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1.
Developmental Impacts of Epigenetics and Metabolism in COVID-19.
Naik, N, Patel, M, Sen, R
Journal of developmental biology. 2024;(1)
Abstract
Developmental biology is intricately regulated by epigenetics and metabolism but the mechanisms are not completely understood. The situation becomes even more complicated during diseases where all three phenomena are dysregulated. A salient example is COVID-19, where the death toll exceeded 6.96 million in 4 years, while the virus continues to mutate into different variants and infect people. Early evidence during the pandemic showed that the host's immune and inflammatory responses to COVID-19 (like the cytokine storm) impacted the host's metabolism, causing damage to the host's organs and overall physiology. The involvement of angiotensin-converting enzyme 2 (ACE2), the pivotal host receptor for the SARS-CoV-2 virus, was identified and linked to epigenetic abnormalities along with other contributing factors. Recently, studies have revealed stronger connections between epigenetics and metabolism in COVID-19 that impact development and accelerate aging. Patients manifest systemic toxicity, immune dysfunction and multi-organ failure. Single-cell multiomics and other state-of-the-art high-throughput studies are only just beginning to demonstrate the extent of dysregulation and damage. As epigenetics and metabolism directly impact development, there is a crucial need for research implementing cutting-edge technology, next-generation sequencing, bioinformatics analysis, the identification of biomarkers and clinical trials to help with prevention and therapeutic interventions against similar threats in the future.
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2.
Optimizing warfarin dosing for patients with atrial fibrillation using machine learning.
Petch, J, Nelson, W, Wu, M, Ghassemi, M, Benz, A, Fatemi, M, Di, S, Carnicelli, A, Granger, C, Giugliano, R, et al
Scientific reports. 2024;(1):4516
Abstract
While novel oral anticoagulants are increasingly used to reduce risk of stroke in patients with atrial fibrillation, vitamin K antagonists such as warfarin continue to be used extensively for stroke prevention across the world. While effective in reducing the risk of strokes, the complex pharmacodynamics of warfarin make it difficult to use clinically, with many patients experiencing under- and/or over- anticoagulation. In this study we employed a novel implementation of deep reinforcement learning to provide clinical decision support to optimize time in therapeutic International Normalized Ratio (INR) range. We used a novel semi-Markov decision process formulation of the Batch-Constrained deep Q-learning algorithm to develop a reinforcement learning model to dynamically recommend optimal warfarin dosing to achieve INR of 2.0-3.0 for patients with atrial fibrillation. The model was developed using data from 22,502 patients in the warfarin treated groups of the pivotal randomized clinical trials of edoxaban (ENGAGE AF-TIMI 48), apixaban (ARISTOTLE) and rivaroxaban (ROCKET AF). The model was externally validated on data from 5730 warfarin-treated patients in a fourth trial of dabigatran (RE-LY) using multilevel regression models to estimate the relationship between center-level algorithm consistent dosing, time in therapeutic INR range (TTR), and a composite clinical outcome of stroke, systemic embolism or major hemorrhage. External validation showed a positive association between center-level algorithm-consistent dosing and TTR (R2 = 0.56). Each 10% increase in algorithm-consistent dosing at the center level independently predicted a 6.78% improvement in TTR (95% CI 6.29, 7.28; p < 0.001) and a 11% decrease in the composite clinical outcome (HR 0.89; 95% CI 0.81, 1.00; p = 0.015). These results were comparable to those of a rules-based clinical algorithm used for benchmarking, for which each 10% increase in algorithm-consistent dosing independently predicted a 6.10% increase in TTR (95% CI 5.67, 6.54, p < 0.001) and a 10% decrease in the composite outcome (HR 0.90; 95% CI 0.83, 0.98, p = 0.018). Our findings suggest that a deep reinforcement learning algorithm can optimize time in therapeutic range for patients taking warfarin. A digital clinical decision support system to promote algorithm-consistent warfarin dosing could optimize time in therapeutic range and improve clinical outcomes in atrial fibrillation globally.
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3.
National and regional prevalence of gestational diabetes mellitus in India: a systematic review and Meta-analysis.
Mantri, N, Goel, AD, Patel, M, Baskaran, P, Dutta, G, Gupta, MK, Yadav, V, Mittal, M, Shekhar, S, Bhardwaj, P
BMC public health. 2024;(1):527
Abstract
BACKGROUND Gestational diabetes mellitus (GDM) is frequently misdiagnosed during pregnancy. There is an abundance of evidence, but little is known regarding the regional prevalence estimates of GDM in India. This systematic review and meta-analysis aims to provide valuable insights into the national and regional prevalence of GDM among pregnant women in India. METHODS We conducted an initial article search on PubMed, Scopus, Google Scholar, and ShodhGanga searches to identify quantitative research papers (database inception till 15th June,2022). This review included prevalence studies that estimated the occurrence of GDM across different states in India. RESULTS Two independent reviewers completed the screening of 2393 articles, resulting in the identification of 110 articles that met the inclusion criteria, which collectively provided 117 prevalence estimates. Using a pooled estimate calculation (with an Inverse square heterogeneity model), the pooled prevalence of GDM in pregnant women was estimated to be 13%, with a 95% confidence interval (CI) ranging from 9 to 16%.. In India, Diabetes in Pregnancy Study of India (DIPSI) was the most common diagnostic criteria used, followed by International Association of Diabetes and Pregnancy Study Groups (IADPSG) and World Health Organization (WHO) 1999. It was observed that the rural population has slightly less prevalence of GDM at 10.0% [6.0-13.0%, I2=96%] when compared to the urban population where the prevalence of GDM was 12.0% [9.0-16.0%, I2 = 99%]. CONCLUSIONS This review emphasizes the lack of consensus in screening and diagnosing gestational diabetes mellitus (GDM), leading to varied prevalence rates across Indian states. It thoroughly examines the controversies regarding GDM screening by analyzing population characteristics, geographic variations, diagnostic criteria agreement, screening timing, fasting vs. non-fasting approaches, cost-effectiveness, and feasibility, offering valuable recommendations for policy makers. By fostering the implementation of state-wise screening programs, it can contribute to improving maternal and neonatal outcomes and promoting healthier pregnancies across the country.
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4.
Network Pharmacology, Molecular Docking, and Molecular Dynamics Simulation to Elucidate the Molecular Targets and Potential Mechanism of Phoenix dactylifera (Ajwa Dates) against Candidiasis.
Adnan, M, Siddiqui, AJ, Ashraf, SA, Bardakci, F, Alreshidi, M, Badraoui, R, Noumi, E, Tepe, B, Sachidanandan, M, Patel, M
Pathogens (Basel, Switzerland). 2023;(11)
Abstract
Candidiasis, caused by opportunistic fungal pathogens of the Candida genus, poses a significant threat to immunocompromised individuals. Natural compounds derived from medicinal plants have gained attention as potential sources of anti-fungal agents. Ajwa dates (Phoenix dactylifera L.) have been recognized for their diverse phytochemical composition and therapeutic potential. In this study, we employed a multi-faceted approach to explore the anti-candidiasis potential of Ajwa dates' phytochemicals. Utilizing network pharmacology, we constructed an interaction network to elucidate the intricate relationships between Ajwa dates phytoconstituents and the Candida-associated molecular targets of humans. Our analysis revealed key nodes in the network (STAT3, IL-2, PTPRC, STAT1, CASP1, ALB, TP53, TLR4, TNF and PPARG), suggesting the potential modulation of several crucial processes (the regulation of the response to a cytokine stimulus, regulation of the inflammatory response, positive regulation of cytokine production, cellular response to external stimulus, etc.) and fungal pathways (Th17 cell differentiation, the Toll-like receptor signaling pathway, the C-type lectin receptor signaling pathway and necroptosis). To validate these findings, molecular docking studies were conducted, revealing the binding affinities of the phytochemicals towards selected Candida protein targets of humans (ALB-rutin (-9.7 kJ/mol), STAT1-rutin (-9.2 kJ/mol), STAT3-isoquercetin (-8.7 kJ/mol), IL2-β-carotene (-8.5 kJ/mol), CASP1-β-carotene (-8.2 kJ/mol), TP53-isoquercetin (-8.8 kJ/mol), PPARG-luteolin (-8.3 kJ/mol), TNF-βcarotene (-7.7 kJ/mol), TLR4-rutin (-7.4 kJ/mol) and PTPRC-rutin (-7.0 kJ/mol)). Furthermore, molecular dynamics simulations of rutin-ALB and rutin-STAT1 complex were performed to gain insights into the stability and dynamics of the identified ligand-target complexes over time. Overall, the results not only contribute to the understanding of the molecular interactions underlying the anti-fungal potential of specific phytochemicals of Ajwa dates in humans but also provide a rational basis for the development of novel therapeutic strategies against candidiasis in humans. This study underscores the significance of network pharmacology, molecular docking and dynamics simulations in accelerating the discovery of natural products as effective anti-fungal agents. However, further experimental validation of the identified compounds is warranted to translate these findings into practical therapeutic applications.
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5.
Is Coffee and Tea a Threat or Ally to Cardiovascular Health?
Mendpara, V, Garg, S, Shah, P, Bhavsar, J, Anamika, F, Patel, M, Munjal, RS, Gupta, V, Garg, N, Jain, R
Cureus. 2023;(12):e49991
Abstract
Tea and coffee have become ingrained in our daily lives and have become the most widely consumed drinks after water. Their effects vary on an individual basis depending upon the amount of daily consumption, genetic polymorphisms, and the presence of comorbidities. Non-habitual individuals experience an initial, brief increase in blood pressure due to caffeine's vasoactive effects. Caffeine also appears to be protective against arrhythmias and heart failure. Along with having a generally cardioprotective profile, they have also demonstrated to have a favorable impact on insulin resistance and reduced risk of diabetes mellitus. Physicians often practice caution and advise patients with known cardiovascular diseases to refrain from drinking caffeine; however, studies have shown that drinking two to three cups a day has either no or some beneficial effects on both patients with or without cardiac disorders like arrhythmias. This article focuses on the effects of tea and coffee on the cardiovascular system as well as the potential mechanisms involved.
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6.
A systematic review and meta-analysis of urinary biomarkers in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Taccori, A, Maksoud, R, Eaton-Fitch, N, Patel, M, Marshall-Gradisnik, S
Journal of translational medicine. 2023;(1):440
Abstract
BACKGROUND Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a multifactorial illness that affects many body systems including the immune, nervous, endocrine, cardiovascular, and urinary systems. There is currently no universal diagnostic marker or targeted treatment for ME/CFS. Urine is a non-invasive sample that provides biomarkers that may have the potential to be used in a diagnostic capacity for ME/CFS. While there are several studies investigating urine-based biomarkers for ME/CFS, there are no published systematic reviews to summarise existing evidence of these markers. The aim of this systematic review was to compile and appraise literature on urinary-based biomarkers in ME/CFS patients compared with healthy controls. METHODS Three databases: Embase, PubMed, and Scopus were searched for articles pertaining to urinary biomarkers for ME/CFS compared with healthy controls published between December 1994 to December 2022. The final articles included in this review were determined through application of specific inclusion and exclusion criteria. Quality and bias was assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Case Control Studies. A meta-analysis according to Cochrane guidelines was conducted on select studies, in particular, those that investigate urinary free cortisol levels in ME/CFS patients compared to healthy controls using the program STATA 17. RESULTS Twenty-one studies were included in this review. All of the studies investigated urinary-based markers in ME/CFS patients compared with healthy controls. The reported changes in urinary outputs include urinary free cortisol (38.10%), carnitine (28.6%), iodine (4.76%), and the metabolome (42.86%). In most cases, there was minimal overlap in the main outcomes measured across the studies, however, differences in urinary free cortisol between ME/CFS patients and healthy controls were commonly reported. Seven studies investigating urinary free cortisol were included in the meta-analysis. While there were significant differences found in urinary free cortisol levels in ME/CFS patients, there was also substantial heterogeneity across the included studies that makes drawing conclusions difficult. CONCLUSIONS There is limited evidence suggesting a consistent and specific potential urinary-based biomarker for ME/CFS. Further investigations using more standardised methodologies and more stringent case criteria may be able to identify pathophysiological differences with diagnostic potential in ME/CFS patients compared with healthy controls.
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7.
Oral Cavity and Candida albicans: Colonisation to the Development of Infection.
Patel, M
Pathogens (Basel, Switzerland). 2022;(3)
Abstract
Candida colonisation of the oral cavity increases in immunocompromised individuals which leads to the development of oral candidiasis. In addition, host factors such as xerostomia, smoking, oral prostheses, dental caries, diabetes and cancer treatment accelerate the disease process. Candida albicans is the primary causative agent of this infection, owing to its ability to form biofilm and hyphae and to produce hydrolytic enzymes and candialysin. Although mucosal immunity is activated, from the time hyphae-associated toxin is formed by the colonising C. albicans cells, an increased number and virulence of this pathogenic organism collectively leads to infection. Prevention of the development of infection can be achieved by addressing the host physiological factors and habits. For maintenance of oral health, conventional oral hygiene products containing antimicrobial compounds, essential oils and phytochemicals can be considered, these products can maintain the low number of Candida in the oral cavity and reduce their virulence. Vulnerable patients should be educated in order to increase compliance.
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A Systematic Review of Mixed Studies Exploring the Effects of Probiotics on Gut-Microbiome to Modulate Therapy in Children With Autism Spectrum Disorder.
Patel, M, Atluri, LM, Gonzalez, NA, Sakhamuri, N, Athiyaman, S, Randhi, B, Gutlapalli, SD, Pu, J, Zaidi, MF, Khan, S
Cureus. 2022;(12):e32313
Abstract
Autism spectrum disorder(ASD) is a complex neurodevelopmental disorder characterized by social deficits, repetitive typical behaviors, insistence on the same routines, and communication impairments. The prevalence of ASD has increased in the past decade. While we are aware that there is no cure for ASD, attempts are being made to reduce its symptoms and improve the learning, overall growth, and well-being of ASD patients. Gastrointestinal (GI) symptoms are frequent occurrences in patients with ASD, but the underlying mechanisms are unknown. Recent studies show that the microbiota-gut-brain axis is the key modulator of neuropsychiatric health. Although fecal transplants have shown positive outcomes in treating dysbiosis and symptoms of autism, lifestyle modifications such as dietary intervention will prevent and treat this disorder without causing major adverse effects. Probiotics enhance the microbiome to provide necessary metabolites, which help in gut permeability, cognitive function, and immunity. In some studies, children with increased GI symptoms have also shown increased behavioral disturbances. In this study, a systematic review of mixed studies is conducted to obtain more robust and conclusive results. We included randomized controlled studies with larger sample sizes and specifications on probiotics.
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Impact of diabetes on COVID-19 mortality and hospital outcomes from a global perspective: An umbrella systematic review and meta-analysis.
Kastora, S, Patel, M, Carter, B, Delibegovic, M, Myint, PK
Endocrinology, diabetes & metabolism. 2022;(3):e00338
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Abstract
INTRODUCTION To date, COVID-19 has claimed 4.9 million lives. Diabetes has been identified as an independent risk factor of serious outcomes in people with COVID-19 infection. Whether that holds true across world regions uniformly has not been previously assessed. METHODS This study offers the first umbrella systematic review and meta-analysis to analyse the collective and geographically stratified mortality, ICU admission, ventilation requirement, illness severity and discharge rate amongst patients with diabetes. Five databases (EMBASE, MEDLINE, CAB Abstracts, PsychInfo and Web of Science) and 3 additional sources (SSRN's eLibrary, Research Square and MedRxiv) were searched from inception to 30 August 2021. Prospective and retrospective cohort studies, reporting the association between diabetes and one or more COVID-19 hospitalization outcomes, were included. This meta-analysis was registered on PROSPERO, CRD42021278579. Abbreviated MeSH terms used for search were as follows: (Diabetes) AND (2019 Novel Coronavirus Disease), adapted per database requirements. Exclusion criteria exclusion criteria were as follows: (1) none of the primary or secondary outcomes of meta-analysis reported, (2) no confirmed COVID-19 infection (laboratory or clinical) and (3) no unexposed population (solely patients with diabetes included). Quality of the included studies were assessed using the Newcastle-Ottawa Scale (NOS) whilst quality of evidence by the GRADE framework. Studies that were clinically homogeneous were pooled. Summative data and heterogeneity were generated by the Cochrane platform RevMan (V. 5.4). RESULTS Overall, 158 observational studies were included, with a total of 270,212 of participants, median age 59 [53-65 IQR] of who 56.5% were male. A total of 22 studies originated from EU, 90 from Far East, 16 from Middle East and 30 from America. Data were synthesized with mixed heterogeneity across outcomes. Pooled results highlighted those patients with diabetes were at a higher risk of COVID-19-related mortality, OR 1.87 [95%CI 1.61, 2.17]. ICU admissions increased across all studies for patients with diabetes, OR 1.59 [95%CI 1.15, 2.18], a result that was mainly skewed by Far East-originating studies, OR 1.94 [95%CI 1.51, 2.49]. Ventilation requirements were also increased amongst patients with diabetes worldwide, OR 1.44 [95%CI 1.20, 1.73] as well as their presentation with severe or critical condition, OR 2.88 [95%CI 2.29, 3.63]. HbA1C levels under <70 mmol and metformin use constituted protective factors in view of COVID-19 mortality, whilst the inverse was true for concurrent insulin use. CONCLUSIONS Whilst diabetes constitutes a poor prognosticator for various COVID-19 infection outcomes, variability across world regions is significant and may skew overall trends.
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Thymus musilii Velen. Methanolic Extract: In Vitro and In Silico Screening of Its Antimicrobial, Antioxidant, Anti-Quorum Sensing, Antibiofilm, and Anticancer Activities.
Noumi, E, Ahmad, I, Bouali, N, Patel, H, Ghannay, S, ALrashidi, AA, Abdulhakeem, MA, Patel, M, Ceylan, O, Badraoui, R, et al
Life (Basel, Switzerland). 2022;(1)
Abstract
Thymus musilii Velen. is a rare plant species cultivated in the Ha'il region (Saudi Arabia) under greenhouse conditions. In this work, we described, for the first time, the phytochemical composition, antimicrobial, antioxidant, anti-quorum sensing, and anticancer activities of T. musilii methanolic extract using both experimental and computational approaches. The obtained results showed the identification of eight small-like peptides and eighteen phyto-compounds by using high-resolution liquid chromatography-mass spectrometry (HR-LCMS) dominated mainly by compounds belonging to isoprenoid, fatty acyl, flavonoid, and alkaloid classes. The tested extracts exhibited high antifungal and antibacterial activity with the mean diameter of growth inhibition zones ranging from 12.33 ± 0.57 mm (Pseudomonas aeruginosa ATCC 27853) to 29.33 ± 1.15 mm (Candida albicans ATCC 10231). Low minimal inhibitory concentrations were recorded for the tested micro-organisms ranging from 0.781 mg/mL to 12.5 mg/mL. While higher doses were necessary to completely kill all tested bacterial and fungal strains. Thyme extract was able to scavenge DPPH•, ABTS•+, β-carotene, and FRAP free radicals, and the IC50 values were 0.077 ± 0.0015 mg/mL, 0.040 ± 0.011 mg/mL, 0.287 ± 0.012 mg/mL, and 0.106 ± 0.007 mg/mL, respectively. The highest percentage of swarming and swimming inhibition was recorded at 100 µg/mL with 39.73 ± 1.5% and 25.18 ± 1%, respectively. The highest percentage of biofilm inhibition was recorded at 10 mg/mL for S. typhimurium ATCC 14028 (53.96 ± 4.21%) and L. monocytogenes ATCC 7644 (49.54 ± 4.5 mg/mL). The in silico docking study revealed that the observed antimicrobial, antioxidant, and anticancer activities of the constituent compounds of T. musilii are thermodynamically feasible, notably, such as those of the tripeptides (Asn-Met-His, His-Cys-Asn, and Phe-His-Gln), isoprenoids (10-Hydroxyloganin), and diterpene glycosides (4-Ketoretinoic acid glucuronide).