title: Sex-specific DNA methylation changes in Alzheimer's disease pathology

abstract: Sex is an important factor that contributes to the clinical and biological heterogeneities in Alzheimers disease (AD), but the regulatory mechanisms underlying sex disparity in AD are still not well understood. DNA methylation is an important epigenetic modification that regulates gene transcription and is known to be involved in AD. We performed the first large-scale sex-specific meta-analysis of DNA methylation changes in AD, by re-analyzing four recent epigenome-wide association studies totaling more than 1000 postmortem prefrontal cortex brain samples using a uniform analytical pipeline. For each cohort we employed two complementary analytical strategies, a sex-stratified analysis that examined methylation-Braak stage associations in male and female samples separately, and a sex-by-Braak stage interaction analysis that compared the magnitude of these associations between different sexes. Our analysis uncovered 14 novel CpGs, mapped to genes such as TMEM39A and TNXB that are associated with AD in a sex-specific manner. TMEM39A is known to be involved in inflammation, dysregulated type I interferon responses, and other immune processes. TNXB encodes tenascin proteins, which are extracellular matrix glycoproteins demonstrated to modulate synaptic plasticity in the brain. Moreover, for many previously implicated AD genes, such as MBP and AZU1, our analysis provided the new insights that they were predominately driven by effects in only one sex. These sex-specific DNA methylation changes were enriched in divergent biological processes such as integrin activation in females and complement activation in males. Importantly, a number of drugs commonly prescribed for AD patients also targeted these genes with sex-specific DNA methylation changes. Our study implicated multiple new loci and biological processes that affected AD in a sex-specific manner and highlighted the importance of sex-specific treatment regimens for AD patients.


title: Development of a Metastatic Uveal Melanoma Prognostic risk Score (MUMPS) for use in patients receiving immune checkpoint inhibitors

abstract:
BackgroundMetastatic uveal melanoma (mUM) is a rare disease for which no systemic therapy has demonstrated overall survival (OS) benefit. There are no robust data on prognostic factors for OS in patients with mUM treated with immune checkpoint inhibitors (ICI).

Retrospective and non-randomized prospective studies have reported response rates of 0-37% for anti-PD1/L1 +/-anti-CTLA4 ICI in mUM, indicating a potential benefit only in a subset of patients. This study evaluates the characteristics associated with ICI benefit in patients with mUM.

MethodsWe performed a single-center retrospective cohort study of patients with mUM who received anti-PD1/L1 +/-anti-CTLA4 ICI between 2014-2019. Clinical and genomic characteristics were collected from chart review. Treatment response and clinical progression were determined by physician assessment. Multivariable Cox regression models and Kaplan-Meier log-rank tests were used to assess differences in clinical progression-free survival (cPFS) and OS between groups and to identify clinical variables associated with ICI outcomes.

ResultsWe identified 71 mUM patients who received 75 lines of ICI therapy. Of these, 54 received anti-PD1/L1 alone, and 21 received anti-PD1/L1 + anti-CTLA4. Patient characteristics were: 53% female, 48% were 65 or older, 72% received one or fewer lines of prior therapy. Within our cohort, 53% of patients had developed stage IV disease < 2 years after their initial diagnosis. Bone metastases were present in 12% of patients. For the entire cohort, the median cPFS was 2.7 months and median OS was 10.0 months. In multivariable analyses for both cPFS and OS, the following variables were associated with good prognosis: [≥] 2yrs from initial diagnosis to stage IV (n=25), LDH <1.5xULN (n=45), and absence of bone metastases (n=66). We developed a Metastatic Uveal Melanoma Prognostic risk Score (MUMPS). Patients were divided into 3 MUMPS risk groups based on the number of the above-mentioned prognostic variables: Poor risk (0-1), Intermediate risk (2) and Good risk (3). Good risk patients experienced longer cPFS (6.0 months) and OS (34.5 months) than patients with intermediate (2.3 months cPFS, 9.4 months OS) and poor risk disease (1.8 months cPFS, 3.9 months OS); P<0.0001.

ConclusionWe developed a MUMPS risk score, based on retrospective data, that is comprised of 3 readily available clinical variables (time to stage IV diagnosis, presence of bone metastases, and LDH). This MUMPS risk score has potential prognostic value. Further validation in independent datasets is warranted to determine the role of this MUMPS risk score in selecting ICI treatment management for mUM.

category: oncology


title: The evaluation of a web-based tool for measuring the uncorrected visual acuity and refractive error in keratoconus eyes: a prospective open-label method comparison study

abstract:
PurposeTo evaluate the outcome of a web-based digital assessment of visual acuity and refractive error, compared to a manifest refraction assessment, in keratoconus patients with complex refractive errors.

Material and methodsKeratoconus patients, aged 18 to 40, with a refractive error between -6 and +4 diopters were eligible. Each participant subsequently underwent an uncorrected visual acuity and a refractive assessment. Refractive error was assessed with the web-based tool (index test), an autorefractor, and a manifest refraction (reference test) by an optometrist. Corrected visual acuity was assessed with the web-based and manifest refractive prescription. Non-inferiority was defined as the 95% limits-of-agreement (95%LoA) of the differences in spherical equivalent between the index and reference test not exceeding +/- 0.5 diopters. Agreement was assessed by an intraclass correlation coefficient and Bland-Altman analyses.

ResultsA total of 100 eyes of 50 patients were examined. The overall mean difference of the uncorrected visual acuity measured -0.01 LogMAR (95%LoA:-0.63-0.60). The variability decreased in the high uncorrected visual acuity subgroup (mean difference: 0.15 LogMAR, 95%LoA:-0.25-0.55). The intraclass correlation coefficient of the three refractive assessments was 0.32. The overall mean difference in spherical equivalent between the index and reference test measured -0.58 diopters (95%LoA:-4.49 - 3.33, P=0.008). The mean differences for myopic and hyperopic subjects were 0.09 diopters (P=0.675) and -2.06 diopters (P<0.001), respectively.

ConclusionsOur results show promising results in the ability of the web-based tool to remotely assess visual acuity in keratoconus patients. The agreement is better in higher visual acuity ranges and could provide physicians with an objective measurement to enhance teleconsultations, especially relevant when access to health care is limited. The assessment of the refractive error using the web-based tool was found to be inferior to the manifest refraction and deserves further training of the tools algorithm.

category: ophthalmology


title: Mendelian randomization analysis identified genes pleiotropically associated with central corneal thickness

abstract:
ObjectiveTo prioritize genes that were pleiotropically or potentially causally associated with central corneal thickness (CCT).

MethodsWe applied the summary data-based Mendelian randomization (SMR) method integrating summarized data of genome-wide association study (GWAS) on CCT and expression quantitative trait loci (eQTL) data to identify genes that were pleiotropically associated with CCT. We performed separate SMR analysis using CAGE eQTL data and GTEx eQTL data. SMR analysis were done for participants of European and East Asian ancestries, separately.

ResultsWe identified multiple genes showing pleiotropic association with CCT in the participants of European ancestry. CLIC3 (ILMN_1796423; PSMR=4.15x10-12), PTGDS (ILMN_1664464; PSMR=6.88x10-9) and C9orf142 (ILMN_1761138; PSMR=8.09x10-9) were the top three genes using the CAGE eQTL data, and RP11-458F8.4(ENSG00000273142.1; PSMR=5.89x10-9), LCNL1 (ENSG00000214402.6; PSMR=5.67x10-8), and PTGDS (ENSG00000107317.7; PSMR=1.92x10-7) were the top three genes using the GTEx eQTL data. No genes showed significantly pleiotropic association with CCT in the participants of East Asian ancestry after correction for multiple testing.

ConclusionWe identified several genes pleiotropically associated with CCT, some of which represented novel genes influencing CCT. Our findings provided important leads to a better understanding of the genetic factors influencing CCT, and revealed potential therapeutic targets for the treatment of primary open-angle glaucoma and keratoconus.


title: Deep learning saliency maps do not accurately highlight diagnostically relevant regions for medical image interpretation

abstract: Saliency methods, which "explain" deep neural networks by producing heat maps that highlight the areas of the medical image that influence model prediction, are often presented to clinicians as an aid in diagnostic decision-making. Although many saliency methods have been proposed for medical imaging interpretation, rigorous investigation of the accuracy and reliability of these strategies is necessary before they are integrated into the clinical setting. In this work, we quantitatively evaluate three saliency methods (Grad-CAM, Grad-CAM++, and Integrated Gradients) across multiple neural network architectures using two evaluation metrics. We establish the first human benchmark for chest X-ray interpretation in a multilabel classification set up, and examine under what clinical conditions saliency maps might be more prone to failure in localizing important pathologies compared to a human expert benchmark. We find that (i) while Grad-CAM generally localized pathologies better than the two other saliency methods, all three performed significantly worse compared with the human benchmark; (ii) the gap in localization performance between Grad-CAM and the human benchmark was largest for pathologies that had multiple instances, were smaller in size, and had shapes that were more complex; (iii) model confidence was positively correlated with Grad-CAM localization performance. Our work demonstrates that several important limitations of saliency methods must be addressed before we can rely on them for deep learning explainability in medical imaging.

category: health informatics


title: Benchmarking saliency methods for chest X-ray interpretation


title: CADA: Phenotype-driven gene prioritization based on a case-enriched knowledge graph

abstract: Many rare syndromes can be well described and delineated from other disorders by a combination of characteristic symptoms. These phenotypic features are best documented with terms of the human phenotype ontology (HPO), which is increasingly used in electronic health records (EHRs), too. Many algorithms that perform HPO-based gene prioritization have also been developed, however, the performance of many such tools suffers from an overrepresentation of atypical cases in the medical literature. This is certainly the case if the algorithm cannot handle features that occur with reduced frequency in a disorder. With CADA we built a knowledge-graph that is based on case annotations and disorder annotations and show that CADA exhibits superior performance particularly for patients that present with the pathognomonic findings of a disease. Crucial in the design of our approach is the use of the growing amount of phenotypic information that diagnostic labs deposit in databases such as ClinVar. By this means CADA is an ideal reference tool for differential diagnostics in rare disorders that can also be updated regularly.


title: Shifting research priorities in maternal and child health in the COVID-19 pandemic era in India: a renewed focus on systems strengthening

abstract:
BackgroundThe remarkable progress seen in maternal and child health (MCH) in India over the past two decades has been impacted by setbacks from the COVID-19 pandemic. We aimed to undertake a rapid assessment to identify key priorities for public health research in MCH in India within the context and aftermath of the COVID-19 pandemic.

MethodsA web-based survey was developed to identify top research priorities in MCH. It consisted of 26 questions on six broad domains: vaccine preventable diseases, outbreak preparedness, primary healthcare integration, maternal health, neonatal health, and infectious diseases. Key stakeholders were invited to participate between September and November 2020. Participants assigned importance on a 5-point Likert scale, and assigned overall ranks to each sub-domain research priority. Descriptive statistics were used to examine Likert scale responses, and a ranking analysis was done to obtain an "average ranking score" and identify the top research priority under each domain.

ResultsAmongst the 84 respondents, 37% were public-health researchers, 25% healthcare providers, 20% academic faculty and 13% were policy makers. Across the six domains, most respondents considered conducting research on systems strengthening as extremely important. The highest ranked research priorities were strengthening the public sector workforce (vaccine preventable diseases), enhancing public-health surveillance networks (outbreak preparedness), nutrition support through community workers (primary care integration), encouraging at least 4-8 antenatal visits (maternal health), neonatal resuscitation to reduce birth asphyxia (neonatal health) and pediatric and maternal screening and treatment of tuberculosis (infectious diseases). Common themes identified through open-ended questions were also systems strengthening priorities across domains.

ConclusionsThe overall focus for research priorities in MCH in India during the COVID-19 pandemic is on strengthening existing services and service delivery, rather than novel research. Our results highlight pivotal steps within the roadmap for advancing and sustaining maternal and child health gains during the ongoing COVID-19 pandemic and beyond.

category: health policy


title: Novel clinical subphenotypes in COVID-19: derivation, validation, prediction, temporal patterns, and interaction with social determinants of health

abstract: The coronavirus disease 2019 (COVID-19) is heterogeneous and our understanding of the biological mechanisms of host response to the novel viral infection remains limited. Identification of meaningful clinical subphenotypes may benefit pathophysiological study, clinical practice, and clinical trials. Here, our aim was to derive and validate COVID-19 subphenotypes using machine learning and routinely collected clinical data, assess temporal patterns of these subphenotypes during the pandemic course, and examine their interaction with social determinants of health (SDoH). We retrospectively analyzed 14418 COVID-19 patients in five major medical centers in New York City (NYC), between March 1 and June 12, 2020. Using clustering analysis, four biologically distinct subphenotypes were derived in the development cohort (N = 8199). Importantly, the identified subphenotypes were highly predictive of clinical outcomes (especially 60-day mortality). Sensitivity analyses in the development cohort, and re-derivation and prediction in the internal (N = 3519) and external (N = 3519) validation cohorts confirmed the reproducibility and usability of the subphenotypes. Further analyses showed varying subphenotype prevalence across the peak of the outbreak in NYC. We also found that SDoH specifically influenced mortality outcome in Subphenotype IV, which is associated with older age, worse clinical manifestation, and high comorbidity burden. Our findings may lead to a better understanding of how COVID-19 causes disease in different populations and potentially benefit clinical trial development. The temporal patterns and SDoH implications of the subphenotypes may add new insights to health policy to reduce social disparity in the pandemic.

category: infectious diseases


title: Clinical subphenotypes in COVID-19: derivation, validation, prediction, temporal patterns, and interaction with social determinants of health


title: The Efficacy of Isoniazid Prophylaxis in Renal Transplant Recipients in a High TB Burden Country

abstract:
IntroductionRenal transplant recipients are at high risk of tuberculosis (TB). We have started Isoniazid (INH) prophylaxis of 1 year duration in all renal transplant recipients from April 2009. Our aim is to assess the incidence of TB on INH prophylaxis and its tolerability.

MethodsThis was a retrospective observational study. The files of renal transplant recipients from April 2009 to December 2011 were reviewed till June 2015. We noted the incidence of TB, INH tolerability and development of resistance. We compared the incidence of TB with the historical controls who never received the prophylaxis.

ResultsA total of 910 patients were reviewed and followed for 4.8 years. INH prophylaxis was completed by 825 (91%) patients. A total of 46 patients (5%) developed active TB as compared to 15% in the historical controls. The median time of TB diagnosis from transplantation was 2.8 years. In the first-year post transplant, out of total TB cases, 52% occurred in the historical controls whereas 13% occurred in study cohort. Around 67% had TB > 2 years after transplant. Overall 1.43% had hepatotoxicity. There was a significant reduction in TB among those who completed prophylaxis to those who did not (p=0.02). Out of 14 cultures one isolate was INH resistant (7%).

ConclusionINH prophylaxis is well tolerated. The incidence of TB has decreased during the first 2 years. However there was a surge in TB cases 1 year after stopping INH therapy. We should consider prolonging the duration of INH prophylaxis in high TB burden countries in renal transplant recipients.


title: Persistent SARS-CoV-2 infection and increasing viral variants in children and young adults with impaired humoral immunity

abstract:
BackgroundThere is increasing concern that persistent infection of SARS-CoV-2 within immunocompromised hosts could serve as a reservoir for mutation accumulation and subsequent emergence of novel strains with the potential to evade immune responses.

MethodsWe describe three patients with acute lymphoblastic leukemia who were persistently positive for SARS-CoV-2 by real-time polymerase chain reaction. Viral viability from longitudinally-collected specimens was assessed. Whole-genome sequencing and serological studies were performed to measure viral evolution and evidence of immune escape.

FindingsWe found compelling evidence of ongoing replication and infectivity for up to 162 days from initial positive by subgenomic RNA, single-stranded RNA, and viral culture analysis. Our results reveal a broad spectrum of infectivity, host immune responses, and accumulation of mutations, some with the potential for immune escape.

InterpretationOur results highlight the need to reassess infection control precautions in the management and care of immunocompromised patients. Routine surveillance of mutations and evaluation of their potential impact on viral transmission and immune escape should be considered.

FundingThe work was partially funded by The Saban Research Institute at Childrens Hospital Los Angeles intramural support for COVID-19 Directed Research (X.G. and J.D.B.), the Johns Hopkins Center of Excellence in Influenza Research and Surveillance HHSN272201400007C (A.P.), NIH/NIAID R01AI127877 (S.D.B.), NIH/NIAID R01AI130398 (S.D.B.), NIH 1U54CA260517 (S.D.B.), an endowment to S.D.B. from the Crown Family Foundation, an Early Postdoc.Mobility Fellowship Stipend to O.F.W. from the Swiss National Science Foundation (SNSF), and a Coulter COVID-19 Rapid Response Award to S.D.B. L.G. is a SHARE Research Fellow in Pediatric Hematology-Oncology.


title: COVID-19 Related Chemosensory Changes in Individuals with Self-Reported Obesity

abstract:
Background/objectivesIndividuals with obesity show alterations in smell and taste abilities. Smell and taste loss are also the most prominent neurological symptoms of COVID-19, yet how chemosensory ability present in individuals with obesity with a positive COVID-19 diagnosis is unknown.

Subjects/MethodsIn this secondary analysis of a cross-sectional global dataset, we compared self-reported chemosensory ability in participants with a respiratory illness reporting a positive (C19+; n = 5156) or a negative (C19-; n = 659) COVID-19 laboratory test outcome, who also self-reported to be obese (C19+; n = 433, C19-; n = 86) or non-obese.

ResultsCompared to the C19- group, C19+ exhibited a greater decline in smell, taste, and chemesthesis during illness, though these symptoms did not differ between participants with obesity and without obesity. In 68% of participants who reported recovery from respiratory illness symptoms (n=3431 C19+ and n= 539 C19-), post-recovery chemosensory perception did not differ in C19+ and C19- diagnosis, and by self-reported obesity. Finally, we found that all chemosensory and other symptoms combined predicted the C19+ diagnosis in participants with obesity with a moderately good estimate (63% accuracy). However, in C19+ participants with obesity, we observed a greater relative prevalence of non-chemosensory symptoms, including respiratory as respiratory and GI symptoms.

ConclusionsWe conclude that despite a presumed lower sensitivity to chemosensory stimuli, COVID-19 respondents with obesity experience a similar self-reported chemosensory loss as those without obesity, and in both groups self-reported chemosensory symptoms are similarly predictive of COVID-19.


title: Distinct systemic and mucosal immune responses to SARS-CoV-2

abstract: Coordinated local mucosal and systemic immune responses following SARS-CoV-2 infection protect against COVID-19 pathologies or fail leading to severe clinical outcomes. To understand this process, we performed an integrated analysis of SARS-CoV-2 spike-specific antibodies, cytokines, viral load and 16S bacterial communities in paired nasopharyngeal swabs and plasma samples from a cohort of clinically distinct COVID-19 patients during acute infection. Plasma viral load was associated with systemic inflammatory cytokines that were elevated in severe COVID-19, and also with spike-specific neutralizing antibodies. In contrast, nasopharyngeal viral load correlated with SARS-CoV-2 humoral responses but inversely with interferon responses, the latter associating with protective microbial communities. Potential pathogenic microrganisms, often implicated in secondary respiratory infections, were associated with mucosal inflammation and elevated in severe COVID-19. Our results demonstrate distinct tissue compartmentalization of SARS-CoV-2 immune responses and highlight a role for the nasopharyngeal microbiome in regulating local and systemic immunity that determines COVID-19 clinical outcomes.


title: Systematic development of an mHealth app to prevent healthcare-associated infections by involving patients: Participatient

abstract:
IntroductionIn hospital care, urinary catheters are frequently used, causing a substantial risk for catheter-associated urinary tract infections (CAUTI). Patient awareness and evaluation of appropriateness of their catheter through mHealth could decrease these healthcare-associated infections. However, patient engagement via mHealth in infection prevention is still limited. Therefore, we describe the systematic development and usability evaluation of the mHealth intervention Participatient, to prevent CAUTI, aiming for optimal adoption of the app in the clinical setting.

MethodThe CeHRes roadmap was used as development guideline, operationalizing phases for (1) contextual inquiry (observations and interviews), (2) value specification (interviews with probing) and (3) design in multiple steps and in co-creation with end-users. During phases 1 and 2, semi-structured interviews were conducted with fifteen patients and three nurses. The design phase was combined with the minimum viable product development strategy, with a focus on early cyclic steps of prototyping.

ResultsIn phase 1, patients acknowledged the risks of catheter use. Patients in phase 2 valued endorsement of a mHealth application by healthcare workers and reported to own a smartphone. Both patients and nurses recognized the need for useful modules in the app besides catheter care. Based on the needs and values as found in phase 2, the Participation app was developed. Based on usability tests in phase 3, content, text size, plain language, and navigation structures were further amended, and images were added.

ConclusionThis study provides real-world insight in the developmental strategy for mHealth interventions by involving both patients and care providers. Development of an app using thorough needs-assessment provided understanding for its content and design. By developing an app providing patients with reliable information and daily checklists, we aim to provide a tailored tool for communication and awareness on catheter use for the whole ward, and a potential blueprint for mHealth development.


title: Persistence of G10P neonatal rotavirus infections in southern India

abstract: Neonatal rotavirus infections are predominantly caused by distinct genotypes restricted to this age-group and are mostly asymptomatic. Stool samples from neonates admitted for >48 hours in neonatal intensive care units (NICUs) in Vellore (2014-2015) and Chennai (2015-2016) in southern India, and from neonates born at hospitals in Vellore but not admitted to NICUs (2015-2016) were tested for rotavirus by ELISA and genotyped by hemi-nested RT-PCR. Of the 791 neonates, 150 and 336 were recruited from Vellore and Chennai NICUs, and 305 were born in five hospitals in Vellore. The positivity rates in the three settings were 49.3% (74/150), 29.5% (99/336) and 54% (164/305), respectively. G10P[11] was the commonly identified genotype in 87.8% (65/74), 94.9% (94/99) and 98.2% (161/164) of the neonates in Vellore and Chennai NICUs, and those born at Vellore hospitals, respectively. Neonates delivered by lower segment caesarean section (LSCS) at Vellore hospitals, not admitted to NICUs, had a significantly higher odds of acquiring rotavirus infection compared to those delivered vaginally [p=0.002, OR=2.4 (1.4-4.3)]. This report demonstrates the persistence of G10P[11] strain in Vellore and Chennai, indicating widespread neonatal G10P[11] strain in southern India and their persistence over two decades, leading to interesting questions about strain stability.


title: Early effectiveness of COVID-19 vaccination with BNT162b2 mRNA vaccine and ChAdOx1 adenovirus vector vaccine on symptomatic disease, hospitalisations and mortality in older adults in England

abstract:
ObjectivesTo estimate the real-world effectiveness of the Pfizer/BioNTech BNT162b2 vaccine and Astrazeneca ChAdOx1 vaccine against Confirmed COVID-19, hospitalisations and deaths. To estimate effectiveness on the UK variant of concern.

DesignTest negative case control design

SettingCommunity COVID-19 PCR testing in England

ParticipantsAll adults in England aged 70 years and older (over 7.5 million). All COVID-19 testing in the community among eligible individuals who reported symptoms between 8th December 2020 and 19th February 2021 was included in the analysis.

InterventionsOne and two doses of BNT162b2 vaccine. One dose of ChAdOx1 vaccine.

Main outcome measuresSymptomatic PCR confirmed SARS-CoV-2 infection, hospitalisations and deaths with COVID-19.

ResultsIndividuals aged >=80 years vaccinated with BNT162b2 prior to 4th January, had a higher odds of testing positive in the first 9 days after vaccination (odds ratio up to 1.48, 95%CI 1.23-1.77), indicating that those initially targeted had a higher underlying risk of infection. Vaccine effectiveness was therefore estimated relative to the baseline post-vaccination period. Vaccine effects were noted from 10-13 days after vaccination, reaching an effectiveness of 70% (95% CI 59-78%) from 28-34 days, then plateauing. From 14 days after the second dose a vaccine effectiveness of 89% (95%CI: 85-93%) was seen.

Individuals aged >=70 years vaccinated from 4th January had a similar underlying risk of COVID-19 to unvaccinated individuals. With BNT162b2, vaccine effectiveness reached 61% (95%CI 51-69%) from 28-34 days after vaccination then plateaued. With the ChAdOx1 vaccine, vaccine effects were seen from 14-20 days after vaccination reaching an effectiveness of 60% (95%CI 41-73%) from 28-34 days and further increasing to 73% (95%CI 27-90%) from day 35 onwards.

On top of the protection against symptomatic disease, cases who had been vaccinated with one dose of BNT162b2 had an additional 43% (95%CI 33-52%) lower risk of emergency hospitalisation and an additional 51% (95%CI 37-62%) lower risk of death. Cases who had been vaccinated with one dose of ChAdOx1 had an additional 37% (95% CI 3-59%) lower risk of emergency hospitalisation. There was insufficient follow-up to assess the effect of ChAdOx1 on mortality due to the later rollout of this vaccine. Combined with the effect against symptomatic disease, this indicates that a single dose of either vaccine is approximately 80% effective at preventing hospitalisation and a single dose of BNT162b2 is 85% effective at preventing death with COVID-19.

ConclusionVaccination with either a single dose of BNT162b2 or ChAdOx1 COVID-19 vaccination was associated with a significant reduction in symptomatic SARS-CoV2 positive cases in older adults with even greater protection against severe disease. Both vaccines show similar effects. Protection was maintained for the duration of follow-up (>6 weeks). A second dose of BNT162b2 provides further protection against symptomatic disease but second doses of ChAdOx1 have not yet been rolled out in England. There is a clear effect of the vaccines against the UK variant of concern.


title: Prediction of intensive care unit mortality based on missing events

abstract:
BackgroundThe increasing availability of electronic health records has made it possible to construct and implement models for predicting intensive care unit (ICU) mortality using machine learning. However, the algorithms used are not clearly described, and the performance of the model remains low owing to several missing values, which is unavoidable in big databases.

MethodsWe developed an algorithm for subgrouping patients based on missing event patterns using the Philips eICU Research Institute (eRI) database as an example. The eRI database contains data associated with 200,859 ICU admissions from many hospitals (>400) and is freely available. We then constructed a model for each subgroup using random forest classifiers and integrated the models. Finally, we compared the performance of the integrated model with the Acute Physiology and Chronic Health Evaluation (APACHE) scoring system, one of the best known predictors of patient mortality, and the imputation approach-based model.

ResultsSubgrouping and patient mortality prediction were separately performed on two groups: the sepsis group (the ICU admission diagnosis of which is sepsis) and the non-sepsis group (a complementary subset of the sepsis group). The subgrouping algorithm identified a unique, clinically interpretable missing event patterns and divided the sepsis and non-sepsis groups into five and seven subgroups, respectively. The integrated model, which comprises five models for the sepsis group or seven models for the non-sepsis group, greatly outperformed the APACHE IV or IVa, with an area under the receiver operating characteristic (AUROC) of 0.91 (95% confidence interval 0.89-0.92) compared with 0.79 (0.76-0.81) for the APACHE system in the sepsis group and an AUROC of 0.90 (0.89-0.91) compared with 0.86 (0.85-0.87) in the non-sepsis group. Moreover, our model outperformed the imputation approach-based model, which had an AUROC of 0.85 (0.83-0.87) and 0.87 (0.86-0.88) in the sepsis and non-sepsis groups, respectively.

ConclusionsWe developed a method to predict patient mortality based on missing event patterns. Our method more accurately predicts patient mortality than others. Our results indicate that subgrouping, based on missing event patterns, instead of imputation is essential and effective for machine learning against patient heterogeneity.

Trial registrationNot applicable.

category: intensive care and critical care medicine


title: Electrocardiographic Manifestations of Immune Checkpoint Inhibitor Myocarditis

abstract:
ImportanceImmune-checkpoint inhibitor (ICI)-myocarditis often presents with arrhythmias, but electrocardiographic (ECG) findings have not been well described. ICI-myocarditis and acute cellular rejection (ACR) following cardiac transplantation share similarities on histopathology; however, whether they differ in arrhythmogenicity is unclear.

ObjectivesTo describe ECG findings in ICI-myocarditis, compare them to ACR, and evaluate their prognostic significance.

DesignCases of ICI-myocarditis were retrospectively identified through a multicenter network. Grade 2R or 3R ACR was retrospectively identified within one center. Two blinded cardiologists interpreted ECGs.

Setting49 medical centers spanning 11 countries.

Participants147 adults with ICI-myocarditis, 50 adults with ACR.

ExposureMyocarditis after ICI exposure per European Society of Cardiology criteria for clinically suspected myocarditis, grade 2R or 3R ACR per the International Society for Heart and Lung Transplantation working formulation for biopsy diagnosis of rejection.

OutcomesAll-cause mortality, myocarditis-related mortality; and composite endpoint (defined as myocarditis-related mortality and life-threatening ventricular arrhythmia).

ResultsOf 147 patients, the median age was 67 years (58-77) with 92 (62.6%) men. At 30 days, ICI-myocarditis had an all-cause mortality of 39/146(26.7%), myocarditis-related mortality of 24/146(16.4%), and composite endpoint of 37/146(25.3%). All-cause mortality was more common in patients who developed complete heart block (12/25[48%] vs 27/121[22.3%], hazard ratio (HR)=2.62, 95% confidence interval [1.33-5.18],p=0.01) or life-threatening ventricular arrhythmias (12/22[55%] vs 27/124[21.8%], HR=3.10 [1.57-6.12],p=0.001) within 30 days after presentation. Compared to ACR, patients with ICI-myocarditis were more likely to experience life-threatening ventricular arrhythmias (22/147 [16.3%] vs 1/50 [2%];p=0.01) or third-degree heart block (25/147 [17.0%] vs 0/50 [0%];p=0.002). In ICI-myocarditis, overall mortality, myocarditis-related mortality, and composite outcome adjusted for age and sex were associated with pathological Q-waves on presenting ECG (hazard ratio by subdistribution model [HR(sh)]=5.98[2.8-12.79],p<.001; 3.40[1.38-8.33],p=0.008; 2.20[0.95-5.12],p=0.07; respectively) but inversely associated with Sokolow-Lyon Index (HR(sh)/mV=0.57[0.34-0.94],p=0.03; HR(sh)=0.54[0.30-0.97],p=0.04; 0.50[0.30-0.85],p=0.01; respectively). The composite outcome was also associated with conduction disorders on presenting ECG (HR(sh)=3.27[1.29-8.34],p=0.01).

ConclusionsICI-myocarditis has more life-threatening arrhythmias than ACR and manifests as decreased voltage, conduction disorders, and repolarization abnormalities. Ventricular tachycardias, complete heart block, low-voltage, and pathological Q-waves were associated with adverse outcomes.

NCTNCT04294771

Key PointsO_ST_ABSQuestionC_ST_ABSWhat are the electrocardiographic manifestations of immune checkpoint inhibitor (ICI)-associated myocarditis? How do they compare to acute cellular rejection (ACR), which is resembling pathophysiologically to ICI-myocarditis? Which electrocardiographic features are associated with adverse outcomes?

FindingsICI-myocarditis results in more frequent ventricular arrhythmias and high-degree atrioventricular blocks compared to ACR. Prolonged QRS intervals, decreased voltage, conduction disorders, and pathological Q-waves are predictors of adverse outcomes in ICI-associated myocarditis.

MeaningICI-associated myocarditis is a highly arrhythmogenic cardiomyopathy. Ventricular arrhythmias, conduction disorders, low-voltage, and pathological Q-waves are associated with a poor prognosis.

category: cardiovascular medicine


title: Prevalence of SARS-CoV-2 antibodies among workers of the public higher education institutions of Porto, Portugal

abstract:
ObjectivesTo assess the prevalence of SARS-CoV-2 specific immunoglobulin (Ig) M and IgG antibodies among workers of the three public higher education institutions of Porto, Portugal, up to July 2020.

MethodsA rapid point of care test for specific IgM and IgG antibodies of SARS-CoV-2 was offered to all workers. Testing was performed to and a questionnaire was completed by 4592 workers on a voluntary basis. We computed the apparent IgM, IgG, and combined IgM or IgG prevalence, along with the true prevalence and 95% credible intervals (95% CI) using Bayesian inference.

ResultsWe found an apparent prevalence of 3.1% for IgM, 1.0% for IgG, and 3.9% for either antibody class. The estimated true prevalence was 2.0% (95% CI 0.1-4.3) for IgM, 0.6% (95% CI 0.0-1.3) for IgG and 2.5% (95% CI 0.1-5.3) for IgM or IgG. A SARS-CoV-2 molecular diagnosis was reported by 21 (0.5%) workers, and of these, 90.5% had a reactive IgG result. Seroprevalence was higher among those reporting known contacts with confirmed cases, having been quarantined, having a previous molecular negative test, or having had symptoms.

ConclusionsThe seroprevalence among workers from the three public higher education institutions of Porto after the first wave of the SARS-CoV-2 infection was relatively low. However, the estimated true seroprevalence was approximately five times higher than the reported SARS-CoV-2 infection based on a molecular test result.

category: epidemiology


title: SARS-CoV-2 infection in households with and without young children: Nationwide cohort study

abstract:
BackgroundInfections with seasonally spreading human coronaviruses (HCoVs) are common among young children during winter months in the northern hemisphere, with immunological response lasting around a year. However, it is not clear whether recent household exposure to HCoVs reduces the risk of SARS-CoV-2 infection.

MethodsIn a nationwide cohort study we followed all adults in Denmark aged 18 to 60 years from February 27 to November 15, 2020. Hazard ratios of SARS-CoV-2 infection by number of young children aged ten months to five years living in the household were estimated using Cox regression adjusted for adult age, gender, and other potential confounders. In sensitivity analyses we investigated the effect of age of children in the household, number of children living outside of the household, and number of other adult household-members.

ResultsAmong 449,915 adults in Denmark living in households with young children, 5,761 were tested positive for SARS-CoV-2, while among 2,629,821 adults without young children in their household, 33,788 were tested positive for SARS-CoV-2 (adjusted hazard ratio, 1.05; 95% confidence interval, 1.02 to 1.09). Sensitivity analyses of age of children in the household, number of children living outside of the household, and number of additional adult household members found increasing number of children, and especially increasing number of older children, to substantially increase the risk of SARS-CoV-2 infection.

ConclusionsLiving in a household with young children was not associated with decreased risk of SARS-CoV-2 infection, thereby suggesting no strong preventive effect of recent exposure to HCoVs against SARS-CoV-2 infection.


title: The Socioeconomic Gradient in Epigenetic Aging Clocks: Evidence from the Multi-Ethnic Study of Atherosclerosis and the Health and Retirement Study

abstract: Epigenetic clocks have been widely used to predict disease risk in multiple tissues or cells. Their success as a measure of biological aging has prompted research on the connection between epigenetic pathways of aging and the socioeconomic gradient in health and mortality. However, studies examining social correlates of epigenetic aging have yielded inconsistent results. We conducted a comprehensive, comparative analysis of associations between various dimensions of socioeconomic status (SES) (education, income, wealth, occupation, neighborhood environment, and childhood SES) and eight epigenetic clocks in two large U.S. aging studies: The Multi-Ethnic Study of Atherosclerosis (MESA) (n=1,211) and the Health and Retirement Study (HRS) (n=4,018). In both studies, we found robust associations between SES measures in adulthood and the GrimAge and DunedinPoAm clocks (Bonferroni corrected p-value<0.01). In the HRS, significant associations with the Levine and Yang clocks are also evident. These associations are only partially mediated by smoking, alcohol consumption, and obesity, which suggests that differences in health behaviors alone cannot explain the SES gradient in epigenetic aging. Further analyses revealed concurrent associations between polygenic risk for accelerated intrinsic epigenetic aging, SES, and the Levine clock, indicating that genetic predisposition and social disadvantage may contribute independently to faster epigenetic aging.


title: Vaccine hesitancy and reasons for refusing the COVID-19 vaccination among the U.S. public: A cross-sectional survey

abstract:
ImportanceAlthough widespread vaccination will be the most important cornerstone of the public health response to the COVID-19 pandemic, a critical question remains as to how much of the United States population will accept it.

ObjectiveDetermine: 1) rate of COVID-19 vaccine hesitancy in the United States public, 2) patient characteristics associated with hesitancy, 3) reasons for hesitancy, 4) healthcare sites where vaccine acceptors would prefer to be vaccinated.

Design43-question cross-sectional survey conducted November 17-18, 2020, distributed on Amazon Mechanical Turk, an online labor marketplace where individuals receive a nominal fee (here, $1.80) for anonymously completing tasks.

Eligible ParticipantsUnited States residents 18-88 years of age, excluding healthcare workers. A total 1,756 volunteer respondents completed the survey (median age 38 years, 53% female).

Main Outcome MeasureMultivariable logistic regression modeled the primary outcome of COVID-19 vaccine hesitancy (defined as non-acceptance or being unsure about acceptance of the COVID-19 vaccine) with respondent characteristics.

ResultsA total 663 respondents (37.8%) were COVID-19 vaccine hesitant (374 [21.3%] non-acceptors and 289 [16.5%] unsure about accepting). Vaccine hesitancy was associated with not receiving influenza vaccination in the past 5 years (odds ratio [OR] 4.07, 95% confidence interval [CI] 3.26-5.07, p<0.01), female gender (OR 2.12, 95%CI 1.70-2.65, p<0.01), Black race (OR 1.54, 95%CI 1.05-2.26, p=0.03), having a high school education or less (OR 1.46, 95%CI 1.03-2.07, p=0.03), and Republican party affiliation (OR 2.41, 95%CI 1.88-3.10, p<0.01). Primary reasons for hesitancy were concerns about side effects, need for more information, and doubts about vaccine efficacy. Preferred sites for vaccination for acceptors were primary doctors offices/clinics, pharmacies, and dedicated vaccination locations.

ConclusionsIn this recent national survey, over one-third of respondents were COVID-19 vaccine hesitant. To increase vaccine acceptance, public health interventions should target vaccine hesitant populations with messaging that addresses their concerns about safety and efficacy.

category: public and global health


title: Optimal mobility restriction minimizing COVID-19 and excess suicide deaths in Japan

abstract:
BackgroundStrict countermeasures for COVID-19 outbreak such as lockdowns and voluntary restrictions against going out might have reduced mortality because of COVID-19 directly, but might have raised suicide rates.

ObjectWe examined best policies for minimizing overall mortality attributable to COVID-19 directly, and excess mortality by suicide because of COVID-19.

MethodWe regressed the estimated excess mortality attributable to suicide deaths against mobility-restrictive measures. Mortality attributable to COVID-19 directly was estimated through association between the effective reproduction number and mobility. We sought the best mobility restriction for minimizing overall deaths.

ResultsSignificant association was found between mobility and suicide, but the data were very few. Results showed the best mobility level as 65.5, which represents a 34.5% reduction in mobility from the normal level.

Discussion and ConclusionAn overly restrictive policy inducing lower than optimal mobility led to higher total mortality.


title: The impact of COVID-19 on primary health care and antibiotic prescribing in rural China: qualitative study

abstract:
IntroductionPrimary health care (PHC) system is designated to be responsible for epidemic control and prevention during the outbreak of COVID-19 in China, while COVID-19 suspected cases in PHC are required to be transferred to specialist fever clinics at higher level hospitals. This study aims to understand to impact of COVID-19 on PHC delivery and antibiotic prescribing at community level in the rural areas of central China.

MethodsQualitative semi-structured interviews were conducted with 18 PHC practitioners and seven patients recruited from two township health centres (THCs) and nine village clinics (VCs) in two rural residential areas of Anhui province. Interviews were transcribed verbatim and thematically analysed.

ResultsPractitioners and patients views and perspectives on COVID-19 impacts on PHC services and antibiotic prescribing are organised into four broad themes: switch from PHC to epidemic prevention and control, concerns and challenges faced by those delivering PHC, diminished PHC, and COVID-19 as a different class of illness.

ConclusionThe COVID-19 epidemic has had a considerable impact on the roles of rural PHC clinics in China that shifted to public health from principal medical, and highlighted the difficulties in rural PHC including inadequately trained practitioners, additional work and financial pressure, particularly in VCs. Antibiotic prescribing practices for non-COVID-19 respiratory tract infections remained unchanged since the knowledge of COVID-19 was not seen as relevant to practitioners antibiotic treatment practices, although overall rates were reduced because fewer patients were attending rural PHC clinics. Since COVID-19 epidemic control work has been designated as a long-term task in China, rural PHC clinics now face the challenge of how to balance their principal clinical and public health roles and, in the case of the VCs, remain financially viable.


title: Elevated T cell repertoire diversity is associated with progression of lung squamous cell premalignant lesions

abstract:
ObjectiveThe immune response to invasive carcinoma has been the focus of published work, but little is known about the adaptive immune response to bronchial premalignant lesions (PMLs), precursors of lung squamous cell carcinoma. This study was designed to characterize the T cell receptor (TCR) repertoire in PMLs and its association with clinical, pathological, and molecular features.

MethodsEndobronchial biopsies (n=295) and brushings (n=137) from high-risk subjects (n=50), undergoing lung cancer screening at approximately 1-year intervals via autofluorescence bronchoscopy and CT, were profiled by RNA-seq. We applied the TCR Repertoire Utilities for Solid Tissue/Tumor (TRUST) tool to the RNA-seq data to identify TCR CDR3 sequences across all samples. In the biopsies, we measured the correlation of TCR diversity with previously derived immune-associated PML transcriptional signatures and outcome. We also quantified the spatial and temporal distribution of shared and clonally expanded TCRs. Using the biopsies and brushes, the ratio of private (i.e., found in one patient only) and public (i.e., found in two or more patients) TCRs was quantified and the CDR3 sequences were compared to those found in curated databases with known antigen specificities.

ResultsWe detected 39,303 unique TCR sequences across all samples. In PML biopsies, TCR diversity was negatively associated with a transcriptional signature of T-cell mediated immune activation (Spearmans rho -0.34, p < 0.001) associated with PML outcome.

Additionally, in lesions of the proliferative molecular subtype, TCR diversity was decreased in regressive versus progressive/persistent PMLs (p=0.045). Within each patient, TCRs were more likely to be shared between biopsies sampled at the same timepoint than biopsies sampled at the same anatomic location at different times. Clonally expanded TCRs, within a biopsied lesion, were more likely to be expanded at future time points than non-expanded clones. The majority of TCR sequences were found in a single sample, with only 3,396 (8.6%) found in more than one sample and 1,057 (2.7%) found in two or more patients (i.e. public), however, when compared to a public database of CDR3 sequences, 4,543 (11.6%) of TCRs were identified as public. TCRs with known antigen specificities were enriched among Public TCRs (p < 0.001).

ConclusionsDecreased TCR diversity may reflect nascent immune responses that contribute to PML elimination. Further studies are needed to explore the potential for immunoprevention of PMLs.

category: respiratory medicine


title: Higher Physical Fitness Regulates In Vitro Tumor Cell Growth in Older Adults with Treatment Naive Chronic Lymphocytic Leukemia (CLL).

abstract: Chronic lymphocytic leukemia (CLL) is associated with physical dysfunction and low overall fitness that predicts poor survival following commencement of treatment. However, it remains unknown whether higher fitness in CLL patients provides anti-oncogenic effects. We identified ten fit (CLL-FIT) and ten less fit (CLL-UNFIT) treatment-naive CLL patients from 144 CLL patients who completed a set of physical fitness and performance tests. Patient plasma was used to determine its effects on in vitro 5-day growth/viability of three B-cell cell lines (OSU-CLL, Daudi and Farage). Plasma exosomal miRNA profiles, circulating lipids, lipoproteins, inflammation levels, and immune cell phenotypes were also assessed. CLL-FIT was associated with fewer viable OSU-CLL cells at Day 1 (p=0.003), Day 4 (p=0.001) and Day 5 (p=0.009). No differences between groups were observed for Daudi and Farage cells. Of 455 distinct exosomal miRNAs identified, 32 miRNAs were significantly different between groups. Of these, 14 miRNAs had [≤]-1 or [≥]1 log2 fold differences. CLL-FIT patients had 5 exosomal miRNAs with lower expression and 9 miRNAs with higher expression. CLL-FIT patients had higher HDL cholesterol, lower inflammation, and lower levels of triglyceride components (all p<0.05). CLL-FIT patients had lower frequencies of low-differentiated NKG2+/CD158a/bneg (p=0.015 and p=0.014) and higher frequencies of NKG2Aneg/CD158b+ mature NK-cells (p=0.047). Absolute numbers of lymphocytes including CD19+/CD5+ CLL-cells were similar between groups (p=0.359). Higher physical fitness in CLL patients is associated with altered CLL-like cell line growth in vitro, and with altered circulating and cellular factors indicative of better immune functions and tumor control.


title: The Risks and Benefits of Providing HIV Services during the COVID-19 Pandemic

abstract:
IntroductionThe COVID-19 pandemic has caused widespread disruptions including to health services. In the early response to the pandemic many countries restricted population movements and some health services were suspended or limited. In late 2020 and early 2021 some countries re-imposed restrictions. Health authorities need to balance the potential harms of additional SARS-CoV-2 transmission due to contacts associated with health services against the benefits of those services, including fewer new HIV infections and deaths. This paper examines these trade-offs for select HIV services.

MethodsWe used four HIV simulation models (Goals, HIV Synthesis, Optima HIV and EMOD) to estimate the benefits of continuing HIV services in terms of fewer new HIV infections and deaths. We used three COVID-19 transmission models (Covasim, Cooper/Smith and a simple contact model) to estimate the additional deaths due to SARS-CoV-2 transmission among health workers and clients. We examined four HIV services: voluntary medical male circumcision, HIV diagnostic testing, viral load testing and programs to prevent mother-to-child transmission. We compared COVID-19 deaths in 2020 and 2021 with HIV deaths occurring now and over the next 50 years discounted to present value. The models were applied to countries with a range of HIV and COVID-19 epidemics.

ResultsMaintaining these HIV services could lead to additional COVID-19 deaths of 0.002 to 0.15 per 10,000 clients. HIV-related deaths averted are estimated to be much larger, 19 - 146 discounted deaths per 10,000 clients.

DiscussionWhile there is some additional short-term risk of SARS-CoV-2 transmission associated with providing HIV services, the risk of additional COVID-19 deaths is at least 100 times less than the HIV deaths averted by those services. Ministries of Health need to take into account many factors in deciding when and how to offer essential health services during the COVID-19 pandemic. This work shows that the benefits of continuing key HIV services are far larger than the risks of additional SARS-CoV-2 transmission.

category: hiv aids


title: Effect Monitoring and Insights from Vaccination program of Healthcare Workforce from a tertiary level hospital in India against SARS-CoV-2.

abstract: Immunization is expected to confer protection against infection and severe disease for vaccinees, while reducing risks to unimmunized populations by inhibiting transmission. Here, based on serial serological studies, we show that during a severe SARS-CoV2 Delta-variant outbreak in Delhi, 25.3% (95% CI 16.9 - 35.2) of previously uninfected, ChAdOx1-nCoV19 double vaccinated, healthcare-workers (HCW) were infected within a period of less than two months, based on serology. Induction of anti-spike response was similar between groups with breakthrough infection (541 U/ml, IQR 374) or not (342 U/ml, IQR 497), as was induction of neutralization activity to wildtype. Most infections were unrecognized. The Delta-variant thus causes frequent unrecognized breakthrough infections in adequately immunized subjects, reducing any herd-effect of immunity, and requiring reinstatement of preventive measures such as masking.


title: High failure rate of ChAdOx1-nCoV19 immunization against asymptomatic infection in healthcare workers during a Delta variant surge: a case for continued use of masks post-vaccination


title: High failure rate of ChAdOx1 in healthcare workers during Delta variant surge: A case for continued use of masks post-vaccination


title: Thyroid Function Analysis in COVID-19: A Retrospective Study from a Single Center

abstract:
Background and ObjectiveCoronavirus disease 2019 (COVID-19) is an on-going epidemic with a multitude of long-ranging effects on the physiological balance of the human body. It can cause several effects on thyroid functions as well. We aimed to assess the lasting sequelae of COVID-19 on thyroid hormone and the clinical course of the disease as a result.

MethodsOut of 76 patients, 48 patients of COVID-19 positive and 28 patients of COVID-19 negative polymerase chain reaction (PCR) were assessed for thyroid functions, IL-6, and Procalcitonin between moderate, severe, and critical pneumonia on HRCT.

ResultsSeventy-five percent of patients with COVID-19 had thyroid abnormalities and higher IL-6 levels (76.10 {+/-} 82.35 vs. 6.99 {+/-} 3.99, 95% CI 52.18-100.01, P-value <0.01). Logistic regression analysis suggested TT3 (P-value 0.01), IL-6 (P-value <0.01), and Procalcitonin (P-value 0.03) as independent risk factors for COVID-19. ROC curve demonstrated IL-6 as the most sensitive marker (P-value <0.01), and TT3, and Procalcitonin as the predictor for COVID-19 disease.

ConclusionThis pilot study from Pakistan demonstrates that changes in serum TSH and TT3 levels may be important manifestations of the courses of COVID-19 pneumonia.


title: Investigation of ventilation conditions associated with CO2 concentration changes in ultrasonographic exam room from the perspective of COVID-19 infection control

abstract:
ObjectivesVentilation is an important factor in preventing COVID-19 infection. To clarify the state of ventilation in ultrasonic exam rooms, as an index of ventilation rate, the carbon dioxide (CO2) concentration in our exam rooms was measured.

MethodsWe measured the CO2 concentration in each exam room before the examination and 0-15 minutes after end of the exam.

The subjects were 70 cases (abdomen: 24, breast: 16, neck: 16, and musculoskeletal: 14). In infant cases, one parent accompanied the patient during the examination.

ResultsThe highest CO2 concentration was 2261 ppm, observed after the breast examination. In all cases, the CO2 concentration in the exam room was highest immediately after the examination or two minutes after. Almost all cases had recovered to within 120% of the pre-examination CO2 concentrations within 15 minutes after the examination. The average CO2 concentration after ultrasonography was significantly higher for breast examinations than others.

ConclusionsEven in a hospital with modern ventilation equipment, the CO2 concentration in the ultrasound room was high after the exam and it takes 15 minutes to recover to the pre-exam state. Care must be taken to ensure adequate ventilation in ultrasonographic facilities.

category: occupational and environmental health


title: Does the use of intraoperative CT scan improve outcomes in Orthopaedic surgery? A protocol for systematic review and meta-analysis.

abstract:
BackgroundIntraoperative 3D imaging is a valuable tool to visualise complex anatomical structures and position implants optimally. This is an emerging technology and there is a paucity in literature of articles describing the same.

ObjectivesThis systematic review aims to compare the outcome of surgeries done under 3D imaging to those done under 2D fluoroscopy by analysing the evidence in literature.

MethodsA systematic review will be conducted adhering to the PRISMA guidelines. Electronic databases of PubMed, Embase and Scopus will be searched with a pre-defined search string. A manual search will also be conducted on the references of the included articles. Original research articles published in English that directly compare the outcomes of intraoperative 3D imaging with fluoroscopy will be included. Review articles, conference abstracts and animal studies will be excluded. Outcome measures will be extracted from the selected studies and analysed with the help of appropriate software.

category: orthopedics


title: Does Telemedicine Reduce health disparities? Longitudinal Evidence during the COVID-19 Pandemic in the US

abstract:
ObjectiveThe COVID-19 pandemic could be a significant health issue for the elderly population and those with pre-excising chronic condition. In response to the pandemic health care services have increased the use of telehealth medicine. The propose of this study is to examine factors associated with access to telemedicine before and after COVID-19 based on sociodemographic factors and type of chronic disease.

MethodWe have used data from the Research and Development Survey (RANDS) at two different time points Data collection for the first wave occurred between June 9, 2020 and July 6, 2020 (n= 6786), second wave was between August 3, 2020 and August 20, 2020 (n=5972). Three questions have been asked from the participant: 1) did the provider offer telemedicine before the pandemic? 2) does the provider offer telemedicine during the pandemic? And 3) have the participants schedule telemedicine appointments?

ResultIn both waves, 62 % of the participants reported providers did not have telemedicine services prior to the COVID-19 pandemic. However, we found a 22% increase in offering telemedicine in six first month of the COVID-19 pandemic. The finding shows almost no change in providing telemedicine between June and August. The data indicates just a 0.5% and 0.1% increase in accessing telemedicine, and scheduling in August than June, respectively. Patients older than 65 had higher access to telemedicine and had higher scheduling frequencies than other age groups, while they had the lowest access prior to the COVID-19. Blacks had the highest access to telemedicine services than other races (40%). Additionally, females, higher education, and living in metropolitan areas were associated with higher access and scheduling during the pandemic. There was a variation of access and scheduling in different chronic diseases, however, providers offered more remote services for those who diagnosed by diabetes.

ConclusionThe aim of telemedicine is to reduce disparities in healthcare access. The findings of this study show telemedicine has reduced racial disparities and provided greater accessibility for older groups. However, spatial and educational disparities are still noticeable. Research is necessary to examine how healthcare must address the socioeconomic heterogeneity in telemedicine by avoiding further disparities.

category: health systems and quality improvement


title: High Initial Titres of Anti-Spike Antibodies following SARS-CoV-2 Infection is Associated with Faster Decay Rates at Four Months Follow-Up

abstract:
BackgroundDynamics of humoral immune responses to SARS-CoV-2 antigens following infection suggests an initial decay of antibody followed by subsequent stabilization. We aim to understand the longitudinal humoral responses to SARS-CoV-2 nucleocapsid (N) protein and spike (S) protein and to evaluate their correlation to clinical symptoms among healthcare workers (HCW).

MethodsIn this cross-sectional longitudinal cohort study done in two phases over four months, HCW underwent serial qualitative serology testing for anti-N antibody, quantitative MSH-ELISA to detect Receptor Binding Domain and full-length S reactive antibodies and completed online surveys about COVID-19 related symptoms and healthcare/community exposure.

ResultsAnti-N antibody positivity was 27% and anti-S positivity was 28% in Phase 1. In Phase 2 anti-S titres were higher in symptomatic than in asymptomatic positive subjects in Phase 1. Marginally higher titers were seen in asymptomatic compared to the symptomatic positive subgroup in Phase 2. A positive correlation was noted between age, number and duration of symptoms, and Phase 1 anti-S antibody titre. A strong correlation was observed between Phase 1 titers and decay of anti-S antibody titres between the two phases. Significant correlation with rate of decay was also noted with fever, GI symptoms, and total number and duration of COVID-19 symptoms.

ConclusionsHigher initial anti-S antibody titres were associated with larger number and longer duration of symptoms as well as faster decay during the two time points.

Key PointsO_ST_ABSQuestionC_ST_ABSWhat is the decay rate of neutralizing antibodies among SARS-CoV-2 infected healthcare workers?

FindingsIn this cohort study that included 178 healthcare workers, over a 4-month period following the COVID-19 pandemic, participants had an initial rise in anti-nucleocapsid (N) and anti-spike (S) antibodies, which was followed by decay and stabilization of the titres. Significant correlation with rate of decay was noted with the symptomatic participants.

MeaningA strong correlation is observed in the decay of anti-S antibody titres based on symptomology, thus eluding to the fact that continued recommendations for infection protection and COVID-19 vaccine campaigns are necessary.


title: Application of 23 novel serological markers for identifying recent exposure to Plasmodium vivax parasites in an endemic population of western Thailand

abstract: Thailand is aiming for malaria elimination by the year 2030. However, the high proportion of asymptomatic infections and the presence of the hidden hypnozoite stage of Plasmodium vivax are impeding these efforts. We hypothesized that a validated surveillance tool utilizing serological markers of recent exposure to P. vivax infection could help to identify areas of ongoing transmission. The objective of this exploratory study was to assess the ability of P. vivax serological exposure markers to detect residual transmission  hot-spots in Western Thailand. Total IgG levels were measured against a panel of 23 candidate P. vivax serological exposure markers using a multiplexed bead-based assay. A total of 4255 plasma samples from a cross-sectional survey conducted in 2012 of endemic areas in the Kanchanaburi and Ratchaburi provinces were assayed. We compared IgG levels with multiple epidemiological factors that are associated with an increased risk of P. vivax infection in Thailand, including age, gender and spatial location, as well as Plasmodium infection status itself. IgG levels to all proteins were significantly higher in the presence of a P. vivax infection (n=144) (t test, p<0.0001). Overall seropositivity rates varied from 2.5% (PVX_097625, merozoite surface protein 8) to 16.8% (PVX_082670, merozoite surface protein 7), with 43% of individuals seropositive to at least 1 protein. Higher IgG levels were associated with older age (>18 years, p<0.05) and males (17/23 proteins, p<0.05), supporting the paradigm that men have a higher risk of infection than females in this setting. We used a Random Forests algorithm to predict which individuals had exposure to P. vivax parasites in the last 9-months, based on their IgG antibody levels to a panel of 8 previously validated P. vivax proteins. Spatial clustering was observed at the village and regional level, with a moderate correlation between PCR prevalence and sero-prevalence as predicted by the algorithm. Our data provides proof-of-concept for application of such surrogate markers as evidence of recent exposure in low transmission areas. These data can be used to better identify geographical areas with asymptomatic infection burdens that can be targeted in elimination campaigns.


title: Dynamic changes in human single cell transcriptional signatures during fatal sepsis

abstract:
Systemic infections, especially in patients with chronic diseases, result in sepsis: an explosive, uncoordinated immune response that can lead to multisystem organ failure with a high mortality rate. Sepsis survivors and non-survivors oftentimes have similar clinical phenotypes or sepsis biomarker expression upon diagnosis, suggesting that the dynamics of sepsis in the critical early stage may have an impact on these opposite outcomes. To investigate this, we designed a within-subject study of patients with systemic gram-negative bacterial sepsis with surviving and fatal outcomes and performed single-cell transcriptomic analyses of peripheral blood mononuclear cells (PBMC) collected during the critical period between sepsis recognition and 6 hours. We observed that the largest sepsis-induced expression changes over time in surviving versus fatal sepsis were in CD14+ monocytes, including gene signatures previously reported for sepsis outcomes. We further identify changes in the metabolic pathways of both monocytes and platelets, the emergence of erythroid precursors, and T cell exhaustion signatures, with the most extreme differences occurring between the non-sepsis control and the sepsis non-survivor. Our single-cell observations are consistent with trends from public datasets but also reveal specific effects in individual immune cell populations, which change within hours. In conclusion, this pilot study provides the first single-cell results with a repeated measures design in sepsis to analyze the temporal changes in the immune cell population behavior in surviving or fatal sepsis. These findings indicate that tracking temporal expression changes in specific cell-types could lead to more accurate predictions of sepsis outcomes. We also identify molecular pathways that could be therapeutically controlled to improve the sepsis trajectory toward better outcomes.

Summary sentenceSingle cell transcriptomics of peripheral blood mononuclear cells in surviving and fatal sepsis reveal inflammatory and metabolic pathways that change within hours of sepsis recognition.


title: Deprivation and Early Involuntary Retirement: Area-Level Analysis across English Local Authorities

abstract:
IntroductionRetirement is a major transition point in life. Falling economic support ratios in many countries have led to a rise in the state retirement age and impending changes to eligibility for state and occupational benefit schemes such as pensions as Governments seek to curb expenditure. Permanently incapacitated individuals from work may face increasing challenges in accessing financial support. Such difficulties may impact those most deprived differentially with potentially significant consequences for morbidity and mortality. Few studies thus far have examined early retirement from a societal perspective. This study explores involuntary retirement in this regard.

MethodsA retrospective analysis of the association between deprivation with IHR success rates for Local Authorities (LA) in England between 2015-18 was conducted. Deprivation status was assigned according to the proportion of Lower-Layer Super Output Areas in the most deprived 10% nationally using data from the National Statistics SocioEconomic Classification 2015. Freedom of Information Requests were sent to all 326 LAs in England to obtain data on successful IHR applications, number of active members of respective pensions schemes and numbers of applications.

Results131 LAs provided complete data for IHR applications, numbers of approved applications and eligible members. Several others provided data on application numbers but not those awarded. he national IHR approval rate was 2.16 per 1000 members, with a range of 0.16 to 8.96. There was a trend towards a greater proportion of approved application per 1000 eligible members in more affluent LAs.

ConclusionThe results from this brief analysis suggest that there is an association between increasing rates of ill-health retirement and higher area-level deprivation. Policy should note that those in more deprived areas face a quadruple whammy; a greater risk of becoming incapacitated from public health and occupational exposures, more limited access to medical support, less opportunities for alternative work and potentially disproportionate disadvantage from stringent pension eligibility criteria.


title: Performance evaluation of the Roche Elecsys Anti-SARS-CoV-2 S immunoassay

abstract:
BackgroundThe Elecsys(R) Anti-SARS-CoV-2 S immunoassay (Roche Diagnostics International Ltd, Rotkreuz, Switzerland) has been developed for the in vitro quantitative detection of antibodies to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein. We evaluated the performance of this assay using samples from seven sites in Germany, Austria, and Switzerland.

MethodsAnonymized frozen, residual serum, or plasma samples from blood donation centers or routine diagnostic testing were used for this study. For specificity and sensitivity analyses, presumed negative samples collected before October 2019 and SARS-CoV-2 PCR-confirmed single or sequential samples were tested, respectively. The performance of the Elecsys Anti-SARS-CoV-2 S immunoassay was also compared with other commercial immunoassays.

ResultsThe overall specificity (n=7880 pre-pandemic samples) and sensitivity (n=240 PCR-positive samples [[≥]14 days post-PCR]) for the Elecsys Anti-SARS-CoV-2 S immunoassay were 99.95% (95% confidence interval [CI]: 99.87-99.99) and 97.92% (95% CI: 95.21- 99.32), respectively. Compared with seven other immunoassays, the Elecsys Anti-SARS-CoV-2 S assay had comparable or greater specificity and sensitivity. The Elecsys Anti-SARS-CoV-2 S immunoassay had significantly higher specificity compared with the LIAISON(R) SARS-CoV-2 S1/S2 IgG, ADVIA Centaur(R) SARS-CoV-2 Total, ARCHITECT SARS-CoV-2 IgG, iFlash-SARS-CoV-2 IgM, and EUROIMMUN Anti-SARS-CoV-2 IgG and IgA assays, and significantly higher sensitivity ([≥]14 days post-PCR) compared with the ARCHITECT SARS-CoV-2 IgG, iFlash-SARS-CoV-2 IgG and IgM, and EUROIMMUN Anti-SARS-CoV-2 IgG assays.

ConclusionThe Elecsys Anti-SARS-CoV-2 S assay demonstrated a robust and favorable performance across samples from multiple European sites, with a very high specificity and sensitivity for the detection of anti-S antibodies.


title: Preliminary Efficacy of the NVX-CoV2373 Covid-19 Vaccine Against the B.1.351 Variant

abstract:
BackgroundThe emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants threatens progress toward control of the Covid-19 pandemic. Evaluation of Covid-19 vaccine efficacy against SARS-CoV-2 variants is urgently needed to inform vaccine development and use.

MethodsIn this phase 2a/b, multicenter, randomized, observer-blinded, placebo-controlled trial in South Africa, healthy human immunodeficiency virus (HIV)-negative adults (18 to 84 years) or medically stable people living with HIV (PLWH) (18 to 84 years) were randomized in a 1:1 ratio to receive two doses, administered 21 days apart, of either NVX-CoV2373 nanoparticle vaccine (5 {micro}g recombinant spike protein with 50 {micro}g Matrix-M1 adjuvant) or placebo. The primary endpoints were safety and vaccine efficacy [≥]7 days following the second dose against laboratory-confirmed symptomatic Covid-19 in previously SARS-CoV-2 uninfected participants.

ResultsA total of 4387 participants were randomized and dosed at least once, 2199 with NVX-CoV2373 and 2188 with placebo. Approximately 30% of participants were seropositive at baseline. Among 2684 baseline seronegative participants (94% HIV-negative; 6% PLWH), there were 15 and 29 predominantly mild to moderate Covid-19 cases in NVX-CoV2373 and placebo recipients, respectively; vaccine efficacy was 49.4% (95% confidence interval [CI]: 6.1 to 72.8). Efficacy in HIV-negative participants was 60.1% (95% CI: 19.9 to 80.1), and did not differ by baseline serostatus. Of the primary endpoint cases with available whole genome sequencing, 38 (92.7%) of 41 were the B.1.351 variant. Post-hoc vaccine efficacy against B.1.351 was 51.0% (95% CI: - 0.6 to 76.2) in HIV-negative participants. Among placebo recipients, the incidence of symptomatic Covid-19 was similar in baseline seronegative vs baseline seropositive participants during the first 2 months of follow-up (5.3% vs 5.2%). Preliminary local and systemic reactogenicity were primarily mild to moderate and transient, and higher with NVX-CoV2373; serious adverse events were rare in both groups.

ConclusionsThe NVX-CoV2373 vaccine was efficacious in preventing Covid-19, which was predominantly mild to moderate and due to the B.1.351 variant, while evidence of prior infection with the presumptive original SARS-CoV-2 did not confer protection against probable B.1.351 disease. (Funded by Novavax, The Bill and Melinda Gates Foundation, and the Coalition for Epidemic Preparedness Innovations; ClinicalTrials.gov number, NCT04533399)


title: Trends in Fentanyl and Fentanyl Derivative Utilization in the United States

abstract:
ObjectiveThe primary objective of this study was to explore fentanyl and fentanyl derivative distribution patterns from 2010 and 2019 across the United States (US). This study builds upon previous literature that has analyzed the trends in opioid distribution and assesses changes in opioid prescription preferences.

MethodsThe amount of fentanyl base distributed in the US from 2010-2019 was obtained from the Drug Enforcement Administrations Automated Reports and Consolidated Ordering System (ARCOS). Fentanyl derivatives (sufentanil, alfentanil, remifentanil) were also analyzed using ARCOS from 2010-2017, the most recent date reported. Census data from the American Community Survey was used to correct for population. Prescriptions, units, and reimbursement of fentanyl and fentanyl citrate formulations for 2010 and 2019 were obtained from Medicaid and prescriber specialty in Medicare Part D.

ResultsTotal grams of fentanyl distributed in the US from 2010 to 2019 decreased by 63%. Correspondingly, there was a 65% decrease in the milligrams per person distributed when correcting for population. From a regional perspective, Ohio had the greatest decrease (-79.3%) while Mississippi saw the smallest (-44.5%). Medicaid reimbursement in 2019 was $165 million for over eight hundred-thousand prescriptions with the majority to generic (99.7%) and injectable (77.6%) formulations. Interventional pain management and anesthesia were over-represented, and hematology/oncology under-represented for fentanyl in Medicare.

ConclusionThe production and distribution of fentanyl-based substances has decreased, although not uniformly, in the US over the last decade. Additionally, the most prescribed formulations of fentanyl have transitioned away from transdermal, potentially in an effort to regulate its availability. Although impactful, the overdose deaths attributed to synthetic opioid deaths continue to increase highlighting the need for public health interventions beyond the pharmaceutical and medical communities.

category: anesthesia


title: Exposure-response analysis of the association of maternal smoking and use of electronic cigarettes (vaping) in relation to preterm birth and small-for-gestational-age in a national US sample, 2016-2018

abstract:
We aimed to estimate exposure-response associations between smoking or vaping, and preterm and small-for-gestational age (SGA) births. We included 99,201 mothers who delivered live singletons in 2016-2018 from the Pregnancy Risk Assessment Monitoring System. We created exposure categories based on participants self-reported average number of cigarettes smoked per day and vaping frequency. Dual users in late pregnancy were a heterogeneous group: 36% heavily smoked and occasionally vaped; 29% lightly smoked and frequently vaped; 19% lightly smoked and frequently vaped; and 15% both heavily smoked and frequently vaped. While dual users who heavily smoked and occasionally vaped had the highest adjusted OR for SGA (3.4, 95% CI 1.7-6.6), all the dual users were on average at about twice the odds of having SGA than non-users. While the risks of preterm birth were higher among sole light smokers (adjusted OR 1.3, 95% CI 1.1-1.5) and sole heavy smokers (adjusted OR 1.4. 95 CI 1.2-1.8) than non-users, the adjusted odds of preterm births for dual users were not noticeably higher than those of non-users, unless they were also heavy smokers. Excess of preterm births among heavy vapers was suggested. Among younger non-Hispanic white women (where vaping is most common), only excess risk of SGA, not preterm, with vaping was apparent. Relative to non-users, both smoking and vaping during pregnancy appear to increase risk of SGA, but excess risk of preterm births appears to be primarily attributable to smoking alone. Higher levels of exposure tended to confer more risk.

HighlightsO_LINo observable change in prevalence of vaping during pregnancy from 2016 to 2018
C_LIO_LIBoth smoking and vaping during pregnancy appear to increase risk of SGA births
C_LIO_LIExcess risk of preterm births appears to be primarily attributable to smoking alone
C_LI


title: Almost significant: trends and P values in the use of phrases describing marginally significant results in 567,758 randomized controlled trials published between 1990 and 2020

abstract:
ObjectiveTo quantitatively map how non-significant outcomes are reported in randomised controlled trials (RCTs) over the last thirty years.

DesignQuantitative analysis of English full-texts containing 567,758 RCTs recorded in PubMed (81.5% of all published RCTs).

MethodsWe determined the exact presence of 505 pre-defined phrases denoting results that do not reach formal statistical significance (P<0.05) in 567,758 RCT full texts between 1990 and 2020 and manually extracted associated P values. Phrase data was modeled with Bayesian linear regression. Evidence for temporal change was obtained through Bayes-factor analysis. In a randomly sampled subset, the associated P values were manually extracted.

ResultsWe identified 61,741 phrases indicating close to significant results in 49,134 (8.65%; 95% confidence interval (CI): 8.58-8.73) RCTs. The overall prevalence of these phrases remained stable over time, with the most prevalent phrases being  marginally significant (in 7,735 RCTs),  all but significant (7,015),  a nonsignificant trend (3,442),  failed to reach statistical significance (2,578) and  a strong trend (1,700). The strongest evidence for a temporal prevalence increase was found for  a numerical trend,  a positive trend,  an increasing trend and  nominally significant. The phrases  all but significant,  approaches statistical significance,  did not quite reach statistical significance,  difference was apparent,  failed to reach statistical significance and  not quite significant decreased over time. In the random sampled subset, the 11,926 identified P values ranged between 0.05 and 0.15 (68.1%; CI: 67.3-69.0; median 0.06).

ConclusionsOur results demonstrate that phrases describing marginally significant results are regularly used in RCTs to report P values close to but above the dominant 0.05 cut-off. The phrase prevalence remained stable over time, despite all efforts to change the focus from P < 0.05 to reporting effect sizes and corresponding confidence intervals. To improve transparency and enhance responsible interpretation of RCT results, researchers, clinicians, reviewers, and editors need to abandon the focus on formal statistical significance thresholds and stimulate reporting of exact P values with corresponding effect sizes and confidence intervals.

Significance statementThe power of language to modify the readers perception of how to interpret biomedical results cannot be underestimated. Misreporting and misinterpretation are urgent problems in RCT output. This may be at least partially related to the statistical paradigm of the 0.05 significance threshold. Sometimes, creativity and inventive strategies of clinical researchers may be used - describing their clinical results to be  almost significant - to get their data published. This phrasing may convince readers about the value of their work. Since 2005 there is an increasing concern that most current published research findings are false and it has been generally advised to switch from null hypothesis significance testing to using effect sizes, estimation, and cumulation of evidence. If this  new statistics approach has worked out well should be reflected in the phases describing non-significance results of RCTs. In particular in changing patterns describing P values just above 0.05 value.

More than five hundred phrases potentially suited to report or discuss non-significant results were searched in over half a million published RCTs. A stable overall prevalence of these phrases (10.87%, CI: 10.79-10.96; N: 61,741), with associated P values close to 0.05, was found in the last three decades, with strong increases or decreases in individual phrases describing these near-significant results. The pressure to pass scientific peer-review barrier may function as an incentive to use effective phrases to mask non-significant results in RCTs. However, this keeps the researchers pre-occupied with hypothesis testing rather than presenting outcome estimations with uncertainty. The effect of language on getting RCT results published should ideally be minimal to steer evidence-based medicine away from overselling of research results, unsubstantiated claims about the efficacy of certain RCTs and to prevent an over-reliance on P value cutoffs. Our exhaustive search suggests that presenting RCT findings remains a struggle when P values approach the carved-in-stone threshold of 0.05.


title: Inflammatory Bowel Disease Risk Variants Are Associated with an Increased Risk of Skin Cancer

abstract:
Background and AimsInflammatory bowel disease is associated with an increased risk of skin cancer. The aims of this study were to determine whether genomic variants associated with IBD susceptibility are also associated with skin cancer susceptibility and if such risk is augmented by the use of immune-suppressive therapy.

MethodsThe discovery cohort included participants in the UK Biobank (n=408,381). The validation cohort included participants in the Michigan Genomics Initiative (n=51,405). The primary outcome of interest was skin cancer, sub-grouped into non-melanoma (NMSC) and melanoma skin cancers (MSC). Multivariable logistic regression was performed to identify genomic predictors of skin malignancy. Validated SNPs were evaluated for effect modification by immune-suppressive medication.

ResultsThe discovery cohort included 11,079 cases of NMSC and 2,054 cases of MSC. The validation cohort included 7,334 cases of NMSC and 3,304 cases of MSC. Thirty variants were associated with risk of NMSC in the discovery cohort, of which six replicated in the validation cohort [Increased risk: rs7773324-A (DUSP22; IRF4), rs2476601-G (PTPN22), rs1847472-C (BACH2), rs72810983-A (CPEB4); Decreased risk: rs6088765-G (PROCR; MMP24), rs11229555-G (ZFP91-CNTF; GLYAT)]. Twelve variants were associated with risk of MSC in the discovery cohort, of which three replicated in the validation cohort (Increased risk: rs61839660-T (IL2RA); Decreased risk: rs17391694-C (GIPC2; MGC27382), rs6088765-G (PROCR; MMP24)]. No effect modification was observed.

ConclusionThe results of this study highlight shared genetic susceptibility across IBD and skin cancer, with increased risk of NMSC in those who carry risk variants in IRF4, PTPN22, CPEB4, and BACH2 and increased risk of MSC in those who carry a risk variant in IL2RA.

category: gastroenterology


title: Development and validation of decision rules models to stratify coronary artery disease, diabetes, and hypertension risk in preventive care: cohort study of returning UK Biobank participants

abstract:
BackgroundA wide range of predictive models exist that predict risk of common lifestyle conditions. However, these have not focused on identifying pre-clinical higher risk groups that would benefit from lifestyle interventions and do not include genetic risk scores.

ObjectiveTo develop, validate, and compare the performance of three decision rule algorithms including biomarkers, physical measurements and genetic risk scores for incident coronary artery disease (CAD), diabetes (T2D), and hypertension in the general population against commonly used clinical risk scoring tools.

MethodsWe identified 60782 individuals in the UK Biobank study with available follow-up data. Three decision rules models were developed and tested for an association with incident disease. Hazard ratios (with 95% confidence interval) for incident CAD, T2D, and hypertension were calculated from survival models. Model performance in discriminating between higher risk individuals suitable for lifestyle intervention and individuals at low risk was assessed using the area under the receiver operating characteristic curve (AUROC).

ResultsWe ascertained 500 incident CAD cases, 1005 incident T2D cases, and 2379 incident cases of hypertension. The higher risk group in the decision rules model had a 40-, 40.9-, and 21.6-fold increase in risk of CAD, T2D, and hypertension, respectively (P < 0.001 for all). Risk increased significantly between the three strata for all three conditions (P < 0.05). Risk stratification based on decision rules identified both a low-risk group (only 1.3% incident disease across all models), as well as a high-risk group where at least 72% of those developing disease within 8 years would have been recommended lifestyle intervention. Based on genetic risk alone, we identified not only a high-risk group, but also a group at elevated risk for all health conditions.

ConclusionWe found that decision rule models comprising blood biomarkers, physical measurements, and polygenic risk scores are superior at identifying individuals likely to benefit from lifestyle intervention for three of the most common lifestyle-related chronic health conditions compared to commonly used clinical risk scores. Their utility as part of digital data or digital therapeutics platforms to support the implementation of lifestyle interventions in preventive and primary care should be further validated.

category: primary care research


title: Public perception of ethical issues related to COVID-19 control measures in Singapore, Hong Kong, and Malaysia: A cross-sectional survey

abstract:
BackgroundSeveral countries have implemented control measures to limit SARS-CoV-2 spread, including digital contact tracing, digital monitoring of quarantined individuals and testing of travelers. These raise ethical issues around privacy, personal freedoms and equity. However, little is known regarding public acceptability of these measures.

MethodsIn December 2020, we conducted surveys among 3635 respondents in Singapore, Hong Kong and Malaysia to understand public perceptions on the ethical acceptability of COVID-19 control measures.

FindingsHong Kong respondents were much less supportive of digital contact tracing and monitoring devices than those in Malaysia and Singapore. Around three-quarters of Hong Kong respondents perceived digital contact tracing as an unreasonable restriction of individual freedom; <20% trusted that there were adequate local provisions preventing these data being used for other purposes. This was the opposite in Singapore, where nearly three-quarters of respondents agreed that there were adequate data protection rules locally. In contrast, only a minority of Hong Kong respondents viewed mandatory testing and vaccination for travelers as unreasonable infringements of privacy or freedom. Less than two-thirds of respondents in all territories were willing to be vaccinated against COVID-19, with a quarter of respondents undecided. However, support for differential travel restrictions for vaccinated and unvaccinated individuals was high in all settings.

InterpretationOur findings highlight the importance of socio-political context in public perception of public health measures and emphasize the need to continually monitor public attitudes towards such measures to inform implementation and communication strategies.

FundingThis work was funded by the World Health Organization.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed and Google Scholar for research articles published between 29 February 2020 to 20 January 2021 to identify empirical studies on public perception of restrictive and control measures imposed during COVID-19. We used the following terms: "COVID-19", "SARS-COV-2", "pandemic", "public", "population", "survey", "cross-sectional", "national", "international", "perception", "attitudes", "opinions", "views", "acceptance", "acceptability", "support", "ethics", "restrictive measures", "restrictions", "control measures", travel", "contact tracing", "testing", "tests", "quarantine", "monitoring", "vaccines" "vaccination", "immunity", "certificates", "passports", "digital", "applications", "apps", "mandatory" and "compulsory". We found 4 peer-reviewed publications: three population surveys on public acceptance of and ethical issues in digital contact tracing in France, Jordan, and Ireland, and one population survey on perceptions of immunity and vaccination certificates in Geneva, Switzerland. We found no studies that studied the relative acceptance of different types of control measures.

Added valueThere is a paucity of literature on public perception of the ethics of control measures that have been or may be implemented in response to the COVID-19 pandemic. In this study, we found differing levels of public support in Singapore, Hong Kong, and Malaysia for digital contact tracing, wearable quarantine monitoring devices, and mandatory testing and vaccination for travelers. Hong Kong respondents sharply differed from Singapore and Malaysia respondents on perceptions of risks and benefits, the extent of intrusion into individual freedom, and assurance of privacy and data protection related to use of digital contact tracing and monitoring devices. These differences are likely to be substantially influenced by socio-political climate and governmental trust. Although less than two-thirds of respondents in all territories expressed a willingness to be vaccinated against COVID-19, we found high support for differential travel restrictions for vaccinated and unvaccinated individuals in all settings.

Implications of all the available evidenceOur survey provides evidence of strong public support of vaccination requirements for travelers within an Asian context, and differential restrictions for vaccinated and non-vaccinated travelers. It highlights the importance of wider socio-political influences on public perception and ethical issues related to control measures and emphasizes the need to continually monitor public attitudes towards such measures to inform implementation and communication strategies.


title: Lack of lockdown, open borders, and no vaccination in sight: is Bosnia and Herzegovina a control group?

abstract:
Bosnia and Herzegovina is among ten countries in the world with the highest mortality rate due to COVID-19 infection. Lack of lockdown, open borders, high mortality rate, no herd immunity, no vaccination plan, and strong domestic anti-vaccination movement present serious COVID-19 concerns in Bosnia and Herzegovina. In such circumstances, we set out to study if the population is willing to receive the vaccine.

A cross-sectional study was conducted among 10,471 adults in Bosnia and Herzegovina to assess the attitude of participants toward COVID-19 vaccination. Using a logistic regression model, we assessed the associations of sociodemographic characteristics with vaccine rejection, reasons for vaccine hesitancy, preferred vaccine manufacturer, and information sources.

Surprisingly, only 25.7% of respondents indicated they would like to get a COVID-19 vaccine, while 74.3% of respondents were either hesitant or completely rejected vaccination. The vaccine acceptance increased with increasing age, education, and income level. Major motivation of pro-vaccination behaviour was intention to achieve collective immunity (30.1%), while the leading incentive for vaccine refusal was deficiency of clinical data (30.2%). The Pfizer-BioNTech vaccine is shown to be eightfold more preferred vaccine compared to the other manufacturers. For the first time, vaccine acceptance among health care professionals has been reported, where only 39.4% of healthcare professionals expressed willingness to get vaccinated.

With the high share of the population unwilling to vaccinate, governmental impotence in securing the vaccines supplies, combined with the lack of any lockdown measures suggests that Bosnia and Herzegovina is unlikely to put COVID-19 pandemic under control in near future.


title: COVID-19 Mortality in California Based on Death Certificates: Disproportionate Impacts Across Racial/Ethnic Groups and Nativity

abstract:
PurposeTo examine characteristics of coronavirus disease 2019 (COVID-19) decedents in California (CA) and evaluate for disproportionate mortality across race/ethnicity and ethnicity/nativity.

MethodsCOVID-19 deaths were identified from death certificates. Age-adjusted mortality rate ratios (MRR) were compared across race/ethnicity. Proportionate mortality rates (PMR) were compared across race/ethnicity and by ethnicity/nativity.

ResultsWe identified 10,200 COVID-19 deaths in CA occurring February 1 through July 31, 2020. Decedents tended to be older, male, Hispanic, foreign-born, and have lower educational attainment. MRR indicated elevated COVID-19 morality rates among Asian/Pacific Islander, Black, and Hispanic groups compared with the White group, with Black and Hispanic groups having the highest MRR at 2.75 (95%CI:2.54-2.97) and 4.18 (95%CI: 3.99-4.37), respectively. Disparities were larger at younger ages. Similar results were observed with PMR, which remained in analyses stratified by education. Elevated PMR were observed in all ethnicity/nativity groups, especially foreign-born Hispanic individuals, relative to U.S.-born non-Hispanic individuals, were generally larger at younger ages, and persisted after stratifying by education.

ConclusionsDifferential COVID-19 mortality was observed in California across racial/ethnic groups and by ethnicity/nativity groups with evidence of greater disparities among younger age groups. Identifying COVID-19 disparities is an initial step towards mitigating disease impacts in vulnerable communities.