title: Estimation of COVID-19 cases prevented by vaccination in California

abstract:
ImportanceDespite widespread vaccination against COVID-19 in the United States, there are limited empirical data quantifying the public health impact in the population.

ObjectiveTo estimate the number of cases of COVID-19 averted due to COVID-19 vaccination

Design, Setting, and ParticipantsThe California Department of Public Health (CDPH) provided person-level data on COVID-19 cases and COVID-19 vaccine administration. To estimate the number of COVID-19 cases that would have occurred in the vaccine era in absence of vaccination, we applied a statistical model that estimated the relationship of COVID-19 cases in the pre-vaccine era between the unvaccinated age group (<12 years) and vaccine-eligible groups ([≥]12 years) to COVID-19 case data after the start of vaccination. The primary study outcome was the difference between predicted number of COVID-19 cases in absence of vaccination and observed COVID-19 cases with vaccination. As a sensitivity analysis, we developed a second independent model that estimated the number of vaccine-averted COVID-19 cases by applying published data on vaccine effectiveness to data on COVID-19 vaccine administration and estimated risk of COVID-19 over time.

InterventionCOVID-19 vaccination

Main Outcomes and MeasuresCOVID-19 cases

ResultsThere were 4,585,248 confirmed COVID-19 cases in California from January 1, 2020 to October 16, 2021, during which 27,164,680 vaccine-eligible individuals [≥]12 years were reported to have received at least 1 dose of a COVID-19 vaccine in the vaccine era (79.5% of the eligible population). We estimated that 1,523,500 [95% prediction interval (976,800-2,230,800)] COVID-19 cases were averted and there was a 34% [95% prediction interval (25-43)] reduction in cases due to vaccination in the primary model. Approximately 66% of total cases averted occurred after the delta variant became the dominant strain of SARS-CoV-2 circulating in California. Our alternative model identified comparable findings.

Conclusions and RelevanceThis study provides robust evidence on the public health impact of COVID-19 vaccination in the United States and further supports the urgency for continued vaccination.

Key PointsO_ST_ABSQuestionC_ST_ABSHow many COVID-19 cases have been prevented by COVID-19 vaccination in California?

FindingsIn this empirical analysis of California using data from the Department of Public Health, we estimated that COVID-19 vaccination has prevented over 1.5 million COVID-19 cases from the introduction of vaccination through October 16, 2021.

MeaningThese findings support that COVID-19 vaccination had a large public health impact in California in terms of averted cases of COVID-19 and can be generalized across the United States.


title: Carbapenem resistant Klebsiella pneumoniae infection across the teaching university affiliated hospitals: risk factors for acquisition among hospitalized patients and molecular subtyping

abstract:
BackgroundCarbapenem-resistant Klebsiella pneumoniae (CRKP) is an important healthcare-associated pathogen. This study aimed to identify factors associated with CRKP isolation among hospitalized patients, describe molecular epidemiology, and mortality associated with CRKP isolation.

MethodsWe performed a retrospective case-control study at the two university-affiliated teaching hospitals. 150 patients were included (30 cases and 120 controls) in this study.

Each patient with CRKP, a case-patient, was matched with four controls by admission facility, age, and sex. Controls, patients without CRKP were randomly selected from a computerized list of inpatients whose admission date was the same as that of the case, within 48 hours of the date of the initial positive culture. We calculated the risk of in-hospital death as the number of deaths divided by the number of cases and evaluated the risk of mortality associated with the site of positive culture. Molecular epidemiology investigation using comparison of restricted DNA patterns of CRKP by pulsed-field gel electrophoresis (PFGE) was conducted.

ResultsA greater proportion of cases than controls had undergone an invasive procedure, including use of a central vein catheter (p=0.007, OR, 3.4, 95% CI, 1.4-8.7), and mechanical ventilation (p=0.002, OR, 3.6, 95% CI, 1.6-8.1), nutrition by tube feeding (p=0.001, OR, 4.2, 95% CI, 1.8 -10).

Pre-admission treatment within two months with the following antibiotic classes was associated with CRKP isolation: carbapenems (p=0.001, OR, 24.4, 95% CI, 2.73-217.96), fluoroquinolones (p<0.0001, OR, 6.17, 95% CI, 2.4 - 15.83), anti-pseudomonal penicillin (p = 0.02; OR, 6.03; 95% CI, 1.98 -18.32), and cephalosporins (p=0.001, OR, 5.36, 95% CI, 2.07 -13.87).

The molecular analysis detected that over 90% of isolates shared similar PFGE patterns.

CRKP isolation was associated with significantly higher In-hospital mortality (36.7% vs 3.3%) in comparison to controls (p<.0001).

Positive cultures from sites other than urine were associated with substantially higher mortality than was a positive urine culture (RR= 4.0).

category: infectious diseases


title: A Delphi process to determine clinicians attitudes and beliefs towards paediatric major incident triage within the United Kingdom.

abstract:
IntroductionTriage is a key principle in the effective management of major incidents, yet there is a paucity of evidence surrounding the optimal method of paediatric major incident triage (MIT). This study aimed to derive consensus on key components of paediatric MIT among healthcare professionals involved in the management of paediatric major incidents.

MethodsThis modified two-round online Delphi consensus study, delivered between July and October 2021, included participants from pre-hospital and hospital specialities involved in managing a paediatric major incident. Statements were derived iteratively based on review of MIT tools, and extant literature. A 5-point Likert agreement scale was used to determine consensus, which was set a priori at 70%.

Results111 clinicians completed both rounds, with 13 of 17 statements reaching consensus. Positive consensus was reached on the use of rescue breaths in mechanisms associated with hypoxia or asphyxiation, use of mobility assessment as a crude discriminator of injury, and use of adult physiology for older children. Whilst positive consensus was reached on the benefits of a single MIT tool for use across the entire adult and paediatric age range, there was negative consensus in relation to the clinical implementation of such a tool. Consensus could not be reached regarding the use of a single tool across the whole paediatric age range specifically, nor on the use of rescue breaths in blunt or penetrating trauma.

ConclusionThis Delphi study has established consensus among a large group of subject matter experts on several key elements of paediatric MIT. Further work is required to develop a triage tool that can be implemented based on emerging and ongoing research, and which is acceptable to clinicians.

What this paper adds?O_ST_ABSSection 1: What is already known on this subject?C_ST_ABS{circ} Whilst triage is a key principle in the effective management of a major incident, there is limited evidence surrounding the use of existing paediatric major incident triage (MIT) tools
{circ}Paediatric MIT tools currently used in the UK are associated with high rates of under-triage, failing to identify those in need of life-saving interventions
{circ}Existing paediatric MIT tools differ from adult tools, including approach to physiological ranges, and recommendation for initiation of rescue breaths

Section 2: What this study adds{circ} Consensus was reached supporting use of rescue breaths for mechanisms associated with hypoxia or asphyxiation, mobility as a crude discriminator for serious injury, and adult physiology for older children
{circ}Whilst consensus was reached on benefits related to use of a single tool across all age ranges (adult and paediatric), the expert panel did not support this approach for actual clinical practice
{circ}There was no consensus on use of rescue breaths in blunt or penetrating trauma, or use of a single triage tool for the entire paediatric age group
{circ}Further work is required to develop and implement a MIT tool that accurately identifies children needing life-saving interventions, and that is acceptable to clinicians

category: emergency medicine


title: Algorithmic Identification of Potentially High Risk Abdominal Presentations (PHRAPs) to the Emergency Department: A Clinically-Oriented Machine Learning Approach

abstract:
BackgroundOlder adults presenting to emergency departments (EDs) with abdominal pain have been shown to be at high risk of subsequent morbidity and mortality. Yet, such presentations are poorly studied in national databases. Claims databases do not record the patients symptoms at the time of presentation to the ED, but rather the diagnosis after testing and evaluation, limiting study of care and outcomes for these high risk abdominal presentations.

ObjectivesWe sought to develop an algorithm to define a patient population with potentially high risk abdominal presentations (PHRAPs) using only variables commonly available in claims data.

Research DesignTrain a machine learning model to predict abdominal pain chief complaints using the National Hospital Ambulatory Medical Care Survey (NHAMCS), a nationally-representative database of abstracted ED medical records.

SubjectsAll patients contained in NHAMCS data from 2013-2018. 2013-2017 were used for predictive modeling and 2018 was used as a hold-out test set.

MeasuresPositive predictive value and sensitivity of the predictive algorithm against a hold-out test set of NHAMCS patients the algorithm was blinded to during training. Predictions were assessed for agreement with either a chief complaint of abdominal pain (contained in "Reason for Visit 1"), or an expanded definition intended to capture visits which were for abdominal concerns. These included secondary or tertiary complaints of abdominal pain or other abdominal conditions, other abdominal-related chief complaint (e.g. nausea or diarrhea, but not pain), discharge diagnosis of an abdominal condition, or reception of an abdominal CT or ultrasound.

ResultsAfter validation on a hold-out data set, a gradient boosting machine (GBM) was the best best-performing machine learning model, but a logistic regression model had similar performance and may be more explainable and useful to future researchers. The GBM predicted a chief complaint of abdominal pain with a positive predictive value of 0.60 (95% CI of 0.56, 0.64) and a sensitivity of 0.29 (95% CI of (0.27, 0.32). Nearly all false positives still exhibited signs of "abdominal concerns" for patients: using the expanded definition of "abdominal concern" the model had a PPV of >0.99 (95% CI of 0.99, 1.00) and sensitivity of 0.12 (95% CI of 0.11, 0.13).

ConclusionThe algorithm we report defines a patient population with abdominal concerns for further study of treatment and outcomes to inform the development of clinical pathways.


title: Does 2x2 airplane passenger contact tracing for infectious respiratory pathogens work? A systematic review of the evidence.

abstract: We critically appraise the literature regarding in-flight transmission of a range of respiratory infections to provide an evidence base for public health policies for contact tracing passengers, given the limited pathogen-specific data for SARS-CoV-2 currently available. Using PubMed, Web of Science, and other databases including preprints, we systematically reviewed evidence of in-flight transmission of infectious respiratory illnesses. A meta-analysis was conducted where total numbers of persons on board a specific flight was known, to calculate a pooled Attack Rate (AR) for a range of pathogens. The quality of the evidence provided was assessed using a bias assessment tool developed for in-flight transmission investigations. We identified 103 publications detailing 165 flight investigations. Overall, 43.7% (72/165) of investigations provided evidence for in-flight transmission. H1N1 influenza A virus had the highest reported pooled attack rate per 100 persons (AR= 1.17), followed by SARS-CoV-2 (AR=0.54) and SARS-CoV (AR = 0.32), Mycobacterium tuberculosis (AR= 0.25), and measles virus (AR= 0.09). There was high heterogeneity in estimates between studies, except for TB. Of the 72 investigations that provided evidence for in-flight transmission, 27 investigations were assessed as having a high level of evidence, 23 as medium, and 22 as low. One third of the investigations that reported on proximity of cases showed transmission occurring beyond the 2x2 seating area. We suggest that for emerging pathogens, in the absence of pathogen-specific evidence, the 2x2 system should not be used for contact tracing. Instead, alternate contact tracing protocols and close contact definitions for enclosed areas, such as the same cabin on an aircraft or other forms of transport, should be considered as part of a whole of journey approach.

category: epidemiology


title: Step forward in epidemiological modeling: Introducing the indicator function to capture waves

abstract: In the last century mathematical modelled have been used to depict the dynamic spread of infectious. The aim is to determine the total numbers of infectious, recovered and susceptible classes, however the classes only represent accumulative. Having these classes one will be unable to predict waves, to determine a day to day numbers of newly infected cases some additional calculations are required. Collected data from real world situations are represented as day to day newly infections, from these data help to determine numbers of waves. The current existing mathematical models cannot be used to predict waves, while having known the predicted numbers of waves one can take several measures to control the situation. To solve this problem, we questioned the fact that the rates of infection and recovery are constant and suggested an indicator function, the function is obtained using experimental data. The indicator function is used as rate and introduced into the mathematical model. We considered a simple SIR model with different types of differential operators including classical and fractional derivatives. The models were solved numerically using well-known numerical schemes. The numerical solutions were plotted for different theoretical parameters, the obtained results depict real-world behaviours. To test the efficiency of this new approach, we collected data from South Afrca and compared with experimental data. Not only our model waves but also it fit experimental data very accurately. This new approach will open new doors of investigation toward revolution to epidemiological modelling.


title: Sero-prevalence of anti-SARS-CoV-2 antibodies in Chattogram Metropolitan Area, Bangladesh

abstract:
BackgroundSeroprevalence studies of coronavirus disease 2019 (COVID-19) assess the degree of undetected transmission in the community. Different groups, such as healthcare workers (HCWs), garment workers, and others, are deemed vulnerable due to their workplace hazards and immense responsibility.

PurposeThe present study was conducted to estimate the seroprevalence of anti-SARS-CoV-2 antibody (IgG) and its association with different explanatory variables. Further, the antibody was quantified to assess the increasing or decreasing trend over different intervention periods and according to other factors.

MethodologyThis cross-sectional study observed health workers - doctor, nurse, hospital staff, etc. in and outpatients (non-COVID-19) and garments workers of Chattogram metropolitan area (CMA, N=748) from randomly selected six government and private hospitals and two garment factories. Study subjects were included upon written consent, fulfilling specific inclusion criteria. Venous blood was collected following standard aseptic methods. Qualitative and quantitative ELISA was used to identify and quantify antibodies (IgG) in serum samples. Descriptive, univariable, and multivariable statistical analysis was performed.

ResultsOverall seroprevalence was estimated as 66.99% (95% CI: 63.40%-70.40%). Seroprevalence among HCWs, in and outpatients, and garments workers were 68.99 % (95% CI: 63.8%-73.7%), 81.37 % (95% CI: 74.7%-86.7%), and 50.56 % (95% CI: 43.5%-57.5%), respectively. Seroprevalence was 44.47 % (95% CI: 38.6%-50.4%) in the non-vaccinated population while it was significantly (p <0.001) higher in the population receiving the first dose (61.66 %, 95% CI: 54.8%-68.0%) and both (first and second) doses of vaccine (100%, 95% CI: 98.4%-100%). The mean titer of the antibody was estimated as 255.46 DU/ml and 159.08 DU/ml in the population with both doses and one dose of vaccine, respectively, compared to 53.71 DU/ml of the unvaccinated population. A decreasing trend in the titer of antibodies with increasing time after vaccination was observed.

ConclusionsSeroprevalence and mean antibody titer varied according to different factors in this study. The second dose of vaccine significantly increased the seroprevalence and titer, which decreased to a certain level over time. Although antibody was produced following natural infection, the mean titer was relatively low compared to antibody after vaccination. This study emphasizes the role of the vaccine in antibody production. Based on the findings, interventions like continuing extensive mass vaccination of the leftover unvaccinated population and bringing the mass population with a second dose under a third dose campaign might be planned.


title: Use of digital technology tools to characterize patient adherence to prescription-grade omega-3 polyunsaturated fatty acid therapy: Primary results of the DIAPAsOn prospective observational study

abstract:
Background, objectives and methodsDIAPAsOn was a 6-month prospective observational multicenter study in the Russian Federation that examined adherence to a preparation of highly purified omega-3 polyunsaturated fatty acids (OMACOR) in adult patients with a history of recent myocardial infarction or endogenous hypertriglyceridemia. A full description of the studys aims and methods has appeared in JMIR Res Protoc. A feature of DIAPAsOn was the use of a bespoke electronic patient engagement and data collection system.

ResultsThe net average reduction from baseline in both total and low-density lipoprotein cholesterol was approximately 1 mmol/L and the net average increment in high-density lipoprotein cholesterol was 0.2{+/-}0.53 mmol/L. Mean triglyceride levels declined by [~]1.3 mmol/, from an initial level of 2.99{+/-}1.29 mmol/L to 1.67{+/-} 0.67 mmol/L. The percentage of patients with triglyceride <1.7 mmol/L rose from 13.1% at baseline to 54% at study-end.

Digital reporting of adherence was registered by 8.3% of patients (n=180) and average scores indicted poor adherence. However, clinic-based enquiry suggested high levels of adherence.

Data on health-related quality of life accrued from digitally-engaged patients identified improvements among patients reporting high adherence to study treatment, but patient numbers were small.

ConclusionsThe lipid and lipoprotein findings indicate that OMACOR had nominally favorable effects on the blood lipid profile. Less than 10% of patients enrolled in DIAPAsOn used the bespoke digital platform piloted in the study and the level of self-reported adherence to medication by those patients was also low. Reasons for this low uptake and adherence are unclear. Better adherence was recorded by clinical report.

category: primary care research


title: Associations between antipsychotic use, substance use and relapse risks in patients with schizophrenia - real-world evidence from two national cohorts

abstract:
BackgroundResearch on the effectiveness of pharmacotherapies for schizophrenia-substance use disorder comorbidity (Sch-SUD) is very sparse and non-existent on the prevention of the development of substance use disorders (SUD) in patients with schizophrenia.

AimsTo compare the real-world effectiveness of antipsychotics in schizophrenia in decreasing risks of: 1) development of an initial SUD; and 2) psychiatric hospitalization and hospitalization due to SUD among patients with SUD.

MethodsTwo independent national cohorts including all persons diagnosed with schizophrenia (N=45,476) were followed up for 22 (Finland: 1996-2017) and 11 years (Sweden: 2006-2016). Risks of developing SUD were calculated with between-individual models, and risks of psychiatric and SUD hospitalization with within-individual models using Cox regression and adjusted Hazard Ratios (aHRs) when using vs. not using certain antipsychotics.

ResultsFor schizophrenia patients without SUDs, clozapine use (aHR 0.20, 95%CI 0.16-0.24, p<0.001, in Finland; 0.35, 0.24-0.50, p<0.001, in Sweden) was associated with lowest risks of developing an initial SUD in both countries. Antipsychotic polytherapy was associated with second lowest risk (0.54, 0.44-0.66) in Sweden, and third lowest risk (0.47, 0.42-0.53) in Finland. Risks of psychiatric hospitalization and hospitalization due to SUD were lowest during use of clozapine, antipsychotic polytherapy, and long-acting injectables in both countries. Results were consistent across both countries.

ConclusionClozapine and antipsychotic polytherapy are most strongly associated with reduced chances of developing SUDs among patients with schizophrenia and with lower relapse rates among patients with both diagnoses.

category: psychiatry and clinical psychology


title: Phylotyping, Pathotyping and Phenotypic Characteristics of Escherichia coli Isolated from Various Street Foods in Bangladesh

abstract: The burden of street food contamination remains significantly higher among developing countries, making its consumers health compromised. This study aimed at identifying Escherichia coli in local street foods, track their sources and characterize their virulence properties, antimicrobial susceptibility patterns, and incidence of recent fecal contamination. Twelve E. coli isolates isolated from 28 types of street foods sold at different locations of Dhaka metropolitan city were confirmed by both culture-based and molecular methods. Phylogroup B1 of environment origin was the most predominant (58%, n=12) among the isolates, followed by commensal phylogroup A (16%), phylogroup C (8%), D (8%), and E (8%). Alarmingly, 8% of the isolates were confirmed to be Enteropathogenic E. coli (EPEC), harboring hlyA gene, and 41% were due to recent fecal contamination cases confirmed by the presence of the eae gene. Isolates showed the highest resistance to ampicillin, followed by chloramphenicol. However, resistance could not be correlated to the presence of class 1 integron as isolates sensitive to these antibiotics also harbored this mobile genetic element. The findings of this study demonstrated the presence of antibiotic-resistant, potentially pathogenic E. coli in street food which emphasizes the health hazard associated with consumption of such foods.

category: public and global health


title: Worldwide antibiotic resistance dynamics: how different is it from one drug-bug pair to another?

abstract:
BackgroundAntibiotic resistance (ABR) is a major concern for global health. However, factors driving its emergence and dissemination are not fully understood. Identification of such factors is crucial to explain heterogeneity in ABR rates observed across space, time and species and antibiotics.

MethodsWe analyzed count data of resistant isolates from 51 countries over 2006-2019 for nine drug-bug pairs from the surveillance database ATLAS. We characterized ABR spatial and temporal patterns and used a mixed-effect negative binomial model, accounting for country-year dependences with random effects (RE), to investigate associations with potential drivers including antibiotic sales, economic and health indicators, meteorological data, population density and tourism.

FindingsABR patterns were strongly country and drug-bug pair dependent. In 2019, median ABR rates ranged from 6{middle dot}3% for carbapenem-resistant (CR) Klebsiella pneumoniae to 72{middle dot}3% for CR-Acinetobacter baumannii, with heterogeneity across countries (up to 50{middle dot}2% of interquartile range for CR-A. baumannii). Over 2006-2019, carbapenem resistance was on the rise in >75% of investigated countries but no global trend was observed for other resistances. Multivariable analyses identified significant associations of ABR with antibiotic sales, but only in fluoroquinolone-resistant Escherichia coli, CR-A. baumannii and penicillin-resistant Streptococcus pneumoniae; with temperature in investigated Enterobacterales but not in other drug-bug pairs; and with the health system quality for most drug-bug pairs, except in Enterococci and S. pneumoniae. Despite wide consideration of possible explanatory variables, drug-bug pairs still showed high spatial RE variance.

InterpretationThese results reflect the diversity found among human bacterial pathogens and stress the difficulty to generalize global antibiotic resistance findings.

FundingIndependent research Pfizer Global Medical Grant; ANR Labex IBEID (ANR-10-LABX-62)


title: DMARD disruption, disease flare, and prolonged symptom duration after acute COVID-19 among participants with rheumatic disease: A prospective study

abstract:
ObjectiveTo describe disease-modifying antirheumatic drug (DMARD) disruption, rheumatic disease flare/activity, and prolonged COVID-19 symptom duration among COVID-19 survivors with systemic autoimmune rheumatic diseases (SARDs).

MethodsWe surveyed patients with SARDs after confirmed COVID-19 at Mass General Brigham to investigate post-acute sequelae of COVID-19. We obtained data on demographics, clinical characteristics, COVID-19 symptoms/course, and patient-reported measures. We examined baseline predictors of prolonged COVID-19 symptom duration (defined as lasting [≥]28 days) using logistic regression.

ResultsWe analyzed surveys from 174 COVID-19 survivors (mean age 52 years, 81% female, 80% White, 50% rheumatoid arthritis) between March 2021 and January 2022. Fifty-one percent of 127 respondents on any DMARD reported a disruption to their regimen after COVID-19 onset. For individual DMARDs, 56-77% had any change, except for hydroxychloroquine (23%) and rituximab (46%). SARD flare after COVID-19 was reported by 41%. Global patient-reported disease activity was worse at the time of survey than before COVID-19 (mean 6.6{+/-}2.9 vs. 7.6{+/-}2.3, p<0.001). Median time to COVID-19 symptom resolution was 14 days (IQR 9,29). Prolonged symptom duration of [≥]28 days occurred in 45%. Hospitalization for COVID-19 (OR 3.54, 95%CI 1.27-9.87) and initial COVID-19 symptom count (OR 1.38 per symptom, 95%CI 1.17-1.63) were associated with prolonged symptom duration. Respondents experiencing prolonged symptom duration had higher RAPID3 scores (p=0.007) and more pain (p<0.001) and fatigue (p=0.03) compared to those without prolonged symptoms.

ConclusionDMARD disruption, SARD flare, and prolonged symptom duration were common in this prospective study of COVID-19 survivors, suggesting substantial impact on SARDs after acute COVID-19.

category: rheumatology


title: Assessing agreement between different polygenic risk scores in the UK Biobank

abstract:
1.1.1 BackgroundPolygenic risk scores (PRS) are proposed to be used in clinical settings for risk stratification, with the public being accustomed to the concept of genetic predisposition to diseases. Much work has focused on developing PRSs for informing people about their risk of future health conditions; however, there are limited investigations on how different PRSs diverge from each other for risk prediction of individuals.

1.2 Methods and FindingsWe compared recently published PRS for three conditions, breast cancer, hypertension and dementia, to assess the stability in practice of running these algorithms for risk prediction in a single large population. We used imputed genotyping data from the UK Biobank (UKB) prospective cohort, limited to the White British subset. We found that

O_LIOnly 65%-79% of SNPs in the first PRS were represented in the more recent PRS for all three diseases, after having taken linkage disequilibrium (LD) into account (R2>0.8).
C_LIO_LIAlthough the difference in the area under the received operator curve (AUC) obtained using the two PRS is hardly appreciable for all three diseases, there were large differences in individual risk prediction between the two PRS.
C_LI

1.3 ConclusionsWe found substantial discordance between different PRS for the same disease, indicating that individuals could receive different medical advice depending on which PRS is used to assess their genetic susceptibility for these disorders. It is desirable to resolving this uncertainty before using PRS for risk stratification in clinical settings.

category: genetic and genomic medicine


title: Safety and immunogenicity of a live recombinant Newcastle disease virus-based COVID-19 vaccine (Patria) administered via the intramuscular or intranasal route: Interim results of a non-randomized open label phase I trial in Mexico

abstract: There is still a need for safe, efficient and low-cost coronavirus disease 2019 (COVID-19) vaccines that can stop transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we evaluated a vaccine candidate based on a live recombinant Newcastle disease virus (NDV) that expresses a stable version of the spike protein in infected cells as well as on the surface of the viral particle (AVX/COVID-12-HEXAPRO, also known as NDV-HXP-S). This vaccine candidate can be grown in embryonated eggs at low cost similar to influenza virus vaccines and it can also be administered intranasally, potentially to induce mucosal immunity. We evaluated this vaccine candidate in prime-boost regimens via intramuscular, intranasal, or intranasal followed by intramuscular routes in an open label non-randomized non-placebo-controlled phase I clinical trial in Mexico in 91 volunteers. The primary objective of the trial was to assess vaccine safety and the secondary objective was to determine the immunogenicity of the different vaccine regimens. In the interim analysis reported here, the vaccine was found to be safe and the higher doses tested were found to be immunogenic when given intramuscularly or intranasally followed by intramuscular administration, providing the basis for further clinical development of the vaccine candidate. The study is registered under ClinicalTrials.gov identifier NCT04871737. Funding was provided by Avimex and CONACYT.


title: Association between Liver Fibrosis and Incident Dementia in the UK Biobank Study

abstract:
BackgroundThere is growing recognition of the role of chronic liver disease in brain health, but the impact of liver fibrosis on dementia risk was unclear. We evaluated the association between liver fibrosis and incident dementia using data from a large prospective cohort study.

MethodsWe performed a cohort analysis using data from the UK Biobank study, which prospectively enrolled approximately 500,000 adults starting 2007 and continues to follow them. Liver fibrosis was defined using validated cutoffs of the Fibrosis-4 (FIB-4) liver fibrosis score. The primary outcome was incident dementia, ascertained using a validated approach based on participants hospital record and mortality data. Secondary outcomes were Alzheimers disease and vascular dementia. We excluded participants with prevalent dementia. We used Cox proportional hazards models to evaluate the association between liver fibrosis and incident dementia while adjusting for potential confounders. In additional models, the FIB-4 score was used as a continuous independent variable. Prespecified interaction analyses tested for effect modification by sex, metabolic syndrome, and apolipoprotein E4 carrier status.

ResultsAmong 455,226 participants included in this analysis, the mean age was 56.5 years and 54% were women. Standard liver chemistries were largely in the normal range. However, 2.17% (95% CI, 2.13-2.22%) had liver fibrosis based on their FIB-4 score. The rate of dementia per 1,000 person-years was 1.76 (95% CI, 1.50-2.07) in participants with liver fibrosis and 0.52 (95% CI, 0.50-0.54) in those without. After adjusting for demographics, socioeconomic deprivation, educational attainment, metabolic syndrome, hypertension, diabetes, dyslipidemia, and tobacco and alcohol use, liver fibrosis was associated with an increased risk of dementia (HR, 1.52; 95% CI, 1.22-1.90). An independent association was also noted between FIB-4, treated as a continuous variable, and dementia (HR per unit, 1.29; 95% CI, 1.20-1.39). Effect modification by sex, metabolic syndrome, and apolipoprotein E4 carrier status was not seen.

ConclusionLiver fibrosis in middle age was associated with an increased risk of incident dementia, independent of metabolic syndrome and shared risk factors. Liver fibrosis may be an underrecognized risk factor for dementia.

category: neurology


title: Innovative Randomized Phase 1 Study and Dosing Regimen Selection to Accelerate and Inform Pivotal COVID-19 Trial of Nirmatrelvir

abstract:
BackgroundCOVID-19 is a continued leading cause of hospitalization and death. Safe and efficacious COVID-19 antivirals are needed urgently. Nirmatrelvir (PF-07321332), the first orally bioavailable, SARS-CoV-2 Mpro inhibitor against the coronaviridae family, has demonstrated potent preclinical antiviral activity and benign safety profile.

MethodsWe report safety, tolerability, and pharmacokinetic data of nirmatrelvir with and without ritonavir as a pharmacokinetic enhancer, from an accelerated randomized, double-blind, placebo-controlled, phase 1 study. Two interleaving single-ascending dose (SAD) cohorts were evaluated in a 3-period crossover. Multiple-ascending dose (MAD) with nirmatrelvir/ritonavir twice daily (BID) dosing was evaluated over 10 days in 5 parallel cohorts. Safety was assessed, including in a supratherapeutic exposure cohort. Dose and dosing regimen for clinical efficacy evaluation in phase 2/3 clinical trials were supported by integrating modelling and simulations of SAD/MAD data with nonclinical data and a quantitative systems pharmacology model (QSP).

ResultsIn SAD, MAD, and supratherapeutic exposure cohorts, nirmatrelvir/ritonavir was safe and well tolerated. Nirmatrelvir exposure and half-life were considerably increased by ritonavir, enabling selection of nirmatrelvir/ritonavir dose and regimen for phase 2/3 trials (300/100 mg BID), to achieve concentrations continuously above those required for 90% inhibition of viral replication in vitro. The QSP model suggested that a 5-day regimen would significantly decrease viral load in SARS-CoV-2-infected patients and prevent development of severe disease, hospitalization, and death.

ConclusionsAn innovative and seamless trial design expedited establishment of phase 1 safety and pharmacokinetics of nirmatrelvir/ritonavir, enabling high confidence in phase 2/3 dose selection and accelerated pivotal trials initiation. NCT04756531


title: Safety and Efficacy of Preventative COVID Vaccines: The StopCoV Study

abstract:
BackgroundTo partially immunize more persons against COVID-19 during a time of limited vaccine availability, Canadian public health officials recommended extending the vaccine dose interval and brand mixing. Impact on the antibody response among the older ambulatory population was unclear.

MethodsDecentralized prospective cohort study with self-report of adverse events and collection of dried blood spots. Data is presented for 1193 (93%) of the 911 older (aged >70 years) and 375 younger (30-50 years) recruits.

FindingsLocal and systemic reactivity rates were high but short-lived, particularly in the younger cohort and with mRNA-1273 vaccine. After a single COVID-19 vaccine, 84% younger but only 46% older participants had positive IgG antibodies to both spike protein and receptor binding domain (RBD) antigens, increasing to 100/98% with the second dose respectively. In multivariable linear regression model, lower normalized IgG RBD antibody ratios two weeks after the second dose were statistically associated with older age, male gender, cancer diagnosis, lower body weight, BNT162b2 relative to mRNA-1273 and longer dose intervals. Antibody ratios in both cohorts declined 12 weeks post second vaccine dose.

InterpretationWe report success of a decentralized serology study. Antibody responses were higher in the younger than older cohort and were greater for those with at least one mRNA-1273 dose. The immunity threshold is unknown but correlations between binding and neutralizing antibodies are strongly positive. Trends with time and at breakthrough infection will inform vaccine booster strategies.

FundingSupported by the Public Health Agency of Canada and the University Health Network Foundation.


title: First cases of infection with the 21L/BA.2 Omicron variant in Marseille, France

abstract: The SARS-CoV-2 21K/BA.1, 21L/BA.2, and BA.3 Omicron variants have recently emerged worldwide. To date, the 21L/BA.2 Omicron variant has remained very minority globally but became predominant in Denmark instead of the 21K/BA.1 variant. Here we describe the first cases diagnosed with this variant in south-eastern France. We identified thirteen cases using variant-specific qPCR and next-generation sequencing between 28/11/2021 and 31/01/2022, the first two cases being diagnosed in travellers returning from Tanzania. Overall, viral genomes displayed a mean ({+/-}standard deviation) number of 65.9{+/-}2.5 (range, 61-69) nucleotide substitutions and 31.0{+/-}8.3 (27-50) nucleotide deletions, resulting in 49.6{+/-}2.2 (45-52) amino acid substitutions (including 28 in the spike protein) and 12.4{+/-}1.1 (12-15) amino acid deletions. Phylogeny showed the distribution in three different clusters of these genomes, which were most closely related to genomes from England and South Africa, from Singapore and Nepal, or from France and Denmark. Structural predictions pointed out a significant enlargement and flattening of the 21L/BA.2 N-terminal domain surface compared with that of the 21K/BA.2 Omicron variant, which may facilitate initial viral interactions with lipid rafts. Close surveillance is needed at global, country and center scales to monitor the incidence and clinical outcome of the 21L/BA.2 Omicron variant.


title: Characterization of the gene expression profile in younger and older low-grade glioma patients

abstract: Low-grade gliomas (LGG) are the slowest growing type of brain cancer that often affects young adults. Of all LGG cases, older patients were associated with the poor prognosis compared to younger patients. However, the molecular mechanism underlying this association remains unclear. Here, we compared genes expression profiles between younger (age[≤]50) and older (age > 50) patients from The Cancer Genome Atlas (TCGA) and demonstrate the age-related gene expressions. Pathway and gene set enrichment analysis reveal that differentially expressed genes (DEGs) between tumors of older and younger patients have been involved in cancer-related biological procedures, such as, transcriptional misregulation in cancer, nucleotide synthesis, mTOR, and DNA damage repair signaling. We also demonstrated that older patients have higher expression of Mitosis Kinase Score (MKS) and Tumor Inflammation Signature (TIS) which reflects high cell proliferation and high immune cell activity; respectively. The comprehensive characterization of gene-expression profiles in younger versus older LGG may explain the age-related prognosis and facilitate the development of potential therapeutic biomarkers for LGG.


title: IS SHORT-TERM ACYCLOVIR TREATMENT RELATED WITH MORE UNFAVOURABLE OUTCOMES IN PATIENTS WITH HSV-1 ENCEPHALITIS?

abstract:
BackgroundHerpes simplex encephalitis (HSE) is the most common form of sporadic encephalitis which is caused by herpes simplex virus type 1 (HSV-1). Current guidelines recommend intravenous Acyclovir for 14-21 days in cases of HSE.

ObjectivesOptimizing the Acyclovir treatment duration is important in regards to preventing Acyclovir-related neurotoxicity and nephrotoxicity.

Study designWe retrospectively evaluated 13 patients, who were diagnosed with HSE by molecular testing (HSV-1 PCR positivity in cerebrospinal fluid), in two university hospitals in Istanbul, between 2010 and 2021. The patients were treated either 10 days or less as a short-term treatment regimen of Acyclovir or for 14 days or more as long-term treatment regimen

ResultsThe median age was 58 years (range 24-82 years) and 54% of them were male. The median follow-up time was 79 days (range 20-670 days) after discharge. Long-term treatment was used in 6 and a short-term treatment regimen was used in 7 cases. One of the patients died on the 4th day of Acyclovir treatment. One patient never received Acyclovir treatment. Of the 5 patients who received long-term treatment, 3 (21-28 days) had amnesia and orientation-cooperation restriction, one (21 days) died on the 2nd day of treatment, while the other (14 days) had no sequelae. There were no sequelae in three out of 5 patients who received short-term treatment.

ConclusionsWe believe that it is necessary to determine the optimal Acyclovir therapy duration should be evaluated in a prospective randomized clinical trial in large patient population.


title: Differential antibody production by symptomatology in SARS-CoV-2 convalescent individuals

abstract: The association between COVID-19 symptoms and antibody responses against SARS-CoV-2 is poorly characterized. We analyzed antibody levels in individuals with known SARS-CoV-2 infection to identify potential antibody-symptom associations. Convalescent plasma from 216 SARS-CoV-2 RNA+ individuals with symptomatology information were tested for the presence of IgG to the spike S1 subunit (Euroimmun ELISA), IgG to receptor binding domain (RBD, CoronaCHEK rapid test), and for IgG, IgA, and IgM to nucleocapsid (N, Bio-Rad ELISA). Logistic regression was used to estimate the odds of having a COVID-19 symptom from the antibody response, adjusting for sex and age. Cough strongly associated with antibodies against S1 (adjusted odds ratio [aOR]= 5.33; 95% CI from 1.51 to 18.86) and RBD (aOR=4.36; CI 1.49, 12.78). In contrast, sore throat significantly associated with the absence of antibodies to S1 and N (aOR=0.25; CI 0.08, 0.80 and aOR=0.31; 0.11, 0.91). Similarly, lack of symptoms associated with the absence of antibodies to N and RBD (aOR=0.16; CI 0.03, 0.97 and aOR=0.16; CI 0.03, 1.01). Cough appeared to be correlated with a seropositive result, suggesting that SARS-CoV-2 infected individuals exhibiting lower respiratory symptoms generate a robust antibody response. Conversely, those without symptoms or limited to a sore throat while infected with SARS-CoV-2 were likely to lack a detectable antibody response. These findings strongly support the notion that severity of infection correlates with robust antibody response.


title: Exon variants associated with asthma and allergy

abstract:
Recent biobank based exon sequencing studies included thousands of traits while the mutational spectrum of asthma and allergy associated genes is still unknown.

MethodsMeta-analysis of exome data from 281,104 UK Biobank samples that were analyzed for association of mostly rare variants with asthma, allergic rhinitis and atopic dermatitis. Variants of interest (VOI) were tabulated, shared genes annotated and compared to earlier GWAS, WGBS, WES and selected candidate gene studies.

Results354 VOI were significantly associated with the traits examined. They cluster mainly in two large regions on chromosome 6 and 17 while there is basically no overlap of atopic dermatitis with both other diseases. After exclusion of the two atopic dermatitis variants, 321 unique VOI remain in 122 unique genes. 30 genes are shared by the group of 87 genes with increased and the group of 65 genes with decreased risk for allergic disease. 85% of genes identified earlier by common SNPs in GWAS can not be replicated.

DiscussionMost identified genes are involved in interferon {gamma} and IL33 signaling pathway. They highlight already known but also new pharmacological targets, including the IL33 receptor ST2/IL1RL1, TLR1, ALOX15, GSDMA, BTNL2, IL13 and IKZF3. Future pharmacological studies will need to included these VOI for stratification of the study population.

category: allergy and immunology


title: Elevated brain-derived cell-free DNA among patients with first psychotic episode - a proof-of-concept study

abstract:
BackgroundSchizophrenia is a common, severe and debilitating psychiatric disorder. Despite extensive research there is as yet no biological marker that can aid in its diagnosis and course prediction. This precludes early detection and intervention. Imaging studies suggest brain volume loss around the onset and over the first few years of schizophrenia, and apoptosis has been proposed as the underlying mechanism. Cell free DNA fragments (cfDNA) are released into the bloodstream following cell death. Tissue-specific methylation patterns allow the identification of the tissue origins of cfDNA.

MethodsWe developed a cocktail of brain specific DNA methylation markers, and used it to assess the presence of brain-derived cfDNA in the plasma of patients with a first psychotic episode.

ResultsWe detected significantly elevated neuron- (p=0.0013), astrocyte- (p=0.0016), oligodendrocyte- (p=0.0129) and whole brain-derived (p=0.0012) cfDNA in the plasma of patients during their first psychotic episode (n=29), compared with healthy controls (n=31). Increased cfDNA levels were not correlated with psychotropic medications use. Area Under the Curve (AUC) was 0.77, with 65% sensitivity at 90% specificity in patients with a psychotic episode.

ConclusionsPotential interpretations of these findings include increased brain cell death, disruption of the blood brain barrier or a defect in clearance of material from dying brain cells. Brain-specific cfDNA methylation markers can potentially assist early detection and monitoring of schizophrenia and thus allow early intervention and adequate therapy.


title: Immune responses after twofold SARS-CoV-2 immunisation in elderly residents and Health Care Workers in nursing homes and homes with assisted living support - Proposal for a correlate of protection

abstract:
In the present study, we were interested in the decline over time of anti SARS-CoV-2 antibodies and SARS-CoV-2 specific T-cell responses after two doses of mRNA vaccines in total and by age group and comorbidity. The second goal was to suggest an immunological correlate for protection on an individual basis and to describe the probability of protection over time after second vaccination.

We analysed blood samples from 228 residents (median age 83.8 years) and from 273 Health Care Workers (HCW; median age 49.7 years) of five nursing homes and one home for the elderly with assisted living support. Participants had received two vaccinations. The blood samples were analysed for SARS-CoV-2 specific antibody and T-cell responses. We compared outcomes in the HCW and residents in the respective institutions. No breakthrough infections occurred during the study period. The initial immune responses in the younger participants were about 30 % higher than in the older ones. Over time, all parameters dropped continuously in all groups within the maximum observation period of 232 days. Comorbidities such as coronary heart disease or diabetes mellitus reduced the initial immune responses, regardless of age. In contrast to an almost linear decline in antibody levels, we observed that the interferon-gamma response remained at a constant level between about day 120 and 180, only to decline further thereafter.

Based on our data, we propose on an individual level a correlate of protection: Persons who have a neutralizing capacity of 75 % (which would correspond to approx. 200 BAU/ml) and an interferon-gamma response above 200 mIU/ml should be considered to be protected resp. sufficiently immunized.


title: Association of Covert Cerebrovascular Disease Identified Using Natural Language Processing and Future Dementia

abstract:
ObjectiveTo estimate the risk of dementia associated with incidentally-discovered covert cerebrovascular disease (CCD), including both covert brain infarction (CBI) and white matter disease (WMD).

Patients and MethodsWe included individuals aged [≥] 50 years enrolled in the Kaiser Permanente Southern California health system receiving a head CT or MRI for a non-stroke indication from January 1, 2009 and December 31, 2019, without prior ischemic stroke, transient ischemic attack, hemipelegia, hemiparesis, dementia/Alzheimers disease or a visit reason / scan indication suggestive of cognitive decline. Using natural language processing (NLP), we identified the presence of CBI and WMD on the neuroimage report; WMD was characterized as mild, moderate, severe, or undetermined.

ResultsAmong 241,050 qualified individuals, NLP identified 69,931 (29.0%) with WMD and 11,328 (4.7%) with CBI. The dementia incidence rates (per 1,000 person-years) were 23.5 (95% CI 22.90 to 24.0) for patients with WMD; 29.4 (95% CI 27.9 to 31.0) with CBI and 6.0 (5.8 to 6.2) without CCD. The effect of WMD on dementia risk was stronger in younger versus older patients and for CT-versus MRI-discovered lesions. For patients with versus without WMD on CT scan, the adjusted HR (aHR) was 2.87 (2.58 to 3.19) for those < age 70 and 1.87 (1.79 to 1.95) for those [≥] age 70. For patients with versus without WMD on MRI, the aHR for dementia risk was 2.28 (1.99 to 2.62) for patients < age 70 and 1.48 (1.32 to 1.66) for those [≥] age 70. The aHR associated with CBI was 2.02 (1.70 to 2.41) for patients age <70 and 1.22 (1.15 to 1.30) for patients age [≥]70 for either modality. Dementia risk with WMD was strongly correlated with WMD severity.

ConclusionIncidentally-discovered CCD is common and identifies patients at high risk of dementia, representing an opportunity for prevention.


title: Somatic mutations reveal hypermutable brains and are associated with neuropsychiatric disorders

abstract: Somatic mutations have causative roles in many diseases and contribute to neuropsychiatric disorders. Here, we analyzed 131 human brains (44 neurotypical, 19 with Tourette syndrome, 9 with schizophrenia, and 59 with autism) for somatic single nucleotide and structural mutations after whole genome sequencing to a depth of over 200X. Typically, brains had 20 to 60 detectable single nucleotide mutations that likely arose in early development; however, about 5% of brains harbored hundreds and up to 2000 somatic mutations. Hypermutability was associated with age and putative damaging mutations in genes previously implicated in cancer and likely reflects in vivo clonal expansions. Somatic duplications of likely early developmental origin were present in 1 out of 20 normal and diseased brains, reflecting background mutagenesis. Brains of individuals with autism were enriched in somatic deletions and in point mutations that create putative transcription factor binding motifs in enhancers that are active in the developing brain. The most affected motifs corresponded to MEIS transcription factors, suggesting a potential link between their involvement in gene regulation and autism.


title: Diurnal modulation of subthalamic beta oscillatory power in Parkinson's disease patients during deep brain stimulation

abstract:
BackgroundBeta band activity in the subthalamic local field potential (LFP) is correlated with Parkinsons disease (PD) symptom severity, and is the therapeutic target and feedback signal for adaptive deep brain stimulation (aDBS). While clinically relevant beta fluctuations in PD patients are well characterised on shorter timescales and in the clinic, it is not known how beta activity evolves around the diurnal cycle, outside a clinical setting.

ObjectiveTo characterise diurnal fluctuations in beta amplitude in PD patients receiving continuous, high frequency DBS.

MethodsWe obtained chronic recordings (34{+/-}13 days) of subthalamic beta power in PD patients implanted with the Percept DBS device during high-frequency DBS, and analysed its diurnal properties. To investigate the influence of non-frequency-specific effects and artifacts, we compared beta to contralateral theta amplitude and recorded LFPs during various movements.

ResultsBeta power had strong 24-hour periodicity, and time of day explained 41{+/-}9% of the variance in all long-term beta power recordings (p<0.001 in all patients). For all patients, beta activity was high during the day and reduced at night. Beta activity was not fully explained by theta activity and could show independent diurnal modulation. Movement artifacts affected the recorded LFPs, influenced band power estimates, and could have contributed to diurnal patterns in some patients.

ConclusionsDiurnal fluctuations in beta amplitude will need to be accommodated in aDBS to prevent suboptimal stimulation, particularly at night. Careful screening and/or mitigation of movement artifacts is needed to ensure that the signal is suitable for adaptive stimulation or neurophysiological investigation.


title: Pilot Plant-Based Lifestyle Medicine Program in an Urban Public Healthcare System: Evaluating Demand and Implementation

abstract:
BackgroundLifestyle interventions that optimize nutrition, physical activity, sleep health, social connections, and stress management, and address substance use can reduce cardiometabolic risk. Despite substantial evidence that healthful plant-based diets are beneficial for long-term cardiometabolic health and longevity, uncertainty lies in how to implement plant-based lifestyle programs in traditional clinical settings, especially in safety-net contexts with finite resources.

MethodsIn this mixed-methods implementation evaluation of the Plant-Based Lifestyle Medicine Program piloted in a large public healthcare system, we surveyed participants and conducted qualitative interviews and focus groups with stakeholders to assess program demand in the eligible population, and feasibility of implementation within the safety-net setting.

FindingsProgram demand was high and exceeded capacity. Participants main motivations for joining the program included gaining more control over life, reducing medication, and losing weight. The program team, approach, and resources were successful facilitators. However, the program faced administrative and payor-related challenges within the safety-net setting, and participants reported barriers to access.

ConclusionsStakeholders found the program to be valuable, despite challenges in program delivery and access. Findings provide guidance for replication. Future research should focus on randomized controlled trials to assess clinical outcomes as a result of program participation.

category: nutrition


title: Added-value of whole exome and RNA Sequencing in advanced and refractory cancer patients with no molecular-based treatment recommendation based on a 90-gene panel

abstract:
ImportanceWhile comprehensive tumor molecular profile by whole exome and RNA sequencing (WES/RNA-Seq) is now feasible in routine practice, it remains unclear whether this increases therapeutic options as compared to a more limited targeted gene panel (TGP) plus array-based comparative genomic hybridization (aCGH) in advanced cancer patients.

ObjectiveTo determine the added value of WES/RNA-Seq in advanced and refractory cancer patients who had no molecular-based treatment recommendation (MBTR) based on a TGP/aCGH in the course of a clinical trial.

DesignRetrospective analysis.

SettingSingle center.

ParticipantsWe selected 50 patients previously included in the PROFILER trial (NCT01774409) for which no molecular-based therapy could be recommended in the course of the clinical trial based on a targeted 90-gene panel and aCGH. For each patient, the frozen tumor sample mirroring the FFPE sample used for TGP/aCGH analysis were processed for WES and RNA-Seq. Data from TGP/aCGH were reanalyzed and together with WES/RNA-Seq, findings were simultaneously discussed at a new molecular tumor board (MTB).

Main outcomes and MeasuresMBTR based on TGP/aCGH versus WES/RNA-Seq were compared.

ResultsAfter exclusion of variants of unknown significance, a total of 167 somatic molecular alterations were identified in 50 patients (median: 3; range: 1-10). Out of these 167 relevant molecular alterations reported by the biologist, 51 (31%) were common to both TGP/aCGH and WES/RNA-Seq, 19 (11%) were identified by the TGP/aCGH only and 97 (58%) were identified by WES/RNA-Seq only, including 2 fusion transcripts in two patients. A MBRT was provided in 4/50 (8%) patients using the information from TGP/aCGH vs. 9/50 (18%) patients using WES/RNA-Seq findings. Three patients had similar recommendations based on TGP/aCGH and WES/RNA-Seq.

Conclusion and RelevanceIn advanced and refractory cancer patients in whom no MBRT was recommended from TGP/aCGH, WES/RNA-Seq allowed to identify more alterations which may in turn, in a limited fraction of patients, lead to new MBRT.

Key PointsO_ST_ABSQuestionC_ST_ABSDoes WES/RNA-Seq provide additional targeted treatment guidance for advanced cancer patients with no molecular-based treatment recommendation (MBTR) from a 90-tumor gene panel (TGP) sequencing and array-based comparative genomic hybridization (aCGH)?

FindingsFor fifty advanced cancer patients included in the PROFILER trial with no treatment recommendation based on a TGP/aCGH, frozen tumor sample was processed for WES and RNA-Seq. MBTR was given in 4/50 (8%) patients using the reanalyzed TGP/aCGH vs. 9/50 (18%) patients using WES/RNA-Seq findings.

MeaningsWES/RNA-Seq increased the number of patients with MBTR as compared to a TGP/aCGH screening to yet only a minority of patients.

category: oncology


title: Visual Acuity alterations in heavily impaired Congenital Zika Syndrome (CZS) children.

abstract: We aim to assess visual acuity (VA) in Congenital Zika Syndrome (CZS)-children to evaluate visual loss. To that end we evaluated 41 CZS- children, from Rio de Janeiro using Teller Acuity Cards. They had Zika virus-infection confirmed by reverse transcription-polymerase chain reaction (RT-PCR) or clinical evaluation. VA below normative values was present in 39/41 (95%). In 10 cases, VA was only marginally below normal; in the remaining 29 cases, VA was more than 0.15 logMAR below the lower limit. There was no relationship between VA and cognitive domain tasks, although there was a relationship between VA and motor domain tasks. Thirty-seven children performed at least one task in the cognitive set, 14 children did not perform any task in the motor set. Children with VA above the lower limit performed better in the cognitive and motor tasks. We concluded that ZIKV- infected children with CSZ were highly VA impaired which correlated with motor performance, but not with cognitive performance. Part of the children had VA within the normal limits and displayed better performance in the cognitive and motor set. Therefore, even if heavily impaired, most children had some degree of visual acuity and visual function and may benefit from visual rehabilitation.

category: ophthalmology


title: Phenome-wide association analysis of substance use disorders in a deeply phenotyped sample

abstract:
BackgroundSubstance use disorders (SUDs) are associated with a variety of co-occurring psychiatric disorders and other SUDs, which partly reflects genetic pleiotropy. Polygenic risk scores (PRS) and phenome-wide association studies (PheWAS) are useful in evaluating pleiotropic effects. The comparatively low prevalence of SUDs and lack of detailed information available in electronic health records limits their informativeness for such analyses.

MethodsWe used the deeply-phenotyped Yale-Penn sample [(N=10,610; 46.3% African ancestry (AFR), 53.7% European ancestry (EUR)], recruited for genetic studies of substance dependence, to examine pleiotropy for 4 major substance-related traits: alcohol use disorder (AUD), opioid use disorder (OUD), smoking initiation (SMK), and lifetime cannabis use (CAN). The sample includes both affected and control subjects interviewed using the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA), a comprehensive psychiatric interview.

ResultsIn AFR individuals PRS for AUD, and in EUR individuals PRS for AUD, OUD, and SMK, were associated with their respective primary DSM diagnoses. These PRS were also associated with additional phenotypes involving the same substance. PheWAS analyses of PRS in EUR individuals identified associations across multiple phenotypic domains, including phenotypes not commonly assessed in PheWAS analyses, such as family environment and early childhood experiences.

ConclusionsSmaller, deeply-phenotyped samples can complement large biobank genetic studies with limited phenotyping by providing greater phenotypic granularity. These efforts allow associations to be identified between specific features of disorders and genetic liability for SUDs, which help to inform our understanding of the pleiotropic pathways underlying them.


title: Implementation and economic effects of local non-pharmaceutical interventions

abstract: In this paper, we analyze economic costs and consequences of local non-pharmaceutical interventions (NPIs) aimed at containing the COVID-19 pandemic. Using comprehensive data on municipal and regional policies in Norway, we implement a difference-in-differences framework identifying impacts of local NPIs from discontinuous differential shifts in outcomes following the implementation of new policies. In treated municipalities, local NPIs lead to persistent reductions in mobility, persistent increases in unemployment, and transient reductions in consumer spending. Analyses of spatial spillovers show that the implementation of local NPIs increases retail mobility in non-treated neighboring municipalities. Overall, our findings suggest that local NPIs have economic consequences for local economies and induce residents to shift their consumption of goods and services to neighboring municipalities.

category: health economics


title: Machine Learning Generalizability Across Healthcare Settings: Insights from multi-site COVID-19 screening

abstract: As patient health information is highly regulated due to privacy concerns, the majority of machine learning (ML)-based healthcare studies are unable to test on external patient cohorts, resulting in a gap between locally reported model performance and cross-site generalizability. Different approaches have been introduced for developing models across multiple clinical sites, however no studies have compared methods for translating ready-made models for adoption in new settings. We introduce three methods to do this - (1) applying a ready-made model "as-is"; (2) readjusting the decision threshold on the output of a ready-made model using site-specific data; and (3) finetuning a ready-made model using site-specific data via transfer learning. Using a case study of COVID-19 diagnosis across four NHS Hospital Trusts, we show that all methods achieve clinically-effective performances (NPV >0.959), with transfer learning achieving the best results (mean AUROCs between 0.870-0.925). Our models demonstrate that site-specific customization improves predictive performance when compared to other ready-made approaches.

category: health informatics


title: Healthy dynamics of CD4 T cells may drive HIV resurgence in perinatally-infected infants on antiretroviral therapy

abstract:
In 2019 there were 490,000 children under five living with HIV. Understanding the dynamics of HIV suppression and rebound in this age group is crucial to optimizing treatment strategies and increasing the likelihood of infants achieving and sustaining viral suppression. Here we studied data from a cohort of 122 perinatally-infected infants who initiated antiretroviral treatment (ART) early after birth and were followed for up to four years. These data included longitudinal measurements of viral load (VL) and CD4 T cell numbers, together with information regarding treatment adherence. We previously showed that the dynamics of HIV decline in 53 of these infants who suppressed VL within one year were similar to those in adults. However, in extending our analysis to all 122 infants, we find that a deterministic model of HIV infection in adults cannot explain the full diversity in infant trajectories. We therefore adapt this model to include imperfect ART adherence and natural CD4 T cell decline and reconstitution processes in infants. We find that individual variation in both processes must be included to obtain the best fits. We also find that, perhaps paradoxically, infants with faster rates of CD4 reconstitution on ART were more likely to experience resurgences in VL. Overall, our findings highlight the importance of combining mathematical modeling with clinical data to disentangle the role of natural immune processes and viral dynamics during HIV infection.

Author SummaryFor infants infected with HIV at or near birth, early and continued treatment with antiretroviral therapy (ART) can lead to sustained suppression of virus and a healthy immune system. However many treated infants experience viral rebound and associated depletion of CD4 T cells. Mathematical models can successfully capture the dynamics of HIV infection in treated adults, but many of the assumptions encoded in these models do not apply early in life. Here we study data from a cohort of HIV-positive infants exhibiting diverse trajectories in response to ART. We show that wide-ranging outcomes can be explained by a modified, but still remarkably simple, model that includes both the natural dynamics of their developing immune systems and variation in treatment adherence. Strikingly, we show that infants with strong rates of recovery of CD4 T cells while on ART may be most at risk of virus resurgence.

category: hiv aids


title: Glycomic Analysis Identifies Pre-Vaccination Markers of Response to Influenza Vaccine, Implicating the Complement Pathway

abstract: Response to vaccination can vary significantly from person to person. A key to improving vaccine design and vaccination strategy is to understand the mechanism behind this variation. The role of glycosylation, a critical modulator of immunity, is unknown in determining vaccine responses. To gain insight into the association between glycosylation and vaccine-induced antibody levels we profiled the pre- and post-vaccination serum protein glycomes of 160 Caucasian adults receiving the FLUZONE influenza vaccine during the 2019-2020 influenza season. Using lectin microarrays, we observed that pre-vaccination levels of Lewis A antigen (Lea) are significantly higher in people who did not mount significant antibody responses, when compared to responders. Glycoproteomic analysis showed that Lea-bearing proteins are enriched in complement activation pathways, suggesting a potential role of glycosylation in tuning the activities of complement proteins, which may be implicated in mounting vaccine responses. We also observed post-vaccination increases in sialyl Lewis X antigen (sLex) and decreases in high mannose glycans among high responders, which were not observed in non-responders. This data suggests that the immune system may actively modulate glycosylation as part of its effort to establish effective protection post-vaccination.


title: The COVID-19 Community Research Partnership: Objectives, Study Design, Baseline Recruitment, and Retention

abstract: The COVID-19 Community Research Partnership (CCRP) is a multisite surveillance platform designed to characterize the epidemiology of the SARS-CoV-2 pandemic. This manuscript describes the CCRP study design and methodology. The CCRP includes two prospective cohorts, one with six health systems in the mid-Atlantic and southern United States, and the other with six health systems in North Carolina. With enrollment beginning April 2020, sites invited persons within their healthcare systems as well as community members to participate in daily surveillance for symptoms of COVID-like illnesses, testing and risk behaviors. Participants with electronic health records were also asked to volunteer data access. Subsets of participants, representative of the general population and including oversampling of populations of interest, were selected for repeated at home serology testing. By October 2021, 65,739 participants (62,261 adult and 3,478 pediatric) were enrolled with 89% providing syndromic data, 74% providing EHR data, and 70% participating in one of two serology sub-studies. An average of 62% of participants completed a daily survey at least once a week, and 55% of serology kits were returned. The CCRP provides rich regional epidemiologic data and opportunities to more fully characterize the risks and sequelae of SARS-CoV-2 infection.


title: Simulation Platforms to Support Teaching and Research in Epidemiological Dynamics

abstract:
An understanding of epidemiological dynamics, once confined to mathematical epidemiologists and applied mathematicians, can be disseminated to a non-mathematical community of health care professionals and applied biologists through simple-to-use simulation applications. We used Numerus Model Builder RAMP(R) (Runtime Alterable Model Platform) technology, to construct deterministic and stochastic versions of compartmental SIR (Susceptible, Infectious, Recovered with immunity) models as simple-to-use, freely available, epidemic simulation application programs. In this paper, we take the reader through simulations that are used to demonstrate the following concepts: 1) disease prevalence curves of unmitigated outbreaks have a single peak and result in epidemics that  burn through the population to become extinguished when the proportion of the susceptible population drops below a critical level; 2) if immunity in recovered individuals wanes sufficiently fast then the disease persists indefinitely as an endemic state with possible dampening oscillations following the initial outbreak phase; 3) the steepness and initial peak of the prevalence curve are influenced by the basic reproductive value R0, which must exceed 1 for an epidemic to occur; 4) the probability that a single infectious individual in a closed population (i.e. no migration) gives rise to an epidemic increases with the value of R0 > 1; 5) behavior that adaptively decreases the contact rate among individuals with increasing prevalence has major effects on the prevalence curve including dramatic flattening of the prevalence curve along with the generation of multiple prevalence peaks; 6) the impacts of treatment are complicated to model because they effect multiple processes including transmission, and both recovery and mortality rates; 7) similarly, the impacts of vaccination are equally complicated and, in addition, when a fixed number of vaccination regimens are available, the rate and timing of delivery are crucially important to maximizing there ability to reducing mortality. Our presentation makes transparent the key assumptions underlying SIR epidemic models. The model and simulations tools described in this paper and the four RAMPs that we provide are meant to augment rather than replace classroom material when teaching epidemiological dynamics. Our RAMPs are sufficiently versatile to be used by students to address a range of research questions for term papers and even dissertations.

HighlightsO_LIBasic concepts used to build epidemiological models and think about epidemics are introduced
- disease class structure and homogeneity
- well-mixed population
- flows of individuals among classes
- rates of change and mathematical representation
- deterministic versus stochastic formulations
- disease reproductive value and R-zero
- cessation of an epidemic versus endemicity
- formulation of transmission
- adaptive contact behavior
- infectious, latent, and immunity waning periods (waiting times)
- competing risks and rates to proportions transformations
- effects of treatment and vaccination measures

C_LIO_LIPrinciples of epidemiological dynamics are illustrated through simulation including:
- rise to peak prevalence, subsequent fall to extirpation as herd immunity level is reached, but some individuals remain uninfected
- level of endemicity inversely related to rate at which immunity wanes
- effects of adaptive contact behavior on flattening the prolonging the prevalence peak
- proportion of stuttering transmission chains that lead to an outbreak is related to size of R0 (basic reproductive rate of the disease)
- complexities involved in incorporating treatment effects
- trade-off between early vaccination rollout and availability of vaccination regimens

C_LIO_LIFour simple-to-use basic and applied deterministic and stochastic runtime alterable model platforms are provided for students to use in replicating illustrative examples, carrying out suggested exercises, and exploring novel idea. These are:
O_LIDeterministic SIRS RAMP
C_LIO_LIStochastic SIRS RAMP
C_LIO_LIDeterministic SIRS+DTV RAMP
C_LIO_LIStochastic SIRS+DTV RAMP
C_LI
C_LI


title: Cov2MS: an automated matrix-independent assay for mass spectrometric detection and measurement of SARS-CoV-2 nucleocapsid protein in infectious patients

abstract:
INTRODUCTIONThe pandemic readiness toolbox needs to be extended, providing diagnostic tools that target different biomolecules, using orthogonal experimental setups and fit-for-purpose specification of detection. Here we build on a previous Cov-MS effort that used liquid chromatography-mass spectrometry (LC-MS) and describe a method that allows accurate, high throughput measurement of SARS-CoV-2 nucleocapsid (N) protein.

MATERIALS and METHODSWe used Stable Isotope Standards and Capture by Anti-Peptide Antibodies (SISCAPA) technology to enrich and quantify proteotypic peptides of the N protein from trypsin-digested samples from COVID-19 patients.

RESULTSThe Cov2MS assay was shown to be compatible with a variety of sample matrices including nasopharyngeal swabs, saliva and blood plasma and increased the sensitivity into the attomole range, up to a 1000-fold increase compared to direct detection in matrix. In addition, a strong positive correlation was observed between the SISCAPA antigen assay and qPCR detection beyond a quantification cycle (Cq) of 30-31, the level where no live virus can be cultured from patients. The automatable "addition only" sample preparation, digestion protocol, peptide enrichment and subsequent reduced dependency upon LC allow analysis of up to 500 samples per day per MS instrument. Importantly, peptide enrichment allowed detection of N protein in a pooled sample containing a single PCR positive sample mixed with 31 PCR negative samples, without loss in sensitivity. MS can easily be multiplexed and we also propose target peptides for Influenza A and B virus detection.

CONCLUSIONSThe Cov2MS assay described is agnostic with respect to the sample matrix or pooling strategy used for increasing throughput and can be easily multiplexed. Additionally, the assay eliminates interferences due to protein-protein interactions including those caused by anti-virus antibodies. The assay can be adapted to test for many different pathogens and could provide a tool enabling longitudinal epidemiological monitoring of large numbers of pathogens within a population, applied as an early warning system.


title: COVID Testing in the Workplace: Return to Work Testing in an Occupational Cohort

abstract:
BackgroundThe Omicron SARS-CoV-2 variant resulted in significant community-based transmission. Numerous occupational settings have employed surveillance testing strategies to minimize occupational exposure and return workers safely to work following isolation.

MethodsFrom an occupational COVID-19 testing program, we obtained longitudinal (February 2021-January 2022) saliva-based RT-qPCR results and starting December 27th, 2021, daily on-site molecular over-the-counter (OTC) nasal swab-based isothermal nucleic acid amplification test (molecular OTC; Cue Health COVID-19 test) results. We quantified the fraction of tests with PCR cycle threshold (Ct) values <30 on each day post detection from suspected and confirmed Omicron infections (n=37), compared results to molecular OTC testing, and measured workplace and household transmission. We evaluated return-to-work timing using a post-isolation, two-test threshold of Ct >30, or two negative molecular OTC tests over a 24 hour period, or a single PCR test >30 plus negative molecular OTC test.

ResultsFrom the paired testing cohort, 37 (48%) individuals tested positive; all 37 were vaccinated. All individuals tested positive [≤]1 day after a previous negative test, and 19 (51.3%) remained PCR-positive with Ct values <30 at day 5. While 3 (8.1%) remained PCR-positive with a Ct value <30 on day 10, no individuals remained PCR-positive on day 12. The average time to PCR clearance/return-to-work was 7.94 days (median=9.5 days). Time to clearance for those boosted (n=8; 7.75 days) and those not yet boosted (8.04 days) did not differ (p=0.49). Peak viral load measured by PCR was 1.97 days from the initial positive test. There were no cases of transmission after returning to work.

ConclusionsA large percentage of individuals remain contagious at day 5 post first positive test based on serial PCR testing and can continue until day 12. Early discontinuation of isolation can utilize a two test framework separated by 24 hours. Rapid onsite tests may be useful.


title: The REinfection in COVID-19 Estimation of Risk (RECOVER) study: Reinfection and serology dynamics in a cohort of Canadian healthcare workers.

abstract:
BackgroundUnderstanding the immune response to natural infection by SARS-CoV-2 is key to pandemic management, especially in the current context of emerging variants. Uncertainty remains regarding the efficacy and duration of natural immunity against reinfection.

MethodWe conducted an observational prospective cohort study in Canadian healthcare workers (HCWs) with a history of PCR-confirmed SARS-CoV-2 infection to : (i) measure the average incidence rate of reinfection and (ii), describe the serological immune response to the primary infection.

ResultsWe detected 5 cases of reinfection over 14 months of follow-up, for a reinfection incidence rate of 3.3 per 100 person-years. Median duration of seropositivity was 420 days in symptomatics at primary infection compared to 213 days in asymptomatics (p<0.0001). Other variables associated with prolonged seropositivity for IgG against the spike protein included age 55 and above, obesity, and non-Caucasian ethnicity.

SummaryAmong healthcare workers, the incidence of reinfection with SARS-CoV-2 following a primary infection remained rare, although our analysis predates the circulation of the Omicron variant.


title: Disparities in Opioid-related Mortality Across United States Census Regions from 1999-2020

abstract:
BackgroundOpioid-related mortality has been on a sharp rise in the decade. This study aims to provide insight into the difference in mortality between white and black population in various census regions of the United States between 1999-2020.

MethodsThe data was extracted from multiple cause of death files from CDC Wonder database. The International Classification of Disease (ICD-10) codes used to extract data include F11 (mental and behavioral disorders due to use of opioids); T40.0 (Opium); T40.1 (Heroin); T40.2 (Other opioids); T40.3 (Methadone); T40.4 (Other synthetic narcotics). The regression analysis was conducted using Joinpoint statistical software.

ResultsThe black population in the Midwest census region showed the highest age-adjusted mortality in the year 2020 (46.14 per 100,000). This was followed by the black (32.71 per 100,000) and white population (30.5 per 100,000) in the northeast census regions respectively. Overall, the opioid-related mortality followed a similar trend across all census regions. Except south census region where age-adjusted mortality was comparable between the black and white populations, blacks had higher opioid-related mortality in all other census regions.

ConclusionThis study provides concise evidence of inequality in opioid-related deaths among various US census regions. Policy changes focused to certain regions are required to significantly address the underlying factors related to disparities in opioid-related mortality among the black population.

category: addiction medicine


title: Examining the Association between Mitochondrial Genome Variation and Coronary Artery Disease

abstract:
BackgroundLarge-scale genome-wide association studies have identified hundreds of single-nucleotide variants (SNVs) significantly associated with coronary artery disease (CAD). However, collectively, these explain <20% of the heritability.

HypothesisHere, we hypothesize that mitochondrial (MT) SNVs might present one potential source of this "missing heritability".

MethodsWe analyzed 265 MT-SNVs in [~]500,000 UK Biobank individuals, exploring two different CAD definitions: a more stringent (myocardial infarction and/or revascularization; HARD=20,405), and a more inclusive (also angina and chronic ischemic heart disease; SOFT=34,782).

ResultsIn HARD cases, the most significant (P<0.05) associations were for m.295C>T (control region) and m.12612A>G (ND5), found more frequently in cases (OR=1.05), potentially related to reduced cardiorespiratory fitness in response to exercise, as well as for m.12372G>A (ND5) and m.11467A>G (ND4), present more frequently in controls (OR=0.97), previously associated with lower ROS production rate. In SOFT cases, four MT-SNVs survived multiple testing correction (at FDR<5%), all potentially conferring increased CAD risk. Of those, m.11251A>G (ND4) and m.15452C>A (CYB) have previously shown significant associations with body height. In line with this, we observed that CAD cases were slightly less physically active and their average body height was [~]2.00 cm lower compared to controls, both traits known to be related to an increased CAD risk. Gene-based tests identified CO2 associated with HARD/SOFT CAD, whereas ND3 and CYB associated with SOFT cases (P<0.05), dysfunction of which has been related to MT oxidative stress, obesity/T2D (CO2), BMI (ND3) and angina/exercise intolerance (CYB). Finally, we observed that macro-haplogroup I was significantly (P<0.05) more frequent in HARD cases vs. controls (3.35% vs. 3.08%), potentially associated with response to exercise.

ConclusionsWe found only spurious associations between MT genome variation and HARD/SOFT CAD and conclude that more MT-SNV data in even larger study cohorts may be needed to conclusively determine the role of MT-DNA in CAD.

category: cardiovascular medicine


title: Sun exposure behavior and knowledge on photoprotection of children and adolescents living in tropical regions

abstract:
BackgroundExcessive and continuous exposure to ultraviolet radiation (UVR) can cause skin cancer (SC), photoaging, and cataracts. Photoprotection (PhP) is the most important tool in preventing against these harmful effects. Elementary and high school students should be targeted in PhP campaigns because the solar radiation that youngers receive increases the risk of SC in adulthood. However, PhP policies are scarce in developing countries.

ObjectivesTo evaluate the use and knowledge of PhP with youngsters living in tropical regions.

Methods2,844 students aged from 4 to 20 years-old were interviewed about their knowledge on sun exposure and PhP habits. Age, sex, family income and skin phototype were statistically related to the proposed questions.

ResultsBrazilian youngsters do not have the habit of wearing long-sleeved clothing (<15% in summer), nor sunglasses (0.0%), and hats (2.1%). More than 40% had no knowledge about UVI while another 30% misinterpret what it is. Less than half of all students wear sunscreen when out in the sun. Despite this low PhP use-rate, more than 90% know that UVR causes SC. Income was the factor that showed the greatest number of significant relationships respect to PhP.

ConclusionsChildren and adolescents showed little knowledge about the sun exposure effects and lack PhP use. The lack of educational programs predisposes these youngsters to an increased chance of SC in the future. These results suggest that PhP campaigns should be part of school curricula from elementary school onwards.

category: dermatology


title: Ethnic disparities in immunisation: analyses of zero-dose prevalence in 64 low- and middle-income countries

abstract:
BackgroundThe Sustainable Development Goals (SDGs) recommend stratification of health indicators by ethnic group, yet there are few studies that have assessed if there are ethnic disparities in childhood immunisation in low- and middle-income countries (LMICs).

MethodsWe identified 64 LMICs with standardized national surveys carried out since 2010, which provided information on ethnicity or a proxy variable and on vaccine coverage; 339 ethnic groups across the 64 countries were identified after excluding those with fewer than 50 children in the sample and countries with a single ethnic group. Lack of vaccination with diphtheria-pertussis-tetanus (DPT) vaccine - a proxy for no access to routine vaccination or  zero-dose status - was the outcome of interest. Differences among ethnic groups were assessed using a chi-squared test for heterogeneity. Additional analyses controlled for household wealth, maternal education and urban-rural residence.

FindingsThe median gap between the highest and lowest zero-dose prevalence ethnic groups in all countries was equal to 10 percentage points (interquartile range 4-22; range 1 to 84) and the median ratio was 3.3 (interquartile range 1.8-6.7; range 1.1-30.4). In 35 of the 64 countries, there was significant heterogeneity in zero-dose prevalence among the ethnic groups. In most countries, adjustment for wealth, education and residence made little difference to the ethnic gaps, but in four countries (Angola, Benin, Nigeria, and Philippines) the high-low ethnic gap decreased by over 15 pp after adjustment. Children belonging to a majority group had 29% lower prevalence of zero-dose compared to the rest of the sample.

InterpretationStatistically significant ethnic disparities in child immunisation were present in over half of the countries studied. Such inequalities have been seldom described in the published literature. Regular analyses of ethnic disparities are essential for monitoring trends, targeting resources and assessing the impact of health interventions to ensure zero-dose children are not left behind in the Sustainable Development Goals era.

FundingBill & Melinda Gates Foundation, Gavi, the Vaccine Alliance, Wellcome Trust, and Associacao Brasileira de Saude Coletiva.

category: epidemiology


title: The effect of competition between health opinions on epidemic dynamics

abstract:
Past major epidemic events showed that when an infectious disease is perceived to cause severe health outcomes, individuals modify health behavior affecting epidemic dynamics. To investigate the effect of this feedback relationship on epidemic dynamics, we developed a compartmental model that couples a disease spread framework with competition of two mutually exclusive health opinions (health-positive and health-neutral) associated with different health behaviors. The model is based on the assumption that individuals switch health opinions as a result of exposure to opinions of others through interpersonal communications. To model opinion switch rates, we considered a family of functions and identified the ones that allow health opinions to co-exist. In the disease-free population, either the opinions cannot co-exist and one of them is always dominating (monobelief equilibrium) or there is at least one stable co-existence of opinions equilibrium. In the latter case, there is multistability between the co-existence equilibrium and the two monobelief equilibria. When two opinions co-exist, it depends on their distribution whether the infection can invade. If presence of the infection leads to increased switching to a health-positive opinion, the epidemic burden becomes smaller than indicated by the basic reproduction number. Additionally, a feedback between epidemic dynamics and health opinion dynamics may result in (sustained) oscillatory dynamics and a switch to a different stable opinion distribution. Our model captures feedback between spread of awareness through social networks and infection dynamics and can serve as a basis for more elaborate individual-based models.

Significance StatementDisease epidemics often co-evolve with opinions on health-related behavior. Most existing models have difficulties understanding co-existence of different opinions in a population when the disease is not present, while we do observe this. We modeled opinion switching process by using an innovative way to capture the dependence of opinion switching rate on the population state. We combined this with network interaction patterns and were able to derive conditions under which a stable co-existence of opinions can occur. We used this insight to explain appearance of epidemic cycles and the population switching between different distributions of opinions. Our work demonstrates that for information interventions accurate understanding of opinion propagation processes is crucial.


title: A scoping review protocol on in vivo human plastic exposure and health impacts

abstract:
BackgroundGlobal plastic production has increased exponentially since the 1960s, with more than 6300 million metric tons of plastic waste generated to date. Studies have found a range of human health impacts associated with exposure to plastic chemicals. However, only a fraction of plastic chemicals used have been studied in vivo, and then often in animals, for acute toxicological effects. With many questions still unanswered about how long-term exposure to plastic impacts human health, there is an urgent need to map human in vivo research conducted to date, casting a broad net by searching terms for a comprehensive suite of plastic chemical exposures and the widest range of health domains.

MethodsThis protocol describes a scoping review that will follow the recommended framework outlined in 2017 Guidance for the Conduct of Joanna Briggs Institute (JBI) Scoping Reviews, to be reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) Checklist. A literature search of primary clinical studies in English from 1960 onwards will be conducted in MEDLINE (Ovid) and EMBASE (Ovid) databases. References eligible for inclusion will be identified through a quality-controlled, multi-level screening process. Extracted data will be presented in diagrammatic and tabular form, with a narrative summary addressing the review questions.

DiscussionThis scoping review will comprehensively map the primary research undertaken to date on plastic exposure and human health. Secondary outputs will include extensive databases on plastic chemicals and human health outcomes/impacts.

RegistrationOpen Science Framework (OSF)-Standard Pre-Data Collection Registration, https://osf.io/gbxps DOI: 10.17605/OSF.IO/GBXPS


title: Enhancing the Discriminatory Power of ADHD and Autism Spectrum Disorder Polygenic Scores in Clinical and Non-Clinical Samples

abstract:
ObjectivePolygenic scores (PGS) are widely used in psychiatric genetic associations studies due to their impressive power to predict focal outcomes. However, they lack in discriminatory power, in part due to the high degree of genetic overlap between psychiatric disorders. The lack of prediction specificity limits the clinical utility of psychiatric PGS, particularly for diagnostic applications. The goal of the study was to enhance the discriminatory power of psychiatric PGS for two highly comorbid and genetically correlated neurodevelopmental disorders in ADHD and autism spectrum disorder (ASD).

MethodsGenomic structural equation modeling (GenomicSEM) was used to generate novel PGS for ADHD and ASD by accounting for the genetic overlap between these disorders (and eight others) to achieve greater discriminatory power in non-focal outcome predictions. PGS associations were tested in two large independent samples - the Philadelphia Neurodevelopmental Cohort (N=4,789) and the Simons Foundation Powering Autism Research for Knowledge (SPARK) ASD and sibling controls (N=5,045) cohort.

ResultsPGS from GenomicSEM achieved superior discriminatory power in terms of showing significantly attenuated associations with non-focal outcomes relative to traditionally computed PGS for these disorders. Additionally, genetic correlations between GenomicSEM PGS for ASD and ADHD were significantly attenuated in cross-trait associations with other psychiatric disorders and outcomes.

ConclusionsPsychiatric PGS associations are likely inflated by the high degree of genetic overlap between the psychiatric disorders. Methods such as GenomicSEM can be used to refine PGS signals to be more disorder-specific, thereby enhancing their discriminatory power for future diagnostic applications.


title: Effectiveness of community-based burden estimation to achieve elimination of lymphatic filariasis: a comparative cross-sectional investigation in Cote dIvoire

abstract:
For lymphatic filariasis (LF) elimination, endemic countries must document the burden of LF morbidity (LFM). Community-based screening (CBS) is used to collect morbidity data, but evidence demonstrating its reliability is limited. Recent pilots of CBS for LFM alongside mass drug administration (MDA) in Cote dIvoire suggested low LFM prevalence (2.1-2.2 per 10,000).

We estimated LFM prevalence in Bongouanou District, Cote dIvoire, using a comparative cross-sectional design. We compared CBS implemented independently of MDA, adapted from existing Ministry of Health protocols, to a population-based prevalence survey led by formally trained nurses. We evaluated the reliability of case identification, coverage, equity, and cost of CBS.

CBS identified 87.4 cases of LFM per 10,000; the survey identified 47.5 (39.4-56.3; prevalence ratio [PR] 1.84; 95% CI 1.64-2.07). CBS identified 39.7 cases of suspect lymphoedema per 10,000; the survey confirmed 35.1 (29.2-41.5) filarial lymphoedema cases per 10,000 (PR 1.13 [0.98-1.31]). CBS identified 100.3 scrotal swellings per 10,000; the survey found 61.5 (55.5-67.8; PR 1.63 [1.41-1.88]); including 26.6 (21.5-32.4) filarial hydrocoele per 10,000 (PR of suspect to confirmed hydrocele 3.77 [3.12-4.64]). Positive predictive values for case identification through CBS were 64.0% (54.5-72.8%) for filarial lymphoedema; 93.2% (88.5-96.4%) for scrotal swellings; and 33.3% (26.4-40.8%) for filarial hydrocoele. Households of lower socioeconomic status and certain minority languages were at risk of exclusion. Direct financial costs were $0.17 per individual targeted and $69.62 per case confirmed. We provide our CBS toolkit.

Our community-based approach to LFM burden estimation appears scalable and provided reliable prevalence estimates for LFM, scrotal swellings and LF-lymphoedema. The results represent a step-change improvement on CBS integrated with MDA, whilst remaining at programmatically feasible costs. Filarial hydrocoele cases were overestimated, attributable to the use of case definitions suitable for mass-screening by informal staff. Our findings are broadly applicable to countries aiming for LF elimination using CBS.

Summary boxO_ST_ABSWhat is already known?C_ST_ABSO_LIIn many lymphatic filariasis (LF) endemic countries, community-based screening (CBS) is used alongside mass drug administration (MDA) campaigns to estimate the burden of disease (LFM), required to achieve WHO targets for disease elimination.
C_LIO_LIPrevious studies have shown that the accuracy of CBS for LFM varies widely and the underlying contextual factors that impact on effectiveness remain unclear.
C_LIO_LIIn Cote dIvoire in 2020, pilot studies alongside MDA suggested low prevalence of LFM, though a process evaluation indicated estimates were negatively affected due to the competing demands of MDA, a challenge reported in other settings.
C_LI

What are the new findingsO_LIWe strengthened CBS in Bongouanou Department, Cote dIvoire, and de-coupled activities from MDA, which led to a 40-fold increase in LFM case estimates. We validated this estimate using a population-based prevalence survey led by formal healthcare workers, which demonstrated a comparable estimate of LFM.
C_LIO_LIThe direct financial cost of CBS was comparable to, or less than, other large-scale NTD interventions and supports scalability as a programmatic activity.
C_LIO_LIWe quantified specific biases of CBS, including poor differentiation between hydrocoele and scrotum swellings of alternative aetiology, and preferential inclusion of household based on sociodemographic characteristics.
C_LI

What do the new findings implyO_LIThe approach we developed for strengthened, standalone CBS can provide estimates of LFM that reflect the true burden of disease, and is applicable to other LF endemic countries utilising large-scale community-based approaches.
C_LIO_LIThere is likely to be a high burden of LFM in endemic districts requiring expansion of morbidity management and disability prevention services.
C_LIO_LIAccurate delineation of hydrocoele from other causes of scrotal swellings appears unfeasible using informal cadres employed during CBS. In settings where CBS is implemented, health providers should consider integration of conditions in activities.
C_LI

Public InvolvementTwo CDDs who had been involved in pilot LFM screening activities in 2020 participated in a review workshop, providing feedback which was used to develop the toolkit for LFM screening.

Prior to the start of study activities, a launch meeting was held with traditional and religious leaders, administrative authorities and representatives of mens, womens and childrens groups of Bongouanou district. Participants were asked for their perspective on the importance of LFM as a health problem in their communities. Through this meeting they were informed about the CBS and nurse-led survey, and asked to cascade information through their communities.

Patients were not involved in the study design.