and water contamination, and diarrhoea. Secondary outcomes include maternal autonomy, enteric infection, nutritional content of meals, and child anthropometry. A secondary structural equation analysis will be conducted to examine the causal relationships between the different outcomes.

ConclusionsThe trial will provide evidence on the effectiveness of community-based behavioural change and educational interventions designed to reduce the burden of diarrhoeal disease in the under fives, and how effectiveness varies across different contexts.

category: gastroenterology


title: Listening to older voices: results of a cross-sectional survey of older patient-reported experiences of facility-based healthcare in Nouna, Burkina Faso

abstract:
BackgroundEnsuring responsive healthcare which meets patient expectations and generates trust is important to increase rates of access and retention. This need is important for aging populations where non-communicable diseases (NCDs) are a growing cause of morbidity and mortality.

MethodsWe performed a cross-sectional household survey including socio-demographic, morbidities, and health system utilization, responsiveness, and quality outcomes in individuals over age 40 in northwestern Burkina Faso. We describe results and use exploratory factor analysis to derive a contextually appropriate grouping of health system responsiveness (HSR) variables. We used linear or logistic regression to explore associations between socio-demographics, morbidities, and the grouped-variable, then between these variables and health system quality outcomes.

ResultsOf 2,639 eligible respondents, 26.8% had least one NCD, 56.3% were frail or pre-frail and 23.9% had a recent visit, including only 1/3 of those with an NCD. Highest ratings of care experience (excellent/very good) included ease of following instructions (86.1%) and trust in provider skills (81.1%). The HSR grouping with the greatest factor loading included involvement in decision-making, clarity in communication, trust in the provider, and confidence in provider skills, termed as Shared Understanding and Decision Making (SUDM). In multivariable analysis, higher quality of life (OR 1.02,95%CI 1.01-1.04), frailty (OR 1.47,95%CI 1.00-2.16), and SUDM (OR 1.06,95%CI 1.05-1.09) were associated with greater health system trust and confidence. SUDM was associated with overall positive assessment of the healthcare system (OR 1.02,95%CI 1.01-1.03) and met healthcare needs (OR 1.09,95%CI 1.08-1.11). Younger age and highest wealth quintile were also associated with higher met needs.

ConclusionsRecent healthcare access was low for people with existing NCDs, and SUDM was the most consistent factor associated with higher health system quality outcomes. Results highlight the need to increase continuity of care for aging populations with NCDs and explore strengthening SUDM to achieve this goal.

What is already known?O_LIHealth system responsiveness and health system quality outcomes including meeting health needs and trust in the system are important to ensure patient centered care and increase access and retention.
C_LIO_LIThe process and outcomes of care experience of older adults in Burkina Faso and factors associated with ratings has not been widely studied, information needed to inform efforts to improve engagement in care particularly for individuals with non-communicable chronic diseases (NCDs)
C_LIO_LIShared decision making is emerging as an important component of care to improve engagement in care for people with chronic diseases with studies largely from high income countries
C_LI

What are the new findings?O_LIWe describe the patterns and gaps in care seeking of people age 40 or older in Burkina Faso, particularly those with non-communicable chronic diseases.
C_LIO_LIHighest ratings of care experience included ease of following instructions and trust in provider skills, with lowest ratings in clarity of communication and involvement in decision making.
C_LIO_LIWe identified a grouped variable was identified using exploratory factors analysis, shared understanding and decision making (SUDM), which was associated with overall positive assessment of the healthcare system and met healthcare needs.
C_LI

What do the new findings imply?O_LIWork is needed to increase longitudinal engagement in care for older adults, particularly those with NCDs,
C_LIO_LISUDM may offer an area for strengthening patient-centeredness of care to achieve these goals, but further research is needed to understand the relationships between SUDM and care outcomes, and the impact of strengthening in Burkina Faso.
C_LI

category: primary care research


title: Real-world data on immune responses following heterologous prime-boost COVID-19 vaccination schedule with Pfizer and AstraZeneca vaccines in England

abstract:
BackgroundThere are limited data on immune responses to heterologous COVID-19 immunisation schedules, especially following an extended [≥]12-week interval between doses.

MethodsSARS-CoV-2 infection-naive and previously-infected adults receiving ChAd-BNT (ChAdOx1 nCoV-19, AstraZeneca followed by BNT162b2, Pfizer-BioNTech) or BNT-ChAd as part of the UK national immunisation programme provided blood samples at 30 days and 12 weeks after their second dose. Geometric mean concentrations (GMC) of anti-SARS-CoV-2 spike (S-antibody) and nucleoprotein (N-antibody) IgG antibodies and geometric mean ratios (GMR) were compared with a contemporaneous cohort receiving homologous ChAd-ChAd or BNT-BNT.

ResultsDuring March-October 2021, 75,827 individuals were identified as having received heterologous vaccination, 9,489 invited to participate, 1,836 responded (19.3%) and 656 were eligible. In previously-uninfected adults, S-antibody GMC at 30 days post-second dose were lowest for ChAd-ChAd (862 [95%CI, 694 - 1069]) and significantly higher for ChAd-BNT (6233 [5522-7035]; GMR 6.29; [5.04-7.85]; p<0.001), BNT-ChAd (4776 [4066-5610]; GMR 4.55 [3.56-5.81]; p<0.001) and BNT-BNT (5377 [4596-6289]; GMR 5.66 [4.49-7.15]; p<0.001). By 12 weeks after dose two, S-antibody GMC had declined in all groups and remained significantly lower for ChAd-ChAd compared to ChAd-BNT (GMR 5.12 [3.79-6.92]; p<0.001), BNT-ChAd (GMR 4.1 [2.96-5.69]; p<0.001) and BNT-BNT (GMR 6.06 [4.32-8.50]; p<0.001). Previously infected adults had higher S-antibody GMC compared to infection-naive adults at all time-points and with all vaccine schedules.

ConclusionsThese real-world findings demonstrate heterologous schedules with adenoviral-vector and mRNA vaccines are highly immunogenic and may be recommended after a serious adverse reaction to one vaccine product, or to increase programmatic flexibility where vaccine supplies are constrained.

O_TEXTBOXWhat is already known?PubMed was searched with the terms "COVID-19 Vaccine" and "heterologous" to identify publications relating to heterologous immunisation schedules with adenoviral-vector and mRNA vaccines from 01 January 2020 until 30 November 2021. Following early reports of vaccine-induced thrombocytosis and thrombocytopenia (VITT) after the first dose of ChAd (ChAdOx1 nCoV-19), several studies reported significantly higher antibody levels, with robust neutralizing activity and cellular immune responses, in adults receiving a heterologous ChAd-mRNA schedule compared to those receiving ChAd-ChAd. Few studies, however, have compared antibody responses after both heterologous schedules (ChAd-mRNA and mRNA-ChAd) with both homologous schedules (ChAd-ChAd and mRNA-mRNA). One UK study (COMCOV) compared all four ChAd and BNT162b2 Pfizer-BioNTech (BNT; mRNA) combinations given four weeks apart and reported very high antibody and T-cell responses four weeks after the second dose for all four schedules.

What are the new findings?We used the national immunisation register to identify adults who received a heterologous vaccine schedule as part of the national immunisation programme in England and collected blood samples to measure SARS-CoV-2 antibody responses after vaccination. We found that both heterologous schedules (ChAd-BNT and BNT-ChAd) provided superior antibody responses compared to ChAd-ChAd and similar responses to BNT-BNT at 30 days and 12 weeks after second vaccine dose. ChAd-BNT induced higher antibody levels then BNT-ChAd at both timepoints. Antibody responses after vaccination were much higher in previously infected individuals, irrespective of their immunisation schedule. A recent Swedish population-based study reported higher vaccine effectiveness against symptomatic disease with ChAd-BNT than ChAd-ChAd providing real-world confirmation of improved protection with heterologous schedules.

What do the new findings imply?Our findings add to the growing body of evidence showing high antibody responses following heterologous vaccination schedules with ChAd and BNT, along with robust antibody neutralising activity and cellular responses, especially when compared to ChAd-ChAd. Given that globally COVID-19 vaccine demand far exceeds vaccine supply, these results have important implications for the future deployment of COVID-19 vaccine programmes; particularly where it is logistically and/or operationally difficult to administer two doses of the same vaccine product.

C_TEXTBOX


title: Multimodal Classification of Mild Traumatic Brain Injury Reveals Local Coupling Between Structural and Functional Connectomes

abstract:
BackgroundFollowing mild traumatic brain injury (mTBI) compromised white matter structural integrity can result in alterations in functional connectivity of large-scale brain networks and may manifest in functional deficit including cognitive dysfunction. Advanced magnetic resonance neuroimaging techniques, specifically diffusion tensor imaging (DTI) and resting state functional magnetic resonance imaging (rs-fMRI), have demonstrated an increased sensitivity for detecting microstructural changes associated with mTBI. Identification of novel imaging biomarkers can facilitate early detection of these changes for effective treatment. In this study, we hypothesize that feature selection combining both structural and functional connectivity increases classification accuracy.

Methods16 subjects with mTBI and 20 healthy controls underwent both DTI and resting state functional imaging. Structural connectivity matrices were generated from white matter tractography from DTI sequences. Functional connectivity was measured through pairwise correlations of rs-fMRI between brain regions. Features from both DTI and rs-fMRI were selected by identifying five brain regions with the largest group differences and were used to classify the generated functional and structural connectivity matrices, respectively. Classification was performed using linear support vector machines and validated with leave-one-out cross validation.

ResultsGroup comparisons revealed increased functional connectivity in the temporal lobe and cerebellum as well as decreased structural connectivity in the temporal lobe. After training on structural connections only, a maximum classification accuracy of 78% was achieved when structural connections were selected based on their corresponding functional connectivity group differences. After training on functional connections only, a maximum classification accuracy of 69% was achieved when functional connections were selected based on their structural connectivity group differences. After training on both structural and functional connections, a maximum classification accuracy of 69% was achieved when connections were selected based on their structural connectivity.

ConclusionsOur multimodal approach to ROI selection achieves at highest, a classification accuracy of 78%. Our results also implicate the temporal lobe in the pathophysiology of mTBI. Our findings suggest that white matter tractography can serve as a robust biomarker for mTBI when used in tandem with resting state functional connectivity.

category: radiology and imaging


title: Urinary sodium excretion is not associated with the incidence of end-stage kidney disease and kidney-related death: results from the UK Biobank

abstract:
BackgroundSodium reduction lowers blood pressure and albuminuria, indicating a hypothesized but yet-to-be proven association between sodium intake and kidney-related endpoints.

ObjectivesWe aimed to investigate the associations of 24-h urinary sodium excretion, reflecting daily sodium intake, with kidney-related outcomes.

MethodsProspective cohort of 444,086 middle- to early late-aged participants from the UK Biobank. The primary outcome was a composite of incident end-stage kidney disease (ESKD) and death due to a kidney-related cause, each of which was separately examined as a secondary outcome. Death due to a non-kidney related cause prior to ESKD was considered a competing event.

ResultsThe mean 24-h urinary sodium excretion estimated from spot urinary biomarkers was 3.3 g. During a median follow-up of 11.8 years, 1,256 composite events occurred. Multivariable-adjusted cause-specific hazards models showed that, with every 1-g increment in 24-h urinary sodium excretion, hazard ratios (95% confidence intervals) were 1.03 (0.91-1.16), 1.08 (0.88-1.32), and 1.01 (0.88-1.16) for the composite outcome, incident ESKD, and kidney-related death, respectively. Similar null results were observed when the exposure was treated as binary (<2 g/d vs. [≥]2 g/d) or multicategorical (quartiles). Nonlinear associations were not detected with restricted cubic splines. The findings also held constant in prespecified sensitivity and subgroup analyses.

ConclusionsEstimated 24-h urinary sodium excretion was not linearly or nonlinearly associated with the incidence of ESKD or death due to kidney-related causes. Our findings did not support the hypothesized notion that sodium intake should be reduced to prevent kidney-related endpoints at the population level.

category: nephrology


title: The association between midwifery staffing levels and the experiences of mothers on postnatal wards: cross sectional analysis of routine data

abstract:
BackgroundWomen have consistently reported lower satisfaction with postnatal care compared with antenatal and labour care. The aim of this research was to examine whether womens experience of inpatient postnatal care in England is associated with variation in midwifery staffing levels.

MethodsAnalysis of data from the National Maternity Survey in 2018 including 17,611 women from 129 organisations. This was linked to hospital midwifery staffing numbers from the National Health Service (NHS) Workforce Statistics and the number of births from Hospital Episode Statistics. A two-level logistic regression model was created to examine the association of midwifery staffing levels and experiences in post-natal care.

ResultsThe median full time equivalent midwives per 100 births was 3.55 (interquartile range 3.26 to 3.78). Higher staffing levels were associated with less likelihood of women reporting delay in discharge (adjusted odds ratio [aOR] 0.849, 95% CI 0.753 to 0.959, p=0.008), increased chances of women reporting that staff always helped in a reasonable time aOR1.200 (95% CI 1.052, 1.369, p=0.007) and that they always had the information or explanations they needed aOR 1.150 (95% CI 1.040, 1.271, p=0.006). Women were more likely to report being treated with kindness and understanding with higher staffing, but the difference was small and not statistically significant aOR 1.059 (0.949, 1.181, p=0.306).

ConclusionsNegative experiences for women on postnatal wards were more likely to occur in trusts with fewer midwives. Low staffing could be contributing to discharge delays and lack of support and information, which may in turn have implications for longer term outcomes for maternal and infant wellbeing.

ExplanationWhile we recognise that not all gestational parents identify as women; this term was chosen as it has been used in the data source which was accessed for this study and represents most people having maternities.

Statement of significance (problem)Women report negative experiences of postnatal care compared with antenatal care and birth. There is a recognised shortage of midwives in maternity services, and this may be impacting on the quality of postnatal care.

What is already known?There is evidence that midwifery staffing levels are associated with birth outcomes but little empirical evidence on the impact of midwifery staffing levels in postnatal care

What this paper adds?This analysis of survey data supports previous findings that increased midwifery staffing is associated with benefits. This is the first study to examine the effects of staffing on womens experience of postnatal care.

category: obstetrics and gynecology


title: Early detection and improved genomic surveillance of SARS-CoV-2 variants from deep sequencing data

abstract:
In the definition of fruitful strategies to contrast the worldwide diffusion of SARS-CoV-2, maximum efforts must be devoted to the early detection of dangerous variants. An effective help to this end is granted by the analysis of deep sequencing data of viral samples, which are typically discarded after the creation of consensus sequences. Indeed, only with deep sequencing data it is possible to identify intra-host low-frequency mutations, which are a direct footprint of mutational processes that may eventually lead to the origination of functionally advantageous variants. Accordingly, a timely and statistically robust identification of such mutations might inform political decision-making with significant anticipation with respect to standard analyses based on con-sensus sequences.

To support our claim, we here present the largest study to date of SARS-CoV-2 deep sequencing data, which involves 220,788 high quality samples, collected over 20 months from 137 distinct studies. Importantly, we show that a rele-vant number of spike and nucleocapsid mutations of interest associated to the most circulating variants, including Beta, Delta and Omicron, might have been intercepted several months in advance, possibly leading to different public-health decisions. In addition, we show that a refined genomic surveillance system involving high- and low-frequency mutations might allow one to pin-point possibly dangerous emerging mutation patterns, providing a data-driven automated support to epidemiologists and virologists.


title: Exome-wide analysis of copy number variation shows association of the human leukocyte antigen region with asthma in UK Biobank

abstract:
BackgroundThe role of copy number variants (CNVs) in susceptibility to asthma is not well understood. This is, in part, due to the difficulty of accurately measuring CNVs in large enough sample sizes to detect associations. The recent availability of whole-exome sequencing (WES) in large biobank studies provides an unprecedented opportunity to study the role of CNVs in asthma.

MethodsWe called common CNVs in 49,953 individuals in the first release of UK Biobank WES using ClinCNV software. CNVs were tested for association with asthma in a stage 1 analysis comprising 7,098 asthma cases and 36,578 controls from the first release of sequencing data. Nominally-associated CNVs were then meta-analysed in stage 2 with an additional 17,280 asthma cases and 115,562 controls from the second release of UK Biobank exome sequencing, followed by validation and fine-mapping.

ResultsFive of 189 CNVs were associated with asthma in stage 2, including a deletion overlapping the HLA-DQA1 and HLA-DQB1 genes, a duplication of CHROMR/PRKRA, deletions within MUC22 and TAP2, and a duplication in FBRSL1. The HLA-DQA1, HLA-DQB1, MUC22 and TAP2 genes all reside within the human leukocyte antigen (HLA) region on chromosome 6. In silico analyses demonstrated that the deletion overlapping HLA-DQA1 and HLA-DQB1 is likely to be an artefact arising from under-mapping of reads from non-reference HLA haplotypes, and that the CHROMR/PRKRA and FBRSL1 duplications represent presence/absence of pseudogenes within the HLA region. Bayesian fine-mapping of the HLA region suggested that there are two independent asthma association signals. The variants with the largest posterior inclusion probability in the two credible sets were an amino acid change in HLA-DQB1 (glutamine to histidine at residue 253) and a multi-allelic amino acid change in HLA-DRB1 (presence/absence of serine, glycine or leucine at residue 11).

ConclusionsAt least two independent loci characterised by amino acid changes in the HLA-DQA1, HLA-DQB1 and HLA-DRB1 genes are likely to account for association of SNPs and CNVs in this region with asthma. The high divergence of haplotypes in the HLA can give rise to spurious CNVs, providing an important, cautionary tale for future large-scale analyses of sequencing data.


title: Performances of community pharmacists and community pharmacies during COVID-19 outbreak: a cross-sectional study

abstract:
BackgroundCommunity pharmacists can play an important role in the management of coronavirus disease-19 (COVID-19) outbreak by providing pharmaceutical care and education services. In addition to providing drug-related services, community pharmacies must take measures to reduce the risk of COVID-19 transmission to customers and technicians in pharmacy. Therefore, a study was designed to assess community pharmacists performance and community pharmacies preparedness during COVID-19 outbreak.

Materials & MethodsA cross-sectional study was conducted in Kerman, Iran. A 20-item checklist consisting of nine items assessing the practice of pharmacists regarding use of personal protective equipment (PPE) and education of people about routes of transmission, prophylaxis and treatment of COVID-19 and eleven items evaluating the adherence of pharmacies to principles of reducing the risk of COVID-19 transmission in public places was used.

ResultsOf 95 enrolled pharmacists, 55 (57.9%) were female and 78.9% had work experience [≤] 10 years. More than 90% of pharmacists used appropriate PPE and provided information about medications for prevention and treatment of COVID-19 and routs of its transmission to the pharmacy customers. Phone consultation was done by 71.6% of pharmacists. Concerning the preparedness of pharmacies, 92% of personnel used PPE, and hand sanitizers were available in 89.5% of pharmacies. However, a clear sheet was not placed at counters in the majority of pharmacies, and home delivery services were not provided by most pharmacies.

ConclusionsThe practice of most community pharmacists was acceptable. However, stricter measures should be taken to diminish the probability of COVID-19 transmission in community pharmacies.

category: health systems and quality improvement


title: Antibodies targeting merozoites induce natural killer cell degranulation and interferon gamma secretion and are associated with immunity against malaria

abstract:
Natural killer cells are potent immune effectors that can be activated via antibody mediated Fc receptor engagement. Using multiparameter flow cytometry, we found that natural killer (NK) cells degranulate and release IFN{gamma} upon stimulation with antibody-opsonized Plasmodium falciparum merozoites. Antibody-dependent NK activity (Ab-NK) was largely strain-transcending and enhanced the inhibition of invasion into erythrocytes. Ab-NK was associated with the successful control of parasitemia following experimental malaria challenge in African adults. In an independent cohort study in children, Ab-NK increased with age, was boosted by concurrent falciparum infections and associated with a lower risk of clinical episodes of malaria. Nine of 14 vaccine candidates tested induced Ab-NK including some less well-studied antigens - P41, P113, MSP11, RHOPH3, and Pf_11363200. These data highlight an important role for ab-NK in immunity against malaria and provide a new mechanism for the evaluation of vaccine candidates

One Sentence SummaryAntibody-dependent natural killer activation is induced by merozoites and associated with immunity against malaria


title: HIV-1 co-infection increases relapse rate and shortens survival in patients with visceral leishmaniasis

abstract:
Visceral leishmaniasis (VL) and HIV co-infection (VL/HIV) has emerged as a significant public health problem in Ethiopia, with up to 30% of VL patients co-infected with HIV. These patients suffer from recurrent VL relapses and increased mortality. Our aim was to assess whether VL/HIV co-infected patients with a previous history of VL relapses (recurrent VL/HIV) have a poorer prognosis as compared to HIV patients presenting with their first episode of VL (primary VL/HIV). Our results show that recurrent VL/HIV patients have a higher parasite load, higher mortality and that their relapse-free survival is significantly shorter. The poorer prognosis of recurrent VL/HIV patients is accompanied by lower weight gain and lower recovery of all blood cell lineages, as well as lower production of IFN{gamma}, lower CD4+ T cell counts and higher expression levels of PD1 on T cells. Furthermore, our results show that prior history of VL relapse is an important risk factor for future relapse. Both CD4+ T cell count and parasite load were also associated with a higher risk of VL relapse, but neither of these was independently associated with relapse risk after adjustment for previous VL relapse history.

We propose that in addition to the current treatments, novel interventions should be considered at the time of VL diagnosis in VL/HIV patients; and suggest that improved anti-leishmanial and antiretroviral treatments, as well as immune therapy, through PD1/PDL-1 blockade and/or through IFN{gamma} administration, could result in more efficient parasite killing and thereby reduce the relapse rate and improve survival.


title: Previous visceral leishmaniasis relapses outperform immunological or clinical signs as predictors of further relapses in patients co-infected with HIV-1


title: Transmission of SARS-CoV-2 by children and young people in households and schools: a meta-analysis of population-based and contact-tracing studies

abstract:
BackgroundThe role of children and young people (CYP) in transmission of SARS-CoV-2 in household and educational settings remains unclear. We undertook a systematic review and meta-analysis of contact-tracing and population-based studies at low risk of bias.

MethodsWe searched 4 electronic databases on 28 July 2021 for contact-tracing studies and population-based studies informative about transmission of SARS-CoV-2 from 0-19 year olds in household or educational settings. We excluded studies at high risk of bias, including from under-ascertainment of asymptomatic infections. We undertook multilevel random effects meta-analyses of secondary attack rates (SAR: contact-tracing studies) and school infection prevalence, and used meta-regression to examine the impact of community SARS-CoV-2 incidence on school infection prevalence.

Findings4529 abstracts were reviewed, resulting in 37 included studies (16 contact-tracing; 19 population studies; 2 mixed studies). The pooled relative transmissibility of CYP compared with adults was 0.92 (0.68, 1.26) in adjusted household studies. The pooled SAR from CYP was lower (p=0.002) in school studies 0.7% (0.2, 2.7) than household studies (7.6% (3.6, 15.9). There was no difference in SAR from CYP to child or adult contacts. School population studies showed some evidence of clustering in classes within schools. School infection prevalence was associated with contemporary community 14-day incidence (OR 1.003 (1.001, 1.004), p<0.001).

InterpretationWe found no difference in transmission of SARS-CoV-2 from CYP compared with adults within household settings. SAR were markedly lower in school compared with household settings, suggesting that household transmission is more important than school transmission in this pandemic. School infection prevalence was associated with community infection incidence, supporting hypotheses that school infections broadly reflect community infections. These findings are important for guiding policy decisions on shielding, vaccination school and operations during the pandemic.

FundingNo funding obtained.


title: The Influence of Age, Sex, and Socioeconomic Status on Glycemic Control Among People with Type 1 and Type 2 Diabetes in Canada: A Patient-Led Longitudinal Retrospective Cohort Study

abstract:
BackgroundClinical guidelines for most adults with diabetes recommend maintaining hemoglobin A1c (HbA1c) [≤]7.0% (<53 mmol/mol) to avoid microvascular and macrovascular complications. People with diabetes of different ages, sexes, and socioeconomic statuses may differ in their ease of attaining this goal. As a team of people with diabetes, researchers, and health professionals, we aimed to explore patterns in HbA1c results among people with type 1 or type 2 diabetes in Canada. Our research question was identified by people living with diabetes.

MethodsWe used generalized estimating equations to analyze the effects of age, sex and socioeconomic status in 947,543 HbA1c results measured from 2010 to 2019 among 90,770 people living with type 1 or 2 diabetes in Canada. People living with diabetes reviewed and interpreted the results.

ResultsHbA1c results at or below 7.0% represented 30.5% (male people living with type 1 diabetes), 21.0% (female people living with type 1 diabetes), 55.0% (male people living with type 2 diabetes) and 59.0% (female people living with type 2 diabetes) of results in each subcategory. We observed higher HbA1c values during adolescence and, for people living with type 2 diabetes, among people living in lower income areas. Among those with type 1 diabetes, female people tended to have lower HbA1c than male people during childbearing years but higher HbA1c than male people during menopausal years. Team members living with diabetes confirmed that the patterns we observed reflected their own life courses and suggested these results be communicated to health professionals and other stakeholders to improve treatment for people living with diabetes.

InterpretationA substantial proportion of people with diabetes in Canada are insufficiently supported to maintain guideline-recommended glycemic control goals. Blood sugar management goals may be particularly challenging for people who are going through adolescence, menopause, or living with fewer financial resources. Health professionals should be aware of the challenging nature of glycemic management and policymakers in Canada should provide more support for people with diabetes to live healthy lives.


title: On the survival of individuals diagnosed with type 2 diabetes mellitus in the United Kingdom: a retrospective matched cohort study

abstract:
ObjectiveTo estimate long-term hazards of all-cause mortality following a diagnosis of type 2 diabetes mellitus (T2DM) using electronic primary care data.

MethodologyRetrospective matched cohort study using electronic health records from THIN primary care database. The study included individuals born between 1930 and 1960, diagnosed with T2DM between 2000 and 2016 and aged 50-74 years and excluded those with pre-existing stroke, cancer, cognitive impairment, lower limb amputation or chronic kidney disease (CKD) stages 3 to 5. T2DM individuals were matched at diagnosis to at most 3 controls by age, gender and general practice (GP) and followed up to 1 January 2017. Time-varying hazards of all-cause mortality were then estimated using Gompertz-double-Cox model with frailty on GP, adjusting for medical history, socio-demographic and lifestyle factors.

ResultsA total of 221 182 (57.6% Males, 30.8% T2DM) individuals were selected for the study of whom 29 618 (13.4%) died during follow-up. The adjusted mortality hazard of type 2 diabetes mellitus (T2DM) was estimated to be 1.21[1.12-1.3] and 1.52[1.44-1.6] among individuals diagnosed at 50-59 years and 60-74 years, respectively, compared to controls. Deprivation, obesity, smoking and comorbidities affected survival of cases and controls equally. Compared to the 1930-39 birth cohort, all-cause mortality hazards were reduced in the 1940-49 cohort, but increased at older ages in the 1950-60 birth cohort for both cases and controls.

ConclusionT2DM is associated with raised all-cause mortality hazards which increase with age of diagnosis. These hazards associated with age at diagnosis are constant across all birth cohorts demonstrating a lack of progress over time in reducing the relative risks of all-cause mortality associated with T2DM. A further study that includes people born after 1960 is needed to fully understand the emerging higher mortality hazards among the younger birth cohorts.

Significancy of this StudyO_ST_ABSWhat is already known about this study?C_ST_ABS- Diagnosis of type 2 diabetes mellitus (T2DM) is associated with increased all-cause mortality risk.

What are the new findings?- The increased all-cause mortality associated with T2DM was lower than previously reported.
- The all-cause mortality risk associated with T2DM increased with increasing age at diagnosis.
- The all-cause mortality risk associated with T2DM remained constant across all birth cohorts.
- The all-cause mortality risk is increased at later ages among the younger birth cohorts in individuals with and without T2DM.

How might these results change the focus of research or clinical practice?- Further research is needed on individuals born after 1960 to explore the increased all-cause mortality hazards in recent birth cohorts.


title: A systematic literature review of individual-level psychological and behavioral responses to the health information of COVID-19 from social media and legacy media

abstract: Covid-19 has been recognized as a terrifying global health threat since its detection, with far-reaching consequences that are unprecedented in the modern era. Since the outbreak of the pandemic, social media and legacy media have collectively delivered health information related to COVID-19 to the public as a catalyst to community perception of risk. However, the existing literature exhibits different viewpoints toward the role of social media and legacy media in disseminating health information of COVID-19. In this regard, this article conducted a systematic literature review to provide an overview of the current state of research concerning individuals-level psychological and behavioral response to COVID-19 related information from different sources, as well as presents the challenges and future research directions.


title: The impact of environmental mycobiomes on geographic variation in COVID-19 mortality

abstract: Mortality rates during the COVID-19 pandemic have varied by orders of magnitude across communities in the United States1. Individual, socioeconomic, and environmental factors have been linked to health outcomes of COVID-192,3,4,5. It is now widely appreciated that the environmental microbiome, composed of microbial communities associated with soil, water, atmosphere, and the built environment, impacts immune system development and susceptibility to immune-mediated disease6,7,8. The human microbiome has been linked to individual COVID-19 disease outcomes9, but there are limited data on the influence of the environmental microbiome on geographic variation in COVID-19 across populations10. To fill this knowledge gap, we used taxonomic profiles of fungal communities associated with 1,135 homes in 494 counties from across the United States in a machine learning analysis to predict COVID-19 Infection Fatality Ratios (the number of deaths caused by COVID-19 per 1000 SARS-CoV-2 infections1;  IFR). Here we show that exposure to increased fungal diversity, and in particular indoor exposure to outdoor fungi, is associated with reduced SARS-CoV-2 IFR. Further, we identify seven fungal genera that are the predominant drivers of this protective signal and may play a role in suppressing COVID-19 mortality. This relationship is strongest in counties where human populations have remained stable over at least the previous decade, consistent with the importance of early-life microbial exposures11. We also assessed the explanatory power of 754 other environmental and socioeconomic factors, and found that indoor-outdoor fungal beta-diversity is amongst the strongest predictors of county-level IFR, on par with the most important known COVID-19 risk factors, including age12. We anticipate that our study will be a starting point for further integration of environmental mycobiome data with population health information, providing an important missing link in our capacity to identify vulnerable populations. Ultimately, our identification of specific genera predicted to be protective against COVID-19 mortality may point toward novel, proactive therapeutic approaches to infectious disease.


title: mRNA COVID-19 vaccine effectiveness against SARS-CoV-2 infection in a prospective community cohort, rural Wisconsin, November 2020-December 2021

abstract: Reduced COVID-19 vaccine effectiveness (VE) has been observed with increasing predominance of the Delta variant. In a prospective rural community cohort of 1265 participants, VE against symptomatic and asymptomatic SARS-CoV-2 infection was 56% for mRNA COVID-19 vaccines.


title: Social isolation and the aging brain. Social isolation is linked to declining grey matter structure and cognitive functions in the LIFE-Adult panel study

abstract:
BackgroundSocial isolation is a risk factor for dementia, a devastating disease with a rapidly growing global prevalence. However, the link between social isolation and changes in brain structure and function is poorly understood, as studies are scarce in number, methodologically inconsistent and small in size. In this pre-registered analysis of a large population-based panel study, we aimed to determine the impact of social isolation on brain structures and cognitive functions central to age associated decline and dementia.

Methods and findingsWe analysed data of 1992 cognitively healthy participants of the LIFE-Adult study at baseline (age range: 50-82 years) and of 1409 particpants at follow-up (average change in age: 5.89 years). We measured social isolation using the 30-point Lubben Social Network Scale (LSNS) and derived measures of grey matter structure from anatomical 3T MRIs. We employed covariate adjusted linear mixed models to test the associations of baseline social isolation and change in social isolation with hippocampal volume, cognitive functions (executive functions, memory, processing speed) and cortical thickness.

We found stronger baseline social isolation to be significantly associated with smaller hippocampal volumes ({beta} = -5.5 mm3/LSNS point(pt), FDR q = 0.004, BF = 14.6) and lower cognitive functions (all {beta} < -0.014 SD/pt, FDR q < 0.003, BF > 49). Increases in social isolation over time were linked to hippocampal volume decline ({beta} = -4.9 mm3/pt, FDR q = 0.01, BF = 2.9) and worse memory performance ({beta} = -0.013 SD/pt, FDR q = 0.04, BF = 1.1). Furthermore, we detected a significant interaction of baseline social isolation with change in age on hippocampal volume ({beta} = -0.556 mm3/pt*a, q = 0.04, BF = 0.5), indicating accelerated brain aging in more isolated individuals. Moreover, social isolation cross-sectionally and longitudinally correlated with lower cortical thickness in multiple clusters in the orbitofrontal cortex, precuneus and other areas (FDR q < 0.05).

ConclusionsHere, we provide evidence that social isolation contributes to hippocampal and cortical atrophy and subtle cognitive decline in non-demented mid-to late-life adults. Importantly, within-subject effects of social isolation were similar to between-subject effects, indicating an opportunity for targeting social isolation to reduce dementia risk.