Understanding the impact of structural modifications at the NNAT gene's post-translational acetylation site: in silico approach for predicting its drug-interaction role in anorexia nervosa.

PURPOSE: Anorexia nervosa (AN) is a neuropsychological public health concern with a socially disabling routine and affects a person's healthy relationship with food. The role of the NNAT (Neuronatin) gene in AN is well established. The impact of mutation at the protein's post-translational modification (PTM) site has been exclusively associated with the worsening of the protein's biochemical dynamics. METHODS: To understand the relationship between genotype and phenotype, it is essential to investigate the appropriate molecular stability of protein required for proper biological functioning. In this regard, we investigated the PTM-acetylation site of the NNAT gene in terms of 19 other specific amino acid probabilities in place of wild type (WT) through various in silico algorithms. Based on the highest pathogenic impact computed through the consensus classifier tool, we generated 3 residue-specific (K59D, P, W) structurally modified 3D models of NNAT. These models were further tested through the AutoDock Vina tool to compute the molecular drug binding affinities and inhibition constant (Ki) of structural variants and WT 3D models. RESULTS: With trained in silico machine learning algorithms and consensus classifier; the three structural modifications (K59D, P, W), which were also the most deleterious substitution at the acetylation site of the NNAT gene, showed the highest structural destabilization and decreased molecular flexibility. The validation and quality assessment of the 3D model of these structural modifications and WT were performed. They were further docked with drugs used to manage AN, it was found that the ΔGbind (kcal/mol) values and the inhibition constants (Ki) were relatively lower in structurally modified models as compared to WT. CONCLUSION: We concluded that any future structural variation(s) at the PTM-acetylation site of the NNAT gene due to possible mutational consequences, will serve as a basis to explore its relationship with the propensity of developing AN. LEVEL OF EVIDENCE: No level of evidence-open access bioinformatics research.

Non-resolving hepatic and lung abscess in a child: a case report from Pakistan.

Chronic granulomatous disease (CGD) is a rare, primary immunodeficiency disorder that occurs due to a defective NADPH (Nicotinamide Adenine Dinucleotide Phosphate) oxidase system. Due to the varying clinical presentation and symptom overlap with other conditions, CGD can often pose as a challenge for paediatricians. This case report describes the approach to diagnosis and management of an infant affected by CGD, with liver abscess.

In silico identification of the rare-coding pathogenic mutations and structural modeling of human NNAT gene associated with anorexia nervosa.

PURPOSE: Increased susceptibility towards anorexia nervosa (AN) was reported with reduced levels of neuronatin (NNAT) gene. We sought to investigate the most pathogenic rare-coding missense mutations, non-synonymous single-nucleotide polymorphisms (nsSNPs) of NNAT and their potential damaging impact on protein function through transcript level sequence and structure based in silico approaches. METHODS: Gene sequence, single nucleotide polymorphisms (SNPs) of NNAT was retrieved from public databases and the putative post-translational modification (PTM) sites were analyzed. Distinctive in silico algorithms were recruited for transcript level SNPs analyses and to characterized high-risk rare-coding nsSNPs along with their impact on protein stability function. Ab initio 3D-modeling of wild-type, alternate model prediction for most deleterious nsSNP, validation and recognition of druggable binding pockets were also performed. AN 3D therapeutic compounds that followed rule of drug-likeness were docked with most pathogenic variant of NNAT to estimate the drugs' binding free energies. RESULTS: Conclusively, 10 transcript (201-205)-based nsSNPs from 3 rare-coding missense variants, i.e., rs539681368, rs542858994, rs560845323 out of 840 exonic SNPs were identified. Transcript-based functional impact analyses predicted rs539681368 (C30Y) from NNAT-204 as the high-risk rare-coding pathogenic nsSNP, deviating protein functions. The 3D-modeling analysis of AN drugs' binding energies indicated lowest binding free energy (ΔG) and significant inhibition constant (Ki) with mutant models C30Y. CONCLUSIONS: Mutant model (C30Y) exhibiting significant drug binding affinity and the commonest interaction observed at the acetylation site K59. Thus, based on these findings, we concluded that the identified nsSNP may serve as potential targets for various studies, diagnosis and therapeutic interventions. LEVEL OF EVIDENCE: No level of evidence-open access bioinformatics research.

Left bundle branch pacing vs biventricular pacing in heart failure patients with left bundle branch block: A systematic review and meta-analysis.

BACKGROUND: Left bundle branch pacing (LBBP) is a novel pacing modality of cardiac resynchronization therapy (CRT) that achieves more physiologic native ventricular activation than biventricular pacing (BiVP). AIM: To explore the validity of electromechanical resynchronization, clinical and echocardiographic response of LBBP-CRT. METHODS: Systematic review and Meta-analysis were conducted in accordance with the standard guidelines as mentioned in detail in the methodology section. RESULTS: In our analysis, the success rate of LBBP-CRT was determined to be 91.1%. LBBP-CRT significantly shortened QRS duration, with significant improvement in echocardiographic parameters, including left ventricular ejection fraction, left ventricular end-diastolic diameter and left ventricular end-systolic diameter in comparison with BiVP-CRT. CONCLUSION: A significant reduction in New York Heart Association class and B-type natriuretic peptide levels was also observed in the LBBP-CRT group vs BiVP-CRT group. Lastly, the LBBP-CRT cohort had a reduced pacing threshold at follow-up as compared to BiVP-CRT.

No difference in myocardial iron concentration and serum ferritin with deferasirox and deferiprone in pediatric patients with hemoglobinopathies: A systematic review and meta-analysis.

OBJECTIVES: Iron overload is a common complication experienced by transfusion-dependent children with hemoglobin disorders. Chelators such as deferasirox (DFX) and deferiprone (DFP) are effective in overcoming this problem. We conducted this systematic review and meta-analysis to evaluate the effectiveness of DFX compared to DFP in treating iron overload amongst pediatric patients with hemoglobin disorders. MATERIAL AND METHODS: PubMed and Cochrane Central were searched from their inception until Dec 21 2021, for randomized clinical trials (RCTs) and observational studies, which assessed the efficacy of DFX compared to DFP in the treatment of inherited hemoglobin disorders. The outcomes of interest included myocardial iron concentration (MRI T2*) at the end of the trial and change in mean serum ferritin (SF) levels at the 6 and 12 months mark. Weighted mean differences (WMDs) with their corresponding 95% confidence intervals (CIs) were calculated for continuous outcomes using random effects model. RESULTS: A total of 5 studies comprising 607 children were included. The results of our analysis revealed no significant difference between DFX and DFP in MRI T2* at the end of treatment (WMD: -0.92; 95% CI [-3.35, 1.52]; p = 0.46; I2 = 0). Moreover, there has been no significant difference noted in SF levels at both 6 months (WMD: 97.31; 95% CI [-236.16, 430.77]; p = 0.57; I2 = 0) and 12 months (WMD: 46.99; 95% CI [-191.42, 285.40]; p = 0.70; I2 = 0) respectively. CONCLUSION: Our analysis shows no significant difference between the efficacy of DFX and DFP in the management of iron overload in children with inherited blood disorders. Future large-scale clinical trials are required to further validate our results.

Willingness and Perceptions Regarding COVID-19 Vaccine Booster Dose in Pakistani Vaccinated Population: A Cross-Sectional Survey.

Objectives: This study was conducted to evaluate COVID-19 vaccine booster dose willingness and identify predictors and factors of willingness and hesitance in the vaccinated population of Pakistan. Methods: A cross-sectional web-based survey was undertaken between January and February 2022 to highlight the public perceptions regarding the COVID-19 booster dose and evaluate the willingness to get the additional dose. Demographic information and booster dose willingness were recorded through the questionnaire. Additionally, a 5-point Likert scale was employed to explore fears and beliefs regarding COVID-19 vaccinations. Univariate and multivariate regression was performed to identify booster dose willingness and hesitance factors. Results: Of the 787 respondents, 69.6% were females, 75.3% fell in the 18-30 years age group, 53.5% were university students or had a Bachelor's degree. Overall, a 77.8% booster dose willingness was reported. Participants showed absence or low fear levels associated with a booster dose (47.3%). 60.1% agreed it was safe to receive an additional vaccine dose, with 44.1% agreeing that boosters are effective against coronavirus variants. Independent predictors of willingness included the absence of comorbidities, whereas not being willing to pay for the booster dose was a predictor of hesitance. Conclusion: This study showed a suboptimal willingness level of booster dose uptake among the vaccinated Pakistani population. Public health policymakers must undertake necessary awareness campaigns to strategize vaccination drives and dispel myths.