title: Evaluation of the United States COVID-19 Vaccine Allocation Strategy

abstract:
BackgroundAnticipating an initial shortage of vaccines for COVID-19, the Centers for Disease Control (CDC) in the United States developed priority vaccine allocations for specific demographic groups in the population. This study evaluates the performance of the CDC vaccine allocation strategy with respect to multiple potentially competing vaccination goals (minimizing mortality, cases, infections, and years of life lost (YLL)), under the same framework as the CDC allocation: four priority vaccination groups and population demographics stratified by age, comorbidities, occupation and living condition (congested or non-congested).

MethodsWe developed a compartmental disease model that incorporates key elements of the current pandemic including age-varying susceptibility to infection, age-varying clinical fraction, an active case-count dependent social distancing level, and time-varying infectivity (accounting for the emergence of more infectious virus strains). Under this model, the CDC allocation strategy is compared to all other possibly optimal allocations that stagger vaccine roll-out in up to four phases (17.5 million strategies).

ResultsThe CDC allocation strategy performed well in all vaccination goals but never optimally. Under the developed model, the CDC allocation deviated from the optimal allocations by small amounts, with 0.19% more deaths, 4.0% more cases, 4.07% more infections, and 0.97% higher YLL, than the respective optimal strategies. The CDC decision to not prioritize the vaccination of individuals under the age of 16 was optimal, as was the prioritization of health-care workers and other essential workers over non-essential workers. Finally, a higher prioritization of individuals with comorbidities in all age groups improved outcomes compared to the CDC allocation.

InterpretationThe developed approach can be used to inform the design of future vaccine allocation strategies in the United States, or adapted for use by other countries seeking to optimize the effectiveness of their vaccine allocation strategies.

FundingThe authors received no funding for this work.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSThe Centers for Disease Control and Prevention (CDC) prioritized population groups for vaccination based on available scientific evidence, the feasibility of different implementation strategies, and ethical considerations. We searched PubMed using the query "(((COVID) AND (vaccin*)) AND (model)) AND ((priorit*) OR alloc*)" up to June 15, 2021, with no date or language restrictions. The search identified 190 articles, of which 15 used predictive models to evaluate the efficacy of vaccine allocation strategies in achieving vaccination campaign goals such as reducing mortality or incidence. All studies compared only a small number of specific, expertise-based allocations. Most studies stratified the population by age, while some considered additional characteristics such as occupation or comorbidity status, but none took into account all characteristics included in the CDC vaccine prioritizations.

Added value of this studyWe developed a compartmental disease model that takes into account several important components of the COVID-19 pandemic, and stratifies the U.S. population by all characteristics included in the CDC vaccine prioritization recommendations. In a novel global optimization approach, we compared the CDC recommendations to all potentially optimal strategies (17.5 million strategies) that also stagger the vaccine roll-out in four phases. The CDC allocation strategy performed well in all considered outcome measures, but never optimally; a higher prioritization of individuals with comorbidities in all age groups improved outcomes. The CDC decision to initially not vaccinate children, as well as the prioritization of health-care workers and other essential workers over non-essential workers proved optimal under all outcome measures.

Implications of all the available evidenceOur study identifies and compares the optimal vaccine allocation strategies for several competing vaccination goals. The developed global optimization approach can be used to inform the design of future vaccine allocation strategies in the United States and elsewhere.


title: The risk of severe COVID-19 and mortality from COVID-19 in people living with HIV compared to individuals without HIV - a systematic review and meta-analysis of 1 268 676 individuals.

abstract:
BackgroundThere is conflicting evidence about the risk of mortality and severe disease due to COVID-19 in people living with HIV (PLHIV).

ObjectivesTo compare mortality, hospitalization, and the need for intensive care services due to COVID-19 between PLHIV and individuals without HIV based on data from the existing literature.

MethodsA comprehensive search in PubMed, Cochrane Library, Scopus, China Academic Journals Full Text Database, the Database of Abstracts of Reviews of Effectiveness (DARE) and and the medRXIV and bioRxiv databases of preprints was carried out. Each data source was searched from 1 January 2020 to 20th of February 2021. Eligible studies were case control, cross-sectional and cohort studies where participants had confirmed COVID-19. From each study, data on numbers of PLHIV and individuals without HIV for each outcome were extracted. Study quality was assessed using the MethodologicAl STandard for Epidemiological Research (MASTER) scale. Data synthesis used a bias adjusted model and predefined age and geographical subgroups were analysed.

ResultsOf a total of 2757 records identified, 11 studies, from 4 countries, the United Kingdom, Spain, the United States of America and South Africa, were included. The total participants assessed for the outcomes in this meta-analysis were 1 268 676 of which 13 886 were PLHIV. Overall, the estimated effect of HIV on mortality suggested some worsening (OR 1.3, 95% CI: 0.9 - 2.0, I2 = 78.6%) with very weak evidence against the model hypothesis at this sample size. However, in individuals aged <60 years, the estimated effect on mortality suggested more worsening in PLHIV (OR 2.7, 95% CI: 1.1 - 6.5, I2 = 95.7%) with strong evidence against the model hypothesis at this sample size. HIV was also associated with an estimated effect on hospitalization for COVID-19 that suggested worsening (OR 1.6, 95% CI: 1.3-2.1, I2 = 96.0%) also with strong evidence against the model hypothesis at this sample size. A secondary analysis of the included studies suggested no difference, by HIV status, in the prevalence of pre-existing conditions.

ConclusionPeople living with HIV have higher risk of death and hospitalisation from COVID-19, compared to individuals without HIV. A secondary analysis suggests this is not due to associated comorbid conditions. The difference in mortality is exaggerated in those younger than 60 years of age.

RegistrationPROSPERO: CRD42020221311 (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=221311)

Evidence before this studyFindings from existing studies have shown conflicting evidence concerning the risk of severe COVID-19 and death from COVID-19 in people living with HIV (PLHIV) compared to people without HIV. Evidence from three existing systematic reviews suggests that the risk of severe COVID-19 and death from COVID-19 in PLHIV may be similar to that in individuals without HIV. However, findings from three large cohort studies and one meta-analysis of four studies suggest that the risk of death from COVID-19 in PLHIV may be higher than that in individuals without HIV. One of the large cohort studies, which is also included in the previous meta-analysis, consisted of individuals with unknown COVID-19 status, and therefore there is still debate concerning the risk of severe COVID-19 outcomes in PLHIV.

Added value of this studyIn this meta-analysis of 11 studies with 1 268 676 individuals with confirmed COVID-19, we found a stronger difference in mortality by HIV status for those individuals below the age of 60 years, and over this age, HIV had an attenuated effect on mortality, suggesting that age-related mortality overshadows PLHIV related mortality. Further, PLHIV had increased odds of being hospitalized and needing intensive cares services, probably related to increased COVID-19 severity in PLHIV. A secondary analysis of the included studies suggested no difference in the prevalence of pre-existing conditions.

Implications of all the available evidenceOur findings suggest that PLHIV are at higher risk than the general population and should be prioritized for vaccine coverage and monitoring if diagnosed with COVID-19. This is especially important for countries in Sub-Saharan Africa that have a high burden of HIV in the younger populations who are more vulnerable.

StrengthsThis study was carried out rigorously following the PRISMA guidelines for systematic reviews and meta-analyses. We used a comprehensive search strategy across most of the main citation databases to ensure that no relevant studies were missed. We included studies where participants had confirmed COVID-19 only and we synthesized the findings from studies using a bias adjustment model that took into consideration the quality of included studies.

LimitationsAll studies included in this review are observational studies and conclusions about causality require cautious interpretation. Due to a lack of data from included studies, we were not able to analyse the effect of being on treatment for HIV, and HIV control variables such as viral load and CD4 counts on COVID-19 hospitalization, intensive care services and mortality. Lastly most of the included studies had small samples overall or for PLHIV and this may affect the effect estimates in this analysis. Future research is therefore indicated to confirm these findings.

category: hiv aids


title: Anti-spike antibody response to natural SARS-CoV-2 infection in the general population

abstract: We estimated the duration and determinants of antibody response after SARS-CoV-2 infection in the general population using representative data from 7,256 United Kingdom COVID-19 infection survey participants who had positive swab SARS-CoV-2 PCR tests from 26-April-2020 to 14-June-2021. A latent class model classified 24% of participants as  non-responders not developing anti-spike antibodies. These seronegative non-responders were older, had higher SARS-CoV-2 cycle threshold values during infection (i.e. lower viral burden), and less frequently reported any symptoms. Among those who seroconverted, using Bayesian linear mixed models, the estimated anti-spike IgG peak level was 7.3-fold higher than the level previously associated with 50% protection against reinfection, with higher peak levels in older participants and those of non-white ethnicity. The estimated anti-spike IgG half-life was 184 days, being longer in females and those of white ethnicity. We estimated antibody levels associated with protection against reinfection likely last 1.5-2 years on average, with levels associated with protection from severe infection present for several years. These estimates could inform planning for vaccination booster strategies.

category: infectious diseases


title: Efficacy and safety of cyclosporine in the management of coronavirus disease 2019: A protocol for systematic review and meta-analysis

abstract:
IntroductionCyclosporine may improve the clinical course and outcomes of Coronavirus disease 2019 (COVID-19) due to its antiviral and anti-cytokine effects as shown in vitro. A few ongoing trials are exploring the benefit of adding it to the standard of care (SOC) of COVID-19 patients.

ObjectivesThe primary objective is to evaluate the severity of COVID-19, determined by oxygen saturation, intensive care unit (ICU) admission, or the World Health Organization COVID-19 clinical severity scale in patients treated with oral or intravenous cyclosporine added to SOC compared SOC alone or placebo. Secondary objectives include mortality, length of hospitalization, length of ICU stay, and laboratory measurements as well as the safety outcomes of cyclosporine.

MethodologyA systematic review and meta-analysis of randomized clinical trials and observational studies that compared cyclosporine to placebo or SOC in COVID-19 patients will be conducted. PubMed, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, Google Scholar, and ClinicalTrials.gov will be explored for studies that satisfy pre-specified inclusion criteria. Quality assessment of all included studies will be performed. Meta-analyses will be done utilizing random effect models to estimate the effect of cyclosporine on the severity of COVID-19. Heterogeneity will be assessed utilizing Q statistics. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines will be followed.

ResultsThe result of this synthesis will inform potential changes in the management of COVID-19 patients, especially regarding the role of calcineurin inhibitors. Additionally, it will serve as hypothesis generating for potential future prospective studies.


title: Assessment and Modeling of COVID-19 Outcomes in a Longitudinal Cohort of Hospitalized Adults

abstract:
BackgroundWhile several demographic and clinical correlates of Coronavirus Disease 2019 (COVID-19) outcome have been identified, they remain imprecise tools for clinical management of disease. Furthermore, there are limited data on how these factors are associated with virological and immunological parameters over time.

Methods and FindingsNasopharyngeal swabs and blood samples were longitudinally collected from a cohort of 58 hospitalized adults with COVID-19 in Chicago, Illinois between March 27 and June 9, 2020. Samples were assessed for SARS-CoV-2 viral load, viral genotype, viral diversity, and antibody titer. Demographic and clinical information, including patient blood tests and several composite measures of disease severity, were extracted from electronic health records. All parameters were assessed for association with three patient outcome groups: discharge without intensive care unit (ICU) admission (n = 23), discharge with ICU admission (n = 29), and COVID-19 related death (n = 6). Higher age, male sex, and higher body mass index (BMI) were significantly associated with ICU admission. At hospital admission, higher 4C Mortality scores and lactate dehydrogenase (LDH) levels were likewise associated with ICU admission. Longitudinal trends in Deterioration Index (DI) score, Modified Early Warning Score (MEWS), and serum neutrophil count were also associated with ICU admission, though only the retrospectively calculated median DI score was predictive of death. While viral load and genotype were not significantly associated with outcome in this study, viral load did correlate positively with C-reactive protein levels and negatively with D-dimer, lymphocyte count, and antibody titer. Intra-host viral genetic diversity resulted in changes in viral genotype in some participants over time, though intra-host evolution was not associated with outcome. A stepwise-generated multivariable model including BMI, lymphocyte count at admission, and neutrophil count at admission was sufficient to predict outcome with a 0.82 accuracy rate in this cohort.

ConclusionsThese studies suggest that COVID-19 disease severity and poor outcomes among hospitalized patients are likely driven by dysfunctional host responses to infection and underlying co-morbid conditions rather than SARS-CoV-2 viral loads. Several parameters, including 4C mortality score, LDH levels, and DI score, were ultimately predictive of participant outcome and warrant further exploration in larger cohort studies for use in clinical management and risk assessment. Finally, the prevalence of intra-host diversity and viral evolution in hospitalized patients suggests a mechanism for population-level change, further emphasizing the need for effective antivirals to suppress viral replication and to avoid the emergence of new variants.


title: COVID-19 vaccines dampen genomic diversity of SARS-CoV-2: Unvaccinated patients exhibit more antigenic mutational variance

abstract: Variants of SARS-CoV-2 are evolving under a combination of immune selective pressure in infected hosts and natural genetic drift, raising a global alarm regarding the durability of COVID-19 vaccines. Here, we conducted longitudinal analysis over 1.8 million SARS-CoV-2 genomes from 183 countries or territories to capture vaccination-associated viral evolutionary patterns. To augment this macroscale analysis, we performed viral genome sequencing in 23 vaccine breakthrough COVID-19 patients and 30 unvaccinated COVID-19 patients for whom we also conducted machine-augmented curation of the electronic health records (EHRs). Strikingly, we find the diversity of the SARS-CoV-2 lineages is declining at the country-level with increased rate of mass vaccination (n = 25 countries, mean correlation coefficient = -0.72, S.D. = 0.20). Given that the COVID-19 vaccines leverage B-cell and T-cell epitopes, analysis of mutation rates shows neutralizing B-cell epitopes to be particularly more mutated than comparable amino acid clusters (4.3-fold, p < 0.001). Prospective validation of these macroscale evolutionary patterns using clinically annotated SARS-CoV-2 whole genome sequences confirms that vaccine breakthrough patients indeed harbor viruses with significantly lower diversity in known B cell epitopes compared to unvaccinated COVID-19 patients (2.3-fold, 95% C.I. 1.4-3.7). Incidentally, in these study cohorts, vaccinated breakthrough patients also displayed fewer COVID-associated complications and pre-existing conditions relative to unvaccinated COVID-19 patients. This study presents the first known evidence that COVID-19 vaccines are fundamentally restricting the evolutionary and antigenic escape pathways accessible to SARS-CoV-2. The societal benefit of mass vaccination may consequently go far beyond the widely reported mitigation of SARS-CoV-2 infection risk and amelioration of community transmission, to include stemming of rampant viral evolution.


title: Association of preoperative plasma suPAR levels with intraoperative sublingual microvascular perfusion in patients undergoing major non-cardiac surgery

abstract:
INTRODUCTIONThe plasma suPAR level has previously been associated with postoperative complications and has been shown to be an independent predictor of coronary microvascular function and flow reserve. We investigated the association between preoperative suPAR levels and intraoperative sublingual microvascular perfusion in patients undergoing elective major non-cardiac surgery.

MethodsThis study included 100 patients undergoing major non-cardiac surgery between February 2019 and September 2020. The primary objective was to investigate the association between preoperative suPAR and intraoperative sublingual De Backer score, Consensus Proportion of Perfused Vessels (Consensus PPV), and Consensus PPV (small). Secondary objectives were to investigate the associations between these sublingual microcirculatory variables and (1) complications and (2) mean arterial pressure. EDTA blood was collected before induction of anesthesia and plasma suPAR levels were determined using the suPARnostic(R) quick triage lateral flow assay. Sublingual microcirculation was monitored with Sidestream DarkField (SDF+) imaging technique at 20 minutes after induction of anesthesia before surgical incision (baseline) and then every 30 minutes until emergence from anesthesia.

ResultsA decrease of 0.7 mm-1 in the De Backer score, 2.5% in the Consensus PPV, and 2.8% in the Consensus PPV (small) from baseline measurement was observed for every 1 ng/ml increase of suPAR or 1 additional minute of intraoperative time. De Baker score did not change significantly from baseline (p=0.404), while Consensus PPV and Consensus PPV (small) decreased significantly from baseline (p<0.001 in both cases). The De Backer score, the Consensus PPV, and the Consensus PPV (small) correlated with postoperative complications. Mean arterial pressure correlated with De Backer score (p=0.487) but not with Consensus PPV (p=0.506) or Consensus PPV (small) (p=0.697) during the intraoperative period.

ConclusionPreoperative suPAR levels and prolonged operative duration were associated with intraoperative impairment of sublingual microvascular perfusion in patients undergoing elective major non-cardiac surgery.

category: anesthesia


title: Heart Rate Variability as a Prospective Predictor of Early COVID-19 Symptoms

abstract: Heart rate variability (HRV) is the fluctuation in the time interval between consecutive heartbeats, the measurement of which is a non-invasive method for assessing the autonomic status. The autonomic nervous system plays an important role in physiological situations, and in various pathological processes such as in cardiovascular diseases and viral infections. This study examined the cardiac autonomic responses, as measured by HRV before, after, and during coronavirus disease. In this study, we used beat interval data extracted from the Welltory app from 14 eligible subjects (9 men and 5 women) with a mean age (SD) of 44 (8.7) years. HRV analysis was performed through an assessment of time-domain indices (SDNN and RMSSD). Group analysis did not reveal any statistical difference between HRV metrics before, during, and after COVID-19. However, HRV at the individual level showed a statistically significant individual change during COVID-19 in some users. These data further support the usefulness of using individual-level HRV tracking for the detection of early diseases inclusive of COVID-19.

category: cardiovascular medicine


title: Treatment of sarcoidosis with cutaneous involvement with tofacitinib

abstract: Sarcoidosis is an idiopathic inflammatory disorder that is commonly treated with glucocorticoids and there are no approved steroid-sparing medications. There is emerging evidence that Janus kinase (JAK) inhibitors, which inhibit JAK-dependent cytokine activity, may hold promise in sarcoidosis. In this open-label trial, 10 patients with recalcitrant sarcoidosis with cutaneous involvement were treated with tofacitinib 5 mg twice daily. There was no washout period and patients were permitted to continue, taper, or discontinue other treatments. The primary outcome was the change in the Cutaneous Sarcoidosis Activity and Morphology Instrument (CSAMI) activity score after 6 months. Change in internal organ disease activity was also assessed using total lesion glycolysis (TLG) determined by full-body positron emission tomography. A mean reduction in the CSAMI activity score of 82.7% was observed, with 6 patients showing a complete response. Internal organ response data was available in 8 patients; a decrease in TLG of [≥]50% was noted in 5 patients, with complete or near complete resolution in 3 (>98% reduction in TLG). Patients were generally able to significantly taper or discontinue their baseline immunosuppressive regimen, which included prednisone in 5 patients. Single cell RNA-sequencing, bulk RNA-sequencing, and high-throughput proteomic analyses were performed on skin and blood as a function of treatment in order to delineate changes in immunologic signals with therapy. We identified CD4+ T cell derived IFN-{gamma} as a central cytokine driver of sarcoidosis and inhibition of its activity was achieved with tofacitinib and correlated closely with clinical improvement. Tofacitinib appears to have impressive activity in treatment of sarcoidosis and likely acts by inhibiting IFN-{gamma}, larger, controlled studies are warranted.

category: dermatology


title: Post-vaccination SARS-COV-2 among healthcare workers in New Jersey: a genomic epidemiological study

abstract:
Emergence of SARS-CoV-2 with high transmission and immune evasion potential, the so-called Variants of Concern (VOC), is a major concern. We describe the early genomic epidemiology of SARS-CoV-2 recovered from vaccinated healthcare professionals (HCP). Our post-vaccination COVID-19 symptoms-based surveillance program among HCPs in a 17-hospital network, identified all vaccinated HCP who tested positive for COVID-19 after routine screening or after self-reporting. From 01/01/2021 to 04/30/2021, 23,687 HCP received either mRNA-1273 or BNT162b2 mRNA vaccine. All available post-vaccination SARS-CoV-2 samples and a random collection from non-vaccinated patients during the similar timeframe were subjected to VOC screening and whole genome sequencing (WGS). 62% (23,697/37,500) of HCPs received at least one vaccine dose, with 95% (22,458) fully vaccinated. We detected 138 (0.58%, 138/23,697) COVID-19 cases, 105 among partially vaccinated and 33 (0.15%, 33/22,458) among fully vaccinated. Five partially vaccinated required hospitalization, four with supplemental oxygen. VOC screening from 16 fully vaccinated HCPs identified 6 (38%) harboring N501Y and 1 (6%) with E484K polymorphisms; concurrent non-vaccinated samples was 37% (523/1404) and 20% (284/1394), respectively. There was an upward trend from January to April for E484K/Q (3% to 26%) and N501Y (1% to 49%). WGS analysis from vaccinated and non-vaccinated individuals indicated highly congruent phylogenies. We did not detect an increased frequency of any RBD/NTD polymorphism between groups (P>0.05). Our results support robust protection by vaccination, particularly among recipients of both doses. Despite VOCs accounting for over 40% of SARS-CoV-2 from fully vaccinated individuals, the genomic diversity appears to proportionally represent those among non-vaccinated populations.

IMPORTANCEA number of highly effective vaccines have been developed and deployed to combat the COVID-19 pandemic. The emergence and epidemiological dominance of SARS-CoV-2 mutants, with high transmission potential and immune evasion properties, the so-called Variants of Concern (VOC), continues to be a major concern. Whether these VOCs alter the efficacy of the administered vaccines is of great concern, and a critical question to study. We describe the initial genomic epidemiology of SARS-CoV-2 recovered from vaccinated healthcare professionals and probe specifically for VOC enrichment. Our findings support the high-level of protection provided by full vaccination despite a steep increase in the prevalence of polymorphisms associated with increased transmission potential (N501Y) and immune evasion (E484K) in the non-vaccinated population. Thus, we do not find evidence of VOC enrichment among vaccinated groups. Overall, the genomic diversity of SARS-CoV-2 recovered post-vaccination appears to proportionally represent the observed viral diversity within the community.

category: epidemiology


title: Circulating metabolic biomarkers consistently predict incident type 2 diabetes in Asian and European populations - a plasma metabolomics analysis of four ethnic groups

abstract:
BackgroundWhile Asians have a higher risk of type 2 diabetes (T2D) than Europeans for a given BMI, it remains unclear whether the same markers of metabolic pathways are associated with diabetes.

ObjectivesWe evaluated associations between metabolic biomarkers and incident T2D in three major Asian ethnic groups (Chinese, Malay, and Indian) and a European population.

MethodsWe analyzed data from adult males and females of two cohorts from Singapore (n = 6,393) consisting of Chinese, Malays and Indians, and three cohorts of European-origin participants from Finland (n = 14,558). We used nuclear magnetic resonance to quantify 154 circulating metabolic biomarkers at baseline and performed logistic regression to assess associations with T2D risk adjusted for age, sex, BMI and glycaemic markers.

ResultsOf the 154 metabolic biomarkers, 59 were associated with higher risk of T2D in both Asians and Europeans (P < 0.0003; Bonferroni-corrected). These included branched-chain and aromatic amino acids, the inflammatory marker glycoprotein acetyls, total fatty acids, monounsaturated fatty acids, apolipoprotein B, larger very low-density lipoprotein particle sizes, and triglycerides. In addition, 13 metabolites were associated with a lower T2D risk in both populations including omega-6 polyunsaturated fatty acids and larger high-density lipoprotein particle sizes. Associations were consistent within the Asian ethnic groups (all Phet [≥] 0.05) and largely consistent for the Asian and European populations (Phet [≥] 0.05 for 128 of 154 metabolic biomarkers).

ConclusionMetabolic biomarkers across several biological pathways were consistently associated with T2D risk in Asians and Europeans.


title: Circulating metabolic biomarkers are consistently associated with incident type 2 diabetes in Asian and European populations - a metabolomics analysis in five prospective cohorts


title: The relationship between Lipoprotein A and other lipids with prostate cancer risk: A multivariable Mendelian randomisation study.

abstract:
BackgroundNumerous epidemiological studies have investigated the role of blood lipids in prostate cancer (PCa) risk though findings remain inconclusive to date. The ongoing research has mainly involved observational studies which are often prone to confounding. This study aimed to identify the relationship between genetically predicted blood lipid concentrations and PCa.

Methods and FindingsData for low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides (TG), apolipoprotein A (apoA) and B (apoB), lipoprotein A (Lp(a)) and PCa were acquired from genome-wide association studies in UK Biobank and the PRACTICAL consortium, respectively. We used a two-sample Mendelian randomisation (MR) approach with both univariable and multivariable (MVMR) models and utilised a variety of robust methods and sensitivity analyses to assess the possibility of MR assumptions violation. No association was observed between genetically predicted concentrations of HDL, TG, apoA and apoB and PCa risk. Genetically predicted LDL concentration was positively associated with total PCa in the univariable analysis but adjustment for HDL, TG and Lp(a) led to a null association. Genetically predicted concentration of Lp(a) was associated with higher total PCa risk in the univariable (ORweighted median per sd = 1.091; 95% CI 1.028-1.157; P=0.004) and MVMR analyses after adjustment for the other lipid traits (ORIVW per sd = 1.068; 95% CI 1.005-1.134; P = 0.034). Genetically predicted Lp(a) was also associated with advanced (MVMR ORIVW per sd = 1.078; 95% CI 0.999-1.163; P=0.055) and early age onset PCa (MVMR ORIVW per sd = 1.150; 95% CI 1.015,1.303; P = 0.028). Although multiple estimation methods were utilized to minimize the effect of pleiotropic traits, the presence of any unmeasured pleiotropy cannot be excluded and may limit our findings.

ConclusionsWe observed that genetically predicted Lp(a) concentrations are associated with an increased PCa risk. Future studies are required to understand the underlying biological pathways of this finding, as it may inform PCa prevention through Lp(a)-lowering strategies.


title: Altered DNA methylation pattern characterizes the peripheral immune cells of patients with autoimmune hepatitis

abstract:
ObjectiveAIH is a chronic liver disease of unknown aetiology with favourable response to immunosuppression. Little is known about the impact of methylation modifications on disease pathogenesis.

Design10 patients with AIH at diagnosis (time-point 1; tp1), 9 with primary biliary cholangitis (PBC) and 10 healthy controls (HC) were investigated. 8/10 AIH patients were also investigated following biochemical remission (time-point 2; tp2). Peripheral CD19(+)- and CD4(+)-cells were isolated to study global DNA methylation (5mC)/hydroxymethylation (5hmC) by ELISA and mRNA of DNA methylation (DNMT1/3A/3B)/hydroxymethylation enzymes (TET1/2/3) by quantitative RT-PCR. Epigenome wide association study (EWAS) was performed in CD4(+)-cells (Illumina HumanMethylation 850K array) in AIH and HC. Differences in total 5mC/5hmC state between AIH-tp1 and HC were also assessed by immunohistochemistry (IHC) on paraffin embedded liver sections.

ResultsReduced TET1 and increased DNMT3A mRNA levels characterized CD19(+) and CD4(+) lymphocytes from AIH-tp1 patients compared to HC and PBC respectively, without affecting global DNA 5mC/5hmC. In AIH-tp1, CD4(+) DNMT3A expression was negatively correlated with serum IgG (p=0.03). In remission (AIH-tp2), DNMT3A decreased in both CD19(+) and CD4(+)-cells (p=0.02, p=0.03, respectively). EWAS in CD4(+)-cells from AIH patients confirmed important modifications in genes implicated in immune responses (HLA-DP, TNF, lnRNAs and CD86). IHC confirmed increased 5hmC staining of periportal infiltrating lymphocytes in AIH-tp1.

ConclusionAltered expression of TET1 and DNMT3A, characterizes peripheral immune cells in AIH. DNMT3A is associated with disease activity and decreased following therapeutic response. Gene specific DNA methylation modifications affect immunologic pathways that may play an important role in AIH pathogenesis.

Summary boxWhat is already known?

Autoimmune hepatitis (AIH) is a non-resolving chronic liver disease of unknown aetiology and favourable response to immunosuppression. Since the interplay between the genetic background and the environment seems to be fundamental for AIH pathogenesis, epigenetic modifications may be of particular importance.

What are the new findings?

We found characteristic alterations of DNA methylation in peripheral immune cells of AIH patients, which were associated with disease activity and modified by immunosuppressive treatment.

How might it impact on clinical practice in the foreseeable future?

These results provide the first evidence that epigenetics play a role in AIH pathogenesis, which may have therapeutic implications for the management of the disease.

category: gastroenterology


title: Soft drinks can be misused to give false false positive SARS-CoV-2 lateral flow device results

abstract:
BackgroundThe COVID-19 pandemic created the need for very large scale, rapid testing to prevent and contain transmission of the SARS-CoV-2 virus. Lateral flow device (LFD) immunoassays meet this need by indicating the presence of SARS-CoV-2 antigen from nose/throat swab washings in 30 minutes without laboratory processing, and can be manufactured quickly at low cost. Since March 2021, UK schools have asked pupils without symptoms to test twice weekly. Pupils have posted on social media about using soft drinks to create positive results. The aim of this study was to systematically test a variety soft drinks to determine whether they can cause false "false positive" LFD results.

MethodsThis study used 14 soft drinks and 4 artificial sweeteners to determine the outcome of misusing them as analyte for the Innova SARS-CoV-2 antigen rapid qualitative LFD. The pH value, sugar content and ingredients of each sample are described. The LFD results were double read and a subset was repeated using the same devices and fake analytes but differently sourced.

FindingsOne sample (1/14; 7%), spring water, produced a negative result. Ten drinks (10/14; 71%) produced a positive or weakly positive result. Three samples (3/14; 21%) produced void results, mostly the fruit concentrate drinks. There was no apparent correlation between the pH value (pH 5.0 in 13/14, 93%; pH 6.5 in 1/14; 7%) or the sugar content (range 0-10.7 grams per 100mls) of the drinks and their LFD result. The 4 artificial sweeteners all produced negative results. A subset of the results was fully replicated with differently sourced materials.

InterpretationSeveral soft drinks can be misused to give false positive SARS-CoV-2 LFD results. Daily LFD testing should be performed first thing in the morning, prior to the consumption of any food or drinks, and supervised where feasible.

FundingThis work was self-funded by author LO and the LFD were gifted for use in this study.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSO_LILateral flow devices (LFD) for SARS-CoV-2 antigen testing have been used extensively in the UK and internationally in COVID-19 pandemic responses, providing rapid testing at low cost
C_LIO_LIRecent reports from young people on social media suggested soft drinks might be misused as LFD analyte and produce a seemingly positive result
C_LI

Added value of this studyO_LIVarious common soft drinks used as fake analyte can produce false positive SARS-CoV-2 LFD results
C_LIO_LIArtificial sweeteners alone in fake analyte solution did not produce false positive results
C_LI

Implications of all the available evidenceO_LISoft drinks misused as analyte can produce false "false positive" SARS-CoV-2 LFD results
C_LIO_LIDaily testing is best done first thing in the morning, prior to any food or drink, and under supervision where possible
C_LI

category: pediatrics


title: Risk factors for SARS-CoV-2 infection and hospitalisation in children and adolescents in Norway: A nationwide population-based study.

abstract:
ObjectiveTo determine risk factors for SARS-CoV-2 infection and hospitalisation among children and adolescents.

DesignNationwide, population-based cohort study. Setting: Norway from 1 March 2020 to 31 April 2021. Participants: All Norwegian residents <18 years of age.

Main outcome measuresPopulation-based health care and population registries were used to study risk factors for SARS-CoV-2 infection, including socioeconomic factors, country of origin, and pre-existing chronic comorbidities. All residents were followed until age 18, emigration, death, or end of follow-up. Hazard ratios (HR) estimated by Cox regression models were adjusted for testing frequency. Further, risk factors for admission to the hospital among the infected were investigated.

ResultsOf 1 182 796 residents, 22608 (1.9%) tested positive by polymerase chain reaction or lateral flow tests, of whom 107 (0.5%) were admitted to a hospital. Low family income (aHR 1.40, 95% confidence interval 1.36 to 1.46), crowded housing (1.35, 1.30 to 1.39), household size, age, and area of living were independent risk factors for infection. A non-Nordic country of origin was the strongest risk factor (aHR 2.37, 95% CI 2.30 to 2.49), whereas chronic comorbidity was not associated with the risk of infection. Chronic comorbidity was associated with hospitalisation (aHR 4.15, 2.63 to 6.56), in addition to age, whereas socioeconomic status and country of origin did not predict hospitalisation among those infected.

ConclusionsSocioeconomic factors, country of origin, and area of living were associated with the risk of SARS-CoV-2 infection. However, these factors did not predict hospitalisation among those infected. Chronic comorbidity was associated with the risk of admission but not with the overall risk of acquiring SARS-CoV-2.

What is already known on this topicHospital admissions rates for covid-19 among children and adolescents are low compared to adults. Admission rates to hospitals and intensive care units for covid-19 have been higher in minority groups and in children and adolescents with chronic comorbidity.

Whether underlying differences in susceptibility for severe disease or the incidence of infections are driving these associations have not been investigated.

What this study addsLow family income, crowded housing and household size, and country of origin outside the Nordic countries were associated with increased risk of infection with SARS-CoV-2.

None of these factors, but chronic comorbidities, were associated with the risk of hospital admission among those infected.


title: Risk factors for intensive care admission and death amongst children and young people admitted to hospital with COVID-19 and PIMS-TS in England during the first pandemic year

abstract:
Identifying which children and young people (CYP) are vulnerable to severe disease following SARS-CoV-2 is important to guide shielding and vaccination policy.

MethodsWe used data for all inpatient hospital admissions in England in CYP aged 0-17 between March 1st 2015 to Feb 28th 2021, linked to paediatric intensive care unit (PICU), SARS-CoV-2 PCR testing, and mortality data. We examined associations between PICU admission and death by sociodemographic factors and comorbidities within COVID-19 and PIMS-TS admissions. We calculated odds ratios and predicted probability of PICU admission using generalized estimation equations, and compared these between COVID-19, PIMS-TS, other admissions in 2020/21, all admissions in 2019/20, and admissions due to influenza in 20219/20. Analyses of deaths were descriptive due to low numbers.

FindingsWithin COVID-19, there were 6,338 hospital admissions, 259 PICU admissions and 8 deaths. Within PIMS-TS there were 712 hospital admissions 312 PICU admissions and <5 deaths. Males were 52.8% of COVID-19 admissions (similar to other causes of admission), but were 63.5% of PIMS-TS admissions. CYP aged 10-17 were 35.6 and 29% of COVID-19 and PIMS-TS admissions respectively, higher than in all admission and influenza admissions in 2019/20. In multivariable models, odds of PICU admission were: increased amongst neonates and decreased amongst 15-17 compared with 1-4 year olds with COVID-19, increased in older CYP and females with PIMS-TS, and increased for Black compared with White ethnicity in COVID-19 and PIMS-TS. Odds of PICU admission with COVID-19 were increased for CYP with any comorbidity and were highest for CYP with multiple medical problems. Increases in risk of PICU admission associated with comorbidities showed similar patterns for COVID-19 and all admissions in 2019/20 and influenza admissions in 2019/20, but were greater for COVID-19. Interpreting associations with comorbidities within PIMS-TS was complex due to the multisystem nature of the disease.

InterpretationCYP were at very low risk of severe disease and death from COVID-19 or PIMS-TS. PICU admission due to PIMS-TS was associated with older non-white CYP. Patterns of vulnerability for severe COVID-19 appear to magnify background risk factors for serious illness in CYP.

Evidence before this studyWe conducted a systematic review and meta-analysis of studies investigating risk factors associated with severe disease among children and young people admitted with COVID-19 and PIMS-TS, [Harwood, R et al. 2021 (submission to the Lancet linked with this paper)]. We identified 81 studies. Infants were found to have increased odds of PICU admission compared with 1-4, but there were no associations by sex. Other factors associated with PICU admission included number of co-morbid conditions, with neurological, cardiac and gastrointestinal associated with the greatest risk. Low numbers of serious SARS-CoV-2 infections or deaths amongst CYP limit these analyses, yet national studies of CYP have not yet been published. Importantly, we found these studies did not take into account background risks for severe illness in CYP who are known to be vulnerable before the pandemic.

What this study addsThis is the first population base study of risk factors for severe disease following SARS-CoV-2 infection in CYP in England. We analyse all admissions to hospital amongst 0-17 year olds nationally between 2015-2021 linked to multiple other health datasets. We explore how socioeconomic factors and co-morbidities are associated with Paediatric Intensive Care Unit (PICU) admission and death amongst CYP admitted with COVID-19 and PIMS-TS, and compare this with other causes for admission during the pandemic and in the year prior. As CYP with PIMS-TS are highly likely to require hospitalization, we were able to analyse total national cases of the condition during 2020/21.

We found extremely low numbers of CYP required PICU or died as a result of SARS-CoV-2 in the first pandemic year. CYP admitted due to COVID-19 disease were older and more likely to be non-white with pre-existing conditions, similar to patterns seen in adults. Patterns of associations between comorbidities and risk of PICU admission amongst COVID-19 were similar to those seen for all admissions and influenza admissions in the year prior to the pandemic. However, the increase in risk associated with comorbidities for COVID-19 admissions were greater than in these cohorts.

We found most cases of PIMS-TS were amongst non-white male adolescents without previous hospital admissions. Interpreting associations between comorbidities and PICU admission for PIMS-TS was complicated by the multi-system nature of the disease.

Implications of all the available evidenceCYP with most vulnerable to COVID-19 were also those most at risk of prior to the pandemic due to other illnesses such as influenza, although COVID-19 appears to amplify this risk profile. It is important to consider this context when advising parents and carers regarding the risk posed by COVID-19, considering potential harms to CYP as a result of shielding precautions.


title: Attempted Suicide and Criminal Justice System in a Sample of Forensic Psychiatric Patients in Malaysia

abstract: Criminalization of suicide attempts is an archaic barrier to suicide prevention. Globally, clinical profiles of prosecuted suicide attempters are an under-researched area. This retrospective study aims to describe the clinical profiles of individuals who were charged for attempted suicide and subsequently sent for criminal responsibility and fitness to plead evaluation in a forensic psychiatric unit in Malaysia from January 1, 2008, to December 31, 2019. We identified 22 cases who were mostly adult males (90.9%). Seventy-three percent have a psychiatric disorder. Mood disorders were more prevalent (32%) followed by psychotic disorders and substance use disorders. For most of these individuals, this was the first contact with any form of mental health services and 41% defaulted their treatment before arrest. This sample illustrates a vulnerable group who has been disengaged with mental healthcare. Future research is warranted to further investigate mechanisms that are effective in addressing unmet needs of persons in suicidal crisis as opposed to utilizing the criminal justice pathway.

category: psychiatry and clinical psychology


title: Adulthood asthma as a consequence of childhood adversity: a systematic review of epigenetically affected genes

abstract: There is an accumulating data that shows relation between childhood adversity and vulnerability to chronic diseases as well as epigenetic influences that in turn give rise to these diseases. Asthma is one of the chronic diseases that is influenced from genetic regulation of the inflammatory biomolecules and therefore the hypothesis in this research was childhood adversity might have caused epigenetic differentiation in the asthma related genes in the population who had childhood trauma. To test this hypothesis, the literature was systematically reviewed to extract epigenetically modified gene data of the adults who had childhood adversity, and affected genes were further evaluated for their association with asthma. PRISMA guidelines were adopted and PubMed and Google Scholar were included in the searched databases, to evaluate epigenetic modifications in asthma related genes of physically, emotionally or sexually abused children. After retrieving a total of 12,085 articles, 36 of them were included in the study. Several genes and pathways that may contribute to pathogenesis of asthma development, increased inflammation or response to asthma treatment were found epigenetically affected by childhood traumas. Childhood adversity, causing epigenetic changes in DNA, may lead to asthma development or influence the course of the disease and therefore should be taken into account for the prolonged health consequences.

category: public and global health


title: Simulated Diagnostic Performance of Ultra-Low-Field MRI: Harnessing Open-Access Datasets to Evaluate Novel Devices

abstract:
The purpose of this study is to demonstrate a method for virtually evaluating novel imaging devices using machine learning and open-access datasets, here applied to a new, ultra-low-field strength (ULF), 64mT, portable MRI device. Paired 3T and 64mT brain images were used to develop and validate a transformation converting standard clinical images to ULF-quality images. Separately, 3T images were aggregated from open-source databases spanning four neuropathologies: low-grade glioma (LGG, N=76), high-grade glioma (HGG, N=259), stroke (N=28), and multiple sclerosis (MS, N=20). The transformation method was then applied to the open-source data to generate simulated ULF images for each pathology. Convolutional neural networks (DenseNet-121) were trained to detect pathology in axial slices from either 3T or simulated 64 mT images, and their relative performance was compared to characterize the potential diagnostic capabilities of ULF imaging. Algorithm performance was measured using area under the receiver operating characteristic curve. Across all cohorts, pathology detection was similar between 3T and simulated 64mT images (LGG: 0.97 vs. 0.98; HGG: 0.96 vs. 0.95; stroke: 0.94 vs. 0.94; MS: 0.90 vs 0.87). Pathology detection was further characterized as a function of lesion size, intensity, and contrast. Simulated images showed decreasing sensitivity for lesions smaller than 4 cm2 ([~]2.25 cm in diameter). While simulations cannot replace prospective trials during the evaluation of medical devices, they can provide guidance and justification for prospective studies. Simulated data derived from open-source imaging databases may facilitate testing and validation of new imaging devices.

HighlightsO_LIUltra-low-field, point-of-care MRI has potential to detect a range of pathologies including brain tumors, strokes, and multiple sclerosis. However, determining the diagnostic capabilities and appropriate use case for such devices requires further prospective studies.
C_LIO_LIOpen-source image datasets provide a powerful tool for accelerating imaging research and enable simulated trials that can guide prospective clinical trials or device development.
C_LI

category: radiology and imaging


title: Assessing our capability to predict the presence of respiratory diseases at the age of four using data available at one month of age

abstract:
AO_SCPLOWBSTRACTC_SCPLOWChronic respiratory diseases are often difficult to cure and are likely to originate early in life. Therefore, early identification of such diseases is of interest for early prevention.

We explored the potential to predict these almost from birth; using data at 1 month of age, we attempted to predict disease occurrence 4 years later in life. Our data came from the Barwon Infant Study; after cleaning and processing, we had measurements on 41 variables from 401 participants.

We considered three respiratory diseases: asthma, wheeze and hay fever. As predictors, we used a variety of information that would be available in a clinical setting. Of particular interest to our investigation was whether lung function measurements (newly available at such an early age) would helpfully improve predictive accuracy. We also investigated whether maternal smoking (previously associated with respiratory illnesses) is a helpful predictor.

Our methods included logistic regression as the main model, multiple imputation to deal with missing values, stepwise selection and LASSO to select variables, and cross-validation to assess performance. We measured predictive performance using AUC (area under the receiver operating characteristic curve), sensitivity and specificity.

Broadly, we found that the best models had only modest predictive power for each disease. For example, for asthma we achieved an AUC of 0.67, a sensitivity of 68% and a corresponding specificity of 63%. Performance for the other two diseases was similar.

We also found that our lung function measurements did not improve predictive performance; some-what surprisingly, this was also true for maternal smoking. The most useful predictors included, among others, family history of these diseases and variables relating to the size of the infants.

Given the modest performance of these models, our findings suggest that very early prediction of respiratory illnesses is still a challenging task.

category: respiratory medicine


title: Online tests for sexually transmitted infections - Friend or Foe? An analysis of providers in the United Kingdom.

abstract:
ObjectivesOnline testing for sexually transmitted infections (STIs) may contribute to overcoming barriers to traditional testing such as stigma and inconvenience. However, regulation of these tests is lacking, and the quality of services is variable, with potential short- and long-term personal, clinical and public health implications. This study aimed to evaluate online tests available in the UK against national standards.

MethodsProviders of online STI tests (self-sampling and self-testing) in the UK were identified by an internet search of Google and Amazon (June 2020). Website information on tests and care was collected, and further information requested from providers via an online survey, sent twice (July 2020, April 2021). The information obtained was compared to British Association for Sexual Health and HIV (BASHH) guidelines for diagnostics and standards of STI management.

Results31 providers were identified: 13 self-test, 18-self-sample, and two laboratories that serviced multiple providers. Seven responded to the online survey. Many conflicts with national guidelines were identified, including: lack of health promotion information, lack of sexual history taking, use of tests licensed for professional use only marketed for self-testing, inappropriate infections tested for, incorrect specimen type used, and lack of advice for post-diagnosis management.

ConclusionsVery few online providers met the BASHH national STI management guidelines standards that were assessed, and there is concern that this will also be the case in areas that were not covered by this study. For-profit providers were the least compliant, with concerning implications for patient care and public health. Regulatory change is urgently needed to ensure that online providers are compliant with national guidelines to ensure high-quality patient care, and providers are held to account if non-compliant.

Key message boxO_LIOnline providers help overcome many barriers to STI testing and are increasingly popular, but quality of services is not assured
C_LIO_LIMany online testing services, particularly for-profit providers, did not comply with national guidelines
C_LIO_LISubstandard services can lead to serious personal, clinical and public health
C_LIO_LIimplications, such as inappropriate testing, inappropriate antimicrobial prescribing, unnecessary emotional distress and missed diagnoses
C_LIO_LIRegulatory change is required to ensure online providers comply with national guidelines and are held to account when they do not
C_LI

category: sexual and reproductive health


title: EFFECTIVE CONNECTIVITY IN SUBCORTICAL VISUAL STRUCTURES IN DE NOVO PATIENTS WITH PARKINSON DISEASE

abstract:
BackgroundPD is associated with non-motor symptoms appearing before the motor symptoms onset. Recent studies report dysfunctions of visual structures at early stages of PD.

ObjectiveThis study addresses effective connectivity in the visual network of PD patients.

MethodsUsing brain functional MRI and Dynamic Causal Modeling analysis, we investigated the connectivity between the superior colliculus, the lateral geniculate nucleus and the primary visual area V1 in 22 de novo untreated PD patients and six months after starting dopaminergic treatment compared to age-matched healthy controls.

ResultsOur findings indicate that the superior colliculus drives cerebral activity for luminance contrast processing both in healthy controls and untreated PD patients. The same effective connectivity was observed with neuromodulatory differences in terms of neuronal dynamic interactions. The modulation induced by luminance contrast changes of the superior colliculus connectivity (self-connectivity and connectivity to the lateral geniculate nucleus) was inhibited in PD patients (effect of contrast: p = 0.79 and p = 0.77 respectively). The introduction of dopaminergic medication failed to restore the effective connectivity modulation observed in the healthy controls.

InterpretationThe deficits in luminance contrast processing in PD seem due to a deficiency in connectivity adjustment from the superior colliculus to the lateral geniculate nucleus and to V1. Administration of a dopaminergic treatment over six months was not able to normalize the observed alterations in inter-regional coupling. These findings highlight the presence of early dysfunctions in primary visual areas, which might be used as early markers of the disease.

category: neurology


title: Investigation on the current situation of stroke patients in northernern Henan Province of China

abstract:
ObjectivesTo analyze the basic situations and clinical characteristics of stroke patients in our hospital from May 2018 to April 2021, lay a foundation for the prevention and reasonable treatment of stroke patients in northern Henan Province.

MethodsThe basic information of 835 stroke patients in our hospital was collected and classified according to age, gender, bad habits, accompanied diseases and drug use before admission to hospital, and severity of the stroke patients were also evaluated according to mRS scoring standard.

ResultsA total of 835 stroke patients were collected from May 2018 to April 2021 in our hospital. The age range of stroke patients was 28-95 years old, 96.29% stroke patients was above 40 years old; there were 202 stroke patients with smoking history and 225 stroke patients with drinking history; Among the 835 stroke patients, hypertension, cerebral infarction and diabetes mellitus were the main accompanied diseases. Antihypertensive drugs (506 cases), antiplatelet drugs (208 cases), statins (173 cases) and antidiabetic drugs (143 cases) were the main therapeutic drugs in stroke patients before admission in the northern Henan Province; the results of mRS scoring standard showed that among 835 stroke patients, there were 609 cases with milder symptoms, accounting for 82.84% (there were 330 stroke patients with 1 points, 279 stroke patients with 2 points, and 83 stroke patients with 3 points), and 120 cases with severe symptoms, accounting for 14.37% (55 cases with 4 points, 65 cases with 5 points).

ConclusionThe age of stroke patients in northern Henan Province was mainly over 40 years old, most of stroke patients were in the early stage of stroke; smoking, drinking, hypertension and diabetes mellitus were main risk factors of stroke. And there was a sex difference between male stroke patients and female stroke patients in stroke risk factors smoking and hypertension. those data may help us for active prevention and rational drug use for stroke in clinic.


title: Cerebral hypoperfusion is a late pathological event in the course of Alzheimer's disease

abstract: Although several studies have shown decreased cerebral blood flow (CBF) in Alzheimers disease (AD), the role of hypoperfusion in the disease pathogenesis remains unclear. Combining arterial spin labeling MRI, positron emission tomography, and biomarkers of cerebrospinal fluid, we investigated the associations between CBF and the key mechanisms in AD including amyloid-{beta} (A{beta}) and tau pathology, synaptic dysfunction and axonal degeneration. Further, we applied a disease progression modeling to characterize the temporal sequence of different AD biomarkers. Lower perfusion was observed in the temporo-occipito-parietal regions in the A{beta}-positive cognitively impaired compared to both the A{beta}-positive and A{beta}-negative cognitively unimpaired individuals. In participants along the AD spectrum (those with A{beta} pathology regardless of their cognitive status), CBF was inversely associated with tau and synaptic dysfunction, but not A{beta}, in similar cortical regions. Moreover, the disease progression modeling revealed that CBF disruption followed the abnormality of biomarkers of A{beta}, tau and brain atrophy. These findings indicate that tau tangles and synaptic degeneration are more closely connected with CBF changes rather than A{beta} pathology. This supports the notion that hypoperfusion is not an early event associated with the build-up of A{beta} during the preclinical phase of AD.


title: Awareness regarding Anemia in Antenatal women attending tertiary care hospitals in South India

abstract: Disclaimer statement: The authors have withdrawn this manuscript because proper permission was not taken from the concerned authorities before the submission of this manuscript. Therefore,the authors do not wish this work to be cited as a reference for the project. If you have any questions, please contact the corresponding author.

category: obstetrics and gynecology


title: ERAP1, ERAP2, and two copies of HLA-Aw19 alleles increase the risk for Birdshot Chorioretinopathy in HLA-A29 carriers

abstract:
PurposeBirdshot Chorioretinopathy (BSCR) is strongly associated with HLA-A29. This study was designed to elucidate the genetic modifiers of BSCR in HLA-A29 carriers.

MethodsWe sequenced the largest BSCR cohort to date, including 286 cases and 108 HLA-A29 positive controls to perform genome wide common and rare variant associations. We further typed the HLA alleles of cases and 45,386 HLA-A29 controls of European ancestry to identify HLA alleles that associate with BSCR risk.

ResultsCarrying a second allele that belongs to the HLA-Aw19 broad antigen family (including HLA-A29, A30, A31, and A33) increases the risk for BSCR (OR=4.44, p=2.2e-03). This result was validated by comparing allele frequencies to large HLA-A29-controlled cohorts (n=45,386, OR>2.5, p<1.3e-06). We also confirm that ERAP1 and ERAP2 haplotypes modulate the risk for disease within our HLA-A29 controlled cohort. A meta-analysis with an independent dataset confirmed that ERAP1 and ERAP2 haplotypes modulate the risk for disease at a genome-wide significant level: ERAP1-rs27432 (OR 2.46; 95% CI 1.85-3.26; p=4.07e-10), an eQTL decreasing ERAP1 expression, and ERAP2-rs10044354 (OR 1.95; 95% CI 1.55-2.44; p=6.2e-09), an eQTL increasing ERAP2 expression. Furthermore, ERAP2-rs2248374 that disrupts ERAP2 expression is protective (OR 0.56; 95% CI [0.45-0.70]; p=2.39e-07). BSCR risk is additively increased when combining ERAP1/ERAP2 risk genotypes with two copies of HLA-Aw19 alleles (OR 13.53; 95% CI 3.79-54.77, p=1.17e-05).

ConclusionsThe genetic factors increasing BSCR risk demonstrate a pattern of increased processing, as well as increased presentation of ERAP2 specific peptides. This suggests a mechanism in which exceeding a peptide presentation threshold activates the immune response in choroids of A29 carriers.

category: ophthalmology


title: Prevalence and Correlates of Parosmia and Phantosmia among Smell Disorders

abstract: Among those many individuals who suffer from a reduced odor sensitivity (hyposmia/anosmia) some individuals also experience disorders that lead to odor distortion, such as parosmia (i.e., distorted odor with a known source), or odor phantoms (i.e., odor sensation without an odor source). We surveyed a large population with at least one olfactory disorder (N = 2031) and found that odor distortions were common (46%), with respondents reporting either parosmia (19%), phantosmia (11%), or both (16%). In comparison to respondents with hyposmia or anosmia, respondents with parosmia were more likely to be female, young, and suffered from post-viral olfactory loss (p < 0.001), while phantosmia occurred most frequently in middle-aged respondents (p < 0.01) and was more likely to be caused by head trauma than parosmia (p < 0.01). A higher prevalence of odor distortion was observed 3 months to a year after their olfactory symptom onset (p < 0.001), which coincides with the timeline of physiological recovery. Additionally, we observed that the frequency and duration of distortions negatively affects quality of life, with parosmia showing a higher range of severity than phantosmia (p < 0.001). Previous research often grouped these distortions together, but our results show that they have distinct patterns of demographics, medical history, and loss in quality of life.

category: otolaryngology


title: Survey of SARS-CoV-2 genetic diversity in two major Brazilian cities using a fast and affordable Sanger sequencing strategy.

abstract: Genetic variants of SARS-CoV-2 have been emerging and circulating in many places across the world. Rapid detection of these variants is essential since their dissemination can impact transmission rates, diagnostic procedures, disease severity, response to vaccines or patient management. Sanger sequencing has been used as the preferred approach for variant detection among circulating human immunodeficiency and measles virus genotypes. Using primers to amplify a fragment of the SARS-CoV-2 genome encoding part of the Spike protein, we showed that Sanger sequencing allowed us to rapidly detect the introduction and spread of three distinct SARS-CoV-2 variants in two major Brazilian cities. In both cities, after the predominance of variants closely related to the virus first identified in China, the emergence of the P.2 variant was quickly followed by the identification of the P1 variant, which became dominant in less than one month after it was first detected.

category: genetic and genomic medicine


title: An Approach for Open Multivariate Analysis of Integrated Clinical and Environmental Exposures Data

abstract: The Integrated Clinical and Environmental Exposures Service (ICEES) provides regulatory-compliant open access to sensitive patient data that have been integrated with public exposures data. ICEES was designed initially to support dynamic cohort creation and bivariate contingency tests. The objective of the present study was to develop an open approach to support multivariate analyses using existing ICEES functionalities and abiding by all regulatory constraints. We first developed an open approach for generating a multivariate table that maintains contingencies between clinical and environmental variables using programmatic calls to the open ICEES application programming interface. We then applied the approach to data on a large cohort (N = 22,365) of patients with asthma or related conditions and generated an eight-feature table. Due to regulatory constraints, data loss was incurred with the incorporation of each successive feature variable, from a starting sample size of N = 22,365 to a final sample size of N = 4,556 (20.5%), but data loss was < 10% until the addition of the final two feature variables. We then applied a generalized linear model to the subsequent dataset and focused on the impact of seven select feature variables on asthma exacerbations, defined as annual emergency department or inpatient visits for respiratory issues. We identified five feature variables--sex, race, obesity, prednisone, and airborne particulate exposure--as significant predictors of asthma exacerbations. We discuss the advantages and disadvantages of ICEES open multivariate analysis and conclude that, despite limitations, ICEES can provide a valuable resource for open multivariate analysis and can serve as an exemplar for regulatory-compliant informatics solutions to open patient data, with capabilities to explore the impact of environmental exposures on health outcomes.

category: health informatics


title: Dynamic, stage-course protein interaction network using high power CpG sites in Head and Neck Squamous Cell Carcinoma

abstract: Head and neck cancer is the sixth leading cause of cancer across the globe and is significantly more prevalent in South Asian countries, including Pakistan. Prediction of pathological stages of cancer can play a pivotal role in early diagnosis and personalized medicine. This project ventures into the prediction of different stages of head and neck squamous cell carcinoma (HNSCC) using prioritized DNA methylation patterns. DNA methylation profiles for each HNSCC stage (stage-I-IV) were used to extensively analyze 485,577 methylation CpG sites and prioritize them on the basis of the highest predictive power using a wrapper-based feature selection method, along with different classification models. We identified 68 high-power methylation sites which predicted the pathological stage of HNSCC samples with 90.62 % accuracy using a Random Forest classifier. We set out to construct a protein-protein interaction network for the proteins encoded by the 67 genes associated with these sites to study its network topology and also undertook enrichment analysis of nodes in their immediate neighborhood for GO and KEGG Pathway annotations which revealed their role in cancer-related pathways, cell differentiation, signal transduction, metabolic and biosynthetic processes. With information on the predictive power of each of the 67 genes in each HNSCC stage, we unveil a dynamic stage-course network for HNSCC. We also intend to further study these genes in light of functional datasets from CRISPR, RNAi, drug screens for their putative role in HNSCC initiation and progression.


title: Analysis of Feature Influence on Covid-19 Death Rate Per Country Using a Novel Orthogonalization Technique

abstract:
We have developed a new technique of Feature Importance, a topic of machine learning, to analyze the possible causes of the Covid-19 pandemic based on country data. This new approach works well even when there are many more features than countries and is not affected by high correlation of features. It is inspired by the Gram-Schmidt orthogonalization procedure from linear algebra. We study the number of deaths, which is more reliable than the number of cases at the onset of the pandemic, during Apr/May 2020. This is while countries started taking measures, so more light will be shed on the root causes of the pandemic rather than on its handling.

The analysis is done against a comprehensive list of roughly 3,200 features. We find that globalization is the main contributing cause, followed by calcium intake, economic factors, environmental factors, preventative measures, and others. This analysis was done for 20 different dates and shows that some factors, like calcium, phase in or out over time. We also compute row explainability, i.e. for every country, how much each feature explains the death rate. Finally we also study a series of conditions, e.g. comorbidities, immunization, etc. which have been proposed to explain the pandemic and place them in their proper context. While there are many caveats to this analysis, we believe it sheds light on the possible causes of the Covid-19 pandemic.

One-Sentence SummaryWe use a novel feature importance technique to find that globalization, followed by calcium intake, economic factors, environmental factors, and some aspects of societal quality are the main country-level data that explain early Covid-19 death rates.


title: Volumetric quantification of wound healing by machine learning and optical coherence tomography in adults with type 2 diabetes: the GC-SHEALD RCT

abstract:
Type 2 diabetes mellitus is associated with impaired wound healing, which contributes substantially to patient morbidity and mortality. Glucocorticoid (stress hormone) excess is also known to delay wound repair. Optical coherence tomography (OCT) is an emerging tool for monitoring healing by "virtual biopsy", but largely requires manual analysis, which is labour-intensive and restricts data volume processing. This limits the capability of OCT in clinical research.

Using OCT data from the GC-SHEALD trial, we developed a novel machine learning algorithm for automated volumetric quantification of discrete morphological elements of wound healing (by 3mm punch biopsy) in patients with type 2 diabetes. This was able to differentiate between early / late granulation tissue, neo-epidermis and clot structural features and quantify their volumetric transition between day 2 and day 7 wounds. Using OCT, we were able to visualize differences in wound re-epithelialisation and re-modelling otherwise indistinguishable by gross wound morphology between these time points. Automated quantification of maximal early granulation tissue showed a strong correlation with corresponding (manual) GC-SHEALD data. Further, % re-epithelialisation was improved in patients treated with oral AZD4017, an inhibitor of systemic glucocorticoid-activating 11{beta}-hydroxysteroid dehydrogenase type 1 enzyme action, with a similar trend in neo-epidermis volume.

Through the combination of machine learning and OCT, we have developed a highly sensitive and reproducible method of automated volumetric quantification of wound healing. This novel approach could be further developed as a future clinical tool for the assessment of wound healing e.g. diabetic foot ulcers and pressure ulcers.

Disclosure SummaryI certify that neither I nor my co-authors have a conflict of interest as described above that is relevant to the subject matter or materials included in this Work.

category: endocrinology


title: Will Vaccine-derived Protective Immunity Curtail COVID-19 Variants in the US?

abstract: Multiple effective vaccines are currently being deployed to combat the COVID-19 pandemic, and are viewed as the major factor in marked reductions of disease burden in regions with moderate to high vaccination coverage. The effectiveness of COVID-19 vaccination programs is, however, significantly threatened by the emergence of new SARS-COV-2 variants that, in addition to being more transmissible than the wild-type (original) strain, may at least partially evade existing vaccines. A two-strain (one wild-type, one variant) and two-group (vaccinated or otherwise) mechanistic mathematical model is designed and used to assess the impact of the vaccine-induced cross-protective efficacy on the spread the COVID-19 pandemic in the United States. Rigorous analysis of the model shows that, in the absence of any co-circulating SARS-CoV-2 variant, the vaccine-derived herd immunity threshold needed to eliminate the wild-type strain can be achieved if 59% of the US population is fully-vaccinated with either the Pfizer or Moderna vaccine. This threshold increases to 76% if the wild-type strain is co-circulating with the Alpha variant (a SARS-CoV-2 variant that is 56% more transmissible than the wild-type strain). If the wild-type strain is co-circulating with the Delta variant (which is estimated to be 100% more transmissible than the wild-type strain), up to 82% of the US population needs to be vaccinated with either of the aforementioned vaccines to achieve the vaccine-derived herd immunity. Global sensitivity analysis of the model reveal the following four parameters as the most influential in driving the value of the reproduction number of the variant strain (hence, COVID-19 dynamics) in the US: (a) the infectiousness of the co-circulating SARS-CoV-2 variant, (b) the proportion of individuals fully vaccinated (using Pfizer or Moderna vaccine) against the wild-type strain, (c) the cross-protective efficacy the vaccines offer against the variant strain and (d) the modification parameter accounting for the reduced infectiousness of fully-vaccinated individuals experiencing breakthrough infection. Specifically, numerical simulations of the model show that future waves or surges of the COVID-19 pandemic can be prevented in the US if the two vaccines offer moderate level of cross-protection against the variant (at least 67%). This study further suggests that a new SARS-CoV-2 variant can cause a significant disease surge in the US if (i) the vaccine coverage against the wild-type strain is low (roughly < 66%), (ii) the variant is much more transmissible (e.g., 100% more transmissible) than the wild-type strain, or (iii) the level of cross-protection offered by the vaccine is relatively low (e.g., less than 50%). A new SARS-CoV-2 variant will not cause such surge in the US if it is only moderately more transmissible (e.g., the Alpha variant, which is 56% more transmissible) than the wild-type strain, at least 66% of the population of the US is fully vaccinated, and the three vaccines being deployed in the US (Pfizer, Moderna, and Johnson & Johnson) offer a moderate level of cross-protection against the variant.


title: Urinary cell mRNA Profiling of Kidney Allograft Recipients: A Systematic Investigation of a Filtration Based Protocol for the Simplification of Urine Processing

abstract:
BackgroundKidney transplantation is a life-restorative therapy, but immune rejection undermines allograft survival. Urinary cell mRNA profiles offer a noninvasive means of diagnosing kidney allograft rejection, but urine processing protocols have logistical constraints. We aimed to determine whether the centrifugation-based method for urinary cell mRNA profiling could be replaced with a simpler filtration-based method without undermining quality.

MethodsWe isolated RNA from urine collected from kidney allograft recipients using the Cornell centrifugation-based protocol (CCBP) or the Zymo filter-based protocol (ZFBP) and compared RNA purity and yield using a spectrophotometer or a fluorometer and measured absolute copy number of transcripts using customized real-time quantitative PCR assays. We investigated the performance characteristics of RNA isolated using ZFBP and stored either at - 80{degrees}C or at ambient temperature for 2 to 4 days and also when shipped to our Gene Expression Monitoring (GEM) Core at ambient temperature. We examined the feasibility of initial processing of urine samples by kidney allograft recipients trained by the GEM Core staff and the diagnostic utility for acute rejection, of urine processed using the ZFBP.

ResultsRNA purity (P=0.0007, Wilcoxon matched paired signed-ranks test) and yield (P<0.0001) were higher with ZFBP vs. CCBP, and absolute copy number of 18S rRNA was similar (P=0.79) following normalization of RNA yield by reverse transcribing a constant amount of RNA isolated using either protocol. RNA purity, yield, and absolute copy numbers of 18S rRNA, TGF-{beta}1 mRNA and microRNA-26a were not different (P>0.05) in the filtrates containing RNA stored either at -80{degrees}C or at ambient temperature for 2 to 4 days or shipped overnight at ambient temperature. RNA purity, yield, and absolute copy numbers of 18S rRNA and TGF-{beta}1 mRNA were also not different (P>0.05) between home processed and laboratory processed urine filtrates. Urinary cell levels of mRNA for granzyme B (P=0.01) and perforin (P=0.0002) in the filtrates were diagnostic of acute rejection in human kidney allografts.

ConclusionsUrinary cell mRNA profiling was simplified using the ZFBP without undermining RNA quality or diagnostic utility. Home processing by the kidney allograft recipients, the stability of RNA containing filtrates at ambient temperature, and the elimination of the need for centrifuges and freezers represent some of the advantages of ZFBP over the CCBP for urinary cell mRNA profiling.

category: transplantation


title: Adherence to the EAT-Lancet Healthy Reference Diet in relation to Coronary Heart Disease, All-Cause Mortality Risk and Environmental Impact: results from the EPIC-NL Cohort

abstract:
ObjectivesTo construct a diet-score measuring the level of adherence to the Healthy Reference Diet (HRD), to explore whether adherence to the HRD is associated with coronary heart disease (CHD), all-cause mortality risk, and to calculate its environmental impact.

DesignProspective cohort study.

SettingThe Dutch contribution to the European Prospective Investigation into Cancer and Nutrition (EPIC-NL).

Participants37,349 adults (20-70y) without CHD at baseline.

Main outcome measuresPrimary outcomes were incident CHD and all-cause mortality. Secondary outcomes were greenhouse gas emission (GHGE), land use, blue water use, freshwater eutrophication, marine eutrophication, and terrestrial acidification.

ResultsDuring a median 15.3-year follow-up, 2,543 cases of CHD occurred, and 5,648 individuals died from all causes. The average HRD-score was 73 (SD=10). High adherence to the HRD was associated with a 15% lower risk of CHD (hazard ratio 0.85, 95% confidence interval 0.75 to 0.96), as well as a 17% lower risk of all-cause mortality (hazard ratio 0.83, 95% confidence interval 0.77 to 0.90) in multivariable-adjusted models. Better adherence to the HRD was associated with lower environmental impact from GHGE ({beta}= -0.10 kg CO2-eq, 95% confidence interval -0.13 to -0.07), land use ({beta}= -0.11 m2 per year, 95% confidence interval -0.12 to -0.09), freshwater eutrophication ({beta}= -0.000002 kg P-eq, 95% confidence interval -0.000004 to -0.000001), marine eutrophication ({beta}= -0.00035 kg N-eq, 95% confidence interval -0.00042 to -0.00029), and terrestrial acidification ({beta} = -0.004 kg SO2-eq, 95% confidence interval -0.004 to -0.003), but with higher environmental impact from blue water use ({beta}=0.044 m3, 95% confidence interval 0.043 to 0.045).

ConclusionHigh adherence to the HRD was associated with lower risk of CHD and all-cause mortality. Additionally, increasing adherence to the HRD could lower some aspects of the environmental impact of diets, but attention is needed for the associated increase in blue water use.

category: nutrition


title: A classification model to predict specialty drug use

abstract:
ObjectivePredicting who is likely to become utilizers of specialty drugs allows care managers to have an early intervention and payers to have financial preparation for the upcoming spending. Our administrative claims-based predictive model is to predict the members who might use specialty drugs.

Materials and MethodsA national database* and a commercial health plan claim data were used to select a total 6.5 million people who were not taking any specialty drugs before the Target Prediction Window. There were about 136,700 members who were older than 65 in the study. We extracted 81 features from past history of medical, pharmacy claims, and demographic data to predict the specialty drug use in the following year. Members having at least three-month continuous enrollment either under medical or pharmacy plan in the previous year immediately before the start of the target prediction window and with no specialty drug taking history were eligible for this study. We trained and tuned on 75% of the data using an extreme gradient boosting binary classifier. We used the remaining 25% of the data to predict the outcomes and evaluate the performance. We also recorded the performance for the age group older than 65 years old.

ResultsThere were 3% of members who used specialty drugs in the cohort under the current study. The important features for prediction included age, monthly pharmacy payment, monthly medical payment, diseases, procedure, or drug-related codes. On the test data with members of all ages, model performance for the area under the receiving operator characteristics curve (AUROC) was 78.6%. For the test set on members older than 65 (prevalence rate 3.6%), we had an AUROC of 79.3%.

DiscussionThere is no similar machine learning model in the field to predict specialty drug use. Our model provides an unparalleled opportunity to allow early intervention for people who might develop diseases that require specialty drug use. It is also important for health plans and providers to know their covered population who might use specialty drugs and predict the increased cost in the next year.

ConclusionA predictive model of specialty drug use can be helpful for both payers and providers to prepare for a spending spike or have an early intervention. In return, this helps to improve patients overall satisfaction.


title: Incidence of outbreak-associated COVID-19 cases by industry in Ontario, Canada, April 1, 2020- March 31, 2021

abstract:
ObjectivesThe objective of our study was to estimate the rate of workplace outbreak-associated cases of COVID-19 by industry in labour market participants aged 15-69 years who reported working the majority of hours outside the home in Ontario, Canada.

MethodsWe conducted a population based cross-sectional study of COVID-19 workplace outbreaks and associated-cases reported in Ontario between April 1, 2020 and March 31, 2021. All outbreaks were manually classified into two digit North American Industry Classification System (NAICS) codes. We obtained denominator data from the Statistics Canada Labour Force Survey in order to estimate the incidence of outbreak-associated cases per 100,000,000 hours amongst individuals who reported the majority of hours were worked outside the home. We performed this analysis across industries and in three distinct time periods.

ResultsOverall, 12% of cases were attributed to workplace outbreaks among working age adults across our study period. While incidence varied across the time periods, the five industries with the highest incidence rates across our study period were agriculture; healthcare and social assistance; food manufacturing; educational services; and, transportation and warehousing.

ConclusionsCertain industries have consistently increased incidence of COVID-19 over the course of the pandemic. These results may assist in ongoing efforts to reduce transmission of COVID-19, by prioritizing resources, as well as industry-specific guidance, vaccination, and public health messaging.

category: infectious diseases


title: Disinfection of SARS-CoV-2 using UVC reveals wavelength sensitivity contributes towards rapid virucidal activity

abstract: SARS-CoV-2 can be disinfected using ultraviolet-C (UVC) light. For effective inactivation strategies, design and implementation, knowledge of UVC wavelength sensitivity, and disinfection rate of the relevant pathogen are required. This study aimed to determine the inactivation profile of SARS-CoV-2 using UVC irradiation with different wavelengths. Specifically, the study determined dosage, inactivation levels, and wavelength sensitivity of SARS-CoV-2. Assessment of SARS-CoV-2 (isolate USA/WA1-2020) inactivation at peak wavelengths of 259, 268, 270, 275 and 280 nm was performed using a plaque assay method. A UVC dose of 3.1 mJ/cm2 using 259 and 268 nm arrays yielded log reduction values (LRV) of 2.32 and 2.44, respectively. With a dose of 5 mJ/cm2, arrays of peak wavelengths at 259 and 268 nm obtained similar inactivation levels (LRV 2.97 and 2.80 respectively). The arrays of longer wavelength (270, 275 and 280 nm), demonstrated lower performances ([≤]LRV 2.0) when applying an irradiation dose of 5 mJ/cm2. Additional study with the 268 nm array revealed that a dose of 6.25 mJ/cm2 is enough to obtain a LRV of 3. These results suggest that 259 and 268 nm are the most efficient wavelengths for SARS-CoV-2 inactivation compared to longer UVC wavelengths, allowing the calculation of disinfection systems efficacy.


title: Impact of regional heterogeneity on the severity of COVID-19

abstract:
BackgroundWe aimed to assess the impact of regional heterogeneity on the severity of COVID-19 in Japan.

MethodsWe included 27,865 cases registered between January 2020 and February 2021 in the COVID-19 Registry of Japan to examine the relationship between the National Early Warning Score (NEWS) of COVID-19 patients on the day of admission and the prefecture where the patients live. A hierarchical Bayesian model was used to examine the random effect of each prefecture in addition to the patients backgrounds. In addition, we compared the results of two models; one model included the number of beds secured for COVID-19 patients in each prefecture as one of the fixed effects, and the other model did not.

ResultsThe results indicated that the prefecture had a substantial impact on the severity of COVID-19 on admission. Even when considering the effect of the number of beds separately, the heterogeneity caused by the random effect of each prefecture affected the severity of the case on admission.

ConclusionsOur analysis revealed a possible association between regional heterogeneity and increased/decreased risk of severe COVID-19 infection on admission. This heterogeneity was derived not only from the number of beds secured in each prefecture but also from other factors.


title: Effectiveness of 13-valent pneumococcal conjugate vaccine against medically-attended lower respiratory tract infection and pneumonia among older adults

abstract:
ImportanceIn 2014, the US Advisory Committee on Immunization Practices (ACIP) extended existing pneumococcal vaccination recommendations for adults aged [≥]65 years to include 13-valent pneumococcal conjugate vaccine (PCV13), primarily to prevent non-bacteremic pneumonia.

ObjectiveTo determine PCV13 effectiveness against all-cause inpatient plus outpatient medically-attended lower-respiratory tract infection (LRTI) and pneumonia among US older adults.

DesignProspective, open cohort study following participants from 2016 to 2019. We conducted analyses in a self-matched framework, comparing outcomes during participants follow-up periods before and after receipt of PCV13.

SettingKaiser Permanente Southern California (KPSC) integrated healthcare delivery system.

ParticipantsAdults aged [≥]65 years who received PCV13 between 2016-2019.

ExposuresReceipt of PCV13 at ages [≥]65 years, concordant with ACIP guidelines.

Main outcomes and measuresWe estimated the adjusted hazards ratio (aHR) for first LRTI and pneumonia episodes during each respiratory season, comparing PCV13-exposed and PCV13-unexposed time at risk for each participant using a self-matched inference framework. We computed aHR estimates using Cox proportional hazards models. We defined vaccine effectiveness (VE) as (1-aHR)x100%. We also estimated PCV13-attributable absolute reductions in incidence of LRTI and pneumonia.

ResultsObservations were available both before and after PCV13 receipt for 42,700 participants. Among these individuals, 1,419 experienced LRTI and 969 experienced pneumonia over approximately 26,000 combined years of follow-up before PCV13 receipt; 3,849 experienced LRTI and 2,727 experienced pneumonia over approximately 74,000 combined years of follow-up after PCV13 receipt. In adjusted analyses, VE was 9.5% (95% confidence interval: 2.2% to 16.3%) against all-cause medically-attended LRTI and 8.8% (-0.2% to 17.0%) against all-cause medically-attended pneumonia. In contrast, we did not identify evidence of protection against LRTI and pneumonia following receipt of 23-valent pneumococcal polysaccharide vaccine. We estimated that PCV13 prevented 0.7 (0.2 to 1.4) and 0.5 (0.0 to 1.0) cases of LRTI and pneumonia, respectively, per 100 vaccinated persons annually. Over a five-year time horizon, one case of LRTI and pneumonia, respectively, was prevented for every 27 (14 to 116) and 42 (-97 to 268) individuals receiving PCV13.

Conclusions and relevancePCV13 vaccination among older adults reduced the burden of medically-attended respiratory illness in this population.

KEY POINTSO_ST_ABSQuestionC_ST_ABSDoes 13-valent pneumococcal vaccine (PCV13) reduce the burden of lower respiratory-tract infection (LRTI) and pneumonia among older adults?

FindingsIn this longitudinal cohort study of adults aged 65 years and older from 2016-2019, PCV13 reduced incidence of LRTI and pneumonia episodes due to any cause by 9.5% and 8.8%, respectively. This effect corresponded to prevention of 0.7 and 0.5 episodes of LRTI and pneumonia, respectively, per 100 vaccinated persons each year. Protection from 23-valent pneumococcal polysaccharide vaccine was not apparent.

MeaningAmong older adults, PCV13 vaccine administration substantially reduces the burden of medically-attended LRTI and pneumonia.

category: epidemiology


title: Considerations for using multiple imputation in propensity score-weighted analysis

abstract: We present our considerations for using multiple imputation to account for missing data in propensity score-weighted analysis with bootstrap percentile confidence interval. We outline the assumptions underlying each of the methods and discuss the methodological and practical implications of our choices and briefly point to alternatives. We made a number of choices a priori for example to use logistic regression-based propensity scores to produce "standardized mortality ratio"-weights and Substantive Model Compatible-Full Conditional Specification to multiply impute missing data (given no violation of underlying assumptions). We present a methodology to combine these methods by choosing the propensity score model based on covariate balance, using this model as the substantive model in the multiple imputation, producing and averaging the point estimates from each multiple imputed data set to give the estimate of association and computing the percentile confidence interval by bootstrapping. The described methodology is demanding in both work-load and in computational time, however, we do not consider the prior a draw-back: it makes some of the underlying assumptions explicit and the latter may be a nuisance that will diminish with faster computers and better implementations.


title: Examining the Relationship between COVID-19 Vaccinations and Reported Incidence

abstract:
As COVID-19 has caused significant morbidity and mortality throughout the world, the development and distribution of an effective vaccine have been swift but not without challenges. Earlier demand and access barriers have seemingly been addressed with more free and accessible vaccines now available for a wide variety of ages. While rates of COVID-19 have decreased overall, some geographic areas continue to experience rapid outbreaks. The purpose of this study was to examine the relationship between vaccination uptake and weekly COVID-19 cases throughout locations in the state of Missouri.

MethodsAmong all Missouri counties and two cities (n=117), weekly COVID-19 incidence and cumulative proportion of residents fully vaccinated were abstracted from the Missouri Department of Health and Senior Services during a 25-week period from January 4 to Jun 26, 2021. Additional ecological variables known to be associated with COVID-19 incidence and prevalence were collected from the U.S. Census Bureau and integrated into data: total population, proportion of nonwhite residents, annual median household income, proportion of residents working in public facing occupations. Descriptive and inferential statistics were completed which included the calculation of both linear and nonlinear models using repeated measure data to determine the quantitative association between vaccination uptake and reported COVID-19 cases in the presence of location characteristics.

ResultsThroughout the 25 weeks of observations, the average weekly number of COVID-19 cases reported was 66.1 (SD=260.8) while the average cumulative proportion vaccinated individuals at the end of the 25 weeks was 25.8% (SD=6.8%) among study locations. While graphing seemed to suggest a more nonlinear relationship between COVID-19 incidence and proportion vaccinated, comparison of crude linear and nonlinear models pointed to the relationship likely being linear during study period. The final adjusted linear model exhibited a significant relationship between COVID-19 cases and proportion vaccinated, specifically every percent increase in population vaccinated resulted in 3 less weekly COVID-19 cases being reported ({beta} -3.74, p<0.001. Additionally, when controlling for other factors, the adjusted model revealed locations with higher proportions of nonwhite residents were likely to experience less weekly COVID-19 cases ({beta} -1.48, p=0.037).

DiscussionOverall, this study determined that increasing the proportion of residents vaccinated decreases COIVD-19 cases by a substantial amount over time. These findings provide insights into possible messaging strategies that can be leveraged to develop more effective implementation and uptake. As the COVID-19 pandemic persists and vaccination numbers begin to plateau, diverse communication strategies become a critical necessity to reach a wider population.


title: Reduced COVID-19 Hospitalizations among New York City Residents Following Age-Based SARS-CoV-2 Vaccine Eligibility: Evidence from a Regression Discontinuity Design

abstract:
BackgroundIn clinical trials, several SARS-CoV-2 vaccines were shown to reduce risk of severe COVID-19 illness. Local, population-level, real-world evidence of vaccine effectiveness is accumulating. We assessed vaccine effectiveness for community-dwelling New York City (NYC) residents using a quasi-experimental, regression discontinuity design, leveraging a period (January 12-March 9, 2021) when [≥]65-year-olds were vaccine-eligible but younger persons, excluding essential workers, were not.

MethodsWe constructed segmented, negative binomial regression models of age-specific COVID-19 hospitalization rates among 45-84-year-old NYC residents during a post-vaccination program implementation period (February 21-April 17, 2021), with a discontinuity at age 65 years. The relationship between age and hospitalization rates in an unvaccinated population was incorporated using a pre-implementation period (December 20, 2020-February 13, 2021). We calculated the rate ratio (RR) and 95% confidence interval (CI) for the interaction between implementation period (pre or post) and age-based eligibility (45-64 or 65-84 years). Analyses were stratified by race/ethnicity and borough of residence. Similar analyses were conducted for COVID-19 deaths.

ResultsHospitalization rates among 65-84-year-olds decreased from pre- to post-implementation periods (RR 0.85, 95% CI: 0.74-0.97), controlling for trends among 45-64-year-olds. Accordingly, an estimated 721 (95% CI: 126-1,241) hospitalizations were averted. Residents just above the eligibility threshold (65-66-year-olds) had lower hospitalization rates than those below (63-64-year-olds). Racial/ethnic groups and boroughs with higher vaccine coverage generally experienced greater reductions in RR point estimates. Uncertainty was greater for the decrease in COVID-19 death rates (RR 0.85, 95% CI: 0.66-1.10).

ConclusionThe vaccination program in NYC reduced COVID-19 hospitalizations among the initially age-eligible [≥]65-year-old population by approximately 15%. The real-world evidence of vaccine effectiveness makes it more imperative to improve vaccine access and uptake to reduce inequities in COVID-19 outcomes.