title: Cost-effectiveness of Ezetimibe plus statin lipid-lowering therapy: A systematic review and meta-analysis of cost-utility studies

abstract:
IntroductionIn addition to statin therapy, Ezetimibe, a non-statin lipid-modifying agent, is increasingly used to reduce low-density lipoprotein cholesterol and atherosclerotic cardiovascular disease risk. Literature suggests the clinical effectiveness of Ezetimibe plus statin (EPS) therapy; however, primary evidence on its economic effectiveness is inconsistent. Hence we pooled incremental net benefit to synthesise the cost-effectiveness of EPS therapy.

MethodsWe identified economic evaluation studies reporting outcomes of EPS therapy compared with other lipid-lowering therapeutic agents or placebo by searching PubMed, Embase, Scopus, and Tufts Cost-Effective Analysis registry. Using random-effects meta-analysis, we pooled Incremental Net Benefit (INB) in the US $ with a 95% confidence interval (CI). We used the modified economic evaluations bias checklist and GRADE quality assessment for quality appraisal. The review was apriori registered with PROSPERO, CRD42021248531.

ResultsThe pooled INB from twenty-one eligible studies showed that EPS therapy was significantly cost-effective compared to other lipid-lowering therapeutic agents or placebo. The pooled INB (95% CI) was $4,274 (621 to 7,927), but there was considerable heterogeneity (I2=84.21). On subgroup analysis EPS therapy is significantly cost-effective in high-income countries [$4,356 (621 to 8,092)], for primary prevention [$4,814 (2,523 to 7,106)], and for payers perspective [$3,255 (571 to 5,939)], and from lifetime horizon [$4,571 (746 to 8,395)].

ConclusionEPS therapy is cost-effective compared to other lipid-lowering therapeutic agents or placebo in high-income countries and for primary prevention. However, there is a dearth of evidence from lower-middle-income countries and the societal perspective.


title: An extended SIR model with vaccine dynamics for SARS-CoV-2 adaptation rate

abstract: The COVID-19 pandemic is caused by infection with a SARS-CoV-2 virus, a RNA virus characterized by high mutation and replication rates. From epidemiological perspective, the trajectory in time of viral adaptation is determined by two opposite forces: (a) proportion of the population who has acquired immunity, exerting thereby a selective pressure on the virus and (b) proportion of infected people in the population, measuring the net viral load in the population. We calculate both the number of advantageous mutations in the population that have accumulated by time t and the amount of viral adaptation transmitted to a susceptible compartment, the latter being called the Evolutionary Infectivity Profile (EIP). To this end we employ first a simple compartmental SIR model with a single parameter describing reduction in transmission due to vaccination. Then we switch to a model which actuates the full vaccine dynamics, including vaccination rate and short duration of immunity. In our models we have never come across a situation where vaccination plays a dominant role in driving new SARS-CoV-2 variants. Nevertheless if the vaccination rate is not high enough, the EIP would continuously grow with time, pointing to a fruitful field for proliferation of genetically variable SARS-CoV-2 viruses.

category: epidemiology


title: Using LASSO regression to estimate the population-level impact of pneumococcal conjugate vaccines

abstract: The pneumococcal conjugate vaccines (PCVs) protect against diseases caused by Streptococcus pneumoniae, such as meningitis, bacteremia, and pneumonia. It is challenging to estimate their population-level impact due to the lack of a perfect control population and the subtleness of signals when the endpoint - like all-cause pneumonia - is non-specific. Here we present a new approach to estimate PCVs impact - using LASSO regression to predict the counterfactual outcome for vaccine impact inference. We first used a simulation study to test the performance of LASSO regression and established methods including the synthetic control (SC) approach. We found that LASSO achieved accurate and precise estimation, even in complex simulation scenarios where the association between outcome and all control variables was non-causal. We then applied LASSO to real-world data and found that it yielded estimates of vaccine impact similar to SC. The LASSO method is accurate, easily implementable, and can be applied to study the impact of PCVs and of other vaccines.


title: Avoidable burden of stomach cancer and potential gains in healthy life years from gradual reductions in salt consumption in Vietnam, 2019 to 2030: a modelling study

abstract:
ObjectiveExcess salt consumption is causally linked with stomach cancer. However, the impact of high salt intake on stomach cancer in Vietnam is not known. The aim of this study was to quantify the future burden of stomach cancer that could be avoided from population-wide salt reduction in Vietnam.

DesignA dynamic simulation model was developed to quantify the impacts of achieving the 2018 National Healthy Vietnam program (8g/day by 2025 and 7g/day by 2030) and the WHO (5g/day) salt reduction targets. Data on salt consumption were obtained from the Vietnam 2015 WHO STEPS survey. Health outcomes were estimated over 6-year (by 2025), 11-year (by 2030) and lifetime horizons. We conducted one-way and probabilistic sensitivity analyses.

SettingVietnam

ParticipantsAll adults aged [≥] 25 years (total of 61 million people, 48.4% men) alive in 2019.

ResultsAchieving the 2025 and 2030 national salt targets could result in 3,500 and 7,700 fewer incident cases of stomach cancer respectively, and avert 1,950 and 5,200 stomach cancer deaths, respectively. Achieving the WHO target by 2030 could prevent 9,280 new cases of, and 6,300 deaths from stomach cancer. Over the lifespan, this translated to 359,000 (8g/day), 416,000 (7g/day) and 505,000 (5g/day) HALYs gained respectively.

ConclusionsA sizeable burden of stomach cancer could be avoided, with gains in healthy life years if national and WHO salt targets were attained. Our findings provide impetus for policy makers in Vietnam and Asia to intensify salt reduction strategies to combat stomach cancer and mitigate pressure on the health systems.


title: Required COVID-19 Vaccination Certification to Attend Certain U.S. Professional Football Games in Fall 2021: A Natural Experiment

abstract:
Four U.S. National Football League teams required vaccination certification against the SARS-CoV-2 virus of attendees at home games during the 2021 season. Using daily data on confirmed cases and vaccinations in counties surrounding these stadiums and stadiums that did not require certification, this study estimates the effects of the certification policy. Ordinary least squares regression was used to estimate the change in community spread of the virus after home games and away games relative to weeks that the teams did not play (bye weeks).

Compared to counties in metropolitan areas near stadiums with no certification requirement, counties near stadiums that had a vaccination requirement had significantly less cases 14 days after home games. In the six weeks leading up to the beginning of the season, percent vaccinated increased in counties that were near stadiums requiring vaccination certification only if the prevalent preseason vaccination rate was relatively low. Required vaccination certification at venues for large gatherings appear to slow virus spread generally in nearby communities and increases vaccination percentages in areas with lower prevalent vaccination percentages.


title: An observation and restoration model for the COVID-19 incidence curves

abstract:
The sanitary crisis of the past two years has focused the publics attention on quantitative indicators of the spread of the COVID-19 pandemic. The daily reproduction number Rt, defined by the average number of new infections caused by a single infected individual at time t, is one of the best metrics for estimating the epidemic trend. In this paper, we give a complete observation model for sampled epidemiological incidence signals obtained through periodic administrative measurements. The model is governed by the classic renewal equation using an empirical reproduction kernel, and subject to two perturbations: a time-varying gain with a weekly period and a white observation noise. We estimate this noise model and its parameters by extending a variational inversion of the model recovering its main driving variable Rt. Using Rt, a restored incidence curve, corrected of the weekly and festive day bias, can be deduced through the renewal equation. We verify experimentally on many countries that, once the weekly and festive days bias have been corrected, the difference between the incidence curve and its expected value is well approximated by an exponential distributed white noise multiplied by a power of the magnitude of the restored incidence curve.

Simple SummaryIn the past two years, the COVID-19 incidence curves and reproduction number Rt have been the main metrics used by policy makers and journalists to monitor the spread of this global pandemic. However, these metrics are not always reliable in the short term, because of a combination of delay in detection, administrative delays and random noise. In this article, we present a complete model of COVID-19 incidence, faithfully reconstructing the incidence curve and reproduction number from the renewal equation of the disease and precisely estimating the biases associated with periodic weekly bias, festive day bias and residual noise.


title: Modeling Covid-19 incidence by the renewal equation after removal of administrative bias and noise


title: Gait stability in ambulant children with cerebral palsy during dual tasks

abstract:
AimThe aim of this prospective cross-sectional study with matched controls was to measure the effect of dual tasks on gait stability in ambulant children with cerebral palsy (CP) compared to typically developing (TD) children.

MethodsThe children of the CP (n= 20) and TD groups (n=20) walked first without a dual task, then while counting and finally while alternatively naming fruits and animals (DTf/a). They then completed the same cognitive exercises while sitting comfortably. We calculated the distance between the foot placement estimator (FPE) and the real foot placement in the anterior direction (DFPEAP) and in the mediolateral direction (DFPEML) as a measure of gait stability, in a gait laboratory using an optoelectronic system. Cognitive scores were computed. Comparisons within and between groups were analysed with linear mixed models.

ResultsThe dual task had a significant effect on the CP group in DFPEAP and DFPEML. The CP group was more affected than the TD group during dual task in the DFPEML. Children in both groups showed significant changes in gait stability during dual tasks.

InterpretationThe impact of dual task on gait stability is possibly due to the sharing of attention between gait and the cognitive task. All children favoured a  posture second strategy during the dual task of alternatively naming animals and fruits. Children with CP increased their mediolateral stability during dual task.

category: pediatrics


title: Development and Pilot Testing of a Five Item Traumatic Stress Screener for Use with Adolescents in Pediatric Primary Care

abstract:
ObjectivesTo develop and assess the psychometric properties of the Adolescent Primary Care Traumatic Stress Screen (APCTSS), a five-item yes/no screener for PTSD symptoms in adolescents, and the first developed for pediatric primary care.

Study DesignThe APCTSS was developed by combining and adapting the UCLA PTSD Reaction Index for DSM-5 with the adult Primary Care PTSD Screen for DSM-5. Adolescent medicine patients were universally approached during clinic visits. With a response rate of 83.6%, 178 patients aged 13-22 (M=18.4, SD=2.3), 64.4% female; 62.1% Black or African-American and 20.7% Hispanic/Latinx, were enrolled. Patients completed APCTSS, Patient Health Questionnaire for Adolescents (PHQ-A), and Child PTSD Symptom Scale for DSM-5 Interview (CPSS-5-I), and 61 completed the Traumatic Events Screening Inventory for Children (TESI-C).

Results56.7% reported a criterion A trauma, 30.1% met criteria for PTSD, 7.4% met criteria for subsyndromal PTSD, and 19.0% for post-event impairing symptoms. Scores [≥] 2 on the APCTSS optimized sensitivity (.79; 95% CI=.66 to .89) and specificity (.68; 95% CI=.55 to .76) for PTSD, with an area under the curve (AUC) of .79. Sensitivity (.86; 95% CI=.65 to .90), specificity (.77; 95% CI=.60 to .90), and AUC (.86) were even stronger when the TESI-C was used to assess criterion A for PTSD diagnosis. Over half (56.0%) of patients who screened positive on the APCTSS were missed by the PHQ-A.

ConclusionsThe APCTSS shows promise as an internally consistent, valid, and effective tool for identifying adolescents at high risk of PTSD and traumatic stress.

category: psychiatry and clinical psychology


title: Prevalence of hepatitis B and hepatitis C in migrants from sub-Saharan Africa newly arrived at Al Kufra in SE Libya in transit toward Europe

abstract:
BackgroundViral hepatitis has become a universally established health care challenge due to its worldwide distribution chronic persistence, complications, and high prevalence with unchecked conditions in areas like sub-Saharan Africa. A high proportion of asymptomatic infections allows serious complications in patients who are infected. These asymptomatic infected people pose a serious risk for the transmission of infection to healthy population. This study aimed to detect and examine the prevalence of both HBV and HCV carriers among 3248 newly arrived migrants from different parts of sub-Saharan Africa in Al Kufra, Libya, a remote agricultural North African city. All these migrants were required by the Libyan authorities to undergo a complete medical check-up for different purposes such as joining for new jobs, and for obtaining licenses for trade and commerce.

MethodologyUAT sera from 3,248 migrants, aged 18-53 years, attending the Al Kufra city hospital from January 01 to December 31, 2019, were screened for HBsAg and anti-HCV antibody by rapid tests and positive samples were further tested by ELISA method.

Resultsthe results showed that 761/3248 (23.4%) of the migrants were positive for HBV and 1014/3248 (31.2%) were positive for HCV.

ConclusionMigrants newly arrived from sub-Saharan African carry high rates of Hepatitis B and C infections. It is important to increase awareness about occupational health, and the risks of HBV and HCV transmission to the local population. The study results indicate the value of preemployment medical check-up and regular investigation and illustrates the importance of understanding the potential impact on migrant destination populations.

category: public and global health


title: Operationalising the Centiloid Scale for florbetapir PET Studies on PET/MR

abstract:
PurposeThe Centiloid scale provides a systematic means of harmonising amyloid-{beta} PET measures across different acquisition and processing methodologies. This work explores the Centiloid transformation of [18F]florbetapir PET data acquired on a combined PET/MR scanner and processed with methods that differ from the standard Centiloid pipeline.

MethodsThe Standard PiB and Florbetapir Calibration datasets were processed using a standardised uptake value ratio (SUVR) pipeline with MRI parcellations from the Geodesic Information Flow (GIF) algorithm in native PET space. We generated SUVRs using whole cerebellum (GIF_WCSUVR) and eroded white matter (GIF_WMSUVR) reference regions, with and without partial volume correction (PVC). Linear regression was used to calibrate these processing pipelines to the standard Centiloid approach. We then applied the resulting transformation to 432 florbetapir scans from the Insight 46 study of mostly cognitively normal individuals aged [~]70 years, and defined Centiloid cutpoints for amyloid-{beta} positivity using Gaussian-mixture modelling.

ResultsGIF-based SUVR processing pipelines were suitable for conversion according to Centiloid criteria. For GIF_WCSUVR, cutpoints translated to 14.2 Centiloids, or 11.8 with PVC. There was a differential relationship between florbetapir uptake in WM and WC regions in Florbetapir Calibration and Insight 46 datasets, causing implausibly low Centiloid values for GIF_WMSUVR. Linear adjustment to account for this difference resulted in Centiloid cutpoints of 18.1 for GIF_WMSUVR (17.0 with PVC).

ConclusionOur results show florbetapir SUVRs acquired on PET/MR scanners can be reliably converted to Centiloids. Acquisition or biological factors can have large effects on Centiloid values from different datasets, we propose a correction to account for these effects.

category: radiology and imaging


title: Intraoperative adjustment of radiographic standard projections of the spine: Interrater- and intrarater variance and consequences of fluoro-hunting considering time and radiation exposure. A cadaveric study

abstract:
BackgroundFor the acquisition of intraoperative fluoroscopic images, standard projections have to be manually adjusted. This process resembles a trial-and-error process and is therefore time-consuming and leads to increased radiation exposure for both patient and staff. In addition, the standard projections adjusted are subject to intra- and interindividual variance. However, to date, only very limited data exist in the literature quantifying the time and radiation exposure caused by the process of manually setting standard projections as well as the intra- and interindividual variance for the manual adjustment of standard projections.

Material and MethodsA.p. and lateral standard projections of the vertebral bodies of two fresh-frozen specimen were manually adjusted by two examiners with a different level of experience using a mobile C-arm. The time needed for manual adjustment as well as the number of X-ray shots acquired and the radiation dose caused during this process were documented. Intra- and interindividual variance of the central beam, the orbital rotation and angulation of the C-arm was analyzed.

ResultsThe median time needed was 75.9s, with no significant difference between the examiners (p=0.13). 7.1 x-ray images were acquired in average to reach subjective satisfaction with the standard projection with significantly more x-ray shots for the lateral standard (p=0.04) and for the examiner with less experience (p<0.001). Accordingly, the dose caused was more than 50% higher than for the experienced examiner (p=0.01). Mean interindividual variance of the central beam was 7.6{degrees} while the intraindividual variance was 4.2{degrees}.

ConclusionIn summary, this study investigated the interrater and intrarater variance for standard manual level setting in the thoracic and lumbar spine. Additionally, we were able to quantify the time and number of radiographs required for this procedure for different levels of experience, as well as the resulting radiation dose.


title: An online mental health informed physical activity intervention for emergency service workers and their families: A stepped-wedge trial

abstract:
ObjectiveEmergency service workers are at risk of experiencing poor mental health due to repeated exposure to potentially traumatic events. Promoting physical activity and diet may help to mitigate some the consequences of emergency work and so this study aimed to evaluate the impact a lifestyle intervention on levels of psychological distress among emergency service workers and their support partners.

MethodsWe delivered a 10-week physical activity intervention via a private Facebook group facilitated by exercise physiologists, a dietitian and peer-facilitators. Weekly education modules and telehealth calls were delivered, and participants were provided with a physical activity tracking device. A stepped-wedge design was applied to compare levels of psychological distress (Kessler-6) during baseline, to intervention by comparing slopes of change. Secondary pre-post outcomes included mental health symptoms, physical activity, quality of life, social support to exercise, sleep quality and suicidal ideation.

ResultsN=90 participants (n=47 emergency service workers and n=43 support partners) were recruited in 4 separate cohorts (mean age 42.3(SD=11.5) years, 51% male). Levels of psychological distress did not change significantly during the baseline (control) slope and reduced significantly during the first 6 weeks of intervention (intervention slope 1). The interaction between slopes were significant, b=-0.351, p = 0.003, (i.e., the trajectories of change were significantly different) and improvements plateaued until the 4-week follow-up. Retention was high (92%) and improvements in mental health symptoms, minutes of physical activity, sedentary time and quality of life were observed.

ConclusionsA physical activity intervention delivered via social media is effective in improving psychological distress among emergency service workers and support partners.

Trial registrationAustralian New Zealand Clinical Trials Registry (ACTRN): 12619000877189.

category: rehabilitation medicine and physical therapy


title: Efficacy of Lactococcus lactis strain plasma (LC-Plasma) in easing symptoms in patients with mild coronavirus disease 2019 (COVID-19): protocol for an exploratory, multicenter, double-blinded, randomized controlled trial (PLATEAU study)

abstract:
IntroductionThe coronavirus disease 2019 (COVID-19) pandemic has been a major concern worldwide; however, easily accessible treatment options for patients with mild COVID-19 remains limited. Since oral intake of Lactococcus lactis strain Plasma (LC-Plasma) enhances both the innate and acquired immune systems through activation of plasmacytoid dendritic cells (pDCs), we hypothesized that the oral intake of LC-Plasma could aid the relief or prevention of symptoms in patients with asymptomatic or mild COVID-19.

Methods and analysisThis is an exploratory, multicenter, double-blind, randomized, placebo-controlled trial. This study was initiated in December 2021 and concludes in April 2023. The planned number of enrolled subjects is 100 (50 patients x 2 groups); subject enrolment will be conducted until October 2022. Patients with asymptomatic or mild COVID-19 will be enrolled and randomly assigned in a 1:1 ratio to Group A (oral intake of LC-Plasma-containing capsule, 200 mg/day, for 14 days) or Group B (oral intake of placebo capsule, for 14 days). The primary endpoint is the change in subjective symptoms measured by the severity score. Secondary endpoints include SARS-CoV-2 viral loads, biomarkers for pDC activation, serum SARS-CoV-2-specific antibodies, serum cytokines, interferon and interferon-inducible antiviral effectors, and the proportion of subjects with emergency room visits to medical institutions or who are hospitalized.

Ethics and disseminationThe study protocol was approved by the Clinical Research Review Board of Nagasaki University, in accordance with the Clinical Trials Act of Japan. The study will be conducted in accordance with the Declaration of Helsinki, Clinical Trials Act, and other current legal regulations in Japan. Written informed consent will be obtained from all participants. The results of this study will be reported in journal publications.

RegistrationThis study was registered in the Japan Registry of Clinical Trials (registration number: jRCTs071210097).

ARTICLE SUMMARYO_ST_ABSStrengths and limitations of this studyC_ST_ABSO_LIThis is the first randomized controlled trial to assess the efficacy of Lactococcus lactis strain Plasma (LC-Plasma) in preventing the onset and attenuation of symptoms in patients with asymptomatic or mild COVID-19.
C_LIO_LIThis study is also the first to evaluate the significance of pDC-related immune responses, including interferon production, clearance of symptoms, and prevention of COVID-19 progression.
C_LIO_LIThe results of this study may contribute to the development of novel treatment options for asymptomatic or mild COVID-19 patients.
C_LIO_LIThis is an exploratory study, due to the lack of previous clinical evidence that evaluated the effect of LC-Plasma intake in patients with COVID-19.
C_LIO_LIOther limitations include the subjective endpoint as the primary endpoint and generalizability, since this study will be conducted only in Japan in Japanese patients.
C_LI

category: respiratory medicine


title: Principles of gait encoding in the subthalamic nucleus of people with Parkinson's disease

abstract:
Disruption of subthalamic nucleus dynamics in Parkinsons disease leads to impairments during walking. Here, we aimed to uncover the principles through which the subthalamic nucleus encodes functional and dysfunctional walking in people with Parkinsons disease. We conceived a neurorobotic platform that allowed us to deconstruct the key components of walking under well-controlled conditions. We exploited this platform in 18 patients with Parkinsons disease, which allowed us to demonstrate that the subthalamic nucleus encodes the initiation, termination, and vigor of leg muscle activation. We found that the same fundamental principles determine the encoding of walking. We translated this understanding into a machine-learning framework that decoded muscle activation, walking states, locomotor vigor, and freezing of gait. These results expose key principles through which subthalamic nucleus dynamics encode walking, opening the possibility to operate neuroprosthetic systems with these signals to improve walking in people with Parkinsons disease.

One Sentence SummaryThe subthalamic nucleus encodes the initiation, termination, and vigor of muscle activity, which supports real-time decoding of gait in people with Parkinsons disease.

category: neurology


title: Assessment of AUC and fold change for precision medicine

abstract: Precision medicine is advancing patient care for complex human diseases. Discovery of biomarkers to diagnose specific subtypes within a heterogeneous diseased population is a key step towards realizing the benefits of precision medicine. However, popular statistical methods for evaluating candidate biomarkers, fold change and AUC, were designed for homogeneous data and we evaluate their performance here. In general, these metrics overlook nearly  ideal biomarkers when they represent less than half of the diseased population. We introduce a new metric to address this shortfall and run a series of trials comprised of simulated and biological data.

category: health informatics


title: Peripheral artery disease affects the legs of claudicating patients in a diffuse manner irrespective of the level of the arterial tree primarily involved.

abstract:
ObjectiveDifferent levels of arterial occlusive disease (aortoiliac, femoropopliteal, multi-level disease) can produce claudication symptoms in different leg muscle groups (buttocks, thighs, calves) in patients with peripheral artery disease (PAD). We tested the hypothesis that different levels of occlusive disease uniquely affect the muscles of PAD legs and produce distinctive patterns in the way claudicating patients walk.

Methods97 PAD patients and 35 healthy controls were recruited. PAD patients were categorized to aortoiliac, femoropopliteal and multi-level disease groups using computerized tomographic angiography. Subjects performed walking trials both pain-free and during claudication and joint kinematics, kinetics, and spatiotemporal parameters were calculated to evaluate the net contribution of the calf, thigh and buttock muscles.

ResultsPAD patients with different levels of arterial occlusions had different patterns of symptoms in their calves, thighs and buttocks. However, no significant biomechanical differences were found between PAD groups during the pain-free conditions with minimal differences between PAD groups in the claudicating state. All statistical differences in the pain-free condition occurred between healthy controls and one or more PAD groups. A discriminant analysis function was able to adequately predict if a subject was a control with over 70% accuracy, but the function was unable to differentiate between PAD groups.

ConclusionsIn-depth gait analyses of claudicating PAD patients indicate that different levels of arterial disease produce symptoms that affect different muscle groups across the lower extremity but impact the function of the leg muscles in a diffuse manner generating similar walking impairments.

category: cardiovascular medicine


title: A Framework for Assessing the Impact of Accelerated Approval

abstract: The FDAs Accelerated Approval program (AA) is a regulatory program to expedite availability of products to treat serious or life-threatening illnesses that lack effective treatment alternatives. Ideally, all of the many stakeholders such as patients, physicians, regulators, and health technology assessment [HTA] agencies that are affected by AA should benefit from it. In practice, however, there is intense debate over whether evidence supporting AA is sufficient to meet the needs of the stakeholders who collectively bring an approved product into routine clinical care. As AAs have become more common, it becomes essential to be able to determine their impact objectively and reproducibly in a way that provides for consistent evaluation of therapeutic decision alternatives. We describe the basic features of an approach for evaluating AA impact that accommodates stakeholder-specific views about potential benefits, risks, and costs. The approach is based on a formal decision-analytic framework combining predictive distributions for therapeutic outcomes (efficacy and safety) based on statistical models that incorporate findings from AA trials with stakeholder assessments of various actions that might be taken. The framework described here provides a starting point for communicating the value of a treatment granted AA in the context of what is important to various stakeholders.

category: pharmacology and therapeutics


title: Heart rate variability as biomarker for bipolar disorder

abstract: Bipolar disorder (BD) is characterized by alterations in mood, energy levels and the ability to function. Accordingly, it is also associated with dysfunction of the autonomic nervous system (ANS), indexed by heart rate variability (HRV). Literature concerning differences in ANS functioning between mood states is still sparse. The main aim of the study was to investigate within-individual changes in HRV from manic to euthymic states in bipolar disorder (BD). This is the first study to do so using wrist-worn sensors. Seventeen patients with BD were equipped with photoplethysmography (PPG) sensor wristbands and provided 24-hour recordings both during a manic state and a euthymic state. We calculated mean heart rate and the commonly used HRV measures SDNN, RMSSD, HF, LF and Sample Entropy in 5-minute segments during rest at night. We compared HRV by mood state within individuals using paired t-tests and linear regression to control for age and sex. Recordings from 15 BD patients were analyzed. There were statistically significant increases in HRV measures SDNN, RMSSD, LF and Sample Entropy from mania to euthymia. Effect sizes were predominately large. Our findings reveal lower HRV in the manic state compared to the euthymic state. This indicates that HRV collected by wrist-worn PPG sensors is a possible biomarker for bipolar mood states. Movement artifacts were problematic and sampling during rest or in combination with actigraphy is recommended. Our findings can be further implemented to develop a monitoring device for bipolar patients.


title: The neuroimmune changes captured by transcriptome in brains of psychiatric and neurological disorders

abstract:
Neuroinflammation has been implicated in multiple brain disorders but the extent and the magnitude of change in immune-related genes (IRGs) across distinct brain disorders has not been directly compared. We curated 1,275 IRGs and investigated their expression changes in 2,467 postmortem brains of controls and patients with six major brain disorders, including schizophrenia (SCZ), bipolar disorder (BD), autism spectrum disorder (ASD), major depressive disorder (MDD), Alzheimers disease (AD), and Parkinsons disease (PD). More than 60% of the IRGs had significantly altered expression in at least one of the six disorders. The differentially expressed immune-related genes (dIRGs) shared across disorders were mainly related to innate immunity. Moreover, we systematically evaluated sex, tissue, and cell type for immune alterations in different neuropsychiatric disorders. Co-expression networks revealed that neuroimmune systems interacted with neuronal-systems, both of which contribute to the risk of disorders. However, only a few genes with expression changes have also been identified as containing risk variants of genome-wide association studies. The transcriptome alterations at gene and network levels may clarify the immune-related pathophysiology and redefine neuropsychiatric and neurological disorders.

One-Sentence SummaryThe brain transcriptome of six neurological and psychiatric disorders showed signature changes in genes related to immunity.


title: Brain cortical changes are related to inflammatory biomarkers in hospitalized SARS-CoV-2 patients with neurological symptoms

abstract: Increasing evidence shows that the brain is a target of SARS-CoV-2. However, the consequences of the virus on the cortical regions of hospitalized patients are currently unknown. The purpose of this study was to assess brain cortical gray matter volume (GMV), thickness (Th), and surface area (SA) characteristics in SARS-CoV-2 hospitalized patients with a wide range of neurological symptoms and their association with clinical indicators of inflammatory processes. A total of 33 patients were selected from a prospective, multicenter, cross-sectional study during the ongoing pandemic (August 2020-April 2021) at Basel University Hospital. Retrospectively biobank healthy controls with the same image protocol served as controls group. For each anatomical T1w MPRAGE image, the Th and GMV segmentation were performed with the FreeSurfer-5.0. Cortical measures were compared between groups using a linear regression model. The covariates were age, gender, age*gender, MRI magnetic field strength, and total intracranial volume/mean Th/Total SA. The association between cortical features and laboratory variables was assessed using partial correlation adjusting for the same covariates. P-values were adjusted using false discovery rate (FDR). Our findings revealed a lower cortical gray matter volume in orbitofrontal and cingulate regions in patients compared to controls. The orbitofrontal grey matter volume was negatively associated with protein levels, CSF-blood/albumin ratio and CSF EN-RAGE level. CSF EN-RAGE and CSF/Blood-albumin ratio, which are neuroinflammatory biomarkers, were associated with cortical alterations in gray matter volume and thickness in frontal, orbitofrontal, and temporal regions. Our data suggest that viral-triggered inflammation leads to increased neurotoxic damage in some cortical areas.


title: Predicting patient-reported outcomes following lumbar spine surgery: development and external validation of multivariable prediction models

abstract:
BackgroundThis study aimed to develop and externally validate prediction models of spinal surgery outcomes based on a retrospective review of a prospective clinical database, uniquely comparing multivariate regression and machine learning approaches, and identifying the most important predictors.

MethodsOutcomes were change in back and leg pain intensity and Core Outcome Measures Index (COMI) from baseline to the last available postoperative follow-up (3-24 months), defined as minimal clinically important change (MCID) and continuous change score. Eligible patients underwent lumbar spine surgery for degenerative pathology between 2011 and 2021. Data were split by surgery date into development (N=2691) and validation (N=1616) sets. Multivariate logistic and linear regression, and random forest classification and regression models, were fit to the development data and validated on the external data.

ResultsAll models demonstrated good calibration in the validation data. Discrimination ability (area under the curve) for MCID ranged from 0.63 (COMI) to 0.72 (back pain) in regression, and from 0.62 (COMI) to 0.68 (back pain) in random forests. The explained variation in continuous change scores spanned 16%-28% in linear, and 15%-25% in random forests regression. The most important predictors included age, baseline scores on the respective outcome measures, type of degenerative pathology, previous spinal surgeries, smoking status, morbidity, and duration of hospital stay.

ConclusionsThe developed models appear robust and generalisable across different outcomes and modelling approaches but produced only borderline acceptable discrimination ability, suggesting the need to assess further prognostic factors. External validation showed no advantage of the machine learning approach.

category: surgery


title: In pursuit of the epileptogenic zone in focal epilepsy: A dynamical network biomarker approach

abstract:
The success of resective surgery for drug-resistant epilepsy patients hinges on the correct identification of the epileptogenic zone (EZ) consisting of the subnetwork of brain regions that underlies seizure genesis in focal epilepsy. The dynamic network biomarker (DNB) method is a dynamical systems-based network analysis approach for identifying subnetworks that are the first to exhibit the transition as a complex system undergoes a bifurcation. The approach was devised and validated in the context of complex disease onset where the dynamics is known to be nonlinear and high-dimensional. We here adapt and implement the DNB approach for the identification of the EZ from the analysis of SEEG data. The method is first successfully tested on simulated data generated with a large-scale brain network model of epilepsy using The Virtual Brain neuroinformatic platform and then applied to clinical SEEG data from focal epilepsy patients. The results are compared with those obtained by expert clinicians that designate the EZ using the Epileptogenicity Index (EI) method. High average precision values are obtained and posit the presented approach as a promising candidate tool for the pursuit of EZ in focal epilepsy.

Author SummaryWe present a novel SEEG signal analysis tool for the identification of EZ regions in patients with drug-resistant focal epilepsy. The proposed method adapts and implements the dynamic network biomarker approach which builds on dynamical systems theory for complex networked systems. The method is first successfully tested on synthetic seizure data generated with The Virtual Brain modeling framework and then applied to retrospective patients clinical SEEG data. High precision values are obtained when the DNB subnetwork is compared with that designated as EZ by expert clinicians using empirical signal analysis measures and indicate that the DNB approach is a promising tool for the identification of EZ regions through SEEG signal analysis.


title: Time for Action: Assessment of Knowledge on Hazard Analysis and Critical Control Points of Food Handlers in Standard Hotels in Lagos State, Nigeria

abstract: According to the World Health Organization (WHO), there are two million reported cases of food poisoning in Nigeria with estimated deaths of 200,000 people from food poisoning and 20,000 deaths from exposure to food pesticides annually - children inclusive. These hotels make provision of letting room, food and refreshment services in restaurant, bars and banqueting rooms, conference/mailing rooms and leisure facilities it was expressed that, threat identified with the production of food items can be minimized to a permissible limit or eliminated through the utilization of HACCP procedure. This study assessed the knowledge of HACCP of food handlers in standard hotels in Lagos State. The study adopted a cross-sectional survey research design and was conducted in Lagos. All the hotels classified by the Nigeria Tourism Development Corporation (NTDC, 2001) as either three, four or five star-rated were targeted. A purposive and stratified sampling technique was used to select the study units who constituted the respondents for the study with a total of 31 hotels involved in the study. A questionnaire was used to get information on knowledge on HACCP and its implementation by 31 food handlers. Data were presented in tables. Findings from this study has revealed that under 20% of the respondents in the various hotels use HACCP has the quality control strategy, less than 50% understand the concept of HACCP. Results also revealed that there is an insignificant relationship between years of service in the food establishment and the knowledge on HACCP at P value (0.05). More results revealed that there is no significant relation between formal training and knowledge on food safety. Results also revealed that there is no significant relationship between knowledge of HACCP by food handlers and their implementation in food preparation with P-value at (0.05). This insignificant relationship between formal training and knowledge on food safety could mean that there may be other factors preventing food handlers from implementing food safety practice, this may include time, cost of carrying out the practices or even personal attitude of the food handlers during food handling. Food handlers should be taught food safety practices practically rather than theoretically.

category: occupational and environmental health


title: Cytoplasmic Expression of LMP1 and its Nuclear Translocation in Nasopharyngeal Carcinoma Correlates with Epithelial-mesenchymal Transition

abstract: Up to now, the prognostic significance of latent membrane protein 1 (LMP1) in nasopharyngeal carcinoma (NPC) tissues still remains controversial. This study aims to investigate aberrant localization of LMP1 and its relationship with epithelial-mesenchymal transition (EMT) in NPC samples by immunohistochemistry and immunofluorescence. Both cytoplasmic and nuclear LMP1 expressions were observed in NPC tissues. In some tissues, nuclear LMP1 was frequently observed at tumor invasive front and tumor buddings. Nuclear LMP1 expression was significantly associated with lymph node metastasis (P=0.031), local recurrence (P=0.002), lymphatic invasion (P= 0.004) and tumor budding (P=0.001). Furthermore, nuclear LMP1 showed significant correlations with EMT markers including E-cadherin (P=0.037), Vimentin (P < 0.001), N-cadherin (P=0.003), Snail (P=0.003) and Twist (P=0.002), but not significantly linked with Fibronectin (P=0.103) and Slug (P=0.503). According to cytoplasmic LMP1, it correlated strongly with lymphatic invasion (P=0.044), vascular invasion (P=0.003) and EMT proteins including E-cadherin (P=0.014), Vimentin (P=0.006), N-cadherin (P=0.003), Snail (P=0.008) and Slug (P=0.007), whereas not significantly associated with Fibronectin (P=0.221) and Twist (P=0.106). However, multivariate analysis showed that nuclear LMP1 (P=0.844) and cytoplasmic LMP1 (P=0.291) were not independent predictors for NPC. In conclusion, we demonstrate firstly that abnormal localization of LMP1 correlates with EMT properties and aggressiveness in NPC, respectively.

category: oncology


title: Leveraging genetics to improve Body Mass Index increase prediction in the first-episode of psychosis

abstract:
BackgroundIndividuals with a first episode of psychosis (FEP) show rapid weight gain during the first months of treatment, which is associated with reduction in psychiatric and physical health. Although genetics is assumed to be a significant contributor to this weight gain, its exact role is unknown.

MethodsReference GWAS from BMI and SCZ were obtained to evaluate the pleiotropic landscape between both traits using the pleioFDR software. In parallel, we gathered a population-based FEP cohort of 381 individuals and BMI Polygenic risk-scores (PRS) were evaluated on a sample of 224 individuals. Subsequently, the PRSs obtained from both BMI and the variants shared between the two traits were incorporated into risk models that included demographic and clinical variable to predict BMI increase ({Delta}BMI) on an independent sample of 157 patients.

ResultsBMI PRS significantly improved the prediction of absolute BMI and {Delta}BMI during the first 12 months after the onset of psychotic symptoms. This improvement, was mainly explained by shared variants between SCZ and BMI. In contrast, absolute BMI was predicted mainly by non-shared variants.

ConclusionsWe validated, for the first time, that genetic factors play a key in the determination of both BMI and {Delta}BMI in FEP. This finding has important clinical implications in identifying individuals who require specific treatment strategies. Improved risk classification may help prevent associated adverse metabolic events, and reduce overtreatment and costs for both individuals and the healthcare system. It also highlights the importance of studying genetic pleiotropy in the context of medically important comorbidities.

category: genetic and genomic medicine


title: Vaccination under the Pandemic and Political Support

abstract: This paper examines the impact of COVID-19 vaccination on political support. We exploit the age-based COVID-19 vaccine roll-out in Japan where those aged 65 years and older are strictly prioritized. A regression discontinuity design based on a large-scale online survey reveals that COVID-19 vaccination increases favorable opinions of the vaccination progress in municipalities and infection control measures of municipal governments whereas there is no significant effect on support for the central government. We also find that the effect is more pronounced among people with chronic diseases and those with low socioeconomic status. These results suggest that both reciprocal motives and political information play an important role in the evaluation of public policies.

category: health economics


title: Cervical and systemic innate immunity predictors of HIV risk linked to genital herpes acquisition and time from HSV-2 seroconversion

abstract:
ObjectivesTo examine innate immunity predictors of HIV-1 acquisition as biomarkers of HSV-2 risk and biological basis for epidemiologically established HIV-1 predisposition in HSV-2 infected women.

MethodsWe analyzed longitudinal samples from HIV-1 negative visits of 1019 women before and after HSV-2 acquisition. We measured cervical and serum biomarkers of inflammation and immune activation previously linked to HIV-1 risk. Protein levels were Box-Cox transformed and odds ratios for HSV-2 acquisition were calculated based on top quartile or below/above median levels for all HSV-2 negative visits. Bivariate analysis determined the likelihood of HSV-2 acquisition by biomarker levels preceding infection. Linear mixed-effects models evaluated if biomarkers differed by HSV-2 status defined as negative, incident, or established infections with an established infection cut-off starting at 6 months.

ResultsIn the cervical compartment, two biomarkers of HIV-1 risk (low SLPI and high BD-2) also predicted HSV-2 acquisition. In addition, HSV-2 acquisition was associated with IL-1{beta}, IL-6, IL-8, MIP-3, ICAM-1 and VEGF when below median levels. Systemic immunity predictors of HSV-2 acquisition were high sCD14 and IL-6, with highest odds when concomitantly increased (OR=2.23, 1.49-3.35). Concomitant systemic and mucosal predictors of HSV-2 acquisition risk included: 1) serum top quartile sCD14 with cervical low SLPI, VEGF and ICAM-1, or high BD-2; serum high IL-6 with cervical low VEGF and ICAM-1, SLPI, IL-1{beta} and IL-6, and 3) serum low CRP with cervical high BD-2. Most cervical biomarkers were decreased after HSV-2 acquisition compared to the HSV-2 negative visits, with incident infections associated with a larger number of suppressed cervical biomarkers and lower serum IL-6 levels compared to established infections.

ConclusionsA combination of systemic immunoinflammatory and cervical immunosuppressed states predicts HSV-2 acquisition. A persistently suppressed innate immunity during incident infection may add to the increased HIV-1 susceptibility.

Key MessagesO_LIA combination of altered systemic and cervical immunity precedes and predicts risk of HSV-2 acquisition.
C_LIO_LIFactors causing cervical mucosal imbalance (low SLPI and high BD-2) may predispose to both HIV-1 and HSV-2 acquisition
C_LIO_LIIn comparison to non-infected, HSV-2 infected women show suppressed cervical innate immunity
C_LIO_LICompared to women with established HSV-2 infection, those with incident infections within 6 months from seroconversion are more immunosuppressed both at the mucosal and peripheral level, adding to the biology of HIV predisposition.
C_LI

category: hiv aids


title: Increased neutralization and IgG epitope identification after MVA-MERS-S booster vaccination against Middle East respiratory syndrome

abstract:
Vaccine development is essential for pandemic preparedness. We previously conducted a Phase 1 clinical trial of the vector vaccine candidate MVA-MERS-S against the Middle East respiratory syndrome coronavirus (MERS-CoV), expressing its full spike glycoprotein (MERS-CoV-S), as a homologous two-dose regimen (Days 0 and 28). Here, we evaluate a third vaccination with MVA-MERS-S in a subgroup of trial participants one year after primary immunization. A booster vaccination with MVA-MERS-S is safe and well-tolerated. Both binding and neutralizing anti-MERS-CoV antibody titers increase substantially in all participants and exceed maximum titers observed after primary immunization more than 10-fold. We identify four immunogenic IgG epitopes, located in the receptor-binding domain (RBD, n=1) and the S2 subunit (n=3) of MERS-CoV-S. The level of baseline anti-human coronavirus antibody titers does not impact the generation of anti-MERS-CoV antibody responses. Our data support the rationale of a booster vaccination with MVA-MERS-S and encourage further investigation in larger trials.

One Sentence SummaryA late booster vaccination with the vector vaccine MVA-MERS-S against MERS-CoV is safe and significantly increases humoral immunogenicity including responses to four IgG epitopes.

category: infectious diseases


title: A randomized clinical trial of a booster dose with low versus standard dose of AZD1222 in adult after 2 doses of inactivated vaccines

abstract:
BackgroundImmunogenicity of inactivated SARS-CoV-2 vaccine has waning antibody over time. With the emergence of the SARS-CoV-2 delta variant, which requires higher neutralizing antibody to prevent infection, a booster dose is needed.

ObjectiveTo evaluate immunogenicity and reactogenicity of standard- versus low-dose ChAdOx1 nCoV-19 vaccine booster after CoronaVac in healthy adults.

MethodsA double-blinded, randomized, controlled trial of adult, aged 18-59 years, with completion of 2-dose CoronaVac at 21-28 days apart for more than 2 months was conducted. Participants were randomized to receive AZD1222 (Oxford/AstraZeneca) intramuscularly; standard dose (SD, 5x1010 viral particles) or low dose (LD, 2.5x1010 viral particles). Surrogate virus neutralization test (sVNT) against wild type and delta variant, and anti-spike-receptor-binding-domain IgG (anti-S-RBD IgG) were compared as geometric mean ratio (GMR) at day 14 and 90 between LD and SD arms.

ResultsFrom July-August 2021, 422 adults with median age of 44 (IQR 36-51) years were enrolled. The median interval from CoronaVac to AZD1222 booster was 77 (IQR 64-95) days. At baseline, geometric means (GMs) of sVNT against delta variant and anti-S-RBD IgG were 18.1%inhibition (95%CI 16.4-20.0) and 111.5 (105.1-118.3) BAU/ml. GMs of sVNT against delta variant and anti-S-RBD IgG in SD were 95.6%inhibition (95%CI 94.3-97.0) and 1975.1 (1841.7-2118.2) BAU/ml at day 14, and 89.4%inhibition (86.4-92.4) and 938.6 (859.9-1024.4) BAU/ml at day 90, respectively. GMRs of sVNT against delta variant and anti-S-RBD IgG in LD compared to SD were 1.00 (95%CI 0.98-1.02) and 0.84 (0.76-0.93) at day 14, and 0.98 (0.94-1.03) and 0.89 (0.79-1.00) at day 90, respectively. LD recipients had significantly lower rate of fever (6.8%vs25.0%) and myalgia (51.9%vs70.7%) compared to SD.

ConclusionHalf-dose AZD1222 booster after 2-dose inactivated SARS-CoV-2 vaccination had non-inferior immunogenicity, yet lower systemic reactogenicity. Fractional low-dose AZD1222 booster should be considered especially in resource-constrained settings.

Highlights- Low dose AZD1222 could boost comparable immunity to standard dose in healthy adult who completed 2 doses of inactivated SARS-CoV-2 vaccines.
- Less reactogenicity occurred in low-dose AZD1222 booster than standard-dose recipients.

Thai Clinical Trials Registry (thaiclinicaltrials.org): TCTR20210722003


title: Experiences of the physicians in the largest COVID-19 dedicated hospital of Bangladesh about COVID-19 and its aftermath

abstract:
BackgroundThe doctors and the other health care workers are the first-line fighters against COVID-19. This study aims to identify the prevalence, risk factors, clinical severity of COVID-19 infection among the doctors working in the COVID unit. We also analyzed the hospital data for admission and RT-PCR positivity among the physicians.

MethodsIt was a cross-sectional survey and review of the hospital database. We surveyed from September 2021 to October 2021 and explored the hospital data from march 2020 to September 2021.We included 342 physicians for analysis in the survey. We reviewed hospital data of 1578 total admitted patients and 336 RT-PCR test positive physicians for analyzing the hospital admission rate, the positivity rate for COVID-19 among the physicians and the other patients in the different COVID-19 surges.

FindingsIn this study, we demonstrated the physicians sufferings during the pandemic era. We have observed four surges in the hospital admission and RT-PCR for COVID-19 positivity rate among the physicians and the general population. The physicians experienced a similar surge in the hospital admission and positivity rate to the general population. The hospital admission was lower in the fourth surge among the physicians than the general population. The positivity rate was higher in the first, second and third surge among the physicians. In the survey, a total of 146(42%) respondents had COVID-19 infection, and among them, 50(34.2%) had re-detectable positive SARS-CoV-2 infection. Most of them experienced mild (77[52.7%]) to moderate (41[28.1%]) symptoms. Increasing age (OR, 95%CI, p-value; 1.15, 1.05-1.25, 0.002), male sex (OR, 95%CI, p-value; 5.8, 3.2-9.8, <0.001), and diabetes (OR, 95%CI, p-value; 25.6, 2-327.2, 0.01) were the risk factor of having COVID-19. Female sex and diabetes were the risk factors for re-detectable positive SARS-CoV-2 infection. (OR, 95%CI, p-value; 0.24, 0.09-0.67, 0.006; 44, 8.9-218.7, <0.001 respectively). Most respondents suffered for 7-14 days. Total 98(67%) suffered from post-COVID fatigue.

ConclusionsThe physicians observed four surges in hospital admission and COVID-19 positivity rate. A significant number of the COVID-warrior became positive for SARS-CoV-2, had re-detectable positive SARS-CoV-2 infection, and suffered in the post-COVID-19 state.


title: Class 1 integrons in clinical and swine industry isolates of Salmonella Typhimurium from Colombia, dating 1997 to 2017

abstract: BackgroundSalmonella enterica subsp. enterica serovar Typhimurium (S. Typhimurium) has been linked to outbreaks of foodborne gastroenteritis disease, and the emergence of antimicrobial-resistant clones. In Colombia, laboratory surveillance of Salmonella spp. between 1997-2018 revealed that S. Typhimurium was the most ubiquitous serovar (27.57% of all Salmonella isolates), with increasing levels of antimicrobial resistance to several families of antibiotics. Hypothesis. Resistant isolates of S. Typhimurium recovered from clinical and swine samples carry class 1 integrons that are linked to antimicrobial resistance genes. Aim. Identify class 1 integrons, and investigate their association with other mobile genetic elements, and their relationship to the antimicrobial resistance of Colombian S. Typhimurium isolates. Methods. In this study, 392 clinical isolates of S. Typhimurium were analyzed, of which 237 were obtained from blood culture, 155 from non-invasive sources and 50 isolates from swine of which 32 were obtained from a slaughterhouse, 10 from a point of sale and 8 from cutting plant. Class 1 integrons and plasmid incompatibility groups were analyzed by PCR and Whole Genome Sequencing (WGS), and the region surrounding of the integrons identified by WGS. The phylogenetic relationship was established by MLST and SNP analysis. Results. Overall, 39.03% (153/392) of the clinical isolates and 22% (11/50) of the swine S. Typhimurium isolates carried complete class 1 integrons. Twelve types of gene cassette arrays were identified, including dfr7-aac-blaOXA-2 (Int1-Col1) as the most frequent in clinical isolates (75.2% = 115/153). Clinical and swine isolates that carried class 1 integrons were resistant to up to 5 and up to 3 antimicrobial families, respectively. The Int1-Col1 integron was most prevalent in stool isolates and was associated with Tn21. The most common plasmid incompatibility group was IncA/C. Conclusions. The widespread presence of the integron (IntI1-Col1) in Colombia since 1997 was striking. We speculate that the relationship between integrons, source and mobile elements favors the dispersion of antibiotic resistance determinants in Colombian S. Typhimurium isolates.


title: Quantitative, multiplexed, targeted proteomics for ascertaining variant specific SARS-CoV-2 antibody response

abstract: Determining the protection an individual has to SARS-CoV-2 variants of concern (VoC) will be crucial for future immune surveillance and understanding the changing immune response. As further variants emerge, current serology tests are becoming less effective in reflecting neutralising capability of the immune system. A better measure of an evolving antigen-antibody immune response is needed. We describe a multiplexed, baited, targeted-proteomic assay for direct detection of multiple proteins in the SARS-CoV-2 anti-spike antibody immunocomplex. This enables a more sophisticated and informative characterisation of the antibody response to vaccination and infection against VoC. Using this assay, we detail different and specific responses to each variant by measuring several antibody classes, isotypes and associated complement binding. Furthermore, we describe how these proteins change using serum from individuals collected after infection, first and second dose vaccination. We show complete IgG1 test concordance with gold standard ELISA (r>0.8) and live virus neutralisation against Wuhan Hu-1, Alpha B.1.1.7, Beta B.1.351, and Delta B.1.617.1 variants (r>0.79). We also describe a wide degree of heterogeneity in the immunocomplex of individuals and a greater IgA response in those patients who had a previous infection. Significantly, our test points to an important role the complement system may play particularly against VoC. Where we observe altered Complement C1q association to the Delta VoC response and a stronger overall association with neutralising antibodies than IgG1. A detailed understanding of an individuals antibody response could benefit public health immunosurveillance, vaccine design and inform vaccination dosing using a personalised medicine approach.


title: Cost and availability of drugs and treatment regimens and availability of drug resistance testing for tuberculosis in Europe

abstract:
BackgroundAccess to comprehensive diagnostics and novel anti-tuberculosis medicines is crucial to improve tuberculosis control at times of emerging Mycobacterium tuberculosis drug resistance.

MethodsWe investigated access to genotypic and phenotypic M tuberculosis drug susceptibility testing (DST), availability of anti-tuberculosis drugs and calculated cost of drugs and treatment regimens at major tuberculosis treatment centers in countries of the World Health Organization (WHO) European region. Results are stratified by middle and high-income countries.

ResultsOverall, 43 treatment centers in 43 countries participated in the study. Phenotypic DST was available for WHO group A drugs levofloxacin/moxifloxacin, bedaquiline and linezolid, in 75%/82%, 48%, and 72% of countries, respectively. Overall, 84% and 56% of countries had access to bedaquiline and delamanid, while only 14% had access to rifapentine. Median cost of regimens for drug-susceptible tuberculosis, multidrug-resistant tuberculosis (shorter regimen, including bedaquiline for six months) and pre-extensively drug-resistant tuberculosis (including delamanid) were {euro}44, {euro}764 and {euro}7 094 in middle income countries (n=12), and {euro}280, {euro}29 765, {euro}207 035 in high income countries (n=29).

ConclusionTuberculosis control in Europe is limited by widespread lack of DST capacity to new and re-purposed drugs, lack of access to essential medications and high treatment cost for drug-resistant tuberculosis.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSAvailability and access to anti-tuberculous treatment are essential for optimal treatment outcomes. Newly developed drugs like bedaquiline have demonstrated an enormous potential to improve outcomes, in particular for the treatment of drug-resistant tuberculosis. However, data on availability and cost of tuberculosis drugs and regimens are scarce. We searched PubMed for original research that reported the cost of anti-tuberculosis drugs and regimens across multiple countries in the WHO European region since Jan 1, 2012. The Pubmed search ((cost[MeSH Major Topic]) AND (tuberculosis[MeSH Major Topic]) AND [(treatment[MeSH Major Topic]) OR (drug[MeSH Major Topic])] AND ("2012/01/01"[Date -Entry] : "3000"[Date - Entry])) did not reveal any comprehensive data on cost of anti-tuberculosis drugs since the introduction of new (bedaquiline, delamanid, pretomanid) and re-purposed drugs in the WHO European region. Recent information on availability of Mycobacterium tuberculosis drug susceptibility testing is limited to a single, laboratory-based survey.

Added value of this studyBuilding on a previous study, performed by the Tuberculosis Network European Trialsgroup (TBnet) in 2013, the current study documents a) the concerning lack of diagnostic capacity of drug susceptibility testing for new and repurposed anti-tuberculosis drugs; b) the lack of availability of adequate regimens for the treatment of multidrug-resistant and (pre-) extensively drug-resistant tuberculosis, in particular in middle income countries; and c) the enormous cost of regimens for the treatment of drug-resistant tuberculosis, in particular in high-income countries.

Implications of all the available evidenceThe lack of availability of drug-resistance testing in the presence of new and re-purposed drugs bears the high risk of undetected amplification of M tuberculosis drug resistance. In addition, it implies that identification of patients with extensively drug-resistant tuberculosis is currently not possible in many countries in the WHO European region. The cost of drugs and regimens for drug-resistant tuberculosis treatment are very high compared to those for drug-susceptible tuberculosis and highly variable across different countries. Access to adequate treatment regimens for (pre-) extensively drug-resistant tuberculosis is suboptimal.

Rapid upscaling of comprehensive M tuberculosis drug resistance testing and provision of novel anti-tuberculosis drugs are urgently required to provide patients affected by drug-resistant tuberculosis with adequate treatment regimens and prevent the emergence of additional drug resistance in M tuberculosis naturally occurring under insufficient treatments.


title: Efficacy and Safety of Tregopil, a Novel, Ultra-Rapid Acting Oral Prandial Insulin Analog, as Part of a Basal-Bolus Regimen in Type 2 Diabetes: A Randomized, Active Controlled Phase 3 Study

abstract:
OBJECTIVEEfficacy and safety of ultra-rapid acting oral prandial insulin Tregopil (Tregopil) was compared with insulin aspart (IAsp) in patients with type-2 diabetes on stable doses of insulin glargine and metformin.

RESEARCH DESIGN AND METHODSIn this open-label, active-controlled trial, patients with type-2 diabetes, with HbA1c [≥]7% and [≤]9% and 2-h postprandial glucose (PPG) [≥]180 mg/dL were randomized (1:1:1) to Tregopil (30 mg [n=30], 45 mg [n=31]) and IAsp (n=30; dose titrated based on self-monitored blood glucose [SMBG]). Postprandial plasma glucose excursion (PPGE) and PPG were assessed from the standardized test meal (STM) and 9- point SMBG. The primary outcome measure was change from baseline (CFB) in HbA1c at week 24.

RESULTSThe Tregopil (30 mg) arm showed significantly lesser 1-h PPGE (CFB) excursion after the STM versus IAsp (Estimated Treatment Difference [ETD], 95% CI, -45.33 mg/dL [-71.91, -8.75], P=0.001) and 1-h PPG trended towards a better control. The combined Tregopil group (30+45 mg) showed lower PPGE at 15 mins as compared to IAsp. Meal-wise analysis showed lower 1-h PPGE and PPG in the Tregopil groups post-breakfast. Clinically significant hypoglycemia was lower with Tregopil groups versus IAsp (rate ratio: 0.69).

CONCLUSIONSTregopil demonstrated an ultra-fast onset and short-duration prandial insulin profile with good safety. Tregopil improved the 1-h PPG and overall PPG control compared to IAsp. A further reduction in HbA1c compared to baseline was not observed, likely as a result of variability in the control of fasting glucose level over the duration of the study.

category: endocrinology


title: Short report: Transitions between metabolically unhealthy and healthy obesity over 27 years from midlife to late-life

abstract:
BackgroundMetabolically healthy obesity may be a transient phenotype, but studies with long follow-up, especially covering late-life, are lacking. We therefore describe transitions between body mass index and metabolic health (BMIxMH) categories in a sample with up to 27 years of follow-up, from midlife to late-life.

MethodsWe used cohort data from 786 Swedish twins with objective measures of BMIxMH. Metabolic health was defined as absence of metabolic syndrome (MetS). Measurements were categorized into age 50-64, 65-79, or [≥]80. Frequencies of transitions between 50-64 and 65-79, and between 65-79 and [≥]80 were calculated. One-hundred individuals had measurements in all three age categories, and their dynamic transitions across time were visualized. We also examined frequencies of attrition due to drop-out or death.

ResultsThe proportion of individuals with MetS and with overweight or obesity increased over time. However, 28% of individuals with metabolically healthy normal weight and around one fifth of those with metabolically healthy overweight or obesity remained stable across all three age categories. Transitions from MetS to metabolic health were also common, occurring in 7-49% of individuals with metabolically unhealthy normal weight, overweight, and obesity. Drop-out and death during follow-up was comparable across BMIxMH categories.

ConclusionsTransitions between metabolically healthy and unhealthy categories were relatively common in both directions across all BMI categories. The similar frequencies of drop-outs and deaths indicate that bias due to differences in attrition between BMIxMH categories is not a major issue in this sample.

category: epidemiology


title: SARS-CoV-2 infection in Africa: A systematic review and meta-analysis of standardised seroprevalence studies, from January 2020 to December 2021

abstract:
IntroductionEstimating COVID-19 cumulative incidence in Africa remains problematic due to challenges in contact tracing, routine surveillance systems and laboratory testing capacities and strategies. We undertook a meta-analysis of population-based seroprevalence studies to estimate SARS-CoV-2 seroprevalence in Africa to inform evidence-based decision making on Public Health and Social Measures (PHSM) and vaccine strategy.

MethodsWe searched for seroprevalence studies conducted in Africa published 01-01-2020 to 30-12-2021 in Medline, Embase, Web of Science, and Europe PMC (preprints), grey literature, media releases and early results from WHO Unity studies. All studies were screened, extracted, assessed for risk of bias and evaluated for alignment with the WHO Unity protocol for seroepidemiological investigations. We conducted descriptive analyses of seroprevalence and meta-analysed seroprevalence differences by demographic groups, place and time. We estimated the extent of undetected infections by comparing seroprevalence and cumulative incidence of confirmed cases reported to WHO. PROSPERO: CRD42020183634.

ResultsWe identified 54 full texts or early results, reporting 151 distinct seroprevalence studies in Africa Of these, 95 (63%) were low/moderate risk of bias studies. SARS-CoV-2 seroprevalence rose from 3.0% [95% CI: 1.0-9.2%] in Q2 2020 to 65.1% [95% CI: 56.3-73.0%] in Q3 2021. The ratios of seroprevalence from infection to cumulative incidence of confirmed cases was large (overall: 97:1, ranging from 10:1 to 958:1) and steady over time. Seroprevalence was highly heterogeneous both within countries - urban vs. rural (lower seroprevalence for rural geographic areas), children vs. adults (children aged 0-9 years had the lowest seroprevalence) - and between countries and African sub-regions (Middle, Western and Eastern Africa associated with higher seroprevalence).

ConclusionWe report high seroprevalence in Africa suggesting greater population exposure to SARS-CoV-2 and protection against COVID-19 disease than indicated by surveillance data. As seroprevalence was heterogeneous, targeted PHSM and vaccination strategies need to be tailored to local epidemiological situations.


title: The impact of changes in mental health services in response to COVID-19 on people with mental health conditions: protocol for a rapid review

abstract:
IntroductionThe COVID-19 pandemic has caused disruptions to mental health services, forcing the rapid implementation of alternative ways of delivering services alongside a greater immediate, and continuously growing, demand across those services. The care and level of mental health service provided are felt to be inadequate to respond to the increasing demand for mental health conditions in the time of the pandemic, leading to an urgent need to learn from service change and consequences to inform solutions and plans to support the NHS post-pandemic plan in the UK. This rapid review aims to understand the changes in mental health services during the pandemic and summarise the impact of these changes on the health outcomes of people with mental health conditions.

Methods and analysisCochrane CENTRAL, MEDLINE, EMBASE, and PsycInfowill be searched for eligible studies with key terms indicating mental health AND COVID-19 AND health services. Studies will be included if objective and subjective effects of changes to mental health services in response to COVID-19 are reported on adults with mental health conditions, peer-reviewed and published in the English language. Study selection and data extraction will be undertaken dependently by two reviewers. Evidence will be summarised narratively and in a logic model.

Ethics and disseminationEthics approval is not required for this review. A list of interventions/services/models of care delivered to people with mental health conditions will be grouped as "Do", "Dont" and "Dont know" based on the evidence on effectiveness and acceptability. The results will be written for publication in an open-access peer-reviewed journal and disseminated to the public and patients, clinicians, commissioners, funders, and academic conferences.

PROSPERO registration numberCRD42022306923

Strengths and limitations of this studyO_LIThis is a rapid review with a systematic search of literature
C_LIO_LIEvidence on changes to mental health services and associated health outcomes will be examined to make practice recommendations
C_LIO_LIThis review will provide the evidence base to inform solutions and plans to support the mental health service provision for the post-pandemic period
C_LIO_LISome limitations to the study design include limited to OECD studies, exclusion of non-English studies, publication bias, quality of data, selection bias, and no quality assessment in the rapid evidence review.
C_LI

category: psychiatry and clinical psychology


title: Occupational safety and health aspects of corporate social responsibility reporting in Japan: comparison between 2012 and 2020

abstract:
BackgroundWe aimed to survey the content of occupational safety and health (OSH) disclosed in corporate social responsibility (CSR)-related reports and integrated reports in 2020 and to compare the changes between 2012 and 2020 according to industry and company size.

MethodsWe surveyed the websites of all 2,172 companies listed in the first section of the Tokyo Stock Exchange in 2020 and examined their CSR-related reports and integrated reports. CSR-related reports contain only non-financial information or are posted on webpages addressing sustainability and CSR. Integrated reports include financial information in addition to non-financial information or are posted in the investor relations section. We calculated the proportion of each report type and the proportion of OSH content in each report by industry sector and company size. To increase the reliability of the survey, five experts independently surveyed the same 40 companies and discussed any differing results. We prepared a survey manual based on these discussions. Twenty-five researchers assessed the presence or absence of each type of report and of OSH.

ResultsAmong all companies, 441 (20.3%) companies issued CSR-related reports and 590 (28.1%) issued integrated reports. The number (percentage) of companies that issued either CSR-related reports or integrated reports was 880 (40.5%). The percentages of both CSR-related reports and integrated reports increased with increased company size. The number (percentage) of companies reporting OSH in CSR-related reports was 391 (88.7%) and that in integrated reports was 493 (83.6%). The percentage of OSH reporting in CSR-related reports and integrated reports was high in secondary industries and low in tertiary industries.

ConclusionsThe companies that issued either a CSR-related report or an integrated report increased by 1.9% in 2020 compared with 2012. The percentage of companies that had described OSH in CSR-related reports and integrated reports were increased in 2020 compared with 2012. Many companies in Japan are emphasizing OSH in their CSR-related and integrated reports.


title: RESIDENTS PERCEPTION ON CENTRAL STORAGE OF SOLID WASTES IN ILORIN METROPOLIS, KWARA STATE. NIGERIA.

abstract:
BackgroundSolid waste management in Nigeria has been a major concern to stakeholders due to inefficient collection and unsafe disposal. In Ilorin, the capital of Kwara state, the problem of wastes is becoming alarming because the more these wastes are evacuated the more they are generated on a daily basis. Thus, the issue of central storage of solid waste situation in Ilorin to say the least, is becoming quite distressing.

ObjectivesThis study addressed issues relating to waste management and perception of residence to central waste storage in Ilorin metropolis.

MethodsA cross-sectional study was conducted among the residents in the three local government that constitute Ilorin metropolis, residents living close to central wastes storages in Ilorin metropolis are purposively chosen and the registered wastes contractors with the Kwara State Environmental Protection Agency (KWASEPA). In accomplishing these objectives, both primary and secondary data sources were used. The primary data were collected via questionnaires and field observations. Secondary data were extracted from different published and unpublished materials. 120 households located on the main road and close to central wastes storage bins and 30 wastes contractors are administered with questionnaires. The data were analyzed using statistical package for social science (SPSS version 23) for descriptive and inferential at 5% level of significance.

ResultsThe operational capacities of wastes contractors showed a low capacity as 66.7% (20) operate with single rickety truck. Dumpsites accessibility and insufficiency is an impediment as the dumpsite was found to be too far and largely inaccessible. Condition of wastes spillage from the central storage and storage on the road meridians are draw backs to effective wastes management and majority of respondents 66.7% are unhappy.

ConclusionsIt was discovered that central wastes storage system in Ilorin metropolis was not effective with constant incidence of wastes spillages and storage on road meridians. Therefore, capacity and competence should be considered in wastes management contract award, provision of more central wastes storage, establishing wastes transfer station, provision of adequate dumpsites at different local government, public enlightenment, regular trainings for wastes consultant, provision of loans for wastes consultants for acquisition of trucks and proper monitoring by regulatory agency will ensure a clean and sanitary environment in the metropolis.


title: Fourth Dose COVID mRNA Vaccines' Immunogenicity & Efficacy Against Omicron VOC

abstract:
BACKGROUNDFollowing the emergence of the Omicron variant of concern, we investigated immunogenicity, efficacy and safety of BNT162b2 or mRNA1273 fourth dose in an open-label, clinical intervention trial.

METHODSPrimary end-points were safety and immunogenicity and secondary end-points were vaccine efficacy in preventing SARS-CoV-2 infections and COVID-19 symptomatic disease. The two intervention arms were compared to a matched control group. Eligible participants were healthcare-workers (HCW) vaccinated with three BNT162b2 doses, and whose IgG antibody levels were [≤]700 BAU (40-percentile). IgG and neutralizing titers, direct neutralization of live VOCs, and T-cell activation were assessed. All participants were actively screened for SARS-CoV-2 infections on a weekly basis.

RESULTSOf 1050 eligible HCW, 154 and 120 were enrolled to receive BNT162b2 and mRNA1273, respectively, and compared to 426 age-matched controls. Recipients of both vaccine types had a [~]9-10-fold increase in IgG and neutralizing titers within 2 weeks of vaccination and an 8-fold increase in live Omicron VOC neutralization, restoring titers to those measured after the third vaccine dose. Breakthrough infections were common, mostly very mild, yet, with high viral loads. Vaccine efficacy against infection was 30% (95%CI:-9% to 55%) and 11% (95%CI:-43% to +43%) for BNT162b2 and mRNA1273, respectively. Local and systemic adverse reactions were reported in 80% and 40%, respectively.

CONCLUSIONSThe fourth COVID-19 mRNA dose restores antibody titers to peak post-third dose titers. Low efficacy in preventing mild or asymptomatic Omicron infections and the infectious potential of breakthrough cases raise the urgency of next generation vaccine development.

Trial registration numberclicaltrials.gov: NCT05231005, NCT05230953


title: Determinants of antibody responses to two doses of ChAdOx1 nCoV-19 or BNT162b2 and a subsequent booster dose of BNT162b2 or mRNA-1273: population-based cohort study (COVIDENCE UK)

abstract:
BackgroundAntibody responses to SARS-CoV-2 vaccination vary for reasons that remain poorly understood.

MethodsWe tested for presence of combined IgG, IgA and IgM (IgGAM) anti-spike antibodies before and after administration of two doses of ChAdOx1 nCoV-19 (ChAdOx1, Oxford-AstraZeneca) or BNT162b2 (Pfizer-BioNTech) in UK adults participating in a population-based longitudinal study who received their first dose of vaccine from December 15, 2020 to July 10, 2021. Information on sixty-six potential sociodemographic, behavioural, clinical, pharmacological and nutritional determinants of serological response to vaccination was captured using serial online questionnaires. We used logistic regression to estimate multivariable-adjusted odds ratios (aORs) for associations between independent variables and risk of seronegativity following two vaccine doses. Participants who were seronegative after receiving two vaccine doses were offered an additional antibody test following subsequent administration of a  booster dose of BNT162b2 or mRNA-1273 (Moderna) from September 23 to December 12, 2021.

FindingsSerology results following two vaccine doses were available for 9,101 participants, of whom 5,770 (63.4%) received ChAdOx1 and 3,331 (36.6%) received BNT162b2. Anti-spike IgGAM was undetectable in 378 (4.2%) participants at a median of 8.6 weeks (IQR 6.4-10.7 weeks) after their second dose of vaccine. Seronegativity following two doses of SARS-CoV-2 vaccination was associated with administration of ChAdOx1 vs BNT162b2 (aOR 7.03, 95% CI 4.39-11.24), shorter interval between first and second vaccine doses (aOR 2.37, 1.06-5.26, for <6 weeks vs >10 weeks; aOR 1.59, 1.18-2.13, for 6-10 weeks vs >10 weeks), poorer self-assessed general health (aOR 3.33, 1.49-7.46, for poor vs excellent), immunodeficiencies (aOR 6.75, 2.63-17.35) and prescription of systemic immunosuppressants (aOR 3.76, 2.44-5.78). By contrast, pre-vaccination SARS-CoV-2 seropositivity (aOR 0.16, 0.04-0.70, for symptomatic seropositives vs seronegatives) and supplemental vitamin D intake (aOR 0.73, 0.53-0.99) were associated with reduced risk of post-vaccination seronegativity. 247/378 (65.3%) of participants who were seronegative after two doses of ChAdOx1 vs BNT162b2 provided a third sample at a median of 7.8 weeks (IQR 5.8-10.4) after receiving a booster dose of BNT162b2 or mRNA-1273: eight (3.2%) of them remained seronegative after three vaccine doses, all of whom either had a primary immunodeficiency or were taking systemic immunosuppressant drugs.

InterpretationWe identify multiple determinants of antibody responses to two doses of ChAdOx1 or BNT162b2, many of which are potentially modifiable. Booster doses of BNT162b2 or mRNA-1273 were highly effective in achieving seroconversion in those who failed to mount antibody responses following two doses of ChAdOx1 or BNT162b2.

Study registrationhttps://clinicaltrials.gov/ct2/show/NCT04330599

FundingBarts Charity, Fischer Family Trust, The Exilarchs Foundation, DSM Nutritional Products, Health Data Research UK

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed, medRxiv, and Google Scholar for papers published from January 1, 2020, to February 1, 2022, using the search terms (antibody OR humoral OR serologic* OR immunogenic*) AND (SARS-CoV-2 vaccine OR ChAdOx1 or BNT162b2 coronavirus), with no language restrictions. Population-based studies investigating multiple potential determinants of vaccine immunogenicity in people with known pre-vaccination SARS-CoV-2 serostatus are lacking.

Added value of this studyThis large population-based study, conducted in a population with known pre-vaccination SARS-CoV-2 serostatus, examines a comprehensive range of potential sociodemographic, behavioural, clinical, pharmacological and nutritional determinants of antibody responses to administration of two major SARS-CoV-2 vaccines (i.e., ChAdOx1 or BNT162b2), many of which have not previously been investigated. It is also the first population-based study to characterise antibody responses to booster doses of SARS-CoV-2 vaccines in adults who were seronegative after their primary course of vaccination.

Implications of all the available evidenceIncreased risk of seronegativity following two doses of SARS-CoV-2 vaccines was associated with administration of ChAdOx1 vs BNT162b2, shorter interval between first and second vaccine doses, poorer self-assessed general health, immunocompromise and SARS-CoV-2 seronegativity pre-vaccination. Regular intake of vitamin D supplements was associated with reduced risk of post-vaccination seronegativity. Randomised controlled trials are now needed to test for causality. Booster doses of BNT162b2 or mRNA-1273 were highly effective in achieving seroconversion in the majority of people who failed to mount antibody responses following a primary course of vaccination, the few exceptions being a subset of those with primary immunodeficiency or systemic immunosuppressant drugs.


title: AugmentA: Patient-specific Augmented Atrial model Generation Tool

abstract: Digital twins of patients hearts are a promising tool to assess arrhythmia vulnerability and to personalize therapy. However, the process of building personalized computational models can be challenging and requires a high level of human interaction. A pipeline to standardize the generation of a patients atrial digital twin from clinical data is therefore desirable. We propose a patient-specific Augmented Atria generation pipeline (AugmentA) as a highly automated framework which, starting from clinical geometrical data, provides ready-to-use atrial personalized computational models. AugmentA consists firstly of a preprocessing step applied to the input geometry. Secondly, the atrial orifices are identified and labelled using only one reference point per atrium. If the user chooses to fit a statistical shape model (SSM) to the input geometry, it is first rigidly aligned with the given mean shape before a nonrigid fitting procedure is applied. AugmentA automatically generates the fiber orientation and finds local conduction velocities by minimizing the error between the simulated and clinical local activation time (LAT) map. The pipeline was tested on a cohort of 29 patients on both segmented magnetic resonance images (MRI) and electroanatomical maps of the left atrium. Moreover, the pipeline was applied to a bi-atrial volumetric mesh derived from MRI. The pipeline robustly integrated fiber orientation and anatomical region annotations in 38.4{+/-}5.7 s. The error between insilico and clinical LAT maps was on average 12.7 ms. In conclusion, AugmentA offers an automated and comprehensive pipeline delivering atrial digital twins from clinical data in procedural time.


title: Ethnic differences in COVID-19 mortality in the second and third waves of the pandemic in England during the vaccine roll-out: a retrospective, population-based cohort study

abstract:
ObjectivesTo assess whether ethnic differences in COVID-19 mortality in England have continued into the third wave and to what extent differences in vaccination rates contributed to excess COVID-19 mortality after accounting for other risk factors.

DesignCohort study of 28.8 million adults using data from the Office for National Statistics Public Health Data Asset.

SettingPeople living in private households or communal establishments in England.

Participants28,816,020 adults (47% male) aged 30-100 years in 2020 (mean age = 56), who were present at the 2011 Census and alive on 8 December 2020.

Main outcome measuresDeath involving COVID-19 during the second (8 December 2020 to 12 June 2021) and third wave (13 June 2021 to 1 December 2021) of the pandemic. We calculated hazard ratios (HRs) separately for males to females to summarise the association between ethnic group and death involving COVID-19 in each wave, sequentially adjusting for age, residence type, geographical factors, sociodemographic characteristics, pre-pandemic health, and vaccination status.

ResultsAge-adjusted HRs of death involving COVID-19 were higher for most ethnic minority groups than the White British group during both waves, particularly for groups with lowest vaccination rates (Bangladeshi, Pakistani, Black African and Black Caribbean). In both waves, HRs were attenuated after adjusting for geographical factors, sociodemographic characteristics, and pre-pandemic health. Further adjusting for vaccination status substantially reduced residual HRs for Black African, Black Caribbean, and Pakistani groups in the third wave. The only groups where fully-adjusted HRs remained elevated were the Bangladeshi group (men: 2.19, 95% CI 1.72 to 2.78; women: 2.12, 95% CI 1.58 to 2.86) and men from the Pakistani group (1.24, 95% CI 1.06 to 1.46).

ConclusionPublic health strategies to increase vaccination uptake in ethnic minority groups could reduce disparities in COVID-19 mortality that cannot be accounted for by pre-existing risk factors.

What is already known on this topicEthnic minority groups in England have been disproportionately affected by the COVID-19 pandemic during the first and second waves.

COVID-19 vaccination uptake is also lower among many ethnic minority groups, particularly Bangladeshi, Black African, Black Caribbean, and Pakistani groups.

There is a paucity of research into whether ethnic disparities in COVID-19 mortality have continued into the third wave and the extent to which differences in vaccination uptake contribute to differences in COVID-19 mortality.

What this study addsUsing linked data on 28.8 million adults in England, we find that rates of COVID-19 mortality have remained higher than the White British group for most ethnic minority groups during the vaccine roll-out, notably for the Bangladeshi, Black African, Black Caribbean, and Pakistani groups.

After adjustment for geographical factors, sociodemographic characteristics, pre-pandemic health status, and vaccination status, the only groups with elevated rates of COVID-19 mortality during the third wave were the Bangladeshi group and men from the Pakistani group, suggesting that increasing vaccination uptake in ethnic minority groups could reduce ethnic disparities in COVID-19 mortality.


title: Bayesian Space-time SIR modeling of Covid-19 in two US states during the 2020-2021 pandemic.

abstract: This paper describes the Bayesian SIR modeling of the 3 waves of Covid-19 in two contrasting US states during 2020-2021. A variety of models are evaluated at the county level for goodness-of-fit and an assessment of confounding predictors is also made. It is found that models with three deprivation predictors and neighborhood effects are important. In addition, the work index from Google mobility was also found to provide an increased explanation of the transmission dynamics.


title: Prediction Model for Detection of Sporadic Pancreatic Cancer (PRO-TECT) in a Population-Based Cohort Using Machine Learning and Further Validation in a Prospective Study

abstract:
OBJECTIVESThere is currently no widely accepted approach to screening for pancreatic cancer (PC). We aimed to develop and validate a risk prediction model for PC across two health systems using electronic health records (EHR).

METHODSThis retrospective cohort study consisted of patients 50-84 years of age meeting utilization criteria in 2008-2017 at Kaiser Permanente Southern California (KPSC, model training, internal validation) and the Veterans Affairs (VA, external validation).  Random survival forests models were built to identify the most relevant predictors from >500 variables and to predict PC within 18 months of cohort entry. A prospective study was then conducted in KPSC to assess feasibility of the model for real-time implementation.

RESULTSThe KPSC cohort consisted of 1.8 million patients (mean age 61.6) with 1,792 PC cases. The estimated 18-month incidence rate of PC was 0.77 (95% CI 0.73-0.80)/1,000 person-years. The three models containing age, abdominal pain, weight change and two laboratory biomarkers (ALT change/HgA1c, rate of ALT change/HgA1c, or rate of ALT change/rate of HgA1c change) had comparable discrimination and calibration measures (c-index: mean=0.77, SD=0.01-0.02; calibration test: p-value 0.2-0.4, SD 0.2-0.3). The VA validation cohort consisted of 2.6 million patients (mean age 66.1) with an 18-month incidence rate of 1.27 (1.23-1.30). A total of 606 patients were screened in the prospective pilot study at KPSC with 9 patients (1.5%) diagnosed with a pancreatic or biliary cancer.

CONCLUSIONSUsing widely available parameters in EHR, we developed a population-based parsimonious model for early detection of sporadic PC suitable for real-time application.

Study HighlightsO_ST_ABSWhat Is KnownC_ST_ABSO_LIPatients with pancreatic cancer are often diagnosed at late stages.
C_LIO_LIEarly detection is needed to impact the natural history of disease progression and improve patient survival.
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What Is New HereO_LIMachine-learning was used to develop a population-based model for early detection of pancreatic cancer. The model was internally and externally validated in cohorts of 1.8 million and 2.6 million individuals, respectively.
C_LIO_LICalibration was excellent in prospective pilot testing for detection of pancreatic malignancy.
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category: gastroenterology


title: Developing and validating polygenic risk scores for colorectal cancer risk prediction in East Asians

abstract:
Background & AimsSeveral polygenic risk scores (PRSs) have been developed to predict the risk of colorectal cancer (CRC) in European descendants. We aimed to develop and validate CRC PRSs for East Asians.

MethodsPRSs were developed using genome-wide association study (GWAS) data from 22,702 cases and 212,486 controls and validated in two case-control studies (1,454 Korean and 1,736 Chinese). Eleven PRSs were derived using three approaches: GWAS-identified CRC risk SNPs; CRC risk variants identified through fine-mapping of known risk loci; and genome-wide risk prediction algorithms. Logistic regression models were used to estimate odds ratios (ORs) and area under the receiver operating characteristic curve (AUC).

ResultsIn the validation sets, PRS115-EAS, a PRS with 115 GWAS-reported risk variants derived from East-Asian data performed significantly better than PRS115-EUR, a PRS derived using GWAS data from European descendants. In the Korea validation set, ORs per SD increase of PRS115-EAS were 1.63 (95%CI = 1.46 - 1.82; AUC = 0.63), compared with OR of 1.44 (95%CI = 1.29 - 1.60, AUC = 0.60) for PRS115-EUR, derived using European-ancestry data. PRS115-EAS/EUR derived using meta-analysis results of both populations slightly improved the AUC to 0.64. Similar but weaker associations were found in the China validation set. Individuals among the highest 5% of PRS115-EAS/EUR have a 2.52-fold elevated CRC risk compared with the average risk group and have a 12-20% risk of developing CRC by age 85.

ConclusionsCRC PRSs are promising in predicting risk of this cancer in East Asians. Using data from East Asians significantly improves model performance.


title: Study protocol for the development and internal validation of SPIRIT (Schizophrenia Prediction of Resistance to Treatment): A clinical tool for predicting risk of treatment resistance to anti-psychotics in First Episode Schizophrenia.

abstract:
IntroductionTreatment Resistant Schizophrenia (TRS) is associated with significant impairment of functioning and high treatment costs. Identification of patients at high risk of TRS at their initial diagnosis may significantly improve clinical outcomes and minimize social and functional disability. We aim to develop a prognostic model for predicting the risk of TRS in patients with First Episode Schizophrenia, and to examine its potential utility and acceptability as a clinical decision tool.

Methods and analysisWe will use two well-characterised UK-based first episode psychosis cohorts: AESOP-10 and GAP for which data has been collected on sociodemographic and clinical characteristics. We will identify candidate predictors for the model based on current literature and stakeholder consultation. Model development will use all data, with the number of candidate predictors restricted according to available sample size and event rate. A model for predicting risk of TRS will be developed based on penalised regression, with missing data handled using multiple imputation. Internal validation will be undertaken via bootstrapping, obtaining optimism-adjusted estimates of the models performance. The clinical utility of the model in terms of clinically relevant risk thresholds will be evaluated using net benefit and decision curves (comparative to competing strategies). Consultation with patients and clinical stakeholders will determine potential thresholds of risk for treatment decision making. The acceptability of embedding the model as a clinical tool will be explored using focus groups with clinicians in early intervention services.

Ethics and disseminationThe development of the prognostic model will be based on anonymised data from existing cohorts, for which ethical approval is in place. Ethical approval has been obtained from Keele University for the qualitative focus groups within Early Intervention in Psychosis services (Ref: MH-210174). Findings will be shared through peer-review publications, conference presentations and social media. A lay summary will be published on collaborator websites.

Strengths and limitations of this studyO_LIThe proposed study is the first step on the road towards the design and evaluation of a prognostic model and decision tool for the identification of treatment resistant schizophrenia. This could be informative to clinicians, patients, and their care providers in shared decision making and improvement of treatment plans.
C_LIO_LIIndividual participant data from two existing cohorts will be used to develop and internally validate the prognostic model.
C_LIO_LIUsing a mixed method design improves the ability to understand the limitations of the tool in a clinical context and create a foundation to develop it to be more effective.
C_LIO_LIA limitation of the development of this tool is that the number of people with TRS may not be sufficiently large to consider all potential predictors for the model
C_LIO_LIFurther testing of the external validity of the prognostic model will be required
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