title: Accuracy of computer-aided chest X-ray screening in the Kenya National Tuberculosis Prevalence Survey

abstract:
BackgroundCommunity-based screening for tuberculosis (TB) could improve detection but is resource intensive. We set out to evaluate the accuracy of computer-aided TB screening using digital chest X-ray (CXR) to determine if this approach met target product profiles (TPP) for community-based screening.

MethodsCXR images from participants in the 2016 Kenya National TB Prevalence Survey were evaluated using CAD4TBv6 (Delft Imaging), giving a probabilistic score for pulmonary TB ranging from 0 (low probability) to 99 (high probability). We constructed a Bayesian latent class model to estimate the accuracy of CAD4TBv6 screening compared to bacteriologically-confirmed TB across CAD4TBv6 threshold cut-offs, incorporating data on Clinical Officer CXR interpretation, participant demographics (age, sex, TB symptoms, previous TB history), and sputum results. We compared model-estimated sensitivity and specificity of CAD4TBv6 to optimum and minimum TPPs.

ResultsOf 63,050 prevalence survey participants, 61,848 (98%) had analysable CXR images, and 8,966 (14.5%) underwent sputum bacteriological testing; 298 had bacteriologically-confirmed pulmonary TB. Median CAD4TBv6 scores for participants with bacteriologically-confirmed TB were significantly higher (72, IQR: 58-82.75) compared to participants with bacteriologically-negative sputum results (49, IQR: 44-57, p<0.0001). CAD4TBv6 met the optimum TPP; with the threshold set to achieve a mean sensitivity of 95% (optimum TPP), specificity was 83.3%, (95% credible interval [CrI]: 83.0%--83.7%, CAD4TBv6 threshold: 55). There was considerable variation in accuracy by participant characteristics, with older individuals and those with previous TB having lowest specificity.

ConclusionsCAD4TBv6 met the optimal TPP for TB community screening. To optimise screening accuracy and efficiency of confirmatory sputum testing, we recommend that an adaptive approach to threshold setting is adopted based on participant characteristics.

Take home messageCAD4TBv6 met the optimal WHO target product profile for a community TB screening tool. Specificity was lower in adults with previous TB and those aged 41 years or older; an adaptive approach to setting CAD thresholds will likely be required to optimize use.


title: COVID-19 vaccine brand hesitancy and other challenges to vaccination in the Philippines

abstract:
BackgroundCOVID-19 vaccines have been developed at a rapid and unprecedented pace to control the spread of the virus, and prevent hospitalisations and deaths. However, there are a series of events and factors that create barriers to vaccination. In this paper, we explore vaccination narratives and challenges experienced and observed by Filipinos during the early vaccination period in the Philippines.

Material and methodsWe conducted 35 interviews from a subsample of 1,599 survey respondents ages 18 and older in the Philippines. The interviews were conducted in Filipino, Cebuano, and/or English via online platforms such as Zoom or via phone call. All interviews were recorded, transcribed verbatim, translated, and analysed using inductive content analysis. To highlight the complex reasons for delaying and/or refusing COVID-19 vaccines, we embedded our findings within the social ecological model.

ResultsOur analysis showed that individual perceptions play a major role on the decision to vaccinate. Such perceptions are shaped by exposure to (mis)information amplified by the media, the community, and the health system. Social networks may either positively or negatively impact vaccination uptake, depending on their views on vaccines. Political issues contribute to vaccine brand hesitancy, resulting to vaccination delays and refusals. Perceived inefficiencies and inflexibility of the system also create additional barriers to the vaccine rollout in the country, especially among vulnerable and marginalised groups.

ConclusionsChallenges to COVID-19 vaccination may be individual, interpersonal, and structural, which work individually and collectively. Among these barriers, our results suggest that many concerns regarding vaccination operate at the individual level. Vaccine brand hesitancy and misinformation are growing public health challenges in the country that need to be addressed. Recognising and addressing concerns at all levels are critical to solutions aimed at improving COVID-19 vaccination uptake and reach.

category: public and global health


title: A Hidden Structural Variation in a Known IRD Gene: A Cautionary Tale of Two New Disease Candidate Genes

abstract:
Rod cone dystrophy (RCD), also known as retinitis pigmentosa, is an inherited condition leading to vision loss, affecting 1/3500 people. Over 270 genes are known to be implicated in the inherited retinal degenerations (IRDs), yet genetic diagnosis for [~]30% IRD of patients remains elusive despite advances in sequencing technologies. The goal of this study was to determine the genetic causality in a family with Rod-cone dystrophy (RCD). Family members were given a full ophthalmic exam at the Retinal Service at MEE and consented to genetic testing. Whole exome sequencing (WES) was performed and variants of interest were Sanger validated. Functional assays were conducted in zebrafish along with splicing assays in relevant cell lines to determine the impact on retinal function.

WES identified variants in two potential candidate genes that segregated with disease: GNL3 (G Protein Nucleolar 3) c.1187+3A>C and c.1568-8C>A; and PDE4DIP (Phosphodiester 4D Interacting Protein) c.3868G>A (p.Glu1290Lys) and c.4603G>A (p.Ala1535Thr). Both genes were promising candidates based on their retinal involvement (development and interactions with IRD-associated proteins), however the functional assays did not validate either gene. Subsequent WES reanalysis with an updated bioinformatics pipeline and widened search parameters led to the detection of a 94bp duplication in PRPF31 (pre-mRNA Processing Factor 31) c.73_266dup (p.Asp56GlyfsTer33) as the causal variant.

Our study demonstrates the importance of thorough functional characterization of new disease candidate genes, and the value of reanalyzing NGS sequence data, which in our case led to identification of a hidden pathogenic variant in a known IRD gene.

category: ophthalmology


title: Cluster detection with random neighbourhood covering: application to invasive Group A Streptococcal disease.

abstract: The rapid detection of outbreaks is a key step in the effective control and containment of infectious diseases. The identification of cases which might be epidemiologically linked is crucial in directing outbreak-containment efforts shaping the intervention of public health authorities. Often this requires the detection of clusters of cases whose numbers exceed those expected by a background of sporadic cases. Quantifying exceedances rapidly is particularly challenging when only few cases are typically reported in a precise location and time. To address such important public health concerns, we present a general method which can detect spatio-temporal deviations from a Poisson point process and estimate the odd of an isolate being part of a cluster. This method can be applied to diseases where detailed geographical information is available. In addition, we propose an approach to explicitly take account of delays in microbial typing. As a case study, we considered invasive group A Streptococcus infection events as recorded and typed by Public Health England from 2015 to 2020.

category: health informatics


title: Improving the diagnosis of severe malaria in African children using platelet counts and plasma PfHRP2 concentrations

abstract:
BackgroundSevere falciparum malaria is difficult to diagnose accurately in children in high transmission settings. Platelet counts and plasma concentrations of P. falciparum histidinerich protein-2 (Pf HRP2) are potential biomarkers to increase diagnostic accuracy.

MethodsWe fitted Bayesian latent class models to platelet counts and Pf HRP2 concentrations in 2,649 patients enrolled in four studies of severe illness in three countries (Bangladesh, Kenya, and Uganda). We estimated receiver operating characteristic curves and compared parasite densities, haematocrits, total white blood cell counts, blood culture positivity rates, and haemoglobin S genotypes (HbAS and HbSS) across the subgroups defined by the probabilistic models.

FindingsThe platelet count and the plasma Pf HRP2 concentration have substantial diagnostic value in severe malaria. In severely ill patients with clinical features consistent with severe malaria, a combined platelet count [≤] 150,000 per {micro}L and a plasma Pf HRP2 concentration [≥] 1,000 ng/mL had an estimated sensitivity of 74% and specificity of 93% in identifying  true severe falciparum malaria. We estimate one third of African children enrolled in the two clinical studies of severe malaria had another cause of severe illness. Under the model, patients with severe malaria had higher parasite densities, lower haematocrits, lower rates of invasive bacterial disease, and a lower prevalence of both HbAS and HbSS than children misdiagnosed. Mortality in  true severe malaria was consistent across the African sites at [~] 10%.

InterpretationStudies of severe falciparum malaria in African children would be improved by including only patients with platelet counts [≤] 150,000 per {micro}L and plasma Pf HRP2 concentrations [≥] 1,000 ng/mL.

FundingWellcome

category: infectious diseases


title: COVID-19 Advanced Respiratory Care Educational Training Program for Healthcare Workers in Lesotho: An Observational Study

abstract:
ObjectivesTo develop and implement a  Low Dose, High Frequency (LDHF) advanced respiratory care training program for COVID-19 care in Lesotho.

DesignProspective pre-post training evaluation.

SettingLesotho has limited capacity in advanced respiratory care.

ParticipantsPhysicians and nurses.

InterventionsDue to limited participation May-September 2020 the LDHF approach was modified into a traditional one-day offsite training November 2020 that reviewed respiratory anatomy and physiology, clinical principles for conventional oxygen, heated high flow nasal cannula, and non-invasive ventilation management. Basic mechanical ventilation principles were introduced.

Outcome measuresParticipants completed a twenty-question multiple choice examination immediately before and after the one-day training. Paired t-tests were used to evaluate the difference in average participant pre- and post-training examination scores.

ResultsPre- and post-training examinations were completed by 46/53 (86.7%) participants, of whom 93.4% (n=43) were nurses. The overall mean pre-training score was 44.8% (standard deviation [SD], 12.4.%). Mean scores improved by an average of 23.7 percentage points (95% confidence interval [CI] 19.7, 27.6 percentage points, p<0.001) on the post-training examination to a mean score of 68.5% (SD, 13.6%). Performance on basic and advanced respiratory categories also improved by 17.7 (95% CI: 11.6, 23.8) and 25.6 percentage points (95% CI: 20.4, 30.8) (p<0.001). Likewise, mean examination scores increased on the post-training test, compared to pre-training, for questions related to respiratory management (29.6 percentage points (95% CI: 24.1, 35.0) and physiology (17.4 percentage points (95% CI: 12.0, 22.8).

ConclusionsA LDHF training approach was not feasible during this relatively early period of the COVID-19 pandemic in Lesotho. Despite clear knowledge gains the modest post-training examination scores coupled with limited physician engagement suggest healthcare workers require alternative educational strategies before higher advanced care like mechanical ventilation is implementable. Conventional and high flow oxygen are better aligned with post-training healthcare worker knowledge levels and rapid implementation.

Strengths and limitations of this studyO_LIThe training aimed to use a  Low Dose, High Frequency approach to improve the competence of doctors and nurses providing advanced respiratory care to severely ill COVID-19 patients during an emergency, pandemic African context with limited advanced respiratory care services.
C_LIO_LITo provide a foundation for future implementation of invasive mechanical ventilation and more immediate application of conventional oxygen, heated high flow nasal cannula, and non-invasive ventilation, the training coupled pragmatic respiratory anatomy and physiology concepts to key clinical principles.
C_LIO_LIChallenges in trainee participation and respiratory equipment availability necessitated modifications to the planned  Low Dose, High Frequency training strategy that reduced both the training duration and approach.
C_LIO_LIThis evaluation provides key lessons for future COVID-19 advanced respiratory care training approaches and the respiratory modalities best aligned with current healthcare worker expertise in Lesotho and likely other similar settings.
C_LI

category: respiratory medicine


title: Deep neural networks learn general and clinically relevant representations of the ageingbrain

abstract: The discrepancy between chronological age and the apparent age of the brain based on neuroimaging data -- the brain age delta -- has emerged as a reliable marker of brain health. With an increasing wealth of data, approaches to tackle heterogeneity in data acquisition are vital. To this end, we compiled raw structural magnetic resonance images into one of the largest and most diverse datasets assembled (n=53542), and trained convolutional neural networks (CNNs) to predict age. We achieved state-of-the-art performance on unseen data from unknown scanners (n=2553), and showed that higher brain age delta is associated with diabetes, alcohol intake and smoking. Using transfer learning, the intermediate representations learned by our model complemented and partly outperformed brain age delta in predicting common brain disorders. Our work shows we can achieve generalizable and biologically plausible brain age predictions using CNNs trained on heterogeneous datasets, and transfer them to clinical use cases.

category: neurology


title: Bi-allelic variants in CHKA cause a neurodevelopmental disorder with epilepsy and microcephaly

abstract:
The Kennedy pathways catalyze the de novo synthesis of phosphatidylcholine and phosphatidylethanolamine, the most abundant components of eukaryotic cell membranes. In recent years, these pathways have moved into clinical focus since four out of ten genes involved have been associated with a range of autosomal recessive rare diseases such as a neurodevelopmental disorder with muscular dystrophy (CHKB), bone abnormalities and cone-rod dystrophy (PCYT1A), and spastic paraplegia (PCYT2, SELENOI).

We identified six individuals from five families with bi-allelic variants in CHKA presenting with severe global developmental delay, epilepsy, movement disorders, and microcephaly. Using structural molecular modeling and functional testing of the variants in a in a cell-based S. cerevisiae model, we determined that these variants reduce the enzymatic activity of CHKA and confer a significant impairment of the first enzymatic step of the Kennedy pathway.

In summary, we present CHKA as a novel autosomal recessive gene for a neurodevelopmental disorder with epilepsy and microcephaly.

category: genetic and genomic medicine


title: Chest X-ray Severity and its Association with Outcomes in Patients with COVID-19 Presenting to the Emergency Department

abstract:
BackgroundSeverity of radiographic abnormalities on chest X-ray (CXR) in patients with COVID-19 has been shown to be associated with worse outcomes, but studies are limited by different scoring systems, sample size, patient age and study duration. Data regarding the longitudinal evolution of radiographic abnormalities and its association with outcomes is scarce. We sought to evaluate these questions using a well-validated scoring system (the Radiographic Assessment of Lung Edema [RALE] score) using data over 6 months from a large, multi-hospital healthcare system.

MethodsWe collected clinical and demographic data and quantified radiographic edema on CXRs obtained in the emergency department (ED) as well as on days 1-2 and 3-5 (in those admitted) in patients with a nasopharyngeal swab positive for SARS-CoV-2 PCR visiting the ED for COVID-19-related complaints between March and September 2020. We examined the association of baseline and longitudinal evolution of radiographic edema with severity of hypoxemia and clinical outcomes.

Results870 patients were included (median age 53.6, 50.8% female). Inter-rate agreement for RALE scores was excellent (ICC = 0.84, 95% CI 0.82 - 0.87, p < 0.0001). RALE scores correlated with hypoxemia as quantified by SpO2-FiO2 ratio (r = -0.42, p < 0.001). Admitted patients had higher RALE scores than those discharged (6 [2, 11] vs 0 [0, 3], p < 0.001). An increase of RALE score of 4 or more was associated with worse 30-day survival (p < 0.01). Larger increases in the RALE score were associated with worse survival.

ConclusionsThe RALE score is reproducible and easily implementable in adult patients presenting to the ED with COVID-19. Its association with physiologic parameters and outcomes at baseline and longitudinally makes it a readily available tool for prognostication and early ICU triage, particularly in patients with worsening radiographic edema.


title: A blood-based miRNA signature predicts immunotherapy efficacy in advanced stage non-small cell lung cancer

abstract:
Immunotherapies have recently gained traction as highly effective therapies in a subset of late-stage cancers. Unfortunately, only a minority of patients experience the remarkable benefits of immunotherapies, whilst others fail to respond or even come to harm through immune related adverse events. For immunotherapies within the PD-1/PD-L1 inhibitor class, patient stratification is currently performed using tumor (tissue-based) PD-L1 expression. However, PD-L1 is an accurate predictor of response in only [~]30% of cases. There is pressing need for more accurate biomarkers for immunotherapy response prediction.

We sought to identify peripheral blood biomarkers, predictive of response to immunotherapies against lung cancer, based on whole blood microRNA profiling. Using three well characterized cohorts consisting of a total of 334 stage IV NSCLC patients, we have defined a 5 microRNA risk score (miRisk) that is predictive of overall survival following immunotherapy in training and independent validation (HR 2.40, 95% CI 1.37-4.19; P < 0.01) cohorts. We have traced the signature to a myeloid origin and performed miRNA target prediction to make a direct mechanistic link to the PD-L1 signalling pathway and PD-L1 itself. The miRisk score offers a potential blood-based companion diagnostic for immunotherapy that outperforms tissue-based PD-L1 staining.

category: oncology


title: A blood-based miRNA signature with prognostic value for overall survival in advanced stage non-small cell lung cancer treated with immunotherapy


title: Study Protocol of A Phase II Study to Evaluate Safety and Efficacy of Neo-adjuvant Pembrolizumab and Radiotherapy in Localized Rectal Cancer

abstract:
BackgroundReshaping the tumor microenvironment by novel immunotherapies represents a key strategy to improve the treatment of cancers. Nevertheless, responsiveness to these treatments is often correlated with the extent of the T cell infiltration at the tumor site. Remarkably, microsatellite stable rectal cancer is characterized by poor infiltration and, therefore, do not respond to immune checkpoint blockade. To date, the only available curative option for these patients relies on extensive surgery. With the aim to broaden the application of promising immunotherapies, it is necessary to develop alternative approaches to promote T cell infiltration into the tumor microenvironment of these tumors. In this regard, recent evidence shows that radiotherapy may have profound immunostimulatory effects, hinting at the possibility of combining it with immunotherapy. The combination of long-course chemoradiotherapy and immunotherapy was recently shown to be safe and yielded promising results in rectal cancer, however short-course radiotherapy and immunotherapy have never been tested in these tumors.

MethodsOur clinical trial investigates the clinical and biological impact of combining pembrolizumab with short-course radiotherapy in the neo-adjuvant treatment of localized microsatellite stable rectal cancer. This phase II non-randomized study will recruit 25 patients who will receive short-course preoperative radiotherapy (5Gy x 5 days) and four injections of pembrolizumab starting on the same day and on weeks 4, 7 and 10. Radical surgery will be performed after three weeks from the last pembrolizumab injection. Our clinical trial also includes an extensive research program involving the transcriptomic and proteomic analysis of blood and tumor samples throughout the course of the treatment.

DiscussionOur study is the first clinical trial to provide with safety and efficacy information of this novel treatment approach in rectal cancer, leading to a major breakthrough in the treatment of this cancer. Additionally, the translational research program will offer better insight into immunological changes within the tumor and blood during treatment. Taken together, our work will help optimizing future treatment combinations and, possibly, better selecting patients.

Trial registrationThis study was registered with www.clinicaltrial.gov: NCT04109755. Registration date: June, 2020.


title: Asparagine metabolism in tumors is linked to poor survival in females with colorectal cancer: A cohort study

abstract:
Background or PurposeThe interplay between the sex-specific differences in tumor metabolome and colorectal cancer (CRC) prognosis has never been studied and represents an opportunity to improve patient outcomes. This study aims to examine the link between tumor metabolome and prognosis by sex for CRC patients.

MethodsUsing untargeted metabolomics analysis, abundances of 91 metabolites were obtained from primary tumor tissues from 197 patients (N=95 females, N=102 males) after surgical colectomy for stage I-III CRC. Cox Proportional Hazards (PH) regression models were applied to estimate the associations between tumor metabolome and 5-year overall survival (OS) and 5-year recurrence-free survival (RFS), and their interactions with sex.

ResultsEleven metabolites had significant sex differences in their associations with 5-year OS, and five metabolites for 5-year RFS (Pinteraction < .05). The metabolites asparagine and serine had sex interactions for both OS and RFS. Furthermore, sex-specific differences were found in the associations between prognosis and metabolic pathways. Notably, in the asparagine synthetase (ASNS)-catalyzed asparagine synthesis pathway, asparagine was associated with substantially poorer OS (hazard ratio [HR] = 6.39, 95% confidence interval [CI] = 1.78-22.91, P = .004) and RFS (HR = 4.36, 95% CI = 1.39-13.68, P = .01) for female patients only (Pinteraction, OS = .02, Pinteraction, RFS = .003). Similar prognostic disadvantages in females were seen in lysophospholipid and polyamine synthesis.

Discussion or ConclusionsUnique metabolite profiles indicated increased asparagine synthesis was associated with poorer prognosis for females only, providing insights into precision medicine for CRC treatment stratified by sex.


title: A multi-ethnic polygenic risk score is associated with hypertension prevalence and progression throughout adulthood

abstract:
BackgroundWe used summary statistics from previously-published GWAS of systolic and diastolic BP and of hypertension to construct Polygenic Risk Scores (PRS) to predict hypertension across diverse populations.

MethodsWe used 10,314 participants of diverse ancestry from BioMe to train trait-specific PRS. We implemented a novel approach to select one of multiple potential PRS based on the same GWAS, by optimizing the coefficient of variation across estimated PRS effect sizes in independent subsets of the training dataset. We combined the 3 selected trait-specific PRS as their unweighted sum, called "PRSsum". We evaluated PRS associations in an independent dataset of 39,035 individuals from eight cohort studies, to select the final, multi-ethnic, HTN-PRS. We estimated its association with prevalent and incident hypertension 4-6 years later. We studied hypertension development within HTN-PRS strata in a longitudinal, six-visit, longitudinal dataset of 3,087 self-identified Black and White participants from the CARDIA study. Finally, we evaluated the HTN-PRS association with clinical outcomes in 40,201 individuals from the MGB Biobank.

ResultsCompared to other race/ethnic backgrounds, African-Americans had higher average values of the HTN-PRS. The HTN-PRS was associated with prevalent hypertension (OR=2.10, 95% CI [1.99, 2.21], per one standard deviation (SD) of the PRS) across all participants, and in each race/ethnic background, with heterogeneity by background (p-value < 1.0x10-4). The lowest estimated effect size was in African Americans (OR=1.53, 95% CI [1.38, 1.69]). The HTN-PRS was associated with new onset hypertension among individuals with normal (respectively, elevated) BP at baseline: OR=1.71, 95% CI [1.55, 1.91] (OR=1.48, 95% CI [1.27, 1.71]). Association was further observed in age-stratified analysis. In CARDIA, Black participants with high HTN-PRS percentiles developed hypertension earlier than White participants with high HTN-PRS percentiles. The HTN-PRS was significantly associated with increased risk of coronary artery disease (OR=1.12), ischemic stroke (OR=1.15), type 2 diabetes (OR=1.19), and chronic kidney disease (OR=1.12), in the MGB Biobank.

ConclusionsThe multi-ethnic HTN-PRS is associated with both prevalent and incident hypertension at 4-6 years of follow up across adulthood and is associated with clinical outcomes.


title: Cost-effectiveness of vitamin D3 supplementation in older adults with vitamin D deficiency in Ireland

abstract:
BackgroundThis study investigated the cost-effectiveness of vitamin D3 supplementation in older adults in Ireland, with year-round vitamin D deficiency (serum 25-hydroxyvitamin D concentration <30 nmol/L) (13% of Irish adults), from the perspective of the Health Service Executive (HSE).

MethodsThree age groups were investigated: (1) [≥]50 years, (2) [≥]60 years, (3) [≥]70 years. Based on the clinical literature, vitamin D3 supplementation may (1) decrease all-cause mortality by 7%, and (2) reduce hip fractures by 16%, and non-hip fractures by 20%. A discount rate of 4% was applied to life years and QALYs gained. The annual healthcare costs per patient used in the model are based on the average annual health resource use over the 5-year time horizon of the model.

ResultsThe cost/QALY estimates in all three age groups are below the usually acceptable cost-effectiveness threshold of {euro}20,000/QALY. The most cost-effective and least costly intervention was in adults [≥]70 years. For this age group, the average annual costs and outcomes would be approx. {euro}6.2 million, 1,043 QALYs gained, with a cost/QALY of approx. {euro}6,000. The results are most sensitive to the mortality risk reduction following vitamin D3 supplementation.

ConclusionThe cost-effectiveness of vitamin D3 supplementation is most robust in adults [≥]70 years. Clinical uncertainty in the magnitude of the benefits of vitamin D3 supplementation could be further addressed by means of (1) performing a clinical research study or (2) conducting a pilot/regional study, prior to reaching a decision to invest in a full nationwide programme.

category: health economics


title: High-Resolution Digital Phenotypes from Consumer Wearables Enhance Prediction of Cardiometabolic Risk Markers

abstract:
BackgroundConsumer-grade wearable devices enable detailed recordings of heart rate and step counts in free-living conditions. Recent studies have shown that summary statistics from these wearable recordings have potential uses for longitudinal monitoring of health and disease states. However, the relationship between higher resolution physiological dynamics from wearables and known markers of health and disease remains largely uncharacterized.

ObjectiveWe aimed to (i) derive high resolution digital phenotypes from observational wearable recordings, (ii) characterize their ability to predict modifiable markers of cardiometabolic disease, and (iii) study their connections with genetic predispositions for cardiometabolic disease and with lifestyle factors.

MethodsWe introduce a principled framework to extract interpretable high resolution phenotypes from wearable data recorded in free-living conditions. The proposed framework standardizes handling of data irregularities, encodes contextual information about underlying physiological state at any given time, and generates a set of 66 minimally redundant features across active, sedentary and sleep states. We applied our approach on a multimodal dataset, from the SingHEART study (NCT02791152), that comprises of heart rate and step count time series from wearables, clinical screening profiles, whole genome sequences and lifestyle survey responses from 692 healthy volunteers. We employed machine learning to model non-linear relationships between the high resolution phenotypes and clinical risk markers for blood pressure, lipid and weight abnormalities. For each risk type, we performed model comparisons based on Brier Skill Scores (BSS) to assess predictive value of the high resolution features over and beyond typical baselines. We then examined associations between the wearable-derived features, polygenic risk for cardiometabolic disease, and lifestyle habits and health perceptions.

ResultsCompared to typical summary statistic measures like resting heart rate, we find that the high-resolution features collectively have greater predictive value for modifiable clinical markers associated with cardiometabolic disease risk (average improvement in Brier Skill Score=52.3%, P<.001). Further, we show that heart rate dynamics from different activity states contain distinct information about type of cardiometabolic risk, with dynamics in sedentary states being most predictive of lipid abnormalities and patterns in active states being most predictive of blood pressure abnormalities (P<.001). Finally, our results reveal that subtle heart rate dynamics in wearable recordings serve as physiological correlates of genetic predisposition for cardiometabolic disease, lifestyle habits and health perceptions.

ConclusionsHigh resolution digital phenotypes recorded by consumer wearables in free-living states have the potential to enhance prediction of cardiometabolic disease risk, and could enable more proactive and personalized health management.

Trial RegistrationClinicalTrials.gov NCT02791152; https://clinicaltrials.gov/ct2/show/NCT02791152


title: Cross-border transmissions of delta substrain AY.29 during Olympic and Paralympic Games

abstract: Tokyo Olympic and Paralympic Games, postponed for COVID-19 pandemic, were finally held in summer of 2021. Just before the games, alpha variant was being replaced with more contagious delta variant (B.1.617.2). AY.4 substrain AY.29, which harbors two additional characteristic mutations of 5239C>T (NSP3 Y840Y) and 5514T>C (NSP3 V932A), emerged in Japan and became the dominant strain in Tokyo by the time of the Olympic Games. As of October 18, 98 AY.29 samples are identified in 16 countries outside of Japan. Phylogenetic analysis and ancestral searches identified 46 distinct introductions of AY.29 strains into those 16 countries. United States has 44 samples with 10 distinct introductions, and United Kingdom has 13 distinct AY.29 strains introduced in 16 samples. Other countries or regions with multiple introductions of AY.29 are Canada, Germany, South Korea, and Hong Kong while Italy, France, Spain, Sweden, Belgium, Peru, Australia, New Zealand, and Indonesia have only one distinct strain introduced. There exists no unambiguous evidence that Olympic and Paralympic Games induced cross-border transmission of the delta substrain AY.29. Since most of unvaccinated countries are also under sampled for genome analysis with longer lead time for data sharing, it will take longer to capture the whole picture of cross-border transmissions of AY.29.


title: IFI27 transcription is an early predictor for COVID-19 outcomes; a multi-cohort observational study

abstract:
BackgroundRobust biomarkers that predict disease outcomes amongst COVID-19 patients are necessary for both patient triage and resource prioritisation. Numerous candidate biomarkers have been proposed for COVID-19. However, at present, there is no consensus on the best diagnostic approach to predict outcomes in infected patients. Moreover, it is not clear whether such tools would apply to other potentially pandemic pathogens and therefore of use as stockpile for future pandemic preparedness.

MethodsWe conducted a multi-cohort observational study to investigate the biology and the prognostic role of interferon alpha-inducible protein 27 (IFI27) in COVID-19 patients.

FindingsWe show that IFI27 is expressed in the respiratory tract of COVID-19 patients and elevated IFI27 expression is associated with the presence of a high viral load. We further demonstrate that systemic host response, as measured by blood IFI27 expression, is associated with COVID-19 severity. For clinical outcome prediction (e.g. respiratory failure), IFI27 expression displays a high positive (0.83) and negative (0.95) predictive value, outperforming all other known predictors of COVID-19 severity. Furthermore, IFI27 is upregulated in the blood of infected patients in response to other respiratory viruses. For example, in the pandemic H1N1/09 swine influenza virus infection, IFI27-like genes were highly upregulated in the blood samples of severely infected patients.

InterpretationThese data suggest that prognostic biomarkers targeting the family of IFI27 genes could potentially supplement conventional diagnostic tools in future virus pandemics, independent of whether such pandemics are caused by a coronavirus, an influenza virus or another as yet-to-be discovered respiratory virus.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched the scientific literature using PubMed to identify studies that used the IFI27 biomarker to predict outcomes in COVID-19 patients. We used the search terms "IFI27", "COVID-19, "gene expression" and "outcome prediction". We did not identify any study that investigated the role of IFI27 biomarker in outcome prediction. Although ten studies were identified using the general terms of "gene expression" and "COVID-19", IFI27 was only mentioned in passing as one of the identified genes. All these studies addressed the broader question of the host response to COVID-19; none focused solely on using IFI27 to improve the risk stratification of infected patients in a pandemic.

Added value of this studyHere, we present the findings of a multi-cohort study of the IFI27 biomarker in COVID-19 patients. Our findings show that the host response, as reflected by blood IFI27 gene expression, accurately predicts COVID-19 disease progression (positive and negative predictive values; 0.83 and 0.95, respectively), outperforming age, comorbidity, C-reactive protein and all other known risk factors. The strong association of IFI27 with disease severity occurs not only in SARS-CoV-2 infection, but also in other respiratory viruses with pandemic potential, such as the influenza virus. These findings suggest that host response biomarkers, such as IFI27, could help identify high-risk COVID-19 patients - those who are more likely to develop infection complications - and therefore may help improve patient triage in a pandemic.

Implications of all the available evidenceThis is the first systemic study of the clinical role of IFI27 in the current COVID-19 pandemic and its possible future application in other respiratory virus pandemics. The findings not only could help improve the current management of COVID-19 patients but may also improve future pandemic preparedness.


title: Automated Interpretable Discovery of Heterogeneous Treatment Effectiveness: A Covid-19 Case Study

abstract: Testing multiple treatments for heterogeneous (varying) effectiveness with respect to many underlying risk factors requires many pairwise tests; we would like to instead automatically discover and visualize patient archetypes and predictors of treatment effectiveness using multitask machine learning. In this paper, we present a method to estimate these heterogeneous treatment effects with an interpretable hierarchical framework that uses additive models to visualize expected treatment benefits as a function of patient factors (identifying personalized treatment benefits) and concurrent treatments (identifying combinatorial treatment benefits). This method achieves state-of-the-art predictive power for Covid-19 in-hospital mortality and interpretable identification of heterogeneous treatment benefits. We first validate this method on the large public MIMIC-IV dataset of ICU patients to test recovery of heterogeneous treatment effects. Next we apply this method to a proprietary dataset of over 3000 patients hospitalized for Covid-19, and find evidence of heterogeneous treatment effectiveness predicted largely by indicators of inflammation and throm-bosis risk: patients with few indicators of thrombosis risk benefit most from treatments against inflammation, while patients with few indicators of inflammation risk benefit most from treatments against thrombosis. This approach provides an automated methodology to discover heterogeneous and individualized effectiveness of treatments.


title: Azithromycin consumption during the COVID-19 pandemic in Croatia, 2020

abstract:
BackgroundDuring the initial phase of the COVID-19 pandemic, there was great enthusiasm for the use of azithromycin with or without hydroxychloroquine.

ObjectivesWe analyzed azithromycin consumption in Croatia in 2020 and compared this to the period 2017-2019.

MethodsAzithromycin consumption was evaluated using the IQVIA Adriatic d.o.o. database which collects data on azithromycin distribution from wholesale pharmacies to hospital and non-hospital pharmacies in Croatia. We analyzed data for the period from January 2017 to December 2020. Azithromycin distribution was measured as days of therapy (DOT) and reported as per 1000 inhabitants or per 1000 inhabitant-days.

ResultsIn the period 2017-2020, total azithromycin DOT in Croatia increased in 2017, 2018, 2019, and 2020 (1.76, 1.91, 1.91 and 2.01/1000 inhabitant-days, respectively). Non-hospital pharmacies received 2.18 times and hospital pharmacies 4.39 times more DOT units/1000 inhabitants of azithromycin in March 2020 compared to the average distribution rate in March 2017-2019. During the peak of the COVID-19 epidemic (November and December 2020) azithromycin distribution increased considerably in hospital (3.62 and 3.19 times, respectively) and non-hospital pharmacies (1.93 and 1.84 times, respectively) compared to the average consumption in the same months in 2017-2019.

ConclusionsOur data showed increased azithromycin distribution in the period 2017 - 2020 which indicates azithromycin overuse. Preliminary information on COVID-19 treatments with a desire to offer and try what is available even in the absence of strong scientific evidence may have influenced practices of antimicrobial prescriptions.


title: Heterogenous pattern of the inflammasome-related markers in the critically ill COVID-19 patients at the ICU admission.

abstract:
PurposeDevelopment of targeted biological therapies for COVID-19 requires reliable biomarkers that could help indicate the responding patients. Hyperactivation of the inflammasome by SARS-CoV2 virus is hypothesized to contribute to severe course of the COVID-19 disease. Therefore, we aimed to evaluate the prognostic value of several inflammasome-related cytokines and proteins at the admission to the intensive care unit (ICU).

Patients and methodsPlasma samples were obtained from 45 critically ill COVID-19 patients and from 10 patients any without any signs of infection (TBI, traumatic brain injury) on admission to the ICU. The concentration of IL-1, IL-1{beta}, IL-18, IL-1RA, galectin-1, ASC, LDH, ferritin, and gasdermin D were analyzed. A novel cell-free caspase-1 plasma assay was developed by inhibitor-based immunoprecipitation followed by Western Blot. Demographic and clinical characteristics were recorded.

ResultsIn-hospital mortality in COVID-19 patients reached 62%. Galectin-1 was 1.8-fold lower in COVID-19 than in TBI patients (17101.84 vs. 30764.20 pg/ml, p=0.007), but other inflammasome-related biomarkers were at similar concentrations. Patients with SOFA score of >9 on admission who were at high risk of death had significantly higher galectin-1 but lower IL-1RA in comparison to low-risk patients (25551.3 pg/ml vs 16302.7 pg/ml, p=0.014; 14.5 pg/ml vs 39.4 pg/ml, p=0.04, respectively). Statistically significant correlations were observed between: IL-1 and platelets (r=-0.37), IL-1{beta} and platelets (r=-0.36), ferritin and INR (r=0.39). Activated caspase-1 p35 was detectable in 12/22 COVID-19 patients but in none of the TBI patients. Its presence was related with higher fibrinogen and lower D-dimers. Moreover, the densitometric analysis showed a significantly higher amount of p35 in patients with SOFA> 9.

ConclusionOur results indicate that the systemic markers of activation of the inflammasome in critically ill COVID-19 patients is not directly related with outcome. Therefore, potential interventions aimed at the inflammasome pathway in this group of patients may be of limited effectiveness and should be biomarker-guided.

category: intensive care and critical care medicine


title: Inflammasome-related markers at the ICU admission are not associated with outcome in the critically ill COVID-19 patients.


title: Interventions to prevent or delay the onset of type 2 diabetes in women with prior gestational diabetes mellitus: protocol for a living systematic review and prospective meta-analysis

abstract:
IntroductionGestational diabetes mellitus (GDM), once considered a transient condition during pregnancy, is now a firmly established risk factor for type 2 diabetes mellitus (T2DM). Women whose blood glucose levels do not return to normal soon after giving birth are particularly at high risk of developing established diabetes and consequent heart and blood vessel disease. Lifestyle interventions are recommended for women with GDM to prevent or delay the subsequent development of T2DM. Recent systematic reviews and meta-analyses have suggested postpartum lifestyle interventions may be beneficial in reducing the risk of developing diabetes in women with GDM, however, included studies were generally small, many had a high risk of bias and subsequent data have become available with new trials likely to complete in the next couple of years. In addition, to the best of our knowledge, formal systematic review and meta-analysis of other approaches to preventing diabetes in this population (e.g. pharmacotherapy) has not been attempted. Therefore, an updated systematic review is needed and will be formulated as a living systematic review to ensure the inclusion of emerging studies.

Methods and analysisA living systematic review and a prospective meta-analysis to examine the effectiveness of postpartum interventions in reducing the risk of developing T2DM in women with recent GDM.

Ethics and disseminationEthics committee approval is not required. The data included will be from published studies, and a continued living systematic review and prospective meta-analysis will occur once a year for the next five years. Results of the review will be disseminated at relevant meetings.

PROSPERO registration numberCRD42021279891

Strengths and limitations of this studyO_LIA living systematic review will allow continuous surveillance of emerging literature on different lifestyle interventions in women with a history of GDM and allow identification of effective strategies for diabetes prevention.
C_LIO_LIWe estimate considerable heterogeneity of interventions which may limit our ability to make clear conclusions.
C_LI

category: endocrinology


title: Self-medication with antibiotics- a survey among traders in the central business district of Accra, Ghana

abstract:
BackgroundThe misuse of antibiotics is a global problem, and the form of misuse varies among different countries and cultures. The study explored antibiotic self-medication practices among traders in Accra, Ghana.

MethodsA paper-based questionnaire survey was conducted among traders found in a convenient sample of shops in the Central Business District (CBD) between November 2016 and January 2017. The data was analyzed with Stata version 14.0. Antibiotic self-medication was defined as the use of antibiotics without the prescription of a recognized practitioner within 12 months of the survey. Descriptive analysis and analytical statistics using multivariate logistic regression analysis were performed to identify the factors associated with antibiotic self-medication.

ResultsFour hundred and seventeen (417) traders (60.0% females) with a mean age of 36 (+10.6) years were surveyed. The prevalence of antibiotic self-medication was 66.7%. Penicillins were the most misused. Upper respiratory infections and gastrointestinal tract infections were the leading reasons for antibiotic self-medication. The most common sources of information on self-medicated antibiotics were community pharmacies (55.2%), doctors (17.8%), and package inserts (17.2%). People with tertiary education were less likely to use antibiotics for self-medication compared to those with no education (OR=0.39 (95% C.I; 0.16-0.98). Persons who sold food items (aOR = 3.56, 95% CI; 1.70-7.45), cosmetics (aOR = 2.61, 95% CI; 1.34-5.09), and clothing (aOR= 3.39, 95% CI; 1.88-6.12) were more likely to use antibiotics for self medication compared to those who sold other items.

ConclusionSelf-medication with antibiotics was high among traders in the CBD of Accra, Ghana. Traders need to be educated on the proper home management of URTIs. Measures are required to restrict their access to antibiotics for self-medication.

category: epidemiology


title: Serological Response to BNT162b2 and ChAdOx1 nCoV-19 Vaccines in Patients with Inflammatory Bowel Disease on Biologic Therapies; A Multi-Center Prospective Study

abstract:
IntroductionImmunogenicity of SARS-CoV-2 vaccines in patients with inflammatory bowel disease (IBD) on biologics are not well studied. The goal of this study is to measure serological response to BNT162b2 and ChAdOx1 nCoV-19 vaccines in patients with IBD receiving different biologic therapies.

MethodWe performed a multi-center prospective study between August 1st, 2021, and September 15th, 2021. We measured seropositivity of SARS-CoV2 antibodies, SARS-CoV-2 IgG and neutralizing antibody concentrations, in patients with IBD receiving biologic therapies between 4-10 weeks after second dose or 3-6 weeks after first dose of vaccination with BNT162b2 or ChAdOx1 nCoV-19 vaccines.

ResultsThere were 126 patients enrolled (mean age, 31 years; 60% male; 71% Crohns disease, 29% ulcerative colitis). 92 patients were vaccinated with BNT162b2 vaccine (73%) and 34 patients with ChAdOx1 nCoV-19 vaccine (27%). The proportion of patients who achieved positive anti-SARS-CoV-2 IgG antibody levels after receiving 2 doses of the vaccine in patients treated with infliximab and adalimumab were 44 out of 59 patients (74.5%) and 13 out of 16 patients (81.2%), respectively. Whereas the proportion of patients who achieved positive anti-SARS-CoV-2 IgG antibody levels after receiving two doses of the vaccine in patients treated with ustekinumab and vedolizumab were 100% and 92.8%, respectively. In patients receiving infliximab and adalimumab, the proportion of patients who had positive anti-SARS-CoV-2 neutralizing antibody levels after two-dose vaccination was 40 out of 59 patients (67.7%) and 14 out 16 patients (87.5%), respectively. Whereas the proportions of patients who had positive anti-SARS-CoV-2 neutralizing antibody levels were 12 out of 13 patients (92.3%) and 13 out of 14 patients (92.8%) in patients receiving ustekinumab and vedolizumab.

ConclusionThe majority of patients with IBD on infliximab, adalimumab, and vedolizumab seroconverted after two doses of SARS-CoV-2 vaccination. All patients on ustekinumab seroconverted after two doses of SARS-CoV-2 vaccine. BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 are both likely to be effective after two doses in patients with IBD on biologics. A follow up larger studies are needed to evaluate if decay of antibodies occurs over time.

category: gastroenterology


title: Longitudinal associations of behavioral problems and text reading skills in school-aged children born term and preterm

abstract: A SummaryWe assessed the contribution of total behavioral problems at 6 years to text reading skills at 8 years in children born term and preterm. Birth group moderated associations among total behavioral problems and reading skills; total behavioral problems predicted reading skills in the term but not preterm group.

category: pediatrics


title: Association between maternal depression and the nutritional status of children under five-years-old in Peru: An analysis of the Demographic and Health Survey 2014-2017

abstract:
ObjectiveTo evaluate the association between maternal depression and nutritional status of children under 5 years old in Peru.

DesignCross-sectional study of the Demographic and Health Survey 2014-2017. Outcomes were mild (height Z-score for age <-2 SD) and moderate/severe (<-3DE) childhood chronic undernutrition and also mild (hemoglobin <11 g/dL) and moderate/severe (hemoglobin <10 g/dL) childhood anemia. Maternal depression was assessed by the questionnaire PHQ-9. Odds ratios and their confidence intervals (CIs) were estimated by multinomial logistic regression models, considering the complex sample design.

SettingPeru

ParticipantsPeruvian women of childbearing age from 15 to 49 years who live with children from 6 to 59 months.

ResultsMaternal depression was significantly associated with a higher odds of moderate/severe chronic undernutrition in children aged 6-59 months (OR = 2.67; 95% CI 1.16-6.16).

ConclusionsThere was evidence that maternal depression was associated with an increased risk of moderate/severe chronic undernutrition


title: The socio-economic difference in the prevalence and treatment of diarrheal disease in children under five years across the geo-political zones in Nigeria

abstract:
BackgroundDiarrhoeal disease is one of the leading causes of mortality among under-5 children globally and affects the low socio-economic population.

ObjectivesThis study aimed at evaluating the socioeconomic differences in the prevalence and its effect on the treatment of diarrheal disease in children in the different geopolitical zone in Nigeria.

MethodsData of children under-5 from the 2018 Nigeria Demographic and Health Survey (NDHS) was used. A total of 30,068 women, that had at least a child under-5 years of age and answered diarrhoea specific questions were analysed for the prevalence, while data on 3885 children that reported symptoms of diarrhoea during the 2 weeks preceding the NDHS survey interview were analysed for treatment intervention offered during diarrhoea episodes. Logistic regression models adjusted for socio-demographic factors were used to study the association.

ResultsThe overall prevalence of diarrhoea was 12.9% with the highest prevalence in the North East (24.7%), among the poor (17.1%) and the children of uneducated mothers (16.4%). Compared to South-West region, children in North-East (AOR 4.64, 95% CI 3.90, 5.51), North-West (AOR 2.34, 95% CI 1.97, 2.78) and North Central (AOR 2.02, 95% CI 1.69, 2.42) had a high likelihood of having diarrhoea. Children from a poor household (AOR 1.49, 95% CI 1.31, 1.70) had more chance of having diarrhoea. Children in North-East (AOR 2.11, 95% CI 1.49, 3.01) and North-West (AOR 2.52, 95% CI 1.77, 3.60) were more likely to receive treatment in a health care facility and also had less likely to receive more amount of drink and food during diarrhoea compared to South-West region.

ConclusionsDiarrhoea prevalence is high in Nigeria with significant regional difference both in the prevalence and treatment of diarrheal disease which is also associated with household socio-economic status.


title: Underlying factors that influence the acceptance of COVID-19 vaccine in a country with a high vaccination rate

abstract: Control of the COVID-19 pandemic largely depends on the effectiveness of the vaccination. Several factors including vaccine hesitancy can affect the vaccination process. Understanding the factors that underlie the willingness to accept vaccination brings pivotal information to control the pandemic. We analyzed the association between the willingness level to accept the COVID-19 vaccine, and vaccine determinants amidst the Chilean vaccination process. Individual-level survey data was collected from nationally representative samples of 744 respondents, and multivariate regression models used to estimate the association between outcome and explanatory variables. We found that trust in the COVID-19 vaccine, scientists, and medical professionals increased the willingness to: accept the vaccine, a booster dose, annual vaccination, and children vaccination. Our results are critical to understand the acceptance of COVID-19 vaccines in the context of a country with one of the worlds highest vaccination rates. We provide information for decision-making, policy design and communication of vaccination programs.


title: Estimating treatment effect for individuals with progressive multiple sclerosis using deep learning

abstract: Modeling treatment effect could identify a subgroup of individuals who experience greater benefit from disease modifying therapy, allowing for predictive enrichment to increase the power of future clinical trials. We use deep learning to estimate the conditional average treatment effect for individuals taking disease modifying therapies for multiple sclerosis, using their baseline clinical and imaging characteristics. Data were obtained as part of three placebo-controlled randomized clinical trials: ORATORIO, OLYMPUS and ARPEGGIO, investigating the efficacy of ocrelizumab, rituximab and laquinimod, respectively. A shuffled mix of participants having received ocrelizumab or rituximab, anti-CD20-antibodies, was separated into a training (70%) and testing (30%) dataset, but we also performed nested cross-validation to improve the generalization error estimate. Data from ARPEGGIO served as additional external validation. An ensemble of multitask multilayer perceptrons was trained to predict the rate of disability progression on both active treatment and placebo to estimate the conditional average treatment effect. The model was able to separate responders and non-responders across a range of predicted effect sizes. Notably, the average treatment effect for the anti-CD20-antibody test set during nested cross-validation was significantly greater when selecting the models prediction for the top 50% (HR 0.625, p=0.008) or the top 25% (HR 0.521, p=0.013) most responsive individuals, compared to HR 0.835 (p=0.154) for the entire group. The model trained on the anti-CD20-antibody dataset could also identify responders to laquinimod, finding a significant treatment effect in the top 30% of individuals (HR 0.352, p=0.043). We observed enrichment across a broad range of baseline features in the responder subgroups: younger, more men, shorter disease duration, higher disability scores, and more lesional activity. By simulating a 1-year study where only the 50% predicted to be most responsive are randomized, we could achieve 80% power to detect a significant difference with 6 times less participants than a clinical trial without enrichment. Subgroups of individuals with primary progressive multiple sclerosis who respond favourably to disease modifying therapies can therefore be identified based on their baseline characteristics, even when no significant treatment effect can be found at the whole-group level. The approach allows for predictive enrichment of future clinical trials, as well as personalized treatment selection in the clinic.


title: Improving Power and Accuracy in Randomized Controlled Trials of Pain Treatments by Accounting for Concurrent Analgesic Use: Statistical Simulations and Analyses of Randomized Controlled Trial Data

abstract: The 0 to 10 numeric rating scale (NRS) of pain intensity is a standard outcome in randomized controlled trials (RCTs) of pain treatments. For individuals taking analgesics, there may be a disparity between "observed" pain intensity (the NRS, irrespective of concurrent analgesic use), and "underlying" pain intensity (what the NRS would be had concurrent analgesics not been taken). Using a contemporary causal inference framework, we compare analytic methods that can potentially account for concurrent analgesic use, first in statistical simulations, and second in analyses of real (non-simulated) data from an RCT of lumbar epidural steroid injections (LESI). The default analytic method was ignoring analgesic use, which is the most common approach in pain RCTs. Compared to ignoring analgesic use and other analytic methods, simulations showed that a quantitative pain and analgesia composite outcome based on adding 1.5 points to observed pain intensity for those who were taking an analgesic (the QPAC1.5) optimized power and minimized bias. Analyses of real RCT data supported the results of the simulations, showing greater power with analysis of the QPAC1.5 as compared to ignoring analgesic use and most other methods examined. We propose alternative methods that should be considered in the analysis of pain RCTs.

category: pain medicine


title: Efficacy and Safety of SOBERANA 02, a COVID-19 conjugate vaccine in heterologous three doses combination

abstract:
BackgroundSOBERANA 02 is a COVID-19 conjugate vaccine (recombinant RBD conjugated to tetanus toxoid). Phase 1 and 2 clinical trials demonstrated its high immunogenicity, promoting neutralizing IgG and specific T-cell response. A third dose, of SOBERANA Plus (RBD-dimer), further increased the specific anti-RBD neutralizing antibodies.

MethodsIn a randomized, double-blind, placebo-controlled, phase-3 trial (https://rpcec.sld.cu/trials/RPCEC00000354-En) we randomly assigned 44 031 participants, aged 19-80 years to three groups to receive a) two doses, SOBERANA 02, or b) two doses, SOBERANA 02 and a third dose, SOBERANA Plus, or c) placebo. Study endpoints are vaccine efficacy (VE) evaluated through confirmed symptomatic COVID-19 and safety. During the trial, the SARS CoV-2 isolates in Havana were 74.0 % {beta}, shifting gradually to 100% {delta}.

ResultsTwo doses of SOBERANA 02 protected against symptomatic COVID-19: 43 cases in the two-dose group (14 371) vs. 155 in the placebo group (14 403), VE 71.0%, adjusted (CI 95%, 58.9-79.1). The heterologous three-dose combination increased the protection: 15 cases in the vaccine groups (13 833) vs. 155 in the placebo group (14 303), VE 92.4%, adjusted (CI 95%, 86.9-95.6%). For the two-dose schedule, VE against severe COVID-19 was 63.0% and for death, 59.0%; for the heterologous three-dose schedule, VE was 100% in both cases.

ConclusionsThis is the first phase-3 study of a three-dose, heterologous COVID-19 vaccine. Two doses of SOBERANA 02 were safe and attained efficacy of 71.0% in the adult population 19-80 y/o; incorporating SOBERANA Plus increased efficacy from 71.0 % to 92.4%.


title: Efficacy and safety of SOBERANA 02, a COVID-19 conjugate vaccine in heterologous three-dose combination


title: Pay-it-forward to improve influenza vaccine uptake and public engagement among children and older adults in China

abstract:
BackgroundChina has low seasonal influenza vaccination rates among children and older adults. This quasi-experimental pragmatic trial examined the effectiveness of a pay-it-forward intervention on influenza vaccination compared to standard-of-care (user-paid vaccination) among children and older people in China. Pay-it-forward offered a free influenza vaccine from a local group and an opportunity to donate financially to support future individuals.

MethodsAt each of the three study sites, participants were recruited into the standard-of-care arm first until expected sample size was reached and then recruited into the pay-it-forward arm. The primary outcome was vaccine uptake. Secondary outcomes included vaccine confidence and costs. Regression methods compared influenza vaccine uptake and vaccine confidence between the two arms.

ResultsAmong 300 participants enrolled, 55/150(36.7%) in the standard-of-care arm 111/150(74.0%) in the pay-it-forward arm received an influenza vaccine. People in the pay-it-forward arm were more likely to receive the vaccine compared to people in the standard-of-care arm (adjusted odds ratio (aOR)= 6.7, 95%CI [2.7, 16.6] among children; aOR=5.0, [2.3, 10.8] among older adults). People in the pay-it-forward arm had greater confidence in vaccine safety, importance, and effectiveness. In the pay-it-forward arm, 107/111 (96.4%) of participants donated money for subsequent vaccinations, and 19 of 60 invited (31.7%) created postcard messages. The pay-it-forward arm had a lower economic cost per person vaccinated ($45.60) than the standard-of-care arm ($64.67).

ConclusionsPay-it-forward was effective in improving influenza vaccine uptake and public engagement. Our data have implications for pro-social interventions to enhance influenza vaccine uptake in countries where influenza vaccines are available for a fee.

Trial registrationChiCTR2000040048

Main point summaryPay-it-forward substantially increased influenza vaccine uptake among children and older adults compared to standard of care user-paid vaccination.


title: Pay-it-forward to improve influenza vaccine uptake and public engagement among children and older adults in China: three-arm quasi-experimental pragmatic trial


title: Pay-it-forward to improve influenza vaccine uptake and public engagement among children and older adults in China: A quasi-experimental pragmatic trial


title: Modelling COVID-19 Pandemic Dynamics Using Transparent, Interpretable, Parsimonious and Simulatable (TIPS) Machine Learning Models: A Case Study from Systems Thinking and System Identification Perspectives

abstract: Since the outbreak of COVID-19, an astronomical number of publications on the pandemic dynamics appeared in the literature, of which many use the susceptible infected removed (SIR) and susceptible exposed infected removed (SEIR) models, or their variants, to simulate and study the spread of the coronavirus. SIR and SEIR are continuous-time models which are a class of initial value problems (IVPs) of ordinary differential equations (ODEs). Discrete-time models such as regression and machine learning have also been applied to analyze COVID-19 pandemic data (e.g. predicting infection cases), but most of these methods use simplified models involving a small number of input variables pre-selected based on a priori knowledge, or use very complicated models (e.g. deep learning), purely focusing on certain prediction purposes and paying little attention to the model interpretability. There have been relatively fewer studies focusing on the investigations of the inherent time-lagged or time-delayed relationships e.g. between the reproduction number (R number), infection cases, and deaths, analyzing the pandemic spread from a systems thinking and dynamic perspective. The present study, for the first time, proposes using systems engineering and system identification approach to build transparent, interpretable, parsimonious and simulatable (TIPS) dynamic machine learning models, establishing links between the R number, the infection cases and deaths caused by COVID-19. The TIPS models are developed based on the well-known NARMAX (Nonlinear AutoRegressive Moving Average with eXogenous inputs) model, which can help better understand the COVID-19 pandemic dynamics. A case study on the UK COVID-19 data is carried out, and new findings are detailed. The proposed method and the associated new findings are useful for better understanding the spread dynamics of the COVID-19 pandemic.


title: Development and Validation of an Interpretable 3-day Intensive Care Unit Readmission Prediction Model Using Explainable Boosting Machines

abstract: Intensive care unit readmissions are associated with mortality and bad outcomes. Machine learning could help to identify patients at risk to improve discharge decisions. However, many models are black boxes, so that dangerous properties might remain unnoticed. In this study, an inherently interpretable model for 3-day ICU readmission prediction was developed. We used a retrospective cohort of 15,589 ICU stays and 169 variables collected between 2006 and 2019. A team of doctors inspected the model, checked the plausibility of each component, and removed problematic parts. Qualitative feedback revealed several challenges for interpretable machine learning in healthcare. The resulting model used 67 features and showed an area under the precision-recall curve of 0.119{+/-}0.020 and an area under the receiver operating characteristic curve of 0.680{+/-}0.025. This is on par with state-of-the-art gradient boosting machines and outperforms the Simplified Acute Physiology Score II. External validation with the Medical Information Mart for Intensive Care database version IV confirmed our findings. Hence, a machine learning model for readmission prediction with a high level of human control is feasible without sacrificing performance.


title: Defining the Proteomic and Phosphoproteomic Landscape of Circulating Extracellular Vesicles in the Diabetes Spectrum

abstract: The purpose of this study was to characterize the proteomic and phosphoproteomic profiles of circulating extracellular vesicles (EVs) from people with normal glucose tolerance (NGT), prediabetes (PDM), and diabetes (T2DM). Archived serum samples from 30 human subjects (N=10 per group, ORIGINS study, ClinicalTrials.gov NCT02226640) were used. EVs were isolated using EVTRAP (Tymora). Mass spectrometry (LC-MS)-based methods were used to detect the global EV proteome and phosphoproteome. Differentially expressed features, correlation networks, enriched pathways, and enriched tissue-specific protein sets were identified using custom R scripts. A total of 2372 unique EV proteins and 716 unique EV phosphoproteins were identified. Unsupervised clustering of the differentially expressed (fold change[≥]2, P<0.05, FDR<0.05) proteins and, particularly, phosphoproteins, showed excellent discrimination among the three groups. Among characteristic changes in the PDM and T2DM EVs, "integrins switching" appeared to be a central feature. Proteins involved in oxidative phosphorylation (OXPHOS), known to be reduced in various tissues in diabetes, were significantly increased in EVs from PDM and T2DM, which suggests that an abnormally elevated EV-mediated secretion of OXPHOS components may underlie development of diabetes. We also detected a highly enriched signature of liver-specific markers among the downregulated EV proteins and phosphoproteins in both PDM and T2DM groups. This suggests that an alteration in liver EV composition and/or secretion may occur early in prediabetes. Levels of signaling molecules involved in cell death pathways were significantly altered in the circulating EVs. Consistent with the fact that patients with T2DM have abnormalities in platelet function, we detected a significant enrichment (FDR<<0.01) for upregulated EV proteins and phosphoproteins that play a role in platelet activation, coagulation, and chemokine signaling pathways in PDM and T2DM. Overall, this pilot study demonstrates the potential of EV proteomic and phosphoproteomic signatures to provide insight into the pathobiology of diabetes and its complications. These insights could lead to the development of new biomarkers of disease risk, classification, progression, and response to interventions that could allow personalization of interventions to improve outcomes.


title: Coordinated regulation of gene expression and microRNA changes in adipose tissue and circulating extracellular vesicles in response to pioglitazone treatment in humans with type 2 diabetes

abstract:
Pioglitazone, a PPAR{gamma} agonist, is used to treat type 2 diabetes (T2D). PPAR{gamma} is highly expressed in adipose tissue (AT), however the effects of pioglitazone to improve insulin sensitivity are also evident in other tissues. We hypothesized that pioglitazone modifies the cargo of circulating AT-derived extracellular vesicles (EVs) to alter interorgan crosstalk. We tested this in a 3-month trial in which 24 subjects with T2D who were well-controlled with diet/exercise or metformin were randomized to treatment with either pioglitazone 45 mg/day or placebo (NCT00656864). Levels of 42 adipocyte-derived EV-miRNAs were measured in plasma EVs. Levels of 5 miRNAs (i.e., miR-7-5p, miR-20a-5p, miR-92a-3p, miR-195-5p, and miR-374b-5p) were significantly downregulated in EVs in response to pioglitazone treatment relative to placebo. However, the opposite occurred for miR-195-5p in subcutaneous AT from the same participants. Changes in miRNA expression in EVs and AT correlated with changes in suppression of lipolysis and improved insulin sensitivity, among others. DICER was downregulated and exosomal miRNA sorting-related genes YBX1 and hnRNPA2B1 displayed a trend toward downregulation in AT. Furthermore, analysis of EV-miRNA targeted genes identified a network of overtargeted transcripts that changed in a coordinated manner in AT. Collectively, our results suggest that some beneficial pharmacologic effects of PIO are mediated by adipose-specific miRNA regulation and exosomal/EV trafficking.

Disclosure summaryThis study was funded by program funds granted to REP by the AdventHealth Translational Research Institute. The clinical trial was supported by an investigator initiated grant to REP from Takeda Pharmaceuticals North America. REP reports grants from Hanmi Pharmaceutical Co.; grants from Janssen; consulting fees from Merck; grants, speaker fees and consulting fees from Novo Nordisk; consulting fees from Pfizer; grants from Poxel SA; grants and consulting fees from Sanofi; consulting fees from Scohia Pharma Inc.; consulting fees from Sun Pharmaceutical Industries. AC reports consulting fees from GlaxoSmithKline. Honoraria and fees for REPs and ACs services were paid directly to AdventHealth, a nonprofit organization. No other potential conflicts of interest relevant to this article were reported.


title: Quantifying the effects of non-pharmaceutical and pharmaceutical interventions against COVID-19 epidemic in the Republic of Korea: Mathematical model-based approach considering age groups and the Delta variant

abstract:
BackgroundEarly vaccination efforts and non-pharmaceutical interventions were insufficient to prevent a surge of coronavirus disease 2019 (COVID-19) cases triggered by the Delta variant. This study aims to understand how vaccination and variants contribute to the spread of COVID-19 so that appropriate measures are implemented.

MethodsA compartment model that includes age, vaccination, and infection with the Delta or non-Delta variants was developed. We estimated the transmission rates using maximum likelihood estimation and phase-dependent reduction effect of non-pharmaceutical interventions (NPIs) according to government policies from 26 February to 8 October 2021. We extended our model simulation until 31 December considering the initiation of eased NPIs. Furthermore, we also performed simulations to examine the effect of NPIs, arrival timing of Delta variant, and speed of vaccine administration.

ResultsThe estimated transmission rate matrices show distinct pattern, with the transmission rates of younger age groups (0 39 years) much larger than non-Delta. Social distancing (SD) level 2 and SD4 in Korea were associated with transmission reduction factors of 0.64 to 0.69 and 0.70 to 0.78, respectively. The easing of NPIs to a level comparable to SD2 should be initiated not earlier than 16 October to keep the number of severe cases below the capacity of Koreas healthcare system. Simulation results also showed that a surge prompted by the spread of the Delta variant can be prevented if the number of people vaccinated daily was larger.

ConclusionsSimulations showed that the timing of easing and intensity of NPIs, vaccination speed, and screening measures are key factors in preventing another epidemic wave.

2 Key MessagesO_LIMaximum likelihood estimation can be utilized to determine the transmission rates of the Delta and non-Delta variants.
C_LIO_LIThe phase-dependent NPIs implemented by the Korean government were effectively quantified in the modelling study.
C_LIO_LIEven with fast vaccination, resurgence of cases is still possible if NPIs are eased too early or screening measures are relaxed.
C_LIO_LIThe model can be used as a guide for policy makers on deciding appropriate SD level that considers not only disease control, but also the socio-economic impact of maintaining strict measures.
C_LI


title: Predictors of COVID testing among Australian youth: Insights from the Longitudinal Study of Australian Children

abstract:
BackgroundTesting has played a crucial role in reducing the spread of COVID. Although COVID symptoms tend to be less severe in children and adolescents, a key concern is young peoples role in the transmission of the virus given their highly social lifestyles. In this study, we aimed to identify the predictors associated with COVID testing in Australian youth using data from the Longitudinal Study of Australian Children (LSAC).

MethodsWe used the latest wave 9C1 of the LSAC, where data were collected from 16-21-year-old Australians via an online survey between October and December 2021. In total, 2291 Australian youths responded to the questions about COVID testing and COVID symptom severity. Data was stratified by living with/without parents, and bivariate and logistic regression analyses examined predictor variables (age, sex, country of birth, remoteness, education level, employment, relationship status, number of household members, living with parents, receiving the COVID financial supplement from government and index of relative socio-economic advantage and disadvantage) and their distributions over the outcome variable COVID testing.

ResultsYouths aged 16-17 were more likely to live at home than youths aged 20-21 years. The strongest predictor of COVID testing was living in major cities (regardless of living with or without parents). Changed household composition was significantly associated with COVID testing among the youths living in the parental home. While among the respondents living without their parents, living with multiple household members and low or no cohesion among household members was associated with higher rates of COVID testing.

ConclusionOur study revealed young people have been very good at getting tested for COVID. To further incentivise testing in this age group, we should consider providing this age group with continued financial and social support while awaiting the outcome of the test and during any isolation.

Strengths and limitations of this studyO_LILarge national cohort of young people strengthened the findings of the study and allowing us to examine the factors associated with COVID testing for the first time in Australia.
C_LIO_LIA broad-based assessment of potential predictors of COVID testing, including sociodemographic and coronavirus specific factor.
C_LIO_LICross-sectional observational design limits causal inference.
C_LIO_LISelf-reported information about COVID testing can be subject to recall as well as social desirability bias.
C_LI


title: Temporal Trends in Racial and Ethnic Disparities in Sleep Duration in the United States: A National Health Interview Survey Analysis from 2004 to 2018

abstract:
ImportanceMinoritized racial and ethnic groups are generally more likely to experience sleep deficiencies. It is unclear how these sleep duration disparities have changed over recent years.

ObjectiveTo determine 15-year trends in the racial and ethnic differences in self-reported sleep duration among adults in the US.

DesignSerial cross-sectional study of the National Health Interview Survey from years 2004- 2018. Analyses were performed between July 26, 2021 and February 10, 2022.

SettingUS population-based.

Participants429,195 non-institutionalized adults.

ExposuresSelf-reported race, ethnicity, household income, and sex/gender.

Main OutcomesTemporal trends and racial/ethnic differences in short- and long-sleep duration (<7 and >9 hours in a 24-hour period, respectively), and racial/ethnic differences in the relationship between sleep duration and age.

ResultsThe study sample consisted of 429,195 individuals (mean age 46.5 [SE, 0.08] years; 51.7% female) of which 5.1% identified as Asian, 11.8% as Black, 14.7% as Latino/Hispanic, and 68.5% as White. In 2004, the adjusted estimated prevalence of short-sleep duration and long-sleep duration, respectively, were 31.3% and 2.5% among Asian individuals, 35.3% and 6.4% among Black individuals, 27.0% and 4.6% among Latino/Hispanic individuals, and 27.8% and 3.5% among White individuals. Over the study period, there was a significant increase in the short sleep prevalence among Black, Latino/Hispanic, and White individuals (P[≤]0.001 for each), whereas prevalence of long sleep changed significantly only among Latino/Hispanic individuals (-1.4 points, P=0.01). In 2018, compared with White individuals, short sleep prevalence among Black and Latino/Hispanic individuals was higher by 10.7 points and 2.4 points, respectively

(P[≤]0.03 each), and long sleep prevalence was higher only among Black people (+1.4 points; P=0.01). The short-sleep disparities were the greatest among women and among those with middle/high household income. In addition, across age groups, Black individuals had a higher short- and long-sleep duration prevalence compared with White individuals of their same age.

ConclusionsIn this serial cross-sectional study from 2004 to 2018, the prevalence of short and long sleep duration was persistently higher among Black individuals. The Black-White disparities in short-sleep were highest among women, individuals who had middle or high income, and among young or middle-aged adults.

KEY POINTSO_ST_ABSQuestionC_ST_ABSHow have racial and ethnic differences in self-reported sleep duration among US adults changed between 2004 and 2018?

FindingsIn this serial cross-sectional study that included 429,195 adults, the prevalence of both short and long sleep duration were persistently higher among Black individuals over the 15-year study period. The disparities in short sleep duration were highest for Black women, Black individuals with middle or high income, and young and middle-aged Black adults.

MeaningThere were marked racial and ethnic differences in sleep duration that persisted from 2004 to 2018, which may be contributing to health disparities.


title: Temporal Trends in Racial and Ethnic Disparities in Sleep Duration in the United States, 2004-2018


title: Regional variability, genotypic effects, and pharmacodynamic impact on prion protein concentration in the central nervous system

abstract: Prion protein (PrP) concentration controls the kinetics of prion replication and is a genetically and pharmacologically validated therapeutic target for prion disease. In order to evaluate PrP concentration as a pharmacodynamic biomarker and assess its contribution to known prion disease risk factors, we developed and validated a plate-based immunoassay reactive for PrP across six species of interest and applicable to brain and cerebrospinal fluid (CSF). PrP concentration varies dramatically between different brain regions in mice, cynomolgus macaques, and humans. PrP expression does not appear to contribute to the known risk factors of age, sex, or common PRNP genetic variants. CSF PrP is lowered in the presence of rare pathogenic PRNP variants, with heterozygous carriers of P102L displaying 55% and of D178N just 31% the CSF PrP concentration of mutation-negative controls. In rodents, pharmacologic reduction of brain Prnp RNA is reflected in brain parenchyma PrP, and in turn in CSF PrP, validating CSF as a sampling compartment for the effect of PrP-lowering therapy. Our findings support the use of CSF PrP as a pharmacodynamic biomarker for PrP-lowering drugs, and suggest that relative reduction from individual baseline CSF PrP concentration may be an appropriate marker for target engagement.


title: PrP concentration in the central nervous system: regional variability, genotypic effects, and pharmacodynamic impact


title: The structure and organization of headache differential diagnoses: A Pilot Study of Subset Relationships between Differentials in ICHD3

abstract:
Structured AbstractO_ST_ABSObjectiveC_ST_ABSDifferential diagnosis is fundamental to medicine. Using DiffNet, a differential diagnosis generator, as a model we studied the structure and organization of how collections of diagnose (i.e. sets of diagnoses) are related in the ICHD3. Specifically, we asked: Which sets of differential diagnoses are subsets of each other? What is the minimum number of sets of differential diagnoses that encompass all ICHD3 codes? Furthermore, we explored the clinical and theoretical implication of these answers.

MethodsDiffNet is a freely distributed differential diagnosis generator for headaches using graph theoretical properties of ICHD3. For each ICHD3 diagnosis, we generated a set of differential diagnoses using DiffNet. We then determined algorithmically the set/subset relationship between these sets. We also determined the smallest list of ICHD3 diagnosis whose differential diagnoses would encompass the totality of ICHD3 diagnoses.

ResultsAll ICHD3 diagnoses can be represented by a minimum of 92 differential diagnosis sets. Differential diagnosis sets for 10 of the 14 first digit subcategories of ICHD3 are represented by more than one differential diagnosis sets. Fifty-one of the 93 differential diagnosis sets contain multiple subset relationships; the remaining 42 do not enter into any set/subset relationship with other differential diagnosis sets. Finally, we included a hierarchical presentation of differential diagnosis sets in ICHD3 according to DiffNet.

ConclusionWe propose a way of interpreting headache differential diagnoses as partial ordered sets (i.e. poset). For clinicians, fluency with the 93 diagnoses and their differential put forth here implies a complete description of ICHD3. On a theoretical level, interpreting ICHD3 differential diagnosis as poset, allows researchers to translate differential diagnoses sets topologically, algebraically, and categorically.


title: The contribution of common regulatory and protein-coding TYR variants in the genetic architecture of albinism

abstract: Genetic diseases have been historically segregated into rare Mendelian and common complex conditions.1,2 Large-scale studies using genome sequencing are eroding this distinction and are gradually unmasking the underlying complexity of human traits.3-8 Aiming to gain insights into the genetic architecture of rare recessive disorders, we studied a cohort of 1,313 individuals with albinism, an archetypal Mendelian condition. We investigated the contribution of protein-coding and regulatory variants both rare and common. We focused on TYR, the gene encoding tyrosinase, and found that a high-frequency promoter variant, TYR c.-301C>T [rs4547091], modulates the penetrance of a prevalent, disease-associated missense change, TYR c.1205G>A [rs1126809]. We also found that homozygosity for a haplotype formed by three common, functionally-relevant variants, TYR c.[-301C;575C>A;1205G>A], is associated with a high probability of receiving an albinism diagnosis (OR>82). This genotype is also associated with reduced visual acuity and increased central retinal thickness in UK Biobank participants. Finally, we report how the combined analysis of rare and common variants increases diagnostic yield and informs genetic counselling in families with albinism.


title: Wikipedia Drug Safety Advisory Committee: Distilling a Drug Adverse Effect Reference Set Using Wisdom of the Crowd

abstract:
BackgroundLarge datasets of relational medical data, such as the adverse effects of drugs or vaccines, typically attain their large size, by relying on automatic, or semi-automatic, methods for generation. This often comes with a compromise on the precision of the generated data, which can be at least partially alleviated by having experts curate the data.

AimSince having experts review a large dataset can be costly and time consuming, here we suggest using Wikipedia for this task - that is, augment the automatic generation step by an automatic curation step based on the expert knowledge accumulated in Wikipedia.

MethodsTo curate a dataset of adverse drug effects (ADEs), we suggest retrieving the Wikipedia page associated with the drug, and checking whether the ADE appears in the sections describing adverse effects. Drug indications, typically described in the opening paragraph of the page, are similarly filtered out.

ResultsWe use the method to curate two large adverse drug effect datasets and show that the obtained datasets have a much higher precision relative to their originating ones.

ConclusionsAlgorithms which aim to infer drug-ADE relations, should at the very least be able to identify the "clear cut" cases. The high-precision benchmark constructed herein may therefore be a valuable resource for the evaluation of such algorithms.


title: Distilling a High Precision Drug Adverse Effect Benchmark Using Wikipedia's Wisdom of the Crowd


title: Anti-SARS-CoV-2 vaccination does not induce the formation of autoantibodies but provides humoral immunity following heterologous and homologous vaccination regimens: Results from a clinical and prospective study within professionals of a German University Hospital

abstract: By the end of 2019 a global pandemic by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV2) causing the coronavirus disease-19 (COVID-19) has emerged. Yet, COVID-19 represents a significant economic burden to healthcare systems, destabilizes global financial markets and has caused the death of almost 5 million people worldwide. In order to prevent severe disease courses of COVID-19 especially in elderly and to establish collective immunity on the long run, different vaccines have been developed, tested and were approved within a very short time period. In Germany, the first vaccines that have been approved by local authorities were AstraZenecas vector virus-based vaccine Vaxzevria and the mRNA vaccines Comirnaty and Spikevax, developed by BioNTech and Moderna, respectively. As it was reported that the novel coronavirus SARS-CoV2 can trigger autoimmunity, it is of significant interest to investigate whether anti-SARS-CoV2 vaccines evoke the formation of autoantibodies and subsequent autoimmunity. Here, we did set out to systematically analyze immune responses after homologous vaccinations with mRNA or vector virus-based vaccines or after heterologous Vector/mRNA vaccinations with respect to anti-COVID-19 immune responses and, in parallel, the development of autoantibodies. In our study, we obtained serum samples one day before and 14 as well as 28 days following booster vaccination and tested them for anti-SARS-CoV2 antibodies and for autoantibodies against Cardiolipin, Prothrombin, {beta}2-Glycoprotein, cyclic citrullinated peptides (CCP), tissue-transglutaminase (TTG) and anti-nuclear antibodies (ANA). We find that compared to homologous mRNA and heterologous Vector/mRNA vaccination, anti-SARS-CoV2 antibody levels were 90% lower after homologous vector vaccination. Of note, heterologous Vector/mRNA vaccination was found to be more effective than homologous mRNA vaccination in terms of IgM and IgA responses against SARS-CoV2. However, in terms of autoantibody generation, we only detected increases after booster vaccination in participants with already pre-existing autoantibodies. In contrast, vaccinees showing no autoantibody formation before vaccination, did not respond with sustained autoantibody production upon vaccination. Taken together, our study suggests that all used SARS-CoV2 vaccines do not significantly foster autoantibody production over time but provide humoral immunity to SARS-CoV2.


title: Patient ABO blood type is a major predictor of a positive DAT following a transfusion reaction

abstract:
BackgroundA direct antiglobulin test (DAT) checks for antibody or complement on the surface of RBCs and is often done following a transfusion reaction. While passive anti-A and anti-B antibodies are known to cause positive DATs, the extent this occurs following transfusion is unknown.

Study Design and methodsDAT results, ABO type and blood product information was recorded on 1097 transfusion reactions at a large academic hospital over 8 years. The effect of patient blood type, product type and plasma compatibility of blood product transfused on DAT results were determined. Statistical significance was determined using Chi-squared testing.

ResultsPlasma compatibility of the product was a strong predictor of a positive DAT with plasma compatible transfusions having a 9.4% positive rate while plasma incompatible transfusions were positive 44% of the time (P<0.0001). Patient ABO blood type was a strong predictor of a positive DAT with Type O patients having 6.6% positive rate and non-O patients having a positive rate of 20.6% (P <0.0001). These results were significant for individual blood types as well. Type A, B or AB patients had higher DAT positive rates even when plasma incompatible transfusions were excluded from the analysis (P<0.0001). Platelets were significantly more likely to be associated with a positive DAT when compared to RBC transfusions.

ConclusionsThese results show plasma compatibility and ABO types are strong predictors of positive DAT results following a transfusion reaction. Anti-A and anti-B antibodies are estimated to account for about 50% of positive DATs in this study.

category: pathology


title: Quantitative insights into effects of intrapartum antibiotics and birth mode on infant gut microbiota in relation to well-being during the first year of life

abstract:
Background and aimsCaesarean section (CS)-birth and maternally administered intrapartum antibiotics (IP) affect colonization of the neonate. We compared the effects of CS delivery and IP antibiotics on infant gut microbiota development and wellbeing over the first year. To understand the developing community dynamics, we focused on absolute bacterial abundance estimates over relative abundances.

MethodsWe studied 144 healthy infants born between gestational weeks 37-42 vaginally without antibiotics (N=58), with IP penicillin (N=25) or cephalosporin (N=13), or by CS with IP cephalosporin (N=34) or other antibiotics (N=14). Gut microbiota composition and temporal development was analysed at 5-7 time points during the first year of life using 16S rRNA gene amplicon sequencing, complemented with qPCR to obtain absolute abundance estimates in 92 infants. A mediation analysis was carried out to identify taxa linked to gastrointestinal function and discomfort (crying, defecation frequency and signs of gastrointestinal symptoms) and birth interventions.

ResultsBased on absolute abundance estimates, depletion of Bacteroides spp. was specific to CS birth while decreased bifidobacteria and increased Bacilli were common to CS birth and exposure to IP antibiotics in vaginal delivery. Abundance of numerous taxa differed between the birth modes among cephalosporin-exposed infants. Penicillin had a milder impact on the infant gut microbiota than cephalosporin. The effects of both CS birth and IP antibiotics on infant gut microbiota associated with increased gastrointestinal symptoms during the first months.

ConclusionCS birth and maternal IP antibiotics have both specific and overlapping effects on infant gut microbiota development. The resulting microbiota deviations were found to associate with gastrointestinal symptoms in infancy.

What You Need to KnowO_ST_ABSBackground and ContextC_ST_ABSBirth mode and maternal intrapartum antibiotics affect infants gut microbiota development but their relative contribution, and effects on absolute bacterial abundances and infant health remain unknown.

New FindingsUtilizing quantitative microbiota profiling, we identified shared and unique microbiota effects of birth mode and intrapartum antibiotics which explained up to 54% of variation in parent-reported gastrointestinal symptoms in infants.

LimitationsDue to the limited sample sizes, especially during the first weeks of life, stratified analyses according to antibiotic dosing could not be performed, and the results on gastrointestinal symptom-microbiota-associations are tentative.

ImpactBirth mode overrules the effects of maternal antibiotics on infant microbiota development, while both birth mode and maternal antibiotic use are associated to common functional gastrointestinal symptoms in infancy.

Lay summaryCaesarean-section birth and maternal antibiotics during vaginal birth affect infants gut microbiota and may increase gastrointestinal discomfort.


title: Electronic cigarette communications between patients and physicians in the United States

abstract:
ImportancePhysicians play a primary role in smoking cessation, and their communication regarding e-cigarettes needs to be understood.

ObjectiveTo examine physician-patient communication regarding e-cigarettes.

DesignA national, repeated cross-sectional survey in 2018 and 2019 was conducted.

SettingParticipants were invited by mail; surveys were completed online.

ParticipantsResponse rates were 51.8% (2018) and 59.1% (2019), resulting in 2,058 board-certified physicians from family medicine, internal medicine, obstetrics/gynecology, cardiology, pulmonary/critical care, and hematology/oncology.

ExposuresPhysician demographics, tobacco use, medical specialty, and harm-reduction beliefs (i.e., not all tobacco products equally harmful); two hypothetical clinical scenarios.

Main outcomes and measuresPhysicians self-reported e-cigarette communication behaviors (being asked about e-cigarettes by patients and recommending e-cigarettes to patients), and hypothetical e-cigarette communication in two clinical scenarios.

ResultsAmong 2,058 physicians, the mean age was 51.6 years and 41.5% were female. Over 60% of physicians believed all tobacco products are equally harmful. Overall, 69.8% of physicians reported ever being asked about e-cigarettes by their patients (35.9% in the past 30 days), while 21.7% reported ever recommending e-cigarettes to a patient (9.8% in the past 30 days). Pulmonologists (adjusted odds ratio [AOR], 2.14, 95% CI, 1.10-4.16) and cardiologists (AOR, 2.04; 95% CI, 1.03-4.05), as well as physicians who implemented the US Public Health Service Clinical Practice Guidelines (AOR, 1.77; 95% CI, 1.12-2.80) had greater odds of recommending e-cigarettes to patients. Physicians who endorsed a harm-reduction perspective (AOR, 3.04, 95% CI, 2.15-4.31) and had ever smoked cigarettes (AOR, 1.98; 95% CI, 1.27-3.08) were significantly more likely to recommend e-cigarettes. Being asked about e-cigarettes by patients was a strong predictor of physicians recommending (AOR,16.6; 95% CI, 10.3-26.7). In clinical scenarios, physicians were overall more likely to recommend e-cigarettes for cessation to an older, heavy smoker with multiple unsuccessful quit attempts than a younger, light smoker with no prior cessation treatments (49.3% vs. 15.2%, p<.001).

Conclusions and relevanceFindings suggest physicians may recommend e-cigarettes for cessation under certain circumstances. Given the role of e-cigarettes in FDAs comprehensive nicotine policy, there is need for continued physician education regarding e-cigarette efficacy, particularly correcting misperceptions regarding harm reduction.

Key PointsO_ST_ABSQuestionC_ST_ABSHow do physicians communicate with their patients about e-cigarettes?

FindingsIn this repeated cross-sectional survey of 2,058 respondents, physicians who were asked about e-cigarettes by their patients, endorsed a harm-reduction perspective, or had ever smoked were significantly more likely to recommend e-cigarettes to patients. Clinical scenarios showed physicians were significantly more likely to recommend e-cigarettes for an older, heavy smoker with prior unsuccessful quit attempts, and use of FDA-approved pharmacotherapy for a younger, light smoker with no prior cessation treatments.

MeaningPhysicians may recommend e-cigarettes for cessation under certain circumstances, warranting continued physician education regarding e-cigarette efficacy.