title: Vaccines against Covid-19, venous thromboembolism, and thrombocytopenia. A population-based retrospective cohort study

abstract:
BackgroundWe aimed at estimating the risk of venous thromboembolism (VTE), thrombocytopenia (TCP), and VTE associated with TCP, by age and sex, after the first dose of both adenovirus vector-based and mRNA-based Covid-19 vaccines, and after the second dose of m-RNA vaccines.

MethodsIn this population-based retrospective cohort study in the national health care databases in Catalonia, we examined three groups: 1 662 719 people 10 years of age and over vaccinated with the first dose of a Covid-19 vaccine, 622 778 with the second dose, and 190 616 diagnosed of Covid-19 in the same period (between1 January 2021 and 18 April 2021). The rates of various clinical presentations of VTE and TCP were compared with those in the reference population (7 013 040 people served by the health care system in 2019). The two primary outcomes were the observed 21 day rate of a composite variable of cerebral venous sinus thrombosis, mesenteric thrombosis, portal vein thrombosis, or any venous thromboembolism (VTE) associated with thrombocytopenia (TCP), and the rate of any VTE associated with TCP (VTE+TCP). Analyses were standardised by age and sex.

ResultsThe 21 day rate per 100 000 of the primary composite variable was 2.15 in the reference population, 5.65 following the first vaccine dose (standardised difference, 2.53 (95% CI [CI], 1.04 to 4.00), and 7.23 following the second dose (standardised difference, 4.07 (95% CI, 1.43 to 6.70). The event rates of VTE+TCP and of all the secondary variables showed the same patterns.

Excess event rates were higher in men than in women, and they were not especially increased in any particular age group. All Covid-19 vaccines were associated with increased rates of the outcome variables.

Excess event rates were much higher in the Covid-19 cohort (35.60 per 100 000 (95% CI, 26.15 to 45.06).

ConclusionsWe observed increases of rates of venous thromboembolism in usual and unusual anatomical sites and of thrombocytopenia in recipients of both adenovirus vector and mRNA vaccines against Covid-19. Excess rates were higher in men than in women and they were not particularly elevated in any specific age group.

category: pharmacology and therapeutics


title: Risk of Myocarditis from COVID-19 Infection in People Under Age 20: A Population-Based Analysis

abstract:
BackgroundThere have been recent reports of myocarditis (including myocarditis, pericarditis or myopericarditis) as a side-effect of mRNA-based COVID-19 vaccines, particularly in young males. Less information is available regarding the risk of myocarditis from COVID-19 infection itself. Such data would be helpful in developing a complete risk-benefit analysis for this population.

MethodsA de-identified, limited data set was created from the TriNetX Research Network, aggregating electronic health records from 48 mostly large U.S. Healthcare Organizations (HCOs). Inclusion criteria were a first COVID-19 diagnosis during the April 1, 2020 - March 31, 2021 time period, with an outpatient visit 1 month to 2 years before, and another 6 months to 2 years before that. Analysis was stratified by sex and age (12-17, 12-15, 16-19). Patients were excluded for any prior cardiovascular condition. Primary outcome was an encounter diagnosis of myocarditis within 90 days following the index date. Rates of COVID-19 cases and myocarditis not identified in the system were estimated and the results adjusted accordingly. Wilson score intervals were used for 95% confidence intervals due to the very low probability outcome.

ResultsFor the 12-17-year-old male cohort, 6/6,846 (0.09%) patients developed myocarditis overall, with an adjusted rate per million of 450 cases (Wilson score interval 206 - 982). For the 12-15 and 16-19 male age groups, the adjusted rates per million were 601 (257 - 1,406) and 561 (240 - 1,313).

For 12-17-year-old females, there were 3 (0.04%) cases of myocarditis of 7,361 patients. The adjusted rate was 213 (73 - 627) per million cases. For the 12-15- and 16-19-year-old female cohorts the adjusted rates per million cases were 235 (64 - 857) and 708 (359 - 1,397).

The outcomes occurred either within 5 days (40.0%) or from 19-82 days (60.0%).

ConclusionsMyocarditis (or pericarditis or myopericarditis) from primary COVID19 infection occurred at a rate as high as 450 per million in young males. Young males infected with the virus are up 6 times more likely to develop myocarditis as those who have received the vaccine.

category: public and global health


title: Safety and efficacy of COVID-19 hyperimmune globulin (HIG) solution in the treatment of active COVID-19 infection- Findings from a Prospective, Randomized, Controlled, Multi-Centric Trial

abstract:
BackgroundCOVID-19 hyper-immune globulin (HIG) solution is a human plasma-derived, highly-purified, concentrated, virus-inactivated preparation of neutralizing antibodies (NAbs) against COVID-19.

MethodsThis was a randomized, two-arm, controlled, multi-center trial to evaluate the efficacy and safety of COVID-19 HIG in patients who were hospitalized with moderate-severe COVID-19 infection.

ResultsA total of 60 patients were randomized (30 in each arm). Overall, COVID-19 HIG was well-tolerated without any serious treatment-emergent adverse event or tolerability issue. The mean change in ordinal scale by day 8 was 1.7{+/-}1.61 in the test arm vs. 2.0{+/-}1.68 in the control arm (mITT; p=0.367). Early and high NAbs were observed in the test arm compared to the control arm.

More patients had negative RT-PCR by day 3 for the test arm vs. the control arm (mITT: 46.67% in test vs. 37.93% in control). The median time to be RT-PCR negative was 5.5 days for the test arm vs. 8.0 days for the control arm for PP population. Patients receiving COVID-19 HIG showed early improvement (reduction) in the biomarkers (CRP, IL-6, and D-dimer).

ConclusionCOVID-19 HIG was found to be safe and well-tolerated. Early and high NAbs were achieved in COVID-19 HIG recipients qualifying the product as a suitable treatment option, particularly in an immunocompromised state. It should be given early in infection to mitigate progression to severe disease. It should be evaluated for post-exposure prophylaxis as well as for prevention (where a vaccine is not suitable or effective). It should be evaluated in the pediatric population as well.

category: infectious diseases


title: Effect of Balloon-Blowing on Dyspnea and Oxygenation in Noncritical Adult Covid19 Patients: A Pilot Study

abstract: Dyspnea and decreased O2 saturation are the most common causes of hospitalization in noncritical covid-19 patients. Breathing exercises and chest physiotherapy are used for managing the patients. These treatments are however not well supported by scientific evidence. In a randomized controlled trial, 80 patients were randomly assigned to planned breathing-exercise (n=40) and control groups (n=40). The participants in the intervention group were instructed to blow into a balloon five times a day while lying down. Other therapies were similar in both groups. The severity of dyspnea at rest/after activity and peripheral oxygen saturation (SpO2) with/without O2 therapy were compared between the two groups on the first, second, and third days. The study findings showed no statistically significant difference in SpO2 with/without O2 therapy on the first, second, and third days between the two groups. Although the severity of dyspnea showed no significant difference between the two groups, the mean score of dyspnea at rest (2.72{+/-}2.25 vs. 1.6{+/-}1.21, p=0.007) and after activity (4.53{+/-}2.04 vs. 3.52{+/-}1.66, P=0.017) improved in the intervention group on the third day. Balloon-blowing exercise improves dyspnea in noncritical Covid-19 patients, but it does not significantly improve oxygenation.


title: A Partition-Based Group Testing Algorithm for Estimating the Number of Infected Individuals

abstract: The dangers of COVID-19 remain ever-present worldwide. The asymptomatic nature of COVID-19 obfuscates the signs policy makers look for when deciding to reopen public areas or further quarantine. In much of the world, testing resources are often scarce, creating a need for testing potentially infected individuals that prioritizes efficiency. This report presents an advancement to Beigel and Kasifs Approximate Counting Algorithm (ACA). ACA estimates the infection rate with a number of tests that is logarithmic in the population size. Our newer version of the algorithm provides an extra level of efficiency: each subject is tested exactly once. A simulation of the algorithm, created for and presented as part of this paper, can be used to find a linear regression of the results with R2 > 0.999. This allows stakeholders and members of the biomedical community to estimate infection rates for varying population sizes and ranges of infection rates.

category: epidemiology


title: Plasma oxylipin levels may predict Covid-19 patient outcomes. An observational and retrospective study.

abstract:
BackgroundThe key role of inflammation in the progression of COVID-19 was evident right from the beginning of the pandemic. Consequently, many authors studied the onset and evolution of the cytokine storm. In contrast, other inflammatory mediators such as oxylipins have received almost no attention.

MethodsWe conducted a monocentric observational and retrospective study (IMPRE-COVID-19) with patients (aged [≥] 18 years) admitted to Pisa University Hospital with COVID-19 related pneumonia. SARS-CoV-2 infection was confirmed by polymerase chain reaction in a nasopharyngeal swab, while pneumonia was demonstrated by CT scan. Oxylipin plasma levels were analysed in a convenient sample of 52 patients randomly selected from those that had a complete set of cytokine values evaluated for clinical purposes. In 12 cases, plasma samples collected on different days were available at the BMS Multispecialistic Biobank of Pisa University Hospital and were analysed to understand the evolution of the oxylipin levels during hospitalization. The two datasets that included oxylipin and cytokine values were analysed by principal component analysis (PCA), computation of Fishers canonical variable, and a multivariate receiver operating characteristic (ROC) curve.

FindingsBetween March and April 2020, 52 patients were enrolled of which 28 were hospitalised in COVID-19 wards, 20 in ICUs, and 4 who were initially hospitalised in the wards and who were then transferred to the ICUs due to deteriorating health conditions. Plasma samples collected on different days were available from 7 patients in the wards, 1 from an ICU, and 4 from patients who were hospitalised in both. The mean age of participants was 61 years (SD 16), 11 were females (21%), and 41 were males (79%), without significant differences between groups in terms of age and gender. PCA of oxylipin data led to a clear differentiation of samples collected in COVID-19 wards and ICUs. This differentiation had not been obtained with cytokine data. In addition, borderline samples were from patients hospitalised in COVID-19 wards that were about to be transferred to the ICUs, thus suggesting that differentiation is not a consequence of a different treatment, but somehow related to a diverse evolution of the pathology. Computation of Fishers canonical variable identified the original input variables that were the most effective in discriminating between the two classes. The combination of the two datasets did not improve the discrimination, thus suggesting that oxylipins are more informative than cytokines for this purpose. A multivariate class model built using the four lowest-order principal components as the input variables, and COVID-19 ward samples as the target class, produced a ROC curve with a resulting area under the curve (AUC) equal to 0{middle dot}92 - which is much higher than most AUC outcomes obtained for individual oxylipins.

InterpretationAfter analysing the metabolic pathways of the most informative oxylipins, we speculate that more severe COVID-19 is associated with a selective deficiency of pro-resolving oxylipins leading to ineffective resolutive mechanisms of inflammation, likely worsened by endothelial damage. We believe that our oxylipin data suggest the possibility to predict the evolution of COVID-19 in individual patients at an early stage.

FundingInstitutional funds from the University of Pisa supported the study.


title: Effectiveness, acceptability and potential harms of peer support for self-harm in non-clinical settings: A rapid review

abstract:
BackgroundMany people who have self-harmed prefer informal sources of support, or support from those with lived experience. However, little is known about whether peer support improves outcomes for people who have self-harmed, and what might be the risks of peer support interventions in non-clinical settings.

ObjectivesThe aims of this review are to examine the effectiveness, acceptability and potential risks of peer support for self-harm, and how these risks might be mitigated.

MethodsWe searched two bibliographic databases and grey literature for papers published since 2000. We included peer support for self-harm that occurred in voluntary sector organisations, providing one-to-one or group support, or via moderated online peer support forums. We excluded peer support within clinical settings, peer support provided by relatives or friends who self-harm, or peer support from unmoderated online forums. Quality appraisal was conducted on included papers, and study findings were summarised using a narrative synthesis.

ResultsTen papers met the inclusion criteria for this review, and most (n=8) were conducted in the United Kingdom. Eight of the papers focused on peer support that was delivered through online mediums and two examined face-to-face self-harm recovery/support groups. Limited conclusions about the effectiveness of peer support interventions for self-harm can be made, as we found no studies comparing this to other treatments or a control group. Peer support for self-harm was found to be acceptable and was viewed as having a range of benefits including a reduction of loneliness, a sense of community and empowerment, improvements in interpersonal skills, and access to information and support. The most commonly perceived risk associated with peer support for self-harm was the potential for triggering self-harm. Other potential risks identified were being re-traumatised by listening to other peoples stories, not having the knowledge or skills to help others, and misunderstandings or disagreements with other peers/group members.

ConclusionsOur findings highlighted a range of benefits of being part of a group with very specific shared experiences. This justifies investment in the provision of such resources, supported by safeguards to mitigate the potential risks from peer support interventions. Suggestions include organisations using professional facilitators for groups, including trigger warnings for online forums, and providing regular supervision and training so that peers are prepared and feel confident to support vulnerable people whilst maintaining their own emotional health.

category: psychiatry and clinical psychology


title: Social gradients in health vary between rural and urban Turkana

abstract:
Background and objectivesUnderstanding the social determinants of health is a major goal in evolutionary biology and human health research. Low socioeconomic status (often operationalized as absolute material wealth) is consistently associated with chronic stress, poor health, and premature death in high income countries. However, the degree to which wealth gradients in health are universal--or are instead made even steeper under contemporary, post-industrial conditions--remains poorly understood.

MethodologyWe quantified absolute material wealth and several health outcomes among a population of traditional pastoralists, the Turkana of northwest Kenya, who are currently transitioning toward a more urban, market-integrated lifestyle. We assessed whether wealth associations with health differed in subsistence-level versus urban contexts. We also explored the causes and consequences of wealth-health associations by measuring serum cortisol, potential sociobehavioral mediators in early life and adulthood, and adult reproductive success (number of surviving offspring).

ResultsHigher socioeconomic status and greater material wealth predicts better self-reported health and more offspring in traditional pastoralist Turkana, but worse cardiometabolic health and fewer offspring in urban Turkana. We do not find robust evidence for either direct biological mediators (i.e., cortisol) or indirect sociobehavioral mediators (e.g., adult diet or health behaviors, early life experiences) of wealth-health relationships in either context.

Conclusions and implicationsWhile social gradients in health are well-established in humans and animals across a variety of socioecological contexts, we show that the relationship between wealth and health can vary within a single population. Our findings emphasize that changes in economic and societal circumstances may directly alter how, why, and under what conditions socioeconomic status predicts health.

Lay summaryHigh socioeconomic status predicts better health and more offspring in traditional Turkana pastoralists, but worse health and fewer offspring in individuals of the same group living in urban centers. Together, our work shows that under different economic and societal circumstances, wealth effects on health may manifest in very different ways.


title: Socioeconomic status effects on health vary between rural and urban Turkana


title: High secondary attack rate and persistence of SARS-CoV-2 antibodies in household transmission study participants, Finland 2020

abstract:
BackgroundHousehold transmission studies offer the opportunity to assess both secondary attack rate and persistence of SARS-CoV-2 antibodies over time.

MethodsWe invited confirmed COVID-19 cases and their household members to attend up to four household visits with collection of nasopharyngeal and serum samples over 28 days after index case onset. We calculated secondary attack rates (SAR) based on the presence of SARS-CoV-2 nucleoprotein IgG antibodies (IgG Ab) and/or neutralizing antibodies (NAb) overall and per households. Three and six months later, we assessed the persistence of SARS-CoV-2 antibodies.

FindingsWe recruited 39 index cases and 90 household members. Among 87 household members evaluated, SAR was 48% (n=42), including 37 symptomatic secondary cases. In total, 80/129 (62%) participants developed both IgG Ab and NAb, while three participants only developed IgG Ab. Among participants who had both IgG Ab and NAb during the initial follow-up, 68/69 (99%) and 63/70 (90%) had IgG Ab and NAb at 3 months, while at 6 months, 59/75 (79%) and 63/75 (84%) had IgG Ab and NAb, respectively. Participants who required hospital care had initially 5-fold IgG Ab concentrations compared to cases with mild symptoms and 8-fold compared to asymptomatic cases.

InterpretationFollowing detection of a COVID-19 case in a household, other members had a high risk of becoming infected. Follow-up of participants showed strong persistence of antibodies in most cases.

FundingThis study was supported by THL coordinated funding for COVID-19 research (Finnish Governments supplementary budget) and by the Academy of Finland (Decision number 336431).

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSHousehold transmission studies are pivotal to the characterization of transmission dynamics of emerging infectious diseases in a closed setting with homogenous exposure, including proportion of asymptomatic cases using serologic assessment of infection. Additionally, data on long-term persistence of immune response, including neutralizing antibodies following COVID-19 remains scarce. Our search on PubMed for articles published between January 1st 2020, and June 1st, 2021 using the search terms "household" AND "transmission" AND ("COVID-19" OR "SARS-CoV-2") retrieved 381 results including 35 relevant articles: 21 original household transmission studies, 5 reviews and 9 statistical transmission, modelling or register linkage studies. Depending on the diagnosis method and the duration of follow-up, secondary attack rates (SAR) ranged from 4.6% when household contacts were followed for 14 days and tested only in case of symptoms to close to 90%. None of the household transmission studies involved long-term convalescent follow-up.

Added value of this studyThis extensive (one month) active follow-up, using RT-PCR diagnosis and serological testing for SARS-CoV-2 nucleoprotein IgG antibodies (IgG Ab) and neutralizing antibodies (NAb) showed that household transmission was high, with a 48% (42/87) SAR overall and 50% [IQR: 0-100%] at the level of the household. All but one out of 64 RT-PCR confirmed participants had developed both IgG Ab and NAb after immediate convalescence. Six months after inclusion, majority of previously seropositive (IgG and/or NAb) participants still had IgG Ab (59/75) or NAb (63/75) showing long-term persistence of humoral immunity to SARS-CoV-2.

Implications of all the available evidenceThe risk of transmission of SARS-CoV-2 infections within households is considerable. Isolation of the primary case, especially from household contacts with a high risk of severe disease, e.g. due to age or comorbidities, should be considered even though viral shedding might occur before confirmed diagnosis in household contacts. Long-term persistence of antibodies following infection, even in asymptomatic and mild cases, suggests enduring natural immunity and possibly protection from severe COVID-19.


title: Metabolite patterns of patients with peripheral arterial disease in response to exercise

abstract: Supervised exercise therapy (SET) is an effective intervention for symptomatic peripheral artery disease. Its effect on metabolism, measured by the circulating metabolome is not well understood. Participants underwent the Gardner graded treadmill test before and after SET and blood was sampled before and after each treadmill test. We tested the average association of metabolite levels with timing of blood draws. We used five models to identify metabolites or changes in metabolites at specific time points that associate with treadmill test performance or inter-individual variability in functional performance after SET. When analyzing individual time points, high levels of anandamide (AEA) before any exercise interventions were associated with shorter, or worse, walking time. Increased arachidonic acid (AA) and decreased levels of AA precursors (dihomo-{gamma}-linolenic acid and diacylglycerol) before any exercise was associated with shorter walking times. Participants who tolerated large increases in AA during acute exercise had longer, or better, walking times before and after SET. We identified two pathways of relevance to individual response to SET: AEA synthesis may increase the activity at endocannabinoid receptors, resulting in worse treadmill test performance. SET may help train patients withstand higher levels of AA and inflammatory signaling, resulting in longer walking times.


title: High blood uric acid is associated with reduced risks of mild cognitive impairment among older adults in China: a 9-year prospective cohort study

abstract:
BackgroundIt remains unsolved that whether blood uric acid (UA) is a neuroprotective or neurotoxic agent. This study aimed to evaluate the longitudinal association of blood UA with mild cognitive impairment (MCI) among older adults in China.

MethodsA total of 3103 older adults (aged 65+ years) free of MCI at baseline were included from the Healthy Aging and Biomarkers Cohort Study (HABCS). Blood UA level was determined by the uricase colorimetry assay and analyzed as categorical (by quartile) variables. Global cognition was assessed using the Mini-Mental State Examination four times between 2008 and 2017, with a score below 24 being considered as MCI. Cox proportional hazards models were used to examine the associations.

ResultsDuring a 9-year follow-up, 486 (15.7%) participants developed MCI. After adjustment for all covariates, higher UA had a dose-response association with a lower risk of MCI (all P for trend< 0.05). Participants in the highest UA quartile group had a reduced risk (hazard ratio [HR], 0.73; 95% [CI]: 0.55-0.96) of MCI, compared with those in the lowest quartile group. The associations were still robust even when considering death as a competing risk. Subgroup analyses revealed that these associations were statistically significant in younger older adults (65-79 years) and those without hyperuricemia.

ConclusionsHigh blood UA level is associated with reduced risks of MCI among Chinese older adults, highlighting the potential of managing UA in daily life for maintaining late-life cognition.


title: Influence of Novel Coronavirus COVID-19 and HIV: A Scoping Review of Hospital Course and Symptomatology

abstract:
BackgroundAn outbreak of novel coronavirus (SARS- CoV-2) was observed on December 2019 in Wuhan, China which led to a global pandemic declared in March 2020. As a consequence, it imposed delirious consequences in patients with underlying co - morbid conditions that make them immunocompromised. The purpose of this paper is to provide an in - depth review of influence of COVID - 19 in patients with underlying HIV in terms of mortality and hospitalization.

Authors also aim to provide a thorough risk analysis of hospitalization, ICU admission and mortality of PLWH and COVID-19. The secondary objective was to analyze the CD4+ count variations and outcome of COVID - 19 and to correlate if ART provided a protective role. Authors also aim to provide an evaluation of typical clinical presentation of COVID-19 in PLWH. ART is found to show activity against SARS-CoV-2 in vitro, and there is some similarity in the structure of HIV-1 gp41 and S2 proteins of SARS-CoV since they both belong to +ssRNA type.

MethodsWe conducted a literature review using search engines namely, Cochrane, PubMed and Google Scholar. The following keywords were targeted: "COVID-19," "SARS-CoV-2," and "HIV." We included case reports, case series, and cohort (retrospective and prospective) studies. We excluded clinical trials and review articles. We came across 23 articles that met the inclusion criteria. PRISMA guidelines were followed for study acquisition (Fig. 9).

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=176 SRC="FIGDIR/small/21260967v1_fig9.gif" ALT="Figure 9">
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org.highwire.dtl.DTLVardef@1df3963org.highwire.dtl.DTLVardef@30c4c8org.highwire.dtl.DTLVardef@1c729a4org.highwire.dtl.DTLVardef@7f0543_HPS_FORMAT_FIGEXP  M_FIG O_FLOATNOFig.9C_FLOATNO PRISMA guidelines for study acquisition

C_FIG ResultsFrom the 23 studies, we found a total of 651 PLWH with confirmed COVID-19 (549, 91, and 11 in cohorts, case series, and case reports, respectively). The overall risk of hospital admission from pooled data of the 23 reviewed articles was 69.13% (450/651), ICU admission was 12.90% (84/651) in total infected patients, and 18.67% (84/450) among hospitalized patients. The overall case fatality rate from the 23 reviewed articles was 11.21 (73/651).A weak positive correlation was found between CD4+ counts and hospital admissions in case series and case reports, while the weak negative correlation was found in cohorts. For mortality, there was a negative weak association in the cohorts and in case series, while a weak positive was seen in case reports (Fig.7). We assessed the presenting symptoms of PLWH with COVID-19, and our review demonstrated this group does not greatly differ from the rest of the population, as their common presenting symptoms were cough, fever, and SOB.

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=93 SRC="FIGDIR/small/21260967v1_fig7.gif" ALT="Figure 7">
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org.highwire.dtl.DTLVardef@132a333org.highwire.dtl.DTLVardef@1788387org.highwire.dtl.DTLVardef@10335a5org.highwire.dtl.DTLVardef@1b70c29_HPS_FORMAT_FIGEXP  M_FIG O_FLOATNOFig.7C_FLOATNO Results: As scoping review of HIV and COVID-19

C_FIG ConclusionOur results indicated that there was a high rate of hospitalization, ICU admission, and mortality among patients living with HIV and COVID-19. PLWH needs to be noted as a high-risk group for COVID-19 complications and severity. We recommend that PLWH be closely monitored by their physicians and strictly adhere to antiretroviral therapy and standard universal COVID-19 precautions.

category: hiv aids


title: Altered pre-existing SARS-CoV-2-specific T cell responses in elderly individuals

abstract: Pre-existing SARS-CoV-2-specific T cells, but not antibodies, have been detected in some unexposed individuals. This may account for some of the diversity in clinical outcomes ranging from asymptomatic infection to severe COVID-19. Although age is a risk factor for COVID-19, how age affects SARS-CoV-2-specific T cell responses remains unknown. We found that some pre-existing T cell responses to specific SARS-CoV-2 proteins, Spike (S) and Nucleoprotein (N), were significantly lower in elderly donors (>70 years old) who were seronegative for S than in young donors. However, substantial pre-existing T cell responses to the viral membrane (M) protein were detected in some elderly donors. These responses likely compensate for loss of T cell responses specific to S and N. In contrast, young and elderly donors exhibited comparable T cell responses to S, N, and M proteins after infection with SARS-CoV-2. M-specific responses were mediated by CD4 T cells producing interferon-{gamma} in both seronegative and seropositive individuals. T cells in seronegative elderly donors responded to various M-derived peptides, while the response after SARS-CoV-2 infection was apparently focused on a single peptide. These data suggest that diversity of target antigen repertoire for pre-existing SARS-CoV-2-specific T cells declines with age, but the magnitude of pre-existing T cell responses is maintained by T cells reactive to specific viral proteins such as M. A better understanding of the role of pre-existing SARS-CoV-2-specific T cells that are less susceptible to age-related loss may contribute to development of more effective vaccines for elderly people.


title: Six Month Safety and Efficacy of the BNT162b2 mRNA COVID-19 Vaccine

abstract:
BackgroundBNT162b2 is a lipid nanoparticle-formulated, nucleoside-modified RNA vaccine encoding a prefusion-stabilized, membrane-anchored SARS-CoV-2 full-length spike protein. BNT162b2 is highly efficacious against COVID-19 and is currently authorized for emergency use or conditional approval worldwide. At the time of authorization, data beyond 2 months post-vaccination were unavailable.

MethodsIn an ongoing, placebo-controlled, observer-blinded, multinational, pivotal efficacy study, 44,165 [≥]16-year-old participants and 2,264 12-15-year-old participants were randomized to receive 2 doses, 21 days apart, of 30 {micro}g BNT162b2 or placebo. Study endpoints reported here are vaccine efficacy (VE) against laboratory-confirmed COVID-19 and safety data, both up to 6 months post-vaccination.

ResultsBNT162b2 continued to be safe and well tolerated. Few participants had adverse events leading to study withdrawal. VE against COVID-19 was 91% (95% CI 89.0-93.2) through up to 6 months of follow-up, among evaluable participants and irrespective of previous SARS-CoV-2 infection. VE of 86%-100% was seen across countries and in populations with diverse characteristics of age, sex, race/ethnicity, and COVID-19 risk factors in participants without evidence of previous SARS-CoV-2 infection. VE against severe disease was 97% (95% CI 80.3-99.9). In South Africa, where the SARS-CoV-2 variant of concern, B.1.351 (beta), was predominant, 100% (95% CI 53.5, 100.0) VE was observed.

ConclusionWith up to 6 months of follow-up and despite a gradually declining trend in vaccine efficacy, BNT162b2 had a favorable safety profile and was highly efficacious in preventing COVID-19. (ClinicalTrials.gov number, NCT04368728)


title: Tolerability, safety and immunogenicity of intradermal delivery of a fractional dose mRNA -1273 SARS-CoV-2 vaccine in healthy adults as a dose sparing strategy

abstract:
BackgroundThere is an urgent need for fair and equitable access to safe and effective vaccines to end the COVID-19 pandemic. Shortages in reagents and vaccines are a major challenge, as well as limited knowledge on dose response relationship with mRNA COVID-19 vaccines. We explored intradermal fractional dose administration of a mRNA SARS-CoV-2/COVID-19 vaccine as a potential dose-sparing strategy.

MethodsWe conducted a proof-of-concept, dose-escalation, open-label, randomised-controlled vaccine trial (IDSCOVA) in healthy adults aged 18-30 years. To test initial safety, ten participants received 10 {micro}g mRNA-1273 vaccine through intradermal injection at day 1 and 29. Following a favourable safety review, thirty participants were 1:1 randomised to receive 20 {micro}g mRNA-1273 either intradermally or intramuscularly. The primary endpoint was tolerability and safety. The secondary endpoint was seroconversion and specific IgG concentration against SARS-CoV-2 spike S1 and Receptor Binding Domain (RBD) after the second dose at day 43. We compared results to two historical cohorts of non-hospitalised COVID-19 patients and vaccinated individuals.

FindingsThirty-eight of forty included participants (median age 25 years) completed the study. There were no serious adverse events. Self-reported local adverse reactions after intradermal delivery were mild, both in the 10 {micro}g and the 20 {micro}g group. In the higher dose group, systemic adverse reactions were more common, but still well tolerated. All 38 participants mounted substantially higher IgG-anti-S1 and IgG-anti-RBD concentrations at day 43 than COVID-19 controls. At day 43, anti-S1 (95% CI) was 1,696 (1,309-2,198) BAU/mL for the 10 {micro}g intradermal group, 1,406 (953{middle dot}5-2,074) BAU/mL for the 20 {micro}g intramuscular group and 2,057 (1,421-2,975) BAU/mL for the 20 {micro}g intradermal group. Anti-S1 was 107{middle dot}2 (63-182{middle dot}2) BAU/mL for the convalescent plasma control group and 1,558 (547{middle dot}8-4,433) BAU/mL for the individuals vaccinated with 100 {micro}g mRNA-1273.

InterpretationIntradermal administration of 10 {micro}g and 20 {micro}g mRNA-1273 vaccine was well tolerated and safe, and resulted in a robust antibody response. Intradermal vaccination has the potential to be deployed for vaccine dose-sparing.

FundingThe trial was supported by crowdfunding (Wake Up to Corona).


title: SARS-CoV-2 Antibody Response in Patients Undergoing Kidney Transplantation

abstract: The response of the immune system to COVID-19 in end stage kidney disease patients who undergo kidney transplantation has yet to be described. We report data on 72 patients who underwent SARS-CoV-2 antibody testing both before and after kidney transplantation and were followed for a median of 186 days (range 83, 277). Of the 25 patients with a positive antibody test at the time of transplant, 17 (68%) remained positive after transplantation. Patients were significantly more likely to have a persistently positive test if they reported a symptomatic COVID-19 infection prior to transplant (p=0.01). SARS-CoV-2 IgG index values were measured in a subset of kidney transplant recipients and compared to wait -listed dialysis patients. These assays demonstrated a more significant decline in IgG (58% versus 14% p = 0.008) in transplant recipients when compared to dialysis patients tested during the same time period. Additional analysis of the quality of the immune response measuring the binding of SARS-CoV-2 antibodies to the receptor-binding domain (RBD binding), the antibody neutralizing capability, and the antibody avidity demonstrated a more pronounced effect when comparing pre-transplant values to post-induction therapy/post transplant values. The attenuated IgG response seen in transplant patients compared to dialysis patients after induction therapy requires further study. These data have important implications for post-transplant management of vaccinated dialysis patients.

category: nephrology


title: Development of a federated learning approach to predict acute kidney injury in adult hospitalized patients with COVID-19 in New York City

abstract: Federated learning is a technique for training predictive models without sharing patient-level data, thus maintaining data security while allowing inter-institutional collaboration. We used federated learning to predict acute kidney injury within three and seven days of admission, using demographics, comorbidities, vital signs, and laboratory values, in 4029 adults hospitalized with COVID-19 at five sociodemographically diverse New York City hospitals, between March-October 2020. Prediction performance of federated models was generally higher than single-hospital models and was comparable to pooled-data models. In the first use-case in kidney disease, federated learning improved prediction of a common complication of COVID-19, while preserving data privacy.


title: Assessment of Ankle Fractures using Deep Learning Algorithms and Convolutional Neural Network

abstract:
Early and accurate detection of ankle fractures is crucial for reducing future complications. Radiographs are the most abundant imaging techniques for assessing fractures. We believe deep learning (DL) methods, through adequately trained deep convolutional neural networks (DCNNs), can assess radiographic images fast and accurate without human intervention. Herein, we aimed to assess the performance of two different DCNNs in detecting ankle fractures using radiographs compared to the ground truth.

In this retrospective study, our DCNNs were trained using radiographs obtained from 1050 patients with ankle fracture and the same number of individuals with otherwise healthy ankles. Inception V3 and Renet50 pretrained models were used in our algorithms. Danis-Weber classification method was used. Out of 1050, 72 individuals were labeled as occult fractures as they were not detected in the primary radiographic assessment. Using single-view radiographs was compared with 3-views (anteroposterior, mortise, lateral) for training the DCNNs.

Our DCNNs showed a better performance using 3-views images versus single-view based on greater values for accuracy, F-score, and area under the curve (AUC). The sensitivity and specificity in detection of ankle fractures using 3-views were 97.5% and 93.9% using Resnet50 compared to 98.7% and 98.6 using inception V3, respectively. Resnet50 missed 3 occult fractures while Inception V3 missed only one case.

Clinical SignificanceThe performance of our DCNNs showed a promising potential that can be considered in developing the currently used image interpretation programs or as a separate assistant to the clinicians to detect ankle fractures faster and more precisely.

Level of evidenceIII

category: orthopedics


title: Cash versus Lotteries: COVID-19 Vaccine Incentives Experiment

abstract: Governments are considering financial incentives to increase vaccine uptake to end the COVID-19 pandemic. Incentives being offered include cash-equivalents such as vouchers or being entered into lotteries. Our experiment involved random assignment of 1,628 unvaccinated participants in the United States to one of three 45 second informational videos promoting vaccination with messages about: (a) health benefits of COVID-19 vaccines (control); (b) being entered into lotteries; or (c) receiving cash equivalent vouchers. After seeing the control health information video, 16% of individuals wanted information on where to get vaccinated. This compared with 14% of those assigned to the lottery video (odds ratio of 0.82 relative to control: 95% credible interval 0.57-1.17) and 22% of those assigned to the cash voucher video (odds ratio of 1.53 relative to control: 95% credible interval 1.11-2.11). These results support greater use of cash vouchers to promote COVID-19 vaccine uptake and do not support the use of lottery incentives.

category: health economics


title: Prior infection with SARS-CoV-2 boosts and broadens Ad26.COV2.S immunogenicity in a variant dependent manner

abstract: The Johnson and Johnson Ad26.COV2.S single dose vaccine represents an attractive option for COVID-19 vaccination in resource limited countries. We examined the effect of prior infection with different SARS-CoV-2 variants on Ad26.COV2.S immunogenicity. We compared participants who were SARS-CoV-2 naive with those either infected with the ancestral D614G virus, or infected in the second wave when Beta predominated. Prior infection significantly boosted spike binding antibodies, antibody-dependent cellular cytotoxicity and neutralizing antibodies against D614G, Beta and Delta, however neutralization cross-reactivity varied by wave. Robust CD4 and CD8 T cell responses were induced after vaccination, regardless of prior infection. T cell recognition of variants was largely preserved, apart from some reduction in CD8 recognition of Delta. Thus, Ad26.COV2.S vaccination following infection may result in enhanced protection against COVID-19. The impact of the infecting variant on neutralization breadth after vaccination has implications for the design of second-generation vaccines based on variants of concern.


title: Immune responses to a single dose of the AZD1222/Covishield vaccine at 16 weeks in individuals in Sri Lanka

abstract:
IntroductionDue to limited access to vaccines, many countries have only administered a single dose of the AZD1222, while the dosage intervals have increased [≥] weeks. We sought to investigate the immunogenicity of a single dose of vaccine at [≥] 16 weeks.

MethodsSARS-CoV-2 specific antibodies in 553 individuals and antibodies to the receptor binding domain (RBD) of the Wuhan virus (WT) and the variants of concern (VOCs), ACE2 receptor blocking antibodies, ex vivo and cultured IFN{gamma} T cell responses and B cell ELISpot responses were investigated in a sub-cohort.

ResultsThe seropositivity rates in those >70 years of age (93.7%) was not significantly different compared to other age groups (97.7 to 98.2, Pearson Chi-Square = 7.8, p-value = 0.05). The antibody titres (antibody index) significantly declined (p<0.0001) with increase in age. 18/69 (26.1%) of individuals did not have ACE2 receptor blocking antibodies, while responses to the RBD of WT (p=0.03), B.1.1.7 (p=0.04) and B.1.617.2 (p=0.02) were significantly lower in those who were >60 years. Ex vivo IFN {gamma} T cell ELISpot responses were seen in 10/66 (15.1%), while only a few expressed CD107a. However, >85% had a high frequency of cultured IFN{gamma} T cell ELISpot responses and B cell ELISpots.

ConclusionVirus specific antibodies were maintained at [≥] 16 weeks after receiving a single dose of AZD1222, although levels were lower to VOCs, especially in older individuals. A single dose induced a high frequency of memory T and B cell responses.

category: allergy and immunology


title: Prospective validation of host transcriptomic biomarkers for pulmonary tuberculosis by real-time PCR

abstract: We tested performance of host-blood transcriptomic tuberculosis (TB) signatures for active case-finding. Among 20,207 HIV-uninfected and 963 HIV-infected adults screened; 2,923 and 861 were enrolled from five South African communities. Eight signatures were measured by microfluidic RT-qPCR and participants were microbiologically-investigated for pulmonary TB at baseline, and actively surveilled for incident disease through 15 months. Diagnostic AUCs for 61 HIV-uninfected (weighted-prevalence 1.1%) and 10 HIV-infected (prevalence 1.2%) prevalent TB cases for the 8 signatures were 0.63-0.79 and 0.65-0.88, respectively. Thereafter, 24 HIV-uninfected and 9 HIV-infected participants progressed to incident TB (1.1 and 1.0 per 100 person-years, respectively). Prognostic AUCs through 15-months follow-up were 0.49-0.66 and 0.54-0.81, respectively. Prognostic performance for incident TB occurring within 6-12 months in HIV-negative participants was higher for all signatures. None of the signatures met WHO Target Product Profile criteria for a triage test to diagnose asymptomatic TB; most signatures met the criteria for symptomatic TB. Prognostic accuracy of most signatures for incident TB within six months of testing met the criteria for an incipient TB test.

category: respiratory medicine


title: Vaccine effectiveness when combining the ChAdOx1 vaccine as the first dose with an mRNA COVID-19 vaccine as the second dose

abstract:
BackgroundThe recommendations in several countries to stop using the ChAdOx1 vaccine has led to vaccine programs combining different vaccine types, which necessitates new knowledge on vaccine effectiveness (VE). In this study, we aimed to estimate the VE when combining the ChAdOx1 vaccine as the first dose and an mRNA vaccine as the second dose.

MethodsThis nationwide population-based cohort study estimated VE against SARS-CoV-2 infection, all-cause and COVID-19 related hospitalization and death after receiving the ChAdOx1 vaccine as the first dose followed by an mRNA vaccine as the second dose. VE estimates were obtained using a Cox regression with calendar time as underlying time and adjusted for sex, age, comorbidity, heritage and hospital admission. Information on all individuals was extracted and linked from high-quality national registries.

ResultsA total of 5,542,079 individuals were included in the analyses (97.6% of the total Danish population). A total of 144,360 were vaccinated with the ChAdOx1 vaccine as the first dose and of these 136,551 individuals received an mRNA vaccine as the second dose. A total of 1,691,464 person-years and 83,034 cases of SARS-CoV-2 infection were included. The VE against SARS-CoV-2 infection when combining the ChAdOx1 and an mRNA vaccine was 88% (95% confidence interval (CI): 83; 92) 14 days after the second dose and onwards. There were no COVID-19 related hospitalizations and deaths among the individuals vaccinated with the combination of the ChAdOx1 and an mRNA vaccine during the study period.

ConclusionIn conclusion, this study found a reduction in the risk of SARS-CoV-2 infection when combining the ChAdOx1 and an mRNA vaccine, compared with unvaccinated individuals. This is similar to the VE of two doses of an mRNA vaccine. Longer follow-up time is needed to confirm vaccine induced protection against severe events, such as COVID-19 related hospitalization and death.


title: Are culturally vibrant communities healthier? Relationships between performing arts activity and health outcomes in the 500 largest US cities

abstract:
AimsRecent reviews have demonstrated broad links between performing arts participation (e.g. music-making; dancing; acting) and receptive engagement (e.g. listening to music; attending a dance/theatre performance) and improved health, including reduced disease and mortality risk. However, no investigations to date have interrogated the links between community-level performing arts activity (i.e. participation + receptive engagement) and health outcomes - i.e. do the performing arts help create healthy communities? This study aims to address this question by examining links between performing arts activity and health outcomes across 500 cities in the United States.

MethodsSecondary analysis of demographic, health outcome, performing arts activity (estimated by annual performing arts revenue), and preventive/unhealthy behaviour data for 500 large cities in the United States - data extracted from the US Centers for Disease Control 500 Cities Project, Dun & Bradstreet Hoovers Database, and US Census. Links between performing arts activity and 12 health/disease outcomes were evaluated using a series of hierarchical beta regression models which progressively controlled for demographic variables and preventive/unhealthy behaviour prevalence.

ResultsThe 500 analysed US cities comprise 33.4% of the total US population and 84,010 performing arts businesses (total annual revenue $27.84 billion). No significant associations were found between performing arts activity and nine of twelve health outcomes in fully adjusted models (p[≥].17). Statistically significant relationships (p<.01) between increased performing arts activity and increased prevalence of chronic kidney disease, coronary heart disease, and stroke were determined to be clinically equivocal.

ConclusionsThis study contributes to a growing body of conflicting epidemiologic evidence regarding the impact of the performing arts on health/disease and mortality outcomes, evaluated using a range of disparate methodologies. A consensus, psychometrically rigorous approach is required to address this prevailing uncertainty in future epidemiologic studies examining effects of performing arts activities both within and across countries and communities.


title: CCL25 mediates inflammatory crosstalk between adipose and liver in non-alcoholic fatty liver disease

abstract:
Background and AimsObesity is closely associated with non-alcoholic fatty liver disease (NAFLD). We investigated expression of the CC-chemokine CCL25 in adipose tissue (AT) and its relation to hepatic inflammation.

MethodsPrimary human tissue was used for all experiments. CCL25 concentration in serum was measured with enzyme-linked immunosorbent assay (ELISA). Gene expression of CCL25 was measured with polymerase chain reaction. Protein expression was assessed with ELISA and immunohistochemistry. Leukocyte trafficking was investigated in a dynamic assay to model the hepatic sinusoid. Expression of CCR9 on liver-infiltrating leukocytes analysed with flow cytometry.

ResultsCirculating CCL25 was increased in obesity. Gene expression of CCL25 in AT was several-fold higher than in liver, although protein levels of CCL25 were comparable. Soluble CCL25 in flow media increased leukocyte trafficking across hepatic endothelium. Greater numbers of CCR9+ cells were seen in liver tissue from patients with NAFLD, where the greatest difference was in the number of CD14+CD16+ monocytes.

ConclusionsCCL25 and its cognate receptor CCR9 mediate a novel pathway of inflammatory crosstalk between adipose and liver tissue in NAFLD.

category: gastroenterology


title: Optimizing clinical dosing of combination broadly neutralizing antibodies for HIV prevention

abstract: Broadly neutralizing antibodies are promising agents to prevent HIV infection and achieve HIV remission without antiretroviral therapy (ART). As learned from effective ART, HIV viral diversity necessitates combination antibody cocktails. Here, we demonstrate how to optimally choose the ratio within combinations based on the constraint of a total dose size. Optimization in terms of prevention efficacy outcome requires a model that synthesizes 1) antibody pharmacokinetics (PK), 2) a mapping between concentration and neutralization against a genetically diverse pathogen (e.g., distributions of viral IC50 or IC80), 3) a protection correlate to translate in vitro potency to clinical protection, and 4) an in vivo interaction model for how drugs work together. We find that there is not a general solution, and the optimal dose ratio likely will be different if antibodies cooperate versus if both products must be simultaneously present. Optimization requires trade-offs between potency and longevity; using an in silico case-study, we show a cocktail can outperform a bi-specific antibody (a single drug with 2 merged antibodies) with superior potency but worse longevity. In another practical case study, we perform a triple antibody optimization of VRC07, 3BNC117, and 10-1074 bNAb variants using empirical PK and a pre-clinical correlate of protection derived from animal challenge studies. Here, a 2:1:1 dose emphasizing VRC07 would optimally balance protection while achieving practical dosing and given conservative judgements about prior data. Our approach can be immediately applied to optimize the next generation of combination antibody prevention and cure studies.


title: Streptococcus pneumoniae colonisation associates with impaired adaptive immune responses against SARS-CoV-2

abstract: Although recent epidemiological data suggest that pneumococci may contribute to the risk of SARS-CoV-2 disease, secondary pneumococcal pneumonia has been reported as infrequent. This apparent contradiction may be explained by interactions of SARS-CoV-2 and pneumococcus in the upper airway, resulting in the escape of SARS-CoV-2 from protective host immune responses. Here, we investigated the relationship of these two respiratory pathogens in two distinct cohorts of a) healthcare workers with asymptomatic or mildly symptomatic SARS-CoV-2 infection identified by systematic screening and b) patients with moderate to severe disease who presented to hospital. We assessed the effect of co-infection on host antibody, cellular and inflammatory responses to the virus. In both cohorts, pneumococcal colonisation was associated with diminished anti-viral immune responses, which affected primarily mucosal IgA levels among individuals with mild or asymptomatic infection and cellular memory responses in infected patients. Our findings suggest that S. pneumoniae modulates host immunity to SARS-CoV-2 and raises the question if pneumococcal carriage also enables immune escape of other respiratory viruses through a similar mechanism and facilitates reinfection occurrence.


title: Dalbavancin in real life: Economic impact of prescription timing in French hospitals

abstract:
SynopsisO_ST_ABSObjectivesC_ST_ABSThe extended half-life of dalbavancin justifies a once-a-week dosing schedule and is supposed to favour early discharge. These advantages may therefore compensate for the cost of dalbavancin. We aimed to assess the real-life budget impact of dalbavancin through its impact on the length of stay in French hospitals.

MethodsA multicentre cohort based on the French registry of dalbavancin use in 2019 was compared to the French national discharge summary database. Lengths of stay and budget impact related to the infection type, the time of introduction of dalbavancin, the type of catheter and patient subgroups were assessed. An early switch was defined when dalbavancin was administered as the first or second treatment and within less than 11 days of hospitalization.

ResultsOne hundred seventy-nine patients were identified in the registry, and 154 were included in our study. Dalbavancin is mostly used for bone and joint infections, infective endocarditis and acute bacterial skin and skin structure infections. When compared to the data for similar patients in the national database, the length of stay was almost always shorter for patients treated with dalbavancin. The budget impact for dalbavancin was heterogeneous but frequently generated savings. Early switching was associated with savings (or lesser costs). Patients who required a deep venous catheter and those with the most severe patients benefited the most from dalbavancin.

ConclusionsOur study confirms that dalbavancin is associated with early discharge, which can offset its cost and generate savings. The greatest benefit is achieved with an early switch.


title: COVID-19 Disease Severity among People with HIV Infection or Solid Organ Transplant in the United States: A Nationally-representative, Multicenter, Observational Cohort Study

abstract:
BackgroundIndividuals with immune dysfunction, including people with HIV (PWH) or solid organ transplant recipients (SOT), might have worse outcomes from COVID-19. We compared odds of COVID-19 outcomes between patients with and without immune dysfunction.

MethodsWe evaluated data from the National COVID-19 Cohort Collaborative (N3C), a multicenter retrospective cohort of electronic medical record (EMR) data from across the United States, on. 1,446,913 adult patients with laboratory-confirmed SARS-CoV-2 infection. HIV, SOT, comorbidity, and HIV markers were identified from EMR data prior to SARS-CoV-2 infection. COVID-19 disease severity within 45 days of SARS-CoV-2 infection was classified into 5 categories: asymptomatic/mild disease with outpatient care; mild disease with emergency department (ED) visit; moderate disease requiring hospitalization; severe disease requiring ventilation or extracorporeal membrane oxygenation (ECMO); and death. We used multivariable, multinomial logistic regression models to compare odds of COVID-19 outcomes between patients with and without immune dysfunction.

FindingsCompared to patients without immune dysfunction, PWH and SOT had a greater likelihood of having ED visits (adjusted odds ratio [aOR]: 1.28, 95% confidence interval [CI] 1.27-1.29; aOR: 2.61, CI: 2.58-2.65, respectively), requiring ventilation or ECMO (aOR: 1.43, CI: 1.43-1.43; aOR: 4.82, CI: 4.78-4.86, respectively), and death (aOR: 1.20, CI: 1.19-1.20; aOR: 3.38, CI: 3.35-3.41, respectively). Associations were independent of sociodemographic and comorbidity burden. Compared to PWH with CD4>500 cells/mm3, PWH with CD4<350 cells/mm3 were independently at 4.4-, 5.4-, and 7.6-times higher odds for hospitalization, requiring ventilation, and death, respectively. Increased COVID-19 severity was associated with higher levels of HIV viremia.

InterpretationIndividuals with immune dysfunction have greater risk for severe COVID-19 outcomes. More advanced HIV disease (greater immunosuppression and HIV viremia) was associated with higher odds of severe COVID-19 outcomes. Appropriate prevention and treatment strategies should be investigated to reduce the higher morbidity and mortality associated with COVID-19 among PWH and SOT.


title: Higher serological responses and increased vaccine effectiveness demonstrate the value of extended vaccine schedules in combatting COVID-19 in England

abstract:
IntroductionIn January 2021, the UK decided to prioritise the delivery of the first dose of BNT162b2 (Pfizer/BioNTech) and AZD1222 (AstraZeneca) vaccines by extending the interval until the second dose up to 12 weeks.

MethodsSerological responses were compared after BNT162b2 and AZD1222 vaccination with varying intervals in uninfected and previously-infected adults aged 50-89 years. These findings are evaluated against real-world national vaccine effectiveness (VE) estimates against COVID-19 in England.

ResultsWe recruited 750 participants aged 50-89 years, including 126 (16.8%) with evidence of previous infection; 421 received BNT162b2 and 329 and AZD1222. For both vaccines, over 95% had seroconverted 35-55 days after dose one, and 100% seroconverted 7+ days after dose 2. Following a 65-84 day interval between two doses, geometric mean titres (GMTs) at 14-34 days were 6-fold higher for BNT162b2 (6703; 95%CI, 5887-7633) than AZD1222 (1093; 806-1483), which in turn were higher than those receiving BNT162b2 19-29 days apart (694; 540 - 893). For both vaccines, VE was higher across all age-groups from 14 days after dose two compared to one dose, but the magnitude varied with interval between doses. Higher two-dose VE was observed with >6 week intervals between BNT162b2 doses compared to the authorised 3-week schedule, including [≥]80 year-olds.

ConclusionOur findings support the UK approach of prioritising the first dose of COVID-19 vaccines, with evidence of higher protection following extended schedules. Given global vaccine constraints, these results are relevant to policymakers, especially with highly transmissible variants and rising incidence in many countries.

FundingPublic Health England


title: Monitoring and forecasting the SARS-Covid-19 pandemic in France

abstract: Over the past year, many countries have resorted multiple times to drastic social restrictions to prevent saturation of their health care system, and to regain control over an otherwise exponentially increasing SARS-CoV-2 pandemic evolution. With the advent of data-sharing, computational approaches have gained a key role in evaluating future scenarios. To design optimal social, hospitalization and economical strategies that guarantee control over the pandemic progression, we developed a data-driven modelling framework with the aim to provide reliable near future predictions under constantly evolving social and pandemic conditions. The framework is flexible enough to be used at a single hospital, regional or national level. We used a variety of data such as social, serological, testing and clinical data to compute the infection dynamics and the hospital workload for France. We developed inference methods to calibrate model parameters from observed hospitalization statistics over adjustable time periods. We applied our model to study the age stratified pandemic evolution inside and outside hospitals until February 2021, and the competition between vaccinations and the novel delta variant. We obtained predictions about hidden pandemic properties such as fractions of infected, infection hospitality and infection fatality ratios. We show that reproduction numbers and herd immunity levels are not universal but depend on the underlying social dynamics, and in presence of the delta variant should be above 90%. Finally, we conclude that vaccination of the young generation should be pursued before all social restrictions are relieved.


title: Monitoring and forecasting the SARS-CoV-2 pandemic in France


title: Analysis of Blood Gene Expression Data Toward Early Detection of Alzheimer's Disease

abstract: Alzheimers Disease (AD) is a progressive neurodegenerative disorder and the most commonly diagnosed cause of dementia, and it is the fifth leading cause of death among people aged 65 and older. During the years, the early diagnosis of AD patients has been a significant concern for researchers, in view of the fact that early diagnosis not only can lead to saving lives of the AD patients but also could bring a considerable amount of saving in health and long-term care expenditures for both people and the government. Mild cognitive impairment (MCI), defined as a transitional state between being healthy and having AD, is considered an established risk factor for AD. Hence, an accurate and reliable diagnosis of MCI and, consequently, discrimination between healthy people, MCI individuals, and AD patients can play a crucial role in the early diagnosis of AD. In recent years, analysis of blood gene expression data has been grabbed more attention than the conventional AD diagnosis method because it provides the opportunity to investigate the biochemical pathways, cellular functions, and regulatory mechanisms for finding the key genes associated with MCI and AD. Therefore, in this study, we employed blood gene expression data from Alzheimers Disease Neuroimaging Initiative (ADNI), two feature selection methods for determining the most prominent genes related to MCI and AD, and three classifiers for the most accurate discrimination between three groups of healthy, MCI and AD. The proposed method yielded the selection of top ten genes from more than 49,000 genes and the best overall classification result between healthy and AD patients with average values of the area under the curve (AUC) of 0.77 {+/-} 0.08. Furthermore, gene ontology (GO) analysis revealed that four genes were enriched with the GO terms of regulation of cell proliferation, negative regulation of cell population proliferation, signaling receptor binding, biological adhesion, and cytokine production.

category: genetic and genomic medicine


title: Tracking Cryptic SARS-CoV-2 Lineages Detected in NYC Wastewater

abstract: Tracking SARS-CoV-2 genetic diversity is strongly indicated because diversifying selection may lead to the emergence of novel variants resistant to naturally acquired or vaccine-induced immunity. To monitor New York City (NYC) for the presence of novel variants, we amplified regions of the SARS-CoV-2 Spike protein gene from RNA acquired from all 14 NYC wastewater treatment plants (WWTPs) and ascertained the diversity of lineages from these samples using high throughput sequencing. Here we report the detection and increasing frequencies of novel SARS-CoV-2 lineages not recognized in GISAIDs EpiCoV database. These lineages contain mutations rarely observed in clinical samples, including Q493K, Q498Y, H519N and T572N. Many of these mutations were found to expand the tropism of SARS-CoV-2 pseudoviruses by allowing infection of cells expressing the human, mouse, or rat ACE2 receptor. In addition, pseudoviruses containing the Spike amino acid sequence of these lineages were found to be resistant to many different classes of receptor binding domain (RBD) binding neutralizing monoclonal antibodies. We offer several hypotheses for the anomalous presence of these mutations, including the possibility of a non-human animal reservoir. Although wastewater sampling cannot provide direct inference of SARS-CoV-2 clinical sequences, our research revealed several lineages that could be relevant to public health and they would not have been discovered if not for wastewater surveillance.


title: Reactive vaccination of workplaces and schools against COVID-19

abstract: AbstractAs vaccination against COVID-19 stalls in some countries, increased accessibility and more adaptive approaches may be useful to keep the epidemic under control. Here, we study the impact of reactive vaccination targeting schools and workplaces where cases are detected, with an agent-based model accounting for COVID-19 natural history, vaccine characteristics, individuals demography and behaviour and social distancing. At an equal number of doses reactive vaccination produces a higher reduction in cases compared with non-reactive strategies, in the majority of scenarios. However, at high initial vaccination coverage or low incidence, few people are found to vaccinate around cases, thus the reactive strategy may be less effective than non-reactive strategies with moderate/high vaccination pace. In case of flare-ups, reactive vaccination could hinder spread if it is implemented quickly, is supported by enhanced test-trace-isolate and triggers an increased vaccine uptake. These results provide key information to plan an adaptive vaccination deployment.


title: Wastewater surveillance for infectious disease: a systematic review

abstract: Wastewater surveillance of SARS-CoV-2 has shown to be a valuable source of information regarding SARS-CoV-2 transmission and COVID-19 cases. Though the method has been used for several decades to track other infectious diseases, there has not been a comprehensive review outlining all of the pathogens surveilled through wastewater. The aim of this study is to identify what infectious diseases have been previously studied via wastewater surveillance prior to the COVID-19 Pandemic and identify common characteristics between the studies, as well as identify current gaps in knowledge. Peer-reviewed articles published as of August 1, 2020 that examined wastewater for communicable and infectious human pathogens on 2 or more occasions were included in the study. Excluded from this list were all reviews and methods papers, single collection studies, and non-human pathogens. Infectious diseases and pathogens were identified in studies of wastewater surveillance, as well as themes of how wastewater surveillance and other measures of disease transmission were linked. This review did not include any numerical data from individual studies and thus no statistical analysis was done. 1005 articles were identified but only 100 were included in this review after applying the inclusion criteria. These studies came from 38 countries with concentration in certain countries including Italy, Israel, Brazil, Japan, and China. Twenty-five separate pathogen families were identified in the included studies, with the majority of studies examining pathogens from the family Picornaviridae, including polio and non-polio enteroviruses. Most studies of wastewater surveillance did not link what was found in the wastewater to other measures of disease transmission. Among those studies that did compare wastewater surveillance to other measures of disease transmission the value observed was dependent upon pathogen and varied by study. Wastewater surveillance has historically been used to assess water-borne and fecal-orally transmitted pathogens causing diarrheal disease. However, numerous other types of pathogens have been surveilled using wastewater and wastewater surveillance should be considered as a potential tool for many infectious diseases. Wastewater surveillance studies can be improved by incorporating other measures of disease transmission at the population-level including disease incidence and hospitalizations.


title: Evaluation Of The Rims2 Locus As A Risk Locus For Parkinson's Disease Dementia

abstract:
In their recent letter entitled "Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in parkinsons disease", Liu and colleagues report that in a genome-wide analysis of progression to dementia in parkinsons disease (PD) the RIMS2 locus is a determinant of dementia in PD (1). In this study we have evaluated the nominated loci in a well-powered longitudinal clinical-genetic study of 2536 individuals in the tracking parkinsons and oxford discovery cohorts. We have not identified any association between the RIMS2 locus or other loci from the discovery phase and the development of Parkinsons dementia. further work is needed to understand the biological determinants of this important aspect of parkinsons and to guide the search for new treatments.

Brief paragraph/AbstractIn their recent letter entitled "Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinsons disease", Liu and colleagues report that in a genome-wide analysis of progression to dementia in Parkinsons disease (PD) the RIMS2 locus is a determinant of dementia in PD (1). In this study we have evaluated the nominated loci in a well-powered longitudinal clinical-genetic study of 2536 individuals in the Tracking Parkinsons and Oxford Discovery cohorts. We have not identified any association between the RIMS2 locus or other loci from the discovery phase and the development of Parkinsons dementia. Further work is needed to understand the biological determinants of this important aspect of Parkinsons and to guide the search for new treatments.

category: neurology


title: Whole-genome sequencing analysis of clozapine-induced myocarditis

abstract: One of the concerns limiting the use of clozapine in schizophrenia treatment is the risk of rare but potentially fatal myocarditis. Our previous genome-wide association study and human leucocyte antigen analyses identified putative loci associated with clozapine-induced myocarditis. However, the contribution of DNA variation in cytochrome P450 genes, copy number variants and rare deleterious variants have not been investigated. We explored these unexplored classes of DNA variation using whole-genome sequencing data from 25 cases with clozapine-induced myocarditis and 25 demographically-matched clozapine-tolerant control subjects. We identified 15 genes based on rare variant gene-burden analysis (MLLT6, CADPS, TACC2, L3MBTL4, NPY, SLC25A21, PARVB, GPR179, ACAD9, NOL8, C5orf33, FAM127A, AFDN, SLC6A11, PXDN) nominally associated (p<0.05) with clozapine-induced myocarditis. Of these genes, 13 were expressed in human myocardial tissue. Although independent replication of these findings is required, our study provides preliminary insights into the potential role of rare genetic variants in susceptibility to clozapine-induced myocarditis.


title: The cost-effectiveness of accelerated partner therapy (APT) compared to standard contact tracing for people with chlamydia: an economic evaluation based on the LUSTRUM population-based chlamydia transmission model

abstract:
ObjectiveTo investigate the cost-effectiveness of accelerated partner therapy (APT) compared with standard contact tracing for people with sexually transmitted chlamydia infection in the United Kingdom

DesignEconomic evaluation using a model consisting of two components: a population-based chlamydia transmission component, to estimate the impact of APT on chlamydia prevalence, and an economic component, to estimate the impact of APT on healthcare costs and health outcomes.

SettingUnited Kingdom

ParticipantsHypothetical heterosexual population of 50,000 men and 50,000 women aged 16-34 years.

Main Outcome MeasuresCost-effectiveness based on quality-adjusted life years (QALYs) gained and major outcomes averted (MOA), defined as mild pelvic inflammatory disease (PID), severe PID, chronic pelvic pain, ectopic pregnancy, tubal factor infertility and epididymitis.

ResultsFor a model population of 50,000 men and 50,000 women and an APT intervention lasting 5 years, the intervention cost of APT ({pound}135,201) is greater than the intervention cost of standard contact tracing ({pound}116,334). When the costs of complications arising from chlamydia are considered, the total cost of APT ({pound}370,657) is lower than standard contact tracing ({pound}379,597). Thus, APT yields a total cost saving of approximately {pound}9000 and leads to 73 fewer major outcomes and 21 fewer QALYs lost. Hence, APT is the dominant PN strategy. APT remained cost-effective across the full range of sensitivity analyses.

ConclusionsBased on cost-effectiveness grounds APT is likely to be recommended as an alternative to standard contact tracing for chlamydia infection in the United Kingdom


title: Machine Learning Applied to Routine Blood Tests and Clinical Metadata to Identify and Classify Heart failure

abstract:
IntroductionWe applied machine learning (ML) to routine bloods, then to advanced haematology data from a full blood count (rawFBC) plus biochemistry, to build predictive models for heart failure, which were then used at population scale.

MethodsRoutine blood results from 8,031 patients with heart failure, with equal number of controls, were used in ML training and testing datasets (Split 80:20). NT-proBNP was used for diagnostic comparison. rawFBC metadata was used in a dataset of 698 patients, 314 of whom had heart failure, to train and test ML models (Split 70:30) from rawFBC, rawFBC plus biochemistry and routine bloods. The rawFBC model was used to predict heart failure in a validation dataset of 69,492 FBCs (2.3% heart failure prevalence).

ResultsHeart failure was predicted from rawFBC and biochemistry versus rawFBC AUROC 0.93 versus 0.91, 95% CI -0.023 to 0.048, P = 0.5, and predicted from routine bloods and NT-proBNP, AUROC 0.87 versus 0.81, 95% CI 0.004 to 0.097, P = 0.03. In the validation cohort heart failure was predicted from rawFBC with AUROC 0.83, 95% CI 0.83 to 0.84, P < 0.001, sensitivity 75%, specificity 76%, PPV 7%, NPV 99.2% (Figure 2). Elevated NT-proBNP ([≥] 34 pmol/L) was predicted from rawFBC with AUROC 0.97, 95% CI 0.93 to 0.99, P < 0.0001. Common predictive features included markers of erythropoiesis (red cell distribution width, haemoglobin, haematocrit).

O_FIG O_LINKSMALLFIG WIDTH=170 HEIGHT=200 SRC="FIGDIR/small/21261115v1_fig2.gif" ALT="Figure 2">
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org.highwire.dtl.DTLVardef@6f84e2org.highwire.dtl.DTLVardef@17d4805org.highwire.dtl.DTLVardef@360d3org.highwire.dtl.DTLVardef@1c9da66_HPS_FORMAT_FIGEXP  M_FIG O_FLOATNOFigure 2.C_FLOATNO Receiver operator curves comparing ECLIPSE models

C_FIG ConclusionHeart failure can be predicted from routine bloods with accuracy equivalent to NT-proBNP. Predictive features included markers of erythropoiesis, with therapeutic monitoring implications.

category: cardiovascular medicine


title: Laboratory Study of Physical Barrier Efficiency for Worker Protection against SARS-CoV-2 while Standing or Sitting

abstract: Transparent barriers were installed as a response to the SARS-COV-2 pandemic in many customer-facing industries. Transparent barriers are an engineering control that are utilized to intercept air traveling between customers to workers. Information on the effectiveness of these barriers against aerosols is limited. In this study, a cough simulator was used to represent a cough from a customer. Two optical particle counters were used (one on each side of the barrier, labeled reference and worker) to determine the number of particles that migrated around a transparent barrier. Nine barrier sizes and a no barrier configuration were tested with six replicates each. Tests of these 10 configurations were conducted for both sitting and standing scenarios to represent configurations common to nail salons and grocery stores, respectively. Barrier efficiency was calculated using a ratio of the particle count results (reference/worker). Barriers had better efficiency when they were 9 to 39 cm (3.5 to 15.5") above cough height and at least 91 cm (36") wide, 92% and 93% respectively. Barriers that were 91 cm (36") above table height for both scenarios blocked 71% or more of the particles between 0.35-0.725 {micro}m and 68% for particles between 1 to 3 {micro}m. A barrier that blocked an initial cough was effective at reducing particle counts. While the width of barriers was not as significant as height in determining barrier efficiency it was important that a barrier be placed where interactions between customers and workers are most frequent.

category: occupational and environmental health


title: Doxycycline is a safe alternative to Hydroxychloroquine + Azithromycin to prevent clinical worsening and hospitalization in mild COVID-19 patients: An open label randomized clinical trial (DOXYCOV)

abstract:
ObjectiveWe aimed to compare the safety and efficacy of a doxycycline-based regimen against the national standard guidelines (Hydroxychloroquine plus Azithromycin) for the treatment of mild symptomatic COVID-19.

MethodsWe conducted an open-label, randomized, non-inferiority trial, in Cameroon comparing Doxycycline 100mg, twice daily for 7 days versus Hydroxychloroquine, 400 mg daily for 5 days and Azithromycin 500mg at day 1 and 250mg from day 2 through 5, in mild COVID-19 patients. Clinical improvement, biological parameters and adverse events were assessed. The primary outcome was the proportion of clinical cure at day 3, 10 and 30. Non-inferiority was determined by the clinical cure rate between protocols with a 20 percentage points margin.

Results194 participants underwent randomization and were treated with Doxycycline (n=97) or Hydroxychloroquine-Azithromycin (n=97). At day 3, 74/92 (80.4%) participants on Doxycycline versus 77/95 (81.1%) on Hydroxychloroquine-Azithromycin -based protocols were asymptomatic (p=0.91). At day 10, 88/92 (95.7%) participants on Doxycycline versus 93/95 (97.9%) on Hydroxychloroquine-Azithromycin were asymptomatic (p=0.44). At day 30 all participants were asymptomatic. SARS-CoV2 PCR was negative at Day 10 in 60/92 (65.2%) participants allocated to Doxycycline and 63/95 (66.3%) participants allocated to Hydroxychloroquine-Azithromycin. None of the participants were admitted for worsening of the disease after treatment initiation.

ConclusionDoxycycline 100 mg twice daily for 7 days is as effective and safe as Hydroxychloroquine-Azithromycin, for preventing clinical worsening of mild symptomatic or asymptomatic COVID-19, and achieving virological suppression.

Strengths and Limitations[tpltrtarr] This study is one of the first randomized trial, assessing the efficacy and tolerance of Doxycycline to treat COVID-19
[tpltrtarr]It is one of the first to evaluate disease progression and need to hospitalization in mild or asymptomatic COVID-19
[tpltrtarr]Patients will not receive identical treatments
[tpltrtarr]Doxycycline has advantages in terms of availability, safety and cost compared to Hydroxychloroquine and Azytromycin
[tpltrtarr]Though this study has encounter 7 lost to follow-up, this does not have a major influence on our results
[tpltrtarr]These data will assist clinicians in their daily practice, and provide a new tool for the fight against COVID-19


title: Prognostic accuracy of triage tools for adults with suspected COVID-19 in a pre-hospital setting: an observational cohort study

abstract:
Study ObjectiveTools proposed to triage patient acuity in COVID-19 infection have only been validated in hospital populations. We estimated the accuracy of five risk-stratification tools recommended to predict severe illness and compare accuracy to existing clinical decision-making in a pre-hospital setting.

MethodsAn observational cohort study using linked ambulance service data for patients attended by EMS crews in the Yorkshire and Humber region of England between 18th March 2020 and 29th June 2020 was conducted to assess performance of the PRIEST tool, NEWS2, the WHO algorithm, CRB-65 and PMEWS in patients with suspected COVID-19 infection. The primary outcome was death or need for organ support.

ResultsOf 7549 patients in our cohort, 17.6% (95% CI:16.8% to 18.5%) experienced the primary outcome. The NEWS2, PMEWS, PRIEST tool and WHO algorithm identified patients at risk of adverse outcomes with a high sensitivity (>0.95) and specificity ranging from 0.3 (NEWS2) to 0.41 (PRIEST tool). The high sensitivity of NEWS2 and PMEWS was achieved by using lower thresholds than previously recommended. On index assessment, 65% of patients were transported to hospital and EMS decision to transfer patients achieved a sensitivity of 0.84 (95% CI 0.83 to 0.85) and specificity of 0.39 (95% CI 0.39 to 0.40).

ConclusionUse of NEWS2, PMEWS, PRIEST tool and WHO algorithm could improve sensitivity of EMS triage of patients with suspected COVID-19 infection. Use of the PRIEST tool would improve sensitivity of triage without increasing the number of patients conveyed to hospital.

category: emergency medicine


title: Potentially inappropriate prescribing of DOACs to patients with mechanical heart valves: a federated analysis of 57.9 million patients' primary care records in situ using OpenSAFELY

abstract: National guidance was issued during the COVID-19 pandemic to switch patients on warfarin to direct oral anticoagulants (DOACs) where appropriate as these require less frequent blood testing. DOACs are not recommended for patients with mechanical heart valves. We conducted a retrospective cohort study of DOAC prescribing in people with a record of a mechanical heart valve between September 2019 and May 2021, and describe the characteristics of this population. We identified 15,457 individuals with a mechanical heart valve recorded in their records, of whom 1058 (6.8%) had been prescribed a DOAC during the study period. 767 individuals with a record of a mechanical heart valve were currently prescribed a DOAC as of May 31st 2021. This is suggestive of inappropriate prescribing of DOACs in individuals with mechanical heart valves. Direct alerts have been issued to clinicians through their EHR software informing the issue. We show that the OpenSAFELY platform can be used for rapid audit and feedback to mitigate the indirect health impacts of COVID-19 on the NHS. We will monitor changes in prescribing for this risk group over the following months.

category: primary care research


title: Patterns of adverse childhood experiences and associations with prenatal substance use and poor infant outcomes in a multi-country cohort of mothers: A Latent Class Analysis

abstract: Aims This paper explores the number and characterization of latent classes of adverse childhood experiences across the Evidence for Better Lives Study cohort and investigates how the various typologies link to prenatal substance use (i.e., smoking, alcohol, and illicit drugs) and poor infant outcomes (i.e., infant prematurity and low birth weight). Participants and setting A total of 1,189 mother-infant dyads residing in eight diverse low- and middle-income countries (LMICs) were recruited. Methods Latent class analysis using the Bolck, Croon, and Hagenaars (BCH) 3-step method with auxiliary multilevel logistic regressions with distal outcomes were performed. Results The LCA identified three high-risk classes and one low-risk class, namely: (1) highly maltreated (7%, n = 89), (2) emotionally and physically abused with intra-familial violence exposure (13%, n = 152), (3), emotionally abused (40%, n = 474), and (4) low household dysfunction and abuse (40%, n = 474). Overall, across all latent classes, there were low probabilities of prenatal substance use and poor infant outcomes. However, pairwise comparisons between classes indicate that class 1 and 3 had higher probabilities of prenatal illicit drug use compared to class 4. Additionally, class 2 had higher probability of low birth weight compared to the three remaining classes. Conclusion The results further our understanding of the dynamic and multifaceted nature of ACEs. More research grounded on LMICs is warranted with more attention to various parameters of risk exposure (i.e., severity, duration, chronicity).

category: public and global health


title: The Economic Costs of Child Maltreatment in UK

abstract: Child maltreatment is a major public health problem with significant consequences for individual victims and for society. In this paper we quantify for the first time the economic costs of fatal and non-fatal child maltreatment in the UK in relation to several short-, medium- and long-term outcomes ranging from physical and mental health problems, to labour market outcomes and welfare use. We combine novel regression analysis of rich data from the National Child Development Study and the English Longitudinal Study of Ageing with secondary evidence to produce an incidence-based estimate of the lifetime costs of child maltreatment from a societal perspective. The discounted average lifetime incidence cost of non-fatal child maltreatment by a primary caregiver is estimated at {pound}89,390 (95% uncertainty interval {pound}44,896 to {pound}145,508); the largest contributors to this are costs from social care, short-term health and long-term labour market outcomes. The discounted lifetime cost per death from child maltreatment is estimated at {pound}940,758, comprising health care and lost productivity costs. Our estimates provide the first comprehensive benchmark to quantify the costs of child maltreatment in the UK and the benefits of interventions aimed at reducing or preventing it.


title: Assessing the Effects of Behavioral Circadian Rhythm Disruption in Shift-Working Police Academy Trainees

abstract:
Night shift work, characterized by behavioral circadian disruption, increases cardiometabolic disease risk. Our long-term goal is to develop a novel methodology to quantify behavioral circadian disruption in field-based settings and to explore relations to four metabolic salivary biomarkers of circadian rhythm. This pilot study enrolled 36 police academy trainees to test the feasibility of using wearable activity trackers to assess changes in behavioral patterns. Using a two-group observational study design, participants completed in-class training during dayshift for six weeks followed by either dayshift or nightshift field-training for six weeks. We developed a novel data-post processing step that improves sleep detection accuracy of sleep episodes that occur during daytime. We next assessed changes to resting heart rate (RHR) and sleep regularity index (SRI) during dayshift versus nightshift field training. Secondarily, we examined changes in field-based assessments of salivary cortisol, uric acid, testosterone, and melatonin during dayshift versus nightshift. Compared to dayshift, nightshift workers experienced larger changes to resting heart rate, sleep regularity index (indicating reduced sleep regularity), and alternations to sleep/wake activity patterns accompanied by blunted salivary cortisol. Salivary uric acid, testosterone, and melatonin did not change. These findings show that nightshift work--a form of behavioral circadian rhythm disruption--was detectable in police trainees using activity trackers alone and in combination with a specialized data analysis methodology.

KEY POINTSO_LINight shift work increases cardiometabolic disease risk and this may be a consequence of behavioral circadian misalignment.
C_LIO_LITo advance this hypothesis, methodologies to quantify behavioral irregularities during nightshift in field-based settings are needed.
C_LIO_LIIn this pilot study, commercially available activity trackers combined with a novel data processing step were used to assess alterations in sleep/wake patterns in police trainees during dayshift versus nightshift.
C_LIO_LIWe also explored relations with four metabolic salivary biomarkers of circadian rhythm during dayshift versus nightshift.
C_LIO_LICompared to dayshift, nightshift resulted in larger perturbations of resting heart rate, sleep regularity index (indicating reduced regularity), and alterations in sleep and activity patterns; this was accompanied by blunted cortisol.
C_LIO_LIThis novel data processing step extends commercially available technology for successful application in real-world shift work settings.
C_LI

category: health informatics


title: Community Mobility and COVID-19 Dynamics in Jakarta, Indonesia

abstract:
BackgroundHuman mobility could act as a vector to facilitate the spread of infectious diseases. In response to the COVID-19 pandemic, Google Community Mobility Reports (CMR) provide the necessary data to explore community mobility further. Therefore, we aimed to examine the relationship between community mobility on COVID-19 dynamics in Jakarta, Indonesia.

MethodsWe utilized the mobility data from Google from February 15 to December 31, 2020. We explored several statistical models to estimate the COVID-19 dynamics in Jakarta. Model 1 was a Poisson Regression Generalized Linear Model (GLM), Model 2 was a Negative Binomial Regression Generalized Linear Model (GLM), and Model 3 was a Multiple Linear Regression (MLR).

ResultsWe found that Multiple Linear Regression (MLR) with some adjustments using Principal Component Analysis (PCA) was the best fit model. It explained 52% of COVID-19 cases in Jakarta (R-Square: 0.52, p<0.05). All mobility variables were significant predictors of COVID-19 cases (p<0.05). More precisely, about 1% change in grocery and pharmacy would contribute to a 4.12% increase of the COVID-19 cases in Jakarta. Retails and recreations, workplaces, transit stations, and parks would result in 3.11%, 2.56%, 2.26%, and 1.93% of more COVID-19 cases, respectively.

ConclusionOur study indicates that increased mobility contributes to increased COVID-19 cases. This finding will be beneficial to assist policymakers to have better outbreak management strategies, to anticipate increased COVID-19 cases in the future at certain public places and during seasonal events such as annual religious holidays or other long holidays in particular.

category: epidemiology


title: The long-term impact of vaginal surgical mesh devices in UK primary care: a cohort study in the CPRD

abstract:
ObjectiveStress urinary incontinence (SUI) and pelvic organ prolapse (POP) are treated with surgical mesh devices; evidence of their long-term complications is lacking. To examine long-term complications in women with SUI and/or POP, with and without surgical mesh implants.

DesignLongitudinal open cohort study from April 01 2006 to November 30 2018

SettingThe Clinical Practice Research Datalink (CPRD) Gold database, linked to Hospital Episodes Statistics (HES) inpatient data, Office for National Statistics mortality data, and Index of Multiple Deprivation socioeconomic status data.

ParticipantsWomen aged [≥]18 years with a diagnostic SUI/POP code.

ExposureMesh surgery coded in HES or CPRD data, compared to no mesh surgery.

Main Outcomes measuresRates of diagnoses of depression, anxiety or self-harm (composite measure) and sexual dysfunction, using Cox proportional hazards regression, and rates of prescriptions for antibiotics and opioids, using negative binomial regression.

ResultsThere were 220,544 women eligible for inclusion; 74% (n=162,687) had SUI, 37% (n=82,123) had POP and 11% (n=24,266) had both. Women undergoing mesh surgery for SUI or POP had higher rates of antibiotic use (SUI: IRR 1.15 (95% CI 1.13 to 1.18; p<0.001); POP: IRR 1.09 (95% CI 1.04 to 1.14; p<0.001)). Women with no previous history of the outcome, who underwent mesh surgery for SUI or POP, had higher rates of depression, anxiety, or self-harm (SUI: HR 2.43 (95% CI 2.19 to 2.70; p<0.001; POP: HR 1.47 (95% CI 1.19 to 1.81; p<0.001)), sexual dysfunction (SUI: HR 1.88 (1.50 to 2.36; p<0.001); POP: HR 1.64 (95% CI 1.02 to 2.63; p=0.04)) and opioid use (SUI: IRR 1.40 (95% CI 1.26 to 1.56, p<0.001); POP: IRR 1.23 (95% CI 1.01 to 1.49; p=0.04)). Women with a history of depression, anxiety and self-harm had lower rates of these outcomes with SUI or POP mesh surgery (SUI: HR 0.70 (95% CI 0.67 to 0.73; p<0.001), POP: HR 0.72 (95% CI 0.65 to 0.79; p<0.001). Women with a history of opioid use who had POP mesh surgery had lower rates of prescriptions (IRR 0.91 95% CI (0.86 to 0.96); p=0.001).

ConclusionsMesh surgery was associated with poor mental and sexual health outcomes, alongside increased opioid and antibiotic use, in women with no history of these outcomes and improved mental health, and lower opioid use, in women with a previous history of these outcomes. Careful consideration of the benefits and risk of mesh surgery for women with SUI or POP on an individual basis is required.

What is known on this topicThere are well publicised concerns about high complication rates and harms associated with surgical mesh, a treatment that has been used in urogynaecological procedures to treat stress urinary incontinence (SUI) and pelvic organ prolapse (POP) for the past 20 years. Yet, there is a consistent lack of long-term evidence over the use of surgical mesh beyond surgical readmission, with NICE, Cochrane, and the FDA all reporting a lack of long-term outcome data. This study reports long-term complications in women with stress urinary incontinence (SUI) and/or pelvic organ prolapse (POP), with and without surgical mesh implants.

What this study addsIn this cohort of 162,687 women with SUI and 82,123 women with POP, rates of depression, anxiety, self-harm, sexual dysfunction and opioid prescriptions were higher in women with mesh-surgery who had no previous history of these outcomes. Lower rates of depression, anxiety and self-harm were seen in women with a history of these outcomes and SUI or POP mesh surgery. Opioid prescribing was lower in women with a previous history of prescriptions and POP mesh surgery. Careful consideration of the benefits and risk of mesh surgery for women with SUI or POP on an individual basis is required.


title: Effectiveness of BNT162b2 and ChAdOx1 vaccines against symptomatic COVID-19 among Healthcare Workers in Kuwait: A retrospective cohort study

abstract:
BackgroundThe COVID-19 BNT162b2 vaccination roll-out in Kuwait started on 24 December 2020 followed by ChAdOx1 on 3 February 2021. The study objectives were to assess the factors associated with vaccine coverage and determine vaccine effectiveness (VE) against SARS-CoV-2 infection in a healthcare worker (HCW) population.

MethodsThis retrospective cohort study was conducted among HCW working at a public secondary hospital in Kuwait. The follow-up period was from 24 December 2020 to 15 June 2021. The primary outcomes were vaccine coverage and PCR-confirmed SARS-CoV-2 infection for the VE analysis. Data on new SARS-CoV-2 infections (with or without symptoms) during study period in addition to HCWs characteristics (sex, age, nationality, and occupation) were extracted from the hospital records. The vaccine coverage and PCR-confirmed SARS-CoV-2 infections were cross-tabulated by the HCWs characteristics. Furthermore, we used Cox regression to estimate time-to-infection hazard ratios in vaccinated (first and second dose) compared to unvaccinated HCWs. Only one ChAdOx1 dose was given during the study period.

ResultsThere were 3246 HCWs included in the analysis. The median age was 38 years (IQR = 33 - 44), 63.4% were females, 46.8% aged 31-40, and 82.3% were non-Kuwaitis. Overall, 82.1% of HCWs received at least one vaccine dose (50.4% received only one dose of ChAdOx1, 3.3% received one dose of BNT162b2, and 28.3% received two doses of BNT162b2). 17.9% of HCWs remained unvaccinated by the end of the study. A significantly lower vaccination coverage percentage was amongst female HCWs, younger age group (20 - 30 years old), and administrative/executive staff. Symptomatic SARS-CoV-2 PCR-confirmed infection prevalence was 7.3%. No asymptomatic infections were reported. The SARS-CoV-2 infection incidence rate was 126 per 100,000 person-days in the unvaccinated group; whereas, the incidence rates in the partially vaccinated groups ([≥] 28 days after ChAdOx1 first dose) and ([≥] 14 days after receiving BNT162b2 through receipt of second dose) were 31.4 and 10.9 per 100,000 person-days, respectively. In the fully vaccinated group ([≥] 14 days after BNT162b2 second dose), the incidence rate was 6.3 per 100,000 person-days. The estimated adjusted vaccine effectiveness of fully vaccinated was 94.5% (95% confidence interval [CI] = 89.4%-97.2%). The VE of partially vaccinated for ChAdOx1 and BNT162b2 was 75.4% (95% CI = 67.2%-81.6%) and 91.4% (95% CI = 65.1%-97.9%), respectively.

ConclusionsBoth BNT162b2 and ChAdOx1 vaccines prevented most symptomatic infections in this population across age groups, nationalities, and occupations. A significant proportion (17.9%) of HCWs were unvaccinated despite the vaccine accessibility. The findings complement other VE studies and demonstrate the vaccine benefit among HCWs.