Nevin Manimala

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

J Water Health. 2021 Oct;19(5):762-774. doi: 10.2166/wh.2021.119.

ABSTRACT

Laguna Lake is an economically important resource in the Philippines, with reports of declining water quality due to fecal pollution. Currently, monitoring methods rely on counting fecal indicator bacteria, which does not supply information on potential sources of contamination. In this study, we predicted sources of Escherichia coli in lake stations and tributaries by establishing a fecal source library composed of rep-PCR DNA fingerprints of human, cattle, swine, poultry, and sewage samples (n = 1,408). We also evaluated three statistical methods for predicting fecal contamination sources in surface waters. Random forest (RF) outperformed k-nearest neighbors and discriminant analysis of principal components in terms of average rates of correct classification in two- (84.85%), three- (82.45%), and five-way (74.77%) categorical splits. Overall, RF exhibited the most balanced prediction, which is crucial for disproportionate libraries. Source tracking of environmental isolates (n = 332) revealed the dominance of sewage (47.59%) followed by human sources (29.22%), poultry (12.65%), swine (7.23%), and cattle (3.31%) using RF. This study demonstrates the promising utility of a library-dependent method in augmenting current monitoring systems for source attribution of fecal contamination in Laguna Lake. This is also the first known report of microbial source tracking using rep-PCR conducted in surface waters of the Laguna Lake watershed.

PMID:34665769 | DOI:10.2166/wh.2021.119

IEEE J Biomed Health Inform. 2021 Oct 19;PP. doi: 10.1109/JBHI.2021.3120662. Online ahead of print.

ABSTRACT

Manual titration of positive airway pressure (PAP) is a gold standard to provide an optimal pressure for the treatment of obstructive sleep apnea-hypopnea syndrome (OSAS). Since manual titration studies were costly and time-consuming, many statistical models for predicting effective PAPs were reported. However, the prediction accuracies of the models associated with nocturnal parameters still remain low. This study proposes a fuzzy neural prediction network (FNPN) with input candidate variables, selected among easily available measurements (e.g., body mass index (BMI), waist circumstance (WC), and body composition) and OSAS related questionnaires, to rapidly predict an optimal PAP. The FNPN comprises fuzzy rules and is characterized with the ability of automatic rule growing and pruning from training data. A total of 147 participants from April 2018 to April 2019 were enrolled in Taichung Veterans General Hospital, Taiwan. After two selection processes for feature extraction, WC and BMI were the significant variables for entering the FNPN to predict optimal PAP. Experimental results showed that the average successful prediction rate of the proposed method was 71.8%. This study also found that Epworth sleepiness scales (ESS) and body composition, such as visceral fat area and percent body fat, were excluded in the final prediction model. Compared with existing models, the proposed prediction approach provided a rapid prediction of optimal PAP with higher accuracy.

PMID:34665745 | DOI:10.1109/JBHI.2021.3120662

Clin Exp Rheumatol. 2021 Oct 18. Online ahead of print.

ABSTRACT

OBJECTIVES: To identify ultrasound (US) features of lymphomas (L) of major salivary glands (SGs) in primary Sjögren’s syndrome (pSS) patients and to differentiate US pattern of L and non-L.

METHODS: prospectively, from September 2019 to March 2021, 27 pSS-patients with clinical findings suspicious for L of the SGs underwent US evaluation followed by US-guided core-needle biopsy (CNB). For each patient, we assessed the OMERACT score, dichotomised (0/1 “lower”, 2/3 “higher”), and we compared it between L-pSS and nonL-pSS groups. For focal lesions, echogenicity, inner appearance, shape, margins, presence of septa, vascularisation and posterior acoustic features were also assessed and compared between the two groups; we planned to consider as “suspicious” features more frequently associated with L. We expected to compare frequencies at which two or more “suspicious” features were simultaneously present between L-pSS and nonL-pSS. P<0.05 were considered statistically significant.

RESULTS: L-pSS showed more inhomogeneous glandular pattern (100% vs. 69.2% higher OMERACT; p=0.0407). For focal lesions, the “suspicious” features identified were: OMERACT grade 3, very hypoechoic, homogenous, oval shape, well-defined margins, presence of septa, colour-Doppler vascularization, posterior acoustic enhancement. 6/8 and 7/8 simultaneous suspicious features were significantly higher among L-pSS patients, compared to nonL-pSS (88.9% vs. 28.6%, p=0.034 for 6/8 features; 77.8% vs. 14.3%, p=0.040 for 7/8 features).

CONCLUSIONS: L of the major SGs in pSS was always associated with OMERACT scores 2 or 3 and presented with diffuse or focal patterns. For focal lesions, the association of more “suspicious” features made the diagnosis of L increasingly more likely. This information can help to improve planning of US-guided CNB.

PMID:34665707

Clin Exp Rheumatol. 2021 Sep 28. Online ahead of print.

ABSTRACT

OBJECTIVES: We aimed to assess the performance of the 2015 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) gout classification criteria in an Italian cohort of patients with crystal-induced arthritis stratified by disease duration and gender in a real-life setting.

METHODS: Consecutive patients referred to Rheumatology Units for suspected acute crystal-induced arthritis were enrolled in a multicentre cohort study by the Italian Society of Rheumatology which was designed to improve the management of crystal-induced arthritis (ATTACk). To test the performance of the criteria (sensitivity and specificity), the presence of monosodium urate (MSU) crystals in synovial fluid (SF) was used as gold standard. Subgroup analyses by gender and disease duration were performed.

RESULTS: Two hundred and seventy-seven patients were enrolled. SF analysis was available in 137 (49%) patients. Complete SF analysis and ACR/EULAR scores were obtained in 44% of patients. MSU crystals were found in 66% of patients. The sensitivity and the specificity of all criteria sets were 78% (95%CI, 67-86) and 98% (95%CI, 87-100), respectively; only clinical criteria yielded 70% (95%CI, 59-80) sensitivity and 93% (95%CI, 80-98) specificity, respectively. In early-stage disease (<2 years), the sensitivity dropped to 58% (95%CI, 39-75), while the specificity was 100% (95%CI, 85-100).

CONCLUSIONS: The ACR/EULAR criteria showed good performance in patients presenting with acute arthritis; changes were observed when a subset of criteria were used, especially in early-stage disease.

PMID:34665701

Nat Commun. 2021 Oct 18;12(1):6071. doi: 10.1038/s41467-021-26282-z.

ABSTRACT

In contrast to the curative effect of allogenic stem cell transplantation in acute myeloid leukemia via T cell activity, only modest responses are achieved with checkpoint-blockade therapy, which might be explained by T cell phenotypes and T cell receptor (TCR) repertoires. Here, we show by paired single-cell RNA analysis and TCR repertoire profiling of bone marrow cells in relapsed/refractory acute myeloid leukemia patients pre/post azacytidine+nivolumab treatment that the disease-related T cell subsets are highly heterogeneous, and their abundance changes following PD-1 blockade-based treatment. TCR repertoires expand and primarily emerge from CD8⁺ cells in patients responding to treatment or having a stable disease, while TCR repertoires contract in therapy^–resistant patients. Trajectory analysis reveals a continuum of CD8⁺ T cell phenotypes, characterized by differential expression of granzyme B and a bone marrow-residing memory CD8⁺ T cell subset, in which a population with stem-like properties expressing granzyme K is enriched in responders. Chromosome 7/7q loss, on the other hand, is a cancer-intrinsic genomic marker of PD-1 blockade resistance in AML. In summary, our study reveals that adaptive T cell plasticity and genomic alterations determine responses to PD-1 blockade in acute myeloid leukemia.

PMID:34663807 | DOI:10.1038/s41467-021-26282-z