Tag: nevin manimala

PLoS Comput Biol. 2022 Oct 5;18(10):e1010278. doi: 10.1371/journal.pcbi.1010278. Online ahead of print.

ABSTRACT

Gene set analysis (GSA) remains a common step in genome-scale studies because it can reveal insights that are not apparent from results obtained for individual genes. Many different computational tools are applied for GSA, which may be sensitive to different types of signals; however, most methods implicitly test whether there are differences in the distribution of the effect of some experimental condition between genes in gene sets of interest. We have developed a unifying framework for GSA that first fits effect size distributions, and then tests for differences in these distributions between gene sets. These differences can be in the proportions of genes that are perturbed or in the sign or size of the effects. Inspired by statistical meta-analysis, we take into account the uncertainty in effect size estimates by reducing the influence of genes with greater uncertainty on the estimation of distribution parameters. We demonstrate, using simulation and by application to real data, that this approach provides significant gains in performance over existing methods. Furthermore, the statistical tests carried out are defined in terms of effect sizes, rather than the results of prior statistical tests measuring these changes, which leads to improved interpretability and greater robustness to variation in sample sizes.

PMID:36197939 | DOI:10.1371/journal.pcbi.1010278

PLoS Comput Biol. 2022 Oct 5;18(10):e1010495. doi: 10.1371/journal.pcbi.1010495. eCollection 2022 Oct.

ABSTRACT

COVID-19 patients display a wide range of disease severity, ranging from asymptomatic to critical symptoms with high mortality risk. Our ability to understand the interaction of SARS-CoV-2 infected cells within the lung, and of protective or dysfunctional immune responses to the virus, is critical to effectively treat these patients. Currently, our understanding of cell-cell interactions across different disease states, and how such interactions may drive pathogenic outcomes, is incomplete. Here, we developed a generalizable and scalable workflow for identifying cells that are differentially interacting across COVID-19 patients with distinct disease outcomes and use this to examine eight public single-cell RNA-seq datasets (six from peripheral blood mononuclear cells, one from bronchoalveolar lavage and one from nasopharyngeal), with a total of 211 individual samples. By characterizing the cell-cell interaction patterns across epithelial and immune cells in lung tissues for patients with varying disease severity, we illustrate diverse communication patterns across individuals, and discover heterogeneous communication patterns among moderate and severe patients. We further illustrate patterns derived from cell-cell interactions are potential signatures for discriminating between moderate and severe patients. Overall, this workflow can be generalized and scaled to combine multiple scRNA-seq datasets to uncover cell-cell interactions.

PMID:36197936 | DOI:10.1371/journal.pcbi.1010495

PLoS One. 2022 Oct 5;17(10):e0273991. doi: 10.1371/journal.pone.0273991. eCollection 2022.

ABSTRACT

BACKGROUND: Over 95% of childhood injury deaths occur in low- and middle-income countries (LMICs). Patients with severe traumatic brain injury (TBI) have twice the likelihood of dying in LMICs than in high-income countries (HICs). In Africa, TBI estimates are projected to increase to upwards of 14 million new cases in 2050; however, these estimates are based on sparse data, which underscores the need for robust injury surveillance systems. We aim to describe the clinical factors associated with morbidity and mortality in pediatric TBI at the Kilimanjaro Christian Medical Centre (KCMC) in Moshi, Tanzania to guide future prevention efforts.

METHODS: We conducted a secondary analysis of a TBI registry of all pediatric (0-18 years of age) TBI patients presenting to the KCMC emergency department (ED) between May 2013 and April 2014. The variables included demographics, acute treatment and diagnostics, Glasgow Coma Scores (GCSs, severe 3-8, moderate 9-13, and mild 14-15), morbidity at discharge as measured by the Glasgow Outcome Scale (GOS, worse functional status 1-3, better functional status 4-6), and mortality status at discharge. The analysis included descriptive statistics, bivariable analysis and multivariable logistic regression to report the predictors of mortality and morbidity. The variables used in the multivariable logistic regression were selected according to their clinical validity in predicting outcomes.

RESULTS: Of the total 419 pediatric TBI patients, 286 (69.3%) were male with an average age of 10.12 years (SD = 5.7). Road traffic injury (RTI) accounted for most TBIs (269, 64.4%), followed by falls (82, 19.62%). Of the 23 patients (5.58%) who had alcohol-involved injuries, most were male (3.6:1). Severe TBI occurred in 54 (13.0%) patients. In total, 90 (24.9%) patients underwent TBI surgery. Of the 21 (5.8%) patients who died, 11 (55.0%) had severe TBI, 6 (30.0%) had moderate TBI (GCS 9-13) and 3 (15.0%) presented with mild TBI (GCS>13). The variables most strongly associated with worse functional status included having severe TBI (OR = 9.45) and waiting on the surgery floor before being moved to the intensive care unit (ICU) (OR = 14.37).

CONCLUSIONS: Most pediatric TBI patients were males who suffered RTIs or falls. Even among children under 18 years of age, alcohol was consumed by at least 5% of patients who suffered injuries, and more commonly among boys. Patients becoming unstable and having to be transferred from the surgery floor to the ICU could reflect poor risk identification in the ED or progression of injury severity. The next steps include designing interventions to reduce RTI, mitigate irresponsible alcohol use, and improve risk identification and stratification in the ED.

PMID:36197935 | DOI:10.1371/journal.pone.0273991

JMIR Form Res. 2022 Oct 5;6(10):e36275. doi: 10.2196/36275.

ABSTRACT

BACKGROUND: Obesity is a global public health concern. Interventions rely predominantly on managing dietary intake and increasing physical activity; however, sustained adherence to behavioral regimens is often poor. The lack of sustained motivation, self-efficacy, and poor adherence to behavioral regimens are recognized barriers to successful weight loss. Avatar-based interventions achieve better patient outcomes in the management of chronic conditions by promoting more active engagement. Virtual representations of self can affect real-world behavior, acting as a catalyst for sustained weight loss behavior.

OBJECTIVE: We evaluated whether a personalized avatar, offered as an adjunct to an established weight loss program, can increase participant motivation, sustain engagement, optimize service delivery, and improve participant health outcomes.

METHODS: A feasibility randomized design was used to determine the case for future development and evaluation of avatar-based technology in a randomized controlled trial. Participants were recruited from general practitioner referrals to a 12-week National Health Service weight improvement program. The main outcome measure was weight loss. Secondary outcome measures were quality-of-life and self-efficacy. Quantitative data were subjected to descriptive statistical tests and exploratory comparison between intervention and control arms. Feasibility and acceptability were assessed through interviews and analyzed using framework approach. Health Research Authority ethics approval was granted.

RESULTS: Overall, 10 men (n=7, 70% for routine care and avatar and n=3, 30% for routine care) and 33 women (n=23, 70% for intervention and n=10, 30% for routine care) were recruited. Participants’ initial mean weight was greater in the intervention arm than in the routine care arm (126.3 kg vs 122.9 kg); pattern of weight loss was similar across both arms of the study in T0 to T1 period but accelerated in T1 to T2 period for intervention participants, suggesting that access to the self-resembling avatar may promote greater engagement with weight loss initiatives in the short-to-medium term. Mean change in participants’ weight from T0 to T2 was 4.5 kg (95% CI 2.7-6.3) in the routine care arm and 5.3 kg (95% CI 3.9-6.8) in the intervention arm. Quality-of-life and self-efficacy measures demonstrated greater improvement in the intervention arm at both T1 (105.5 for routine care arm and 99.7 for intervention arm) and T2 (100.1 for routine care arm and 81.2 for intervention arm). Overall, 13 participants (n=11, 85% women and n=2, 15% men) and two health care professionals were interviewed about their experience of using the avatar program.

CONCLUSIONS: Participants found using the personalized avatar acceptable, and feedback reiterated that seeing a future self helped to reinforce motivation to change behavior. This feasibility study demonstrated that avatar-based technology may successfully promote engagement and motivation in weight loss programs, enabling participants to achieve greater weight loss gains and build self-confidence.

TRIAL REGISTRATION: ISRCTN Registry 17953876; https://doi.org/10.1186/ISRCTN17953876.

PMID:36197703 | DOI:10.2196/36275

RMD Open. 2022 Sep;8(2):e002449. doi: 10.1136/rmdopen-2022-002449.

ABSTRACT

BACKGROUND: Nailfold videocapillaroscopy (NVC) non-specific abnormalities may be present in subjects with isolated Raynaud’s phenomenon (RP) before the potential transition to systemic sclerosis (SSc) specific microvascular alterations (‘scleroderma pattern’). This study aims to investigate NVC non-specific abnormalities, notably capillary dilations, in RP patients, as possible forerunners of the ‘scleroderma pattern’.

METHODS: A 10-year retrospective NVC-based investigation evaluated 55 RP patients sorted into 3 sex-matched and age-matched groups according to clinical evolution: 18 later developing SSc (cases), 19 later developing other connective tissue disease and 18 maintaining primary RP at long-term follow-up (controls). All patients had a basal NVC showing non-specific abnormalities, namely non-specific >30 µm dilated capillaries (30-50 μm diameter). Sequential NVCs were longitudinally evaluated using current standardised approach. Statistical analysis assessed the risk for developing a ‘scleroderma pattern’.

RESULTS: Significantly larger capillary diameters were observed in cases versus controls both at basal NVC and during follow-up NVC (p=<0.05 to <0.001). Interestingly, controls showed stable NVC non-specific abnormalities over the study follow-up. The number of >30 µm dilated capillaries/mm at basal NVC was the strongest single predictor of ‘scleroderma pattern’ evolution with 24% increased risk per each dilated capillary (OR 1.24, 95% CI 1.17,1.32). Additionally, a tree-based analysis suggested the efferent (venous) diameter of the most dilated capillary on basal NVCas a variable of interest to identify patients maintaining primary RP.

CONCLUSION: This is the first study to describe an NVC ‘prescleroderma signature’ to potentially identify RP patients later developing a ‘scleroderma pattern’.

PMID:36197673 | DOI:10.1136/rmdopen-2022-002449

JAMA Netw Open. 2022 Oct 3;5(10):e2234862. doi: 10.1001/jamanetworkopen.2022.34862.

ABSTRACT

IMPORTANCE: Childhood lipid levels have been associated with adult subclinical atherosclerosis; however, life-course lipid trajectories and their associations with cardiovascular disease risk are poorly characterized.

OBJECTIVES: To examine the associations of lipid levels at different ages and discrete lipid trajectory patterns from childhood to adulthood with subclinical atherosclerosis in midlife.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study used data from the Bogalusa Heart Study, a prospective, population-based cohort study conducted in a semirural, biracial community in Bogalusa, Louisiana, with follow-up from 1973 to 2016 (median follow-up, 36.8 years). Participants had 4 to 16 repeated measurements of lipids, including total cholesterol (TC), non-high-density lipoprotein cholesterol (non-HDL-C), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG), from childhood to midlife and adult measurement of carotid intima-media thickness (IMT). Statistical analyses were conducted from July 1 to December 31, 2021.

EXPOSURES: Age-specific lipid levels were estimated, and lipid trajectory patterns were identified using latent mixture modeling.

MAIN OUTCOMES AND MEASURES: Subclinical atherosclerosis measured by carotid IMT.

RESULTS: The study evaluated 1201 adults (mean [SD] age, 45.7 [6.8] years; 691 [57.5%] women and 510 [42.5%] men; 392 Black [32.6%] and 809 White [67.4%] individuals). Levels of all lipids at each age from 5 to 45 years were significantly associated with adult IMT. The magnitude of associations generally increased with age, and non-HDL-C (age 5 y: β, 0.040; 95% CI, 0.025-0.055; age 45 y, β, 0.049; 95% CI, 0.026-0.072) and LDL-C (age 5 y: β, 0.039; 95% CI, 0.024-0.054; age 45 y, β, 0.043; 95% CI, 0.023-0.063) showed the strongest associations. After adjusting for race, sex, and other cardiovascular risk factors, mean IMT values were significantly higher in the low-slow increase, low-rapid increase, and high-stable trajectory groups for TC (eg, high-stable group: mean difference, 0.152 mm; 95% CI, 0.059-0.244 mm), the low-slow increase, low-rapid increase, moderate-stable, and high-stable trajectory groups for non-HDL-C (eg, low-slow increase group: mean difference, 0.048 mm; 95% CI, 0.012-0.085 mm) and LDL-C (eg, low-rapid increase group: mean difference, 0.104 mm; 95% CI, 0.056-0.151 mm) and the low-rapid increase and moderate-stable trajectory groups for TG (eg, moderate-stable group: mean difference, 0.071 mm; 95% CI, 0.019-0.122 mm) vs the corresponding low-stable trajectory groups. These associations were slightly attenuated after further adjustment for lipid levels at baseline or follow-up. There were no significant differences in mean IMT among HDL-C trajectory groups.

CONCLUSIONS AND RELEVANCE: In this cohort study, discrete life-course lipid trajectories were associated with the development of atherosclerosis in midlife. The findings emphasize the importance of maintaining optimal lipid levels across the lifespan.

PMID:36197664 | DOI:10.1001/jamanetworkopen.2022.34862

J Mol Neurosci. 2022 Oct 5. doi: 10.1007/s12031-022-02072-0. Online ahead of print.

ABSTRACT

Neurexin1 gene is essential for formulating synaptic cell adhesion to establish synapses. In a previous work, 38 SNPs in Neurexin1 recoded in mental disorder patients have been collected. Five computational prediction tools have been used to predict the effect of SNPs on protein function and stability. Only four SNPs in Neurexin1α have deleterious prediction results from at least four tools. The current work aims to use molecular dynamic simulation (MD) to study the effects of the four mutations on Neurexin1α both on the whole protein as well as identifying affected domains by mutations. A protein model that consists of five domains out of six domains in the real protein was used; missing residues were added, and model was tested for quality. The MD experiment has last for 1.5 μs where four parameters have been used for studying the whole protein in addition to three more parameters for the domain analysis. The whole protein study has shown that two mutations E427I for Autism and R525C for non-syndromic intellectual disability (NSID) have distinctive behavior across the four used parameters. Domain study has confirmed the previous results where the five domains of R525C have acted differently from wild type (WT), while E427I has acted differently for four domains from wild type. The other two mutations D104H and G379E have three domains that only acted differently from wild type. The fourth domain of all mutations has an obvious distinctive behavior from wild type. Further study of E427I and R525C mutations can lead to better understanding of autism and NSID.

PMID:36197641 | DOI:10.1007/s12031-022-02072-0

JAMA Dermatol. 2022 Oct 5. doi: 10.1001/jamadermatol.2022.4053. Online ahead of print.

ABSTRACT

IMPORTANCE: To our knowledge, no study has prospectively investigated sunburn patterns over age periods from childhood to adulthood and their associations with skin cancer risk.

OBJECTIVE: To identify lifetime trajectories of sunburns and compare the association between these trajectories and subsequent risk of cutaneous melanoma and squamous cell carcinoma (cSCC).

DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study included participants from the Norwegian Women and Cancer Study, established in 1991, with follow-up through 2018. Baseline questionnaires were issued from 1991 to 2007, with follow-up questionnaires every 5 to 7 years. Data analysis was performed from March 16, 2021, to December 4, 2021.

EXPOSURES: Participants reported pigmentation factors, sunbathing vacations, and indoor tanning. Annual frequencies of sunburns were reported for childhood, adolescence, and adulthood.

MAIN OUTCOMES AND MEASURES: Information on cancer diagnoses, emigration, and death were obtained through linkage to the Cancer Registry of Norway using the unique personal identification number of Norwegian citizens.

RESULTS: Of the 172 472 women (age range, 31-70 years) who returned questionnaires, 169 768 received questions about sunburns at study inclusion. Five classes (stable low, low-moderate-low, low to high, high to low, and stable high) of individual lifetime sunburn trajectories with similar shapes were estimated in 3 samples up to 39 years (n = 159 773), up to 49 years (n = 153 297), and up to 59 years (n = 119 170). Mean follow-up ranged from 14.3 to 19.5 years in the 3 samples, during which 1252 to 1774 women were diagnosed with incident primary melanoma and 739 to 871 women with incident primary cSCC. With hazard ratios (HRs) and 95% CIs estimated using a Cox proportional hazards model, the stable high and high to low trajectories showed statistically significant increased melanoma and cSCC risks compared with the stable low trajectory across all samples (≤39 years for stable high and high to low trajectories: melanoma: HR, 1.50 [95% CI, 1.28-1.75] and HR, 1.44 [95% CI, 1.20-1.73]; cSCC: HR, 1.51 [95% CI, 1.22-1.87] and HR, 1.47 [95% CI, 1.14-1.91]). Other trajectories showed increased risk, though generally weaker and mainly estimates that were not statistically significant. There was no statistically significant heterogeneity between melanoma and cSCC estimates.

CONCLUSION AND RELEVANCE: This cohort study showed that high sunburn frequency throughout life was associated with increased melanoma and cSCC risk. Furthermore, sunburns in childhood are especially important for subsequent risk of these skin cancers. Avoiding sunburns throughout life, in particular in childhood, is therefore crucial.

PMID:36197657 | DOI:10.1001/jamadermatol.2022.4053

Drugs. 2022 Oct 5. doi: 10.1007/s40265-022-01782-4. Online ahead of print.

ABSTRACT

Increasing endogenous tear film production via pharmacological neuroactivation of the nasolacrimal reflex [NLR; also known as the trigeminal parasympathetic pathway (TPP)] is a novel therapeutic approach to treating dry eye disease (DED). An intranasal formulation of the water-soluble, small-molecule, nicotinic acetylcholine receptor (nAChR) agonist varenicline (Tyrvaya™) has been approved in the USA for the treatment of DED. Twice-daily administration of varenicline solution nasal spray resulted in rapid, statistically significant and clinically meaningful improvements in the signs and symptoms of DED over a period of 4 weeks in two pivotal studies (ONSET-1 and -2). The efficacy of varenicline solution was maintained over a longer-term period of 12 weeks in a third study (MYSTIC). Consistent with the nasal route of delivery, the most common adverse events reported by varenicline solution recipients were non-ocular in nature (mild and transient sneezing and cough). Thus, varenicline solution nasal spray is a rapidly-acting, effective and generally well tolerated treatment for DED that offers several potentially useful advantages over existing topical ocular therapies in terms of increasing endogenous tear secretion and reducing ophthalmic treatment burden.

PMID:36197638 | DOI:10.1007/s40265-022-01782-4

Environ Sci Pollut Res Int. 2022 Oct 5. doi: 10.1007/s11356-022-23149-8. Online ahead of print.

ABSTRACT

Rising temperatures across the world is posing a serious challenge to the longevity of earth’s natural cycle. Use of private and conventional cars is growing year by year as standard of living continues to increase and affordability remaining no more of an issue for a significant proportion of the population. However, there has been a growing voice from segments of the society for a behavioural shift towards more sustainable modes of transport like usage of electric vehicles (EVs), mobility sharing and rental services and public transportation powered by electricity. One of the biggest importers of foreign crude oil, India, is reeling under immense pressure to reduce its carbon dioxide emissions and thereby contributing to environment protection. In India, the statistics or stock of EVs continues to remain poor when compared to its counterparts like China. Hence, this study is conducted to predict the influence of factors on purchase intention of consumers with respect to EVs in the Indian context. A questionnaire was prepared and circulated in New Delhi region to gather the responses people hold about this new technology based on the diffusion of innovation framework. The data of 225 respondents was analysed with the help of SPSS and AMOS software. Structural equation modelling technique was applied to test the hypotheses of this research. The results indicate that attitude has the most influential impact on purchase intention followed by related advantages but consumers also believe EVs to be complex in terms of their usability, limited availability and the absence of required public charging infrastructure. The mediating role of attitude between determinants of diffusion and purchase intention was also established except in the case of complexity. This study is contemporary and adds to the limited literature available on EV adoption in the Indian market by integrating attitudinal factor within the DOI framework. It also provides suitable insights to further the development of EVs in the domestic and global market.

PMID:36197612 | DOI:10.1007/s11356-022-23149-8