title: Duration of COVID-19 mRNA Vaccine Effectiveness against Severe Disease

abstract:
BackgroundWaning immunity following administration of mRNA based COVID-19 vaccines remains a concern for many health systems. We undertook a study of SARS-CoV-2 infections, with and without requirement for intensive care to shed more light on the duration of vaccine effectiveness for protection against the need for intensive care.

MethodsWe used a matched case-control study design with the study base being all individuals with first infection with SARS-CoV-2 reported in the State of Qatar between 1 Jan 2021 and 20 Feb 2022. Cases were those requiring intensive care while controls were those who recovered without need for intensive care. Vaccine effectiveness against requiring intensive care and number needed to vaccinate (NNV) to prevent one more case of COVID-19 requiring intensive care were computed for the mRNA (BNT162b2 / mRNA-1273) vaccines.

ResultsVaccine effectiveness against requiring intensive care was 59% (95% confidence interval [CI], 50 to 76) between the first and second dose and strengthened to 89% (95% CI, 85 to 92) between the second dose and 4 months post the second dose in persons who received a primary course of the vaccine. There was no waning of vaccine effectiveness in the period from 4 to 12 months after the second dose.

ConclusionsThis study demonstrates that vaccine effectiveness against requiring intensive care remains robust till at least 12 months after the second dose of mRNA based vaccines.


title: Prospective validation of diffusion-weighted MRI as a biomarker of tumor response and oncologic outcomes in head and neck cancer: Results from an observational biomarker pre-qualification study.

abstract:
Purpose/Objective(s)To determine diffusion-weighted imaging (DWI) MRI parameters associated with tumor response and oncologic outcomes in head and neck (HNC) patients treated with definitive radiation therapy (RT).

Materials/MethodsEighty-six HNC patients enrolled in an active prospective imaging study at The University of Texas MD Anderson Cancer Center were included in the analysis. Patients had MRIs pre-, mid-, and post-RT completion. Inclusion criteria included adults with histologic evidence of malignant head and neck neoplasm indicated for curative-intent treatment with RT with/without chemotherapy, good performance status (ECOG score 0-2), and with no contraindications to MRI. Patients were scanned using a MAGNETOM Aera 1.5T MR scanner (Siemens Healthcare, Germany) with two large four-channel flex phased-array coils. We used fat-suppressed T2-weighted turbo spin echo sequences for tumor segmentation which were co-registered to respective DWIs for extraction of apparent diffusion coefficient (ADC) measurements. Treatment response was assessed at mid-RT and at 8-12 weeks post-RT using RECIST 1.1 criteria and was defined as: complete response (CR) vs. non-complete response (non-CR). Pre-RT ADC was correlated with RT response (CR vs. non-CR) at mid- and post-RT. The Mann-Whitney U test was used to compare ADC values between the mid-treatment CR group and the non-CR group. Recursive partitioning analysis (RPA) was performed to identify ADC threshold associated with relapse. Cox proportional hazards models were done for clinical vs. clinical and imaging parameters and internal validation was done using bootstrapping technique.

ResultsEighty-one patients were included in this analysis. Median follow-up was 31 months. Pre-treatment ADC was not correlated with tumor response or oncologic outcomes (P>0.05). For patients with post-RT CR, there was a significant increase in mean ADC at mid-RT compared to baseline ((1.8 {+/-} 0.29) x 10-3 mm2/s versus (1.37 {+/-} 0.22) x 10- 3 mm2/s, p < 0.0001), while patients with non-CR had no statistically significant increase (p >0.05). RPA identified GTV-P delta ({Delta}) ADCmean <7% at mid-RT as the most significant parameter associated with worse LC and RFS (p=0.01). Univariable and multivariable analysis of prognostic outcomes showed that GTV-P {Delta}ADCmean at mid-RT [≥]7% was significantly associated with better LC and RFS. The addition of {Delta}ADCmean significantly improved the c-indices of LC and RFS models compared with standard clinical variables (0.85 vs. 0.77 and 0.74 vs. 0.68 for LC and RFS, respectively, p<0.0001 for both).

ConclusionADC change at mid-RT is a strong predictor of oncologic outcomes in HNC patients. Patients with no significant increase of primary tumor site ADC at mid-RT relative to baseline values are at high risk of disease relapse. Multi-institutional data are needed for validation of our results.

category: oncology


title: Women Carry the Weight of Deprivation on Physical Inactivity: Moderated Mediation Analyses in Two Large-Scale Samples

abstract: Physical activity is unequally practiced across populations: relative to more privileged individuals, deprived people are less likely to be physically active. However, pathways underlying the association between deprivation and physical activity remain overlooked. Here, we examined whether the association between several indicators of deprivation (administrative area deprivation and self-reported individual material and social deprivation) and physical activity was mediated by body mass index (BMI). In addition, consistent with an intersectional perspective, we tested whether this mediating pathway was moderated by participants gender and we hypothesized that the mediating effect of BMI would be stronger among women, relative to men. We used two independent large-scale studies to test the proposed pathways cross-sectionally and prospectively. In a first sample composed of 5,723 British adults (Study 1), BMI partly mediated the cross-sectional association between administrative area deprivation and self-reported physical activity. Moreover, relative to men, the detrimental effect of deprivation on BMI was exacerbated among women, with BMI mediating 3.1% of the association between deprivation and physical activity among women (vs 1.5% among men). In a second sample composed of 8,358 European older adults (Study 2), our results confirmed the findings observed in Study 1: BMI partly mediated the prospective association between perceived material and social deprivation and self-reported physical activity. Moreover, compared to men, the effect of deprivation on BMI was more pronounced among women, with BMI respectively mediating 8.1% and 3.4% of the association between material and social deprivation and physical activity among women (vs 1.3% and 1.2% among men). These findings suggest that BMI partly explained the detrimental association between deprivation and physical activity, with this effect being stronger among women. Our study highlights the need to further consider how gender may shape the mechanisms behind the association between disadvantaged socio-economic circumstances and physical activity.

category: public and global health


title: The methodologies to assess the effects of non-pharmaceutical interventions during COVID-19: a systematic review

abstract: Non-pharmaceutical interventions, such as school closures and stay-at-home orders, have been implemented around the world to control the spread of SARS-CoV-2. Their effects on health-related outcomes have been the subject of numerous empirical studies. However, these studies show fairly large variation among methodologies in use, reflecting the absence of an established methodological framework. On the one hand, variation in methodologies may be desirable to assess the robustness of results; on the other hand, a lack of common standards can impede comparability among studies. To establish a comprehensive overview over the methodologies in use, we conducted a systematic review of studies assessing the effects of non-pharmaceutical interventions on health-related outcomes between January 1, 2020 and January 12, 2021 (n=248). We identified substantial variation in methodologies with respect to study setting, outcome, intervention, methodological approach, and effect assessment. On this basis, we point to shortcomings of existing studies and make recommendations for the design of future studies.

category: health policy


title: Pre-procedural testing improves estimated COVID-19 prevalence and trends

abstract:
BackgroundCOVID-19 positivity rates reported to the public may provide a distorted view of community trends because they tend to be inflated by high-risk groups, such as symptomatic patients and individuals with known exposures to COVID-19. This positive bias within high-risk groups has also varied over time, depending on testing capability and indications for being tested. In contrast, throughout the pandemic, routine COVID-19 screening tests for elective procedures and operations unrelated to COVID-19 risk have been administered by medical facilities to reduce transmission to medical staffing and other patients. We propose the use of these pre-procedural COVID-19 patient datasets to reduce biases in community trends and better understand local prevalence.

MethodsUsing patient data from the Maui Medical Group clinic, we analyzed 12,640 COVID-19 test results from May 1, 2020 to March 16, 2021, divided into two time periods corresponding with Mauis outbreak.

ResultsMean positivity rates were 0.1% for the pre-procedural group, 3.9% for the symptomatic group, 4.2% for the exposed group, and 2.0% for the total study population. Post-outbreak, the mean positivity rate of the pre-procedural group was significantly lower than the aggregate group (all other clinic groups combined). The positivity rates of both pre-procedural and aggregate groups increased over the study period, although the pre-procedural group showed a smaller rise in rate.

ConclusionsPre-procedural groups may produce different trends compared to high-risk groups and are sufficiently robust to detect small changes in positivity rates. Considered in conjunction with high-risk groups, pre-procedural marker groups used to monitor understudied, low-risk subsets of a community may improve our understanding of community COVID-19 prevalence and trends.

category: infectious diseases


title: Treatment group outcome variance difference after dropout as an indicator of missing-not-at-random bias in randomized clinical trials

abstract: Randomized controlled trials (RCTs) are considered the gold standard for assessing the causal effect of an exposure on an outcome, but are vulnerable to bias from missing data. When outcomes are missing not at random (MNAR), estimates from complete case analysis (CCA) will be biased. There is no statistical test for distinguishing between outcomes missing at random (MAR) and MNAR, and current strategies rely on comparing dropout proportions and covariate distributions, and using auxiliary information to assess the likelihood of dropout being associated with the outcome. We propose using the observed variance difference across treatment groups as a tool for assessing the risk of dropout being MNAR. In an RCT, at randomization, the distributions of all covariates should be equal in the populations randomized to the intervention and control arms. Under the assumption of homogeneous treatment effects, the variance of the outcome will also be equal in the two populations over the course of followup. We show that under MAR dropout, the observed outcome variances, conditional on the variables included in the model, are equal across groups, while MNAR dropout may result in unequal variances. Consequently, unequal observed conditional group variances are an indicator of MNAR dropout and possible bias of the estimated treatment effect. Heterogeneity of treatment effect affects the intervention group variance, and is another potential cause of observing different outcome variances. We show that, for longitudinal data, we can isolate the effect of MNAR outcome-dependent dropout by considering the variance difference at baseline in the same set of patients that are observed at final follow-up. We illustrate our method in simulation and in applications using individual-level patient data and summary data.

category: epidemiology


title: From menarche to menopause: the impact of reproductive factors on the metabolic profile of over 65,000 women

abstract: We explored the relation between age at menarche, parity and age at natural menopause with 249 metabolic traits, measured using nuclear magnetic resonance (NMR), in up to 65,487 UK Biobank women using multivariable regression (MV), Mendelian randomization (MR) and a male negative control (parity only). Older age of menarche was related to a more atherogenic metabolic profile in MV and MR, which was largely attenuated when accounting for adult body mass index. In MV, higher parity related to complex changes in lipoprotein-related traits; these were not observed in male negative controls and were imprecisely estimated in MR. In MV and MR, older age at natural menopause was related to lower concentrations of inflammation markers, but inconsistent results were observed for LDL-related traits. Our findings support a role of reproductive traits on later life metabolic profile and provide insights into identifying novel markers for the prevention of adverse cardiometabolic outcomes in women.


title: COVID-19 vaccine effectiveness against severe disease from the Omicron BA.1 and BA.2 subvariants: surveillance results from southern Sweden, December 2021 to March 2022

abstract: We compared vaccine effectiveness (VE) against severe COVID-19 during calendar periods from December 2021 to March 2022 when Omicron BA.1 and BA.2, respectively, were the dominating virus variants in Scania county, Sweden. We used continuous density case-control sampling matched for sex and age, and with further adjustment for differences in comorbidities and prior infection. VE remained relatively stable after the transition from BA.1 to BA.2 among people with at least three doses but decreased markedly among those with only two doses. Protection from prior infection was also lower after the transition to BA.2. These findings suggest that booster vaccination is needed to maintain sufficient protection against severe COVID-19.


title: Genetic risk and incident venous thromboembolism in middle-aged and older adults following 1 Covid-19 vaccination

abstract:
BACKGROUNDCovid-19 vaccination has been associated with an increased risk of venous thromboembolism (VTE). However, it is unknown whether genetic predisposition to VTE is associated with an increased risk of thrombosis following vaccination.

METHODSUsing data from the UK Biobank, which contains in-depth genotyping data and linked vaccination and health outcomes information, we generated a polygenic risk score (PRS) using 299 genetic variants identified from a previous large genome-wide association study. We prospectively assessed associations between PRS and incident VTE after first and the second-dose vaccination separately. We conducted sensitivity analyses stratified by vaccine type (adenovirus- and mRNA-based) and using two historical unvaccinated cohorts. We estimated hazard ratios (HR) for PRS-VTE associations using Cox models.

RESULTSOf 359,310 individuals receiving one dose of a Covid-19 vaccine, 160,327 (44.6%) were males, and the mean age at the vaccination date was 69.05 (standard deviation [SD] 8.04) years. After 28- and 90-days follow-up, 88 and 299 individuals developed VTE respectively, equivalent to an incidence rate of 0.88 (95% confidence interval [CI] 0.70 to 1.08) and 0.92 (95% CI 0.82 to 1.04) per 100,000 person-days. The PRS was significantly associated with a higher risk of VTE (HR per 1 SD increase in PRS, 1.41 (95% CI 1.15 to 1.73) in 28 days and 1.36 (95% CI 1.22 to 1.52) in 90 days). Similar associations were found after stratification by vaccine type, in the two-dose cohort and across the historical unvaccinated cohorts.

CONCLUSIONSThe genetic determinants of post-Covid-19-vaccination VTE are similar to those seen in historical data. This suggests that, at the population level, post-vaccine VTE has similar aetiology to conventional VTE. Additionally, the observed PRS-VTE associations were equivalent for adenovirus- and mRNA-based vaccines.


title: Distinct metabolic features of genetic liability to type 2 diabetes and coronary artery disease: a reverse Mendelian randomization study

abstract:
BackgroundType 2 diabetes (T2D) and coronary artery disease (CAD) both have roots in disordered metabolism and known genetic determinants. The mechanisms through which their associated genetic variants lead to disease onset remain poorly understood. Here, we used large-scale metabolomics data to directly compare the metabolic features of genetic liability to T2D and to CAD.

MethodsWe performed two-sample reverse Mendelian randomization (MR) to estimate effects of genetic liability to T2D and CAD on 249 circulating metabolites from targeted nuclear magnetic resonance spectroscopy in the UK Biobank (N=118,466) using 167 and 145 genetic instruments, respectively. We examined the potential for medication use to distort effect estimates by examining effects of disease liability on metformin and statin use and by conducting age-stratified metabolite analyses.

ResultsUsing inverse variance weighted (IVW) models, higher genetic liability to T2D was estimated to decrease high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) (e.g., HDL-C: -0.05 SD; 95% CI -0.07, -0.03, per doubling of liability), whilst increasing all triglyceride groups and branched chain amino acids (BCAAs). Estimates for CAD liability suggested an effect on reducing HDL-C as well as raising very-low density lipoprotein cholesterol (VLDL-C) and LDL-C, and LDL triglycerides. Liability to each disease was estimated to decrease apolipoprotein-A1, whilst only CAD liability was estimated with IVW to increase apolipoprotein-B (0.10 SD; 95% CI 0.03, 0.17). In pleiotropy-robust sensitivity models, T2D liability was still estimated to increase BCAAs, but several effect estimates for higher CAD liability reversed and supported decreased LDL-C and apolipoprotein-B. Moreover, higher T2D liability uniquely increased the odds of using metformin, whereas higher CAD liability uniquely increased the odds of using statins. Estimated effects of CAD liability differed uniquely and substantially by age for non-HDL-C traits in particular, with, e.g., pleiotropy-robust models suggesting that higher CAD liability lowers LDL-C only at older ages when use of statins is common.

ConclusionsOur results support largely distinct metabolic features of genetic liability to T2D and to CAD, particularly higher BCAAs in T2D and lower LDL-C and apolipoprotein-B in CAD. Such apparently protective effects of CAD liability differ substantially by age and likely reflect mediation by statin use in adulthood.


title: Genetic variability in proteoglycan biosynthetic genes reveals new facets of heparan sulfates diversity. A systematic review and analysis

abstract: Proteoglycans are complex macromolecules formed of glycosaminoglycan chains covalently linked to core proteins through a linker tetrasaccharide common to heparan sulfate proteoglycans (HSPG) and chondroitin sulfate proteoglycans (CSPG). Biosynthesis of a single proteoglycan requires the expression of dozens of genes, which together create the large structural and functional diversity reflected by the numerous diseases or syndromes associated to their genetic variability. Among proteoglycans, HSPG are the most structurally and functionally complex. To decrease this complexity, we retrieved and linked information on pathogenic variants, polymorphism, expression, and literature databases for 50 genes involved in the biosynthesis of HSPG core proteins, heparan sulfate (HS) chains, and their linker tetrasaccharide. This resulted in a new gene organization and biosynthetic pathway representation in which the phenotypic continuum of disorders as linkeropathies and other pathologies could be predictable. Moreover, ubiquitous NDST1, GLCE, HS2ST1, and HS6ST1 appeared to generate ubiquitous heparan sulfate (HS) sequences essential for normal development and homeostasis, whereas the tissue restricted NDST2-4, HS6ST2-3, and HS3ST1-6 appeared to generate specialized HS sequences mainly involved in responsiveness to stimuli. Supported by data on genetic polymorphism and clinical variants, we afford a new vision of HSPG involvement in homeostasis, disease, vulnerability to disease, and behavioral disorders.

category: pathology


title: Variability in proteoglycan biosynthetic genes reveals new facets of heparan sulfates diversity. A systematic review and analysis


title: The Cerebellum Plays More Than One Role in Appetite Control: Evidence From Typical and Pathological Populations

abstract:
BackgroundDysregulated appetite control is characteristic of anorexia nervosa (AN) and obesity (OB). Studies using a broad range of methods suggest the cerebellum plays an important role in appetite control, and it is implicated in both AN and OB with reports of aberrant grey matter volume (GMV) compared to non-clinical populations. As functions of the cerebellum are anatomically segregated, specific localization of aberrant anatomy may indicate how it affects appetite control in different states.

ObjectiveTo determine if there were consistencies in regions of cerebellar GMV changes affected in AN and OB, and across normative variation.

Methodsystematic review and meta-analysis using Ginger ALE.

ResultsTwenty publications were identified as either case-control studies (with total n=619) or regressed weight from normative data against brain volume (with total n=3,518). AN and OB analyses both showed consistently decreased GMV within the left cerebellum, but volume reduction was anterior for AN and posterior for OB, with minimal overlap. Analysis of the normative dataset identified a cluster in right posterior lobe.

DiscussionThese findings suggest that more than one area of the cerebellum is involved in control of eating behaviour and is differentially affected in normal variation and pathological conditions. Specifically, we hypothesise an association with sensorimotor and emotional learning in AN, but with executive function in OB.

category: psychiatry and clinical psychology


title: The Validity of the Parsley Symptom Index: an e-PROM designed for Telehealth

abstract:
Background / PurposeThe Parsley Symptom Index (PSI) is a recently developed symptom assessment for adults with chronic disease in telehealth settings. The purpose of this study was to validate the PSI against the Self-Rated Health (SRH) item.

Materials and MethodsThis prospective cohort study took place from January 15, 2021 to December 15, 2021 among a sample of 10,519 adult patients at Parsley Health, a subscription based holistic medical practice. The PSI and the SRH were completed by patients via an online portal. The association between the PSI and SRH was assessed via polyserial and polychoric correlations, while weighted kappa scores provided information related to agreement between the PSI and SRH.

ResultsFrom 22,748 responses, there were moderate levels of association (polyserial r=0.51; polychoric r=0.52) and agreement (weighted {square} = 0.46) between the PSI and SRH. In total 74.2% (16865) of responses between the PSI and SRH were relatively congruent while 36.2% (8229) were literally congruent.

ConclusionsThe PSI demonstrates validity with the SRH for adults with chronic disease in a telehealth setting.


title: Functional Magnetic Resonance Imaging of the amygdala and subregions at 3 Tesla: A scoping review protocol

abstract:
BackgroundFunctional Magnetic Resonance Imaging (fMRI) is a widely accepted and utilised method of investigating neural activation within the brain. There has been increasing awareness and understanding in the field of neuropsychology over the last 10-15 years that the amygdala plays an important role in many mental health conditions. Functional connectivity (FC) of the amygdala with other parts of the brain is well-documented in the literature; however the role of the amygdala and its reported connections is still not well understood and this can be attributed, in part, to its very small size. It is challenging to achieve adequate spatial resolution to visualise amygdala activation using 3T MRI systems that are in widespread use for this type of clinical research. Optimisation of protocols for improved data accuracy and reproducibility may potentially lead to standardisation and subsequent advancements in overall image quality in this field.

MethodsThe protocol for this scoping review was developed in line with the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) and registered with the Open Science Framework (OSF). A literature search of five databases (Medline, Embase, Web of Science, Google Scholar and Scopus) will be undertaken using a refined search strategy; peer-reviewed publications identified as being relevant will then be imported into Covidence software for abstract screening and data extraction by two reviewers working independently. The quantitative findings will be tabulated to provide an overview of the current methodologies for comparison. This will be accompanied by a narrative report summarising the extracted data in relation to the stated research questions.

DiscussionThe objective of this scoping review is to identify and map the range of existing protocols used in fMRI for imaging the activation and FC patterns of the amygdala at 3 Tesla. This will be achieved by collating and presenting quantitative data relating to protocol parameter choices as well as other qualitative aspects of the data acquisition process.

RegistrationOpen Science Framework (OSF) - Registration type: OSF Pre-registration

Registration: https://osf.io/e3c28, DOI: 10.17605/OSF.IO/KW58P

category: radiology and imaging


title: Ukrainian refugee integration and flows analysis with an approach of Big Data: Social media insights

abstract:
BackgroundThe Ukrainian refugee crisis shows a lack of reliable data about refugee flows, demographic structure, and integration. But those data are necessary for the UNHCR and governments in preparing high-quality projections for emergencies and the conditions for the integration of refugees who intend to stay in immigration societies. Although Facebook, Instagram and YouTube are social platforms with the most users, very few studies have been written about their potential for migration studies and integration.

ObjectiveThe objective was to test the usefulness of Big Data insights from social network platforms to gain first demographic insights into refugees age and gender structure, migration flows, and integration trends.

MethodsThe primary methodological concept of our approach is to monitor the so-called "digital trace" of refugees left on social networks Facebook, Instagram and YouTube and their geo-locations. We focus on users that use social network platforms in Ukrainian and Russian language. We sampled the data before and during the war outbreak, standardised the data and compared it with the first official data from UNHCR and national governments. We selected specific keywords, i.e. migration and integration-related queries, using YouTube insight tools. Using FB and Instagram, we collected our own data archive because Meta offers data only for the present day with the ability to compare this day with the average of the past 12 months. In the next step, we collected signals that indicate integration willingness.

ResultsOur approach shows that the number of Facebook and Instagram users is growing rapidly in Ukrainian neighbouring countries and Germany after the war outbreak in Ukraine. Testing performed matches the trend of immigration of Ukrainian refugees in Poland and Germany, as well in the cities and the German Bundeslander. The tested correlation between the number of Ukrainian refugees in Poland and FB and Instagram users in Ukrainian in Poland shows that the increase in frequency index is correlated with stepped-up emigration from Ukraine. R2 is 0.1324 and shows a positive correlation, and a p-value is statistically significant. The analysis of the FB group of Ukrainian in the EU shows that those groups can be a valuable source for studying integration. Ukrainians are increasingly expressing interest in learning the German language, which is a good indication of integration willingness. One of the contributions of the second used method, YouTube insights, is that it shows that by searching for video material on the YouTube platform, the intention of users to migrate, or in this case, to flee from Ukraine, can be estimated.

ConclusionThe usefulness and the main advantage of this approach are enabling first insights into integration willingness and identification of trends in the movement and intentions of refugees when there is no official data. On the one side, this method allows governments to estimate how many refugees intend to enter the labour market and integrate into the immigration society and, on the other, better respond to the recent humanitarian crisis. Despite its beneficiaries, this approach has many limitations, and there is a need for many more studies to perfect this method.

category: occupational and environmental health


title: The testing of the DAC algorithm for classifying Lymphoma Cell of Origin samples using HTG's targeted gene expression system

abstract: An implementation of the windows based DLBCL automatic classification (DAC) algorithm for determining cell of origin (COO) written in the R language and designed for use with the HTG EdgeSeq Reveal Software package is described. Classifications using the new implementation (DAC-R) were compared to the those using the original version (DAC-Win), the HTG DLBCL COO classifier, the HTG EdgeSeq Reveal DLBCL algorithm. Classifications made using HTG data were tested for concordance with those made using WG-DASL data for the same samples. To analyse small numbers of samples a background dataset was developed to allow for the reliable classification of individual cases. Classification accuracy was assessed using percentage of agreement of discrete classification groups and Pearson correlation of probability scores where appropriate. In the data tested it was seen that the correlation of probability scores for DAC-R and DAC-Win was 0.9985 or higher. Agreement with the HTG DLBCL COO classifier was 85.1% and agreement with the HTG EdgeSeq Reveal DLBCL algorithm was also high (Pearson correlation of GCB probabilities = 0.91). Agreement between classifications made using HTG and WG-DASL data was also high (83.7%). In summary, the R based algorithm of DAC successfully replicates the functionality of the original routine and produces comparable COO calls in data produced from the HTG Pan B-Cell Lymphoma Panel to the other methods listed.


title: Data and care integration for post-acute intensive care program of stroke patients: effectiveness assessment using a disease-matched comparator cohort

abstract:
PurposeTo assess the effectiveness of an integrated care program for post-acute care of stroke patients, the return home program (RHP program), deployed in Barcelona (North-East Spain) between 2016 and 2017 in a context of health and social care information systems integration.

DesignThe health outcomes and resource use of the RHP program participants were compared with a population-based matched control group built from central healthcare records of routine care data.

FindingsThe study included 92 stroke patients attended within the RHP program and their matched-controls. Patients in the intervention group received domiciliary care service, home rehabilitation, and telecare significantly earlier than the matched-controls. Within the first two years after the stroke episode, recipients of the RHP program were less frequently institutionalized in a long-term care facility (5% vs. 15%). The use of primary care services, non-emergency transport, and telecare services were more frequent in the RHP group.

OriginalityOur analysis shows that an integrated care program can effectively promote and accelerate delivery of key domiciliary care services, reducing institutionalization of stroke patients in the mid-term. The integration of health and social care information allows not only a better coordination among professionals but also to monitor health and resource use outcomes of care delivery

category: health systems and quality improvement


title: Association of Covid-19 Vaccine Hesitancy with Demographics, Mental Health, and Disability

abstract:
BackgroundThe world is witnessing a pandemic caused by the novel coronavirus named Covid-19 by WHO that has claimed millions of lives since its advent in December 2019. Several vaccine candidates and treatments have emerged to mitigate the effect of virus, along with came an increased confusion, mistrust on their development, emergency authorization and approval process. Increased job losses, jump in divorce rate, and the generic nature of staying home has also led to various mental health issues.

MethodsWe analyzed two publicly available datasets to better understand vaccine hesitancy. The first dataset was extracted from ICPSR Covid-19 database (https://doi.org/10.3886/E130422V1).[1].This cross-sectional survey was conducted to assess the prevalence of vaccine hesitancy in the US, India, and China. The second dataset was obtained from the United States Census Bureaus Household Pulse Survey (HPS) Phase 3.2.

For the ICPSR dataset, proportions and summary statistics are reported to give an overview of the global picture of vaccine hesitancy. The HPS dataset was analyzed using multinomial and binary logistic regression. Chi-square test of independence and exploratory data analysis supplemented provided insight into the casual factors involved in vaccine hesitancy.

ResultsO_ST_ABSICPSR Global DataC_ST_ABSFor India, 1761 participants completed the survey as of November, 2020 of which 90.2% indicated acceptance of a Covid-19 vaccine. 66.4% are parents of 18 years old or younger, and 79.0% respondent has a parent 50 years or older. Vaccine acceptance rate was 99.8% among 928 out of 1761 participants who had a child. 1392 participants either had a parent or child of which 83.4% will encourage their parents and 90.5% will encourage their children to get the covid-19 vaccine. In this Indian survey, 16.2% identified as belonging to the rural population of which 51.2% showed vaccine hesitancy. A binary logistic regression model with vaccine hesitancy as a dichotomous variable showed that rural population had an odds ratio (OR) of 3.45 (p-value<0.05). Income seems to influence vaccine hesitancy, with income level of (7501-15,000 Indian Rupees (INR)/month) having an OR of 1.41 as compared to other income groups.

In the US, 1768 individuals participated in the survey from August-November 2020. 67.3% respondents indicated the will to accept the vaccine. 1129 of them either had a parent or a child, of which 67.6% will take the vaccine; 66% will encourage their parents and 83% will encourage their children for taking the vaccination. 40.3% responded as vaccine hesitant, 31% identified as staying in rural areas, of which 52.5% are vaccine hesitant. In the binary logistic regression analysis, race, past flu shot history, rural living, income turned out to be significant. White race had OR >1 as compared to other races, low-income group (US dollar $2000-4999/month) had an OR of 1.03.

In China, there were 1727 participants, of which 1551(90.0%) indicated that they will accept a vaccine. 90.1% of them who had either a parent or child will accept vaccine, 80.4% will influence parents, and 83.4% will encourage children to get vaccination needle in the arm. 30% had vaccine hesitancy. 262 belonged to the rural population, of which 34.8% are vaccine hesitant. Income and Northern region (OR = 3.17) were significant in saying "yes" to a vaccine. High income groups were least resistant (OR=0.96) as compared to other groups.

HPS USA dataData used in this study was collected from United States Census Bureaus Household Pulse Survey (HPS) Phase 3.2 Weeks 34-39, which covers data collected from July 21, 2021, to October 11, 2021. The HPS data helped to understand the effect of several demographic and psychological, and health-related factors upon which responses were provided, thus helping to understand the social and economic effects during the COVID-19 pandemic.

ConclusionAmong the three countries, it appears based on this survey that US has the highest rate of vaccine hesitancy. may contribute towards this result gender, education, religious beliefs, disbelief in science, government which remains unexplored due to data limitation.


title: Comprehensive analyses reveal the impacts of vaccination status and physiological variables in early infection on viral persistence in COVID-19 patients: a retrospective single-center cohort study

abstract:
BACKGROUNDViral persistence is a crucial factor that influences the communicability of SARS-CoV-2 infection. However, the impacts of vaccination status and physiological variables on viral RNA shedding have not been adequately clarified.

METHODSIn this study, we retrospectively collected the clinical records of 377 hospitalized COVID-19 patients, which contained unvaccinated patients and patients received two doses of an inactivated vaccine or an mRNA vaccine. Firstly, we analyzed the impacts of vaccination on disease severity and viral RNA persistence. Next, to clarify the impacts of physiological variables on viral RNA shedding in COVID-19 patients, we retrieved 49 laboratory variables and analyzed their correlations with the duration of viral RNA shedding. Finally, we established a multivariate regression model to predict the duration of viral RNA shedding.

RESULTSOur results showed that both inactivated and mRNA vaccines significantly reduced the rate of moderate cases, while the vaccine related shortening of viral RNA shedding were only observed in moderate patients. Correlation analysis showed that 10 significant laboratory variables were shared by the unvaccinated mild patients and mild patients inoculated with an inactivated vaccine, but not by the mild patients inoculated with an mRNA vaccine. Moreover, we demonstrated that a multivariate regression model established based on the variables correlating with viral persistence in unvaccinated mild patients could predict the duration of viral shedding for all groups of patients.

CONCLUSIONSVaccination contributed limitedly to the clearance viral RNA in COVID-19 patients. While, laboratory variables in early infection could predict the persistence of viral RNA.


title: Previous SARS-CoV-2 infection or a third dose of vaccine elicited cross-variant neutralizing antibodies in vaccinated solid organ transplant recipients

abstract: The SARS-CoV-2 pandemic poses a great threat to global health, particularly in solid organ transplant recipients (SOTRs). Although a 3-dose mRNA vaccination protocol has been implemented for the majority of SOTRs, its effectiveness was still largely unknown. We analyzed 113 vaccinated SOTRs, and 30 healthy controls (HCs), some of whom had recovered from COVID, for their immune responses against the original vaccine strain and variants of concern (VOC), including the highly mutated-omicron variant. Here, we report that 3 doses of the mRNA vaccine had only a modest effect in eliciting anti-viral responses against all viral strains in the fully vaccinated SOTRs who did not contract the virus. Only 34.0% (16/47) of this group of patients demonstrated both detectable anti-RBD IgG and neutralization activities against alpha, beta, and delta variants, and only 8.5% (4/47) of them showed additional omicron-neutralizing capacities. In contrast, 79.5% (35/44) of the vaccinated recovered-SOTRs demonstrated both higher anti-RBD IgG levels and neutralizing activities against all VOC, including omicron. These findings illustrate a significant impact of previous infection on the development of anti-COVID immune responses in vaccinated SOTRs and highlight the need for alternative strategies to protect a subset of a lesser-vaccine responsive population.


title: Baseline profile of intrinsic cytokines predicting prognosis of chronic hepatitis B patients responding to HBV therapeutic vaccinations

abstract:
ObjectiveTo explore relevant biomarkers in chronic HBV (CHB) infected individuals, and whether their presence can be related to the prognosis of CHB (i.e., used as a prediction tool) and used as inclusion and exclusion criteria in clinical trials.

MethodsThirty-four (34) cytokines and chemokines were analyzed in the baseline plasma of 130 chronic HBV infected patients and were matched with the clinical outcomes of these patients regarding to their responses to anti-HBV treatment by a mathematic model based on the Boolean method. A retrospective analysis was implemented to establish the prediction model, and a perspective analysis was performed to verify the prediction efficacy.

ResultsThrough analyzing 34 cytokines and chemokines in the baseline plasma of 130 chronic HBV infected patients by Boolean methods, we generated a predicting model successfully capable of screening out therapy non-responded patients. In this prediction model, six cytokines, including IL-8, IL-10, IL-17, IL-1RA, IFN-, IL-18, defined as expressed or not-expressed, contributed to 21 possibilities, every of which predicts a clinical outcome. The model was verified in a separate chronic HBV infected population database, which included 76 patients, with 100% responders and 50% who are not responded to the immunotherapy identified.

ConclusionsThe prediction model can be used to screen CHB patients as the inclusion incorporated into HBV clinical design and practice. By screening out inappropriate participants in clinical trials, therapy response rate may rise and lead to a more homogeneous responding population. For Boolean method which requires continuous iteration, more accurate prediction models will be established with more homogeneous data. This is very helpful for revealing the reason why certain CHB individuals can be functionally cured and others were not. The method may also have great potential and possible applications for other immunotherapies in the future.

Significance of this studyO_ST_ABSWhat is already known about the subject?C_ST_ABSO_LIChronic hepatitis B virus (CHB) infection can be controlled while rarely cured, or functionally cured. The exact reason why certain CHB individuals can be functionally cured and others were not, regarding to different treatment strategies, remains unclear.
C_LIO_LILack of relevant immunological biomarkers are often to blame clinical failures in immunotherapeutic treatments, particularly for the hepatitis B virus (HBV) therapeutic vaccination, since such trials use virological parameters as inclusion and exclusion criteria of patients, but seldom more relevant immunological biomarkers.
C_LI

What are the new findings?O_LIUsing patterns of cytokines, instead of single cytokines, to present CHB individuals immune status can help discovering the prognosis of their responses or not response to HBV therapeutic vaccination.
C_LIO_LIBy utilizing the model, we predicted 10 patients out of 10 who were sensitive to the anti-HBV immunotherapy and 33 out of 66 who were not, in a distinct CHB population, and verified the predicting efficacy.
C_LI

How might it impact on clinical practice in the foreseeable future?O_LIImmune status, presented by different patterns of cytokines/chemokines, might be used as an in/exclusion criteria in clinical trials to select a more appropriate treatment for CHB individuals.
C_LIO_LIBy screening out inappropriate participants in clinical trials, therapy response rate may rise and lead to a more homogeneous responding population. For Boolean method which requires continuous iteration, more accurate prediction models will be established with such more homogeneous data. This is very helpful for revealing the reason why certain CHB individuals can be responsive to the treatments and toward the functionally cured and others could not.
C_LI


title: Comprehensive validation of fasting- and oral glucose tolerance test-based indices of insulin secretion against gold-standard measures

abstract:
Background and aimsWith prediabetes and diabetes increasingly recognized as heterogenous conditions, assessment of beta-cell function is gaining clinical importance to identify disease subphenotypes. Our study aims to comprehensively validate all types of surrogate indices based on OGTT- and fasting-measurements in comparison with gold standard methods.

Materials and methodsThe hyperglycaemic clamp extended with GLP-1 infusion and IVGTT, as well as OGTT, was performed in two well-phenotyped cohorts. The gold-standard-derived indices were compared with surrogate insulin secretion markers, derived from fasting state and OGTT, using both Pearsons and Spearmans correlation coefficients. The insulin- and C-peptide-based indices were analysed separately in different groups of glucose tolerance and the entire cohorts.

ResultsThe highest correlation coefficients were found for AUC (I0-30)/AUC (G0-30), first-phase Stumvoll and Kadowaki model. These indices have high correlation coefficients with measures obtained from both insulin and C-peptide levels from IVGTT and hyperglycaemic clamp. AUC (I0-30)/AUC (G0-30), first-phase Stumvoll, AUC (I0-120)/AUC (G0-120) and BIGTT-AIR0-60-120 demonstrated the strongest association with incretin-stimulated insulin response.

ConclusionWe have identified glucose- and GLP-1-stimulated insulin secretion indices, derived from OGTT and fasting state, that have the strongest correlation with gold-standard measures and could be potentially used in future researches and clinical practice.

category: endocrinology


title: High-resolution characterization of recent tuberculosis transmission in Botswana using geospatial and genomic data - the Kopanyo Study

abstract:
IntroductionCombining genomic and geospatial data can be useful for understanding Mycobacterium tuberculosis (Mtb) transmission in high tuberculosis burden settings.

MethodsWe performed whole genome sequencing (WGS) on Mtb DNA extracted from sputum cultures from a population-based tuberculosis study conducted in 2012-2016 in Gaborone, Botswana. We used kernel density estimation, spatial K-functions, and created spatial distributions of phylogenetic trees. WGS-based clusters of isolates [≤]5 single nucleotide polymorphisms were considered recent transmission, and large WGS-based clusters ([≥]10 members) were considered outbreaks.

ResultsWe analyzed data from 1449 participants with culture-confirmed TB. Among these, 946 (65%) participants had both molecular and geospatial data. A total of 62 belonged to five large outbreaks (10-19 participants each). Geospatial clustering was detected in two of the five large outbreaks, suggesting heterogeneous spatial patterns within the community.

ConclusionsIntegration of genomic and geospatial data identified distinct patterns of tuberculosis transmission in a high-tuberculosis burden setting. Targeted interventions in these smaller geographies may interrupt on-going transmission.


title: Multi-faceted analysis of COVID-19 epidemic in the Republic of Korea considering Omicron variant: Mathematical modeling-based study

abstract:
BackgroundThe most recent variant of concern, Omicron (B.1.1.529), has caused numerous cases worldwide including the Republic of Korea due to its fast transmission and reduced vaccine effectiveness.

MethodsA mathematical model considering age-structure, vaccine, antiviral treatment, and influx of the Omicron variant was developed. We estimated transmission rates among age groups using maximum likelihood estimation for the age-structured model. The impact of nonpharmaceutical interventions (in community and border), quantified by a parameter in the force of infection, and vaccination were examined through a multi-faceted analysis. A theory-based endemic equilibrium study was performed to find the manageable number of cases according to Omicron-and healthcare-related factors.

ResultsBy fitting the model to the available data, the estimated values of  ranged from 0.31 to 0.73, representing the intensity of nonpharmaceutical interventions such as social distancing level. If  < 0.55 and 300,000 booster shots were administered daily from February 3, 2022, the number of severe cases was forecasted to exceed the severe bed capacity. Moreover, the number of daily cases is reduced as the timing of screening measures is delayed. If screening measure was intensified as early as November 24, 2021 and the number of overseas entrant cases was contained to 1 case per 10 days, simulations showed that the daily incidence by February 3, 2022 could have been reduced by 87%. Furthermore, we found that the incidence number in mid-December 2021 exceeded the theory-driven manageable number of daily cases.

ConclusionNonpharmaceutical interventions, vaccination, and antiviral therapy influence the spread of Omicron and number of severe cases in the Republic of Korea. Intensive and early screening measures during the emergence of a new variant is key in controlling the epidemic size. Using the endemic equilibrium of the model, a formula for the manageable daily cases depending on the severity rate and average length of hospital stay was derived so that the number of severe cases does not surpass the severe bed capacity.


title: Causal effects of maternal circulating amino acids on offspring birthweight: a Mendelian randomisation study

abstract: Amino acids are key to protein synthesis, energy metabolism, cell signaling and gene expression; however, the contribution of specific maternal amino acids to fetal growth is unclear. We explored the effect of maternal circulating amino acids on fetal growth, proxied by birthweight, using two-sample Mendelian randomization and summary data from a genome-wide association study (GWAS) of serum amino acids levels (sample 1, n = 86,507) and a maternal GWAS of offspring birthweight, adjusting for fetal genotype effects (sample 2, n = 406,063 with maternal and/or fetal genotype effect estimates). A total of 106 independent single nucleotide polymorphisms (SNPs) robustly associated with 19 amino acids (p < 4.9 x 10-10) were used as genetic instrumental variables. Our results provide evidence that maternal circulating glutamine (59 g offspring birthweight increase per SD increase in maternal amino acid level, 95% CI: 7, 110) and serine (27 g, 95% CI: 9, 46) raise, while leucine (-59 g, 95% CI: -106, -11) and phenylalanine (-25 g, 95% CI: -47, -4) lower offspring birthweight. Our findings strengthen evidence for key roles of maternal circulating amino acids in healthy fetal growth.


title: A comparative analysis of pediatric mental health-related emergency department utilization in Montreal, Canada before and during the COVID-19 pandemic

abstract:
BackgroundReports on longitudinal trends in mental health-related (MHR) emergency department (ED) utilization spanning the pre- and post-pandemic periods are lacking, along with evidence comparing healthcare services utilization by sociodemographic subgroups. The aim of this study was to evaluate COVID-19-associated changes in MHR ED utilization among youth overall and by age, sex, and socioeconomic status (SES).

MethodsThis retrospective cross-sectional study analyzed MHR ED utilization before and during the COVID-19 pandemic at a large urban pediatric tertiary care hospital in Montreal, Canada. All ED visits for children (5-11 years) and adolescents (12-17 years) between April 1, 2016 and November 30, 2021 were included. The main outcome was the monthly count of MHR ED visits. Pre-pandemic and pandemic periods were compared using an interrupted time series design. The effect of seasonality (in months), age (in years), sex (male or female), and SES (low, average, high) were compared using a generalized additive model.

ResultsThere were a total of 437,147 ED visits (204,215 unique patients) during the five-year study period of which 9,748 (5.8%) were MHR visits (7,686 unique patients). We observed an increase of 69% (95% CI, +53% to +85%; p = .001) in the mean monthly count of MHR ED visits during the pandemic period, which remained significant after adjusting for seasonality (44% increase, 95% CI, +38% to +51%; p = .001). The chance of presenting for a MHR ED visit increased non-linearly with age. There were increased odds of presenting for a MHR ED visit among girls between the pre-pandemic and pandemic periods (OR 1.42, 95% CI 1.29-1.56). No difference by SES group during and before the COVID-19 pandemic was found (OR 1.01, 95% CI 0.89-1.15 [low]; OR 1.09, 95% CI 0.96-1.25 [high]).

ConclusionsOur study shows important increases in MHR ED utilization among youth, and especially among girls, during the first 20 months of the COVID-19 pandemic, highlighting the need for sustained, targeted and scalable mental health resources to support youth mental health during the current and future crises.


title: Effectiveness of Four Vaccines in Preventing SARS-CoV-2 Infection in Kazakhstan

abstract:
BACKGROUNDIn February 2021 Kazakhstan began offering COVID-19 vaccines to adults. Breakthrough SARS-CoV-2 infections raised concerns about real-world vaccine effectiveness. We aimed to evaluate effectiveness of four vaccines against SARS-CoV-2 infection.

METHODSWe conducted a retrospective cohort analysis among adults in Almaty using aggregated vaccination data and individual-level breakthrough COVID-19 cases ([≥]14 days from 2nd dose) using national surveillance data. We ran time-adjusted Cox-proportional-hazards model with sensitivity analysis accounting for varying entry into vaccinated cohort to assess vaccine effectiveness for each vaccine (measured as 1-adjusted hazard ratios) using the unvaccinated population as reference (N=565,390). We separately calculated daily cumulative hazards for COVID-19 breakthrough among vaccinated persons by age and vaccine month.

RESULTSFrom February 22 to Sept 1, 2021 in Almaty, 747,558 (57%) adults were fully vaccinated (received 2 doses) and 108,324 COVID-19 cases (11,472 breakthrough) were registered. Vaccine effectiveness against infection was 78% (sensitivity estimates: 74-82%) for QazVac, 77% (72- 81%) for Sputnik V, 71% (69-72%) for Hayat-Vax, and 69% (64-72%) for CoronaVac. Among vaccinated persons, the 90-day follow-up cumulative hazard for breakthrough infection was 2.2%. Cumulative hazard was 2.9% among people aged [≥]60 years versus 1.9% among persons aged 18-39 years (p<0.001), and 1.2% for people vaccinated in February-May versus 3.3% in June-August (p<0.001).

CONCLUSIONOur analysis demonstrates high effectiveness of COVID-19 vaccines against infection in Almaty similar to other observational studies. Higher cumulative hazard of breakthrough among people >60 years of age and during variant surges warrants targeted booster vaccination campaigns.

What is already known on this topicO_LIPlenty of data are published on effectiveness of mRNA vaccines; however, these vaccines were not widely available in many low- and middle-income countries in 2021.
C_LIO_LIThere are no real-world effectiveness studies on several vaccines available in the Central Asia region, including QazVac vaccine, an inactivated vaccine developed by Kazakhstan.
C_LIO_LIUnderstanding how these vaccines are performing outside of clinical trials is critical for the COVID-19 response and lack of published data can contribute to vaccine hesitancy.
C_LI

What this study addsO_LIOur study demonstrated that at the population-level the four vaccines against COVID-19 used in Kazakhstan were effective at preventing SARS-CoV-2 infection.
C_LIO_LIVaccination reduced the risk of infection by 76% and prevented over 100,000 cases of SARS-CoV-2 infection in Almaty, the countrys most populous city.
C_LIO_LIThis is also the first study that demonstrated high vaccine effectiveness in real-world conditions of QazVac, developed in Kazakhstan.
C_LI

How this study might affect research, practice or policyO_LIPolicy makers in Kazakhstan and the Central Asia region need data on vaccines provided in the region to update evidence-based vaccine guidelines for different populations.
C_LI


title: How did the COVID-19 Pandemic impact self-reported cancer screening rates in 12 Midwestern states?

abstract:
ObjectiveIn the early months of the COVID-19 pandemic, the U.S. healthcare system reallocated resources to emergency response and mitigation. This reallocation impacted essential healthcare services, including cancer screenings.

MethodsTo examine how the pandemic impacted cancer screenings at the population-level, this study analyzes 2018 and 2020 Behavioral Risk Factor Surveillance System (BRFSS) data to estimate the change in the proportion of eligible adults reporting a recent cancer screen (mammogram, pap smear, colon/sigmoidoscopy, blood stool test). All analyses accounted for response rates and sampling weights, and explored differences by gender and region across 12 Midwestern states.

ResultsWe found that the proportion of adult women completing a mammogram declined across all states (-0.9% to -18.1%). The change in colon/sigmoidoscopies, pap smears, and blood stool tests were mixed, ranging from a 9.7% decline in pap smears to a 7.1% increase in blood stool tests. Declines varied considerably between states and within states by gender or metro/urban/rural status.

ConclusionsThe COVID-19 pandemic led to delayed breast, cervical, and colorectal cancer detection services. Policymakers should aim to advance cancer control efforts by implementing targeted screening initiatives.


title: Genome-wide association analysis and Mendelian randomization proteomics identify novel protein biomarkers and drug targets for primary prevention of heart failure

abstract: We conducted a large-scale meta-analysis of heart failure (HF) genome-wide association studies (GWAS) consisting of over 90,000 HF cases and more than 1 million control individuals of European ancestry to uncover novel genetic determinants for HF. Using the GWAS results and blood protein quantitative loci (pQTLs), we performed Mendelian randomization (MR) and colocalization analyses on human proteins to provide causal evidence for the role of druggable proteins in the genesis of HF. We identified 39 genome-wide significant HF risk variants, of which 18 are previously unreported. Using a combination of MR proteomics and genetic cis-only colocalization analyses, we identified 10 additional putatively causal genes for HF. Findings from GWAS and MR-proteomics identified seven (CAMK2D, PRKD1, PRKD3, MAPK3, TNFSF12, APOC3 and NAE1) proteins as potential targets for interventions to be used in primary prevention of HF.

category: genetic and genomic medicine


title: A boost with SARS-CoV-2 BNT162b2 mRNA vaccine elicits strong humoral responses independently of the interval between the first two doses

abstract: Due to the recrudescence of SARS-CoV-2 infections worldwide, mainly caused by Omicron BA.1 and BA.2 variants of concern, several jurisdictions are administering a mRNA vaccine boost. Here, we analyzed humoral responses induced after the second and third doses of mRNA vaccine in naive and previously-infected donors who received their second dose with an extended 16-week interval. We observed that the extended interval elicited robust humoral responses against VOCs, but this response was significantly diminished 4 months after the second dose. Administering a boost to these individuals brought back the humoral responses to the same levels obtained after the extended second dose. Interestingly, we observed that administering a boost to individuals that initially received a short 3-4 weeks regimen elicited humoral responses similar to those elicited in the long interval regimen. Nevertheless, humoral responses elicited by the boost in naive individuals did not reach those present in previously-infected vaccinated individuals.


title: Effectiveness and waning of protection with different SARS-CoV-2 primary and booster vaccines during the Delta pandemic wave in 2021 in Hungary (HUN-VE 3 study)

abstract:
BackgroundIn late 2021, the pandemic wave was dominated by the Delta SARS-CoV-2 variant in Hungary. Booster vaccines were offered starting from August 2021.

MethodsThe nationwide HUN-VE 3 study examined the effectiveness and durability of primary immunization and single booster vaccinations on SARS-CoV-2-related infection, hospitalization and mortality during the Delta wave.

ResultsThe study population included 8,087,988 individuals aged 18-100 years at the beginning of the pandemic. During the Delta wave, after adjusting for age, sex, calendar day, and chronic diseases, vaccine effectiveness (VE) of primary vaccination against registered SARS-CoV-2 infection was between 11% to 77% and 18% to 79% 14-120 days after primary immunization in the 16-64 and 65-100 years age cohort respectively, while it decreased to close to zero in the younger age group and around 40% or somewhat less in the elderly after 6 months for almost all vaccine types. In the population aged 65-100 years, we found high, 88.1%-92.5% adjusted effectiveness against Covid-19 infection after the Pfizer-BioNTech, and 92.2%-95.6% after the Moderna booster dose, while Sinopharm and Janssen booster doses provided 26.5%-75.3% and 72.9%-100.0% adjusted VE, respectively. Adjusted VE against Covid-19 related hospitalization was high within 14-120 days for Pfizer-BioNTech: 76.6%, Moderna: 83.8%, Sputnik-V: 78.3%, AstraZeneca: 73.8%, while modest for Sinopharm: 45.7% and Janssen: 26.4%. The waning of protection against Covid-19 related hospitalization was modest and booster vaccination with mRNA vaccines or the Janssen vaccine increased adjusted VE up to almost 100%, while the Sinopharm booster dose proved to be less effective. VE against Covid-19 related death after primary immunization was high or moderate: for Pfizer-BioNTech: 81.5%, Moderna: 93.2%, Sputnik-V: 100.0%, AstraZeneca: 84.8%, Sinopharm: 58.6%, Janssen: 53.3%). VE against this outcome also showed moderate decline over time, while booster vaccines restored effectiveness up to almost 100%, except for the Sinopharm booster.

ConclusionsThe HUN-VE 3 study demonstrated waning VE with all vaccine types for all examined outcomes during the Delta wave and confirmed the outstanding benefit of booster vaccination with the mRNA or Janssen vaccines. This is the first study to provide comparable effectiveness results for six different booster types during the Delta pandemic wave.


title: SARS-CoV-2 evolution and immune escape in immunocompromised patients treated with exogenous antibodies

abstract:
BackgroundSARS-CoV-2 mutations conferring escape from neutralizing antibodies can arise in immunocompromised patients with prolonged infection, but the conditions that facilitate immune escape are still not fully understood.

MethodsWe characterized endogenous immune responses, within-host SARS-CoV-2 evolution, and autologous neutralization of the viral variants that arose in five immunocompromised patients with prolonged infection and B cell deficiencies.

ResultsIn two patients treated with the monoclonal antibody bamlanivimab, viral resistance to autologous serum arose early and persisted for several months, accompanied by ongoing evolution in the spike protein. These patients exhibited deficiencies in both T and B cell arms, and one patient succumbed to disease. In contrast, we did not observe spike mutations in immunologically important regions in patients who did not receive exogenous antibodies or who received convalescent plasma and had intact T cell responses to SARS-CoV-2.

ConclusionsOur results underscore the potential importance of multiple factors - the absence of an effective endogenous immune response, persistent virus replication, and selective pressure such as single-agent bamlanivimab - in promoting the emergence of SARS-CoV-2 mutations associated with immune evasion. These findings highlight the need for larger clinical studies in immunocompromised populations to better understand the ramifications of different therapies. Our results also confirm that patients with B cell deficiencies can elicit effector T cells and may suggest an important role for T cells in controlling infection, which is relevant to vaccines and therapeutics.

category: intensive care and critical care medicine


title: Global reports of takotsubo (stress) cardiomyopathy following COVID-19 vaccination: First systematic review and meta-analysis

abstract:
Background and aimsConcerns have been raised recently about takotsubo cardiomyopathy after receiving COVID-19 vaccines, particularly the messenger RNA (mRNA) vaccines. The goal of this study was to compile case reports in order to provide a comprehensive overview of takotsubo cardiomyopathy associated with COVID-19 vaccines.

MethodsFrom inception until March 10, 2022, a systematic literature search was conducted in PubMed and Google Scholar. The study included individuals who developed cardiac takotsubo cardiomyopathy as a result of receiving COVID-19 vaccinations, regardless of the type of vaccine or dose.

ResultsEight studies, including 8 cases, participated in the current systematic review. The median age was 61.6 years; 87.5% were female, while 12.5% were male. 75% of the patients received the mRNA COVID-19 vaccines, while 25% received other types. In addition, takotsubo cardiomyopathy occurred in 62.5% of patients after receiving the first dose and another 25% after the second dose of COVID-19 vaccines. Moreover, the mean number of days to the onset of symptoms was 2.62 days. All cases had an elevated troponin test and abnormal ECG findings. The left ventricular ejection fraction (LVEF) was above 50% among all cases. In terms of the average length of stay in the hospital, 62.5% stayed for 10.2 days, and all cases recovered from their symptoms.

ConclusionTakotsubo (stress) cardiomyopathy complications that are associated with COVID-19 vaccination are rare, they can be life-threatening. Chest pain should be considered an alarming symptom, especially in those who had received a second dose of the vaccine in the last 3 days. For diagnosis, CK-MB and troponin are better biomarkers to confirm myocarditis than CRP, ESR, and NT-proBNP. All of cases completely recovered.

category: cardiovascular medicine


title: Global reports of takotsubo (stress) cardiomyopathy following COVID-19 vaccination: a systematic review and meta-analysis


title: Estimating the risk of hospitalisation and death in England's remaining unvaccinated population

abstract: The roll-out of COVID-19 vaccines in the England has generally been very good - with over 80% of over 12s having received two doses of vaccine by the start of February 2022, and 67% having received a further booster dose. Despite this, there is a small section of the population who remain unvaccinated, either due to lack of access, hesitancy or resistant to vaccination. In this report we estimate that, during 2021, there were approximately 3,500 deaths in unvaccinated people, who could otherwise have reasonably been expected to receive a vaccination. Further, we show that if all of the remaining unvaccinated population in England were to become infected (or reinfected) with the Omicron variant of COVID-19, we would expect to see approximately 11,700 further deaths and 29,600 hospitalisations. These number could fall to 5,300 and 19,600 respectively, if all but the most vaccine resistant individuals become fully vaccinated.


title: Methadone overdoses increased 48% during the COVID-19 epidemic

abstract:
BackgroundThe United States (US) is in the middle of an opioid overdose epidemic that has spanned over two decades and continues to escalate. Methadone is long-acting full opioid agonist which has been approved to treat opioid use disorder (OUD). Methadone can cause respiratory depression that may result in mortality. The restrictions on methadone availability including take-home dosing were loosened during the COVID-19 pandemic although there have been concerns about the high street value of diverted methadone. This report examined how fatal overdoses involving methadone have changed over the past two-decades including during the pandemic.

MethodsThe Center for Disease Control and Preventions Wide-ranging Online Data for Epidemiologic Research (WONDER) database, which draws data from death certificates, was used to find the unintentional methadone related overdose death rate from 1999-2020. Unintentional methadone deaths were defined using the International Statistical Classification of Diseases (ICD), 10th revision codes: X40-44 with only data which was coded for methadone (T40.3). Data from the Automation of Reports and Consolidated Orders System (ARCOS) on methadone overall use, narcotic treatment programs use, and pain management use was gathered for all states, including the District of Columbia, for 2020 and corrected for population.

ResultsThere have been dynamic changes over the past two-decades in overdoses involving methadone. Overdoses increased from 1999 (0.9/million) to 2007 (15.9) and declined until 2019 (6.5). Overdoses in 2020 (9.6) were 48.1% higher than in 2019 (t(50) = 3.05, p < .005).

The correlations between overall methadone use (r(49) = +0.75, p < 0.001), and narcotic treatment program use (r(49) = +0.77, p < 0.001) were positive, strong, and statistically significant. However, methadone use for pain treatment was not associated with overdoses (r(49) = -.08, p = .57).

ConclusionsOverdoses involving methadone significantly increased by 48.1% in 2020 relative to 2019. This mortality increase is much larger than the 5.3% elevation in calls involving methadone reported to poison control centers in the year following the March 16, 2020 loosening of methadone take-home regulations. Policy changes that were implemented following the COVID-19 pandemic involving methadone may warrant reconsideration.

category: toxicology


title: Coding Long COVID: Characterizing a new disease through an ICD-10 lens

abstract:
Naming a newly discovered disease is always challenging; in the context of the COVID-19 pandemic and the existence of post-acute sequelae of SARS-CoV-2 infection (PASC), which includes Long COVID, it has proven especially challenging. Disease definitions and assignment of a diagnosis code are often asynchronous and iterative. The clinical definition and our understanding of the underlying mechanisms of Long COVID are still in flux. The deployment of an ICD-10-CM code for Long COVID in the US took nearly two years after patients had begun to describe their condition. Here we leverage the largest publicly available HIPAA-limited dataset about patients with COVID-19 in the US to examine the heterogeneity of adoption and use of U09.9, the ICD-10-CM code for "Post COVID-19 condition, unspecified."

Our results include a characterization of common diagnostics, treatment-oriented procedures, and medications associated with U09.9-coded patients, which give us insight into current practice patterns around Long COVID. We also established the diagnoses most commonly co-occurring with U09.9, and algorithmically clustered them into three major categories: cardiopulmonary, neurological, and metabolic. We aim to apply the patterns gleaned from this analysis to flag probable Long COVID cases occurring prior to the existence of U09.9, thus establishing a mechanism to ensure patients with earlier cases of Long-COVID are no less ascertainable for current and future research and treatment opportunities.


title: The gut microbiome and early-life growth in a population with high prevalence of stunting

abstract:
Stunting affects one-in-five children globally and is associated with greater infectious morbidity, mortality and neurodevelopmental deficits. Recent evidence suggests that the early-life gut microbiome affects child growth through immune, metabolic and endocrine pathways, and microbiome perturbations may contribute to undernutrition. We examined early-life fecal microbiome composition and function in 875 stool samples collected longitudinally in 335 children from 1-18 months of age in rural Zimbabwe, from a cluster-randomized trial of improved water, sanitation, and hygiene (WASH), and improved infant and young child feeding (IYCF). Using whole metagenome shotgun sequencing, we examined the effect of the interventions, in addition to environmental or host factors including maternal HIV infection, on the succession of the early-life gut microbiome, and employed extreme gradient boosting machines (XGBoost) to model microbiome maturation and to predict child growth. WASH and IYCF interventions had little impact on the fecal microbiome, however children who were HIV-exposed but uninfected exhibited over-diversification and over-maturity of the early-life gut microbiome in addition to reduced abundance of Bifidobacteria species. Taxonomic microbiome features were poorly predictive of linear and ponderal growth, however functional metagenomic features, particularly B-vitamin and nucleotide biosynthesis pathways, moderately predicted both attained linear and ponderal growth and growth velocity. We find that the succession of the gut microbiome in a population at risk of stunting is unresponsive to WASH and IYCF interventions, but is strongly associated with maternal HIV infection, which may contribute to deficits in growth. New approaches targeting the gut microbiome in early childhood may complement efforts to combat child undernutrition.

One sentence summaryThe gut microbiome of rural Zimbabwean infants undergoes programmed maturation that is unresponsive to sanitation and nutrition interventions but is comprehensively modified by maternal HIV infection and can moderately predict linear growth.

category: nutrition


title: Impact of OSA Treatment Success on Changes in Hypertension and Obesity: A Retrospective Cohort Study

abstract:
ObjectivePediatric obstructive sleep apnea (OSA) has been shown to lead to the development of chronic cardiometabolic conditions, including obesity and cardiovascular disease. We sought to describe the impact of the success of continuous positive airway pressure (CPAP) and surgery, common treatment options for pediatric OSA, on cardiometabolic conditions.

MethodsA retrospective review of patients ([≤]18 years) diagnosed with OSA based on a polysomnogram at a tertiary care pediatric otolaryngology practice from 2015 to 2019 was conducted. Clinical data, including the systolic blood pressure (SBP) values, body mass index (BMI), overall apnea/hypopnea index (AHI) values, and CPAP compliance, were collected. Linear mixed-effects models were developed to observe the relationship between the clinical measurements of each comorbidity and OSA treatment modalities.

Results507 patients were included. BMI and SBP measures were collected for 230 and 277 patients respectively. The difference-in-difference estimate for the SBP z-score percentile after successful treatment was -5.3 {+/-} 2.0 percentile units per 100 days. The difference-in-difference estimate for SBP z-score percentile after successful CPAP treatment was -14.4 {+/-} 4.9 percentile units per 100 days while the estimate after successful surgical treatment was -4.6 {+/-} 2.3 percentile units per 100 days. No significant differences were found between clinical measures for obese patients in any treatment cohort.

ConclusionsThe success of OSA management was shown to have a positive impact on SBP in hypertensive patients and no impact on BMI in obese patients. In hypertensive patients, CPAP success tripled improvements in SBP z-score percentile compared to surgical treatment success.

category: otolaryngology


title: Examining the experiences of Indigenous families seeking health information for their sick or injured child: a scoping review protocol

abstract:
IntroductionThe Truth and Reconciliation Commission drew attention to the inequalities and systemic harms experienced by Indigenous peoples in Canada and called on the Canadian government and healthcare professionals to close the gap related to Indigenous communities access to appropriate healthcare services. The Manitoba Metis Federation (self-governing organization representing Red River Metis) identified a need for Red River Metis families to have meaningful resources when seeking emergency care for their children. A better understanding of Metis families experiences in seeking child health information is needed to develop culturally relevant pediatric resources. To date, the literature on Indigenous families experiences seeking child health information has not been synthesized. A scoping review will map the literature on Indigenous families experiences seeking health information to care for a sick or injured child; and identify the barriers and facilitators to accessing this information.

Methods and analysisJoanna Briggs Institute methodology was used to develop the research question, What is the extent and nature of the literature available on the experiences of Indigenous families seeking health information for their sick or injured child? The search strategy, developed with a research librarian with extensive experience in Indigenous Peoples health, includes searching MEDLINE, EMBASE PsycINFO, CINAHL, and Scopus databases; grey literature, by searching the internet and consulting reference lists of key publications; examining key Indigenous research journal articles not indexed in the major biomedical databases; and snowball sampling. Two independent reviewers will screen titles and abstracts against the inclusion criteria, then screen the full texts of selected citations. Data will be extracted, collated and charted to summarize the types of studies, healthcare contexts, health information accessed, how health information was accessed, barriers and facilitators to accessing information and related measures.

Ethics and DisseminationA consultation exercise with a community advisory committee will review results and inform future research. Results will be integrated with findings from other project stages to inform the adaptation of a child health resource for Red River Metis families.

category: pediatrics


title: A retrospective cross-sectional analysis of community perceptions of flu and COVID-19 vaccines at Turtle Creek Primary Care Center

abstract:
BackgroundInfluenza (flu) and COVID-19 vaccination rates are subpar across the US, especially in racial and/or socioeconomic minority groups who are understudied in public health literature.

ObjectiveThe objective of this study was to elucidate the attitudes of Turtle Creek patients towards flu and COVID-19 vaccines, with the goal of establishing targetable vaccine education gaps and ultimately increasing vaccine uptake in the community.

Design/PatientsThis study was conducted as a retrospective cross-sectional analysis. Authors completed 123 patient phone surveys of patients cared for at the Turtle Creek Primary Care Center inquiring about flu and COVID-19 infection status and vaccination uptake (August 26 - October 10, 2021).

Approach/Key ResultsOur data revealed a significant association between COVID-19 and flu vaccine acceptance. Additionally, we found a strong association between vaccine acceptance and age, with older patients being more likely to be vaccinated against COVID-19. Using multivariable logistic regression models, we assessed how flu and COVID-19 vaccine acceptance was affected by informational sources participants trusted most. In the COVID-19 models, those who cited "trusting medical professionals" had higher odds of vaccine acceptance while participants who cited "trusting social media" had significantly decreased odds of vaccine acceptance.

ConclusionOur study revealed significant trends for flu and COVID-19 vaccine acceptance by sociodemographic factors and trust in the medical system. Using these data, we can create future interventions to overcome vaccine hesitancy.

category: public and global health


title: Predictors of COVID-19 vaccine uptake: An online longitudinal study of US Veterans and non-Veterans

abstract:
BackgroundTo effectively promote vaccine uptake, it is important to understand which people are most and least inclined to be vaccinated and why.

PurposeTo identify predictors of COVID-19 vaccine uptake and reasons for non-vaccination.

DesignA longitudinal English-language survey study.

SettingOnline in December-2020, January-2021, and March-2021. Participants. 930 US respondents (63% Veterans).

MeasurementsSurveys included questions about respondents behaviors, well-being, healthcare experiences, and attitudes regarding the pandemic.

ResultsThe proportion of respondents who received [≥]1-dose of a COVID-19 vaccine increased from 18% in January to 67% in March. Older age predicted vaccine uptake in January (OR=2.02[95%CI=1.14-3.78], p<.001) and March (10.92[6.76-18.05], p<.001). In January, additional predictors of vaccine uptake were higher numeracy (1.48[1.20-1.86], p<.001), COVID-19 risk perceptions (1.35[1.03-1.78], p=.029), and believing it is important that adults get the COVID-19 vaccine (1.66[1.05-2.66], p=.033). In March, additional predictors of vaccine uptake were believing it is important that adults get the COVID-19 vaccine (1.63[1.15- 2.34], p=.006), previous (January) COVID-19 vaccine intentions (1.37[1.10-1.72], p=.006), and belief in science (0.84[0.72-0.99], p=.041). Concerns about side effects and the vaccine development process were the most common reasons for non-vaccination. Unvaccinated respondents with no interest in getting a COVID-19 vaccine were younger (0.27[0.09-0.77], p=.016), held negative views about COVID-19 vaccines for adults (0.15[0.08-0.26], p<.001), had lower trust in healthcare (0.59[0.36-0.95], p=.032), and preferred to watch and wait in clinically ambiguous medical situations (0.66[0.48-0.89], p=.007).

LimitationsReliance on the accuracy and consistency of self-reported data.

ConclusionThese findings offer important insights regarding key predictors of vaccine uptake during the early stages of the COVID-19 vaccine rollout in the US, which can help guide health communications and public outreach. Evidence that attitudes and intentions towards COVID-19 vaccines are important predictors of uptake provides validation for studies which have used these measures and reinforces the need to develop effective strategies for addressing concerns about vaccine safety and development which continue to be at the forefront of vaccine hesitancy.

RegistrationThe pre-registration document associated with this manuscript is available at: https://aspredicted.org/MKS_HRZ.


title: On the hip abduction moment required to balance on one leg: an experimental study

abstract: 1.Although the time a patient can stand on one leg is a common clinical test of balance in those prone to fall, a surprising knowledge gap is how much hip abduction muscle strength is required. This is important because hip abduction strength has been shown to be important for compensating for impairments in diabetic neuropathy, for example. As a start we tested the hypothesis that maximum hip abduction muscle endurance time at 50% effort would be longer than the time that 18 young and 17 older healthy adults can stand on one leg. First, maximum hip abduction endurance time at 50% effort as well as maximum abduction strength were measured in the gravity-free plane. Then subjects were asked to balance on their left foot for as long as they could while body segment kinematics and ground reaction data were measured. The results showed that the mean intensity of the hip abduction moment required to stand on one leg exceeded 50% of the maximum hip abduction strength for all four groups (young women and men 53% and 55%, and older women and men 94% and 72% respectively). However, unipedal stance times were not limited by hip abduction 50% effort endurance time (p = 0.9). Therefore a significant portion of the hip abduction moment required to stand on one leg must be carried by passive tissues. The underlying mechanism remains to be explained.

category: rehabilitation medicine and physical therapy


title: System Integrated Digital Empowerment and Rehabilitation to promote patient Activation and well-Being (SIDERA^B): Protocol for a Randomized Crossover Trial on Effectiveness and Implementation.

abstract:
CONTEXTthe current increasing demand for rehabilitation among people with Non-Communicable Diseases (NCDs) requires the identification of home-based digital solutions alternative to conventional in-clinic interventions.

OBJECTIVEthis protocol proposes to test the effectiveness of an individualized telerehabilitation platform (SIDERA^B), with respect to the traditional face-to-face rehabilitation, in ensuring the continuity of care in patients with NCDs.

DESIGN, SETTING, AND SUBJECTSthis randomized, single-blind, controlled two-period crossover trial will involve about 150 outpatients with NCDs (N=40 with Chronic Heart Failure - CHF, N=60 with Chronic Obstructive Pulmonary Disease - COPD, and N=50 with Parkinsons Disease - PD) from the rehabilitation units of IRCCS Fondazione Don Carlo Gnocchi of Milan. Each participant will experience, consequently, two different types of interventions: rehabilitation with the SIDERA^B system (SIDERA^B - S), which allow for both tele-rehabilitation activities and tele-monitoring of vital parameters, and rehabilitation as usual (Usual Care - U) including a manual of rehabilitative exercises and self-monitoring of vital parameters.

INTERVENTIONSsubjects will be randomly assigned to one of the two specified sequences of interventions: U/S/U (the USU group), and S/U (the SU group). Both groups will be assessed at the baseline (T1), after the first intervention (T2), and after the second intervention (T3), with a follow-up evaluation (T4) scheduled only for the USU group.

MAIN OUTCOME MEASURESa multifaceted evaluation including quality of life and clinical/functional measures will be conducted at each time-point of assessment. The primary outcome measures will be 1) change in activation of patients measured by the Patient Activation Measure scale, and 2) change in subjects level of activity and participation measured by the WHO Disability Assessment Schedule 2.0.

CONCLUSIONSIDERA^B could represent a promising innovative digital solution able to support the ongoing migration of rehabilitation care from the clinic to the patients home, for the optimal long-term management of NCDs.

Trial registrationThe SIDERA^B trial was registered in the clinicaltrials.gov database (identifier NCT04041193) on August 1, 2019.


title: Plasma biomarkers for diagnosis of Alzheimer's disease and prediction of cognitive decline in individuals with mild cognitive impairment

abstract:
BackgroundThe last few years have seen major advances in blood biomarkers for Alzheimers Disease (AD) with the development of ultrasensitive immunoassays, promising to transform how we diagnose, prognose, and track progression of neurodegenerative dementias.

MethodsWe evaluated a panel of four novel ultrasensitive electrochemiluminescence (ECL) immunoassays against presumed CNS derived proteins of interest in AD in plasma [phosphorylated-Tau181 (pTau181), total Tau (tTau), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP)]. 366 plasma samples from the Massachusetts Alzheimers Disease Research Centers longitudinal cohort study were examined to differentiate definite AD, other neurodegenerative diseases (OND), and cognitively normal (CN) individuals. A subset of samples were selected to have longitudinal follow up to also determine the utility of this plasma biomarker panel in predicting 4-year risk for cognitive decline in individuals with different levels of cognitive impairment.

ResultspTau181, tTau and GFAP were higher in AD compared to CN and OND, while NfL was elevated in AD and further increased in OND. pTau181 performed the best (AD vs CN: AUC=0.88, 2-fold increase; AD vs OND: AUC=0.78, 1.5-fold increase) but tTau also showed excellent discrimination (AD vs CN: AUC=0.79, 1.5-fold increase; AD vs OND: AUC=0.72, 1.3-fold increase). Participants with MCI who progressed to AD dementia had higher baseline plasma concentrations of pTau181, NfL, and GFAP compared to non-progressors with the best discrimination for pTau181 (AUC=0.82, 1.7-fold increase) and GFAP (AUC=0.81, 1.6-fold increase).

ConclusionsThese new ultrasensitive ECL plasma assays for pTau181, tTau, NfL, and GFAP detect CNS disease with high specificity and accuracy. Moreover, the absolute baseline plasma levels of pTau and GFAP reflect clinical disease aggressiveness over the next 4 years, providing diagnostic and prognostic information that may have utility in both clinical and clinical trial populations.

Classification of EvidenceThis study provides Class II evidence that plasma levels of pTau181, tTau, NfL, and GFAP are associated with AD and that pTau181 and GFAP are associated with progression from MCI to AD dementia.

category: neurology


title: Genetically proxied PCSK9 inhibition provides indication of lower prostate cancer risk: a Mendelian randomization study

abstract:
BackgroundProstate cancer (PrCa) is the second most prevalent malignancy in men worldwide. Observational studies have linked the use of low-density lipoprotein cholesterol (LDL-c) lowering therapies with reduced risk of PrCa, which may potentially be attributable to confounding factors. In this study, we performed a drug target Mendelian randomization (MR) analysis to evaluate the association of genetically proxied inhibition of LDL-c lowering drug targets on risk of PrCa.

Methods and FindingsSingle-nucleotide polymorphisms (SNPs) in and around HMGCR, NPC1L1 and PCSK9 genes associated with LDL-c (P<5x10-8) from the Global Lipids Genetics Consortium genome-wide association study (GWAS) (N=173,082) were used to proxy the therapeutic inhibition of these targets. Association estimates for the risk of total, advanced and early-onset PrCa were obtained from the PRACTICAL consortium. Replication was performed using genetic instruments from an LDL-c GWAS conducted on male UK Biobank participants of European ancestry (N=201,678), as well as instruments selected based on liver-derived gene expression and circulation plasma levels of targets. We also investigated whether putative mediators may play a role in findings for traits previously implicated in PrCa risk (i.e., lipoprotein a (Lp(a)), body mass index (BMI) and testosterone).

Applying MR using the inverse-variance weighted approach accounting for genetic correlations between instruments provided strong evidence supporting an effect of genetically proxied inhibition of PCSK9 (equivalent to a standard deviation (SD) reduction in LDL-c) on lower risk of total PrCa (odds ratio (OR)=0.84, 95% confidence interval (CI)=0.74 to 0.96, P=7.86x10-3) and early-onset PrCa OR=0.70, 95% CI=0.52 to 0.95, P=0.021. Analyses using male-stratified instruments provided consistent results. In contrast, there was little evidence of an association of genetically proxied HMGCR (OR=0.83, 95% CI=0.67 to 1.03, P=0.093) or NPC1L1 (OR=1.27, 95% CI=0.87 to 1.87, P=0.218) inhibition on PrCa risk.

Secondary analyses supported a genetically proxied effect of liver-specific PCSK9 expression (OR=0.90, 95% CI=0.86 to 0.95, P=5.50x10-5) and circulating plasma levels of PCSK9 (OR=0.93 per SD reduction in PCSK9, 95% CI=0.87 to 0.997, P=0.04) on PrCa risk. Colocalization using eCAVIAR identified evidence (colocalization posterior probability=0.103) of a shared genetic variant (rs553741) between liver-derived PCSK9 expression and PrCa risk. Moreover, genetically proxied PCSK9 inhibition was strongly associated with Lp(a) levels (Beta= -0.07, 95% CI= -0.10 to -0.03, P=1.44x10-4), but not BMI or testosterone, indicating a putative mediatory role of Lp(a).

ConclusionsOur study supports a strong association between genetically proxied inhibition of PCSK9 and a lower risk of total and early-onset PrCa. Further evidence from clinical studies is needed to confirm this finding as well as the putative mediatory role of Lp(a).

category: oncology


title: More efficient and inclusive time-to-event trials with covariate adjustment: a simulation study

abstract:
Adjustment for prognostic covariates increases the statistical power of randomized trials. The factors influencing increase of power are well-known for trials with continuous outcomes. Here, we study which factors influence power and sample size requirements in time-to-event trials. We consider both parametric simulations and simulations derived from the TCGA cohort of hepatocellular carcinoma (HCC) patients to assess how sample size requirements are reduced with covariate adjustment. Simulations demonstrate that the benefit of covariate adjustment increases with the prognostic performance of the adjustment covariate (C-index) and with the cumulative incidence of the event in the trial. For a covariate that has an intermediate prognostic performance (C-index=0.65), the reduction of sample size varies from 1.7% when cumulative incidence is of 10% to 26.5% when cumulative incidence is of 90%. Broadening eligibility criteria usually reduces statistical power while our simulations show that it can be maintained with adequate covariate adjustment. In a simulation of HCC trials, we find that the number of patients screened for eligibility can be divided by 2.7 when broadening eligibility criteria. Last, we find that the Cox-Snell [Formula] is a good approximation of the reduction in sample size requirements provided by covariate adjustment. This metric can be used in the design of time-to-event trials to determine sample size. Overall, more systematic adjustment for prognostic covariates leads to more efficient and inclusive clinical trials especially when cumulative incidence is large as in metastatic and advanced cancers.

Key messagesO_LICovariate adjustment is a statistical technique that leverages prognostic scores within the statistical analysis of a trial. We study its benefits for time-to-event trials.
C_LIO_LIPower gain achieved with covariate adjustment is determined by the prognostic performance of the covariate and by the cumulative incidence of events at the end of the follow-up period.
C_LIO_LITrials in indications with large cumulative incidence such as metastatic cancers can benefit from covariate adjustment to improve their statistical power.
C_LIO_LICovariate adjustment maintains statistical power in trials when eligibility criteria are broadened.
C_LI