Nevin Manimala

Nat Commun. 2021 Apr 12;12(1):2177. doi: 10.1038/s41467-021-22495-4.

ABSTRACT

The recent advancements in single-cell technologies, including single-cell chromatin accessibility sequencing (scCAS), have enabled profiling the epigenetic landscapes for thousands of individual cells. However, the characteristics of scCAS data, including high dimensionality, high degree of sparsity and high technical variation, make the computational analysis challenging. Reference-guided approaches, which utilize the information in existing datasets, may facilitate the analysis of scCAS data. Here, we present RA3 (Reference-guided Approach for the Analysis of single-cell chromatin Accessibility data), which utilizes the information in massive existing bulk chromatin accessibility and annotated scCAS data. RA3 simultaneously models (1) the shared biological variation among scCAS data and the reference data, and (2) the unique biological variation in scCAS data that identifies distinct subpopulations. We show that RA3 achieves superior performance when used on several scCAS datasets, and on references constructed using various approaches. Altogether, these analyses demonstrate the wide applicability of RA3 in analyzing scCAS data.

PMID:33846355 | DOI:10.1038/s41467-021-22495-4

Sci Rep. 2021 Apr 12;11(1):7857. doi: 10.1038/s41598-021-82810-3.

ABSTRACT

Given that a substantial proportion of the subgroup of COVID-19 patients that face a severe disease course are younger than 60 years, it is critical to understand the disease-specific characteristics of young COVID-19 patients. Risk factors for a severe disease course for young COVID-19 patients and possible non-linear influences remain unknown. Data were analyzed from COVID-19 patients with clinical outcome in a single hospital in Wuhan, China, collected retrospectively from Jan 24th to Mar 27th. Clinical, demographic, treatment and laboratory data were collected from patients’ medical records. Uni- and multivariable analysis using logistic regression and random forest, with the latter allowing the study of non-linear influences, were performed to investigate the clinical characteristics of a severe disease course. A total of 762 young patients (median age 47 years, interquartile range [IQR] 38-55, range 18-60; 55.9% female) were included, as well as 714 elderly patients as a comparison group. Among the young patients, 362 (47.5%) had a severe/critical disease course and the mean age was statistically significantly higher in the severe subgroup than in the mild subgroup (59.3 vs. 56.0, Student’s t-test: p < 0.001). The uni- and multivariable analysis suggested that several covariates such as elevated levels of serum amyloid A (SAA), C-reactive protein (CRP) and lactate dehydrogenase (LDH), and decreased lymphocyte counts influence disease severity independently of age. Elevated levels of complement C3 (odds ratio [OR] 15.6, 95% CI 2.41-122.3; p = 0.039) are particularly associated with the risk of developing severe COVID-19 specifically in young patients, whereas no such influence seems to exist for elderly patients. Additional analysis suggests that the influence of complement C3 in young patients is independent of age, gender, and comorbidities. Variable importance values and partial dependence plots obtained using random forests delivered additional insights, in particular indicating non-linear influences of risk factors on disease severity. This study identified increased levels of complement C3 as a unique risk factor for adverse outcomes specific to young COVID-19 patients.

PMID:33846344 | DOI:10.1038/s41598-021-82810-3

Sci Rep. 2021 Apr 12;11(1):7927. doi: 10.1038/s41598-021-86487-6.

ABSTRACT

Seizures are common in patients with gliomas; however, the mechanisms of epileptogenesis in gliomas have not been fully understood. This study hypothesized that analyzing quantified metabolites using magnetic resonance spectroscopy (MRS) might provide novel insights to better understand the epileptogenesis in gliomas, and specific metabolites might be indicators of preoperative seizures in gliomas. We retrospectively investigated patient information (gender, age at diagnosis of tumor, their survival time) and tumor information (location, histology, genetic features, and metabolites according to MRS) in patients with gliomas. The data were correlated with the incidence of seizure and analyzed statistically. Of 146 adult supratentorial gliomas, isocitrate dehydrogenase (IDH) mutant tumors significantly indicated higher incidence of preoperative seizures than IDH wild-type gliomas. However, MRS study indicated that glutamate concentration in IDH wild-type gliomas was higher than that in IDH mutant gliomas. Glutamate was not associated with high frequency of preoperative seizures in patients with gliomas. Instead, increased total N-acetyl-L-aspartate (tNAA) was significantly associated with them. Moreover, multivariable analysis indicated that increased level of tNAA was an independent predictor of preoperative seizures. According to MRS analysis, tNAA, rather than glutamate, might be a useful to detect preoperative seizures in patient with supratentorial gliomas.

PMID:33846339 | DOI:10.1038/s41598-021-86487-6

Nat Commun. 2021 Apr 12;12(1):2188. doi: 10.1038/s41467-021-22366-y.

ABSTRACT

Unprecedented public health interventions including travel restrictions and national lockdowns have been implemented to stem the COVID-19 epidemic, but the effectiveness of non-pharmaceutical interventions is still debated. We carried out a phylogenetic analysis of more than 29,000 publicly available whole genome SARS-CoV-2 sequences from 57 locations to estimate the time that the epidemic originated in different places. These estimates were examined in relation to the dates of the most stringent interventions in each location as well as to the number of cumulative COVID-19 deaths and phylodynamic estimates of epidemic size. Here we report that the time elapsed between epidemic origin and maximum intervention is associated with different measures of epidemic severity and explains 11% of the variance in reported deaths one month after the most stringent intervention. Locations where strong non-pharmaceutical interventions were implemented earlier experienced much less severe COVID-19 morbidity and mortality during the period of study.

PMID:33846321 | DOI:10.1038/s41467-021-22366-y

Nat Commun. 2021 Apr 12;12(1):2147. doi: 10.1038/s41467-021-22375-x.

ABSTRACT

Tissue mononuclear phagocytes (MNP) are specialised in pathogen detection and antigen presentation. As such they deliver HIV to its primary target cells; CD4 T cells. Most MNP HIV transmission studies have focused on epithelial MNPs. However, as mucosal trauma and inflammation are now known to be strongly associated with HIV transmission, here we examine the role of sub-epithelial MNPs which are present in a diverse array of subsets. We show that HIV can penetrate the epithelial surface to interact with sub-epithelial resident MNPs in anogenital explants and define the full array of subsets that are present in the human anogenital and colorectal tissues that HIV may encounter during sexual transmission. In doing so we identify two subsets that preferentially take up HIV, become infected and transmit the virus to CD4 T cells; CD14⁺CD1c⁺ monocyte-derived dendritic cells and langerin-expressing conventional dendritic cells 2 (cDC2).

PMID:33846309 | DOI:10.1038/s41467-021-22375-x

Pediatrics. 2021 Apr 12:e2020042903. doi: 10.1542/peds.2020-042903. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVES: The Best Pharmaceuticals for Children Act (BPCA) incentivizes the study of on-patent medicines in children and mandates that the National Institutes of Health sponsor research on off-patent drugs important to pediatric therapeutics. Failing to enroll cohorts that reflect the pediatric population at large restricts the generalizability of such studies. In this investigation, we evaluate racial and ethnic minority representation among participants enrolled in BPCA-sponsored studies.

METHODS: Data were obtained for all participants enrolled in 33 federally funded studies of drugs and devices conducted from 2008 through June 2020. Observed racial and ethnic distributions were compared with expected distributions by sampling Census data at the same geographic frequency as in the studies. Racial and ethnic enrollment was examined by demography, geography, study type, study burden, and expected bias. Standard descriptive statistics, χ², generalized linear models, and linear regression were applied.

RESULTS: A total of 10 918 participants (51% male, 6.6 ± 8.2 years) were enrolled across 46 US states and 4 countries. Studies ranged from treatment outcome reviews to randomized, placebo-controlled trials. Minority enrollment was comparable to, or higher than, expected (+0.1% to +2.6%) for all groups except Asian Americans (-3.7%, P < .001). American Indian and Alaskan Native and multiracial enrollment significantly increased over the evaluation period (P < .01). There were no significant differences in racial distribution as a function of age or sex, although differences were observed on the basis of geography, study type, and study burden.

CONCLUSIONS AND RELEVANCE: This study revealed no evidence of racial and ethnic bias in enrollment for pediatric studies conducted with funding from BPCA, fulfilling the legislation’s expectation to ensure adequate representation of all children.

PMID:33846237 | DOI:10.1542/peds.2020-042903

J Investig Med. 2021 Apr 12:jim-2021-001818. doi: 10.1136/jim-2021-001818. Online ahead of print.

ABSTRACT

Undoubtedly, identification of the chemical composition of organic extracts or secondary metabolites of plant materials and evaluation of their potential bioactivity are among the main objectives of natural products-based investigations. In the present study, we report the chemical composition and antidiabetic activity of Sophora pachycarpa (Family Fabaceae) seeds extract (SPE) for the first time. First, the plant seeds were macerated in ethanol. The extract was subjected to analysis on a gas chromatography-mass spectrometry (GC-MS) system to identify the chemical composition. In vivo assay was run to evaluate the antidiabetic activity of the extract. Forty mice were divided into four groups, namely healthy mice, untreated diabetic mice, diabetic mice treated with metformin and diabetic mice treated with SPE. The antidiabetic activity of SPE was analyzed using three statistical methods, namely analysis of variance, K-means, and principal component analysis. According to GC-MS analysis, alkaloids of sophoridine, oleic acid, linoleic acid, and n-hexadecanoic acid were among the most abundant constituent components of SPE. The extract also exhibited a notable antidiabetic activity and remarkably decreased the levels of alkaline phosphatase (ALP), serum glutamic pyruvic transaminase (SGPT), and serum glutamic oxaloacetic transaminase (SGOT) enzymes. The statistical analyses revealed there are no significant differences between the ability of SPE and metformin in the regulation of fasting blood sugar level and liver enzymes (ALP, SGPT, and SGOT). A quinolizidine alkaloid, namely sophoridine, along with fatty acids, viz oleic, linoleic, and n-hexadecanoic acid, were characterized as the major compounds in S. tachycardia seeds extract. The plant extract was also found as a potent agent to reduce blood glucose and liver enzymes.

PMID:33846211 | DOI:10.1136/jim-2021-001818

Br J Sports Med. 2021 Apr 12:bjsports-2020-103604. doi: 10.1136/bjsports-2020-103604. Online ahead of print.

ABSTRACT

The inter-relationship between physical activity, sedentary behaviour and sleep (collectively defined as physical behaviours) is of interest to researchers from different fields. Each of these physical behaviours has been investigated in epidemiological studies, yet their codependency and interactions need to be further explored and accounted for in data analysis. Modern accelerometers capture continuous movement through the day, which presents the challenge of how to best use the richness of these data. In recent years, analytical approaches first applied in other scientific fields have been applied to physical behaviour epidemiology (eg, isotemporal substitution models, compositional data analysis, multivariate pattern analysis, functional data analysis and machine learning). A comprehensive description, discussion, and consensus on the strengths and limitations of these analytical approaches will help researchers decide which approach to use in different situations. In this context, a scientific workshop and meeting were held in Granada to discuss: (1) analytical approaches currently used in the scientific literature on physical behaviour, highlighting strengths and limitations, providing practical recommendations on their use and including a decision tree for assisting researchers’ decision-making; and (2) current gaps and future research directions around the analysis and use of accelerometer data. Advances in analytical approaches to accelerometer-determined physical behaviours in epidemiological studies are expected to influence the interpretation of current and future evidence, and ultimately impact on future physical behaviour guidelines.

PMID:33846158 | DOI:10.1136/bjsports-2020-103604

Antimicrob Agents Chemother. 2021 Apr 12:AAC.01573-20. doi: 10.1128/AAC.01573-20. Online ahead of print.

ABSTRACT

Discordant results for Mycobacterium tuberculosis isolates with disputed mutations between genotypic drug susceptibility testing (DST) (gDST) and phenotypic DST (pDST) impact RIF-resistant (RR) and multidrug-resistant (MDR) tuberculosis (TB) treatments due to a lack of practical clinical guidelines. To investigate the role of disputed rpoB mutations in M. tuberculosis and TB treatment outcomes, initial isolates of 837 clinical RR or MDR-TB cases confirmed during 2014-2018 were retested using agar-based RIF pDST and rpoB gene sequencing. Minimum inhibitory concentrations (MICs) were determined for isolates with disputed rpoB mutations. Disputed rpoB mutations were identified in 77 (9.2%) M. tuberculosis isolates, including 50 (64.9%) and 14 (18.2%) phenotypic RIF- and rifabutin (RFB)-resistant isolates, respectively. The predominant single mutations were L533P (44.2%) and L511P (20.8%). Most of the isolates harboring L511P (87.5%), H526N (100%), D516Y (70.0%) and L533P (63.6%) mutations had MICs ≤1 mg/L, whereas isolates harboring H526L (75%) had MICs > 1 mg/L. Of the 63 cases with treatment outcomes, 11 (17.5%) cases died, 1 (1.6%) case transferred out and 51 (81%) cases had favorable outcomes, including 8 and 20 cases treated with standard-dose RIF- and RFB-containing regimens, respectively. Excluding cases transferred out, received no or 1-day treatment, we observed statistically significant differences between active and inactive fluoroquinolones (FQs) [P =0.004, Odds ratio =0.05 (95% confidence intervals, 0.01-0.38)] in 57 cases. We concluded that disputed rpoB mutations are not rare. Depending on resources, sequencing and/or MIC testing is recommended for better management of RR and MDR-TB cases.

PMID:33846134 | DOI:10.1128/AAC.01573-20

BMJ Support Palliat Care. 2021 Apr 12:bmjspcare-2020-002878. doi: 10.1136/bmjspcare-2020-002878. Online ahead of print.

ABSTRACT

OBJECTIVES: To ask all clinical, administrative and support staff affiliated with a large network of healthcare facilities to identify the conditions that they consider as non-negotiable for their own deaths to be regarded as good.

METHODS: All 3495 staff of a healthcare network were asked to rank 10 conditions according to how non-negotiable they would be for themselves during their final 3 months or few hours for their own deaths to be considered as good. They were also asked about whether they had thought about their own death in the last 3 months, if they had a will, believed in God, and in the possibility of a good death, and the intensity of their fear of death.

RESULTS: 2971 (85%) completed the survey. Most were female (79%) and clinical staff (65%). 93% believed in God, 60% had thought about their death recently, 33% had an intense fear of death, and 4% had a will. 64% considered a good death possible. Participants ranked dying at a preferred place, emotional support from family and friends and relief from physical symptoms as their top priorities. The lowest ranked conditions were (from the bottom) relief from psychological distress, performance of rituals and the right to terminate life. There were no statistically significant differences across genders or individual occupational groups.

CONCLUSION: Most of conditions for a good death of interest to healthcare professionals could be provided without sophisticated medical infrastructure or specialised knowledge, opening the door for new support services to make it possible for everyone, anywhere.

PMID:33846127 | DOI:10.1136/bmjspcare-2020-002878