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ABSTRACT: Background: Contemporary 0.55T magnetic resonance imaging (MRI) is promising for fetal MRI, due to the larger bore, reduced safety concerns, lower acoustic noise, and improved fast imaging capability. In this work, we explore improved fetal cardiovascular magnetic resonance (CMR) without relying on any synchronizing devices, prospective, or retrospective gating, to determine the feasibility of real-time MRI evaluation of fetal cardiac function as well as cardiac and great vessel anatomies by using spiral balanced steady-state free precession (bSSFP) at 0.55T. Methods: A real-time spiral bSSFP pulse sequence for fetal CMR was implemented and optimized on a 0.55T whole-body MRI. Fetal CMR was prospectively performed between May 2022 and August 2023. The protocol included (1) real-time images at standard cardiac views, for 10–20 s/view and 40–43.6 ms/frame and (2) 4–9 stacks of slices at standard cardiac views that each cover the whole heart, with 15–30 slices/stack, and 2–5 s/slice, at 320–349 ms/frame. Images were evaluated by a fetal cardiologist. Quantitative measurements of cardiothoracic area ratio and cardiac axis were compared with previous reports. Diagnostic accuracy was compared against postnatal echocardiographic findings. Results: Twenty-nine participants were enrolled for 32 CMR exams, with mean maternal age 33.6 ± 5.8 years (range 22–44 years) and mean gestational age 32.8 ± 3.9 weeks (range 23–38 weeks). The proposed sequence enabled evaluation of the fetal heart in

Using computational approaches, the potential efficacy and specificity of 1,3,4 trisubstituted pyrazole derivatives as MtInhA inhibitors which will aid in rational drug design for tubercular therapy were forecasted. QSARINS software was used to investigate the ability of compound to inhibit MtInhA. Three noteworthy descriptors with significant correlations and impressive statistical values were identified by the produced QSAR model: Correlation of coefficient(R2)= 0.8789, Cross-validation leave one out correlation coefficient (Q2LOO)= 0.8402, Cross-validation leave-many-out correlation coefficient(Q2LMO)=0.7321, Concordance Correlation Coefficient for cross-validation(CCCtr)=0.9355, CCCext =0.888. The descriptor generated by the QSAR model includes Centered Broto-Moreau autocorrelation weighted by Sanderson electronegativities (ATSC1e), Radial distribution functions at 15.0 and 2.0 Å inter-atomic distances weighted by relative van der Waals volumes (RDF150v), Radial distribution function – 145/weighted by relative I-state (RDF145s). Using these, three descriptor model was developed and the designed compounds were evaluated for their MtInhA inhibitory activity. Further, ADMET prediction and Molecular docking studies were carried out using Schrodinger's Software. ADMET prediction were used to evaluate drug likeliness and molecular docking was used to determine the interactions of designed compounds with the target protein. After the docking studies, the compounds were subjected for MM-GBSA calculations and MD simulation. Among the designed compounds, AP2 had the strongest binding affinity towards the MtInhA enzyme. The result of this work helps to understand the key interactions between 1,3,4 trisubstituted pyrazole derivatives and MtInhA protein that may be necessary to develop new lead compounds against tuberculosis.

Summary: In Caenorhabditis elegans, targeted genome editing techniques are now routinely used to generate germline edits. The remarkable ease of C. elegans germline editing is attributed to the syncytial nature of the pachytene ovary which is easily accessed by microinjection. This protocol describes the step-by-step details and troubleshooting tips for the entire CRISPR-Cas genome editing procedure, including gRNA design and microinjection of ribonucleoprotein complexes, followed by screening and genotyping in C. elegans, to help accessing this powerful genetic animal system.For complete details on the use and execution of this protocol, please refer to Ghanta and Mello (2020).

Introduction: A number of guidelines are available for management of congenital heart diseases from infancy to adult life. However, these guidelines are for patients living in high-income countries. Separate guidelines, applicable to Indian children, are required when recommending an intervention for congenital heart diseases, as often these patients present late in the course of the disease and may have co-existing morbidities and malnutrition. Process: Guidelines emerged following expert deliberations at the National Consensus Meeting on Management of Congenital Heart Diseases in India, held on the 10th and 11th of August, 2018 at the All India Institute of Medical Sciences. Objectives: The aim of the study was to frame evidence-based guidelines for (i) indications and optimal timing of intervention in common congenital heart diseases and (ii) follow-up protocols for patients who have undergone cardiac surgery/catheter interventions for congenital heart diseases. Recommendations: Evidence-based recommendations are provided for indications and timing of intervention in common congenital heart diseases, including left-to-right shunts, obstructive lesions, and cyanotic congenital heart diseases. In addition, protocols for follow-up of postsurgical patients are also described. Keywords: Congenital heart disease, Intervention, Surgery

Abstract Background Following acute myocardial infarction (AMI), microvascular integrity and function may be compromised as a result of microvascular obstruction (MVO) and vasodilator dysfunction. It has been observed that both infarcted and remote myocardial territories may exhibit impaired myocardial blood flow (MBF) patterns associated with an abnormal vasodilator response. Arterial spin labeled (ASL) CMR is a novel non-contrast technique that can quantitatively measure MBF. This study investigates the feasibility of ASL-CMR to assess MVO and vasodilator response in swine. Methods Thirty-one swine were included in this study. Resting ASL-CMR was performed on 24 healthy swine (baseline group). A subset of 13 swine from the baseline group underwent stress ASL-CMR to assess vasodilator response. Fifteen swine were subjected to a 90-min left anterior descending (LAD) coronary artery occlusion followed by reperfusion. Resting ASL-CMR was performed post-AMI at 1–2 days (N = 9, of which 6 were from the baseline group), 1–2 weeks (N = 8, of which 4 were from the day 1–2 group), and 4 weeks (N = 4, of which 2 were from the week 1–2 group). Resting first-pass CMR and late gadolinium enhancement (LGE) were performed post-AMI for reference. Results At rest, regional MBF and physiological noise measured from ASL-CMR were 1.08 ± 0.62 and 0.15 ± 0.10 ml/g/min, respectively. Regional MBF increased to 1.47 ± 0.62 ml/g/min with dipyridamole vasodilation (P 0.60). Conclusions ASL-CMR can assess vasodilator response in healthy swine and detect significant reduction in regional MBF at rest following AMI. ASL-CMR is an alternative to gadolinium-based techniques for assessment of MVO and microvascular integrity within infarcted, as well as salvageable and remote myocardium. This has the potential to provide early indications of adverse remodeling processes post-ischemia.

Summary: Hepatocellular carcinoma (HCC) is an aggressive primary liver cancer. However, its origin remains a debated question. Using human data and various hepatocarcinogenesis mouse models, we show that, in early stages, transformed hepatocytes, independent of their proliferation status, activate hepatic progenitor cell (HPC) expansion. Genetic lineage tracing of HPCs and hepatocytes reveals that, in all models, HCC originates from hepatocytes. However, whereas in various models tumors do not emanate from HPCs, tracking of progenitors in a model mimicking human hepatocarcinogenesis indicates that HPCs can generate benign lesions (regenerative nodules and adenomas) and aggressive HCCs. Mechanistically, galectin-3 and α-ketoglutarate paracrine signals emanating from oncogene-expressing hepatocytes instruct HPCs toward HCCs. α-Ketoglutarate preserves an HPC undifferentiated state, and galectin-3 maintains HPC stemness, expansion, and aggressiveness. Pharmacological or genetic blockage of galectin-3 reduces HCC, and its expression in human HCC correlates with poor survival. Our findings may have clinical implications for liver regeneration and HCC therapy. : Tummala et al. demonstrate that hepatocytes and hepatic progenitor cells participate in liver tumor heterogeneity. Malignant hepatocytes crosstalk and activate the neighboring progenitor cells through releases of galectin-3 and α-ketoglutarate. Blocking galectin-3 reduces hepatocarcinogenesis and may have important clinical implications. Keywords: hepatic progenitor cells, hepatocytes, lineage tracking, HCC, adenomas, regenerative nodules, galectin-3, α-ketoglutarate, NAD+, DNA damage

The present study was designed to evaluate the antioxidant potential of three natural origin drugs, namely crocin, kaempferol and podophyllotoxin by chemical, biochemical and electrochemical assays. The chemical assay was carried out by DPPH and reducing power assays while the biochemical assay evaluated the lipid peroxidation inhibition capacity, using brain cells as models; the electrochemical characterization was performed by cyclic voltammetry and differential pulse voltammetry using multi-walled carbon nanotube paste electrode (MWCNTPE) in 0.02 M acetate buffer (pH 4.5). The superoxide radical scavenging activity was performed at dropping mercury electrode (DME) in 0.1 M KCl. All the species proved to have antioxidant activity, and particularly, by the electrochemical techniques, it has been shown that these drugs showed scavenging ability on superoxide anion produced by electrochemical reduction of oxygen. The highest scavenging property of crocin may be due to the hydroxyl and glucose moieties that could provide the necessary component as a radical scavenger.

Differential pulse voltammetry (DPV) has been used to develop an electro-analytical procedure for the determination of flutamide and evaluate its interaction with DNA immobilised on the carbon paste electrode (CPE) surface. In 0.3 M phosphate buffer (pH 7.0 ± 0.01) as supporting electrolyte flutamide produced a well defined DPV peak at Ep = −0.75 V vs. SCE. The DPV study on the DNA–flutamide interaction clearly demonstrated that flutamide interacts preferentially with adenine and guanine groups in DNA. Thus, enabling to assign mechanism of action of the anticancer drug, flutamide. The developed method was successfully applied to the determination of flutamide in pharmaceutical formulations. The work has been supplemented by UV spectral study.

Objective: To estimate the burden of active infection and anti-SARS-CoV-2 IgG antibodies in Karnataka, India, and to assess variation across geographical regions and risk groups. Methods: A cross-sectional survey of 16,416 people covering three risk groups was conducted between 3–16 September 2020 using the state of Karnataka’s infrastructure of 290 healthcare facilities across all 30 districts. Participants were further classified into risk subgroups and sampled using stratified sampling. All participants were subjected to simultaneous detection of SARS-CoV-2 IgG using a commercial ELISA kit, SARS-CoV-2 antigen using a rapid antigen detection test (RAT) and reverse transcription-polymerase chain reaction (RT-PCR) for RNA detection. Maximum-likelihood estimation was used for joint estimation of the adjusted IgG, active and total prevalence (either IgG or active or both), while multinomial regression identified predictors. Results: The overall adjusted total prevalence of COVID-19 in Karnataka was 27.7% (95% CI 26.1–29.3), IgG 16.8% (15.5–18.1) and active infection fraction 12.6% (11.5–13.8). The case-to-infection ratio was 1:40 and the infection fatality rate was 0.05%. Influenza-like symptoms or contact with a COVID-19-positive patient were good predictors of active infection. RAT kits had higher sensitivity (68%) in symptomatic people compared with 47% in asymptomatic people. Conclusion: This sentinel-based population survey was the first comprehensive survey in India to provide accurate estimates of the COVID-19 burden. The findings provide a reasonable approximation of the population immunity threshold levels. Using existing surveillance platforms coupled with a syndromic approach and sampling framework enabled this model to be replicable.

Abstract Background In patients with ischemic heart disease, accurate assessment of the extent of myocardial perfusion deficit may be important in predicting prognosis of clinical cardiac outcomes. The aim of this study was to compare the ability of three dimensional (3D) and of two dimensional (2D) multi-slice myocardial perfusion imaging (MPI) using cardiovascular magnetic resonance (CMR) in determining the size of defects, and to demonstrate the feasibility of 3D MPI in healthy volunteers at 3 Tesla. Methods A heart phantom was used to compare the accuracy of 3D and 2D multi-slice MPI in estimating the volume fraction of seven rubber insets which simulated transmural myocardial perfusion defects. Three sets of cross-sectional planes were acquired for 2D multi-slice imaging, where each set was shifted along the partition encoding direction by ± 10 mm. 3D first-pass contrast-enhanced (0.1 mmol/kg Gd-DTPA) MPI was performed in three volunteers with sensitivity encoding for six-fold acceleration. The upslope of the myocardial time-intensity-curve and peak SNR/CNR values were calculated. Results Mean/standard deviation of errors in estimating the volume fraction across the seven defects were -0.44/1.49%, 2.23/2.97%, and 2.59/3.18% in 3D, 2D 4-slice, and 2D 3-slice imaging, respectively. 3D MPI performed in healthy volunteers produced excellent quality images with whole left ventricular (LV) coverage. Peak SNR/CNR was 57.6 ± 22.0/37.5 ± 19.7 over all segments in the first eight slices. Conclusion 3D performed better than 2D multi-slice MPI in estimating the size of perfusion defects in phantoms. Highly accelerated 3D MPI at 3T was feasible in volunteers, allowing whole LV coverage with excellent image quality and high SNR/CNR.

Naturally occurring gas clathrates are a significant methane resource-the primary component of natural gas, regarded as the cleanest hydrocarbon and a key feedstock for producing gray and blue hydrogen. Despite the global abundance of gas hydrate reserves, extraction via depressurization has yet to achieve commercially viable production rates. The primary limitation lies in the low permeability of hydrate-bearing sediments, where solid clathrates obstruct porous pathways, hindering dissociation and slowing gas recovery. Hydraulic fracturing has emerged as a promising technique to enhance conductivity, with initial studies indicating substantial increases in production rates when stimulation is applied. This study investigates the integration of thermodynamic hydrate inhibitors (THIs), such as methanol and polyethylene glycol 200 (PEG-200), into conventional polymer-based linear and crosslinked fracturing gels to improve performance. By targeting both rock and the embedded gas hydrates, these inhibitor integrated fracturing gels aim to facilitate faster fracture propagation and accelerate hydrate dissociation. The rheological performance of THI-integrated gels at varying concentrations is analysed, crucial for fracture formation, propagation, and proppant transport efficiency. Additionally, microscopic observations of additive interactions followed by fluid disintegration according to time are compared to evaluate residue formation and long-term integrity. Results indicate that methanol slightly increased the viscosity of linear gels at low concentrations and improved stability, reducing residue and slowing degradation, while higher concentrations required additional polymerizing agents to maintain performance. PEG-200 enhanced viscosity and stability in guar-based gels at low concentrations but caused shear-thinning at higher levels, limiting its suitability for high-viscosity operations. Crosslinked gels demonstrated superior proppant suspension and stability, generating less sediment-damaging residue compared to linear gels, with methanol further enhancing performance. Optimized integration of PEG-200 during borate crosslinking is critical, as higher concentrations risk premature gel degradation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: Osteoradionecrosis (ORN) following radiation therapy (RT) is a serious complication for patients undergoing head and neck cancer treatment. Recent literature has found an association between ipsilateral external carotid artery (ECA) diameter and the development of ORN. This study evaluates microvascular free-flap arterial anastomosis diameter and the development of ORN., Materials and Methods: Sixty-six patients underwent fibular free-flap reconstruction followed by RT between 2012-2019 at the University of Florida. Anastomosis and ECA diameters pre- and post-RT were measured from computed tomography images. Multivariate regression analysis identified significant factors in the development of ORN., Results: Incidence of ORN was 33.3 % (N = 22/66). Mean post-RT anastomosis diameters were 2.3 and 2.2 for the ORN group and no-ORN group, respectively (p = 0.548). Mean post-RT ipsilateral ECA diameters were 4.7 and 4.2 for the ORN group and no-ORN groups, respectively (p = 0.040). The change in pre-RT versus post-RT ipsilateral ECA diameters was different in patients with RT dose above and below 55 Gy (p = 0.041). Neither post-RT anastomosis (OR = 1.78, 95% CI: 0.43, 8.65, p = 0.434), nor ECA (OR = 1.44, 95% CI: 0.78, 2.83, p = 0.250) diameters were associated with development of ORN while controlling RT dose (OR = 1.15, 95% CI: 1.04, 1.28, p = 0.006), post-operative fistula (OR = 9.11, 95% CI: 1.65, 93.7, p = 0.010), and post-operative infection (OR = 3.48. 95% CI = 1.01, 12.7, p = 0.048), and CCI (OR = 0.61, 95 % CI: 0.36, 0.96, p = 0.031)., Conclusion: A higher degree of narrowing in ipsilateral ECA following RT may be linked to development of ORN. RT doses ≥ 55 Gy were associated with a high risk of ORN., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Objectives: Salvage oropharyngeal surgery with free-flap reconstruction after failed radiation therapy (RT) presents unique challenges and complications. The aim of this retrospective review is to examine surgical complications and functional outcomes in patients who received salvage surgery for recurrent or persistent oropharyngeal cancer following RT., Patients and Methods: Patients diagnosed with oropharyngeal cancer and underwent salvage oropharyngectomy at the University of Florida between 2016-2021 were identified from inpatient and outpatient records of the Head and Neck Oncology Team. Outcomes measured were tracheostomy dependence, tube-feed dependence, and intact oral intake status. Survival outcomes using Kaplan-Meier product limit method were calculated., Results and Conclusion: Twenty-six patients were included in the analysis. Average age was 63.7 years. Fourteen (53.8 %) oropharyngectomies used a transmandibular approach, ten (38.5 %) through a combined transoral and transcervical approach, and two (7.7 %) through a transcervical approach. Average time to tracheostomy decannulation was 25.1 days. At 6 months, twenty (83.3 %) patients were gastric tube independent with twelve (54.2 %) patients tolerating any oral intake. At 12 months, gastric tube independent feeds decreased to nine (60 %) patients with thirteen (92.9 %) patients tolerating oral intake. The median overall survival was 27 months with local cancer recurrence being the most common cause of death. Patients undergoing salvage oropharyngectomy for recurrent disease continue to face prolonged tracheostomy and tube dependent feedings. Despite intact swallowing function, patients preferred to use gastric tube feedings, likely for speed, ease, and convenience. Further studies are needed to analyze factors influencing these conflicting functional outcomes and predictive factors impacting survival., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Neuroblastoma is the most common extra-cranial solid tumor diagnosed mostly in children below the age of five years and comprises of about 15 % of all paediatric cancer deaths. Tumor initiating cancer stem cells (CSCs) can be targeted for better treatment approaches. BASP1-AS1 is a long non coding (Lnc) RNA that is a divergent LncRNA for its coding gene brain abundant membrane attached signal protein 1 (BASP1). We had earlier demonstrated it to be expressed in foetus derived human neural progenitor cells (hNPCs), where it was a positive regulator of BASP1 and was critical for neural differentiation. In this study, we have investigated the role of BASP1-AS1 in CSCs derived from the human neuroblastoma cell line SH-SY5Y. We cultured SH-SY5Y cells on Poly-d-Lysine coated flasks in serum free media supplemented with growth factors, which led to the enrichment of CSCs as determined by marker expression. When grown on ultra-low attachment flasks, these cells formed CSCs enriched neurospheres. We examined the effects of BASP1-AS1 siRNA mediated knockdown on CSCs enriched SH-SY5Y cells and SH-SY5Y derived neurospheres. BASP1-AS1 knockdown decreased the levels of the corresponding gene BASP1 and the rate of cell proliferation of CSCs enriched cells along with low expression of Ki67. It also reduced the mRNA levels of stem cell and pluripotency gene markers (CD133, CD44, c-KIT, SOX2, OCT4 and NANOG), as also Wnt 2 and the Wnt pathway effector β catenin. It also abrogated the formation of neurospheres in ultra-low attachment flasks. A similar effect on proliferation and stemness related properties was seen on BASP1 knockdown. BASP1-AS1 and its related pathways may provide a point of intervention for the CSCs population in neuroblastoma., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Single stranded RNA viruses are primary causative agents for pandemics, causing extensive morbidity and mortality worldwide. A pivotal question in pandemic preparedness and therapeutic intervention is what are the specific mutations which are more likely to emerge during such global health crises? This study aims to identify markers for mutations with the highest probability of emergence in these pandemics, focusing on the SARS-CoV-2 spike protein, an essential and therapeutically significant viral protein, starting from sequence information from the onset of the pandemic until July 2022. Quite consistently, we observed that emerged mutations tended to demonstrate a high genetic score, which reflects high similarity of the type of codon required for translation between an amino acid and to the mutated one. Further, this pattern is also observed in therapeutically significant proteins of other ssRNA pandemic viruses, including influenza (HA, NA), spike proteins of Ebola, envelope of Dengue and Chikungunya. We propose that the genetic score serves as an initial indicator, preceding the actual impact of the mutation on viral fitness. Finally, we developed a comprehensive computational pipeline to further explore and predict the subsequent effects of mutations on viral fitness. We believe that our pipeline can narrow down and predict future mutations in therapeutically important viral proteins during a pandemic., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: To assess the correlation between primary open-angle glaucoma (POAG) and the risk of developing diabetic retinopathy (DR) in patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM)., Design: A retrospective cohort study leveraging the global patient database of TriNetX Research Network., Participants: The study included 44 359 patients with diabetes mellitus (DM) with POAG and 4 393 300 patients with DM without any glaucoma ≥ 18 years of age. Propensity score matching harmonized the cohorts to 39 680 patients each, covering diagnoses from January 1, 2005, to January 1, 2023., Methods: We analyzed data using specific International Classification of Diseases, 10 th Revision (ICD-10) codes for DM and glaucoma. We matched the cohorts using propensity score matching, adjusting for age, sex, race/ethnicity, blood markers, relevant medical history, and ophthalmic service use., Main Outcome Measures: The primary outcome was the first-time occurrence of DR, including nonproliferative DR (NPDR) and proliferative DR (PDR), in patients with DM with and without glaucoma at 1-, 5-, and 10-year intervals from their individual index dates., Results: At 10 years, patients with T1DM with POAG exhibited a heightened risk for any DR (adjusted risk ratios [RRs], 4.12; 95% confidence interval [CI], 3.05-5.57, P < 0.0001) and PDR (RR, 7.02; 95% CI, 3.62-13.61, P < 0.0001). Patients with T2DM and POAG also faced an increased 10-year risk for any DR (RR, 2.47; 95% CI, 2.28-2.68, P < 0.0001) and PDR (RR, 3.82; 95% CI, 3.09-4.70, P < 0.0001). The combined association of POAG on DR risk in those with T1DM and T2DM at 10 years was found to be significantly higher among patients with POAG (5.45%) compared with those without glaucoma (2.12%) (adjusted hazard ratio [aHR], 2.33; 95% CI, 2.14-2.53). The cumulative incidence of DR was significantly higher in the POAG group compared with nonglaucoma counterparts after a decade (log-rank P < 0.001)., Conclusions: Our findings underscore a substantial association between POAG and DR development in both T1DM and T2DM patients, emphasizing the need for vigilant screening and comprehensive management in glaucomatous patients with DM to mitigate the risk of DR. Future research should delve into elucidating the causal mechanisms driving these observed associations., Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article., (Copyright © 2024 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Objective: We aimed to compare the electroclinical correlates of truncating and missense variants of SCN1A variants in children with Dravet syndrome (DS) and to determine phenotypic features in relation to variants identified and seizure outcomes., Methods: A single center prospective study was carried out on a South Indian cohort. Patients below 18 years of age who met the clinical criteria for DS who had undergone genetic testing and completed a minimum of one year follow up were included. We compared the differences in clinical profile, seizure outcome, developmental characteristics and anti-seizure medication (ASM) responsiveness profiles between patients with missense and truncating variants., Results: Out of a total of 3967 children with drug-resistant epilepsy during the period 2015-2021, 49 patients who fulfilled the inclusion criteria were studied. Thirty-seven had positive genetic tests, out of which 29 were SCN1A variants and 9 were other novel variants. The proportion of missense (14; 48.3%) and truncating SCN1A variants (15; 51.7%) was similar. A significant trend for developing multiple seizure types was noted among children with truncating variants (p = 0.035) and seizure freedom was more likely among children with missense variants (p = 0.042). All patients with truncating variants had ASM resistant epilepsy (p = 0.020). Developmental outcomes did not differ between the variant subtypes., Conclusion: Our results show that children harbouring missense variants demonstrated a significantly lower propensity for multiple seizure subtypes and a higher proportion with seizure freedom. However developmental implications appear to be independent of variant subtype., Competing Interests: Declaration of competing interest Nil., (Copyright © 2024 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Background: Nonalcoholic fatty liver disease (NAFLD) among Latinos is partially attributed to a prevalent C>G polymorphism in the patatin-like phospholipase 3 (PNPLA3) gene. Cross-sectional analyses in Latino children showed the association between dietary sugar and liver fat was exacerbated by GG genotype. Pediatric feeding studies show extreme sugar restriction improves liver fat, but no prior trial has examined the impact of a clinical intervention or whether effects differ by PNPLA3 genotype., Objectives: We aimed to test effects of a clinical intervention to reduce dietary sugar compared with standard dietary advice on change in liver fat, and secondary-endpoint changes in liver fibrosis, liver enzymes, and anthropometrics; and whether effects differ by PNPLA3 genotype (assessed retrospectively) in Latino youth with obesity (BMI ≥ 95th percentile)., Methods: This parallel-design trial randomly assigned participants (n = 105; mean baseline liver fat: 12.7%; mean age: 14.8 y) to control or sugar reduction (goal of ≤10% of calories from free sugar) for 12 wk. Intervention participants met with a dietitian monthly and received delivery of bottled water. Changes in liver fat, by MRI, were assessed by intervention group via general linear models., Results: Mean free sugar intake decreased in intervention compared with control [11.5% to 7.3% compared with 13.9% to 10.7% (% energy), respectively; P = 0.02], but there were no significant effects on liver outcomes or anthropometrics (Pall > 0.10), and no PNPLA3 interactions (Pall > 0.10). In exploratory analyses, participants with whole-body fat mass (FM) reduction (mean ± SD: -1.9 ± 2.4 kg), irrespective of randomization, had significant reductions in liver fat compared with participants without FM reduction (median: -2.1%; IQR: -6.5% to -0.8% compared with 0.3%; IQR: -1.0% to 1.1%; P < 0.001)., Conclusions: In Latino youth with obesity, a dietitian-led sugar reduction intervention did not improve liver outcomes compared with control, regardless of PNPLA3 genotype. Results suggest FM reduction is important for liver fat reduction, confirming clinical recommendations of weight loss and a healthy diet for pediatric NAFLD.This trial was registered at clinicaltrials.gov as NCT02948647., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

The increase in frequency and severity of heat waves during the pre-monsoon season (March-May) over Northwest India in recent decades is alarming. This study investigates the causative mechanism for warming through the forcing induced by planetary albedo changes over Northwest India, a hotspot for land-cover change. We use satellite-measured planetary albedo (α) and satellite-derived land-use-land-cover (LULC) data to estimate the impact of LULC changes from 2001 to 2018 on α and the associated radiative forcing. Over Northwest India, significant area under native land-cover, viz., barren, shrub and grass-lands, has been converted to cropland. The associated land-cover-induced changes have perturbed the radiation-budget by modifying the absorption of shortwave radiation, thereby contributing to the pronounced reduction of α as observed over this region. The diurnal-mean α has decreased by 0.016 ± 0.001 from 2001 to 2018 during pre-monsoon season which dominates α-decrease during the annual cycle over this region and contributes to the overall decreasing trend over India. Conversion of barren and shrub-lands to cropland is observed to be the greatest contributor to the α-decrease as compared to other land-cover changes. The radiative forcing due to decline in diurnal-mean α over Northwest India from 2001 to 2018 is highest during pre-monsoon at 5.99 ± 0.34 W/m 2 . This α-induced forcing averaged over the global land surface (0.02 W/m 2 ) is equivalent to the corresponding direct forcing from rise in atmospheric methane concentrations during this period. We find an enhancement in near-surface heating to be associated with change in α; the decreasing trend in α during pre-monsoon has substantially enhanced near-surface extreme effective temperatures by 3.15 ± 2.61 K thus far and may further lead to more extreme heatwaves in future. Further, our findings highlight a decreasing (warming) and increasing (cooling) trend in clear-sky planetary albedo respectively over Northwest India and coastal regions, suggesting that sudden climate change could occur if one forcing dominates over the other., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

B-cell lymphoma 2 (BCL-2) family is one of the chief regulators of cellular apoptosis. The intricate interactions between pro-apoptotic and anti-apoptotic genes of the BCL-2 family dictate the apoptotic balance of the cell. An overexpression of the anti-apoptotic members of BCL-2 is indicative of cell death evasion and cancer metastasis. Among the four BCL-2 homology domains, the BH3 domain plays a key role in the suppression of BCL-2 expression. Therefore, BH3-mimetic drugs are currently investigated for their suitability as BCL-2 inhibitors. In the present study, we followed a structure-based pharmacophore modelling approach to identify BH3-mimetic small molecules, to formulate a more precise and targeted cancer treatment regimen. To identify proteins with similar binding features, a structure-based pharmacophore model was generated based on the structure of Bcl-2 complexed with Venetoclax (PDB-ID:6O0K). Compounds with good fitness score and pharmacophore features, screened from the ZINC database, were subjected to (i) molecular docking studies, (ii) molecular mechanics-generalized Born surface area (MM-GBSA), and (iii) absorption, distribution, metabolism, excretion and toxicity (ADMET) prediction. From the analysis, two molecules were identified: ZINC68728276 and ZINC14166367, with docking scores of -7.323 and -8.649 kcal/mol and free binding energies (MM-GBSA) of -72.913 and -72.291 kcal/mol, respectively. The structural parameters and binding affinity of these complexes were validated through molecular dynamics simulation and molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) free energy calculations and compared with Venetoclax. The results indicated stability and good binding affinity of both the compounds. The study identified ZINC68728276 and ZINC14166367 as in silico potential Bcl-2 inhibitors, which can be further considered for in vitro studies., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Coronavirus disease 2019 (COVID-19) is a viral respiratory disease that has been spreading across the globe. The World Health Organization (WHO) declared it as a public health emergency. The treatment of COVID-19 has been hampered due to the lack of effective therapeutic efforts. Main Protease (M pro ) is a key enzyme in the viral replication cycle and its non-specificity to human protease makes it a potential drug target. Cyperus rotundus Linn, which belongs to the Cyperaceae family, is a traditional herbal medicine that has been widely studied for its antiviral properties. In this study, a computational approach was used to screen natural compounds from C. rotundus Linn using BIOVIA Discovery Suite and novel potential molecules against M pro of SARS-CoV-2 were predicted. Molecular docking was performed using LibDock protocol and selected ligands were further subjected to docking analysis by CDOCKER. The docking scores of the selected ligands were compared with standard antiretroviral drugs such as lopinavir and ritonavir to assess their binding potentials. Interaction pharmacophore analysis was then performed for the compounds exhibiting good binding scores to evaluate their protein-ligand interactions. The selected protein-ligand complexes were subjected to molecular dynamics simulation for 50 ns. Results of binding free energy analysis revealed that two compounds-β-amyrin and stigmasta-5,22-dien-3-ol-exhibited the best binding interactions and stability. Finally, absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies were performed to understand the pharmacokinetic properties and safety profile of the compounds. The overall results indicate that the phytochemicals from Cyperus rotundus Linn, namely β-amyrin and stigmasta-5,22-dien-3-ol, can be screened as potential inhibitors of SARS-CoV-2 M pro ., (Copyright © 2021 Elsevier Ltd. All rights reserved.)