title: Magnitude, pattern and correlates of multimorbidity among patients attending chronic outpatient medical care in Bahir Dar, northwest Ethiopia: the application of latent class analysis model

abstract:
ObjectiveThis study aimed to investigate the magnitude, pattern and associated factors of multimorbidity in Bahir Dar, Ethiopia.

MethodsA multi-centered facility based study was conducted among 1440 participants aged 40+ years attending chronic outpatient medical care. Two complimentary methods (interview and review of medical records) were employed to collect the data on socio-demographic, behavioral and disease related characteristics. The data were analyzed by STATA V.16 and R Software V.4.1.0. We run descriptive statistics and fitted logistic regression and latent class analyses (LCA) models to determine associated factors and patterns of multimorbidity. Statistical significance was considered at p-value [≤]0.05.

ResultsThe magnitude of individual chronic conditions ranged from 1.4% to 37.9%, and multimorbidity was identified in 54.8% (95% CI=52.2%-57.4%) of the sample. The likelihood of developing multimorbidity was higher among participants aged from 45-54 years (AOR: 1.5, 95%CI= 1.1, 2.1), 55-64 years (AOR: 2.5, 95%CI=1.7, 3.5) and 65 years or more (AOR: 2.4, 95%CI=1.7, 3.5), among individuals classified as overweight (AOR: 1.6, 95%CI=1.2, 2.1) or obese (AOR: 1.9, 95%CI=1.3, 3.0) and among those individuals who believe in external locus of control (AOR: 1.8, 95%CI=1.3, 2.5). Four patterns of multimorbidity were identified, the cardiovascular category being the largest class (50.2%), followed by the metabolic group (32.6%). Advanced age, overweight and obesity predicted latent class membership, adjusting for relevant confounding factors.

ConclusionThe magnitude of multimorbidity in this study was high. The most frequently diagnosed chronic conditions shaped the patterns of multimorbidity. Advanced age, overweight and obesity were the factors profoundly associated with multimorbidity. Health service organization and provision in the study area need to be oriented by the realities in disease burden and pattern of multimorbidity. Further research is required to better understand the impact of multimorbidity on individuals wellbeing, survival and health service delivery.

category: primary care research


title: Neandertal introgression dissects the genetic landscape of neuropsychiatric disorders and associated behavioral phenotypes

abstract:
BackgroundAdvances have recently been made in identifying the genetic basis of psychiatric and neurological disorders, however, fundamental questions about their evolutionary origins remain elusive. Here, introgressed variants from archaic humans such as Neandertals can serve as an intriguing research paradigm.

MethodsWe compared the number of associations for Neandertal variants to the number of associations of frequency-matched non-archaic variants with regard to human CNS disorders (neurological and psychiatric), nervous system drug prescriptions as a proxy for disease, and related non-disease phenotypes in the UK biobank (UKBB), the NESDA cohort and the Biobank Japan.

ResultsWhile no enrichment for Neandertal genetic variants were observed in the UKBB for psychiatric or neurological disease categories, we found significant associations with certain behavioral phenotypes including pain, chronotype/sleep, smoking and alcohol consumptions. Several of these associations were also observed in NESDA and the Biobank Japan, suggesting their evolutionary relevance across different ancestry backgrounds. Intriguingly, in some instances, the enrichment signal was driven by Neandertal variants that represented the strongest association genome-wide.

ConclusionsOur data suggest that evolutionary processes in recent human evolution like admixture with Neandertals significantly contribute to behavioral phenotypes but not psychiatric and neurological diseases. These findings help to link genetic variants in a population to putative past beneficial effects, which likely only indirectly contribute pathology in modern humans, possibly due to changes in lifestyle and maladaptation.

category: psychiatry and clinical psychology


title: The impact of mandatory COVID-19 certificates on vaccine uptake: Synthetic Control Modelling of Six Countries

abstract:
BackgroundCOVID certification has been introduced, yet there are no empirical evaluations of its impact on vaccine uptake.

MethodsMirroring an RCT, we designed a synthetic control model comparing six countries (Denmark, Israel, Italy, France, Germany, Switzerland) that introduced certification (May-August 2021), with 20 control countries. Our estimates provide a counterfactual trend estimating what would have happened in virtually identical circumstances if certificates were not introduced. The primary outcome was daily COVID-19 vaccine doses, with supplementary analyses of COVID-19 infections.

FindingsCOVID-19 certification led to increased vaccinations 20 days prior to implementation, with a lasting effect up to 40 days after. Countries with lower than average pre-intervention uptake had a more pronounced increase. In France, doses exceeded 25,895 vaccines per million capita (pmc) or in absolute terms, 1,749,589 doses prior to certification and 11,434 pmc after (772,563 doses). There was no effect in countries with higher uptake (Germany) or when introduced during limited supply (Denmark). There was higher uptake for <20 years and 20-29 years. Access restrictions linked to certain settings (nightclubs, events >1,000) were associated with higher uptake <20 years. When extended to broader settings, uptake remained high in the youngest group, but also observed in older age groups. The relationship of the intervention with reported infections was difficult to assess based on available data.

InterpretationWe provide the first empirical assessment of the relationship between COVID-19 certification and vaccine uptake. Interpretation should recognise additional factors, including age eligibility changes and pandemic trajectories. We provide evidence that certification could increase vaccine uptake.

Funding and Competing Interest StatementMCM receives funding from the Leverhulme Trust (Large Centre Grant), European Research Council (835079) and participates in UKs SAGE SPI-B (behavioural insights) committee. The funders had no role in study design, data collection, analysis, interpretation, or writing of the report.

Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSThe introduction of COVID-19 certification or vaccine passports has been linked to lower self-reported vaccine intentions, yet national media and health offices report increases in vaccinations. No empirical studies could be located that had examined the impact of the implementation of mandatory COVID-19 certification on vaccine uptake.

Added value of this studyTo our knowledge, this is the first empirical analysis of the relationship of the introduction of COVID-19 certification on vaccine uptake.

Implications of all the available evidenceOur study provides the first evidence that mandatory COVID-19 certification restricting access to certain settings can influence vaccine uptake for those groups affected by the intervention. Given higher vaccine complacency in certain groups, such as youth who perceive lower risks of infection, this intervention could be an additional policy lever to increase vaccine uptake and population level immunity. Future studies examining more countries and variation by eligibility criteria and factors beyond age are warranted.

category: public and global health


title: ATP-citrate lyase as a therapeutic target in chronic kidney disease: a Mendelian Randomization analysis

abstract:
BackgroundATP-citrate lyase (ACLY) inhibition is a promising therapeutic target for dyslipidemia, atherosclerotic cardiovascular disease, non-alcoholic steatohepatitis, and metabolic syndrome. Genetic analysis of its role in chronic kidney disease (CKD) has not been performed.

MethodsWe constructed a genetic instrument by selecting variants associated with ACLY expression level in the expression quantitative trait loci genetics consortium (eQTLGen) that includes blood samples from 31,684 participants. In a two-sample Mendelian randomization analysis, we then evaluated the effect of genetically predicted ACLY expression on risk of CKD, estimated glomerular filtration rate (eGFR), and microalbuminuria using the CKD Genetics consortium (CKDGen), United Kingdom biobank, and the Finnish Genetics consortium (FinnGen) totaling 66,396 CKD cases and 958,517 controls.

ResultsACLY is constitutively expressed in all cell types including in whole blood. The genetic instrument included 13 variants and explained 1.5% of variation in whole blood ACLY gene expression. A 34% reduction in genetically predicted ACLY expression was associated with a 0.04 mmol/L reduced low-density lipoprotein cholesterol (P = 3.4 x 10-4) and a 9% reduced risk of CKD (stage 3,4,5, dialysis or eGFR below 60 ml/min/1.73m2) (OR = 0.91, 95% C.I. 0.85-0.98, P = 0.008), but no association was observed with eGFR nor microalbuminuria.

ConclusionMendelian Randomization analysis provides cautious optimism regarding the possibility of ACLY as a therapeutic target for CKD.

category: nephrology


title: The Repercussion of SARS-CoV-2 on the Blood Glucose Level of Diabetes Patients Prior and During the Lockdown in Bangladesh

abstract:
PurposeDiabetes Mellitus (DM) patients were exposed to subacute risk as a result of the unanticipated lockdown. Furthermore, most DM patients were unable to engage in physical activity during that period. This impediment to proper healthcare management had increased Blood Glucose Levels (BGL). Therefore, initiatives must be adopted to prevent the same result in the second lockdown in 2021 for the well-being of patients.

MethodThis statistical analysis aimed to assess the rise in BGL of diabetic patients before and during the lockdown. A survey was conducted among the DM patients in the Bangladeshi cohort, who came from various socioeconomic backgrounds and included both men and women. The statistical modeling, performed with the help of stat-ease software, was conducted by applying the Analysis of Variance (ANOVA) method to Response Surface Methodology (RSM).

ResultOut of the 3 models applied (quadratic, main effect and sequential sum of squares for 2 factor interaction (2FI)) in 2 different response vectors the 2FI model was the best suited (p value - 0.0441 and 0.0015). The results yielded by the 2FI model were used to evaluate RSM.

ConclusionThe analysis had shown a significant rise in the BGL among the DM patients during the lockdown, and the patients with the higher BMI tend to have a more significant increment in the BGL. Male patients experienced a greater rise in BGL. Furthermore, elderly patients with high Random Blood Glucose (RBG) levels before lockdown were more likely to have high RBG levels during the lockdown.

category: epidemiology


title: Safely return to schools and offices: early and frequent screening with high sensitivity antigen tests effectively identifies COVID-19 patients

abstract:
BackgroundIn-person interaction at school and offices offers invaluable experience to students and benefits to companies. In the midst of the pandemic, ways to safely go back to schools and offices have been argued. Centers for Disease Control and Prevention (CDC) recommends taking all precautions such as vaccination and universal indoor masking. However, even if all the precautions are implemented and transmission is perfectly prevented in the facilities, they may be infected outside of the facilities, which would be a source of transmission in the facilities. Therefore, identifying those infected outside of the facility through screening is essential to safely go back to schools or offices. However, studies investigating the effectiveness of screening are limited. Further, it is not well clarified now which screening strategy (e.g., low or high sensitivity antigen tests, intervals and the number of tests) effectively identify infected and infectious individuals to avoid transmission in facilities

MethodsWe assessed the effectiveness of various screening strategies in schools and offices through quantitative simulation. The effectiveness was assessed by the proportion of identified infected and infectious participants. Infection dynamics in the facility is governed by transmission dynamics of the population they belong to, and the screening is initiated at different epidemic phases: growth, peak, and declining phases. The viral load trajectory over time for each infected individual was modelled by the viral dynamics model, and the transmission process at the population level was modelled by a deterministic compartment model. The model parameters were estimated from clinical and epidemiological data. Screening strategies were varied by antigen tests with different sensitivity and schedules of screening over 10 days.

ResultsUnder the daily screening, we found high sensitivity antigen tests (the detection limit: 6.3 x 104 copies/mL) yielded 88% (95%CI 86-89) of effectiveness by the end of 10 days screening period, which is about 20% higher than that with low sensitivity antigen tests (2.0 x 106 copies/mL). Comparing screening scenarios with different schedules, we found early and frequent screening is the key to maximize the effectiveness. Sensitivity analysis revealed that less frequent tests might be an option when the number of antigen tests is limited especially when the screening is performed at the growth phase.

DiscussionHigh sensitivity antigen tests, high frequency screening, and immediate initiation of screening are the key to safely restart educational and economic activities allowing in-person interactions. Our computational framework is useful in assessment of screening strategies by incorporating additional factors for specific situations.


title: Psychiatric polygenic risk scores: Child and adolescent psychiatrists' knowledge, attitudes, and experiences

abstract:
ObjectivePsychiatric polygenic risk scores (PRS) have the potential to transform aspects of psychiatric care and prevention, but there are concerns about their implementation. We sought to assess child and adolescent psychiatrists (CAP) experiences, perspectives, and potential uses of psychiatric PRS.

MethodsA survey of 960 US-based practicing CAP.

ResultsMost respondents (54%) believed psychiatric PRS are currently at least slightly useful and 87% believed they will be so in five years. Yet, 77% rated their knowledge of PRS as poor or very poor. Ten percent have had a patient/family bring PRS to them, and 25% would request PRS if a patient/caregiver asked. Respondents endorsed different actions in response to a hypothetical child with a top 5th percentile psychiatric PRS but no diagnosis: 48% would increase prospective monitoring of symptoms, 42% would evaluate for current symptoms, and 4% would prescribe medications. Most respondents were concerned that high PRS results could lead to overtreatment and negatively impact patients emotional well-being.

ConclusionFindings indicate emerging use of psychiatric PRS within child and adolescent psychiatry in the US. Thus, it is critical to examine the ethical and clinical challenges that PRS may generate and begin efforts to promote their informed and responsible use.


title: Aberrant modularity and lower resiliency of structural covariance network in first-episode antipsychotic-naive psychoses

abstract:
ObjectiveDivergent findings in structural brain alterations in psychoses suggest that often-observed regions may exist within a network of susceptible regions. We built structural covariance networks (SCN) of volumes, cortical thickness, and surface area using the Human Connectome Project atlas-based parcellation of 358 regions on structural MRI data from 79 first-episode antipsychotic-naive psychosis patients (FEAP) and 68 controls.

MethodsUsing graph theoretic methods, we obtained representative graph metrics of integration, segregation, resilience, centrality, importance, community structure, and hub distribution for all 3-morphometric features. We compared networks for resilience by simulated removal ("attacks") of nodes and hubs, and simulated replacement of correlations among nodes in FEAP with that of controls using DeltaCon metric.

ResultsVolume and thickness SCNs of FEAP showed differences in many graph metrics in opposite directions compared to controls but not surface area SCN. Network resilience did not show differences in the replacement simulation and hub "attacks, but betweenness centrality-based node "attacks" showed FEAP network disintegrating with relatively fewer node removals with preserved global efficiency compared to controls. In FEAP, communities consisted of regions from different lobes and hubs were more distributed than in controls.

ConclusionsOur findings suggest decreased heterogeneity and less differentiated community structure of FEAP network that may not be attributed to illness chronicity and medications. Contribution of cortical thickness but not surface area suggests that disease/developmental processes may preferentially affect cortical thickness. Near-similar resilience of FEAP and control networks may shield controls from developing illness but may prevent fuller long-term recovery in FEAP.


title: Distinctive modularity and resilience of structural covariance network in first-episode antipsychotic-naive psychoses


title: Exoskeleton-assisted walking improves pulmonary and exercise performances more than conventional exercise program in individuals with spinal cord injury: a randomised controlled study

abstract:
QuestionIn people with spinal cord injury, does exoskeleton-assisted walking training improve pulmonary ventilation function, motor function and related body structure, walking, and activities of daily life equally comparing those with conventional exercise program?

DesignRandomised controlled trial with concealed allocation, assessor blinding and intention-to-treat analysis.

InterventionBoth groups undertook 16 sessions of 50-60min training (4 days/week, 4 weeks). Participants in the experimental group received EAW trainings using AIDER system, which assisted standing, walking, and climbing the stairs. The control group received a conventional exercise program which combined aerobic, resistance, flexibility and walking training.

Outcome measuresThe primary outcome was the pulmonary function test. The secondary outcomes included: a 6-minute walk test with Borg scale (0 to 10) rating of exertion, 10-metre walk test, basic activities of daily living, trunk control test, lower extremity motor score, muscle tone of lower limb, bone mineral density, and distal femoral cartilage at baseline and upon completion of treatment.

ResultsAfter 4 weeks of trainings, the experimental group improved more on the forced vital capacity (MD 0.53, 95%CI 0.01 to 1.06), predicted FVC% (MD 19.59, 95%CI 6.63 to 32.54) and forced expiratory volume in 1s (MD 0.61, 95%CI 0.15 to 1.07); BADL (MD 19.75, 95%CI 10.88 to 28.62); and distal femoral cartilage than the control group. Participants completed 6-minute walk test with median 17.3 meters while wearing the exoskeleton. There was no difference in trunk control test, lower extremity motor score, muscle tone, bone mineral density and adverse event.

ConclusionsIn people with lower thoracic neurological level of spinal cord injury, exoskeleton-assisted walking training instead of a conventional excise program has potential benefits to facilitate pulmonary ventilation function, walking, basic activities of daily living and thickness of cartilage.

Trial registrationChiCTR2000034623

category: rehabilitation medicine and physical therapy


title: Novel Investigation of SARS-CoV-2 in COVID-19 Survivors' Semen in Surabaya, Indonesia

abstract: The emergence and the widespread of Coronavirus disease 2019 (COVID-19) demands an accurate detection method to establish a diagnosis. Real-time polymerase chain reaction (real-time PCR) is accounted for the perfect point of reference in detecting this virus. The notion that this virus also invades the male reproductive tract requires further investigation to prove the presence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in the semen. This investigation was designed to detect SARS-CoV-2 in COVID-19 survivors semen. This study design was a cross-sectional examination and conducted between November 2020 and March 2021 in the Andrology Unit of Dr. Soetomo General Hospital and Professor Nidom Foundation, both located in the City of Surabaya, Indonesia. The sample was 34 male participants aged above 18 years old and had been confirmed COVID-19 by nasopharyngeal swab PCR test. Part of the semen was taken for real-time PCR testing with the QuantStudio 5 Applied Biosystem (AB) PCR machine and the kits utilized were the STANDARD M nCOV Real-Time Detection Kit and mBioCov-19 RT-PCR Kit. Furthermore, the mean of participants ages was 35.74 years old with 25% of them had had a history of primary infertility and 21.8% of secondary infertility. From the real-time PCR COVID-19 of the semen examination, this investigation found that 27 participants had been negatives (74.4%), six inconclusive (17.6%), and one positive (3%) of SARS CoV-2. In summary, SARS-CoV-2 could be found in the semen of COVID-19 survivors. This should be a concern for the potential impact of COVID-19 in male fertility and the possibility of transmission reproductively.

category: sexual and reproductive health


title: Linking Profiles of Pathway Activation with Clinical Motor Improvements - a Retrospective Computational Study

abstract: Deep brain stimulation (DBS) is an established therapy for patients with Parkinsons disease. In silico computer models for DBS allow to pre-select a set of potentially optimal stimulation parameters. If efficacious, they could further carry insight into the mechanism of action of DBS and foster the development of more efficient stimulation approaches. In recent years, the focus has shifted towards DBS-induced firing in myelinated axons, deemed particularly relevant for the external modulation of neural activity. We use the concept of pathway activation modeling, which incorporates advanced volume conductor models and anatomically authentic fiber trajectories to estimate DBS-induced action potential initiation in anatomically plausible pathways that traverse in close proximity to targeted nuclei. We apply the method on a retrospective dataset with the aim of providing a model-based prediction of clinical improvement following DBS (as measured by the motor part of the Unified Parkinsons Disease Rating Scale). Based on differences in outcome and activation rates for two DBS protocols in a training cohort, we compute a theoretical 100% improvement profile and enhance it by analyzing the importance of profile matching for individual pathways. Finally, we validate the performance of our profile-based predictive model in a test cohort. As a result, we demonstrate the clinical utility of pathway activation modeling in the context of motor symptom alleviation in Parkinsons patients treated with DBS.

category: neurology


title: Effects of environmental polycyclic aromatic hydrocarbon exposure and pro-Inflammatory activity on Type 2 Diabetes Mellitus.

abstract:
BackgroundPolycyclic aromatic hydrocarbons (PAHs) are formed due to incomplete combustion and known for their potential impact and persistence in the environment. PAHs exposure have been linked to cause adverse health effect including cancer and genetic mutations. The understanding of metabolic effects of PAH exposure are still less clear especially in the presence of pro-inflammatory stress like alcoholism or diabetes.

ObjectiveThe aim of this article is to understand the metabolic effects of PAH exposure by analyzing the clinical biomarkers. This study has also accessed the interactive impact of PAH and other proinflammatory factors, like alcohol intake on the metabolic syndrome, especially Type 2 Diabetes Mellitus (T2DM).

MethodsAll the data in this study are retrieved from CDC NHANES (2015-16). We investigated urinary levels of hydroxylated PAH metabolites (OH-PAHs) along with demographic, clinical and laboratory data. Questionnaire data for alcohol use and diabetes status were also included along with laboratory data. Laboratory measures included in the study were levels of PAHs, glycohemoglobin, glucose, cholesterol, lipids, triglyceride, complete blood count, lymphocytes, and monocytes. Generalize linear model Univariate factorial ANOVA was used to evaluate the group differences (both between the groups; as well as across all the groups) in the demographics, PAH exposure, drinking patterns, clinical data, and biomarker levels. Linear regression model was used to analyze the association of biomarkers, PAH exposure and drinking data. Multivariable regression model was used for multi-independent model to assess comorbidity association and their effect sizes on the clinical outcomes.

ResultsBMI (p=0.002), and age ([≤]0.001) are independent demographic risk factors for T2DM in high PAH exposure. Acute proinflammatory activity characterized by CRP, is augmented by elevated monocyte levels (p[≤]0.001) and stepwise addition of 1-HN (p=0.005), and 2-HN (p=0.001) independently. Prevalence of highest average drinks over time is observed in the high PAH exposure; with males drinking almost twice compared to females in Gr.3. Pathway response of T2DM shows sexual dimorphism; with males showing association with triglycerides (p[≤]0.001), and females with CRP (p=0.015) independently with HbA1C. The arrangement of CRP, absolute monocyte levels, serum triglycerides and average drinks over time predict the HbA1C levels (adjusted R2=0.226, p[≤]0.001) in individuals with high PAH exposure.

DiscussionIn this large dataset investigation on humans, the adverse effects of high exposure of PAHs identified candidate demographic risk factors. Preclinical experimental studies on mice have suggested that PAHs exposure induces lipid metabolic disorders in a time-dependent manner, which we found in humans too. Sexual dimorphism is observed in alcohol drinking with males drinking more in the high PAH exposure group. Alcohol drinking as an independent factor associated with the DMT2 indicator, HbA1C in individuals with high PAH exposure.

HighlightsO_LIBMI and Age are demographic risk factors for Diabetes Mellitus Type 2 (DMT2) in high PAH exposure
C_LIO_LIAcute proinflammatory activity characterized by CRP, is augmented by elevated monocyte levels and 1-HN and 2-HN independently
C_LIO_LIPrevalence of higher average drinks over time is observed with high PAH exposure
C_LIO_LIPathway of DMT2 shows sexual dimorphism, with males showing association with triglycerides, and females with CRP independently with HbA1C
C_LIO_LIThe arrangement of CRP, absolute monocyte levels, serum triglycerides and average drinks over time predict the HbA1C levels in individuals with high PAH exposure.
C_LI

category: occupational and environmental health


title: Integrating de novo and inherited variants in over 42,607 autism cases identifies mutations in new moderate risk genes

abstract: Despite the known heritable nature of autism spectrum disorder (ASD), studies have primarily identified risk genes with de novo variants (DNVs). To capture the full spectrum of ASD genetic risk, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases recruited online by SPARK. In the first stage, we analyzed 19,843 cases with one or both biological parents and found that known ASD or neurodevelopmental disorder (NDD) risk genes explain nearly 70% of the genetic burden conferred by DNVs. In contrast, less than 20% of genetic risk conferred by rare inherited loss-of-function (LoF) variants are explained by known ASD/NDD genes. We selected 404 genes based on the first stage of analysis and performed a meta-analysis with an additional 22,764 cases and 236,000 population controls. We identified 60 genes with exome-wide significance (p < 2.5e-6), including five new risk genes (NAV3, ITSN1, MARK2, SCAF1, and HNRNPUL2). The association of NAV3 with ASD risk is entirely driven by rare inherited LoFs variants, with an average relative risk of 4, consistent with moderate effect. ASD individuals with LoF variants in the four moderate risk genes (NAV3, ITSN1, SCAF1, and HNRNPUL2, n = 95) have less cognitive impairment compared to 129 ASD individuals with LoF variants in well-established, highly penetrant ASD risk genes (CHD8, SCN2A, ADNP, FOXP1, SHANK3) (59% vs. 88%, p= 1.9e-06). These findings will guide future gene discovery efforts and suggest that much larger numbers of ASD cases and controls are needed to identify additional genes that confer moderate risk of ASD through rare, inherited variants.

category: genetic and genomic medicine


title: Innate immune activation restricts priming and protective efficacy of the radiation-attenuated PfSPZ malaria vaccine

abstract: Baseline innate immune signatures can influence protective immunity following vaccination. Here, we used systems transcriptional analysis to assess the molecular mechanisms underlying differential immunogenicity and protective efficacy results of a clinical trial of the radiation-attenuated whole sporozoite PfSPZ Vaccine in African infants. Innate immune activation and myeloid signatures at pre-vaccination baseline correlated with protection from Plasmodium falciparum infection in placebo controls, while the same signatures predicted susceptibility to infection among infants who received the highest and most protective dose of the PfSPZ Vaccine. Machine learning identified monocytes and an antigen presentation signature as pre-vaccination features predictive of malaria infection after highest-dose PfSPZ vaccination. Consistent with these human data, innate stimulation in vivo conferred protection against malaria infection in mice while diminishing the CD8+ T cell response to radiation-attenuated sporozoites. These data establish a dichotomous role of innate stimulation for malaria protection and induction of protective immunity of whole-sporozoite malaria vaccines.

category: infectious diseases


title: Defining the analytical and clinical sensitivity of the ARTIC method for the detection of SARS-CoV-2

abstract: The SARS-CoV-2 ARTIC amplicon protocol is the most widely used genome sequencing method for SARS-CoV-2, accounting for over 43% of publicly-available genome sequences. The protocol utilises 98 primers to amplify [~]400bp fragments of the SARS-CoV-2 genome covering all 30,000 bases. Understanding the analytical performance metrics of this protocol will improve how the data is used and interpreted. Different concentrations of SARS-CoV-2 control material were used to establish the limit of detection (LoD) of the ARTIC protocol. Results demonstrated the LoD was a minimum of 25-50 virus particles per mL. The sensitivity of ARTIC was comparable to the published sensitivities of commercial diagnostics assays and could therefore be used to confirm diagnostic testing results. A set of over 3,600 clinical samples from three UK regions were then evaluated to compare the protocols performance to clinical diagnostic assays (Roche Lightcycler 480 II, AusDiagnostics, Roche Cobas, Hologic Panther, Corman RdRp, Roche Flow, ABI QuantStudio 5, Seegene Nimbus, Qiagen Rotorgene, Abbott M2000, Thermo TaqPath, Xpert). We developed a Python tool, RonaLDO, to perform this validation (available under the GNU GPL3 open-source licence from https://github.com/quadram-institute-bioscience/ronaldo). Positives detected by diagnostic platforms were generally supported by sequencing data; platforms that used RT-qPCR were the best predictors of whether the sample would subsequently sequence successfully. To maximise success of sample sequencing for phylogenetic analysis, samples with Ct <31 should be chosen. For diagnostic tests that do not provide a quantifiable Ct value, adding a quantification step is recommended. The ARTIC SARS-CoV-2 sequencing protocol is highly sensitive, capable of detecting SARS-CoV-2 in samples with Cts in the high 30s. However, to routinely obtain whole genome coverage, samples with Ct <31 are recommended. Comparing different virus detection methods close to their LoD was challenging and significant discordance was observed.


title: Dynamics of gut mucosal colonisation with extended spectrum beta-lactamase producing Enterobacterales in Malawi

abstract: Shortening courses of antimicrobials has been proposed to reduce risk of antimicrobial resistant (AMR) infections, but acquisition and selection dynamics under antimicrobial pressure at the individual level are poorly understood. We combine multi-state modelling and whole-genome sequencing to understand colonisation dynamics of extended-spectrum beta-lactamase producing Enterobacterales (ESBL-E) in Malawian adults. We demonstrate prolonged post-exposure antibiotic effect, meaning short courses exert similar colonisation pressure to longer ones. Genome data does not identify widespread hospital-associated ESBL-E transmission, hence apparent acquisitions may be selected from the patient microbiota by antimicrobial exposure. Understanding ESBL-E dynamics under antimicrobial pressure is crucial for evidence-based stewardship protocols.


title: Decline in prenatal buprenorphine/naloxone fills during the COVID-19 pandemic in the United States

abstract:
Background and AimsPregnancy provides a critical opportunity to engage women with substance use disorder in care. Buprenorphine/naloxone treatment is associated with improved pregnancy and fetal outcomes, but prior to the COVID-19 pandemic, there were multiple barriers to accessing buprenorphine/naloxone during pregnancy. Care disruptions during the pandemic may have further exacerbated these already existing barriers. To quantify these changes, we examined trends in the number of individuals filling prescriptions for prenatal buprenorphine/naloxone prescriptions during the COVID-19 pandemic.

MethodsWe estimated an interrupted time series model using linked national pharmacy claims and medical claims data from May 2019 to December 2020. We estimated changes in the level and trend in the monthly number of individuals filling prescriptions for prenatal buprenorphine/naloxone during the COVID-19 pandemic. We then stratified our analyses by payer.

ResultsWe identified 2,947 pregnant patients filling buprenorphine/naloxone prescriptions. Before the pandemic, there was positive growth in the monthly number of individuals filling prescriptions for prenatal buprenorphine/naloxone (4.83% (95% confidence interval (CI): 3.40% to 6.26%). During the pandemic, the monthly growth rate in individuals filling prescriptions for prenatal buprenorphine/naloxone declined for both patients on commercial insurance and patients on Medicaid (all payers: -5.53% (95% CI: -7.28% to -3.78%); Medicaid: -7.66% (95% CI: -10.42% to -4.90%); Commercial: -3.59% (95% CI: -5.53% to -1.66%)).

ConclusionThe number of pregnant individuals filling buprenorphine/naloxone prescriptions was increasing prior to the pandemic, but this growth has been lost during the pandemic.

category: addiction medicine


title: ToxPi*GIS Toolkit: Creating, viewing, and sharing integrative visualizations for geospatial data using ArcGIS

abstract:
BackgroundPresenting a comprehensive picture of geographic data comprising multiple factors is an inherently integrative undertaking. Visualizing such data in an interactive form is essential for public sharing and geographic information systems (GIS) analysis. The Toxicological Prioritization Index (ToxPi) framework has been used as an integrative model layered atop geospatial data, and its deployment within the dynamic ArcGIS universe would open up powerful new avenues for sophisticated, interactive GIS analysis.

ObjectiveWe propose an actively developed suite of software, the ToxPi*GIS Toolkit, for creating, viewing, sharing, and analyzing interactive ToxPi figures in ArcGIS.

MethodsThe ToxPi*GIS Toolkit is a collection of methods for creating interactive feature layers that contain ToxPi diagrams. It currently includes an ArcGIS Toolbox (ToxPiToolbox.tbx) for drawing geographically located ToxPi diagrams onto a feature layer, a collection of modular Python scripts that create predesigned layer files containing ToxPi feature layers from the command line, and a collection of Python routines for useful data manipulation and preprocessing. We present workflows documenting ToxPi feature layer creation, sharing, and embedding for both novice and advanced users looking for additional customizability.

ResultsMap visualizations created with the ToxPi*GIS Toolkit can be made freely available on public URLs, allowing users without ArcGIS Pro access or expertise to view and interact with them. Novice users with ArcGIS Pro access can create de novo custom maps, and advanced users can exploit additional customization options. The ArcGIS Toolbox provides a simple means for generating ToxPi feature layers. We illustrate its usage with current COVID-19 data to compare drivers of pandemic vulnerability in counties across the United States.

SignificanceDevelopment of new features, which will advance the interests of the scientific community in many fields, is ongoing for the ToxPi*GIS Toolkit, which can be accessed from www.toxpi.org.

Impact StatementPresenting a comprehensive picture of geographic data comprising multiple factors is an inherently integrative undertaking. Visualizing this data in an interactive form is essential for public sharing and geographic analysis. The ToxPi framework provides such integration, and ArcGIS offers interactive geographic mapping capability, but, so far, producing ToxPi figures in ArcGIS maps has not been possible. We propose the ToxPi*ArcGIS Toolkit, which enables the generation of ArcGIS feature layers that include interactive ToxPi figures. Further, we document the living code repository created for this method and outline workflows for sharing, creating, and embedding maps within a web dashboard.

Availability and ImplementationAll applications, usage instructions, sample data, example visualizations, and open-source code are freely available from a dedicated GitHub page linked from www.toxpi.org. ArcGIS Pro can be obtained at https://www.esri.com/en-us/arcgis/products/arcgis-pro/overview.


title: Reducing the use of sleep-inducing drugs during hospitalization by a multi-faceted intervention - a pilot study

abstract:
ObjectivesMany patients receive benzodiazepines or Z-drugs during hospitalization due to sleeping problems. In a pilot study, we aimed to find out whether, and to what degree, a multi-faceted intervention can reduce the use of these drugs, especially in older patients and those without a psychiatric or neurological disorder. The results of this pilot study should inform the design of a randomised controlled trial (RCT).

MethodsIn a quasi-experimental design, we implemented the intervention in a German hospital with the support of the hospital director, medical and nursing staff and employee representatives. We compared prescription data for sleep-inducing drugs before and after the intervention by Fishers exact test and used Odds-Ratios (ORs) with their 95 % confidence intervals (CI) as measure of effect size.

ResultsThe data from 960 patients aged 65 and older before intervention and 1049 patients after intervention were analysed. Before intervention, 483 (50.3%) of the patients received sleep-inducing drugs at some time during their hospital stay. After the intervention, 381 (36.3%) patients received a sleep-inducing drug, resulting in an OR of 0.56 (95% CI: 0.47 to 0.68; p <0.001). The reduction was particularly pronounced in patients without a psychiatric or neurological disorder (from 45.0% to 28.8%). Especially benzodiazepines were significantly reduced (from 24.3% to 8.5%; OR: 0.31 (0.23-0.4); <0.001).

ConclusionsA multi-faceted intervention to change the practice of the use of sleep-inducing drugs in one hospital was successful in terms of drug reduction, particularly for benzodiazepines. The intervention was effective especially for target persons, i.e. those without a psychiatric or neurological disease. Being aware of the magnitude of the change and the role of important stakeholders could help researchers, hospital physicians and hospital pharmacists to design a large RCT, including control hospitals, to evaluate the success of a multi-faceted intervention on a scientifically sound basis.

KEY MESSAGESO_ST_ABSWhat is already known on this subjectC_ST_ABSO_LIBenzodiazepines and Z-drugs are still too often used for sleep problems in hospitals.
C_LIO_LISimple interventions, such as training seminars to reduce the use of benzodiazepines, Z-drugs, and other drugs for insomnia treatment are limited in their effect.
C_LI

What this study addsO_LIThe intervention significantly reduced the rate of sleep-inducing drugs by 14 percentage points.
C_LIO_LIThe results of this pilot study give a first impression of the possible impact of the interventions and provide essential information for the design of a randomized controlled study.
C_LI

category: pharmacology and therapeutics


title: Ondansetron use is associated with lower COVID-19 mortality in a Real-World Data network-based analysis

abstract:
ObjectiveThe COVID-19 pandemic generated a massive amount of clinical data, which potentially holds yet undiscovered answers related to COVID-19 morbidity, mortality, long term effects, and therapeutic solutions. The objective of this study was to generate insights on COVID-19 mortality-associated factors and identify potential new therapeutic options for COVID-19 patients by employing artificial intelligence analytics on real-world data.

MethodsA Bayesian statistics-based artificial intelligence data analytics tool (bAIcis(R)) within Interrogative Biology(R) platform was used for network learning, inference causality and hypothesis generation to analyze 16,277 PCR positive patients from a database of 279,281 inpatients and outpatients tested for SARS-CoV-2 infection by antigen, antibody, or PCR methods during the first pandemic year in Central Florida. This approach generated causal networks that enabled unbiased identification of significant predictors of mortality for specific COVID-19 patient populations. These findings were validated by logistic regression, regression by least absolute shrinkage and selection operator, and bootstrapping.

ResultsWe found that in the SARS-CoV-2 PCR positive patient cohort, early use of the antiemetic agent ondansetron was associated with increased survival in mechanically ventilated patients.

ConclusionsThe results demonstrate how real world COVID-19 focused data analysis using artificial intelligence can generate valid insights that could possibly support clinical decision-making and minimize the future loss of lives and resources.


title: The military as a neglected pathogen transmitter and its implications for COVID-19: A systematic review

abstract:
BackgroundThe risk of outbreaks escalating into pandemics has soared with globalization. Therefore, understanding transmission mechanisms of infectious diseases has become critical to formulating global public health policy. This systematic review assessed evidence in the medical and public health literature for the military as a disease vector.

MethodsWe searched 3 electronic databases without temporal restrictions. Two researchers independently extracted study data using a standardized form. Through team discussions, studies were grouped according to their type of transmission mechanism and direct quotes were extracted to generate themes and sub-themes. A content analysis was later performed and frequency distributions for each theme were generated.

ResultsOf 6477 studies, 210 met our inclusion criteria and provided evidence, spanning over two centuries (1810 - 2020), for the military as a pathogen transmitter, within itself or between it and civilians. Biological mechanisms driving transmission included person-to-person transmission, contaminated food and water, vector-borne, and airborne routes. Contaminated food and/or water were the most common biological transmission route. Social mechanisms facilitating transmission included crowded living spaces, unhygienic conditions, strenuous working, training conditions, absent or inadequate vaccination programs, pressure from military leadership, poor compliance with public health advice, contractor mismanagement, high-risk behaviours, and occupation-specific freedom of movement. Living conditions were the most common social transmission mechanism, with young, low ranking military personnel repeatedly reported as the most affected group. Selected social mechanisms, such as employment-related freedom of movement, were unique to the military as a social institution. While few studies explicitly studied civilian populations, considerably more contained information that implied that civilians were likely impacted by outbreaks described in the military.

ConclusionsThis study identified features of the military that pose a significant threat to global health, especially to civilian health in countries with substantial military presence or underdeveloped health systems. While biological transmission mechanisms are shared by other social groups, selected social transmission mechanisms are unique to the military. As an increasingly interconnected world faces the challenges of COVID-19 and future infectious diseases, the identified features of the military may exacerbate current and similar challenges and impair attempts to implement successful and equitable global public health policies.


title: The military as a neglected pathogen transmitter, from the 19th century to COVID-19: A systematic review


title: Clinical implementation of a machine learning system to detect deteriorating patients reduces time to response and intervention

abstract:
IntroductionAcute physiological deterioration is a major contributor to in-hospital morbidity and mortality. Early detection and intervention of deteriorating patients is key to improving patient outcomes. Prior research has demonstrated the effectiveness of Early Warning Systems and other algorithmic approaches in automatically identifying these patients from passively monitoring vital signs.

MethodsIn this work, we conduct a prospective pilot study of clinical deployment of the Mayo Clinic Bedside Patient Rescue (BPR) system using an escalating alerting logic enabled by machine learning. Among four units where the BPR system was deployed, time to response and time to intervention for deteriorating patients were significantly reduced relative to matched control units.

ResultsIn pilot units, time to response decreased by 35.4% (from 63.2 minutes to 40.8 minutes) and time to intervention decreased by 48.5% (from 106.3 minutes to 55.9 minutes). No significant differences were observed in counterbalance metrics of mortality, ICU transfer rate, and Rapid Response Team activation rate. Furthermore, the automated alerting system was well-received by clinicians participating in the pilot study, as assessed by survey.

DiscussionThese results demonstrate a successful clinical deployment of a practice-changing machine learning alert system with demonstrable impact on improving patient care.

category: health informatics


title: The Biomedical Research Hub: A Federated Platform for Patient Research Data

abstract:
ObjectiveThe objective was to develop and operate a cloud-based federated system for managing, analyzing and sharing patient data for research purposes, while allowing each resource sharing patient data to operate their component based upon their own governance rules. The federated system is called the Biomedical Research Hub (BRH).

MethodsThe BRH is a cloud-based federated system built over a core set of software services called framework services. BRH framework services include authentication and authorization, services for generating and assessing FAIR data, and services for importing and exporting bulk clinical data. The BRH includes data resources providing data operated by different entities and workspaces that can access and analyze data from one or more of the data resources in the BRH.

ResultsThe BRH contains multiple data commons that in aggregate provide access to over 6 PB of research data from over 400,000 research participants.

Discussion and conclusionWith the growing acceptance of using public cloud computing platforms for biomedical research, and the growing use of opaque persistent digital identifiers for datasets, data objects, and other entities, there is now a foundation for systems that federate data from multiple independently operated data resources that expose FAIR APIs, each using a separate data model. Applications can be built that access data from one or more of the data resources.


title: Is 7-days home BP measurement comparable to 24-hours Ambulatory BP Measurement?

abstract: High blood pressure (BP) or hypertension is a significant risk factor for the global burden of cardiovascular diseases. Home blood pressure measurements (HBPM) have been recommended for hypertension diagnosis, treatment initiation and medication titration, but guidelines for the number of measurements and duration are inconsistent. This study compared the accuracy of 3 home BP measurements per day for seven days with 24-hour ambulatory BP measurements. We examined 24-hour ambulatory BP measurements (ABPM) and HBPM during-morning, afternoon, and evening each day for seven days in healthy community living volunteers. Standardized Bland-Altman scatterplots and limits of agreement (LOA) were used to assess absolute reliability and the variability of measurement biases. We used nonparametric Mann-Whitney U-tests to compare the mean (SD) of the devices. Correlations between HBPM and 24-hour ABPM measurements were statistically significant at p<0.05. The high correlation coefficient (r=0.75) was observed between the systolic BP retrieved from two devices compared to moderate correlation (r=0.46) among diastolic BP. A significant difference was found for systolic BP (P<0.05) between the HBPM and ABPM but was non-significant for diastolic BP (P>0.05). In Bland-Altman plots, the LOA between HBPM and ABPM was 0.07-26.23 mmHg for SBP and 11.24 -16.20 mmHg for DBP. The overall mean difference (bias) in SBP and DBP was 13.08 and 2.48, respectively. Our results suggest that HBPM three times per day for seven days can potentially be used where ABPM is unavailable. Further studies in a diverse group of people with hypertension are needed.

category: cardiovascular medicine


title: Genomic answers for children: Dynamic analyses of >1000 pediatric rare disease genomes

abstract:
PURPOSETo provide comprehensive diagnostic and candidate analyses in a pediatric rare disease cohort through the Genomic Answers for Kids (GA4K) program.

METHODSExtensive analyses of 960 families with suspected genetic disorders including short-read exome (ES) and genome sequencing (srGS); PacBio HiFi long-read GS (HiFi-GS); variant calling for small-nucleotide (SNV), structural (SV) and repeat variants; and machine-learning variant prioritization. Structured phenotypes, prioritized variants and pedigrees are stored in PhenoTips database, with data sharing through controlled access (dbGAP).

RESULTSDiagnostic rates ranged from 11% for cases with prior negative genetic tests to 34.5% in naive patients. Incorporating SVs from GS added up to 13% of new diagnoses in previously unsolved cases. HiFi-GS yielded increased discovery rate with >4-fold more rare coding SVs than srGS. Variants and genes of unknown significance (VUS/GUS) remain the most common finding (58% of non-diagnostic cases).

CONCLUSIONComputational prioritization is efficient for diagnostic SNVs. Thorough identification of non-SNVs remains challenging and is partly mitigated by HiFi-GS sequencing. Importantly, community research is supported by sharing real-time data to accelerate gene validation, and by providing HiFi variant (SNV/SV) resources from >1,000 human alleles to facilitate implementation of new sequencing platforms for rare disease diagnoses.


title: Characterizing menstrual bleeding changes occurring after SARS-CoV-2 vaccination

abstract:
Early in 2021, many people began sharing that they experienced unexpected menstrual bleeding after SARS-CoV-2 inoculation. We investigated this emerging phenomenon of changed menstrual bleeding patterns among a convenience sample of currently and formerly menstruating people using a web-based survey. In this sample, 42% of people with regular menstrual cycles bled more heavily than usual while 44% reported no change after being vaccinated. Among respondents who typically do not menstruate, 71% of people on long-acting reversible contraceptives, 39% of people on gender-affirming hormones, and 66% of post-menopausal people reported breakthrough bleeding. We found increased/breakthrough bleeding was significantly associated with age, systemic vaccine side effects (fever, fatigue), history of pregnancy or birth, and ethnicity. Generally, changes to menstrual bleeding are not uncommon nor dangerous, yet attention to these experiences is necessary to build trust in medicine.

TeaserIncreased bleeding can occur post SARS-CoV-2 vaccines; this study investigates patterns in who experiences these changes.

category: obstetrics and gynecology


title: Investigating trends in those who experience menstrual bleeding changes after SARS-CoV-2 vaccination


title: Baricitinib plus Standard of Care for Hospitalised Adults with COVID-19 on Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation: Results of a Randomized, Placebo-Controlled Trial.

abstract:
BackgroundThe oral, selective Janus kinase (JAK)1/JAK2 inhibitor baricitinib demonstrated efficacy in hospitalised adults with COVID-19. This study evaluates the efficacy and safety of baricitinib in critically ill adults with COVID-19 requiring invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO).

MethodsCOV-BARRIER was a global, phase 3, randomised, double-blind, placebo-controlled trial in patients with confirmed SARS-CoV-2 infection (ClinicalTrials.gov NCT04421027). This addendum trial added a critically ill cohort not included in the main COV-BARRIER trial. Participants on baseline IMV/ECMO were randomly assigned 1:1 to baricitinib 4-mg (n=51) or placebo (n=50) for up to 14 days in combination with standard of care (SOC). Prespecified endpoints included all-cause mortality through days 28 and 60, and number of ventilator-free days, duration of hospitalisation, and time to recovery through day 28. Efficacy and safety analyses included the intent-to-treat and safety populations, respectively.

FindingsSOC included baseline systemic corticosteroid use in 86% of participants. Treatment with baricitinib significantly reduced 28-day all-cause mortality compared to placebo (39{middle dot}2% vs 58{middle dot}0%; hazard ratio [HR]=0{middle dot}54 [95%CI 0{middle dot}31-0{middle dot}96]; p=0{middle dot}030). One additional death was prevented for every six baricitinib-treated participants. Significant reduction in 60-day mortality was also observed (45{middle dot}1% vs 62{middle dot}0%; HR=0{middle dot}56 [95%CI 0{middle dot}33-0{middle dot}97]; p=0{middle dot}027).

Baricitinib-treated participants showed numerically more ventilator-free days (8.1 vs 5.5 days, p=0.21) and spent over 2 days less in the hospital than placebo-treated participants (23{middle dot}7 vs 26{middle dot}1 days, p=0{middle dot}050). The rates of infections, blood clots, and adverse cardiovascular events were similar between treatment arms.

InterpretationIn critically ill patients with COVID-19 already receiving IMV/ECMO, treatment with baricitinib as compared to placebo (in combination with SOC, including corticosteroids) showed mortality HR of 0{middle dot}56, corresponding to a 44% relative reduction at 60 days. This is consistent with the mortality reduction observed in less severely ill hospitalised primary COV-BARRIER study population.

FundingEli Lilly and Company.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe evaluated current and prior studies assessing the efficacy and safety of interventions in patients requiring invasive mechanical ventilation (IMV) and searched current PubMed using the terms "COVID-19", "SARS-CoV-2", "treatment", "critical illness", "invasive mechanical ventilation", "baricitinib", and "JAK inhibitor" for articles in English, published until December 1, 2020, regardless of article type. We also reviewed the NIH and IDSA COVID-19 guidelines and reviewed similar terms on clinicaltrials.gov. When the critical illness addendum study to COV-BARRIER study was designed, there was only one open-label study of dexamethasone showing mortality benefit in hospitalised patients with COVID-19 requiring IMV. Small studies of interleukin-6 inhibitors had shown no effect and larger trials were underway. Guidelines recommended use of dexamethasone with or without remdesivir and recommended against the use of interleukin-6 inhibitors, except in a clinical trial. Overall, there were no reported double-blind, placebo-controlled phase 3 trials which included corticosteroids as part of SOC investigating the efficacy and safety of novel treatments in the NIAID-OS 7 population. Baricitinibs mechanism of action as a JAK1 and JAK2 inhibitor was identified as a potential intervention for the treatment of COVID-19 given its known anti-cytokine properties and potential antiviral mechanism for targeting host proteins mediating viral endocytosis Data from the NIAID sponsored ACTT-2 trial showed that baricitinib when added to remdesivir improved time to recovery and other outcomes including mortality compared to placebo plus remdesivir. A numerically larger proportion of participants who received baricitinib plus remdesivir showed an improvement in ordinal scale compared to those who received placebo plus remdesivir at day 15 in participants requiring IMV (NIAID-OS score of 7) at baseline. We designed COV-BARRIER, a phase 3, global, double-blind, randomised, placebo-controlled trial, to evaluate the efficacy and safety of baricitinib in combination with SOC (including corticosteroids) for the treatment of hospitalised adults with COVID-19 who did not require mechanical ventilation (i.e., NIAID-OS 4-6). A significant reduction in mortality was found after 28 days between baricitinib and placebo (HR 0{middle dot}57, corresponding to a 43% relative reduction, p=0{middle dot}0018); one additional death was prevented per 20 baricitinib-treated participants. In the more severely ill NIAID-OS 6 subgroup, one additional death was prevented per nine baricitinib-treated participants (HR 0{middle dot}52, corresponding to a 48% relative reduction, p=0{middle dot}0065). We therefore implemented an addendum to the COV-BARRIER trial to evaluate the benefit/risk of baricitinib in the critically ill NIAID-OS 7 population and considered the sample size of 100 participants sufficient for this trial.

Added value of this studyThis was the first phase 3 study to evaluate baricitinib in addition to the current standard of care (SOC), including antivirals, anticoagulants, and corticosteroids, in patients who were receiving IMV or extracorporeal membrane oxygenation at enrolment. This was a multinational, randomised, double-blind, placebo-controlled trial in regions with high COVID-19 hospitalisation rates. Treatment with baricitinib reduced 28-day all-cause mortality compared to placebo (HR 0{middle dot}54, 95% CI 0{middle dot}31-0{middle dot}96; nominal p=0{middle dot}030), corresponding to a 46% relative reduction, and significantly reduced 60-day all-cause mortality (HR 0{middle dot}56, 95% CI 0{middle dot}33-0{middle dot}97; p=0{middle dot}027); overall, one additional death was prevented per six baricitinib-treated participants. Numerical improvements in endpoints such as number of ventilator-free days, duration of hospitalisation, and time to recovery were demonstrated. The frequency of serious adverse events, serious infections, and venous thromboembolic events was similar between baricitinib and placebo, respectively.

The COV-BARRIER study overall trial results plus these COV-BARRIER addendum study data in mechanically ventilated and ECMO patients provide important information in context of other large, phase 3 randomised trials in participants with invasive mechanical ventilation at baseline. The RECOVERY study reported mortality of 29{middle dot}3% following treatment with dexamethasone compared to 41{middle dot}4% for usual care (rate ratio of 0{middle dot}64, corresponding to a 36% relative reduction) and 49% mortality in participants who received tocilizumab compared to 51% for usual care (rate ratio of 0.93, corresponding to a 7% relative reduction). The ACTT-2 study reported 28-day mortality of 23{middle dot}1% and 22{middle dot}6% in the baricitinib plus remdesivir and placebo plus remdesivir groups, respectively, in this critically ill patient population; however, the primary outcome of this trial was time to recovery, so was not powered to detect a change in mortality.

Implications of all the available evidenceIn this phase 3 addendum trial, baricitinib given in addition to SOC (which predominantly included corticosteroids) had a significant effect on mortality reduction by 28 days in critically ill patients, an effect which was maintained by 60 days. These data were comparable with those seen in the COV-BARRIER primary study population of hospitalised patients, but which excluded patients who required IMV or extracorporeal membrane oxygenation at enrolment. These findings suggest that baricitinib has synergistic effects to other SOC treatment modalities including remdesivir and dexamethasone. Based on the available evidence, baricitinib is a novel treatment option to decrease mortality in hospitalised, critically ill patients with COVID-19 even when started late in the disease process after steroids, mechanical ventilation, and ECMO have already been implemented.


title: Impact of Antibody Cocktail Therapy Combined with Casirivimab and Imdevimab on Clinical Outcome for Covid-19 patients in A Real-Life Setting: A Single Institute Analysis

abstract:
BackgroundRecent data from clinical trial suggest that antibody cocktail therapy, a combination of the monoclonal antibodies casirivimab and imdevimab, has been shown to rapidly reduce the viral load and markedly decrease the risk of hospitalization or death among high-risk patients with coronavirus disease 2019 (Covid-19). However, it remains unclear how effective in a real-life clinical setting the therapy is.

MethodsWe retrospectively analyzed mild to moderate Covid-19 patients with one or more high-risk factors for severe disease who consecutively underwent the antibody cocktail therapy of the disease in our institute in June 2021 through early September 2021, compared to those with high-risk factors who were isolated in non-medical facilities consecutively during the same period, thereby being not given the antibody cocktail therapy there. The key outcome was the percentage of patients with Covid-19-related deterioration which needed additional medical interventions, such as oxygen support or other antiviral therapies.

ResultsData from 55 patients with initially receiving antibody cocktail therapy and 53 patients with isolation into non-medical facilities are analyzed. 22 (41.5 %) of 53 patients with isolation facilities were finally hospitalized to receive medical interventions. On the other hand, 13 (23.6 %) of 55 patients with antibody cocktail therapy in our hospital subsequently underwent further medical interventions because of the progression. In multivariate analysis with variables of age, BMI, and high-risk factors, the antibody cocktail therapy significantly reduced 70 % in the need for further medical interventions compared to the initial isolation in the non-medical facilities (odds ratio=0.30, 95%CI [0.10-0.87], p=0.027). Furthermore, patients with 96% or above of SPO2 were significantly more favorable for the therapy than those with 95% or below of SPO2.

ConclusionThe treatment of antibody cocktail was closely linked to reduction in the need for further medical interventions. The result indicates that the antibody cocktail therapy is associated with reducing the strain on hospitals, which is related to the improvement of medical management for public health care in Covid-19 pandemic era.


title: Trans Sodium Crocetinate (TSC) to Improve Oxygenation in COVID-19

abstract:
BackgroundTrans Sodium Crocetinate (TSC) is a bipolar synthetic carotenoid under development as a drug to enhance oxygenation to hypoxic tissue in addition to standard of care. TSC acts via a novel mechanism of action, improving the diffusivity of oxygen in blood plasma. Thus, it is based on physical-chemical principles, unlike most drugs which are based on biochemistry-based mechanisms. We explored the use of escalating doses and multiple daily dosing of TSC as a potential therapeutic for patients suffering from hypoxemia due to SARS-CoV-2 infection.

MethodsIndividuals [≥]18 years who were hospitalized with confirmed SARS-CoV-2 infection and hypoxemia, defined as SpO2 < 94% on room air or requiring supplemental oxygen, WHO ordinal scale 3 through 7 (exclusive of Extra Corporeal Membrane Oxygenation [ECMO]) were enrolled in cohorts of six subjects, each of whom received the same dose (0.25, 0.5, 1.0, or 1.5 mg/kg) of TSC via intravenous bolus every 6 hours in addition to standard of care (SOC).

This report describes the safety and efficacy results from the lead-in phase of the study and the population pharmacokinetics (PK) analyses. Safety was assessed as the number of serious adverse events and dose-limiting toxicities (DLTs) observed with each dose. Several efficacy parameters were examined in the lead-in phase and descriptive statistics of efficacy parameters are provided. No formal statistical analyses were performed. The population PK analyses were based on previous analyses and examination of the concentration profiles, and two-compartment linear pharmacokinetic models were evaluated and validated. Covariates, including body size, age, sex, organ function, and dose level, were evaluated for inclusion into the model.

ResultsTSC was well tolerated. There were no treatment emergent adverse events (TEAEs) reported. There were 2 serious adverse events (SAEs) reported during the study, neither were considered treatment-related. A total of 24 (96%) subjects survived. One subject (4.0%) died during the study as a result of an SAE (respiratory failure), and that event was determined to be due to COVID-19 complications and not related to study drug.

There was an observed reduction in the time to improvement in WHO Ordinal Scale with increasing dose. The median time to 1-point reduction in subjects receiving 0.25 mg/kg was 11.5 days versus 7.5 days in the 1.5 mg/kg treatment cohort. The overall range across all doses was 1 day to 28 days. A total of 36.0% of subjects had a 1-point improvement in WHO Ordinal Scale to Day 7. The 1.5 mg/kg dose resulted in observed superior outcomes for multiple secondary clinical outcomes: time to 1-point WHO Ordinal Score improvement through Day 29/discharge, 1-point improvement by Day 7, days to return to room air, and hospital length of stay.

The PK results showed that the two-compartment model fit the data well. Clearance decreased with increasing dose level and there was no evidence that clearance was affected by covariates other than dose level.

ConclusionsThese findings suggest that TSC administration every 6 hours at doses up to 1.5 mg/kg for up to 15 days is safe and well tolerated with predictable pharmacokinetics and demonstrated an observed clinical benefit in the treatment of COVID-19-related hypoxemia.

(ClinicalTrials.gov number, NCT04573322)

category: intensive care and critical care medicine


title: Covid-19 Epidemic Prediction in France: the Multimodal Case.

abstract: In two previous papers we have proposed models to estimate the Covid-19 epidemic when the number of daily positive cases has a bell shaped form that we call a mode. We have observed that each Covid variant produces this type of epidemic shape at a different moment, resulting in a multimodal epidemic shape. We will show in this document that each mode can still be estimated with models described in the two previous papers provides we replace the cumulated number of positive cases y by the cumulated number of positive cases reduced by a parameter P to be estimated. Therefore denoting z the logarithm of y -P, z follows approximately the differential equation [z] = b -azr where a, b, r have also to be estimated from the observed data. We will show the obtained predictions on the four French modes April, November 2020, May and September 2021. The comparison between the prediction obtained before the containment decisions made by the French government and the observed data afterwards suggests the inefficiency of the epidemic lockdowns.


title: Breakthrough SARS-CoV-2 Infections after Vaccination in North Carolina

abstract:
ImportanceReal-world data are needed to assess incidence and factors associated with breakthrough SARS-CoV-2 infections following vaccination.

ObjectiveEstimate incidence of breakthrough infections and assess associations with risk factors using self-reported data from a large NC population sample.

DesignProspective observational cohort study utilizing daily online survey data to capture information about COVID-19 symptoms, testing, and vaccination status.

SettingSix health care systems in North Carolina with data collected between January 15, 2021 and September 24, 2021.

ParticipantsAdult study participants who reported full vaccination with a COVID-19 mRNA or J&J non-replicating viral vector vaccine (n =16,020).

ExposuresPotential community exposure to SARS-CoV-2.

Main Outcome and MeasuresSelf-reported breakthrough infection.

ResultsSARS-CoV-2 infection after vaccination was self-reported in 1.9% of participants, with an incidence rate of 7.3 per 100,000 person-years. Younger age (45-64 vs. 18-44: HR (95% CI) = 0.65 (0.51 - 0.82); 65+ vs. 18-44: HR (95% CI) = 0.59 (0.39 - 0.90)), and vaccination with J&J Ad26.COV2.S were associated with a higher risk of breakthrough infection compared to vaccination with Pfizer BNT162b2 (Ad26.COV2.S vs. BNT162b2: HR (95% CI) = 2.23 (1.40 - 3.56)), while participants vaccinated with mRNA-1273 (mRNA-1273 vs. BNT162b2: HR (95% CI) = 0.69 (0.50 - 0.96) and those residing in urban counties experienced a lower rate of SARS-CoV-2 breakthrough infection compared with those from suburban (HR (95% CI) = 1.39 (1.01 - 1.90) or rural (HR (95% CI) = 1.57 (1.16 - 2.11) counties. There was no significant association between breakthrough infection and participant sex, race, healthcare worker status, prior COVID-19 infection, routine mask use, or overall vaccination rate in the county of residence.

Conclusions and RelevanceThis NC community-based observational study showed that the proportion of the cohort who self-report breakthrough SARS-CoV-2 infections was 7.3 events per 100,000 person-years. Younger adults, those vaccinated with J&J Ad26.COV2.S, and those residing in suburban or rural counties were at higher risk of breakthrough infections and should be targeted for additional risk mitigation strategies to decrease community transmission.

Trial RegistrationThe COVID-19 Community Research Partnership is listed in clinicaltrials.gov (NCT04342884).

Key PointsO_ST_ABSQuestionC_ST_ABSWhat are the characteristics of those with breakthrough infections after SARS-CoV-2 vaccination in North Carolinaa

FindingsIn this NC-based observational study of 16,020 participants, 1.9% self-reported a positive SARS-CoV-2 viral test at least 2 weeks following full vaccination, reflecting an event rate of 7.3 infections per 100,000 person years. Rates were higher among younger participants, participants from more rural areas in North Carolina, and those vaccinated with J&J Ad26.COV2.S.

MeaningOur results show a relatively low rate of COVID-19 infection following full vaccination. Younger adults and those vaccinated with J&J Ad26.COV2.S should be targeted for additional risk mitigation strategies.


title: Highly sensitive and specific detection of the SARS-CoV-2 Delta variant by double-mismatch allele-specific PCR

abstract: The highly transmissible Delta variant of SARS-CoV-2 (B.1.617.2), first identified in India, is currently replacing pre-existing variants in Europe, the USA, and many other parts of the world. It is essential to monitor efficiently its spread to help guide public health policies. Genome sequencing is the gold standard for identification of Delta, but is time-consuming, expensive, and unavailable in many regions. We describe here a rapid and relatively inexpensive alternative to sequencing for specific identification of the Delta variant, by application of double-mismatch allele-specific RT-PCR (DMAS-RT-PCR). The technique exploits forward and reverse allele-specific primers, targeting two spike gene mutations, L452R and T478K, within the same amplicon. The discriminatory power of each primer is enhanced by the presence of an additional mismatch located at the fourth nucleotide from the 3' end. Amplicons are detected in real-time by means of a conventional fluorescently-labelled hydrolysis probe. Specificity was assessed by testing a range of well characterised cell culture-derived viral isolates and clinical samples, most of which had previously been fully sequenced. In all cases the results of viral genotyping by DMAS-RT-PCR were entirely concordant with the results of sequencing, and the assay was shown to discriminate reliably between the Delta variant and other variants of concern (Alpha, B.1.1.7 and Beta, B.1.351), and  wild-type SARS-CoV-2. Other respiratory viruses, including influenza A and respiratory syncytial virus, were non-reactive in the assay. The sensitivity of DMAS-RT-PCR matched that of the diagnostic SARS-CoV-2 RT-qPCR screening assay, which targets the E gene. Several samples that could not be sequenced due to insufficient virus could successfully be genotyped by DMAS-RT-PCR. The method we describe would be simple to establish in any laboratory that has the ability to conduct PCR assays and should greatly facilitate monitoring of the spread of the Delta variant throughout the world, and its proportional representation in any SARS-CoV-2-infected population.


title: A molecular surveillance-guided vector control response to concurrent dengue and West Nile virus outbreaks in a COVID-19 hotspot of Florida

abstract:
Simultaneous dengue virus (DENV) and West Nile virus (WNV) outbreaks in Florida, USA, in 2020 resulted in 71 dengue virus serotype 1 and 86 WNV human cases. Our outbreak response leveraged a molecular diagnostic screen of mosquito populations for DENV and WNV in Miami-Dade County to quickly employ targeted mosquito abatement efforts. We detected DENV serotypes 2 and 4 in mosquito pools, highlighting the silent circulation of diverse dengue serotypes in mosquitoes. Additionally, we found WNV-positive mosquito pools in areas with no historical reports of WNV transmission. These findings demonstrate the importance of proactive, strategic arbovirus surveillance in mosquito populations to prevent and control outbreaks, particularly when other illnesses (e.g., COVID-19), which present with similar symptoms are circulating concurrently. Growing evidence for substantial infection prevalence of dengue in competent mosquito vectors in the absence of local index cases suggests a higher level of dengue endemicity in Florida than previously thought.

Article Summary LineEvidence of increasing dengue endemicity in Florida: Vector surveillance during dengue and West Nile virus outbreaks revealed widespread presence of other dengue virus serotypes in the absence of local index cases.


title: High risk of SARS-CoV-2 infection among frontline healthcare workers in Northeast Brazil: a respondent-driven sampling approach

abstract:
IntroductionThe disparities in the risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among frontline health care workers (HCWs) and the unique work circumstances are poorly documented for low-and middle-income countries.

MethodsWe assessed the frequency of SARS-CoV-2 infection, personal protective equipment (PPE) shortages, PPE use, and accidents involving biological material among HCWs in the Recife metropolitan area, Northeast Brazil. Using respondent driven sampling, we included HCWs attending suspected or confirmed COVID-19 patients from May 2020 to February 2021.

ResultsWe analyzed 1,525 HCWs (527 physicians, 471 registered nurses, 263 nursing assistants/technicians, and 264 physical therapists). Women predominated in all categories (81.1%). Nurses were older and had more comorbidities (hypertension and overweight/obesity) than the other HCWs. The overall prevalence of SARS-CoV-2 infection was 61.8% after adjustment for the cluster random effect, weighted by network, and reference population size. The independent risk factors for a positive RT-PCR test were being a nursing assistant (OR adjusted: 2.56), not always using all recommended PPE in routine practice (ORadj: 2.15), and reporting a splash of biological fluid/respiratory secretion in the eyes (ORadj: 3.37).

ConclusionsThe high risk of infection among HCWs reflects PPE shortages and younger, possibly less experienced, frontline HCWs. There were disparities in the risk of SARS-CoV-2 infection among HCWs, with nursing assistants being the most vulnerable, possibly due to their longer and frequent contact with COVID-19 patients.


title: Effects of Age, Sex, Serostatus and Underlying Comorbidities on Humoral Response Post-SARS-CoV-2 Pfizer-BioNTech Vaccination: A Systematic Review

abstract: With the advent of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic, several vaccines have been developed to mitigate its spread and prevent adverse consequences of the Coronavirus Disease 2019 (COVID-19). The mRNA technology is an unprecedented vaccine, usually given in two doses to prevent SARS-CoV-2 infections. Despite effectiveness and safety, inter-individual immune response heterogeneity has been observed in recipients of mRNA-based vaccines. As a novel disease, the specific immune response mechanism responsible for warding off COVID-19 remains unclear at this point. However, significant evidence suggests that humoral response plays a crucial role in affording immunoprotection and preventing debilitating sequelae from COVID-19. As such this paper focused on the possible effects of age, sex, serostatus, and comorbidities on humoral response (i.e., total antibodies, IgG and/or IgA) of different populations post-mRNA-based Pfizer-BioNTech vaccination. A systematic search of literature was performed through PubMed, Cochrane CENTRAL, and Google Scholar. Studies were included if they reported humoral response to COVID-19 mRNA vaccines. A total of 32 studies was identified and reviewed, and the percent difference of means of reported antibody levels were calculated for comparison. Findings revealed that older individuals, the male sex, seronegativity, and those with more comorbidities mounted less humoral immune response. Given these findings, several recommendations were proposed regarding the current vaccination practices. These include giving additional doses of vaccination for immunocompromised and elderly populations. Another recommendation is conducting clinical trials in giving a combined scheme of mRNA vaccines, protein vaccines, and vector-based vaccines.


title: Remote patient monitoring to interrupt chains of respiratory infections in outpatient care - a case-control study during the 2020/21 infection season

abstract:
Aim of the studyThe aim of the study was to investigate satisfaction, saving of time and the possible reduction of patient visits to practices that use Remote Patient Monitoring (RPM) during treatment compared to usual care.

MethodsIn a case-control study between October 2020 and May 2021, the participating practices were randomized into three groups (two different RPM systems, one control). The doctors were required to enroll patients with acute respiratory infection [≥] 18 years who have a web-enabled device. After a three-month study phase, the doctors were asked to describe the treatment of their patients via online survey. The patients were also questioned. The analysis was carried out descriptively and with group comparisons.

Results51 practices with 121 patients were included. Overall, the results show a positive assessment of digital care on the patient side. As for the doctors, handling and integration of the systems into consisting practice processes seem to be a challenge. Further, the number of patient visits to the practice was not reduced by using the systems and the doctors did not save time, but the relationship to the patients was intensified.

ConclusionEven if there were no indications for more efficiency by using the RPM systems, the doctors see great potential to intensify the interaction between doctor and patient. In particular, more intensive contact with patients with chronic diseases (e. g. COPD, long-COVID) could be of long-term interest and importance for doctors in outpatient care.

Trial RegistrationDRKS00023553


title: Current surgical practice for children born with a cleft lip and/or palate in the United Kingdom

abstract:
BackgroundThis study describes primary surgical reconstructions performed for children born with a cleft lip and/or palate in the United Kingdom.

MethodsData were obtained from the Cleft Collective, a national longitudinal cohort study. Data forms completed at the time of surgery included details on timing, technique and adjuncts used during the operative period. Demographic data on participants were validated via parental questionnaires.

ResultsBetween 2015 and 2021, 1782 Cleft Collective surgical forms were included, relating to the primary reconstructions of 1514 individual children. The median age at primary cheiloplasty was 4.3 months. Unilateral cleft lips were reconstructed with an anatomical subunit approximation technique in 53%, whereas bilateral cleft lips were reconstructed with a broader range of eponymous techniques. Clefts of the soft palate were reconstructed at a median age of 10.3 months with an intravelar veloplasty in 94% cases. Clefts of the hard palate were reconstructed with a vomer flap in 84% cases in a bi-modal age distribution, relating to reconstruction carried out simultaneously with either lip or soft palate reconstruction. Antibiotics were used in 96% of cases, with an at-induction-only regimen used more commonly for cheiloplasties (p<0.001) and a 5-7day post-operative regime used more commonly for soft palatoplasties (p<0.001). Peri-operative steroids were used more commonly in palatoplasties than cheiloplasties (p<0.001) but tranexamic acid use was equivalent (p=0.73).

ConclusionThis study contributes to our understanding of current cleft surgical pathways in the United Kingdom and will provide a baseline for analysis of the effectiveness of utilised protocols.

category: surgery


title: Modelling the effect of COVID-19 mass vaccination on acute admissions in a major English healthcare system

abstract:
BackgroundManaging high levels of severe COVID-19 in the acute setting can impact upon the quality of care provided to both affected patients and those requiring other hospital services. Mass vaccination has offered a route to reduce societal restrictions while protecting hospitals from being overwhelmed. Yet, early in the mass vaccination effort, the possible effect on future bed pressures remained subject to considerable uncertainty. This paper provides an account of how, in one healthcare system, operational decision-making and bed planning was supported through modelling the effect of a range of vaccination scenarios on future COVID-19 admissions.

MethodsAn epidemiological model of the Susceptible-Exposed-Infectious-Recovered (SEIR) type was fitted to local data for the one-million resident healthcare system located in South West England. Model parameters and vaccination scenarios were calibrated through a system-wide multi-disciplinary working group, comprising public health intelligence specialists, healthcare planners, epidemiologists, and academics. From 4 March 2021 (the time of the study), scenarios assumed incremental relaxations to societal restrictions according to the envisaged UK Government timeline, with all restrictions to be removed by 21 June 2021.

ResultsAchieving 95% vaccine uptake in adults by 31 July 2021 would not avert a third wave in autumn 2021 but would produce a median peak bed requirement approximately 6% (IQR: 1% to 24%) of that experienced during the second wave (January 2021). A two-month delay in vaccine rollout would lead to significantly higher peak bed occupancy, at 66% (11% to 146%) of that of the second wave. If only 75% uptake was achieved (the amount typically associated with vaccination campaigns) then the second wave peak for acute and intensive care beds would be exceeded by 4% and 19% respectively, an amount which would seriously pressure hospital capacity.

ConclusionModelling provided support to senior managers in setting the number of acute and intensive care beds to make available for COVID-19 patients, as well as highlighting the importance of public health in promoting high vaccine uptake among the population. Forecast accuracy has since been supported by actual data collected following the analysis, with observed peak bed occupancy falling comfortably within the inter-quartile range of modelled projections.


title: Child mental and behavioral health services during the COVID-19 pandemic: Trends and implications for service outcomes during telehealth expansion

abstract: Transportation to/from care is a significant barrier to healthcare access and utilization. The novel coronavirus pandemic prompted a widespread expansion of telehealth service delivery throughout much of 2020. We used propensity score matching to generate two comparison groups of children served in a large public mental and behavioral health system between (1) April-December 2019 (pre-pandemic; n=2,794), and (2) between April-December 2020 (during the COVID-19 pandemic, n=2,794), followed by longitudinal linear mixed-effects modelling to explore the relationship between caregiver transportation needs and child-level outcomes. Our analyses indicated a statistically significant association between the resolution of caregivers transportation needs and childrens clinical improvement in the 2019 (pre-pandemic) sample; there was no such association found in the 2020 (pandemic) sample. Our findings suggest that the use of telehealth may mitigate the effect of caregiver transportation needs on child-level clinical outcomes.


title: An objective systematic comparison of the most common adverse events of COVID-19 vaccines

abstract:
BackgroundVaccination is an important tool in the fight against pandemics. However, the associated adverse events (AEs) may negatively impact the public perception of vaccines, therefore leading to decreased vaccination willingness. Interestingly, pharmacovigilance data of the three COVID-19 vaccines with a two-dose schedule approved in the EU (AstraZeneca, BioNTech and Moderna) already revealed country-specific differences in their safety profile early on (as of February 2021), at a time when the accumulated occurrence of specific AEs was not yet known. In the safety outcome assessment presented here, we aimed to establish whether these country-specific differences in pharmacovigilance data could be explained by differences in the frequency of AEs as reported in the respective approval studies of each vaccine.

MethodsA systematic search was performed to identify all publications regarding the randomized controlled trials (RCTs) of two-dose vaccines approved in the EU (AstraZeneca, BioNTech and Moderna), including regulatory reports and journal articles. All obtained safety data was manually entered into an SQL database. In order to enable the comparability among the data, the solicited AEs for all vaccines (i.e. those AEs actively sought after vaccination) were investigated. The data was standardized to promote comparability and overcome data heterogeneity and complexity.

FindingsTwelve documents regarding the RCTs for the three COVID-19 vaccines with a two-dose schedule approved in the EU (AstraZeneca, BioNTech and Moderna) were included in the safety outcome analysis. The entire safety data compiled in the SQL database amounted to 66 different study arms. The data structure revealed 13 different age thresholds or ranges and three different data sets regarding doses (first dose vs. second dose vs. all doses). After standardization and identification of subgroups, the analyses demonstrated that the highest rates of AEs occur after the first dose with the AstraZeneca vaccine, whereas with Moderna and BioNTech most AEs occur after the second dose. Astonishingly, the absolute frequencies of each AE after the first AstraZeneca dose correspond to those of the second dose of the mRNA vaccines (BioNTech and Moderna). Reversely, the absolute frequencies of the same AEs after the second AstraZeneca dose correspond to those of the first dose with the mRNA vaccines. The most common AEs with any vaccine were fatigue, headache and myalgia. Moreover, middle-aged subjects (18 to 55 years) had more side effects than older individuals (> 55 years), an observation that persisted among vaccines.

InterpretationThis is the first indirect comparison of these vaccines that uses all available RCT data. The absolute frequency of each AE is similar between the first AstraZeneca dose and the second dose of BioNTech or Moderna; their occurrence was thus independent of platform (vector or mRNA) or the vaccine itself. This assessment demonstrates that the varying frequencies of AEs reported in early pharmacovigilance data for the vaccines in distinct countries, at a time when the accumulated occurrence of specific AEs with certain vaccines was not yet known, cannot be explained by different frequencies being reported in the respective RCTs.

ConclusionThe approach presented here could help to objectify future discussions on vaccine preferences. Therefore, it may serve as basis for future public awareness campaigns and may also allow the comparison of vaccine performance in different subgroups (e.g. virus variants, high-risk patients). This approach may also be applied to a broad range of other challenges across the R&D process and various disease categories.


title: Heterologous SARS-CoV-2 Booster Vaccinations: Preliminary Report

abstract:
BackgroundWhile Coronavirus disease 2019 (Covid-19) vaccines are highly effective, breakthrough infections are occurring. Booster vaccinations have recently received emergency use authorization (EUA) for certain populations but are restricted to homologous mRNA vaccines. We evaluated homologous and heterologous booster vaccination in persons who had received an EUA Covid-19 vaccine regimen.

MethodsIn this phase 1/2 open-label clinical trial conducted at ten U.S. sites, adults who received one of three EUA Covid-19 vaccines at least 12 weeks prior to enrollment and had no reported history of SARS-CoV-2 infection received a booster injection with one of three vaccines (Moderna mRNA-1273 100-g, Janssen Ad26.COV2.S 5x1010 virus particles, or Pfizer-BioNTech BNT162b2 30-g; nine combinations). The primary outcomes were safety, reactogenicity, and humoral immunogenicity on study days 15 and 29.

Results458 individuals were enrolled: 154 received mRNA-1273, 150 received Ad26.CoV2.S, and 153 received BNT162b2 booster vaccines. Reactogenicity was similar to that reported for the primary series. Injection site pain, malaise, headache, and myalgia occurred in more than half the participants. Booster vaccines increased the neutralizing activity against a D614G pseudovirus (4.2-76-fold) and binding antibody titers (4.6-56-fold) for all combinations; homologous boost increased neutralizing antibody titers 4.2-20-fold whereas heterologous boost increased titers 6.2-76-fold. Day 15 neutralizing and binding antibody titers varied by 28.7-fold and 20.9-fold, respectively, across the nine prime-boost combinations.

ConclusionHomologous and heterologous booster vaccinations were well-tolerated and immunogenic in adults who completed a primary Covid-19 vaccine regimen at least 12 weeks earlier.

(Funded by National Institute of Allergy and Infectious Diseases; Clinical Trials.gov number, NCT04889209)


title: Genetically determined serum testosterone level and Covid-19 illness level: A mendelian randomization study

abstract:
BackgroundIt is hypothesized that different levels of hormones especially serum testosterone level could explain the sex differences between men and women on the susceptibility and case fatality rate of COVID-19. However, traditional observational studies that support this hypothesis could not effectively establish the causal effects.

ObjectiveUtilizing recently published genome-wide associations studies (GWAS) on serum Testosterone level and on COVID-19 related phenotypes, we sought to assess the causality through Mendelian Randomization (MR) analyses. We further applied a suite of statistical genomics methods to further explore the biological mechanisms.

ResultsWe found that testosterone level is significantly associated with Covid-19 critical illness. All six MR methods yielded significant associations. There is no significant association between Testosterone and COVID-19 respiratory failure or COVID-19 susceptibility.

ConclusionBased on the GWAS currently available, we provide support for a causal role of Testosterone on COVID-19 critical illness.Nevertheless, we recognize that the COVID-19 susceptibility GWAS effort is still ongoing and there is no such strong locus as CCR5 for HIV discovered for COVID-19.


title: One-shot immunization with Sputnik Light (the first component of Sputnik V vaccine) is effective against SARS-CoV-2 Delta variant: efficacy data on the use of the vaccine in civil circulation in Moscow

abstract:
ObjectivesVaccination remains the most effective response to the COVID-19 pandemic. Most vaccines use two-dose regimens. In turn, single-dose vaccines also have high potential, since, on the one hand, they simplify the vaccination program, make it more accessible and convenient for more people around the world, and on the other hand, they are better suited for subsequent revaccination. However, there is not enough data on the effectiveness of single-dose vaccine variants against new genetic lines to assess their current potential. It is not clear how much a single dose of immunization protects against the globally dominant delta variant. In this work, we investigated the effectiveness of a single dose vaccine (Sputnik Light, the first component of Sputnik V vaccine) against the Delta variant in Moscow.

MethodsTo assess the effectiveness of one dose of viral vector vaccine based on rAd26 against the delta variant in Moscow, we used data from the Moscow registries of vaccination against COVID-19 and the incidence of COVID-19. The availability of data on the number of seropositive residents of Moscow made it possible to consider the size of the immune layer formed because of a previous COVID-19 disease or vaccination. To calculate the effectiveness, the proportion of COVID-19 cases among those vaccinated with a single dose and the proportion of cases among those who were not vaccinated in July 2021.

ResultsOur data indicate that throughout July 2021, the dominant variant of the coronavirus at the level of 99.5% in Moscow was the SARS-CoV-2 delta variant and its subsidiary lines. Considering the immune layer of 46% allowed us to calculate the effectiveness of a one-shot vaccine against the delta variant in Moscow during the first three months after vaccination at the level of 69.85% (95% confidence interval [CI], 64.08 to 74.70). In the 18-29-year-old group, the overall vaccine efficacy against the delta variant was 88.61%, in the 18-59 group - 75.28%. Sputnik Light demonstrates higher efficacy against Delta variant than many two-shot vaccines.

ConclusionThe results indicate a high efficacy of a single immunization first component of Sputnik V vaccine against delta variant among young and middle-aged people, at least during the first 3 months after receiving the one-shot vaccine.


title: Predictive value of circulating NMR metabolic biomarkers for type 2 diabetes risk in the UK Biobank study

abstract:
BackgroundEffective targeted prevention of type 2 diabetes (T2D) depends on accurate prediction of disease risk. We assessed the role of metabolomic profiling in improving T2D risk prediction beyond conventional risk factors.

MethodsNMR-metabolomic profiling was undertaken on baseline plasma samples in 65,684 UK Biobank participants without diabetes and not taking lipid-lowering medication. Cox regression yielded adjusted hazard ratios for the associations of 143 individual metabolic biomarkers (including lipids, lipoproteins, fatty acids, amino acids, ketone bodies and other low molecular weight metabolic biomarkers) and 11 metabolic biomarker principal components (PCs) (accounting for 90% of total variance in individual biomarkers) with incident T2D. These 11 PCs were added to established models for T2D risk prediction, and measures of risk discrimination (c-statistic) and reclassification (continuous net reclassification improvement [NRI], integrated discrimination index [IDI]) were assessed.

FindingsDuring median 11.9 (IQR 11.1-12.6) years follow-up, 1719 participants developed T2D. After accounting for multiple testing, 118 metabolic biomarkers showed independent associations with T2D risk (false discovery rate controlled p<0.05), of which 103 persisted after additional adjustment for HbA1c. Overall, 10 metabolic biomarker PCs were independently associated with T2D. Addition of PCs to the established risk prediction model (including age, sex, parental history of diabetes, body mass index and HbA1c) improved T2D risk prediction as assessed by the c-statistic (increased from 0.802 [95% CI 0.791-0.812] to 0.830 [0.822-0.841]), continuous NRI (0.44 [0.38-0.49]), and relative (15.0% [10.5%-20.4%]) and absolute (1.5 [1.0-1.9]) IDI.

InterpretationWhen added to conventional risk factors, circulating NMR-based metabolic biomarkers enhanced T2D risk prediction.

FundingBHF, MRC, CRUK

category: endocrinology