bluuebunny/crossref_metadata_2025 huggingface dataset:
Sensory Impairments and Social Isolation Among Hispanic Older Adults: Towards Culturally Sensitive Measurement of Social Isolation
Authors: Tanner Corinna Trujillo , Yorgason Jeremy B. , Richardson Stephanie , Redelfs Alisha H. , Serrao Hill Melanie M. Y. , White Avalon , Markides Kyriakos S. , Stagg Brian , Ehrlich Joshua R.
Published: November 2021

Objectives

Sensory 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.

Methods

We 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.

Results

Social 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.

Discussion

Initially, 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.
A Deep Learning-based Genome-wide Polygenic Risk Score for Common Diseases Identifies Individuals with Risk
Authors: Peng Jiajie , Li Jingyi , Han Ruijiang , Wang Yuxian , Han Lu , Peng Jinghao , Wang Tao , Hao Jianye , Shang Xuequn , Wei Zhongyu
Published: November 2021

Identifying individuals at high risk in the population is a key public health need. For many common diseases, individual susceptibility may be influenced by genetic variation. Recently, the clinical potential of polygenic risk score (PRS) has attracted widespread attention. However, the performance of traditional methods is limited in fitting capabilities of the linear model and unable to capture the interaction information between single nucleotide polymorphisms (SNPs). To fill this gap, a novel deep-learning-based model named DeepPRS is developed for scoring the risk of common diseases with genome-wide genotype data. Using the UK Biobank dataset, the evaluation shows that DeepPRS performs better than the other two existing state-of-art methods on Alzheimer’s disease, inflammatory bowel disease, type 2 diabetes and breast cancer. Since DeepPRS does not only rely on the addictive effect of risk SNPs, DeepPRS has the chance to identify high-risk individuals even with few known risk SNPs.
SARS-CoV-2 testing in the community: Testing positive samples with the TaqMan SARS-CoV-2 Mutation Panel to find variants in real-time
Authors: Ashford Fiona , Best Angus , Dunn Steven , Ahmed Zahra , Siddiqui Henna , Melville Jordan , Wilkinson Samuel , Mirza Jeremy , Cumley Nicola , Stockton Joanna , Ferguson Jack , Wheatley Lucy , Ratcliffe Elizabeth , Casey Anna , Plant Tim ,   The COVID-19 Genomics UK (COG-UK) Consortium, Quick Joshua , Richter Alex , Loman Nicolas , McNally Alan
Published: November 2021

Genome sequencing is a powerful tool for identifying SARS-CoV-2 variant lineages, however there can be limitations due to sequence drop-out when used to identify specific key mutations. Recently, Thermo Fisher Scientific have developed genotyping assays to help bridge the gap between testing capacity and sequencing capability to generate real-time genotyping results based on specific variants. Over a 6-week period during the months of April and May 2021, we set out to assess the Thermo Fisher TaqMan Mutation Panel Genotyping Assay, initially for three mutations of concern and then an additional two mutations of concern, against SARS-CoV-2 positive clinical samples and the corresponding COG-UK sequencing data. We demonstrate that genotyping is a powerful in-depth technique for identifying specific mutations, an excellent complement to genome sequencing and has real clinical health value potential allowing laboratories to report and action variants of concern much quicker.
Krebs von den Lungen 6 levels in COVID-19 ICU Patients are Associated with Mortality
Authors: Scarpati Giuliana , Baldassarre Daniela , Lacava Graziella , Oliva Filomena , Pascale Gabriele , Boffardi Massimo , Pagliano Pasquale , Calabrese Vincenzo , Tripepi Giovanni L. , Piazza Ornella
Published: November 2021

abstract

Rationale

Krebs von den Lungen 6 (KL-6) is a high molecular weight mucin-like glycoprotein produced by type II pneumocytes and bronchial epithelial cells. Elevated circulating levels of KL-6 may denote disorder of the alveolar epithelial lining.

Objective

Aim of this study was to verify if KL-6 values may help to risk stratify and triage severe COVID-19 patients.

Methods

We performed a retrospective prognostic study on 110 COVID-19 ICU patients, evaluating the predictive role of KL-6 for mortality.

Measurements and Main Results

The study sample was divided in two groups related according to the median KL-6 value [Group A (KL-6 lower than the log-transformed median (6.73)) and Group B (KL-6 higher than the log-transformed median)]. In both linear and logistic multivariate analyses, ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (P/F) was significantly and inversely related to KL-6. Death rate was higher in group B than in group A (80.3 versus 45.9%) (p<0.001), Accordingly, the Cox regression analysis showed a significant prognostic role of KL-6 on mortality in the whole sample as well as in the subgroup with SOFA lower than its median value.

Conclusions

At ICU admission, KL-6 serum level was significantly lower in the survivors group. Our findings shown that, in severe COVID19 patients, elevated KL-6 was strongly associated with mortality in ICU.
SeroTracker-RoB: a decision rule-based algorithm for reproducible risk of bias assessment of seroprevalence studies
Authors: Bobrovitz Niklas , Noël Kim , Li Zihan , Cao Christian , Deveaux Gabriel , Selemon Anabel , Clifton David A. , Yanes-Lane Mercedes , Yan Tingting , Arora Rahul K.
Published: November 2021

Background

Risk of bias (RoB) assessments are a core element of evidence synthesis but can be time consuming and subjective. We aimed to develop a decision rule-based algorithm for RoB assessment of seroprevalence studies.

Methods

We developed the SeroTracker-RoB algorithm. The algorithm derives seven objective and two subjective critical appraisal items from the Joanna Briggs Institute Critical Appraisal Checklist for Prevalence studies and implements decision rules that determine study risk of bias based on the items. Decision rules were validated using the SeroTracker seroprevalence study database, which included non-algorithmic RoB judgements from two reviewers. We quantified efficiency as the mean difference in time for the algorithmic and non-algorithmic assessments of 80 randomly selected articles, coverage as the proportion of studies where the decision rules yielded an assessment, and reliability using intraclass correlations comparing algorithmic and non-algorithmic assessments for 2,070 articles.

Results

A set of decision rules with 61 branches was developed using responses to the nine critical appraisal items. The algorithmic approach was faster than non-algorithmic assessment (mean reduction 2.32 minutes [SD 1.09] per article), classified 100% (n=2,070) of studies, and had good reliability compared to non-algorithmic assessment (ICC 0.77, 95% CI 0.74-0.80). We built the SeroTracker-RoB Excel Tool which embeds this algorithm for use by other researchers.

Conclusions

The SeroTracker-RoB decision-rule based algorithm was faster than non-algorithmic assessment with complete coverage and good reliability. This algorithm enabled rapid, transparent, and reproducible RoB evaluations of seroprevalence studies and may support evidence synthesis efforts during future disease outbreaks. This decision rule-based approach could be applied to other types of prevalence studies.
Enhancing Cognitive Restructuring with Concurrent fMRI-guided Neurostimulation for Emotional Dysregulation: A Randomized Controlled Trial
Authors: Neacsiu Andrada D. , Beynel Lysianne , Graner John L. , Szabo Steven T. , Appelbaum Lawrence G. , Smoski Moria J. , LaBar Kevin S.
Published: November 2021

Background

Transdiagnostic clinical emotional dysregulation is a key component of psychopathology and offers an avenue to address multiple disorders with one transdiagnostic treatment. In the current study, we pilot a one-time intervention that combines cognitive restructuring (CR) with repetitive transcranial magnetic stimulation (rTMS), targeted using functional magnetic resonance imaging (fMRI).

Methods

Thirty-seven clinical adults with high emotional dysregulation were enrolled in this randomized, double-blind, placebo-controlled trial. fMRI was collected as participants were reminded of lifetime stressors and asked to downregulate their distress using CR tactics. fMRI BOLD data were analyzed to identify the cluster of voxels within the left dorsolateral prefrontal cortex (dlPFC) with the highest activation when participants attempted to downregulate, versus passively remember, distressing memories. Participants underwent active or sham rTMS (10 Hz) over the target while practicing CR following autobiographical emotional induction.

Results

Receiving active versus sham rTMS led to significantly higher high frequency heart rate variability during regulation, lower regulation duration, and higher likelihood to use CR during the week following the intervention. There were no differences between conditions when administering neurostimulation without CR compared to sham. Participants in the sham versus active condition experienced less distress the week after the intervention. There were no differences between conditions at the one-month follow up.

Conclusion

This study demonstrated that combining active rTMS with emotion regulation training significantly enhances emotion regulation and augments the impact of training for as long as a week. These findings are a promising step towards a combined intervention for transdiagnostic emotion dysregulation.
Integrated multi-omics data analysis identifies a novel genetics-risk gene ofIRF4associated with prognosis of oral cavity cancer
Authors: Lv Yan , Huang Yukuang , Xu Xuejun , Wang Zhiwei , Yu Yanfang , Ma Yunlong , Wu Mengjie
Published: November 2021

Background

Oral cavity cancer (OCC) is one of the most common carcinoma diseases. Recent genome-wide association studies (GWAS) have reported numerous genetic variants associated with OCC susceptibility. However, the regulatory mechanisms of these genetic variants underlying OCC remain largely unclear.

Objective

This study aimed to identify OCC-related genetics risk genes contributing to the prognosis of OCC.

Methods

By combining GWAS summary statistics (N = 4,151) with expression quantitative trait loci (eQTL) across 49 different tissues from the GTEx database, we performed an integrative genomics analysis to uncover novel risk genes associated with OCC. By leveraging various computational methods based on multi-omics data, risk genes were prioritized as promising candidate genes for drug repurposing in OCC.

Results

Using two independent computational algorithms, we found that 14 risk genes whose genetics-modulated expressions showed a notable association with OCC. Among them, nine genes were newly identified, such asIRF4(P = 2.5×10-9and P = 1.06×10-4), TNS3(P = 1.44×10-6and P = 4.45×10-3), ZFP90(P = 2.37×10-6and P = 2.93×10-4), andDRD2(P = 2.0×10-5and P = 6.12×10-3).

These 14 genes were significantly overrepresented in several cancer-related terms, and 10 of 14 genes were enriched in 10 potential druggable gene categories. Based on differential gene expression analysis, the majority of these genes (71.43%) showed remarkable differential expressions between OCC patients and paracancerous controls. Integration of multi-omics-based evidence from genetics, eQTL, and gene expression, we identified that the novel risk gene ofIRF4exhibited the highest ranked risk score for OCC. Survival analysis showed that dysregulation ofIRF4expression was significantly associated with cancer patients outcomes (P = 8.1×10-5).

Conclusions

In summary, we prioritized 14 OCC-associated genes with nine novel risk genes, especially theIRF4gene, which provides a drug repurposing resource to develop therapeutic drugs for oral cancer.
Causal Inference and COVID-19 Nursing Home Patients: Identifying Factors That Reduced Mortality Risk
Authors: Ahmed Amina , Goldberg Robert , Swiader Joseph , Wintrob Zachary A.P. , Yilmaz Margaret
Published: November 2021

Less than 1% of the US population lives in long-term care facilities, yet this subset of the population accounts for 22% of total COVID-19 related deaths.1 Because of a lack of experimental evidence to treat COVID-19, analysis of real-world data to identify causal relationships between treatments/policies to mortality and morbidity among high-risk individuals is critical. We applied causal inference (CI) analysis to longitudinal patient-level health data of 4,091 long-term care high-risk patients with COVID-19 to determine if any actions or therapies delivered from January to August of 2020 reduced COVID-19 patient mortality rates during this period.

Causal inference findings determined that certain supportive care interventions caused reduced mortality rates for nursing home residents regardless of severity of disease (as measured by oxygen saturation level, presence of pneumonia and organ failure), comorbidities or social determinants of health such as race, age, and weight.2 While we do not address the biological mechanisms associated with specific medical interventions and their impact on mortality, this analysis suggests methods to validate and optimize treatment protocols using domain knowledge and causal inference analysis of real-world data across patient populations and care settings.
Failure of Concentric Regulatory Zones to Halt the Spread of COVID-19 in South Brooklyn, New York: October-November 2020
Authors: Harris Jeffrey E.
Published: November 2021

We relied on reports of confirmed case incidence and test positivity, along with data on the movements of devices with location-tracking software, to evaluate a novel scheme of three concentric regulatory zones introduced by then New York Governor Cuomo to address an outbreak of COVID-19 in South Brooklyn in the fall of 2020. The regulatory scheme imposed differential controls on access to eating places, schools, houses of worship, large gatherings and other businesses within the three zones, but without restrictions on mobility. Within the central red zone, COVID-19 incidence temporarily declined from 131.2 per 100,000 population during the week ending October 3 to 62.5 per 100,000 by the week ending October 31, but then rebounded to 153.6 per 100,000 by the week ending November 28. Within the intermediate orange and peripheral yellow zones combined, incidence steadily rose from 28.8 per 100,000 during the week ending October 3 to 109.9 per 100,000 by the week ending November 28. Data on device visits to pairs of eating establishments straddling the red-orange boundary confirmed compliance with access controls. More general analysis of device movements showed stable patterns of mobility between and beyond zones unaffected by the Governor’s orders. A geospatial regression model of COVID-19 incidence in relation to device movements across zip code tabulation areas identified a cluster of five high-mobility ZCTAs with estimated reproduction number 1.91 (95% confidence interval, 1.27-2.55). In the highly populous area of South Brooklyn, controls on access alone, without restrictions on mobility, were inadequate to halt an advancing COVID-19 outbreak.
Very high relative seroprevalence of anti-SARS-CoV-2 antibodies among communities in Bangui, Central African Republic
Authors: Manirakiza Alexandre , Malaka Christian , Yambiyo Brice Martial , Diemer Saint-Calver Henri , Longo Jean de Dieu , Namseneï Joella , Coti-Reckoundji Cathy Sandra Gomelle , Bouhouda Modeste , Darnycka Belizaire Marie Roseline , Roungou Jean Baptiste , Komas Narcisse Patrice , Grésenguet Gérard , Vernet Guy , Vernet Marie-Astrid , Nakoune Emmanuel
Published: November 2021

Background

Large-scale population-based seroprevalence studies of SARS-CoV-2 are essential to characterize the cumulative incidence of SARS-CoV-2 infection and to extrapolate the prevalence of presumptive immunity at the population level.

Objective

The objective of our survey was to estimate the cumulative population immunity for COVID-19 and to identify individual characteristics associated with a positive serostatus.

Method

This was a clustered cross-sectional study conducted from July 12 to August 20, 2021, in households in the city of Bangui, the capital of the Central African Republic. Information regarding demographic characteristics (age, gender, and place of residence), comorbidities (chronic diseases) was collected. A venous blood sample was obtained for each participant to determine the level of total anti-SARS-CoV-2 antibodies using a WANTAI SARS-CoV-2 Ab ELISA kit.

Results

All up, 799 participants were surveyed. The average age was 27 years, and 45·8% of the respondents were male (sex ratio: 0.8). The overall proportion of respondents with a positive serostatus was 74·1%. Participants over 20 years of age were twice as likely to have a positive serostatus, with an OR of 2.· ·2 (95% CI: [1·6, 3·1]).

Interpretation

The results of this survey revealed a high cumulative level of immunity in Bangui, thus indicating a significant degree of spread of SARS-CoV-2 in the population. The public health implications of this high level of immunity to SARS-CoV-2, particularly on its variants burden, remain to be determined.

Funding

This study was funded by the French Ministry for Europe and Foreign Affairs through the REPAIR COVID-19-Africa project coordinated by the Pasteur International Network association.
Interpretation of mendelian randomization using one measure of an exposure that varies over time
Authors: Morris Tim T , Heron Jon , Sanderson Eleanor , Smith George Davey , Tilling Kate
Published: November 2021

Background

Mendelian randomization (MR) is a powerful tool through which the causal effects of modifiable exposures on outcomes can be estimated from observational data. Most exposures vary throughout the life course, but MR is commonly applied to one measurement of an exposure (e.g., weight measured once between ages 40 and 60). It has been argued that MR provides biased causal effect estimates when applied to one measure of an exposure that varies over time.

Methods

We propose an approach that emphasises the liability that causes the entire exposure trajectory. We demonstrate this approach using simulations and an applied example.

Results

We show that rather than estimating the direct or total causal effect of changing the exposure value at a given time, MR estimates the causal effect of changing the liability as induced by a specific genotype that gives rise to the exposure at that time. As such, results from MR conducted at different time points are expected to differ (unless the liability of exposure is constant over time), as we demonstrate by estimating the effect of BMI measured at different ages on systolic blood pressure.

Conclusions

Practitioners should not interpret MR results as timepoint-specific direct or total causal effects, but as the effect of changing the liability that causes the entire exposure trajectory. Estimates of how the effects of a genetic variant on an exposure vary over time are needed to interpret timepoint-specific causal effects.
Glutamate-Weighted Magnetic Resonance Imaging (GluCEST) Detects Effects of Transcranial Magnetic Stimulation to the Motor Cortex
Authors: Cember Abigail T.J. , Deck Benjamin L. , Kelkar Apoorva , Faseyitan Olu , Zimmerman Jared P. , Erickson Brian , Elliott Mark A. , Coslett H. Branch , Hamilton Roy H. , Reddy Ravinder , Medaglia John D.
Published: November 2021

Transcranial magnetic stimulation (TMS) is used in several FDA-approved treatments and, increasingly, to treat neurological disorders in off-label uses. However, the mechanism by which TMS causes physiological change is unclear, as are the origins of response variability in the general population. Ideally, objective in vivo biomarkers could shed light on these unknowns and eventually inform personalized interventions. Continuous theta burst stimulation (cTBS) is a form of TMS which has been observed to reduce motor evoked potentials (MEPs) for 60 minutes or longer post-stimulation, although the consistency of this effect and its mechanism continue to be under debate. Here, we use glutamate-weighted chemical exchange saturation transfer (gluCEST) magnetic resonance imaging (MRI) at ultra-high magnetic field (7T) to measure changes in glutamate concentration at the site of cTBS. We find that gluCEST signal in the ipsilateral hemisphere of the brain generally decreases in response to cTBS, whereas consistent changes were not detected in the contralateral or in subjects receiving a sham stimulation.

One Sentence Summary

We used glutamate-weighted Chemical Exchange Saturation Transfer (GluCEST) imaging to detect changes in glutamate contrast in the brains of young, healthy adults undergoing transcranial magnetic stimulation (TMS) to the motor cortex.
Neoantigen DNA vaccines are safe, feasible, and capable of inducing neoantigen-specific immune responses in patients with triple negative breast cancer
Authors: Zhang Xiuli , Goedegebuure S. Peter , Myers Nancy B. , Vickery Tammi , McLellan Michael D. , Gao Feng , Sturmoski Mark A. , Chen Michael Y. , Kim Samuel W. , Chen Ina , Davidson Jesse T , Sankpal Narendra V. , Hundal Jasreet , Li Lijin , Myles Stephanie , Suresh Rama , Ma Cynthia X. , Foluso Ademuyiwa , Wang-Gillam Andrea , Davies Sherri , Hagemann Ian , Mardis Elaine R. , Griffith Malachi , Miller Christopher A. , Hansen Ted H. , Fleming Timothy P. , Schreiber Robert D. , Gillanders William E.
Published: November 2021

PURPOSE

Cancer 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 DESIGN

Expressed 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.

RESULTS

18 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).

CONCLUSIONS

Neoantigen 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.
Effectiveness of Vaccination against Reported SARS-CoV-2 Infection in United States Coast Guard Personnel between May and August 2021: A Time-Series Analysis
Authors: Iskander John , Frost Jamie , Russell Sharon , Ahluwalia Jaspal , Ward Emily , Steiner Shane , Thomas Dana , Michaud Paul
Published: November 2021

Background

The United States Coast Guard (CG) began voluntary use of SARS-CoV-2 vaccines under an Emergency Use Authorization on December 16, 2020. Vaccination status is monitored through a service-wide immunization registry. Active Duty and Reserve (military) CG members are required to report any new positive test for COVID-19 to a centralized database.

Methods

Between May and August 2021, vaccination effectiveness (VE) against any new report of COVID-19 was calculated according to standard formulas, using registry immunization status of cases and monthly mid-point vaccine coverage data. CG members recorded as fully vaccinated with a two-dose vaccine were compared with those with any other vaccine status. Sub-analyses were also conducted according to geographic area (Atlantic vs Pacific), age, and type of vaccine received.

Results

Effectiveness of full vaccination reached a peak of 89.0% in June, then declined over the rest of the study period to 62.7% in August. In July and August, steeper declines in VE were seen in the Atlantic region. The rate of breakthrough infections remained under 1% in two-dose vaccine recipients, and did not differ between those who received the Moderna or Pfizer vaccines. No hospitalizations or deaths due to COVID-19 disease were recorded in fully vaccinated Coast Guard members.

Conclusion

Coincident with the national spread of the Delta variant of SARS-CoV-2, overall vaccine effectiveness among CG personnel decreased during the summer months of 2021, but continued to provide substantial protection, as well as full protection against the most serious outcomes. Policy initiatives and outreach intended to increase vaccine coverage within this and other military populations could extend the disease prevention benefits seen in this study.
Antibody titers before and after booster doses of SARS-CoV-2 mRNA vaccines in healthy adults
Authors: Demonbreun Alexis R. , Sancilio Amelia , Vaught Lauren A. , Reiser Nina L. , Pesce Lorenzo , McNally Elizabeth M. , McDade Thomas W.
Published: November 2021

Two-dose messenger RNA vaccines (BNT162b2/Pfizer and mRNA-1273/Moderna) against SARS-CoV-2 were rolled out in the US in December 2020, and provide protection against hospitalization and death from COVID-19 for at least six months. Breakthrough infections have increased with waning immunity and the spread of the B.1.617.2 (Delta) variant in summer 2021, prompting approval of boosters for all adults over 18. We measured anti-receptor binding domain (RBD) IgG and surrogate virus neutralization of the interaction between SARS-CoV-2 spike protein and the human angiotensin-converting enzyme (ACE2) receptor, before and after boosters in N=33 healthy adults. We document large antibody responses 6-10 days after booster, with antibody levels that exceed levels documented after natural infection with COVID-19, after two doses of vaccine, or after both natural infection and vaccination. Surrogate neutralization of B.1.617.2 is high but reduced in comparison with wild-type SARS-CoV-2. These data support the use of boosters to prevent breakthrough infections and suggest that antibody-mediated immunity may last longer than after the second vaccine dose.
Longitudinal SARS-CoV-2 RNA Wastewater Monitoring Across a Range of Scales Correlates with Total and Regional COVID-19 Burden in a Well-Defined Urban Population
Authors: Acosta Nicole , Bautista María A. , Waddell Barbara J. , McCalder Janine , Beaudet Alexander Buchner , Man Lawrence , Pradhan Puja , Sedaghat Navid , Papparis Chloe , Bacanu Andra , Hollman Jordan , Krusina Alexander , Southern Danielle , Williamson Tyler , Li Carmen , Bhatnagar Srijak , Murphy Sean , Chen Jianwei , Kuzma Darina , Meddings Jon , Hu Jia , Cabaj Jason L. , Conly John M. , Ruecker Norma J. , Achari Gopal , Ryan M. Cathryn , Frankowski Kevin , Hubert Casey R.J. , Parkins Michael D.
Published: November 2021

Wastewater-based epidemiology (WBE) is an emerging surveillance tool that has been used to monitor the ongoing COVID-19 pandemic by tracking SARS-CoV-2 RNA shed into wastewater. WBE was performed to monitor the occurrence and spread of SARS-CoV-2 from three wastewater treatment plants (WWTP) and six neighborhoods in the city of Calgary, Canada (population 1.3 million). A total of 222 WWTP and 192 neighborhood samples were collected from June 2020 to May 2021, encompassing the end of the first-wave (June 2020), the second-wave (November end to December, 2020) and the third-wave of the COVID-19 pandemic (mid-April to May, 2021). Flow-weighted 24-hour composite samples were processed to extract RNA that was then analyzed for two SARS-CoV-2-specific regions of the nucleocapsid gene, N1 and N2, using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Using this approach SARS-CoV-2 RNA was detected in 98.06 % (406/414) of wastewater samples. SARS-CoV-2 RNA abundance was compared to clinically diagnosed COVID-19 cases organized by the three-digit postal code of affected individuals’ primary residences, enabling correlation analysis at neighborhood, WWTP and city-wide scales. Strong correlations were observed between N1 & N2 gene signals in wastewater and new daily cases for WWTPs and neighborhoods. Similarly, when flow rates at Calgary’s three WWTPs were used to normalize observed concentrations of SARS-CoV-2 RNA and combine them into a city-wide signal, this was strongly correlated with regionally diagnosed COVID-19 cases and clinical test percent positivity rate. Linked census data demonstrated disproportionate SARS-CoV-2 in wastewater from areas of the city with lower socioeconomic status and more racialized communities. WBE across a range of urban scales was demonstrated to be an effective mechanism of COVID-19 surveillance.
Pragmatic Randomized Trial Assessing the Impact of Digital Health Technology on Quality of Life in Patients With Congestive Heart Failure: Design and Rationale
Authors: Victoria-Castro Angela M. , Martin Melissa L. , Yamamoto Yu , Ahmad Tariq , Arora Tanima , Calderon Frida , Desai Nihar R. , Gerber Brett , Lee Kyoung A. , Jacoby Daniel , Melchinger Hannah , Nguyen Andrew , Shaw Melissa M. , Simonov Michael , Williams Alyssa , Weinstein Jason , Wilson F. Perry
Published: November 2021

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.gov

NCT04394754
COVID-19 Vaccine Rollouts and the Reproduction of Urban Spatial Inequality: Disparities Within Large U.S. Cities in March and April 2021 by Racial/Ethnic and Socioeconomic Composition
Authors: DiRago Nicholas V. , Li Meiying , Tom Thalia , Schupmann Will , Carrillo Yvonne , Carey Colleen M. , Gaddis S. Michael
Published: November 2021

Rollouts of COVID-19 vaccines in the U.S. were opportunities to redress disparities that surfaced during the pandemic. Initial eligibility criteria, however, neglected geographic, racial/ethnic, and socioeconomic considerations. Marginalized populations may have faced barriers to then-scarce vaccines, reinforcing disparities. Inequalities may have subsided as eligibility expanded. Using spatial modeling, we investigate how strongly local vaccination levels were associated with socioeconomic and racial/ethnic composition as authorities first extended vaccine eligibility to all adults. We harmonize administrative, demographic, and geospatial data across postal codes in eight large U.S. cities over three weeks in Spring 2021. We find that, although vaccines were free regardless of health insurance coverage, local vaccination levels in March and April were negatively associated with poverty, enrollment in means-tested public health insurance (e.g., Medicaid), and the uninsured population. By April, vaccination levels in Black and Hispanic communities were only beginning to reach those of Asian and White communities in March. Increases in vaccination were smaller in socioeconomically disadvantaged Black and Hispanic communities than in more affluent, Asian, and White communities. Our findings suggest vaccine rollouts contributed to cumulative disadvantage. Populations that were left most vulnerable to COVID-19 benefited least from early expansions in vaccine availability in large U.S. cities.
Ignoring transmission dynamics leads to underestimation of the impact of a novel intervention against mosquito-borne disease
Authors: Cavany Sean M. , Huber John H. , Wieler Annaliese , Tran Quan Minh , Alkuzweny Manar , Elliott Margaret , España Guido , Moore Sean M. , Perkins T. Alex
Published: November 2021

New vector-control technologies to fight mosquito-borne diseases are urgently needed, the adoption of which depends on efficacy estimates from large-scale cluster-randomized trials (CRTs). The release ofWolbachia-infected mosquitoes is one promising strategy to curb dengue virus (DENV) transmission, and a recent CRT reported impressive reductions in dengue incidence following the release of these mosquitoes. Such trials can be affected by multiple sources of bias, however. We used mathematical models of DENV transmission during a CRT ofWolbachia-infected mosquitoes to explore three such biases: human movement, mosquito movement, and coupled transmission dynamics between trial arms. We show that failure to account for each of these biases would lead to underestimated efficacy, and that the majority of this underestimation is due to a heretofore unrecognized bias caused by transmission coupling. Taken together, our findings suggest thatWolbachia-infected mosquitoes could be even more promising than the recent CRT suggested. By emphasizing the importance of accounting for transmission coupling between arms, which requires a mathematical model, our results highlight the key role that models can play in interpreting and extrapolating the results from trials of vector control interventions.
Race-Specific, U.S. State-Specific COVID-19 Vaccination Rates Adjusted for Age
Authors: Wrigley-Field Elizabeth , Berry Kaitlyn M. , Persad Govind
Published: November 2021

We provide the first age-standardized race/ethnicity-specific, state-specific vaccination rates for the United States, encompassing all states reporting race/ethnicity-specific vaccinations. The data reflect vaccinations through mid-October 2021. We use indirect age standardization to compare racial/ethnic state vaccination rates to national age-specific vaccination patterns. Results show that white and Black state median vaccination rates are, respectively, 89% and 76% of what would be predicted based on age; Hispanic and Native rates are almost identical to what would be predicted; and Asian-American/Pacific Islander rates are 110% of what would be predicted. We also find that racial/ethnic group vaccination rates are associated with state politics, as proxied by 2020 Trump vote share: for each percentage point increase in 2020 Trump vote share, vaccination rates decline by 1.08 percent of what would be predicted based on age. This decline is sharpest for Native American populations, although Native vaccinations are reported for relatively few states.
Beyond gradients: Factorized, geometric control of interference and generalization
Authors: Scott Daniel Nelson , Frank Michael J
Published: November 2021

Interference and generalization, which refer to counter-productive and useful interactions between learning episodes, respectively, are poorly understood in biological neural networks. Whereas much previous work has addressed these topics in terms of specialized brain systems, here we investigated how learning rules should impact them. We found that plasticity between groups of neurons can be decomposed into biologically meaningful factors, with factor geometry controlling interference and generalization. We introduce a "coordinated eligibility theory" in which plasticity is determined according to products of these factors, and is subject to surprise-based metaplasticity. This model computes directional derivatives of loss functions, which need not align with task gradients, allowing it to protect networks against catastrophic interference and facilitate generalization. Because the model's factor structure is closely related to other plasticity rules, and is independent of how feedback is transmitted, it introduces a widely-applicable framework for interpreting supervised, reinforcement-based, and unsupervised plasticity in nervous systems.
Listeriaspp. Isolated from Soil Samples Collected in the Great Smoky Mountains
Authors: Claxton Michelle L. , Hudson Lauren K. , Bryan Daniel W. , Denes Thomas G.
Published: November 2021

Listeria monocytogenes,a foodborne pathogen, and otherListeriaspp. are present in natural environments. Isolating and characterizing strains from natural reservoirs can provide insight into the prevalence and diversity ofListeriaspp. in these environments, elucidate their contribution to contamination of agricultural and food processing environments and food products, and lead to the discovery of novel species. In this study, we evaluated the diversity ofListeriaspp. isolated from soil samples in a small region of the Great Smoky Mountains National Park (GSMNP), which is the most biodiverse national park in the United States National Park system. Of the 17Listeriaisolates that were recovered, whole-genome sequencing revealed that 14 were unique strains. The unique strains were shown to represent a diversity ofListeriaspp., includingL. monocytogenes(n=9),L. cossartiaesubsp.cossartiae(n=1),L. marthii(n=1),L. booriae(n=1), and a novel Listeria sp. (n=2). TheListeriaisolated in this study were collected from high elevation sites near a creek that drains into a series of rivers ultimately leading to the Mississippi River; thus, theListeriapresent in this natural environment could potentially travel downstream to a large region that includes portions of nine southeastern and midwestern states in the U.S. TheListeriaspp. isolated and described in this study provide insight into the diversity ofListeriaspp. found in the Great Smoky Mountains and indicate that this environment is a reservoir of novelListeriaspp.

IMPORTANCE

Listeria monocytogenesis a foodborne pathogen that can cause serious systemic illness that, although rare, usually results in hospitalization and has a relatively high mortality rate compared to other foodborne pathogens. Identification of novel and diverseListeriaspp. provides insight into the genomic evolution, ecology, and evolution and variance of pathogenicity of this genus, especially in natural environments. ComparingL. monocytogenesandListeriaspp. isolates from natural environments, such as those recovered in this study, to contamination and/or outbreak strains may provide more information about the original natural sources of these strains and the pathways and mechanisms that lead to contamination of food products and agricultural or food processing environments.
Strict adherence to Mendel’s First Law across a large sample of human sperm genomes
Authors: Carioscia Sara A. , Weaver Kathryn J. , Bortvin Andrew N. , Ariad Daniel , Bell Avery Davis , McCoy Rajiv C.
Published: November 2021

Mendel’s Law of Segregation states that the offspring of a diploid, heterozygous parent will inherit either allele with equal probability. While the vast majority of loci adhere to this rule, research in model and non-model organisms has uncovered numerous exceptions whereby “selfish” alleles are disproportionately transmitted to the next generation. Evidence of such “transmission distortion” (TD) in humans remains equivocal in part because scans of human pedigrees have been under-powered to detect small effects. Recently published single-cell sequencing data from individual human sperm (n= 41,189; 969-3,377 cells from each of 25 donors) offer an opportunity to revisit this question with unprecedented statistical power, but require new methods tailored to extremely low-coverage data (∼0.01 × per cell). To this end, we developed a method, named rhapsodi, that leverages sparse gamete genotype data to phase the diploid genomes of the donor individuals, impute missing gamete genotypes, and discover meiotic recombination breakpoints, benchmarking its performance across a wide range of study designs. After applying rhapsodi to the sperm sequencing data, we then scanned the gametes for evidence of TD. Our results exhibited close concordance with binomial expectations under balanced transmission, in contrast to tenuous signals of TD that were previously reported in pedigree-based studies. Together, our work excludes the existence of even weak TD in this sample, while offering a powerful quantitative framework for testing this and related hypotheses in other cohorts and study systems.
Respiratory Syncytial virus NS1 protein targets the transactivator binding domain of MED25
Authors: Basse Vincent , Dong Jiawei , Peres de Oliveira Andressa , Vidalain Pierre-Olivier , Tangy Frederic , Galloux Marie , Eleouet Jean-Francois , Sizun Christina , Bajorek Monika
Published: November 2021

Respiratory syncytial virus has evolved a unique strategy to evade host immune response by coding for two non-structural proteins NS1 and NS2. Recently it was shown that in infected cells, nuclear NS1 could be involved in transcription regulation of host genes linked to innate immune response, via an interaction with chromatin and the Mediator complex. Here we identified the MED25 Mediator subunit as an NS1 interactor in a yeast two-hybrid screen. We demonstrate that NS1 directly interacts with MED25 in vitro and in cellula, and that this interaction involves the C-terminal α3 helix of NS1 and the MED25 ACID domain. More specifically we showed by NMR that the NS1 α3 sequence primarily binds to the MED25 ACID H2 face, which is a transactivation domain (TAD) binding site for transcription regulators such as ATF6α, a master regulator of ER stress response activated upon viral infection. Moreover, we found out that the NS1 α3 helix could compete with ATF6α TAD binding to MED25. This finding points to a mechanism of NS1 interfering with innate immune response by impairing recruitment by cellular TADs of the Mediator via MED25 and hence transcription of specific genes by RNA polymerase II.

Importance

Human RSV is the leading cause of infantile bronchiolitis in the world and one of the major causes of childhood deaths in resource-poor settings. It is a major unmet target for vaccines and anti-viral drugs. RSV non-structural protein NS1 is known to antagonize the cellular immune response and was recently shown to be involved in transcription regulation of infected cells. However, the exact mechanism of this regulation is not well defined. Here we show that nuclear NS1 interacts directly with the Mediator subunit MED25 and is able to compete with a cellular transcription activator, which is activated during viral infection. We hypothesize that this interaction may underlie regulation of the expression of genes involved in the innate immune response.
Glycated haemoglobin measurements from UK Biobank are different to those in linked primary care records: implications for combining biochemistry data from research studies and routine clinical care
Authors: Young Katherine G , McDonald Timothy J , Shields Beverley M
Published: November 2021

Data linkage of cohort or RCT data with routinely collected data is becoming increasingly commonplace, and this often involves combining biomarker measurements from different sources. However, sources may have different biases due to differences in assay method and calibration. Combining these measurements, or diagnoses based on these measurements, is therefore not always valid. We highlight an example using glycated haemoglobin A1c (HbA1c) test results from two different sources in UK Biobank data.
Predictive Modelling of Brain Disorders with Magnetic Resonance Imaging: A Systematic Review of Modelling Practices, Transparency, and Interpretability in the use of Convolutional Neural Networks
Authors: O’Connell Shane , Cannon Dara M , Ó Broin Pilib
Published: November 2021

Brain disorders comprise several psychiatric and neurological disorders which can be characterised by impaired cognition, mood alteration, psychosis, depressive episodes, and neurodegeneration. Clinical diagnoses primarily rely on a combination of life history information and questionnaires, with a distinct lack of discriminative biomarkers in use for psychiatric disorders. Given that symptoms across brain conditions are associated with functional alterations of cognitive and emotional processes, which can correlate with anatomical variation, structural magnetic resonance imaging (MRI) data of the brain are an important focus of research studies, particularly for predictive modelling. With the advent of large MRI data consortia (such as the Alzheimer’s Disease Neuroimaging Initiative) facilitating a greater number of MRI-based classification studies, convolutional neural networks (CNNs) – deep learning models suited to image processing – have become increasingly popular for research into brain conditions. This has resulted in a myriad of studies reporting impressive predictive performances, demonstrating the potential clinical value of deep learning systems. However, modelling practices, transparency, and interpretability vary widely across studies, making them difficult to compare and/or reproduce, thus potentially limiting clinical applications. Here, we conduct a qualitative systematic literature review of 60 studies carrying out CNN-based predictive modelling of brain disorders using MRI data and evaluate them based on three principles – modelling practices, transparency, and interpretability. We furthermore propose several recommendations aimed at maximising the potential for the integration of CNNs into clinical frameworks.