title: Optimizing one-dose and two-dose cholera vaccine allocation in outbreak settings: A modeling study

abstract:
BackgroundA global stockpile of oral cholera vaccine (OCV) was established in 2013 for use in outbreak response and are licensed as two-dose regimens. Vaccine availability, however, remains limited. Previous studies have found that a single dose of OCV may provide substantial protection against cholera.

MethodsUsing a mathematical model with two age groups paired with optimization algorithms, we determine the optimal vaccination strategy with one and two doses of vaccine to minimize cumulative overall infections, symptomatic infections, and deaths. We explore counterfactual vaccination scenarios in three distinct settings: Maela, the largest refugee camp in Thailand, with high in- and out-migration; NDjamena, Chad, a densely populated region; and Haiti, where departments are connected by rivers and roads.

ResultsOver the short term under limited vaccine supply, the optimal strategies for all objectives prioritize one dose to the older age group (over five years old), irrespective of setting and level of vaccination coverage. As more vaccine becomes available, it is optimal to administer a second dose for long-term protection. With enough vaccine to cover the whole population with one dose, the optimal strategies can avert up to 30% to 90% of deaths and 36% to 92% of symptomatic infections across the three settings over one year. The one-dose optimal strategies can avert 1.2 to 1.8 times as many cases and deaths as a two-dose pro-rata strategy.

ConclusionsIn an outbreak setting, speedy vaccination campaigns with a single dose of OCV may avert more cases and deaths than a two-dose pro-rata campaign under a limited vaccine supply.


title: Associations and prognostic accuracy of electrolyte imbalances in predicting poor COVID-19 outcome: a systematic review and meta-analysis of 28 observational studies

abstract:
BackgroundSerum electrolyte imbalances are highly prevalent in COVID-19 patients. However, their associations with COVID-19 outcomes are inconsistent, and of unknown prognostic value.

ObjectivesTo systematically clarify the associations and prognostic accuracy of electrolyte imbalances (sodium, calcium, potassium, magnesium, chloride and phosphate) in predicting poor COVID-19 clinical outcome.

MethodsPubMed, Embase and Cochrane Library were searched. Odds of poor clinical outcome (a composite of mortality, intensive-care unit (ICU) admission, need for respiratory support and acute respiratory distress syndrome) were pooled using mixed-effects models. The associated prognostic sensitivity, positive and negative likelihood ratios (LR+, LR-) and predictive values (PPV, NPV; assuming 25% pre-test probability), and area under the curve (AUC) were computed.

ResultsWe included 28 observational studies from 953 records with low to moderate risk-of-bias. Hyponatremia (OR=2.08, 95%CI=1.48-2.94, I2=93%, N=8), hypernatremia (OR=4.32, 95%CI=3.17-5.88, I2=45%, N=7) and hypocalcemia (OR=3.31, 95%CI=2.24-4.88, I2=25%, N=6) were associated with poor COVID-19 outcome. These associations remained significant on adjustment for covariates such as demographics and comorbidities. Hypernatremia was 97% specific in predicting poor outcome (LR+ 4.0, PPV=55%, AUC=0.80) despite no differences in CRP and IL-6 levels between hypernatremic and normonatremic patients. Hypocalcemia was 76% sensitive in predicting poor outcome (LR- 0.44, NPV=87%, AUC=0.71). Overall quality of evidence ranged from very low to moderate.

ConclusionHyponatremia, hypernatremia and hypocalcemia are associated with poor COVID-19 clinical outcome. Hypernatremia is 97% specific for a poor outcome and the association is independent of inflammatory marker levels. Further studies should evaluate if correcting these imbalances help improve clinical outcome.

category: infectious diseases


title: C-reactive protein and lactate dehydrogenase are useful biomarkers for predicting the requirement for oxygen therapy in outpatients with coronavirus disease 2019

abstract:
BackgroundIt is critical for clinicians seeing outpatients with coronavirus disease 2019 (COVID-19) to identify those who will require oxygen therapy after the hospital visit. Although studies on biomarkers predicting mortality or ventilator requirement in hospitalized patients with COVID-19 have been conducted, research on biomarkers predicting the need for oxygen therapy in outpatients is sparse.

MethodsPatients with COVID-19 who visited Asahikawa City Hospital on an outpatient basis were included in the study. In total, 287 new outpatients visited between April 2021 and September 2021, and 142 underwent blood testing. All blood tests were performed before any treatments for COVID-19 were started. Demographic information, laboratory data, and clinical treatment information were extracted from the electronic medical records. Risk factors associated with oxygen therapy were explored.

ResultsIn total, 40 of 142 patients who underwent blood testing required oxygen therapy within 7 days after blood samples were taken, and all other patients recovered without oxygen therapy. C-reactive protein (CRP) and lactate dehydrogenase (LDH) levels were significantly higher in patients who required oxygen therapy, and their cutoffs were 36 mg/L (sensitivity, 0.802; specificity, 0.725) and 267 U/L (sensitivity, 0.713; specificity, 0.750), respectively. Multivariate logistic regression identified age, body mass index, CRP [≥] 36 mg/L, and LDH [≥] 267 U/L as significant risk factors for oxygen therapy requirement. This study suggests that elevated CRP and LDH levels are independent risk factors for oxygen therapy in outpatients with COVID-19. Further confirmatory studies are needed.


title: C-reactive protein and lactate dehydrogenase as prognostic indicators in COVID-2019 outpatients


title: Diagnostic signature for Heart Failure with Preserved Ejection Fraction (HFpEF): A Machine Learning Approach Using Multi-Modality Electronic Health Record Data

abstract:
AimsHeart failure with preserved ejection fraction (HFpEF) is thought to be highly prevalent yet remains underdiagnosed. We sought to develop a data-driven diagnostic model to predict from electronic health records (EHR) the likelihood of HFpEF among patients with unexplained dyspnea and preserved left ventricular EF.

Methods & ResultsThe derivation cohort comprised patients with dyspnea and echocardiography results. Structured and unstructured data were extracted using an automated informatics pipeline. Patients were retrospectively diagnosed as HFpEF (cases), non-HF (control cohort I), or HF with reduced EF (HFrEF; control cohort II). The ability of clinical parameters and investigations to discriminate cases from controls was evaluated by extreme gradient boosting. A likelihood scoring system was developed and validated in a separate test cohort.

The derivation cohort included 1585 consecutive patients: 133 cases of HFpEF (9%), 194 non-HF cases (Control cohort I) and 1258 HFrEF cases (Control cohort II). Two HFpEF diagnostic signatures were derived, comprising symptoms, diagnoses and investigation results. A final prediction model was generated based on the averaged likelihood scores from these two models. In a validation cohort consisting of 269 consecutive patients (with 66 HFpEF cases (24.5%)), the diagnostic power of detecting HFpEF had an AUROC of 90% (P<0.001) and average precision (AP) of 74%.

ConclusionThis diagnostic signature enables discrimination of HFpEF from non-cardiac dyspnea or HFrEF from EHR and can assist in the diagnostic evaluation in patients with unexplained dyspnea.

category: cardiovascular medicine


title: Use of commercially available natural language processing software to identify bleeding from the medical record

abstract:
BackgroundReal-world evidence derived from the electronic medical record (EMR) is increasingly prevalent. How best to ascertain cardiovascular outcomes from EMRs is unknown. We sought to validate a commercially available natural language processing (NLP) software to extract bleeding events.

MethodsWe included patients with atrial fibrillation and cancer seen at our cancer center from 1/1/2016 to 12/31/2019. A query set based on SNOMED CT expressions was created to represent bleeding from 11 different organ systems. We ran the query against the clinical notes and randomly selected a sample of notes for physician validation. The primary outcome was the positive predictive value (PPV) of the software to identify bleeding events stratified by organ system.

ResultsWe included 1370 patients with mean age 72 years old (SD 1.5) and 35% female. We processed 66,130 notes; the NLP software identified 6522 notes including 654 unique patients with possible bleeding events. Among 1269 randomly selected notes, the PPV of the software ranged from 0.921 for neurologic bleeds to 0.571 for OB/GYN bleeds. Patterns related to false positive bleeding events identified by the software included historic bleeds, hypothetical bleeds, missed negatives, and word errors.

ConclusionsNLP may provide an alternative for population-level screening for bleeding outcomes in cardiovascular studies. Human validation is still needed, but an NLP-driven screening approach may improve efficiency.


title: Causal effect of adiposity on the risk of 19 gastrointestinal diseases: a Mendelian randomization study

abstract:
ObjectivesWe applied Mendelian randomization (MR) to investigate the causal associations of body mass index (BMI) and waist circumference (WC) with 19 gastrointestinal (GI) disorders.

DesignMR study.

SettingThe UK Biobank, Genetic Investigation of Anthropometric Traits (GIANT) Consortium, FinnGen consortium, and genome-wide association studies.

ParticipantsOverall, >400,000 UK Biobank participants, >170,000 participants of Finnish descent, and numerous consortia participants with predominantly European ancestry.

InterventionsSingle-nucleotide polymorphisms associated with BMI and WC were used as instrumental variables to estimate the causal associations with the GI conditions.

Main outcome measuresRisk of developing 19 GI diseases

ResultsAfter correction for multiple testing (Bonferroni-corrected threshold of P<0.05/19) and testing for consistencies using several MR methods with varying assumptions (inverse variance weighted, weighted median, MR-Egger, and MR-PRESSO), genetically predicted BMI was associated with increased risks of non-alcoholic fatty liver disease (NAFLD), cholecystitis, cholelithiasis, and primary biliary cholangitis. The odds ratio (OR) per one standard deviation (SD) increased in genetically predicted BMI (4.77 kg/m2) from 1.22 (95% confidence interval [CI] 1.12-1.34; P<0.0001) for NAFLD to 1.65 (95% CI 1.31-2.06; P<0.0001) for cholecystitis. Genetically predicted WC was associated with increased risks of NAFLD, alcoholic liver disease (ALD), cholecystitis, cholelithiasis, colon cancer, and gastric cancer. ALD was associated with WC even after adjustment for alcohol consumption in multivariable MR analysis. The OR per 1 SD increased in genetically predicted WC (12.52 cm) from 1.41 (95% CI 1.17-1.70; P=0.0015) for gastric cancer to 1.74 (95% CI 1.21-1.78; P<0.0001) for cholelithiasis.

ConclusionsHigher BMI and WC are causally associated with an increased risk of GI abnormalities, particularly of hepatobiliary organs (liver, biliary tract, and gallbladder) that are functionally related to fat metabolism. Abdominal obesity measured by WC might be more influential and relevant with a diverse span of GI diseases than BMI, highlighting a possible pathophysiological role of visceral abdominal fats in the development of GI disorders and cancers.

Graphical Abstract

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category: gastroenterology


title: Impact of the COVID-19 pandemic on community antibiotic prescribing and stewardship: a qualitative interview study with general practitioners in England

abstract: The COVID-19 pandemic has had a profound impact on the delivery of primary care services. We aimed to identify general practitioners (GPs) perceptions and experiences of how the COVID-19 pandemic influenced antibiotic prescribing and antimicrobial stewardship (AMS) in general practice in England. Twenty-four semi-structured interviews were conducted with 18 GPs at two time-points: autumn 2020 (14 interviews) and spring 2021 (10 interviews). Interviews were audio-recorded, transcribed and analysed thematically, taking a longitudinal approach. Participants reported a lower threshold for antibiotic prescribing (and fewer consultations) for respiratory infections and COVID-19 symptoms early in the pandemic, then returning to more usual (pre-pandemic) prescribing. They perceived less impact on antibiotic prescribing for urinary and skin infections. Participants perceived the changing ways of working and consulting (e.g., proportions of remote and in-person consultations), and the changing patient presentations and GP workload as influencing the fluctuations in antibiotic prescribing. This was compounded by decreased engagement with, and priority of, AMS due to COVID-19-related urgent priorities. Re-engagement with AMS is needed, e.g., through reviving antibiotic prescribing feedback and targets/incentives. While the pandemic disrupted the usual ways of working, it also produced opportunities, e.g., for re-organising ways of managing infections and AMS in the future.

category: primary care research


title: Novel insights into the common heritable liability to addiction: a multivariate genome-wide association study

abstract: Addiction to nicotine, alcohol and cannabis commonly co-occurs, which is thought to partly stem from a common heritable liability. To elucidate its genetic architecture, we modelled the common liability to addiction, inferred from genetic correlations among six measures of dependence and frequency of use of nicotine, alcohol and cannabis. Forty-two genetic variants were identified in the multivariate genome-wide association study on the common liability to addiction, of which 67% were novel and not associated with the six phenotypes. Mapped genes highlighted the role of dopamine (e.g., dopamine D2 gene), and showed enrichment for several components of the central nervous systems (e.g., mesocorticolimbic brain regions) and molecular pathways (dopaminergic, glutamatergic, GABAergic) that are thought to modulate drug reinforcement. Genetic correlations with other traits were most prominent for reward-related behaviours (e.g., risk-taking, cocaine and heroin use) and mood (e.g., depression, insomnia). These genome-wide results triangulate and expand previous preclinical and human studies focusing on the neurobiological substrates of addiction, and help to elucidate the common genetic architecture underlying addiction.

category: psychiatry and clinical psychology


title: Kindness By Post: A Mixed-Methods Evaluation of A Participatory Public Mental Health Project

abstract:
BackgroundRandom acts of kindness can improve wellbeing. However, less is known about the impacts of giving and receiving acts of kindness with strangers on wellbeing and loneliness. Therefore, this studys objectives were to evaluate a participatory public mental health project involving sending and receiving a card with goodwill messages, to understand how such acts of kindness influence wellbeing and loneliness, and to investigate the potential mechanisms underlying the projects impacts.

Materials and methodsThis study was a secondary analysis of anonymised service evaluation data collected in the  Kindness by Post (KBP) project in 2020. It used a mixed-methods single-group design and data from 289 participants. Changes in wellbeing, loneliness, sense of belonging and hope from baseline to follow-up were analysed using linear or multinomial logistic regression. Regression models also examined the associations between changes in wellbeing and baseline loneliness or participation level. Free text responses about experiences and suggestions for the project were analysed using thematic analysis.

ResultsParticipants had a small, but statistically significant improvement, in wellbeing equating to 0.21 standard deviations (SD) (95% CI: 0.12 to 0.30) after taking part in the project, as well as improvements in loneliness, sense of belonging and hope. How lonely a participant was at baseline and whether participants both sent and received a kindness card were not associated with improvements in wellbeing. In the qualitative analysis, a desire to help others emerged as the main motivator to take part in the card exchange. Participants reported enhanced personal fulfilment, leading to improvements in wellbeing. Receiving a card could make people feel special and cherished, which was reported to establish a sense of connection with others, with potential benefits for reducing loneliness.

ConclusionsThis study provided preliminary evidence that the KBP project might improve wellbeing, loneliness, sense of belonging and hope. Sending a kindness card in this project played a predominant role in wellbeing enhancement, and receiving a kindness card could reduce loneliness. This study suggests that the KBP project can be replicated in more contexts in the future, and might improve wellbeing and loneliness in large communities.

category: public and global health


title: Polygenic Risk Scores for Prediction of Breast Cancer in Korean women

abstract:
BackgroundPolygenic risk scores (PRS) developed in large European GWAS have been shown to predict breast cancer risk in European-ancestry women and perform well in Asian women relative to PRS developed in smaller Asian studies. However, prospective validation of absolute risk predictions from models combining lifestyle and PRS in Asian women is limited.

ObjectivesHere we evaluate the calibration of four PRS developed using Asian or European training samples; two PRS were restricted to genome-wide significant SNPs (GRS-11ASN and GRS-136EUR) and two included sub-genome-wide significant SNPs (PRS-42ASN and PRS-209EUR). We also assessed the improvement in risk prediction and risk stratification by incorporating the PRS into classical risk factor model.

MethodsFor each PRS, we compared discrimination (area under the curve [AUC]) and calibration (expected-to-observed ratio [E/O]) of three absolute risk models in a cohort of 41,031 women from the Korean Cancer Prevention Study-II Biobank: (i) a model using incidence, mortality, and risk factor distributions among U.S. non-Hispanic white women and European-ancestry relative risks; (ii) a recalibrated model, using Korean incidence mortality and risk factor distributions but European-ancestry relative risks; and (iii) a fully Korean-based model using Korean incidence mortality and risk factor distributions and relative risk estimates from the KCPS.

ResultsAll Asian and European PRS improved risk prediction for breast cancer in Korean women under 50 (Qx: AUC=0.65, Qx+PRS-42ASN: AUC=0.68, Qx+PRS-209EUR: AUC=0.69 in Korean-based model for age<50). European PRS had larger effect sizes and greater discrimination than Asian PRS in a Korean population (PRS-42ASN: HR per SD = 1.40, AUC = 0.60 vs. PRS-209EUR: HR per SD = 1.54, AUC = 0.62). We found that the U.S.-based absolute risk models overestimated the risks for women age [≥]50 years (PRS-42ASN: E/O=1.93, 95% CI=1.69, 2.19, PRS-209EUR: E/O = 1.92, 95% CI=1.69, 2.19). Our absolute risk projections suggest that risk-reducing lifestyle changes would lead to larger absolute risk reductions among women at higher PRS.

ConclusionsIncorporation of PRS previously developed in Asian and European-ancestry populations can improve discrimination in Korean women. Our finding suggests that PRS may be useful for prioritizing individuals for targeted intervention on their lifestyle such as alcohol intake and obesity. Larger Asian training samples should improve PRS discrimination among Korean women. Further studies are needed to evaluate the value of incorporating PRS into risk models in ancestrally diverse populations.

category: genetic and genomic medicine


title: Uptake of Covid-19 vaccines among frontline workers in California state prisons

abstract:
BackgroundPrisons are high-risk environments for Covid-19. Vaccination levels among prison staff remain troublingly low - lower than levels among residents and members of the surrounding community. The situation is troubling because prison staff are a key vector for Covid-19 transmission.

ObjectiveTo assess patterns and timing of staff vaccination in California state prisons and identify individual- and community-level factors associated with being unvaccinated.

DesignWe calculated fractions of prison staff and incarcerated residents in California state prisons who remained unvaccinated. Adjusted analyses identified demographic, community, and peer factors associated with vaccination uptake among staff.

SettingCalifornia Department of Corrections and Rehabilitation prisons.

ParticipantsCustody and healthcare staff who worked in direct contact with residents.

Main Outcomes and MeasuresRemaining unvaccinated through June 30, 2021.

ResultsA total of 26% of custody staff and 52% of healthcare staff took [≥]1 dose in the first two months of vaccine offer; uptake stagnated thereafter. By June 30, 2021, 61% of custody and 37% of healthcare staff remained unvaccinated. Remaining unvaccinated was positively associated with younger age, prior Covid-19, residing in a community with relatively low vaccination rates, and sharing shifts with co-workers who had relatively low vaccination rates.

Conclusions and RelevanceVaccine uptake among prison staff in California in regular contact with incarcerated residents has plateaued at levels that pose ongoing risks--both of further outbreaks in the prisons and transmission into surrounding communities. Staff decisions to forego vaccination appear to be complex and multifactorial. Achieving safe levels of vaccine protection among frontline staff may necessitate requiring vaccination as condition of employment.

category: health policy


title: The clinical efficacy of faecal microbiota transplantation: An umbrella review of randomized controlled trials

abstract:
INTRODUCTIONFaecal microbiota transplantation (FMT) therapeutic strategy has been associated with positive outcomes in multiple diseases. We conducted an umbrella review of the meta-analysis to summarize the available evidence and assess its credibility.

METHODSWe evaluated a meta-analysis of randomized controlled trials that investigated the efficacy and safety of FMT for any condition. We used the random-effects model to obtain estimates and corresponding 95% confidence intervals, heterogeneity estimates, and small-study effects. We used AMSTAR 2 to assess methodological quality and GRADE tools to grade the evidence.

RESULTSSeven meta-analyses with a total of 33 outcomes were included in the current umbrella review to evaluate the efficacy and safety of FMT. Overall, there is a moderate certainty of evidence supporting the associations of the use of FMT with better clinical remission in patients with Clostridium difficile infection (RR = 1.74; 95% CI: 1.37-2.22) and inflammatory bowel disease (RR = 1.70; 95% CI: 1.12-2.56). A very low certainty evidence supports the use of FMT to treat antibiotic-resistant bacteria (RR = 5.67; 95% CI: 2.20-14.63) and functional constipation (RR = 1.35; 95% CI: 1.14-1.60) but does not support irritable bowel syndrome (RR = 1.08; 95% CI: 0.65-1.77).

DISCUSSIONThe umbrella review of the current meta-analysis demonstrates that FMT intervention is associated with positive outcomes for several diseases. However, the credibility of the evidence is not high. Further high-quality randomized controlled trials should be carried out to improve the strength and credibility of the evidence base.


title: Understanding the interrelationships of type-2 diabetes and hypertension with brain and cognitive health: a UK Biobank study

abstract:
Aims/hypothesisDiabetes and hypertension are associated with poorer cognitive and brain health. Less is known about comorbid diabetes and hypertension and: cognitive and brain health in mid-life. We hypothesised that individuals with both diabetes and hypertension have worse cognitive and brain health.

MethodsWe used the UK Biobank cohort, a population-based study which recruited 500,000 individuals, aged 40-69 years. Type-2 diabetes was assigned using self-report, HbA1c and clinical data, while hypertension was defined based on self-report. Our outcomes included a breadth of brain structural magnetic resonance imaging (MRI) parameters and cognitive function tests in a maximum of 38918 individuals. We tested associations in a cross sectional design firstly between those with diabetes (n = 2043) versus those without (reference category, n = 36875) then we tested associations between comorbid diabetes/hypertension (reference category, n=1283) and our outcomes by comparing this group with those with only diabetes (n=760), hypertension (n=9649) and neither disease (n=27226). Our analytical approach comprised linear regression models, with adjustment for a range of demographic and health factors.

ResultsThose with diabetes had worse overall brain health, as indexed by multiple neuroimaging parameters, with the exception of gFA (white matter integrity) and the amygdala. The largest difference was observed in the pallidum ({beta}=0.179, 95%CI=0.137;0.220). Individuals with diabetes had poorer performance on certain cognitive tests, with the largest difference observed in the symbol digit substitution test ({beta}=0.132, 95%CI=0.079;0.187). Compared to individuals with comorbid diabetes and hypertension, those with only hypertension had better brain health overall, with the largest difference observed in the pallidum ({beta}=0.189, 95%CI=0.241;0.137), while those with only diabetes differed in total grey volume ({beta}=0.150, 95%CI=0.122;0.179). Compared with individuals who had comorbid diabetes and hypertension, those with only diabetes performed distinctly better on the verbal and numeric reasoning task ({beta}=0.129, 95%CI=0.077;0.261), whereas those with only hypertension performed better on the symbol digit substitution task ({beta}=0.117, 95%CI=0.048;0.186)

Conclusions/interpretationIndividuals with comorbid diabetes and hypertension have worse brain and cognitive health compared to those with only one of these diseases. These findings potentially suggest that prevention of both diabetes and hypertension may delay changes in brain structure, as well as cognitive decline and dementia diagnosis.

Research in contextO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIDiabetes and hypertension are both independently associated with poorer brain health, cognition and increase in dementia risk
C_LIO_LI50% of adults with diabetes also have hypertension
C_LIO_LIComorbid diabetes and hypertension are associated with excess dementia risk
C_LI

What is the key question?O_LIDo individuals with both diabetes and hypertension have worse cognitive and brain health?
C_LI

What are the new findings?O_LIIndividuals with diabetes have poorer brain health and cognitive performance using a breadth of neuroimaging measures and cognitive tests
C_LIO_LIThose with both diabetes and hypertension have worse brain health and cognitive performance (particularly processing speed) compared to those with only hypertension
C_LI

How might this impact on clinical practice in the foreseeable future?O_LIPrevention of both diabetes and hypertension may help delay changes in brain structure and cognitive decline as well as reduce future dementia risk.
C_LI

category: endocrinology


title: Economic evaluation of a cluster randomized, non-inferiority trial of differentiated service delivery models of HIV treatment in Zimbabwe

abstract:
BackgroundAbout 85% of Zimbabwes >1.4 million people living with HIV are on antiretroviral treatment (ART). Further expansion of its treatment program will require more efficient use of existing resources. Two promising strategies for reducing resource utilization per patient are multi-month medication dispensing and community-based service delivery. We evaluated the costs to providers and patients of community-based, multi-month ART delivery models in Zimbabwe.

MethodsWe used resource and outcome data from a cluster-randomized non-inferiority trial of three differentiated service delivery (DSD) models targeted to patients stable on ART: 3-month facility-based care (3MF), community ART refill groups (CAGs) with 3-month dispensing (3MC), and CAGs with 6-month dispensing (6MC). Using local unit costs, we estimated the annual cost in 2020 USD of providing HIV treatment per patient from the provider and patient perspectives.

ResultsIn the trial, retention at 12 months was 93.0% in the 3MF, 94.8% in the 3MC, and 95.5% in the 6MC arms. The total average annual cost of HIV treatment per patient was $187 (standard deviation $39), $178 ($30), and $167 ($39) in each of the three arms, respectively. The annual cost/patient was dominated by ART medications (79% in 3MF, 87% in 3MC; 92% in 6MC), followed by facility visits (12%, 5%, 5%, respectively) and viral load (8%, 8%, 2%, respectively). When costs were stratified by district, DSD models cost slightly less, with 6MC the least expensive in all districts. Savings were driven by differences in the number of facility visits made/year, as expected, and low uptake of annual viral load tests in the 6-month arm. The total annual cost to patients to obtain HIV care was $10.03 ($2) in the 3MF arm, $5.12 ($0.41) in the 3MC arm, and $4.40 ($0.39) in the 6MF arm.

ConclusionsFor stable ART patients in Zimbabwe, 3- and 6-month community-based multi-month dispensing models cost less for both providers and patients than 3-month facility-based care and had non-inferior outcomes.

category: health economics


title: Trajectories: a framework for detecting temporal clinical event sequences from health data standardized to the OMOP Common Data Model

abstract:
ObjectiveTo develop a framework for identifying prominent clinical event trajectories from OMOP-formatted observational healthcare data.

MethodsA four-step framework based on significant temporal event pair detection is described and implemented as an open-source R package. It is used on a population-based Estonian dataset to first replicate a large Danish population-based study and second, to conduct a disease trajectory detection study for Type 2 Diabetes patients in the Estonian and Dutch databases as an example.

ResultsAs a proof of concept, we apply the methods in the Estonian database and provide a detailed breakdown of our findings. All Estonian population-based event pairs are shown. We compare the event pairs identified from Estonia to Danish and Dutch data and discuss the causes of the differences.

ConclusionsFor the first time, there is a complete software package for detecting disease trajectories in health data.

category: health informatics


title: Monitoring of SARS-CoV-2 Antibodies Using Dried Blood Spot for At-Home Collection

abstract: The utilization of vaccines to fight the spread of SARS-CoV-2 has led to a growing need for expansive serological testing. To address this, an EUA approved immunoassay for detection of antibodies to SARS-CoV-2 in venous serum samples was investigated for use with dried blood spot (DBS) samples. Results from self-collected DBS samples demonstrated a 98.1% categorical agreement to venous serum with a correlation (R) of 0.9600 while professionally collected DBS samples demonstrated a categorical agreement of 100.0% with a correlation of 0.9888 to venous serum. Additional studies were performed to stress aspects of at-home DBS collection, including shipping stability, interference effects, and other sample-specific robustness studies. These studies demonstrated a categorical agreement of at least 95.0% and a mean bias less than {+/-}20.0%. Furthermore, the ability to track antibody levels following vaccination with the BioNTech/Pfizer vaccine was demonstrated with self-collected DBS samples from pre-dose (Day 0) out to 19 weeks.


title: Low neutralizing antibody titers against the Mu variant of SARS-CoV-2 in BNT162b2 vaccinated individuals

abstract:
BackgroundGlobal surveillance programs for the virus that causes COVID-19 are showing the emergence of variants with mutations in the Spike protein, including the Mu variant, recently declared a Variant of Interest (VOI) by the World Health Organization. Genomic and laboratory surveillance is important in these types of variants because they may be more infectious or less susceptible to antiviral treatments and vaccine-induced antibodies.

ObjectivesTo evaluate the sensitivity of the Mu variant (B.1.621) to neutralizing antibodies induced by the BNT162b2 vaccine.

Study designThree of the most predominant SARS-CoV-2 variants in Colombia during the epidemiological peaks of 2021 were isolated. Microneutralization assays were performed by incubating 120 TCDI50 of each SARS-CoV-2 isolate with five 2-fold serial dilutions of sera from 14 BNT162b2 vaccinated volunteers. The MN50 titer was calculated by the Reed-Muench formula

ResultsThe three isolated variants were Mu, a Variant of Interest (VOI), Gamma, a variant of concern (VOC), and B.1.111 that lacks genetic markers associated with greater virulence. At the end of August, the Mu and Gamma variants were widely distributed in Colombia. Mu was predominant (49%), followed by Gamma (25%). In contrast, B.1.111 became almost undetectable. The evaluation of neutralizing antibodies suggests that patients vaccinated with BNT162-2 generate neutralizing antibody titers against the Mu variant at significantly lower concentrations relative to B.1.111 and Gamma.

ConclusionsThis study shows the importance of continuing with surveillance programs of emerging variants as well as the need to evaluate the neutralizing antibody response induced by other vaccines circulating in the country against Mu and other variants with high epidemiological impact.

HighlightsO_LIMu and Gamma variants represented 49% and 25% of cases in Colombia by August 2021.
C_LIO_LIIncreased proportion of SARS-COV-2 cases were mostly associated with Mu variant, despite being detected simultaneously with the VOC Gamma
C_LIO_LIThe Mu variant remarkably escapes from neutralizing antibodies elicited by the BNT162b2-vaccine
C_LIO_LILaboratory studies of neutralizing antibodies are useful to determine the efficacy of SARS-CoV-2 vaccines against VOC and VOI.
C_LI


title: Humoral immune response after COVID-19 infection or BNT162b2 vaccine among older adults: evolution over time and protective thresholds.

abstract:
INTRODUCTIONThe objectives of this study were to assess the dynamics of the SARS-CoV-2 anti-RBD IgG response over time among older people after COVID-19 infection or vaccination and its comparison with speculative levels of protection assumed by current data.

METHODSFrom November 2020 to October 2021, we included geriatric patients with serological test results for COVID-19.

We considered antibody titre thresholds thought to be high enough to protect against SARS-CoV-2 infection: 141 BAU/ml for protection/vaccine efficacy > 89.3%.

Three cohorts are presented. A vaccine group (n=34) that received two BNT162b2/Comirnaty injections 21 days apart, a group of natural COVID-19 infection (n=32) and a third group who contracted COVID-19 less than 15 days after the first BNT162b2/Comirnaty injection (n=17).

RESULTS83 patients were included, the median age was 87 (81-91) years.

In the vaccine group at 1 month since the first vaccination, the median BAU/ml with IQR was 620 (217-1874) with 87% of patients above the threshold of 141 BAU/ml. Seven months after the first vaccination the BAU/ml was 30 (19-58) with 9.5% of patients above the threshold of 141 BAU/ml.

In the natural COVID-19 infection group, at 1 month since the date of first symptom onset, the median BAU/ml was 798 (325-1320) with 86.7% of patients above the threshold of 141 BAU/ml and fell to 88 (37-385) with 42.9% of patients above the threshold of 141 BAU/ml at 2 months. The natural infection group was vaccinated three months after the infection. Five months after the end of the vaccination cycle the BAU/ml was 2048 (471-4386) with 83.3% of patients above the threshold of 141 BAU/ml.

DISCUSSIONOn the humoral level, this supports the clinical results describing the decrease in vaccine protection over time.


title: Anti-SARS-CoV-2 antibodies seroprevalence among patients submitted to treatment for tuberculosis in Rio de Janeiro, Brazil: a cross-sectional study.

abstract: Due to tuberculosis (TB) patients pulmonary damages, some authors believe that a SARS-CoV-2 coinfection may result in unfavorable outcomes. A cross-sectional anti-SARS-CoV-2 antibodies seroprevalence study was conducted at a TB treatment tertiary referral unit in Rio de Janeiro, Brazil, to estimate the proportion (in %) of TB patients exposed to the new coronavirus and their main outcomes. Of 83 patients undergoing TB treatment, 26.5% have already been infected by the new coronavirus. Most patients were asymptomatic (69%) or had mild COVID-19 cases (31%). Only one patient required hospitalization. Among the symptoms and signs presented, the most frequently reported were: fever, headache, and myalgia. People with less education and less purchasing power seemed to had been more exposed to SARS-CoV-2.

category: epidemiology


title: The unmitigated profile of COVID-19 infectiousness

abstract: Quantifying the temporal dynamics of infectiousness of individuals infected with SARS-CoV-2 is crucial for understanding the spread of the COVID-19 pandemic and for analyzing the effectiveness of different mitigation strategies. Many studies have tried to use data from the onset of symptoms of infector-infectee pairs to estimate the infectiousness profile of SARS-CoV-2. However, both statistical and epidemiological biases in the data could lead to an underestimation of the duration of infectiousness. We correct for these biases by curating data from the initial outbreak of the pandemic in China (when mitigation steps were still minimal), and find that the infectiousness profile is wider than previously thought. For example, our estimate for the proportion of transmissions occurring 14 days or more after infection is an order of magnitude higher - namely 19% (95% CI 10%-25%). The inferred generation interval distribution is sensitive to the definition of the period of unmitigated transmission, but estimates that rely on later periods are less reliable due to intervention effects. Nonetheless, the results are robust to other factors such as the model, the assumed growth rate and possible bias of the dataset. Knowing the unmitigated infectiousness profile of infected individuals affects estimates of the effectiveness of self-isolation and quarantine of contacts. The framework presented here can help design better quarantine policies in early stages of future epidemics using data from the initial stages of transmission.


title: A study protocol for community use of digital auscultation to improve diagnosis of paediatric pneumonia in Bangladesh

abstract:
IntroductionThe World Health Organisations Integrated Management of Childhood Illnesses (IMCI) algorithm relies on counting respiratory rate and observing respiratory distress to diagnose childhood pneumonia. IMCI performs with high sensitivity but low specificity, leading to over-diagnosis of child pneumonia and unnecessary antibiotic use. Including lung auscultation in IMCI could improve pneumonia diagnosis. Our objectives are: (i) assess lung sound recording quality by primary health care workers (HCWs) from under-five children with the Feelix Smart Stethoscope; and (ii) determine the reliability and performance of recorded lung sound interpretations by an automated algorithm compared to reference paediatrician interpretations.

Methods and analysisIn a cross-sectional design, Community HCWs will record lung sounds of [~]1,000 under-five-year-old children with suspected pneumonia at first-level facilities in Zakiganj sub-district, Sylhet, Bangladesh. Enrolled children will be evaluated for pneumonia, including oxygen saturation, and have their lung sounds recorded by the Feelix Smart stethoscope at four sequential chest locations: two back and two front positions. A novel sound-filtering algorithm will be applied to recordings to address ambient noise and optimize recording quality. Recorded sounds will be assessed against a pre-defined quality threshold. A trained paediatric listening panel will classify recordings into one of the following categories: normal, crackle, wheeze, crackle and wheeze, or uninterpretable. All sound files will be classified into the same categories by the automated algorithm and compared with panel classifications.

ConclusionsLung auscultation and reliable interpretation of lung sounds of children are usually not feasible in first-level facilities in Bangladesh and other low- and middle-income countries (LMICs). Incorporating automated lung sound classification within the current IMCI pneumonia diagnostic algorithm may improve childhood pneumonia diagnostic accuracy at LMIC first-level facilities.

Ethics and disseminationEthical review has been obtained in Bangladesh (BMRC Registration Number: 09630012018) and in Edinburgh, Scotland, United Kingdom (REC Reference: 18-HV-051). Dissemination will be through conference presentations, peer-reviewed journals and stakeholder engagement meetings in Bangladesh.

Trial registration numberNCT03959956

Article summayStrengths and limitations of this study

O_LIEvaluating the quality of lung sound recordings in a first-level facility where auscultation is usually unavailable and challenging to obtain due to a typically crowded and noisy environment and providers may not get enough time to calm the child due to time pressure from a high-volume patient.
C_LIO_LIThis study will assess the feasibility of recording lung sounds by front line community health workers who do not usually use conventional stethoscopes during clinical care.
C_LIO_LITwo standardised paediatricians masked to the childs clinical status will independently classify the recorded lung sounds, and a third masked and independent paediatrician will arbitrate any discrepancies.
C_LIO_LIA machine-learning algorithm developed by Johns Hopkins and Sonavi Labs will detect abnormal lung sounds and be compared with classifications by human listeners/paediatricians.
C_LIO_LIThe study will not have chest radiography findings of enrolled children, which is considered by many a gold standard for pneumonia diagnosis, as chest radiography is not available at this level of the health system in Bangladesh. Instead, this study will measure the peripheral oxyhaemoglobin saturation and evaluate clinical examination findings, including respiratory danger signs data.
C_LI

category: pediatrics


title: Effects of trust, risk perception, and health behavior on COVID-19 disease burden: Evidence from a multi-state US survey

abstract: Early public health strategies to prevent the spread of COVID-19 in the United States relied on non-pharmaceutical interventions (NPIs) as vaccines and therapeutic treatments were not yet available. Implementation of NPIs, primarily social distancing and mask wearing, varied widely between communities within the US due to variable government mandates, as well as differences in attitudes and opinions. To understand the interplay of trust, risk perception, behavioral intention, and disease burden, we developed a survey instrument to study attitudes concerning COVID-19 and pandemic behavioral change in three states: Idaho, Texas, and Vermont. We designed our survey (n = 1034) to detect whether these relationships were significantly different in rural populations. The best fitting structural equation models show that trust indirectly affects protective pandemic behaviors via health and economic risk perception. We explore two different variations of this social cognitive model: the first assumes behavioral intention affects future disease burden while the second assumes that observed disease burden affects behavioral intention. In our models we include several exogenous variables to control for demographic and geographic effects. Notably, political ideology is the only exogenous variable which significantly affects all aspects of the social cognitive model (trust, risk perception, and behavioral intention). While there is a direct negative effect associated with rurality on disease burden, likely due to the protective effect of low population density in the early pandemic waves, we found a marginally significant, positive, indirect effect of rurality on disease burden via decreased trust (p = 0.095). This trust deficit creates additional vulnerabilities to COVID-19 in rural communities which also have reduced healthcare capacity. Increasing trust by methods such as in-group messaging could potentially remove some of the disparities inferred by our models and increase NPI effectiveness.


title: A territory-wide study of arrhythmogenic right ventricular cardiomyopathy patients from Hong Kong

abstract:
BackgroundArrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a hereditary disease characterized by fibrofatty infiltration of the right ventricular myocardium that predisposes affected patients to malignant ventricular arrhythmias, dual-chamber cardiac failure and sudden cardiac death (SCD). The present study aims to investigate the risk of detrimental cardiovascular events in an Asian population of ARVC/D patients, including the incidence of malignant ventricular arrhythmias, new-onset heart failure with reduced ejection fraction (HFrEF), as well as long-term mortality.

Methods and ResultsThis was a territory-wide retrospective cohort study of patients diagnosed with ARVC/D between 1997 and 2019 in Hong Kong. This study consisted of 109 ARVC/D patients (median age: 61 [46-71] years; 58% male). Of these, 51 and 24 patients developed incident VT/VF and new-onset HFrEF, respectively. Five patients underwent cardiac transplantation, and 14 died during follow-up. Multivariable Cox regression identified prolonged QRS duration as a predictor of VT/VF (p < 0.05). Female gender, prolonged QTc duration, the presence of epsilon waves and T-wave inversion (TWI) in any lead except aVR/V1 predicted new-onset HFrEF (P < 0.05. The presence of epsilon waves, in addition to the parameters of prolonged QRS duration and worsening ejection fraction predicted all-cause mortality (p<0.05). Clinical scores were developed to predict incident VT/VF, new-onset HFrEF and all-cause mortality, and all were significantly improved by machine learning techniques.

ConclusionClinical and electrocardiographic parameters are important for assessing prognosis in ARVC/D patients and should in turn be used in tandem to aid risk stratification in the hospital setting.


title: Clinical impact of the rapid molecular detection of RSV and influenza A and B virus in the emergency room

abstract:
IntroductionUsing respiratory viruses rapid diagnostic tests in the emergency room (ER) could allow a better and faster clinical management. Point-of-care PCR instruments provide now results in less than 30 minutes. The objective of this study was to assess the impact of the use of the cobas(R) Influenza A/B & RSV Assay for use on Roches cobas(R) Liat(R) instrument on the clinical management of ER patients.

MethodsPatients (adults and children) requiring admission or suffering from an underlying condition at risk of respiratory complication were prospectively recruited in the ER of four hospitals in the Brussels region. Physicians intentions regarding admission, isolation, antibiotic and antiviral use were collected before and after performing a cobas(R) Influenza A/B & RSV molecular test. Additionally, a comparison of the analytical performance of this test against antigen rapid tests and viral culture was performed as well as a time-to-result evaluation.

ResultsPCR yielded twice more positive results than antigen rapid diagnostic tests. It allowed a decrease in the overall need for isolation and treatment by limiting the isolation of negative patients and the antibiotic use for positive patients. Meanwhile, antiviral treatments better targeted patients with a positive influenza PCR.

ConclusionThe use of a rapid influenza and RSV molecular test improves the clinical management of patients admitted to the ER by providing a fast and reliable result. Their additional cost compared to antigen tests should be balanced with the benefit of their analytical performance, leading to efficient reductions in the need of isolation and antibiotic use.

category: emergency medicine


title: Clinical impact of the rapid molecular detection of RSV and influenza A and B viruses in the emergency department


title: A prospective study of asymptomatic SARS-CoV-2 infection among individuals involved in academic research under limited operations during the COVID-19 pandemic

abstract:
BackgroundEarly in the pandemic, transmission risk from asymptomatic infection was unclear making it imperative to monitor infection in workplace settings. Further, data on SARS-CoV-2 seroprevalence within university populations has been limited.

MethodsWe performed a longitudinal study of University research employees on campus July-December 2020. We conducted questionnaires on COVID-19 risk factors, RT-PCR testing, and SARS-CoV-2 serology using an in-house spike RBD assay, laboratory-based Spike NTD assay, and standard nucleocapsid platform assay. We estimated prevalence and cumulative incidence of seroconversion with 95% confidence intervals using the inverse of the Kaplan-Meier estimator.

Results910 individuals were included in this analysis. At baseline, 6.2% (95% CI 4.29-8.19) were seropositive using the spike RBD assay; four (0.4%) were seropositive using the nucleocapsid assay, and 44 (4.8%) using the Spike NTD assay. Cumulative incidence was 3.61% (95% CI: 2.04-5.16). Six asymptomatic individuals had positive RT-PCR results.

ConclusionsPrevalence and incidence of SARS-CoV-2 infections was low; however differences in target antigens of serological tests provided different estimates. Future research on appropriate methods of serological testing in unvaccinated and vaccinated populations is needed. Frequent RT-PCR testing of asymptomatic individuals is required to detect acute infections, and repeated serosurveys are beneficial for monitoring subclinical infection.


title: Developmental Deconvolution for Classification of Cancer Origin

abstract: Cancer is a disease manifesting in abrogation of developmental programs, and malignancies are named based on their cell or tissue of origin. However, a systematic atlas of tumor origins is lacking. Here we map the single cell organogenesis of 56 developmental trajectories to the transcriptomes of over 10,000 tumors across 33 cancer types. We use this map to deconvolute individual tumors into their constituent developmental trajectories. Based on these deconvoluted developmental programs, we construct a Developmental Multilayer Perceptron (D-MLP) classifier that outputs cancer origin. The D-MLP classifier (ROC-AUC: 0.974 for top prediction) outperforms classification based on expression of either oncogenes or highly variable genes. We analyze tumors from patients with cancer of unknown primary (CUP), selecting the most difficult cases where extensive multimodal workup yielded no definitive tumor type. D-MLP revealed insights into developmental origins and diagnosis for most patient tumors. Our results provide a map of tumor developmental origins, provide a tool for diagnostic pathology, and suggest developmental classification may be a useful approach for otherwise unclassified patient tumors.

category: pathology


title: Symptomatic and asymptomatic transmission of SARS-CoV-2 in K-12 schools, British Columbia, April to June 2021

abstract: We prospectively studied SARS-CoV-2 transmission at schools in an era of Variants of Concern (VoCs), offering all close contacts serial viral asymptomatic testing up to 14 days. Of 229 school close contacts, 3 tested positive (1.3%), of which 2 were detected through asymptomatic testing. Most secondary transmission (90%) occurred in households. Routine asymptomatic testing of close contacts should be examined in the context of local testing rates, preventive measures, programmatic costs, and health impacts of asymptomatic transmission.


title: Cumulative Effects of Resting-state Connectivity Across All Brain Networks Significantly Correlate with ADHD Symptoms

abstract:
BackgroundThe clinical utility of MRI neuroimaging studies of psychopathology has been limited by a constellation of factors--small sample sizes, small effect sizes, and heterogeneity of methods and samples across studies--that hinder generalizability and specific replication. An analogy is early genomics studies of complex traits, wherein a move to large, multi-site samples and a focus on cumulative effects (polygenic scores) led to reproducible and clinically applicable effects from genome-wide association studies. A similar logic in MRI may provide a way to improve reproducibility, precision, and clinical utility for brain-wide MRI association studies.

MethodsPolyneuro scores (PNS) represent the cumulative effect of brain-wide measures--in the present case, resting-state functional connectivity (rs-fcMRI) associated with ADHD symptoms. These scores were constructed and validated using baseline data from the Adolescent Brain Cognitive Development (ABCD, N=5666) study, with a reproducible matched subset as the discovery cohort (N=2801). Association between the PNS and ADHD symptoms was further tested in an independent case-control cohort, the Oregon-ADHD-1000 (N=533).

ResultsThe ADHD PNS was significantly associated with ADHD symptoms in both the ABCD and Oregon cohorts after accounting for relevant covariates (p-values < 0.001). While the strongest effects contributing to the PNS were concentrated among connections involving the default mode and cingulo-opercular networks, the most predictive PNS involved connectivity across all brain networks. These findings were robust to stringent motion thresholds. In the longitudinal Oregon-ADHD-1000, non-ADHD comparison youth had significantly lower ADHD PNS ({beta}=-0.309, p=0.00142) than children with persistent ADHD (met diagnostic criteria at two or more time points from age 7 to 19). The ADHD PNS, however, did not reliably mediate polygenic risk for ADHD. Instead, the PNS and an ADHD polygenic score were independently associated with ADHD symptoms.

ConclusionsA polyneuro risk score representing cumulative ADHD-associated resting-state connectivity was robustly associated with ADHD symptoms in two independent cohorts using distinct sampling designs, yet was independent of polygenic liability for ADHD, suggesting the need to examine environmental influences. The polyneuro score approach holds promise for improving the reproducibility of neuroimaging studies, identifying their clinical utility, and unraveling the complex relationships between brain connectivity and the etiology of behavioral disorders.

category: radiology and imaging


title: Durability of anti-Spike antibodies in the infant after maternal COVID-19 vaccination

abstract: COVID-19 vaccination in pregnancy generates functional anti-Spike IgG antibodies that are known to cross the placenta. However, the durability of vaccine-induced maternal anti-S IgG in infant circulation, and how it compares to durability of antibody from maternal natural infection, is unknown. We quantified anti-S IgG in 92 2-month and 6-month-old infants whose mothers were vaccinated in pregnancy, and in 12 6-month-old infants after maternal natural infection with SARS-CoV-2. In the vaccinated group, 94% (58/62) of infants had detectable anti-S IgG at 2 months, and 60% (18/30) had detectable antibody at 6 months. In contrast, 8% (1/12) of infants born to women infected with SARS-CoV-2 in pregnancy had detectable anti-S IgG at the 6-month timepoint. Vaccination resulted in significantly higher maternal and cord titers at delivery and significantly greater antibody persistence in infants at 6 months, compared to natural infection.

category: obstetrics and gynecology


title: Mutant IDH Inhibitors Induce Lineage Differentiation in IDH-mutant Oligodendroglioma

abstract: Recent data showed promising signs of objective tumor responses in subsets of patients with low grade glioma treated with inhibitors of mutant IDH (IDHi) (1). However, the molecular and cellular underpinnings of such responses are not known. Here, we profiled 6,039 transcriptomes by single-cell or single-nucleus RNA-sequencing isolated from three IDH-mutant oligodendroglioma patients with clinical response to IDHi. Importantly, the tissues were sampled on-drug, four weeks from treatment initiation and our dataset includes a matched pre- and on-treatment sample pair. We integrate our findings with analysis of 8,241 transcriptomes from seven untreated samples, 134 bulk samples from the TCGA and experimental models.(2,3) We find that IDHi treatment induces a robust differentiation towards glial lineages, accompanied by a depletion of stem-like cells and a reduction of cell proliferation. Our study provides the first evidence in patients of the differentiating potential of IDHi on the cellular hierarchies that drive oligodendrogliomas.

category: oncology


title: A pilot randomised prospective comparison of two approaches for tibial nailing using clinical and novel imaging outcome measures - study protocol

abstract:
Fractures of the tibia are frequently treated with an intra-medullary nail. This can be inserted through either a supra-patella or infra-patella surgical incision. Concerns over potential damage to the cartilage of the knee with supra-patella insertion has impacted upon its adoption despite benefits in terms of easier nail placement and potentially reduced blood loss and pain.

This randomised pilot study will use patient reported outcome measures (PROMS) and novel MRI sequences designed to assess damage to the structure of cartilage to compare these two methods of tibial intra-medullary nailing.

Twenty individuals with tibial shaft fractures will be randomised to either method of nail insertion (ten individuals in each arm). MRI scans and PROMS will be used to assess cartilage damage and general function up to 6 months post operatively.

The results of the study will be used to inform a potential multi-centre study.

category: orthopedics


title: Genetic regulation of serum IgA levels and susceptibility to common immune, infectious, kidney, and cardio-metabolic traits

abstract: Immunoglobulin A (IgA) mediates mucosal responses to food antigens and the intestinal microbiome and has a known role in susceptibility to mucosal pathogens, celiac disease, inflammatory bowel disease, and IgA nephropathy. We performed genetic analyses of serum IgA levels in 41,263 individuals of diverse ancestries. We observed unexpected variability in IgA levels across major ancestral populations, with African ancestry being reproducibly associated with higher serum IgA levels compared to other ancestries. The trans-ethnic GWAS analysis identified 20 genome-wide significant loci associated with serum IgA levels, including nine known and 11 novel loci. Systematic co-localization analysis with blood and primary immune cell expression QTLs prioritized candidate genes for 14 of 20 loci. Most GWAS loci encoded genes that produce immune defects and IgA abnormalities when genetically manipulated in mice. We uncovered positive genetic correlations of serum IgA levels with IgA nephropathy, type 2 diabetes and body mass index, as well as negative genetic correlations with celiac disease, inflammatory bowel disease, several infections, and intestinal microbiome diversity. Our findings provide novel insights into the genetic regulation of IgA production and its potential role in human disease.


title: Encounters after Appointments Cancelled Due to COVID-19 in the Veterans Affairs Health Care System

abstract: This statistical brief examines subsequent encounters after a cancellation due to COVID-19 in the Veterans Affairs System. We find that he vast majority of VA patients that had appointments cancelled in mid-March to mid-April of 2020 had another encounter within 180 days. The most common next encounter was a virtual visit with a VA provider on the same day of the original appointment. We also find that patients that saw a provider through VA community care had a lower median time to next encounter.


title: Immunoglobulin G1 Fc glycosylation as an early hallmark of severe COVID-19

abstract:
BackgroundImmunoglobulin G1 (IgG1) effector functions are impacted by the structure of fragment crystallizable (Fc) tail-linked N-glycans. Low fucosylation levels on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein specific (anti-S) IgG1 has been described as a hallmark of severe coronavirus disease 2019 (COVID-19) and may lead to activation of macrophages via immune complexes thereby promoting inflammatory responses, altogether suggesting involvement of IgG1 Fc glycosylation modulated immune mechanisms in COVID-19.

MethodsIn this prospective, observational single center cohort study, IgG1 Fc glycosylation was analyzed by liquid chromatography - mass spectrometry following affinity capturing from serial plasma samples of 159 SARS-CoV-2 infected patients.

FindingsAt baseline close to disease onset, anti-S IgG1 glycosylation was highly skewed when compared to total plasma IgG1. A rapid, general reduction in glycosylation skewing was observed during the disease course. Low anti-S IgG1 galactosylation and sialylation as well as high bisection were early hallmarks of disease severity, whilst high galactosylation and sialylation and low bisection were found in patients with low disease severity. In line with these observations, anti-S IgG1 glycosylation correlated with various inflammatory markers.

InterpretationAssociation of low galactosylation, sialylation as well as high bisection with disease severity suggests that Fc-glycan modulated interactions contribute to disease mechanism. Further studies are needed to understand how anti-S IgG1 glycosylation may contributes to disease mechanism and to evaluate its biomarker potential.

FundingThis project received funding from the European Commissions Horizon2020 research and innovation program for H2020-MSCA-ITN IMforFUTURE, under grant agreement number 721815.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSAntibody glycosylation against the spike (S) protein of patients infected with severe acute respiratory syndrome SARS-CoV-2 has been reported as a potentially important determinant of COVID-19 disease severity. Studies have hitherto focused on afucosylation, a modification on immunoglobulin G1 (IgG) Fc-tail-linked N-glycans that enhances effector functions. Most of these studies featured limited sample numbers or were imperfectly matched with respect to demographic and other important confounding factors. Our lab has contributed to some of these studies, and we additionally searched for research articles on PubMed and Google Scholar from January 2020 to October 2021. To date, only two groups studied anti-S IgG1 glycosylation, which resulted in overall three publications found. However, none of these groups found a severity marker between hospitalized non-ICU and ICU patients or studied dynamic changes. Instead, exclusively fucosylation at the first available timepoint has been associated with disease severity between severely ill inpatients and mild outpatients.

Added value of this studyIn this prospective, observational single center cohort study, we investigated the severity marker potential of anti-S IgG1 glycosylation in severe and mild hospitalized COVID-19 cases, and correlated these findings with numerous inflammation and clinical markers. Our study reveals low galactosylation and sialylation as well as high bisection on anti-S IgG1 as early hallmarks of severe COVID-19, after correction for age and sex effects. In line with these observations, anti-S IgG1 glycosylation correlated with many inflammatory markers. As days since onset is one of the major confounders of anti-S IgG1 glycosylation due to its highly dynamic nature, we additionally confirmed our findings in time-matched patient subgroups. We believe anti-S IgG1 glycosylation may be applicable for patient stratification upon hospitalization.

Implications of all the available evidenceDemographic factors as well as temporal differences should be taken into consideration when analyzing IgG1 glycosylation of COVID-19 patients. Anti-S IgG1 glycosylation is highly dynamic, but is a promising early severity marker in COVID-19.

category: infectious diseases


title: HLA-A*03:01 is associated with increased risk of fever, chills, and more severe reaction to Pfizer-BioNTech COVID-19 vaccination

abstract: COVID-19 vaccines are safe and highly effective, but some individuals experience unpleasant reactions to vaccination. As the majority of adults in the US have received a COVID-19 vaccine this year, there is an unprecedented opportunity to study the genetics of reactions to vaccination via surveys of individuals who are already part of genetic research studies. Here, we have queried 17,440 participants in the Helix DNA Discovery Project and Healthy Nevada Project about their reactions to COVID-19 vaccination. Our GWAS identifies an association between severe difficulties with daily routine after vaccination and HLA-A*03:01. This association was statistically significant only for those who received the Pfizer-BioNTech vaccine (BNT162b2; p=4.70E-11), but showed a trending association in those who received the Moderna vaccine (mRNA-1273; p=0.005) despite similar sample sizes for study. In Pfizer-BioNTech recipients, HLA-A*03:01 was associated with a two-fold increase in risk of severe vaccine reactions. The effect was consistent across ages, sexes, and whether the person had previously had a COVID-19 infection. The reactions experienced by HLA-A*03:01 carriers were driven by associations with chills, fever, fatigue, and in general feeling unwell.


title: COVID-19 management in social care in England: a systematic review of changing policies and newspaper reported staff perspectives.

abstract:
Adult social care has been a major focus of public attention and infection control guidance during the COVID-19 pandemic, with a high mortality both for carers and those receiving care. To protect themselves and others from infection, staff in residential and domiciliary care settings had to quickly adapt to infection control measures that heavily impacted on their working and every-day life, whilst navigating new responsibilities, uncertainties and anxieties. We sought to explore the production and reception of guidance and look at ways these can be adapted to improve the working life of care staff in domiciliary and residential care whilst reducing the risk of SARS-CoV-2 transmission amid this pandemic and of future emerging infections.

We conducted two complementary and integrated systematic reviews of published documents in the pre-vaccination era: (1) National guidance for social care (conducted between 29 July to 28 October 2020), and (2) Newspaper coverage of infection control issues in social care (conducted between 27th July to 10th September 2020).

Three higher order common themes emerged in the integrated systematic review of guidance documents and newspaper articles: a) Testing, b) Personal Protective Equipment, c) Employment. The reviews revealed a sharp disjunction between the content of infection control guidance and its usability and applicability in social care settings. We suggest that infection control guidance needs to be better adapted to social care settings and informed by the sector. The practicalities of care work and care settings need to be at the core of the process for guidance to be relevant and effective. Modes and timings of communications also need to be optimised.


title: Impact of dexamethasone on persistent symptoms of COVID-19: an observational study

abstract:
IntroductionDexamethasone has been shown to reduce mortality for patients hospitalised with acute COVID-19 pneumonia. However, a significant proportion of patients suffer persistent symptoms following COVID-19 and little is known about the longer-term impact of this intervention on symptom burden.

MethodsPatients initially hospitalised with COVID-19 were prospectively recruited to an observational study (April-August 2020) with follow-up at 8 months (Dec 2020-April 2021) post-admission. A review of ongoing symptoms using a standardised systems-based proforma was performed alongside health-related quality of life assessment. In the UK, patients with COVID-19 (requiring oxygen) only received dexamethasone following the pre-print of the RECOVERY trial (June 2020), or as part of randomisation to that trial, allowing for a comparison between patients treated and not treated with dexamethasone.

ResultsBetween April to August 2020, 198 patients were recruited to this observational study. 87 required oxygen and were followed up at 8-months, so were eligible for this analysis. Of these 39 received an inpatient course of dexamethasone (cases) and 48 did not (controls). The groups were well matched at baseline in terms of age, comorbidity and frailty score. Over two-thirds of patients reported at least 1 ongoing symptom at 8-month follow-up. Patients in the dexamethasone group reported fewer symptoms (n=73, 1.9 per patient) than the non-dexamethasone group (n=152, 3.2 per patient) (p = 0.01).

ConclusionsIn conclusion, in this case-control observational study, patients who received oral dexamethasone for hospitalised COVID-19 were less likely to experience persistent symptoms at 8-month follow-up. These are reassuring results for physicians administering dexamethasone to this patient group.


title: A SARS-CoV-2 Delta Variant Containing Mutation in the Probe Binding Region Used for qRT-PCR Test in Japan Exhibited Atypical PCR Amplification and Might Induce False Negative Result

abstract: A recent pandemic of SARS-CoV-2 infection has caused severe health problems and substantially restricted social and economic activities. To cope with such an outbreak, the identification of infected individuals with high accuracy is vital. qRT-PCR plays a key role in the diagnosis of SARS-CoV-2 infection. The N protein-coding region is widely analyzed in qRT-PCR for the diagnosis of SARS-CoV-2 infection in Japan. We recently encountered two cases of SARS-CoV-2-positive specimens showing atypical amplification curves in the qRT-PCR. We performed whole-genome sequencing and found that the virus was a Delta-type variant of SARS-CoV-2 with a single nucleotide mutation in the probe-binding site. To evaluate the extent of spread of the variant in the area, we performed whole viral genome sequencing of samples collected from 61 patients infected with SARS-CoV-2 during the same time and in the same area. There were no other cases with the same mutation, indicating that the variant had not spread in the area. Furthermore, we performed phylogenetic analysis with various SARS-CoV-2 sequences deposited in the public database. Hundreds of variants were reported globally, and one in Japan were found to contain the same mutation. Phylogenetic analysis showed that the variant was very close to other Delta variants endemic in Japan but quite far from the variants containing the same mutation reported from outside Japan, suggesting that the variant would have been sporadically generated in some domestic areas. These findings propose two key points: i) mutations in the region used for SARS-CoV-2 qRT-PCR can cause abnormal amplification curves; therefore, the qRT-PCR result should not just be judged in an automated manner, but also manually checked by the examiner to prevent false-negative results, and ii) various mutations can be generated sporadically and unpredictably; therefore, efficient and robust screening systems are needed to promptly monitor the emergence of de novo variants.


title: Modeling COVID-19 care capacity in a major health system

abstract: Hospital resources, especially critical care beds and ventilators, have been strained by additional demand throughout the COVID-19 pandemic. Rationing of scarce critical care resources may occur when available resource limits are exceeded. However, the dynamic nature of the COVID-19 pandemic and variability in projections of the future burden of COVID-19 infection pose challenges for optimizing resource allocation to critical care units in hospitals. Connecticut experienced a spike in the number of COVID-19 cases between March and June 2020. Uncertainty about future incidence made it difficult to predict the magnitude and duration of the increased COVID-19 burden on the healthcare system. In this paper, we describe a model of COVID-19 hospital capacity and occupancy that generates estimates of the resources necessary to accommodate COVID-19 patients under infection scenarios of varying severity. We present the model structure and dynamics, procedure for parameter estimation, and publicly available web application where we implemented the tool. We then describe calibration using data from over 3,000 COVID-19 patients seen at the Yale-New Haven Health System between March and July 2020. We conclude with recommendations for modeling tools to inform decision-making using incomplete information during future crises.

category: intensive care and critical care medicine


title: Association between Fat-enlarged Axillary Lymph Nodes on Screening Mammography and Cardiometabolic Disease

abstract:
ObjectiveEctopic fat deposition within and around organs is a stronger predictor of cardiometabolic disease status than body mass index. Fat deposition within the lymphatic system is poorly understood. This study examined the association between the prevalence of cardiometabolic disease and ectopic fat deposition within axillary lymph nodes (LNs) visualized on screening mammograms.

MethodsA cross-sectional study was conducted on 834 women presenting for full-field digital screening mammography. The status of fat-infiltrated LNs was assessed based on the size and morphology of axillary LNs from screening mammograms. The prevalence of cardiometabolic disease was retrieved from the electronic medical records, including type 2 diabetes mellitus (T2DM), hypertension, dyslipidemia, high blood glucose, cardiovascular disease, stroke, and non-alcoholic fatty liver disease.

ResultsFat-infiltrated axillary LNs were associated with a high prevalence of T2DM among all women (adjusted odds ratio: 3.92, 95% CI: [2.40, 6.60], p-value < 0.001) and in subgroups of women with and without obesity. Utilizing the status of fatty LNs improved the classification of T2DM status in addition to age and BMI (1.4% improvement in the area under the receiver operating characteristic curve).

ConclusionFat-infiltrated axillary LNs visualized on screening mammograms were associated with the prevalence of T2DM. If further validated, fat-infiltrated axillary LNs may represent a novel imaging biomarker of T2DM in women undergoing screening mammography.


title: Association between Fat-Infiltrated Axillary Lymph Nodes on Screening Mammography and Cardiometabolic Disease


title: Evaluation of a novel direct capture method for virus concentration n wastewater from COVID-19 infectious ward and correlation analysis with the number of inpatients.

abstract: The global outbreak of the SARS-CoV-2 pandemic has increased the focus of Wastewater-based epidemiology (WBE) studies as a tool for understanding the epidemic and risk management. A highly sensitive and rapid method for the virus concentration from wastewater is needed to obtain the accurate information for early detection of SARS-CoV-2 outbreak and epidemic. In this study, we evaluated the efficiency of the direct capture method provided from Promega, based on column adsorption using the wastewater from actual infectious diseases ward. The efficiency of the nucleic acid extraction-purification process was also evaluated by Maxwell(R) RSC instrument (fully automated extraction) and QIAamp Viral RNA mini kit (manual extraction). The obtained SARS-CoV-2 data from wastewater were analyzed with the number of inpatients which is the consideration of the severity and the days of onset. The combination of direct capture and Maxwells method (DC-MW) was suggested to be a highly sensitive and simple method with better concentration efficiency and quantification than other methods. Moreover, the inpatient conditions (severity and days of after onset) should be considered to accurately understand the actual status of the correlation between the number of inpatients and SARS-CoV-2 concentration in wastewater. The highly sensitive method of DC-MW was suggested to assess more actual situation of SARS-CoV-2 shedding into the wastewater.


title: Strategy for a rapid screening and surveillance of SARS-CoV-2 variants by real time RT-PCR: a key tool that allowed control and delay in Delta spread in Cordoba, Argentina

abstract:
BackgroundSARS-CoV-2 variants of concern (VOC) and interest (VOI) present mutations in reference to the original virus, being more transmissible. We implemented a rapid strategy for the screening of SARS-CoV-2 VOC/VOIs using real time RT-PCR and performed monitoring and surveillance of the variants in our region.

Methodsconsecutive real-time RT-PCRs for detection of the relevant mutations/deletions present in the Spike protein in VOC/VOIs (TaqMan SARS-CoV-2 Mutation Panel, Applied Biosystems) were implemented. An algorithm was established and 3941 SARS-CoV-2 RNA samples (Cts<30) obtained from oropharyngeal swabs from infected individuals in Cordoba, Argentina, between January and October 2021, were analyzed.

Resultsthe strategy of choice included a first screening of 3 mutations (N501Y, E484K, L452R) followed by the detection of other mutations/deletions based on the results. The analyses of the samples showed introductions of VOCs Alpha and Gamma in February and March 2021, respectively. Since then, Alpha presented a low to moderate circulation (1.7% of the SARS-CoV-2 currently detected). Gamma showed an exponential increase, with a peak of detection in July (72%), until reaching a current frequency of 41.1%. VOC Delta was first detected in July in travellers and currently represents 35% of detections in the community. VOI Lambda presented a gradual increase, showing a current frequency of 29%.

Conclusionswe report a useful tool for VOC/VOI detection, innovative for Argentina, capable to quickly and cost-effectively monitor currently recognized variants. It was key in the early detection of Delta, being able to implement measures to delay its dissemination.


title: Experiences of staff providing specialist palliative care during COVID-19: A multiple qualitative case study.

abstract:
ObjectivesTo explore the experiences of, and impact on, staff working in palliative care during the COVID-19 pandemic.

DesignQualitative multiple case study using semi-structured interviews between November 2020 and April 2021 as part of the CovPall study. Data were analysed using thematic framework analysis.

SettingOrganisations providing specialist palliative services in any setting.

ParticipantsStaff working in specialist palliative care, purposefully sampled by the criteria of role, care setting and COVID-19 experience.

Main outcome measuresExperiences of working in palliative care during the COVID-19 pandemic.

ResultsFive cases and 24 participants were recruited (n=12 nurses, 4 clinical managers, 4 doctors, 2 senior managers, 1 healthcare assistant, 1 allied healthcare professional). Central themes demonstrate how infection control constraints prohibited and diluted participants ability to provide care that reflected their core values, resulting in experiences of moral distress. Despite organisational, team, and individual support strategies, continually managing these constraints led to a  crescendo effect in which the impacts of moral distress accumulated over time, sometimes leading to burnout. Solidarity with colleagues and making a valued contribution provided  moral comfort for some.

ConclusionsThis study provides a unique insight into why and how healthcare staff have experienced moral distress during the pandemic, and how organisations have responded. Despite their experience of dealing with death and dying, the mental health and well-being of palliative care staff was affected by the pandemic. Organisational, structural, and policy changes are urgently required to mitigate and manage these impacts.

category: palliative medicine


title: GWAS defines pathogenic signaling pathways and prioritizes drug targets for IgA nephropathy

abstract: IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. We performed a genome-wide association study involving 10,146 kidney biopsy-diagnosed IgAN cases and 28,751 matched controls across 17 international cohorts. We defined 30 independent genome-wide significant risk loci jointly explaining 11% of disease risk. A total of 16 loci were novel, including TNFSF4, REL, CD28, CXCL8/PF4V1, LY86, LYN, ANXA3, TNFSF8/15, REEP3, ZMIZ1, RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The SNP-based heritability of IgAN was estimated at 23%. We observed a positive genetic correlation between IgAN and total serum IgA levels, allergy, tonsillectomy, and several infections, and a negative correlation with inflammatory bowel disease. All significant non-HLA loci shared with serum IgA levels had a concordant effect on the risk of IgAN. Moreover, IgAN loci were globally enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. The explained heritability was enriched in the regulatory elements of cells from the immune and hematopoietic systems and intestinal mucosa, providing support for the pathogenic role of extra-renal tissues. The polygenic risk of IgAN was associated with early disease onset, increased lifetime risk of kidney failure, as well as hematuria and several other traits in a phenome-wide association study of 590,515 individuals. In the comprehensive functional annotation analysis of candidate causal genes across genome-wide significant loci, we observed the convergence of biological candidates on a common set of inflammatory signaling pathways and cytokine ligand-receptor pairs, prioritizing potential new drug targets.


title: Persistent Autoimmune Activation and Proinflammatory State in Post-COVID Syndrome

abstract:
BackgroundThe immunopathological pathways enabling post-COVID syndrome (PCS) development are not entirely known. We underwent a longitudinal analysis of patients with COVID-19 who developed PCS aiming to evaluate the autoimmune and immunological status associated with this condition.

MethodsThirty-three patients were included for longitudinal clinical and autoantibody analyses of whom 12 patients were assessed for cytokines and lymphocyte populations. Patients were followed during 7-11 months after acute COVID-19. Autoimmune profile and immunological status were evaluated mainly by enzyme-linked-immunosorbent assays and flow cytometry.

ResultsLatent autoimmunity and overt autoimmunity persisted over time. A proinflammatory state was observed in patients with PCS characterized by upregulated IFN-, TNF-, G-CSF, IL-17A, IL-6, IL-1{beta}, and IL-13, whereas IP-10 was decreased. In addition, PCS was characterized by increased levels of Th9, CD8+ effector T cells, naive B cells, and CD4+ effector memory T cells. Total levels of IgG S1-SARS-CoV-2 antibodies remained elevated over time.

DiscussionThe clinical manifestations of PCS are associated with the persistence of a proinflammatory, and effector phenotype induced by SARS-CoV-2 infection. This long-term persistent immune activation may contribute to the development of latent and overt autoimmunity. Results suggest the need to evaluate the role of immunomodulation in the treatment of PCS.

category: rheumatology


title: Neoantigen DNA vaccines are safe, feasible, and capable of inducing neoantigen-specific immune responses in patients with triple negative breast cancer

abstract:
PURPOSECancer neoantigens are important targets of cancer immunotherapy. Neoantigen vaccines have the potential to induce or enhance highly specific antitumor immune responses with minimal risk of autoimmunity. We have developed a neoantigen DNA vaccine platform capable of efficiently presenting both HLA class I and II epitopes. To test the safety, feasibility and efficacy of this platform, we performed a phase 1 clinical trial in triple negative breast cancer patients with persistent disease following neoadjuvant chemotherapy, a patient population at high risk of disease recurrence.

EXPERIMENTAL DESIGNExpressed somatic mutations were identified by tumor/normal exome sequencing and tumor RNA sequencing. The pVACtools software suite was used to identify and prioritize cancer neoantigens. Neoantigen DNA vaccines were designed and manufactured in an academic GMP facility at Washington University School of Medicine. Neoantigen DNA vaccines were administered via electroporation following completion of standard of care therapy. Safety was measured by clinical and laboratory evaluation. Immune responses were assessed by ELISPOT, flow cytometry and TCR sequencing.

RESULTS18 subjects received three doses of a personalized neoantigen DNA vaccine encoding on average 11 neoantigens per patient (range 4-20). The vaccinations were well tolerated with limited adverse events, primarily related to injection site reactions. Neoantigen-specific immune responses were induced in 16/18 patients as measured by ELISPOT and flow cytometry. At a median follow-up of 36 months, progression-free survival was 87.5% (95% CI: 72.7-100%) in the cohort of vaccinated patients compared to 49% (95% CI: 36.4-65.9%) in a cohort of institutional historical control patients (p=0.011).

CONCLUSIONSNeoantigen DNA vaccines are safe, feasible, and capable of inducing a neoantigen-specific immune response. There is preliminary evidence of improved disease-free survival compared to historical controls.


title: Sensory Impairments and Social Isolation Among Hispanic Older Adults: Towards Culturally Sensitive Measurement of Social Isolation

abstract:
ObjectivesSensory disabilities, including vision disability and hearing disability, increase risk for social isolation, which is associated with multiple negative health outcomes. Existing literature suggests that the cultural value of familism may provide a buffer against social isolation. We examined the longitudinal trajectory of social isolation among Hispanic older adults with self-reported vision disability (SRVD) and self-reported hearing disability (SRHD) and tested a modified measure of social isolation incorporating familism.

MethodsWe compared 8-year trajectories of social isolation among Hispanics (n = 445) and non-Hispanic Whites (n = 4,861) from the National Health and Aging Trends Study. We used structural equation modeling to explore the longitudinal relationships between sensory disability and social isolation while comparing two measures of social isolation.

ResultsSocial isolation increased longitudinally for both groups, with SRVD significantly associated with higher initial levels. Social isolation started and remained higher across time among Hispanics. Using an adjusted measure of social isolation (added familial support), neither initial levels nor trajectories of social isolation differed between Hispanic and non-Hispanic White participants.

DiscussionInitially, Hispanics appeared more socially isolated, reporting less social support from outside the home. Yet, we found that they were more likely to report family social connections. Traditional measures of social isolation focusing on social support outside of the home (neglecting support by family) may lack content validity among Hispanic groups. Culturally sensitive measures of social isolation will be increasingly consequential for future research and health policy to meet the needs of a diverse older population.

category: geriatric medicine


title: Efficacy and safety of pre-exposure of antibiotic prophylaxis for leptospirosis: protocol of a systematic review and meta-analysis

abstract:
IntroductionLeptospirosis is the most widespread zoonosis in the world. It represents a public health problem especially in tropical and subtropical regions, but it is also present in temperate regions. Spirochetes from leptospira genus cause the disease, they affect humans as an intermediate host. About pre-exposure prophylaxis for people at risk, antibiotics such as doxycycline or azithromycin were used to prevent the development of leptospirosis and its related adverse outcomes. However, the evidence about the efficacy and safety of this intervention is limited.

ObjectivesTo determine whether pre-exposure antibiotic administration prevents infection, hospitalization, or mortality from leptospirosis, without causing severe adverse effects.

MethodsWe propose to do a systematic review and meta-analysis. We will search in Pubmed (Medline), Embase.com, Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, Web of Science, LILACS and ClinicalTrials.gov. Individual randomized controlled trials, non-randomized controlled trials, cohorts, and cases-control studies will be included according to the inclusion and exclusion criteria set. The flow chart for selecting studies to be included will be presented in accordance with the PRISMA guide. The methodological quality of the studies will be evaluated by duplicate. Subsequently, the qualitative analysis of the data will be carried out and the feasibility of a quantitative meta-analysis will be evaluated. Finally, a summary of findings table will be presented according to the feasibility of the meta-analysis.

ResultsThe results will be published in a peer-reviewed journal.

ConclusionThis systematic review will sum up-to-date evidence about the efficacy and safety of pre-exposure antibiotic prophylaxis for preventing laboratory-confirmed leptospirosis, hospitalization and mortality.


title: Pragmatic Randomized Trial Assessing the Impact of Digital Health Technology on Quality of Life in Patients With Congestive Heart Failure: Design and Rationale

abstract:
Heart failure is a complex syndrome that contributes significantly to mortality and morbidity in the Unites States. Self-management is an ACC/AHA-recommended management tool for chronic conditions, however, those with congestive heart failure have historically poor compliance, low health literacy, and comorbidities that lead to reduced adherence to therapies and lifestyle modifications. Digital health technologies have the potential to enhance care and improve self-management. This manuscript describes the rationale and challenges of the design and implementation of a pragmatic randomized controlled trial to evaluate the efficacy of three digital health technologies in the management of congestive heart failure. Leveraging the use of a fully electronic enrollment and consent platform, the trial will randomize 200 patients across heart failure clinics in the Yale New Haven Health system to receive either usual care or one of three distinct digital technologies designed to promote self-management and provide critical data to clinicians. Our primary outcome will measure the change in quality of life as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ) at 3 months. Initial recruitment efforts have highlighted the large digital divide in our population of interest. Assessing not only clinical outcomes, but patient usability and ease of clinical integration of digital technologies will prove beneficial in determining the feasibility and success of the integration of such technologies into the healthcare system. Future learnings will illustrate strategies to improve patient engagement with, and integration of, digital health technologies to enhance the patient-clinician relationship.

Clinicaltrials.govNCT04394754

category: cardiovascular medicine


title: Prescribing of antibiotics and other drugs to children from birth to age 5 in the United States: an observational study

abstract:
ObjectivesTo inform efforts to reduce pediatric antibiotic use, we measured cumulative pediatric prescriptions for antibiotics and non-antibiotics and how this varies across geography and patient subgroups.

DesignObservational study.

SettingUnited States, 2008-2018.

Participants207,814 children under age 5 born in the United States between 2008 and 2013 with private medical insurance coverage.

InterventionsNone.

Main outcome measuresStudy outcomes included (1) the cumulative number of prescriptions received per child by age 5, (2) the proportion of these prescriptions that were attributable to respiratory infections, (3) the proportion of children who received at least one prescription by age 5, and (4) the fraction of total prescriptions received by the top 20% of prescription recipients.

ResultsChildren received a mean of 8.21 (95% confidence interval [CI] (8.19, 8.22)) prescriptions for antibiotics and 9.81 (95% CI 9.80, 9.82) prescriptions for non-antibiotics by age five. Most antibiotic prescriptions (64%, 95% CI 63, 65) and many non-antibiotic prescriptions (25%, 95% CI 24, 26) were associated with outpatient visits for respiratory infections. By age 5, 93.8% (95% CI 93.4, 94.2) of children had received at least one antibiotic prescription while 88.3% (95% CI 87.9, 88.7) had received at least one prescription for a non-antibiotic. The top 20% of antibiotic prescription recipients accounted for 50.6% of all antibiotic prescriptions, and the top 20% of non antibiotic prescription recipients accounted for 64.2% of all non-antibiotic prescriptions. Relative to other regions, the South featured higher prescribing rates and earlier time to first prescription.

ConclusionsChildren in the US receive a substantial number of antibiotics and other prescription drugs early in their lives, largely related to respiratory infections.


title: Ignoring transmission dynamics leads to underestimation of the impact of a novel intervention against mosquito-borne disease

abstract: Wolbachia is an intracellular bacterium that many hope could have a major impact on dengue and other mosquito-borne diseases that are notoriously difficult to control. The balance of future investments in Wolbachia versus other public health needs will be informed to a great extent by efficacy estimates from large-scale trials, which can be affected by multiple sources of bias. We used mathematical models to quantify the possible magnitude of these biases, finding that efficacy would have been severely underestimated in a recent trial in Indonesia if the spatial scale of clusters had been smaller than it was. We also identified a previously unrecognized source of bias owing to the coupled nature of transmission dynamics across clusters. This too led to a consistent underestimate of the protection afforded by Wolbachia. Taken together, our findings suggest that this intervention may be even more promising than currently recognized.


title: Electroconvulsive therapy effects on anhedonia and reward circuitry anatomy: a dimensional structural neuroimaging approach

abstract: Anhedonia is a core symptom of major depressive disorder (MDD) resulting from maladaptive reward processing. Electroconvulsive therapy (ECT) appears to be an effective treatment for patients with treatment-resistant depression (TRD). However, no previous neuroimaging studies have taken a dimensional approach to assess whether ECT-induced gray matter (GM) volume changes are specifically related to improvements in anhedonia and positive valence emotional constructs. Here we aimed to assess the relationship between right unilateral (RUL) ECT-induced brain volumetric changes and improvement in anhedonia and reward processing in patients with TRD. We evaluated 15 patients at two time points (before the first ECT session and after acute ECT completion) using magnetic resonance imaging (MRI), clinical scales (i.e., Quick Inventory of Depressive Symptomatology [QIDS] for syndromal depression severity and Snaith-Hamilton Pleasure Scale [SHAPS] for anhedonia) and the Temporal Experience of Pleasure Scale (TEPS) for anticipatory and consummatory experiences of pleasure. Patients with TRD showed a significant improvement in anhedonia symptoms and both anticipatory and consummatory pleasure after RUL ECT completion. Moreover, GM volume increases within the right reward system were related to anhedonia responders and, specifically, improvement in anticipatory (but not consummatory) reward. We highlight the importance of a dimensional and circuit-based approach to understanding target engagement and the mechanism of action of ECT, with the goal to define symptom- and circuit-specific response biomarkers for device neuromodulation therapies.

category: pharmacology and therapeutics