Nevin Manimala

PLoS One. 2021 Oct 19;16(10):e0258858. doi: 10.1371/journal.pone.0258858. eCollection 2021.

ABSTRACT

Longstanding social and economic inequities elevate health risks and vulnerabilities for Black, Indigenous and People of Color (BIPOC) communities. Engagement of BIPOC communities in infectious disease research is a critical component in efforts to increase vaccine confidence, acceptability, and uptake of future approved products. Recent data highlight the relative absence of BIPOC communities in vaccine clinical trials. Intentional and effective community engagement methods are needed to improve BIPOC inclusion. We describe the methods utilized for the successful enrollment of BIPOC participants in the U.S. Government (USG)-funded COVID-19 Prevention Network (CoVPN)-sponsored vaccine efficacy trials and analyze the demographic and enrollment data across the efficacy trials to inform future efforts to ensure inclusive participation. Across the four USG-funded COVID-19 vaccine clinical trials for which data are available, 47% of participants enrolled at CoVPN sites in the US were BIPOC. White enrollment outpaced enrollment of BIPOC participants throughout the accrual period, requiring the implementation of strategies to increase diverse and inclusive enrollment. Trials opening later benefitted considerably from strengthened community engagement efforts, and greater and more diverse volunteer registry records. Despite robust fiscal resources and a longstanding collaborative and collective effort, enrollment of White persons outpaced that of BIPOC communities. With appropriate resources, commitment and community engagement expertise, the equitable enrollment of BIPOC individuals can be achieved. To ensure this goal, intentional efforts are needed, including an emphasis on diversity of enrollment in clinical trials, establishment of enrollment goals, ongoing robust community engagement, conducting population-specific trials, and research to inform best practices.

PMID:34665829 | DOI:10.1371/journal.pone.0258858

PLoS One. 2021 Oct 19;16(10):e0258554. doi: 10.1371/journal.pone.0258554. eCollection 2021.

ABSTRACT

At birth, human infants are poised to survive in harsh, hostile conditions. An understanding of the state of newborn skin development and maturation is key to the maintenance of health, optimum response to injury, healing and disease. The observational study collected full-thickness newborn skin samples from 27 infants at surgery and compared them to skin samples from 43 adult sites protected from ultraviolet radiation exposure, as the standard for stable, mature skin. Transcriptomics profiling and gene set enrichment analysis were performed. Statistical analysis established over 25,000 differentially regulated probe sets, representing 10,647 distinct genes, in infant skin compared to adult skin. Gene set enrichment analysis showed a significant increase in 143 biological processes (adjusted p < 0.01) in infant skin, versus adult skin samples, including extracellular matrix (ECM) organization, cell adhesion, collagen fibril organization and fatty acid metabolic process. ECM organization and ECM structure organization were the biological processes in infant skin with the lowest adjusted P-value. Genes involving epidermal development, immune function, cell differentiation, and hair cycle were overexpressed in adults, representing 101 significantly enriched biological processes (adjusted p < 0.01). The processes with the highest significant difference were skin and epidermal development, e.g., keratinocyte differentiation, keratinization and cornification intermediate filament cytoskeleton organization and hair cycle. Enriched Gene Ontology (GO) biological processes also involved immune function, including antigen processing and presentation. When compared to ultraviolet radiation-protected adult skin, our results provide essential insight into infant skin and its ability to support the newborn’s preparedness to survive and flourish, despite the infant’s new environment laden with microbes, high oxygen tension and potential irritants. This fundamental knowledge is expected to guide strategies to protect and preserve the features of unperturbed, young skin.

PMID:34665817 | DOI:10.1371/journal.pone.0258554

PLoS Biol. 2021 Oct 19;19(10):e3001413. doi: 10.1371/journal.pbio.3001413. eCollection 2021 Oct.

ABSTRACT

Light plays a fundamental role in the ecology of organisms in nearly all habitats on Earth and is central for processes such as vision and the entrainment of the circadian clock. The poles represent extreme light regimes with an annual light cycle including periods of Midnight Sun and Polar Night. The Arctic Ocean extends to the North Pole, and marine light extremes reach their maximum extent in this habitat. During the Polar Night, traditional definitions of day and night and seasonal photoperiod become irrelevant since there are only “twilight” periods defined by the sun’s elevation below the horizon at midday; we term this “midday twilight.” Here, we characterize light across a latitudinal gradient (76.5° N to 81° N) during Polar Night in January. Our light measurements demonstrate that the classical solar diel light cycle dominant at lower latitudes is modulated during Arctic Polar Night by lunar and auroral components. We therefore question whether this particular ambient light environment is relevant to behavioral and visual processes. We reveal from acoustic field observations that the zooplankton community is undergoing diel vertical migration (DVM) behavior. Furthermore, using electroretinogram (ERG) recording under constant darkness, we show that the main migratory species, Arctic krill (Thysanoessa inermis) show endogenous increases in visual sensitivity during the subjective night. This change in sensitivity is comparable to that under exogenous dim light acclimations, although differences in speed of vision suggest separate mechanisms. We conclude that the extremely weak midday twilight experienced by krill at high latitudes during the darkest parts of the year has physiological and ecological relevance.

PMID:34665816 | DOI:10.1371/journal.pbio.3001413

PLoS Comput Biol. 2021 Oct 19;17(10):e1009536. doi: 10.1371/journal.pcbi.1009536. Online ahead of print.

ABSTRACT

Ectopic beats (EBs) are cellular arrhythmias that can trigger lethal arrhythmias. Simulations using biophysically-detailed cardiac myocyte models can reveal how model parameters influence the probability of these cellular arrhythmias, however such analyses can pose a huge computational burden. Here, we develop a simplified approach in which logistic regression models (LRMs) are used to define a mapping between the parameters of complex cell models and the probability of EBs (P(EB)). As an example, in this study, we build an LRM for P(EB) as a function of the initial value of diastolic cytosolic Ca2+ concentration ([Ca2+]iini), the initial state of sarcoplasmic reticulum (SR) Ca2+ load ([Ca2+]SRini), and kinetic parameters of the inward rectifier K+ current (IK1) and ryanodine receptor (RyR). This approach, which we refer to as arrhythmia sensitivity analysis, allows for evaluation of the relationship between these arrhythmic event probabilities and their associated parameters. This LRM is also used to demonstrate how uncertainties in experimentally measured values determine the uncertainty in P(EB). In a study of the role of [Ca2+]SRini uncertainty, we show a special property of the uncertainty in P(EB), where with increasing [Ca2+]SRini uncertainty, P(EB) uncertainty first increases and then decreases. Lastly, we demonstrate that IK1 suppression, at the level that occurs in heart failure myocytes, increases P(EB).

PMID:34665814 | DOI:10.1371/journal.pcbi.1009536

PLoS One. 2021 Oct 19;16(10):e0258731. doi: 10.1371/journal.pone.0258731. eCollection 2021.

ABSTRACT

Failure to thrive (FTT) impairs the expected normal physical growth of children. This study aimed to evaluate the effects of cyproheptadine hydrochloride on growth parameters in prepubertal children with FTT. The medical records of prepubertal children who were newly diagnosed with FTT at China Medical University Hospital between 2007 and 2016 were retrospectively examined. The patients were divided into two groups depending on whether they had (T-group) or had not (NT-group) received cyproheptadine hydrochloride (0.3 mg/kg daily) for at least 14 days. The mean length of the treatment period was 97.22 days (range: 14-532 days). Weight, height, and body mass index were adjusted for age using the median values in the growth charts for Taiwanese boys and girls as the reference. A total of 788 patients aged 3-11 years were enrolled, 50 in the T-group and 738 in the NT-group. No statistically significant difference in the median age-adjusted weight value was noted between the T-group and NT-group during the follow up period. In the T-group, age-adjusted weight and body mass index were inversely associated with age (P <0.001, P <0.001) and positively associated with medication duration (P = 0.026, P = 0.04). Our findings underscore the positive association between cyproheptadine hydrochloride treatment and weight gain among prepubertal children. Further prospective clinical studies with a. longer and consistent treatment course is warranted.

PMID:34665812 | DOI:10.1371/journal.pone.0258731

PLoS Negl Trop Dis. 2021 Oct 19;15(10):e0009888. doi: 10.1371/journal.pntd.0009888. Online ahead of print.

ABSTRACT

BACKGROUND: Albendazole (ALB) is administered annually to millions of children through global deworming programs targeting soil-transmitted helminths (STHs: Ascaris lumbricoides, Trichuris trichiura and hookworms, Necator americanus and Ancylostoma duodenale). However, due to the lack of large individual patient datasets collected using standardized protocols and the application of population-based statistical methods, little is known about factors that may affect individual responses to treatment.

METHODOLOGY/PRINCIPAL FINDINGS: We re-analyzed 645 individual patient data from three standardized clinical trials designed to assess the efficacy of a single 400 mg oral dose of ALB against STHs in schoolchildren from different study sites, each with varying history of drug pressure based on duration of mass drug administration programs: Ethiopia, low; Lao People’s Democratic Republic (PDR), moderate; Pemba Island (Tanzania), high. Using a Bayesian statistical modelling approach to estimate individual responses (individual egg reduction rates, ERRi), we found that efficacy was lower in Pemba Island, particularly for T. trichiura. For this STH, the proportion of participants with a satisfactory response (ERRi ≥50%), was 65% in Ethiopia, 61% in Lao PDR but only 29% in Pemba Island. There was a significant correlation between ERRi and infection intensity prior to drug administration (ERRi decreasing as a function of increasing infection intensity). Individual age and sex also affected the drug response, but these were of negligible clinical significance and not consistent across STHs and study sites.

CONCLUSIONS/SIGNIFICANCE: We found decreased efficacy of ALB against all the STHs analyzed in Pemba Island (Tanzania), an area with high drug pressure. This does not indicate causality, as this association may also be partially explained by differences in infection intensity prior to drug administration. Notwithstanding, our results indicate that without alternative treatment regimens, program targets will not be achievable on Pemba Island because of inadequate efficacy of ALB.

TRIAL REGISTRATION: The study was registered on Clinicaltrials.gov (ID: NCT03465488) on March 7, 2018.

PMID:34665810 | DOI:10.1371/journal.pntd.0009888

PLoS Comput Biol. 2021 Oct 19;17(10):e1009464. doi: 10.1371/journal.pcbi.1009464. Online ahead of print.

ABSTRACT

Gene selection in unannotated large single cell RNA sequencing (scRNA-seq) data is important and crucial step in the preliminary step of downstream analysis. The existing approaches are primarily based on high variation (highly variable genes) or significant high expression (highly expressed genes) failed to provide stable and predictive feature set due to technical noise present in the data. Here, we propose RgCop, a novel regularized copula based method for gene selection from large single cell RNA-seq data. RgCop utilizes copula correlation (Ccor), a robust equitable dependence measure that captures multivariate dependency among a set of genes in single cell expression data. We raise an objective function by adding a l1 regularization term with Ccor to penalizes the redundant co-efficient of features/genes, resulting non-redundant effective features/genes set. Results show a significant improvement in the clustering/classification performance of real life scRNA-seq data over the other state-of-the-art. RgCop performs extremely well in capturing dependence among the features of noisy data due to the scale invariant property of copula, thereby improving the stability of the method. Moreover, the differentially expressed (DE) genes identified from the clusters of scRNA-seq data are found to provide an accurate annotation of cells. Finally, the features/genes obtained from RgCop can able to annotate the unknown cells with high accuracy.

PMID:34665808 | DOI:10.1371/journal.pcbi.1009464

PLoS Med. 2021 Oct 19;18(10):e1003793. doi: 10.1371/journal.pmed.1003793. eCollection 2021 Oct.

ABSTRACT

BACKGROUND: The importance of infectious disease epidemic forecasting and prediction research is underscored by decades of communicable disease outbreaks, including COVID-19. Unlike other fields of medical research, such as clinical trials and systematic reviews, no reporting guidelines exist for reporting epidemic forecasting and prediction research despite their utility. We therefore developed the EPIFORGE checklist, a guideline for standardized reporting of epidemic forecasting research.

METHODS AND FINDINGS: We developed this checklist using a best-practice process for development of reporting guidelines, involving a Delphi process and broad consultation with an international panel of infectious disease modelers and model end users. The objectives of these guidelines are to improve the consistency, reproducibility, comparability, and quality of epidemic forecasting reporting. The guidelines are not designed to advise scientists on how to perform epidemic forecasting and prediction research, but rather to serve as a standard for reporting critical methodological details of such studies.

CONCLUSIONS: These guidelines have been submitted to the EQUATOR network, in addition to hosting by other dedicated webpages to facilitate feedback and journal endorsement.

PMID:34665805 | DOI:10.1371/journal.pmed.1003793

PLoS Negl Trop Dis. 2021 Oct 19;15(10):e0009754. doi: 10.1371/journal.pntd.0009754. eCollection 2021 Oct.

ABSTRACT

Brazil presents one of the highest COVID-19 death tolls in the world. The initial SARS-CoV-2 epicenter was São Paulo city. As of 2019, the homeless population of São Paulo city was estimated at 24,344 individuals, the largest national homeless population. The present study aimed to concomitantly assess the molecular and serological prevalence and associated risk factors of SARS-CoV-2 infection in a homeless population and related shelter workers from a day-shelter. Serum samples, nasopharyngeal and oropharyngeal swabs of persons who are homeless and shelter workers collected from August 25th to 27th, 2020 were tested for the presence of anti-SARS-CoV-2 IgM and IgG antibodies by ELISA and SARS-CoV-2 RNA by RT-qPCR, respectively. All swab samples tested negative by RT-qPCR. Seropositivity of IgM and IgG was 5/203 (2.5%) and 111/203 (54.7%) in persons who are homeless, and 5/87 (5.7%) and 41/87 (47.1%) in shelter workers, respectively, with no statistical differences between groups. The high seroprevalence found herein indicates early environmental and urban spreading of SARS-CoV-2, associated with sociodemographic and economic vulnerability.

PMID:34665803 | DOI:10.1371/journal.pntd.0009754

JCI Insight. 2021 Oct 19:e151922. doi: 10.1172/jci.insight.151922. Online ahead of print.

ABSTRACT

BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is a rare, devastating, and life-threatening inherited skin fragility disorder due to a lack of functional type VII collagen, for which no effective therapy exists. ABCB5-positive dermal mesenchymal stem cells (ABCB5+ MSCs) possess immunomodulatory capacities, a favorable skin homing potential and the ability to secrete type VII collagen. In a COL7A1-/- mouse model of RDEB, treatment with ABCB5+ MSCs markedly extended the animals’ lifespans.

METHODS: In this international, multicentric, single-arm, phase I/IIa clinical trial, 16 patients (aged 4-36 years) enrolled into four age cohorts received three intravenous infusions of 2×106 ABCB5+ MSCs/kg on days 0, 17 and 35. Patients were followed up for 12 weeks regarding efficacy and 12 months regarding safety.

RESULTS: At 12 weeks, statistically significant median (IQR) reductions in the Epidermolysis Bullosa Disease Activity and Scarring Index activity (EBDASI activity) score of 13.0% (2.9%-30%; P = 0.049) and the Instrument for Scoring Clinical Outcome of Research for Epidermolysis Bullosa clinician (iscorEB c) score of 18.2% (4.1%-41.7%; P = 0.037) were observed. Reductions in itch and pain numerical rating scale scores were greatest on day 35, amounting to 37.5% (0.0%-42.9%; P = 0.033) and 25.0% (-8.4%-46.4%; P = 0.168), respectively. Three adverse events were considered related to the cell product, one mild lymphadenopathy and two hypersensitivity reactions. The latter two were serious but resolved without sequelae shortly after withdrawal of treatment.

CONCLUSION: This trial demonstrates good tolerability, manageable safety and potential efficacy of intravenous ABCB5+ MSCs as a readily available disease-modifying therapy for RDEB and provides a rationale for further clinical evaluation.

TRIAL REGISTRATION: clinicaltrials.gov NCT03529877; EudraCT 2018-001009-98FUNDING. The trial was sponsored by RHEACELL GmbH & Co. KG, Heidelberg, Germany. Contributions by NY Frank and MH Frank to this work were supported by the National Institutes of Health (NIH)/National Eye Institute (NEI) grants RO1EY025794 and R24EY028767.

PMID:34665781 | DOI:10.1172/jci.insight.151922