title: Seroresponse to SARS-CoV-2 vaccines among maintenance dialysis patients over six months

abstract:
Background and ObjectivesWhile most maintenance dialysis patients exhibit initial seroresponse to vaccination, concerns remain regarding the durability of this antibody response. This study evaluated immunity over time.

Design, setting, participants, and measurementsThis retrospective cohort study included maintenance dialysis patients from a midsize national dialysis provider who received a complete SARS-CoV-2 vaccine series and had at least one antibody titer checked after full vaccination. Immunoglobulin G spike antibodies (SAb-IgG) titers were assessed monthly with routine labs beginning after full vaccination and followed over time; the semiquantitative SAb-IgG titer reported a range between 0 and [≥] 20 U/L. Descriptive analyses compared trends over time by prior history of COVID-19 and type of vaccine received. Time-to-event analyses were conducted for the outcome of loss of seroresponse (SAb-IgG < 1 U/L or development of COVID-19). Cox proportional hazards regression was used to adjust for additional clinical characteristics of interest.

ResultsAmong 1898 maintenance dialysis patients, 1567 (84%) had no prior history of COVID-19. Patients without a history of COVID-19 had declining titers over time. Among 441 BNT162b2/Pfizer recipients, median [IQR] SAb-IgG titer declined from 20 [5.99-20] U/L in month 1 to 1.30 [0.15-3.59] U/L by month 6. Among 779 mRNA-1273/Moderna recipients, median [IQR] SAb-IgG titer declined from 20 [20-20] in month 1 to 6.20 [1.74-20] by month 6. The 347 Ad26.COV2.S/Janssen recipients had a lower titer response than mRNA vaccine recipients over all time periods. In time-to-event analyses, Ad26.COV2.S/Janssen and mRNA-1273/Moderna recipients had the shortest and longest time to loss of seroresponse, respectively. The maximum titer reached in the first two months after full vaccination was predictive of the durability of the SAb-IgG seroresponse; patients with SAb-IgG titer 1-19.99 U/L were more likely to have loss of seroresponse compared to patients with SAb-IgG titer [≥] 20 U/L (HR 23.9 [95% CI: 16.1-35.5]).

ConclusionsVaccine-induced seroresponse wanes over time among maintenance dialysis patients across vaccine types. Early titers after full vaccination predict the durability of seroresponse.


title: Women's views and experiences of accessing vaccination in pregnancy during the COVID-19 pandemic: A multi-methods study in the United Kingdom

abstract:
BackgroundCOVID-19 changed access to healthcare, including vaccinations, in the United Kingdom (UK). This study explored UK womens experiences of accessing pertussis vaccination during pregnancy and infant vaccinations during COVID-19.

MethodsAn online cross-sectional survey was completed, between 3rd August-11 th October 2020, by 1404 women aged 16+ years who were pregnant at some point after the first UK lockdown from March 23rd, 2020. Ten follow-up semi-structured interviews were conducted.

ResultsMost women surveyed were pregnant (65.7%) and a third postnatal (34.3%). Almost all women (95.6%) were aware that pertussis vaccination is recommended in pregnancy. Most pregnant (72.1%) and postnatal women (84.0%) had received pertussis vaccination; however, access issues were reported.

Over a third (39.6%) of women had a pregnancy vaccination appointment changed. COVID-19 made it physically difficult to access pregnancy vaccinations for one fifth (21.5%) of women and physically difficult to access infant vaccinations for almost half of women (45.8%). Nearly half of women (45.2%) reported feeling less safe attending pregnancy vaccinations and over three quarters (76.3%) less safe attending infant vaccinations due to COVID-19. The majority (94.2%) felt it was important to get their baby vaccinated during COVID-19.

Pregnant women from ethnic-minorities and lower-income households were less likely to have been vaccinated. Minority-ethnicity women were more likely to report access problems and feeling less safe attending vaccinations for both themselves and their babies.

Qualitative analysis found women experienced difficulties accessing antenatal care and relied on knowledge from previous pregnancies to access vaccines in pregnancy.

ConclusionDuring the ongoing and future pandemics, healthcare services should prioritise equitable access to routine vaccinations, including tailoring services for ethnic-minority families who experience greater barriers to vaccination.

HighlightsO_LIAccess to pregnancy vaccines in the United Kingdom was disrupted by the COVID-19 pandemic.
C_LIO_LIUK women reported difficulties in physically accessing vaccine appointments and feeling less safe accessing vaccine appointments for themselves when pregnant and for their babies during COVID-19, with women from ethnic minorities in the UK were more likely to report difficulties.
C_LIO_LIVaccine services must ensure equitable access to vaccine appointments during the ongoing COVID-19 pandemic including tailoring services for lower income and ethnic minority families.
C_LI

category: infectious diseases


title: Improved detection of SBDS gene mutation by a new method of next-generation sequencing analysis based on the Chinese mutation spectrum

abstract: Next-generation sequencing (NGS) is a useful molecular diagnostic tool for genetic diseases. However, due to the presence of highly homologous pseudogenes, it is challenging to use short-read NGS for analyzing mutations of the Shwachman-Bodian-Diamond syndrome (SBDS) gene. The SBDS mutation spectrum was analyzed in the Chinese population, which revealed that SBDS variants were primarily from sequence exchange between SBDS and its pseudogene at the base-pair level, predominantly in the coding region and splice junction of exon two. The c.258+2T>C and c.185_184TA>GT variants were the two most common pathogenic SBDS variants in the Chinese population, resulting in a total carrier frequency of 1.19%. When analyzing pathogenic variants in the SBDS gene from the NGS data, the misalignment was identified as a common issue, and there were different probabilities of misalignment for different pathogenic variants. Here, we present a novel mathematical method for identifying pathogenic variants in the SBDS gene from the NGS data, which utilizes read-depth of the paralogous sequence variant (PSV) loci of SBDS and its pseudogene. Combined with PCR and STR orthogonal experiments, the results of SBDS gene mutation analysis were improved in 40% of clinical samples, and various types of mutations such as homozygous, compound heterozygous, and uniparental diploid were explored. The findings effectively reduce the impact of misalignment in NGS-based SBDS mutation analysis and are helpful for the clinical diagnosis of SBDS-related diseases, the research into population variation, and the carrier screening.

category: geriatric medicine


title: Distributed Counterfactual Modeling Approach for Investigating Hospital-Associated Racial Disparities in COVID-19 Mortality

abstract: Several studies have found that black patients are more likely than white patients to test positive for or be hospitalized with COVID-19, but many of these same studies have found no difference in in-hospital mortality. These studies may have underestimated racial differences due to reliance on data from a single hospital system, as adequate control of patient-level characteristics requires aggregation of highly granular data from several institutions. Further, one factor thought to contribute to disparities in health outcomes by race is site of care. Several differences between black and white patient populations, such as access to care and referral patterns among clinicians, can lead to patients of different races largely attending different hospitals. We sought to develop a method that could study the potential association between attending hospital and racial disparity in mortality for COVID-19 patients without requiring patient-level data sharing among collaborating institutions. We propose a novel application of a distributed algorithm for generalized linear mixed modeling (GLMM) to perform counterfactual modeling and investigate the role of hospital in differences in COVID-19 mortality by race. Our counterfactual modeling approach uses simulation to randomly assign black patients to hospitals in the same distribution as those attended by white patients, quantifying the difference between observed mortality rates and simulated mortality risk following random hospital assignment. To illustrate our method, we perform a proof-of-concept analysis using data from four hospitals within the OneFlorida Clinical Research Consortium. Our approach can be used by investigators from several institutions to study the impact of admitting hospital on COVID-19 mortality, a critical step in addressing systemic racism in modern healthcare.

category: health informatics


title: Detection of SARS-CoV-2 in the community by nucleic acid amplification testing of saliva

abstract: Efficient wide-scale testing for SARS-CoV-2 is crucial for monitoring the incidence of the infection in the community. The gold standard for COVID-19 diagnosis is the molecular analysis of epithelial secretions from the upper respiratory system captured by nasopharyngeal (NP) swabs, which requires the intervention of trained personnel. Given the ease of collection, saliva has been proposed as a possible substitute to support testing at the population level. Here we describe the set-up of a laboratory, in an academic context, for the high-throughput screening of SARS-CoV-2 in the saliva from the community. A novel saliva collection device was designed to favour the safe and correct acquisition of the sample as well as the processivity of the downstream molecular analysis. To test the performance of the system,1025 paired saliva and nasopharyngeal samples were collected from individuals recruited at a public drive through testing facility and analysed in parallel. An overall moderate concordance (68%) between the two tests was found, with evidence that neither test can diagnose the infection in 100% of the cases. While the two tests performed equally well in symptomatic individuals, their discordance was mainly restricted to samples from convalescent individuals. The saliva test was at least as effective as NP swabs in asymptomatic individuals recruited for contact tracing. Our study, therefore, indicates that saliva testing can be a reliable tool for wide-scale COVID-19 screening in the community.


title: Self-reported and physiological reactions to the third BNT162b2 mRNA COVID-19 (booster) vaccine dose

abstract:
BackgroundThe rapid rise in hospitalizations associated with the Delta-driven COVID-19 resurgence, and the imminent risk of hospital overcrowding, led the Israeli government to initialize a national third (booster) COVID-19 vaccination campaign in early August 2021, offering the BNT162b2 mRNA vaccine to individuals who received their second dose over five months ago. However, the safety of the third (booster) dose has not been fully established yet.

ObjectiveEvaluate the short-term, self-reported and physiological reactions to the third BNT162b2 mRNA COVID-19 (booster) vaccine dose.

DesignA prospective observational study, in which participants are equipped with a smartwatch and fill in a daily questionnaire via a dedicated mobile application for a period of 21 days, starting seven days before the vaccination.

SettingAn Israel-wide third (booster) vaccination campaign.

ParticipantsA group of 1,609 (18+ years of age) recipients of at least one dose of the BNT162b2 vaccine between December 20, 2020, and September 15, 2021, out of a larger cohort of 2,912 prospective study participants. 1,344 of the participants were recipients of the third vaccine dose.

MeasurementsDaily self-reported questionnaires regarding local and systemic reactions, mood level, stress level, sport duration, and sleep quality. Heart rate, heart rate variability and blood oxygen saturation level were continuously measured by Garmin Vivosmart 4 smartwatches.

ResultsThe extent of systemic reactions reported following the third (booster) dose administration is similar to that reported following the second dose (p-value=0.305) and considerably greater than that reported following the first dose (p-value<0.001). Our analyses of self-reported well-being indicators as well as the objective heart rate and heart rate variability measures recorded by the smartwatches further support this finding. Focusing on the third dose, reactions were more apparent in younger participants (p-value<0.01), in women (p-value<0.001), and in participants with no underlying medical conditions (p-value<0.001). Nevertheless, reported reactions and changes in physiological measures returned to their baseline levels within three days from inoculation with the third dose.

LimitationsParticipants may not adequately represent the vaccinated population in Israel and elsewhere.

ConclusionOur work further supports the safety of a third COVID-19 BNT162b2 mRNA (booster) vaccine dose from both a subjective and an objective perspective, particularly in individuals 65+ years of age and those with underlying medical conditions.

Primary funding sourceEuropean Research Council (ERC) project #949850


title: Quantitative measurement of infectious virus in SARS-CoV-2 Alpha, Delta and Epsilon variants reveals higher infectivity (viral titer:RNA ratio) in clinical samples containing the Delta and Epsilon variants.

abstract:
BackgroundNovel SARS-CoV-2 Variants of Concern (VoC) pose a challenge to controlling the COVID-19 pandemic. Previous studies indicate that clinical samples collected from individuals infected with the Delta variant may contain higher levels of RNA than previous variants, but the relationship between viral RNA and infectious virus for individual variants is unknown.

MethodsWe measured infectious viral titer (using a micro-focus forming assay) as well as total and subgenomic viral RNA levels (using RT-PCR) in a set of 165 clinical samples containing SARS-CoV-2 Alpha, Delta and Epsilon variants that were processed within two days of collection from the patient.

ResultsWe observed a high degree of variation in the relationship between viral titers and RNA levels. Despite the variability we observed for individual samples the overall infectivity differed among the three variants. Both Delta and Epsilon had significantly higher infectivity than Alpha, as measured by the number of infectious units per quantity of viral E gene RNA (6 and 4 times as much, p=0.0002 and 0.009 respectively) or subgenomic E RNA (11 and 7 times as much, p<0.0001 and 0.006 respectively).

ConclusionIn addition to higher viral RNA levels reported for the Delta variant, the infectivity (amount of replication competent virus per viral genome copy) may also be increased compared to Alpha. Measuring the relationship between live virus and viral RNA is an important step in assessing the infectivity of novel SARS-CoV-2 variants. An increase in the infectivity of the Delta variant may further explain increased spread and suggests a need for increased measures to prevent viral transmission.

SIGNIFICANCE STATEMENTCurrent and future SARS-CoV-2 variants threaten our ability to control the COVID-19 pandemic. Variants with increased transmission, higher viral loads, or greater immune evasion are of particular concern. Viral loads are currently measured by the amount of viral RNA in a clinical sample rather than the amount of infectious virus. We measured both RNA and infectious virus levels directly in a set of 165 clinical specimens from Alpha, Epsilon or Delta variants. Our data shows that Delta is more infectious compared to Alpha, with [~] six times as much infectious virus for the same amount of RNA. This increase in infectivity suggests increased measures (vaccination, masking, distancing, ventilation) are needed to control Delta compared to Alpha.


title: The Geography of Chronic Pain in the United States and Canada.

abstract: Our understanding of population pain epidemiology is largely based on national-level analyses. This focus, however, neglects potential cross-national, and especially sub-national, geographic variations in pain, even though geographic comparisons could shed new light on factors that drive or protect against pain. This article presents the first comparative analysis of pain in the U.S. and Canada, comparing the countries in aggregate and analyzing variation across states and provinces. Analyses are based on cross-sectional data collected in 2020 from 2,124 U.S. and 2,110 Canadian adults 18 years and older. Our pain measure is a product of pain frequency and pain-related interference with daily activities. We use regression and decomposition methods to link socioeconomic characteristics and pain, and inverse-distance weighting spatial interpolation to map pain scores. We find significantly and substantially higher pain in the U.S. than in Canada. The difference is accounted for by Americans lower economic wellbeing. Additionally, we find variation in pain within countries; the variation is statistically significant across U.S. states. Further, we identify nine hotspot states in the Deep South, Appalachia, and the West where respondents have significantly higher pain than those in the rest of the U.S. or Canada. This excess pain is partly attributable to economic distress, but a large part remains unexplained; we speculate that it may reflect the sociopolitical context of the hotspot states. Overall, our findings identify areas with high need for pain prevention and management; they also other scholars to consider geographic factors as important contributors to population pain.

category: epidemiology


title: Spatiotemporal analyses illuminate the competitive advantage of a SARS-CoV-2 variant of concern over a variant of interest

abstract: The emergence of novel SARS-CoV-2 variants in late 2020 and early 2021 raised alarm worldwide and prompted reassessment of the management, surveillance, and projected future of COVID-19. Mutations that confer competitive advantages by increasing transmissibility or immune evasion have been associated with the localized dominance of single variants. Thus, elucidating the evolutionary and epidemiological dynamics among novel variants is essential for understanding the trajectory of the COVID-19 pandemic. Here we show the interplay between B.1.1.7 (Alpha) and B.1.526 (Iota) in New York (NY) from December 2020 to April 2021 through phylogeographic analyses, space-time scan statistics, and cartographic visualization. Our results indicate that B.1.526 likely evolved in the Bronx in late 2020, providing opportunity for an initial foothold in the heavily interconnected New York City (NYC) region, as evidenced by numerous exportations to surrounding locations. In contrast, B.1.1.7 became dominant in regions of upstate NY where B.1.526 had limited presence, suggesting that B.1.1.7 was able to spread more efficiently in the absence of B.1.526. Clusters discovered from the spatial-time scan analysis supported the role of competition between B.1.526 and B.1.1.7 in NYC in March 2021 and the outsized presence of B.1.1.7 in upstate NY in April 2021. Although B.1.526 likely delayed the rise of B.1.1.7 in NYC, B.1.1.7 became the dominant variant in the Metro region by the end of the study period. These results reveal the advantages endemicity may grant to a variant (founder effect), despite the higher fitness of an introduced lineage. Our research highlights the dynamics of inter-variant competition at a time when B.1.617.2 (Delta) is overtaking B.1.1.7 as the dominant lineage worldwide. We believe our combined spatiotemporal methodologies can disentangle the complexities of shifting SARS-CoV-2 variant landscapes at a time when the evolution of variants with additional fitness advantages is impending.


title: Evolution of COVID-19 mortality over time: results from the Swiss hospital surveillance system (CH-SUR)

abstract:
BackgroundWhen comparing the periods of time during and after the first wave of the ongoing SARS-CoV-2/COVID-19 pandemic in Europe, the associated COVID-19 mortality seems to have decreased substantially. Various factors could explain this trend, including changes in demographic characteristics of infected persons, and the improvement of case management. To date, no study has been performed to investigate the evolution of COVID-19 in-hospital mortality in Switzerland, while also accounting for risk factors.

MethodsWe investigated the trends in COVID-19 related mortality (in-hospital and in-intermediate/intensive-care) over time in Switzerland, from February 2020 to May 2021, comparing in particular the first and the second wave. We used data from the COVID-19 Hospital-based Surveillance (CH-SUR) database. We performed survival analyses adjusting for well-known risk factors of COVID-19 mortality (age, sex and comorbidities) and accounting for competing risk.

ResultsOur analysis included 16,030 episodes recorded in CH-SUR, with 2,320 reported deaths due to COVID-19 (13.0% of included episodes). We found that overall in-hospital mortality was lower during the second wave of COVID-19 compared to the first wave (HR 0.71, 95% CI 0.69 - 0.72, p-value < 0.001), a decrease apparently not explained by changes in demographic characteristics of patients. In contrast, mortality in intermediate and intensive care significantly increased in the second wave compared to the first wave (HR 1.48, 95% CI 1.42 - 1.55, p-value < 0.001), with significant changes in the course of hospitalisation between the first and the second wave.

ConclusionWe found that, in Switzerland, COVID-19 mortality decreased among hospitalised persons, whereas it increased among patients admitted to intermediate or intensive care, when comparing the second wave to the first wave. We put our findings in perspective with changes over time in case management, treatment strategy, hospital burden and non-pharmaceutical interventions. Further analyses of the potential effect of virus variants and of vaccination on mortality would be crucial to have a complete overview of COVID-19 mortality trends throughout the different phases of the pandemic.


title: Making colonoscopy-based screening more efficient: a "gateopener" approach

abstract:
ObjectivesTo assess the potential of an innovative approach to colonoscopy-based screening for colorectal cancer (CRC), by use of a single, low threshold fecal immunochemical test (FIT) as a  gateopener for screening colonoscopy.

DesignSimulation study using COSIMO, a validated Markov-based simulation model, in a hypothetical German population.

SettingModelled scenarios included either direct invitation to screening colonoscopy or mailing a single ( gateopener) FIT along with an invitation to colonoscopy contingent on a FIT value above a low threshold yielding a 50% positivity rate (i.e., every other pre-test will be positive). The main analyses focused on scenarios assuming identical colonoscopy uptake, resulting from higher adherence to the gateopener FIT than to primary use of colonoscopy and avoidance of colonoscopy in those with below-threshold FIT values.

ParticipantsHypothetical cohorts of 100,000 previously unscreened men and women using screening at different ages and with varying levels of adherence.

InterventionsScreening colonoscopy without and with preceding gateopener FIT.

Main outcome measureDetected and prevented CRC cases and deaths within 10 years.

ResultsAcross all ages and both sexes, use of screening colonoscopy contingent on a positive gateopener FIT yielded approximately doubled cancer detection rates as compared to conventional screening. In those spared from undergoing screening colonoscopy due to a negative FIT pretest, numbers needed to screen were 10-times higher as compared to those for individuals with a positive FIT, peaking in more than 2500 and more than 3800 (hypothetically) needed colonoscopies to detect one case of cancer in 50-year-old men and women, respectively. At identical levels of colonoscopy use, gateopener screening resulted in 51-53% and 63-68% more prevented CRC cases and deaths, respectively.

ConclusionsBy directing colonoscopy capacities to those most likely to benefit from it, offer of screening colonoscopy contingent on a  gateopener low-threshold FIT would substantially enhance efficiency of colonoscopy screening.

Summary BoxO_ST_ABSWhat is already known on this topicC_ST_ABSO_LIScreening colonoscopy as primary examination is inefficient as most of the screened subjects would never develop colorectal cancer even without screening.
C_LIO_LIEfficiency could be enhanced by pre-selecting those most likely to benefit, e.g., by use of a single low-threshold faecal immunochemical test ( gateopener FIT)
C_LI

What this study addsO_LIA simulation where only individuals with positive gateopener FIT proceeded to screening colonoscopy resulted in 50% fewer colonoscopies required to detect one case of cancer vs conventional screening colonoscopy.
C_LIO_LIAt identical colonoscopy uptake rates, the gateopener approach implied approximately 50% and 70% more prevented colorectal cancer cases and deaths, respectively.
C_LIO_LIInviting subjects to undergo pre-testing with low-threshold FITs would markedly improve efficiency of colonoscopy-based screening.
C_LI

category: gastroenterology


title: Correlates of COVID-19 vaccine acceptance, hesitancy and refusal among employees of a safety net California county health system with an early and aggressive vaccination program: Results from a cross-sectional survey

abstract: Information on vaccine acceptance among healthcare workers is needed as health professionals provide front line care to COVID-19 patients. We developed and implemented an anonymous internet-based cross-sectional survey with direct solicitation among employees of a safety net health system. Items queried demographic and health-related characteristics, experience with and knowledge of COVID-19, and determinants of decisions to vaccinate. COVID-19 vaccine acceptance groups (acceptors, hesitant, refusers) were defined; an adapted version of the WHO vaccine hesitancy scale was included. The survey demonstrated good reliability (Cronbachs alpha = 0.92 for vaccine hesitancy scale; 0.93 for determinants). General linear and logistic regression methods examined factors which were univariately associated with vaccine hesitancy and vaccine acceptance, respectively. Multivariable models were constructed with stepwise model-building procedures. Race/ethnicity, marital status, job classification, immunocompromised status, flu vaccination and childhood vaccination opinions independently predicted hesitancy scale scores. Gender, education, job classification and BMI independently predicted acceptance, hesitancy and refusal groups. Among hesitant employees, uncertainty was reflected in reports of motivating factors influencing their indecision. Despite a strong employee-support environment and job protection, respondents reported physical and mental health effects. Appreciation of varied reasons for refusing vaccination should lead to culturally sensitive interventions to increase vaccination rates in healthcare workers.

category: public and global health


title: Proton pump inhibitors use and risk of preeclampsia

abstract: Preeclampsia is one of the common complications of pregnancy and is characterized by high blood pressure. Proton pump inhibitors (PPIs) are commonly used for the management of gastroesophageal reflux disease among pregnant women. Recently, multiple epidemiological studies suggested the association between PPIs use and the risk of preeclampsia. This study aims to review the evidence and meta-analyse the pooled risk of preeclampsia in PPI users from epidemiological studies. Databases-MEDLINE, Embase, Scopus, Web of Science Core Collection, Emcare, and CINAHL (EBSCO) as well as sources of grey literature, ProQuest Dissertations & Theses Global, ClinicalTrials.gov and WHO International Clinical Trials Registry Platform will be searched to identify the epidemiological studies assessing the association between PPIs use and the risk of preeclampsia. Study selection, data extraction, and quality assessment will be performed by two independent authors. The risk of bias among included studies will be evaluated by using the Newcastle-Ottawa scale. The pooled effect of PPIs use on the risk of preeclampsia in pregnant women is the primary outcome of interest. Meta-analysis will be performed using Review Manager version 5.4.

category: obstetrics and gynecology


title: COVID-19 Vaccination and Healthcare Demand

abstract: One of the driving concerns during any epidemic is the strain on the healthcare system. As we have seen many times over the globe with the COVID-19 pandemic, hospitals and ICUs can quickly become overwhelmed by cases. While strict periods of public health mitigation have certainly helped decrease incidence and thus healthcare demand, vaccination is the only clear long-term solution. In this paper, we develop a two-module model to forecast the effects of relaxation of non-pharmaceutical intervention and vaccine uptake on daily incidence, and the cascade effects on healthcare demand. The first module is a simple epidemiological model which incorporates non-pharmaceutical intervention, the relaxation of such measures and vaccination campaigns to predict caseloads into the the Fall of 2021. This module is then fed into a healthcare module which can forecast the number of doctor visits, the number of occupied hospital beds, number of occupied ICU beds and any excess demand of these. From this module we can also estimate the length of stay of individuals in ICU. For model verification and forecasting, we use the four most populous Canadian provinces as a case study.

category: health economics


title: SARS-CoV-2 variants in Paraguay: Detection and surveillance with a readily modifiable, multiplex real-time RT-PCR

abstract:
ObjectivesThe objective of the current study was to develop a lower-cost and scalable protocol to identify and monitor SARS-CoV-2 variants in Paraguay by pairing real-time RT-PCR detection of spike mutations with amplicon Sanger sequencing and whole-genome Nanopore sequencing.

Methods201 acute-phase nasopharyngeal samples from SARS-CoV-2-positive individuals were tested with two rRT-PCRs: 1) N2RP assay to confirm SARS-CoV-2 RNA detection (CDC N2 target), and 2) the Spike SNP assay to detect mutations in the spike receptor binding domain. The assay was performed with probes to identify mutations associated with the following variants: alpha (501Y), beta/gamma (417variant/484K/501Y), delta (452R/478K), and lambda (452Q/490S).

ResultsAll samples were positive for SARS-CoV-2 in the N2RP assay (mean Ct, 20.8; SD 5.6); 198/201 (98.5%) tested positive in the Spike SNP assay. The most common genotype was 417variant/484K/501Y, detected in 102/198 samples (51.5%) and most consistent with P.1 lineage (gamma variant) in Paraguay. No mutations (K417 only) were found in 64/198 (32.3%); and K417/484K was identified in 22/198 (11.1%), consistent with P.2 (zeta). Seven samples (3.5%) tested positive for 452R without 478K, and one sample with genotype K417/501Y was confirmed as B.1.1.7 (alpha). Results were confirmed by Sanger sequencing in 181/181 samples (100%) with high-quality amplicon sequences, and variant calls were consistent with Nanopore sequencing in 29/29 samples.

ConclusionsThe Spike SNP assay provides accurate detection of mutations associated with SARS-CoV-2 variants. This can be implemented in laboratories performing rRT-PCR to improve population-level surveillance for these mutations and inform the judicious use of scarce sequencing resources.


title: Impaired Lymphocyte Responses in Pediatric Sepsis Vary by Pathogen Type

abstract:
BackgroundSepsis is the leading cause of death in hospitalized children worldwide. Despite its hypothesized immune-mediated mechanism, targeted immunotherapy for sepsis is not available for clinical use.

ObjectiveTo determine the association between cytometric, proteomic, bioenergetic, and metabolomic abnormalities and pathogen type in pediatric sepsis.

MethodsSerial PBMC samples were obtained from 14 sepsis patients (34 samples) and 7 control patients for this pilot study. Flow cytometry was used to define immunophenotype, including T cell subset frequency and activation state, and assess intracellular cytokine production. Global immune dysfunction was assessed by TNF-production capacity and monocyte HLA-DR expression. Mitochondrial function was assessed by bulk respirometry. Plasma cytokine levels were determined via Luminex assay. Metabolites were measured by liquid chromatography-mass spectrometry. Results were compared by timepoint and pathogen type.

ResultsSepsis patients were older and had higher illness severity compared to controls; demographics were otherwise similar. Compared to controls, sepsis patients demonstrated global immune dysfunction, loss of peripheral of non-naive CD4+ T cells, and reduced PBMC mitochondrial function. Metabolomic findings in sepsis patients were most pronounced at sepsis onset and included elevated uridine and 2-dehydrogluconate and depleted citrulline. Loss of peripheral non-naive CD4+ T cells was associated with immune dysfunction and reduced cytokine production despite increased T cell activation. CD4+ T cell differentiation and corresponding pro- and anti-inflammatory cytokines varied by pathogen.

ConclusionPediatric sepsis patients exhibit a complex, dynamic physiologic state characterized by immunometabolic dysregulation which varies by pathogen type.

category: intensive care and critical care medicine


title: Risk of cancer in regular and low meat-eaters, fish-eaters, and vegetarians: a prospective analysis of UK Biobank participants

abstract:
BackgroundFollowing a vegetarian diet has become increasingly popular and some evidence suggests that being vegetarian may be associated with a lower risk of cancer overall. However, for specific cancer sites, the evidence is limited.

AimTo assess the associations of vegetarian and non-vegetarian diets with risks of all cancer, colorectal cancer, postmenopausal breast cancer, and prostate cancer, and to explore the role of potential mediators between these associations.

MethodsWe conducted a prospective analysis of 472,377 UK Biobank participants who were free from cancer at recruitment. Participants were categorised into regular meat-eaters (n=247,571), low meat-eaters (n=205,385), fish-eaters (n=10,696), and vegetarians (n=8,685) based on dietary questions completed at recruitment. Multivariable-adjusted Cox regressions were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for all cancer incidence and separate cancer sites across diet groups.

ResultsAfter an average follow-up of 11.4 years, 54,961 incident cancers were identified, including 5,882 colorectal, 7,537 postmenopausal breast, 9,501 prostate cancer cases. Compared with regular meat-eaters, being a low meat-eater, fish-eater, or vegetarian were all associated with a lower risk of all cancer (HR: 0.98, 95% CI: 0.96-1.00; 0.90, 0.84-0.96; 0.86, 0.80-0.93, respectively). Being a low meat-eater was associated with a lower risk of colorectal cancer in comparison to regular meat-eaters (0.91, 0.86-0.96); there was heterogeneity in this association by sex (p=0.007), with an inverse association across diet groups in men, but not in women. Vegetarian postmenopausal women had a lower risk of breast cancer (0.82, 0.68-0.99), which was attenuated and non-significant after adjusting for body mass index (BMI; 0.87, 0.72-1.05); in mediation analyses, BMI was found to possibly mediate the observed association. In men, being a fish-eater or a vegetarian was inversely associated with prostate cancer risk (0.80, 0.65-0.99 and 0.69, 0.54-0.89, respectively).

ConclusionLow and non-meat-eaters had a lower risk of being diagnosed with cancer in comparison to regular meat-eaters. We also found that low meat-eaters had a lower risk of colorectal cancer, vegetarian women had a lower risk of postmenopausal breast cancer, and vegetarians and fish-eaters had a lower risk of being diagnosed with prostate cancer. The lower risk of colorectal cancer in low meat-eaters is consistent with previous evidence suggesting an adverse impact of meat intake. The lower risk of postmenopausal breast cancer in vegetarian women may be explained by their lower BMI. It is not clear whether the other differences observed, for all cancers and for prostate cancer, reflect any causal relationships or are or due to other factors such as residual confounding or differences in cancer detection.


title: Environmental factors and mobility predict COVID-19 seasonality

abstract:
BackgroundWe recently showed that seasonal patterns of COVID-19 incidence and Influenza-Like Illnesses incidence are highly similar, in a country in the temperate climate zone, such as the Netherlands (latitude: 52{degrees}N). We hypothesize that in The Netherlands the same environmental factors and mobility trends that are associated with the seasonality of flu-like illnesses are predictors of COVID-19 seasonality as well.

MethodsWe used meteorological, pollen/hay fever and mobility data from the Netherlands with its 17.4 million inhabitants. For the reproduction number of COVID-19 (Rt), we used data from the Dutch State Institute for Public Health. This Rt metric is a daily estimate that is based on positive COVID-19 tests in the Netherlands in hospitals and municipalities. For all datasets we selected the overlapping period of COVID-19 and the first allergy season: from February 17, 2020 till September 21, 2020 (total number of measurements: n = 218), the end of pollen season. Backward stepwise multiple linear regression was used to develop an environmental prediction model of the Rt of COVID-19. Next, we studied whether adding mobility trends to an environmental model improved the predictive power.

ResultsBy means of stepwise backward multiple linear regression four highly significant (p value < 0.01) predictive factors are selected in our combined model: temperature, solar radiation, hay fever incidence, and mobility to indoor recreation locations. Our combined model explains 87.5% of the variance of Rt of COVID-19 and has a good and highly significant fit: F(4, 213) = 374.2, p-value < 0.00001. The combined model had a better overall predictive performance compared to a solely environmental model, which still explains 77.3% of the variance of Rt, and a good and highly significant fit: F(4, 213) = 181.3, p < 0.00001.

ConclusionsWe conclude that the combined mobility and environmental model can adequately predict the seasonality of COVID-19 in a country with a temperate climate like the Netherlands. In this model higher solar radiation, higher temperature and hay fever are related to lower COVID-19 reproduction, and mobility to indoor recreation locations with increased COVID-19 spread.

HighlightsO_LIThe seasonality of COVID-19 can be well-explained by environmental factors and mobility.
C_LIO_LIA combined model explains 87.5% of the variance of the reproduction number of COVID-19
C_LIO_LIInhibitors of the reproduction number of COVID-19 are higher solar radiation, and seasonal allergens/allergies.
C_LIO_LIMobility, especially to indoor recreation locations, increases the reproduction number of COVID-19.
C_LIO_LITemperature has no direct effect on the reproduction number of COVID-19, but affects mobility and seasonal allergens.
C_LIO_LIAdding mobility trends to an environmental model improves the predictive value regarding the reproduction number of COVID-19.
C_LI


title: Impact of multiple sclerosis disease-modifying therapies on SARS-CoV-2 vaccine-induced antibody and T cell immunity

abstract: Vaccine-elicited adaptive immunity is an essential prerequisite for effective prevention and control of coronavirus 19 (COVID-19). Treatment of multiple sclerosis (MS) involves a diverse array of disease-modifying therapies (DMTs) that target antibody and cell-mediated immunity, yet a comprehensive understanding of how MS DMTs impact SARS-CoV-2 vaccine responses is lacking. We completed a detailed analysis of SARS-CoV-2 vaccine-elicited spike antigen-specific IgG and T cell responses in a cohort of healthy controls and MS participants in six different treatment categories. Two specific DMT types, sphingosine-1-phosphate (S1P) receptor modulators and anti-CD20 monoclonal antibodies (mAb), resulted in significantly reduced spike-specific IgG responses. Longer duration of anti-CD20 mAb treatment prior to SARS-CoV-2 vaccination were associated with absent antibody responses. Except for reduced CD4+ T cell responses in S1P-treated patients, spike-specific CD4+ and CD8+ T cell reactivity remained robust across all MS treatment types. These findings have important implications for clinical practice guidelines and vaccination recommendations in MS patients and other immunosuppressed populations.

category: neurology


title: EFFICACY OF THE MEASLES-MUMPS-RUBELLA (MMR) VACCINE IN THE REDUCING THE SEVERITY OF COVID-19: AN INTERIM ANALYSIS OF A RANDOMISED CONTROLLED CLINICAL TRIAL

abstract:
BackgroundCOVID-19 is still a challenge, both with regard to its treatment and to the actual efficacy of the vaccines available to date, especially with the emergence of new variants. We evaluated the efficacy of the measles-mumps-rubella (MMR) vaccine in preventing SARS-CoV-2 infection and severity of COVID-19 in health workers.

MethodsThis analysis includes data from one ongoing blinded, randomized, placebo-controlled trial with participants aged 18-60 years were randomly assigned to receive the MMR vaccine or a placebo. The primary efficacy analysis included all participants with a positive nasopharyngeal RT-PCR test since their inclusion.

ResultsThe MMR vaccine did not prevent the SARS-CoV-2 infection. Participants in the MMR group, compared with those in the placebo group, had a 48% risk reduction in symptomatic COVID-19 (RR = 0.52; 95% CI: 0.33-0.83; p=0.004) and a 76% risk reduction in COVID-19 treatment (RR = 0.24; 95% CI: 0.06 - 0.88; p = 0.020) with one dose and a 51% risk reduction in COVID-19 symptoms (RR = 0.49; 95% CI: 0.31 - 0.78; p = 0.001) and a 78% risk reduction in COVID-19 treatment (RR = 0.22; 95% CI: 0.06 - 0.82; p = 0.015) with two doses.

ConclusionsThis interim analysis of an ongoing clinical trial suggests that compared with a placebo, the vaccine reduces the risk of COVID-19 symptoms and reduces the need for COVID-19 treatment.

Clinical Trials RegistryBrazilian Clinical Trials Registry (ReBEC n{degrees} RBR-2xd6dkj - https://ensaiosclinicos.gov.br/rg/RBR-2xd6dkj).

HIGHLIGHTSO_LIThe MMR vaccine can stimulate the innate immunity inducing a nonspecific protection against other infections, called heterologous immunity.
C_LIO_LIRepeated exposure to the antigen (innate immune response training) results in an extension of the action time of this immune response (innate immune response memory) and consequently in protection against other infections (heterologous immunity) for a longer time.
C_LIO_LIThe MMR vaccine has been used by national immunization programs in the world for many years, it is very safe and can be stored and distributed at 2-8{degrees}C, making it particularly suitable for global distribution.
C_LIO_LIAmong participants who received at least one dose, compared with those in the placebo group, participants in the MMR group had a significant risk reduction in symptomatic COVID-19 and of cases requiring treatment.
C_LIO_LIThe use of MMR vaccine can be useful in several populations in the world that do not have access to the COVID-19 vaccine and in a future epidemic or pandemic as an emergency measure until specific treatments or vaccines for each case are available to the general population.
C_LI


title: Masking significantly reduces, but does not eliminate COVID-19 infection in a spatial agent-based simulation of a University dormitory floor

abstract: COVID-ADAPT is a stochastic, discrete-space, agent-based simulation model of airborne infection and public health interventions, capable of modeling SARS-CoV-2 transmission. Using a map of a real university dormitory floor, the model simulates agents moving about and potentially infecting each other. Health interventions tested are vaccination and masking, including whether the solitary initial infectious agent was masked. Universal masking with N95 masks and 100% vaccination of susceptible people resulted in significantly lower prevalence after 3 weeks compared to all other scenarios, but still led to a substantial number of infections. Increased vaccination levels from 52% to 100% by itself did not result in a significant difference in prevalence due to symptomatic and asymptomatic breakthrough infections. These results suggest that vaccination alone is insufficient to stem outbreaks, and the best way to reduce COVID-19 infections is to ensure that all infectious people are masked. However, because asymptomatic infections are common, the only way to ensure this is universal masking, which also reduces prevalence by protecting susceptible individuals from infection. Universal masking is the best way forward, especially under threat of the Delta variant, to keep facilities open and safe for occupants, while minimizing the number of infections.


title: Correlates of COVID-19 vaccination status among college students

abstract:
ObjectivesDespite the widespread availability of COVID-19 vaccines in the United States, vaccine hesitancy remains high among certain groups. This study examined the correlates of being unvaccinated among a sample of university students (N=2900) during the spring and summer of 2021, when the campus had been closed for over a year and students were preparing to return to in-person learning.

MethodsStudents responded to an email invitation and completed electronic surveys. Results. In multivariable logistic regression analyses, students were more likely to be unvaccinated if they were African American, identified with any political affiliation other than Democrat, were undergraduates or international students, had not traveled outside the Los Angeles during the pandemic, and/or had previously been ill with COVID-19.

ConclusionFindings indicate that culturally resonant educational interventions, and possibly vaccine requirements, are needed to promote vaccination among university students.


title: Shatavari Supplementation in Postmenopausal Women Improves Handgrip Strength and Increases Vastus Lateralis Myosin Regulatory Light Chain Phosphorylation But Does Not Alter Markers of Bone Turnover: A Randomised Controlled Trial.

abstract:
BackgroundShatavari has long been used as an Ayurvedic herb for womens health, but empirical evidence for its effectiveness has been lacking. Shatavari contains phytoestrogenic compounds that bind to the estradiol receptor, and may therefore benefit postmenopausal women since postmenopausal estradiol deficiency contributes to sarcopenia and osteoporosis.

MethodsIn a randomised double-blind trial, 20 postmenopausal women (68.5 {+/-} 6 y) ingested either placebo (N=10) or shatavari (N=10; 1000 mg/d, equivalent to 26,500 mg/d fresh weight shatavari) for 6 weeks. Handgrip and knee extensor strength were measured at baseline and at 6 weeks. Vastus lateralis (VL) biopsy samples were obtained. Data are presented and analysed (t test/Mann Whitney U) as difference scores (Week 6 - baseline, median {+/-} interquartile range).

ResultsHandgrip, (but not knee extensor) strength was improved by shatavari supplementation (shatavari +0.7 {+/-} 1.1 kg, placebo -0.4 {+/-} 1.3 kg; p=0.04). Myosin regulatory light chain phosphorylation, a known marker of improved myosin contractile function, was increased in VL following shatavari supplementation (immunoblotting; placebo -0.08 {+/-} 0.5 a.u. shatavari +0.3 {+/-} 1 arbitrary units (a.u.); p=0.03). Shatavari increased phosphorylation of Aktser473 (Aktser473 (placebo -0.6 {+/-} 0.6 a.u. shatavari +0.2 {+/-} 1.3 a.u; p=0.03) in VL. Shatavari supplementation did not alter plasma markers of bone turnover (P1NP, {beta}-CTX) and stimulation of human osteoblasts with pooled sera (N=8 per condition) from placebo and shatavari supplementation conditions did not alter cytokine or metabolic markers of osteoblast activity.

ConclusionsShatavari may improve muscle function and contractility via myosin conformational change and warrants further investigation of its utility in conserving musculoskeletal function in postmenopausal women.

Trial RegistrationRetrospectively registered at clinicaltrials.gov as NCT05025917 on 30/08/21.

category: nutrition


title: Safety and Immunogenicity of an Inactivated Recombinant Newcastle Disease Virus Vaccine Expressing SARS-CoV-2 Spike: Interim Results of a Randomised, Placebo-Controlled, Phase 1/2 Trial

abstract:
BackgroundProduction of affordable coronavirus disease 2019 (COVID-19) vaccines in low- and middle-income countries is needed. NDV-HXP-S is an inactivated egg-based Newcastle disease virus vaccine expressing the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Its being developed in Thailand, Vietnam, and Brazil; herein are initial results from Thailand.

MethodsThis phase 1 stage of a randomised, dose-escalation, observer-blind, placebo-controlled, phase 1/2 trial was conducted at the Vaccine Trial Centre, Mahidol University (Bangkok). Healthy adults aged 18-59 years, non-pregnant and negative for SARS-CoV-2 antibodies were eligible. Participants were block randomised to receive one of six treatments by intramuscular injection twice, 28 days apart: 1 {micro}g{+/-}CpG1018 (a toll-like receptor 9 agonist), 3 {micro}g{+/-}CpG1018, 10 {micro}g, or placebo. Participants and personnel assessing outcomes were masked to treatment. The primary outcomes were solicited and spontaneously reported adverse events (AEs) during 7 and 28 days after each vaccination, respectively. Secondary outcomes were immunogenicity measures (anti-S IgG and pseudotyped virus neutralisation). An interim analysis assessed safety at day 57 in treatment-exposed individuals and immunogenicity through day 43 per protocol. ClinicalTrials.gov (NCT04764422).

FindingsBetween March 20 and April 23, 2021, 377 individuals were screened and 210 were enrolled (35 per group); all received dose one; five missed dose two. The most common solicited AEs among vaccinees, all predominantly mild, were injection site pain (<63%), fatigue (<35%), headache (<32%), and myalgia (<32%). The proportion reporting a vaccine-related AE ranged from 5{middle dot}7% to 17{middle dot}1% among vaccine groups and was 2{middle dot}9% in controls; there was no vaccine-related serious adverse event. The 10 {micro}g formulations immunogenicity ranked best, followed by 3 {micro}g+CpG1018, 3 {micro}g, 1 {micro}g+CpG1018, and 1 {micro}g formulations. On day 43, the geometric mean concentrations of 50% neutralising antibody ranged from 122{middle dot}23 IU/mL (1 {micro}g, 95% CI 86{middle dot}40-172{middle dot}91) to 474{middle dot}35 IU/mL (10 {micro}g, 95% CI 320{middle dot}90-701{middle dot}19), with 93{middle dot}9% to 100% of vaccine groups attaining a [≥]4-fold increase over baseline.

InterpretationNDV-HXP-S had an acceptable safety profile and potent immunogenicity. The 3 {micro}g and 3 {micro}g+CpG1018 formulations advanced to phase 2.

FundingNational Vaccine Institute (Thailand), National Research Council (Thailand), Bill & Melinda Gates Foundation, National Institutes of Health (USA)


title: High- Versus Low-Dose Dexamethasone for the Treatment of COVID-19-related Acute Respiratory Distress Syndrome: A Multicenter and Randomized Open-label Clinical Trial

abstract:
PurposeTo determine whether high-dose dexamethasone increases the number of ventilator-free days (VFD) among patients with acute respiratory distress syndrome due to coronavirus disease 2019 (C-ARDS)

MaterialsA multicenter randomized controlled trial in adults with C-ARDS. Patients received 16 mg/d of dexamethasone intravenously for five days followed by 8 mg/d of dexamethasone for five days, or 6 mg/d of dexamethasone intravenously for 10 days.

ResultsData from 98 patients who received at least one dose of dexamethasone were analyzed. At 28 days after randomization, there was no difference between high- and low-dose dexamethasone groups in VFD (median, 0 d [interquartile range (IQR) 0-14 d] versus 0 d [IQR 0-1 d]; P=0.231). The cumulative hazard of successful discontinuation from mechanical ventilation was increased by the high-dose treatment (adjusted sub-distribution hazard ratio: 1.84; 95% CI: 1.31 to 2.5; P<0.001). None of the prespecified secondary and safety outcomes showed a significant difference between treatment arms.

ConclusionsAmong patients with C-ARDS, the use of higher doses of dexamethasone compared with the recommended low-dose treatment did not show an increase in VFD. However, the higher dose significantly improved the time required to liberate them from the ventilator

Clinical Trial Registered: NCT04395105


title: Association of inflammatory markers with severity of disease and mortality in COVID-19 patients: a systematic review and meta-analysis

abstract:
PurposeLiterature suggests association of inflammatory markers with the severity and mortality related to COVID-19, but there are varying conclusions available. We aimed to provide an overview of the association of inflammatory markers with the severity and mortality of COVID-19 patients.

MethodsWe searched Medline (via PubMed), Cochrane, Clinicaltrials.gov databases until Sept 1, 2020.

ResultsA total of 21 studies comprising 4023 patients with COVID-19 were included in our analysis. Levels of IL-6 (WMD=18.17 95%CI 3.38 to 32.96, p=0.016), IL-8 (WMD=12.09 95%CI 4.41 to 19.77, p=0.002), MCP-1 (WMD=146.66 95%CI 88.16 to 205.16, p<0.001), CRP (WMD=31.09 95%CI 10.08 to 52.10, p=0.004), PCT (WMD= -31.23 95%CI -37.70 to -24.76, p<0.001), IL-2R (WMD=861.93 95%CI 275.45 to 1448.41, p=0.004), ferritin (WMD= 1083.34 95%CI 431.99 to 1734.70, p=0.001) were found significantly higher in the severe group compared with the non-severe group of COVID-19 patients. Moreover, non-survivors had a higher levels of IL-2R (WMD= -666.06 95%CI -782.54 to -549.59, p<0.001), IL-8 (WMD= -26.63 95%CI -33.031 to -20.236, p<0.001), IL-10 (WMD= -7.60 95%CI -8.93 to -6.26, p<0.001), TNF- (WMD= -4.60 95%CI -5.71 to -3.48, p<0.001), IL-1{beta} (WMD=22.66 95%CI 8.13 to 37.19, p=0.002), CRP (WMD= -96.40 95%CI -117.84 to -74.97, p<0.001), and ferritin (WMD= -937.60 95%CI -1084.15 to -791.065, p<0.001) when compared to the non-survivor group.

ConclusionThis meta-analysis highlights the association of inflammatory markers with the severity and mortality of COVID-19 patients. Measurement of these inflammatory markers may assist clinicians to monitor and evaluate the severity and prognosis of COVID-19 thereby reducing the mortality rate.


title: Characterisation of the blood RNA host response underpinning severity in COVID-19 patients

abstract: Infection with SARS-CoV-2 has highly variable clinical manifestations, ranging from asymptomatic infection through to life-threatening disease. Host whole blood transcriptomics can offer unique insights into the biological processes underpinning infection and disease, as well as severity. We performed whole blood RNA Sequencing of individuals with varying degrees of COVID-19 severity. We used differential expression analysis and pathway enrichment analysis to explore how the blood transcriptome differs between individuals with mild, moderate, and severe COVID-19, performing pairwise comparisons between groups. Increasing COVID-19 severity was characterised by an abundance of inflammatory immune response genes and pathways, including many related to neutrophils and macrophages, in addition to an upregulation of immunoglobulin genes. Our insights into COVID-19 severity reveal the role of immune dysregulation in the progression to severe disease and highlight the need for further research exploring the interplay between SARS-CoV-2 and the inflammatory immune response.


title: Blood biochemical parameters as predictors of disease severity and mortality in COVID-19 patients- an updated systematic review and meta-analysis

abstract:
BackgroundThe outbreak of coronavirus disease 2019 (COVID-19) has been rapidly spreading across the globe and poses a great risk to human health. Patients with abnormalities in laboratory parameters are more susceptible to COVID-19. Therefore, we explored the association of blood biochemical parameters with severity and mortality of COVID-19 amongst 3695 patients across seventeen studies.

MethodsWe searched PubMed, Cochrane library and LitCOVID database until February 28, 2021. Seventeen studies were included in the meta-analysis with 3695 COVID-19 patients.

ResultsThe pooled analysis showed that compared to non-severe group, severe group was characterised by significantly elevated alanine aminotransferase (ALT) (standardised mean difference [SMD]: 0.65, 95% confidence interval [CI]: 0.23 to 1.06; p<0.001, erythrocyte sedimentation rate (ESR) (SMD: 0.55, 95%CI: 0.02 to 1.07 p=0.004) and lymphopenia (SMD: -1.22, 95% CI: -2.15 to -0.30; p<0.01), decreased serum albumin (SMD: -1.60, 95% CI: -2.96 to -0.22 ; p<0.001), creatinine (SMD: 0.54, 95% CI: 0.17 to 0.90; p<0.001), lactate dehydrogenase (LDH)(SMD: -1.54, 95% CI: - 2.27 to -0.80; p=0.002) and haemoglobin (SMD:-0.89, 95% CI: ; p<0.001). Additionally, in the non-survivor group, elevated lactate dehydrogenase (LDH) (SMD: 1.54 95% CI: -2.27 to 0.80; p=0.002), decreased serum albumin (SMD: 1.08, 95% CI: 0.75 to 1.42; p<0.001) were reported. There was no comorbidity which was found to be significant in the severe group.

ConclusionSerum albumin, ALT, ESR, lymphopenia, haemoglobin, and leucocytosis can reflect the severity of COVID-19, while the LDH, leucocytosis and albumin can be considered as risk factor to higher mortality.

SummaryOur manuscript discusses the various blood biochemical markers as potential predictors of disease severity and mortality in COVID-19 patients. The timely detection of these parameters can help in providing appropriate course of treatment and reducing the mortality rate in the patients. We have found an association between the blood biochemical markers and disease severity and mortality in COVID-19 patients. Serum albumin, alanine aminotransferase (ALT), Erythrocyte Sedimentation Rate (ESR), lymphopenia, hemoglobin, and leukocytosis can reflect the severity of the disease, while the LDH, leukocytosis and albumin can be considered as risk factor to higher mortality.


title: Metformin: We need to either put it in our drinking water or rethink how we study it

abstract:
STRUCTURED ABSTRACTO_ST_ABSObjectivesC_ST_ABSTo expose the potential impact of residual confounding in common observational study designs investigating metformin using a type 2 diabetes cohort; to propose a more robust study design for future observational studies of metformin.

DesignRetrospective cohort studies using a prevalent user design conducted in two distinct cohorts: individuals with type 2 diabetes and individuals with prediabetes.

SettingInsurance claims database for Medicare Advantage beneficiaries in the United States, 2018-2019. An identical analysis of commercial insurance beneficiaries appears in the supplement.

Participants404,765 individuals with type 2 diabetes, 81,791 individuals with prediabetes.

Main outcome measuresTotal inpatient admission days in 2019, total medical spend (excluding prescription drugs) in 2019. Each of these measures is treated as a binary outcome: greater than zero inpatient days and top 10% medical spend.

ResultsWe implement a common observational study design and observe a strong metformin effect estimate associated with reduced inpatient admissions and reduced medical expenditures; we also implement a more robust study design that suggests any estimated effect is attributable to residual confounding related to individuals overall health.

ConclusionsCommon observational study designs examining metformin in a type 2 diabetes population are likely impacted by significant residual confounding. By additionally considering numerous negative control outcomes and a complementary prediabetes cohort, the study design proposed here demonstrates efficacy at exposing residual confounding related to overall health, nullifying the claim derived from a standard study design.

Trial registrationPreregistration available at https://osf.io/qf49p.

category: pharmacology and therapeutics


title: Protocol: A two-wave cross-sectional study in England investigating suicidal behaviour and self-harm amongst healthcare workers during the Covid-19 pandemic

abstract:
IntroductionThere have been longstanding concerns regarding an increased risk of suicide amongst healthcare workers. The Covid-19 pandemic has placed an additional burden on staff, yet few studies have investigated the impact of the pandemic on their risk of suicide and self-harm. We aimed to investigate the cumulative incidence, prevalence and correlates of suicidal ideation, suicide attempts and non-suicidal self-injury amongst healthcare workers during the Covid-19 pandemic.

Methods and AnalysisNHS Check is an online survey that was distributed to all staff (clinical and non-clinical), students, and volunteers in 18 NHS Trusts across England during the Covid-19 pandemic. Data collected in wave 1 (collected between April 2020 and January 2021) and wave 2 (collected 6-month after wave 1) will be analysed. The full cohort of wave 1 participants will be weighted to represent the age, sex, ethnicity, and roles profile of the workforce at each Trust, and the weighted prevalence and cumulative incidence of suicidal ideation, suicide attempts and non-suicidal self-injury will be described. Two-level random effects logistic regression models will be used to investigate the relationship between suicidal behaviour and self-harm, and demographic characteristics (age, sex, ethnicity) and workplace factors (concerns regarding access to personal protective equipment, re-deployment status, moral injury, confidence around raising and the management of safety concerns, support by supervisors or managers, satisfaction with standard of care provided). Results will be stratified by role (clinical/non-clinical).


title: Access to personal protective equipment in healthcare workers during the COVID-19 pandemic in the United Kingdom: results from a nationwide cohort study (UK-REACH)

abstract:
ObjectivesTo determine the prevalence and predictors of self-reported access to appropriate personal protective equipment (aPPE) for healthcare workers (HCWs) in the United Kingdom (UK) during the first UK national COVID-19 lockdown (March 2020) and at the time of questionnaire response (December 2020 - February 2021).

DesignTwo cross sectional analyses using data from a questionnaire-based cohort study.

SettingNationwide questionnaire from 4th December 2020 to 28th February 2021.

ParticipantsA representative sample of HCWs or ancillary workers in a UK healthcare setting aged 16 or over, registered with one of seven main UK healthcare regulatory bodies.

Main outcome measureBinary measure of self-reported aPPE (access all of the time vs access most of the time or less frequently) at two timepoints: the first national lockdown in the UK (primary analysis) and at the time of questionnaire response (secondary analysis).

Results10,508 HCWs were included in the primary analysis, and 12,252 in the secondary analysis. 3702 (35.2%) of HCWs reported aPPE at all times in the primary analysis; 6806 (83.9%) reported aPPE at all times in the secondary analysis. After adjustment (for age, sex, ethnicity, migration status, occupation, aerosol generating procedure exposure, work sector, work region, working hours, night shift frequency and trust in employing organisation), older HCWs (per decade increase in age: aOR 1.2, 95% CI 1.16-1.26, p<0.001) and those working in Intensive Care Units (1.61, 1.38 - 1.89, p<0.001) were more likely to report aPPE at all times. Those from Asian ethnic groups compared to White (0.77, 0.67-0.89, p<0.001), those in allied health professional (AHPs) and dental roles (vs those in medical roles; AHPs: 0.77, 0.68 - 0.87, p<0.001; dental: 0.63, 0.49-0.81, p<0.001), and those who saw a higher number of COVID-19 patients compared to those who saw none ([≥]21 patients 0.74, 0.61-0.90, p=0.003) were less likely to report aPPE at all times in the primary analysis. aPPE at all times was also not uniform across UK regions (reported access being better in South West and North East England than London). Those who trusted their employing organisation to deal with concerns about unsafe clinical practice, compared to those who did not, were twice as likely to report aPPE at all times (2.18, 1.97-2.40, p<0.001). With the exception of occupation, these factors were also significantly associated with aPPE at all times in the secondary analysis.

ConclusionsWe found that only a third of HCWs in the UK reported aPPE at all times during the period of the first lockdown and that aPPE had improved later in the pandemic. We also identified key sociodemographic and occupational determinants of aPPE during the first UK lockdown, the majority of which have persisted since lockdown was eased. These findings have important public health implications for HCWs, particularly as cases of infection and long-COVID continue to rise in the UK.

Trial registrationISRCTN 11811602

What is already known on this topicAccess to personal protective equipment (PPE) is crucial to protect healthcare workers (HCWs) from infection. Limited data exist concerning the prevalence of, and factors relating to, PPE access for HCWs in the United Kingdom (UK) during the COVID-19 pandemic.

What this study addsOnly a third of HCWs reported having access to appropriate PPE all of the time during the first UK national lockdown. Older HCWs, those working in Intensive Care Units and those who trusted their employing organisation to deal with concerns about unsafe clinical practice, were more likely to report access to adequate PPE. Those from Asian ethnic groups (compared to White ethnic groups) and those who saw a high number of COVID-19 were less likely to report access to adequate PPE. Our findings have important implications for the mental and physical health of HCWs working during the pandemic in the UK.


title: Dynamics of mask use as a prevention strategy against SARS-Cov-2 in Panama

abstract:
BackgroundEarly in the SARS-CoV-2 pandemic, many national public health authorities implemented non-pharmaceutical interventions to mitigate disease outbreaks. Panama established mandatory mask use two months after its first documented case. Initial compliance was high, but diverse masks were used in public areas. We studied behavioral dynamics of mask use through the first two COVID waves in Panama, to improve implementation of effective, low-cost public health containment measures, when populations are exposed to novel air-borne pathogens.

MethodsMask use behavior was recorded from pedestrians in four Panamanian populations (August to December 2020). We recorded facial coverings; and if used, the type of mask, and gender and estimated age of the wearer.

FindingsPeople were highly compliant (> 95%) with mask mandates, and demonstrated important population-level behaviours: 1) decreasing use of cloth masks over time, and increasing use of surgical masks; 2) mask use was 3-fold lower in sub-urban neighborhoods than other public areas; and 3) young people were least likely to wear masks.

InterpretationResults help focus highly-effective, low-cost, public health interventions for managing and controlling a pandemic. Considerations of behavioural preferences for different masks, relative to pricing and availability, are essential for optimizing public health policies. Policies to increase availability of effective masks, and behavioral nudges to increase acceptance, and to facilitate mask usage, during the on-going SARS-CoV-2 pandemic, and for future pandemics of respiratory pathogens, are key tools, especially for nations lagging in access to expensive vaccines and pharmacological approaches.

Funding11-2020 SNI Grant, SENACYT.


title: PCR test positive rate revealing the real infection epidemic status examined in the COVID-19 epidemic in Tokyo, Japan

abstract: In order to come up with effective infectious disease countermeasures, we need a method to evaluate the effectiveness of the countermeasures. As the most reliable epidemic diagnosis, we propose the PCR test positive rate. Examining the COVID-19 epidemic in Tokyo shows that the positive rate follows the epidemic accurately, without being affected by medical institution closures or the psychology of people. By comparing with the change of the positive rate, we argue that the psychology of people was the cause of the observed asymmetry and shallow valleys in the number of confirmed cases. We discuss that the positive rate as large as 1-5% in the valleys of the epidemic implies that many people are already infected and immune. The observed fact that the positive rate followed the number of positives accurately and the value lower than those reported in the test-negative design studies of influenza are attributable to the governments policy of finding as many patients as possible. We mention three possibilities as the causes of the repeated COVID-19 epidemic in Japan.


title: Socially stratified DNA-methylation profiles are associated with disparities in child and adolescent mental health

abstract:
ImportanceEconomic and racial inequality is linked to disparities in childrens mental health. Biomarkers that reflect these social disparities are lacking.

ObjectiveWe examined the hypothesis that salivary DNA-methylation patterns of higher inflammation and faster pace of biological aging are economically, racially and ethnically stratified and are associated with child mental health.

DesignThe Texas Twin Project is an on-going, observational, longitudinal study that began in May 2012. Analyses were preregistered on May 7, 2021, and completed on August 23, 2021.

SettingThe population-based study identified and recruited participants from public school rosters in the greater Austin area.

ParticipantsParticipants in the analytic data set included all participants that agreed to contribute DNA samples and whose samples were assayed by January 2021.

ExposuresFamily- and neighborhood-level socioeconomic inequality, racial and ethnic identities (White, Latinx, Black, Asian).

Main Measure(s)Environmental exposures were analyzed in relation to salivary DNA- methylation profiles of higher inflammation (DNAm-CRP) and faster pace of biological aging (DunedinPoAm). Child internalizing problems, attention problems, aggression, rule-breaking, ADHD, oppositional defiant disorder, and conduct disorder were measured using parent-reports and self-reports on abbreviated versions of the Achenbach Child Behavior Checklist and Conners 3.The hypotheses being tested were formulated after data collection of the present data freeze and were pre-registered prior to analyses being conducted.

ResultsIn a sample of N=1,183 8-to-19-year-olds (609 female, age M=13.38y), childrens salivary DNA-methylation profiles and psychiatric symptoms differed by socioeconomic conditions, race and ethnicity. Children with more parent-reported internalizing symptoms had higher DNAm-CRP (r=0.15, 95% CI=0.05 to 0.25, P=0.004) and DunedinPoAm (r=0.15, CI=0.05 to 0.25, P=0.002), and children with more parent-reported aggression problems had higher DNAm-CRP (r=0.17, CI=0.04 to 0.31, P=0.013). DNAm-CRP partially mediated advantage of higher family socioeconomic status (16% of total effect) and White racial identity (12% of total effect) on reduced internalizing symptoms. DunedinPoAm also partially mediated advantage of White racial identity on internalizing (19% of total effect).

Conclusions and RelevanceSocioeconomic and racial inequality are visible in childrens epigenetic profiles of inflammation and the rate of biological aging in a manner that is tied to social disparities in mental health.

Key PointsO_ST_ABSQuestionC_ST_ABSWe examined whether salivary DNA-methylation profiles are socially stratified and associated with child mental health.

FindingsIn this preregistered, cross-sectional observational study of 1,183 children and adolescents, socioeconomic, racial, and ethnic disparities in mental health were associated with salivary DNA-methylation profiles of inflammation and the pace of biological aging.

MeaningDNA-methylation biomarkers hold promise as tools to quantify the biological impact of socioeconomic inequality and being racially minoritized in a manner that is tied to social disparities in mental health.

category: pediatrics


title: Assessment of Environmental and Occupational Risk Factors for the Mitigation and Containment of a COVID-19 Outbreak in a Meat Processing Plant

abstract: Throughout the COVID-19 pandemic, meat processing plants have been vulnerable to outbreaks of SARS-CoV-2 infection. Transmission of the virus is difficult to control in these settings because of a combination of factors including environmental conditions and the specific nature of the work. This paper describes a retrospective outbreak investigation in a meat processing plant, a description of the measures taken to prevent or contain further outbreaks, and insights on how those with specific knowledge of the working environment of these plants can collaborate with public health authorities to ensure optimal outbreak control. The plant experienced 111 confirmed positive asymptomatic cases in total with an estimated attack rate of 38% during a five-week period. Four weeks after the first case, mass screening of all workers was conducted by the public health authorities. Thirty-two workers tested positive, of which 16 (50%) worked in one particular area of the plant, the boning hall (n=60). The research team prepared and carried out semi-structured interviews with the plant personnel who were charged with COVID control within the plant. They carried out assessments of operational risk factors and also undertook air quality monitoring in the boning hall and abattoir. The air quality measurements in the boning hall showed a gradual build-up of carbon dioxide and aerosol particles over the course of a work shift, confirming that this poorly ventilated area of the plant had an environment that was highly favourable for aerosol transmission of SARS-CoV-2. Assessment of operational conditions incorporated visual surveys of the plant during the working day. Prior to and during the first two weeks of the outbreak, multiple measures were introduced into the plant by management, including physical distancing, provision of educational material to workers, visitor restrictions, and environmental monitoring. After the implementation of these measures and their progressive refinement by plant management, the factory had no further linked cases (clusters) or outbreaks for the following 198 days. The tailored approach to risk mitigation adopted in this meat processing plant shows that generic risk mitigation measures, as recommended by public health authorities, can be successfully adapted and optimized by designated plant emergency response teams.

category: occupational and environmental health


title: Prognostic and Immunological Significance of ARID1A Status in Endometriosis-Associated Ovarian Carcinoma

abstract: ARID1A (BAF250a) is a component of the SWI/SNF chromatin modifying complex, plays an important tumor suppressor role, and is considered prognostic in several malignancies. However, in ovarian carcinomas there are contradictory reports on its relationship to outcome, immune response, and correlation with clinicopathological features. We assembled a series of 1623 endometriosis-associated ovarian carcinomas, including 1078 endometrioid (ENOC) and 545 clear cell (CCOC) ovarian carcinomas through combining resources of the Ovarian Tumor Tissue Analysis (OTTA) Consortium, the Canadian Ovarian Unified Experimental Resource (COEUR), local, and collaborative networks. Validated immunohistochemical surrogate assays for ARID1A mutations were applied to all samples. We investigated associations between ARID1A loss/mutation, clinical features, outcome, CD8+ tumor-infiltrating lymphocytes (CD8+ TIL), and DNA mismatch repair deficiency (MMRd). ARID1A loss was observed in 42% of CCOC and 25% of ENOC. We found no associations between ARID1A loss and outcomes, stage, age, or CD8+ TIL status in CCOC. Similarly, we found no association with outcome or stage in endometrioid cases. In ENOC, ARID1A loss was more prevalent in younger patients (p=0.012), and associated with MMRd (p<0.001), and presence of CD8+ TIL (p=0.008). Consistent with MMRd being causative of ARID1A mutations, in a subset of ENOC we also observed an association between ARID1A loss-of-function mutation as a result of small indels (p=0.011, vs. single nucleotide variants). In ENOC, the association between ARID1A loss, CD8+ TIL, and age, appears confounded by MMRd status. Although this observation does not explicitly rule out a role for ARID1A influence on CD8+ TIL infiltration in ENOC, given current knowledge regarding MMRd, it seems more likely that effects are dominated by the hypermutation phenotype. This large dataset with consistently applied biomarker assessment now provides a benchmark for the prevalence of ARID1A loss-of-function mutations in endometriosis-associated ovarian cancers and brings clarity to the prognostic significance.


title: The longitudinal kinetics of antibodies in COVID-19 recovered patients over 14 months

abstract: Here, we describe the longitudinal kinetics of the serological response in COVID-19 recovered patients over the period of 14 months. The antibody kinetics in a cohort of 200 recovered patients with 89 follow up samples at 2-4 visits reveal that RBD-specific antibodies decay over the period of 14 month following the onset of symptoms. The decay rate is associated with the robustness of the response thus, recovered patients that exhibit elevated antibody levels at the first visit, experience faster decay. We further explored the longitudinal kinetics differences between recovered patients and naive BNT162b2 vaccinees. We found a significantly faster decay in naive vaccinees compared to recovered patients suggesting that the serological memory following natural infection is more robust compared to vaccination. Our data highlights the differences between serological memory induced by natural infection vs. vaccination, facilitating the decision making in Israel regarding the 3rd dose vaccination.


title: Immunogenicity of a third dose viral-vectored COVID-19 vaccine after receiving two-dose inactivated vaccines in healthy adults

abstract: In June 2021, Thailand was hit by the delta variant of SARS-CoV-2 resulting in the biggest wave of COVID-19. Due to the widespread delta variant, more than 600 healthcare workers had COVID-19 despite completion of two-dose CoronaVac. The Ministry of Public Health recommended that healthcare workers received a third dose of AZD1222 to increase level of protection against SARS-CoV-2. However, immune response after the third vaccination with AZD1222 are limited. In this study, sera from those who received a booster of AZD1222 in June-July 2021 were tested for SARS-CoV-2 spike receptor-binding-domain (RBD) IgG, anti-RBD total immunoglobulins and anti-spike protein 1 (S1) IgA. The neutralizing activities in a subset of serum samples were tested against the wild type and variants of concern (B.1.1.7, B.1.617.2, and B.1.351) using an enzyme-linked immunosorbent assay-based surrogate virus neutralization test. Participants who received the booster of AZD1222 possessed higher levels of spike RBD-specific IgG, total immunoglobulins, and anti-S1 IgA than that two-dose vaccines (p < 0.001). They also elicited higher neutralizing activity against the wild type and all variants of concern than those in the recipients of the two-dose vaccines. This study demonstrated a high immunogenicity of the AZD1222 booster who completed the two-dose inactivated vaccines.

category: allergy and immunology


title: Germinal center responses to SARS-CoV-2 mRNA vaccines in healthy and immunocompromised individuals

abstract: Vaccine-mediated immunity often relies on the generation of protective antibodies and memory B cells, which commonly stem from germinal center (GC) reactions. An in-depth comparison of the GC responses elicited by SARS-CoV-2 mRNA vaccines in healthy and immunocompromised individuals has not yet been performed due to the challenge of directly probing human lymph nodes. In this study, through a fine-needle-aspiration-based approach, we profiled the immune responses to SARS-CoV-2 mRNA vaccines in lymph nodes of healthy individuals and kidney transplant (KTX) recipients. We found that, unlike healthy subjects, KTX recipients presented deeply blunted SARS-CoV-2-specific GC B cell responses coupled with severely hindered T follicular helper cells, SARS-CoV-2 receptor-binding-domain-specific memory B cells and neutralizing antibodies. KTX recipients also displayed reduced SARS-CoV-2-specific CD4 and CD8 T cell frequencies. Broadly, these data indicate impaired GC-derived immunity in immunocompromised individuals, and suggest a GC-origin for certain humoral and memory B cell responses following mRNA vaccination.


title: SARS-CoV-2 epidemic in the South American Southern cone: can combined immunity from vaccination and infection prevent the spread of Gamma and Lambda variants while easing restrictions?

abstract: All South American countries from the Southern cone (Argentina, Brazil, Chile, Paraguay and Uruguay) experienced severe COVID-19 epidemic waves during early 2021 driven by the expansion of variants Gamma and Lambda, however, there was an improvement in different epidemic indicators since June 2021. To investigate the impact of national vaccination programs and natural infection on viral transmission in those South American countries, we analyzed the coupling between population mobility and the viral effective reproduction number Rt. Our analyses reveal that population mobility was highly correlated with viral Rt from January to May 2021 in all countries analyzed; but a clear decoupling occurred since May-June 2021, when the rate of viral spread started to be lower than expected from the levels of social interactions. These findings support that populations from the South American Southern cone probably achieved the conditional herd immunity threshold to contain the spread of regional SARS-CoV-2 variants.


title: Risk of heart disease following breast cancer: results from a population-based cohort study

abstract:
BACKGROUNDThere is a rising concern about treatment-associated cardiotoxicities in breast cancer patients.

OBJECTIVESThis study aimed to determine the time- and treatment-specific incidence of arrhythmia, heart failure and ischemic heart disease in women diagnosed with breast cancer.

METHODSA register-based matched cohort study was conducted including 8338 breast cancer patients diagnosed from 2001-2008 in the Stockholm-Gotland region and followed-up until 2017. Overall and time dependent risks of arrhythmia, ischemic heart disease and heart failure in breast cancer patients were assessed using flexible parametric models as compared to matched controls from general population. Treatment-specific effects were estimated in breast cancer patients using Cox model.

RESULTSDuring a median follow-up of 10.8 years, the hazard ratios for arrhythmia, heart failure and ischemic heart disease, were 1.27 (95% CI = 1.18-1.37), 1.38 (95% CI = 1.23-1.55), and 0.93 (95% CI = 0.84-1.03), respectively. Time-dependent analyses revealed long-term increased risks of arrhythmia, and heart failure in breast cancer patients compared to matched controls. The risk of ischemic heart disease was only elevated in the first year after cancer diagnosis. Trastuzumab and anthracyclines were associated with increased risk of heart failure. Aromatase inhibitors, but not tamoxifen, were associated with risk of ischemic heart disease. No increased risk of heart disease was identified following loco-regional radiotherapy.

CONCLUSIONSAdministration of systemic adjuvant therapies appear to be associated with increased risks of heart disease. The risk estimates observed in this study may serve as reference to aid adjuvant therapy decision-making and patient counseling in oncology practices.


title: Influence of Built Environment on Bike Sharing Usage under COVID-19

abstract: Bike sharing, as an important component of urban public transportation, has played a more important role during the COVID-19 pandemic because users could ride bikes in open space and avoid the risk of infection. Leveraging the trip data of the Divvy bike sharing system in Chicago, this study sets to explore the change of ridership that COVID-19 has brought and the built environment factors that influence the spatial variation of ridership under the pandemic. Results show that the ridership declines by xx% in total. To account for the spatially heterogeneous relationship between the built environment and the ridership, the geographically weighted regression (GWR) model and the semi-parametric GWR (S-GWR) model are constructed. By comparing the model results, we find that the S-GWR model outperforms the GWR and the multiple linear regression model. The results of the S-GWR model indicates that education employment density, distance to subway, COVID-19 cases and ridership before COVID-19 are global variables. The ridership between residential density, office employment density and the ridership vary across space. The results of this study could provide useful reference to transportation planners and bike sharing operators to determine the high bike sharing demand area under the pandemic and to make adjustment on the locations and capacity of the stations and the rebalancing schemes accordingly.


title: SARS-CoV-2 wastewater surveillance in Germany: long-term PCR monitoring, suitability of primer/probe combinations and biomarker stability

abstract: In recent months, wastewater-based epidemiology (WBE) has been shown to be an important tool for early detection of SARS-CoV-2 circulation in the population. In this study, a detection methodology for SARS-CoV-2 RNA (wild-type and variants of concern) in wastewater was developed based on the detection of different target genes (E and ORF1ab) by PEG precipitation and digital droplet PCR. This methodology was used to determine the SARS-CoV-2 concentration and the proportion of N501Y mutation in raw sewage of the wastewater treatment plant of the city of Karlsruhe in southwestern Germany over a period of 1 year (June 2020 to July 2021). Comparison of SARS-CoV-2 concentrations with reported COVID-19 cases in the catchment area showed a significant correlation. Viral RNA titre trends appeared more than 12 days earlier than clinical data, demonstrating the potential of wastewater-based epidemiology as an early warning system. Parallel PCR analysis using seven primer and probe systems revealed similar gene copy numbers with E, ORF, RdRP2 and NSP9 assays. RdPP1 and NSP3 generally resulted in lower copy numbers, and in particular for N1 there was low correlation with the other assays due to outliers. The occurrence of the N501Y mutation in the wastewater of Karlsruhe was consistent with the occurrence of the alpha-variant (B.1.1.7) in the corresponding individual clinical tests. In batch experiments SARS-CoV-2 RNA was stable for several days under anaerobic conditions, but the copy numbers decreased rapidly in the presence of dissolved oxygen. Overall, this study shows that wastewater-based epidemiology is a sensitive and robust approach to detect trends in the spread of SARS-CoV-2 at an early stage, contributing to successful pandemic management.


title: Deleterious drugs in COVID-19: a rapid systematic review and meta-analysis

abstract:
BackgroundConcerns have been expressed about a number of drugs that potentially worsen outcomes in patients with COVID-19. We sought to identify all potentially deleterious drug groups in COVID-19 and critically assess the underpinning strength of evidence pertaining to the harmful effects of these drugs.

Methods and findingsWe performed a rapid systematic review, searching Medline, Embase and two COVID-19 portfolios (WHO COVID-19 database and NIH iSearch COVID-19 portfolio) for papers and preprints related to primary studies investigating drugs identified as potentially deleterious. Primary outcomes were direct measures of susceptibility to infection, disease severity and mortality. Study quality was assessed using the National Heart, Lung, and Blood Institute quality assessment tools. Random-effects meta-analyses were used for data synthesis with further subgroup analyses where possible for specific outcome, study design, statistical adjustment and drug groups when two were combined. Sensitivity analyses were performed by removing any studies at high risk of bias and by publication status.

49 observational studies (15 peer-reviewed papers and 34 preprints) reported primary outcomes for eight drug groups hypothesised to be deleterious. Meta-analysis showed that acute inpatient corticosteroid use was associated with increased mortality (OR 2.22, 95% CI 1.26-3.90), however this result appeared to have been biased by confounding via indication. One subgroup analysis indicated an association between immunosuppressant use and susceptibility to COVID-19 among case control and cross-sectional studies (OR 1.29, 95% CI 1.19-1.40) but this was not found with cohort studies (OR 1.11, 95% CI 0.86-1.43). Studies which adjusted for multiple confounders showed that people taking angiotensin-converting-enzyme inhibitors (ACEIs) or angiotensin-II-receptor blockers (ARBs) required a lower level of care (OR 0.85, 95% CI 0.74-0.98). Furthermore, studies which combined these two drug groups in their analysis demonstrated an association with a lower mortality (OR 0.68, 95% CI 0.55-0.85).

ConclusionsWe found minimal high quality or consistent evidence that any drug groups increase susceptibility, severity or mortality in COVID-19. Converse to initial hypotheses, we found some evidence that regular use of ACEIs and ARBs prior to infection may be effective in reducing the level of care required, such as requiring intensive care, in patients with COVID-19.


title: COVID-19 vaccination rates among health care workers by immigrant background. A nation-wide registry study from Norway.

abstract:
BackgroundStudies have suggested that some minority groups tend to have lower vaccination rates than the overall population. This study aims to examine COVID-19 vaccination rates among health care workers (HCWs) in Norway, according to immigrant background.

MethodsWe used individual-level, nation-wide registry data from Norway to identify all HCWs employed full-time at 1 December 2020. We examined the relationship between country of birth and COVID-19 vaccination from December 2020 to August 2021, both crude and adjusted for e.g. age, sex, municipality of residence, and detailed occupation codes in logistic regression models.

ResultsAmong all HCWs in Norway, immigrants had a 9 percentage point lower vaccination rate (85%) than HCWs without an immigrant background (94%) at 31 August 2021. The overall vaccination rate varied by country of birth, with immigrants born in Russia (71%), Serbia (72%), Lithuania (72%), Romania (75%), Poland (76%), Eritrea (77%), and Somalia (78%) having the lowest crude vaccination rates. When we adjusted for demographics and detailed occupational codes, immigrant groups that more often worked as health care assistants, such as immigrants from Eritrea and Somalia, increased their vaccination rates.

ConclusionSubstantial differences in vaccination rates among immigrant groups employed in the health care sector in Norway indicate that measures to improve vaccine uptake should focus specific immigrant groups rather than all immigrants together. Lower vaccination rates in some immigrant groups appears to be largely driven by the occupational composition, suggesting that some of the differences in vaccine rates can be attributed to variation in vaccine access.


title: Nepalese version of Douleur Neuropathique 4 (DN4) questionnaire for Assessment of Neuropathic pain: A Validation Study

abstract:
ObjectiveThis study aimed to translate and validate DN4 questionnaire into Nepalese version.

DesignAn observational study design was adopted.

SettingA tertiary level teaching hospital of Kathmandu, Nepal

ParticipantsWe included 166 purposively selected patients visiting pain clinics of the hospital over one year time

MethodsThe Nepalese version of the DN4 questionnaire was used to detect neuropathic pain among the chronic pain patients of the hospital. The English version of the questionnaire was translated into Nepali based on the standard guideline with the help of linguistic experts. The patients diagnosed with nociceptive or neuropathic pain were interviewed twice in two weeks interval. We analyzed test-retest reliability and strength of the test by using Intra-class correlation coefficient (ICC) and Receiver Operating Characteristics (ROC) Curve, respectively. Internal Consistency reliability was assessed using Cronbachs alpha ({infty}). Diagnostic accuracy was assessed through measures like sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratio.

ResultsThe study showed a good test-retest reliability (ICC=0.877) and internal consistency reliability ({infty}=0.710). The AUC were 0.932 (0.894-0.971) for the first test, and 0.955 (0.921-0.990) for the second test. The sensitivity and specificity values were found highest at the 4 cut-off point (4 score out of 10), that are 75% and 95.3% for test 1, and 76.2% and 98.8% for test 2. Similarly positive and negative predictive values are 93.8% and 80.4% respectively for the first test and 98.4% and 81.7% respectively for the second test.

ConclusionsThe Nepalese version of DN4 questionnaire is a valid and reliable tool for the diagnosis of neuropathic pain. This can be used for screening neuropathic and non-neuropathic pain in clinical as well as epidemiological settings.

Article SummaryO_ST_ABSStrengths and Limitations of this StudyC_ST_ABSO_LIThis study validated Nepalese version of DN4 questionnaire, so, it can be used as a standard tool to assess neuropathic pain among the Nepalese population.
C_LIO_LIAs interview was conducted with the patients, this might minimize the reliability and validity issue.
C_LIO_LIThis questionnaire is only applicable to those who can communicate properly in Nepalese language.
C_LIO_LIThere can be problem of understanding among the participants as few words do not have exact Nepali words with the same meaning.
C_LI

category: pain medicine


title: Nurse staffing levels and patient outcomes: a systematic review of longitudinal studies

abstract:
BackgroundThe contribution of registered nurses (RN) towards safe patient care has been demonstrated by several studies. However, most of the evidence is cross-sectional, hence the inability to demonstrate that staffing levels precede patient outcomes. No reviews have summarised longitudinal studies considering nurse staffing and patient outcomes.

ObjectivesTo synthesise longitudinal studies focusing on associations between nurse staffing levels and patient outcomes.

MethodsSystematic review. We conducted our search in 2020 and updated it in July 2021. We searched Medline, CINAHL, Embase and the Cochrane Library. We used the ROBINS-I tool for assessing risk of bias. We reported results narratively grouped by outcome.

Results28 papers were included. Most studies were either at serious (n=12) or critical (n=6) risk of bias, with 3 studies at low risk of bias. Studies were conducted in a variety of settings and populations. Notwithstanding the limitations, findings are consistent with an overall picture of a beneficial effect from higher RN staffing on preventing patient death. Studies with the greatest risk of bias were judged as most likely to underestimate the effect of higher RN staffing. The evidence is less clear for other patient outcomes, but estimates, though at moderate or serious risk of bias, indicate that higher RN staffing is likely to lead to better patient outcomes. Evidence about the contribution of other nursing staff groups and skill mix of the team is unclear.

ConclusionThere is a likely causal relationship between low RN staffing and harm to patients, although uncertainties remain regarding the magnitude of effect. To address these uncertainties, future studies should be conducted in more than one hospital and using standardised measures when reporting staffing levels.

category: health systems and quality improvement


title: Single-Dose SARS-CoV-2 Vaccination With BNT162b2 and AZD1222 Induce Disparate Th1 Responses and IgA Production

abstract: While vaccination programs against SARS-CoV-2 are globally ongoing, disparate strategies for the deployment of spike antigen show varying effectiveness. In order to explore this phenomenon, we sought to compare the early immune responses against AZD1222 and BNT162b2. SARS-CoV-2 seronegative participants received a single dose of either vaccine and were analyzed for immune cell, effector T cell and antibody dynamics. AZD1222 induced transient leukopenia and major changes among innate and adaptive subpopulations. Both vaccines induced spike protein specific effector T cells which were dominated by Th1 responses following AZD1222 vaccination. A significant reduction of anti-inflammatory T cells upon re-stimulation was also restricted to AZD1222 vaccinees. While IgM and IgG were the dominant isotypes elicited by AZD1222, BNT162b2 led to a significant production of IgG and IgA. Our results suggest that the strategy for spike antigen delivery impacts on how and to what extent immune priming against the main SARS-CoV-2 antigen proceeds.

category: infectious diseases