👤 Bhavik Shah

Metabolic and Bariatric Surgery (MBS) has evolved from being historically contraindicated for pediatric special needs populations to be an evidence-based standard of care. As obesity acts as a morbidity multiplier within this cohort, success with MBS is dependent on the strength of support ecosystems available to caregivers of these patients, rather than cognitive capacity. Although specific pathophysiology's such as intractable hyperphagia associated with Prader-Willi syndrome or complete MC4R deficiency may pose long-term durability challenges, many of these patients achieve weight loss and resolution of comorbidities comparable to their neurotypical peers. By applying a multidisciplinary ethical framework during the unique window of metabolic plasticity in children, clinicians can reverse life-threatening diseases prior to irreversible end organ damage occurs. This paradigm shift ensures that the most vulnerable patients are no longer denied transformative treatment based on underlying diagnoses alone. Show less

Alzheimer's disease (AD) is a neurodegenerative disorder and the predominant cause of dementia, characterized by amyloid β (Aβ) plaques and tau tangles that disrupt neurons in memory-related brain regions. This study explores the therapeutic potential of santonin using integrated Show less

The utility of emerging lipid markers-apolipoprotein B (apoB) and lipoprotein(a) (Lp[a])-for improving atherosclerotic cardiovascular disease (ASCVD) risk assessment beyond traditional lipid measures remains uncertain, particularly in young adults. To evaluate associations of traditional and emerging lipid markers with ASCVD and assess the incremental value of emerging markers beyond established risk models. This prospective cohort study included adults aged 18 years or older without cardiovascular disease from 3 US cohort studies (Coronary Artery Risk Development in Young Adults, the Framingham Heart Study Offspring, and the Multi-Ethnic Study of Atherosclerosis [MESA]). Data were analyzed from April to June 2025. Lipid markers, including low-density lipoprotein (LDL) cholesterol, non-high-density lipoprotein (HDL) cholesterol, remnant cholesterol, total-to-HDL cholesterol ratio, apoB, and Lp(a). Hazard ratios (HRs) for incident ASCVD per-SD increase in lipid marker levels, estimated using Cox proportional hazards regression models adjusted for demographic and clinical factors, and model performance metrics (Harrell concordance index [C-index], net reclassification improvement [NRI], and mean calibration) comparing models including the risk estimated by the Predicting Risk of Cardiovascular Disease Events (PREVENT) base equations against models that additionally included each lipid marker. Among 10 519 participants (mean [SD] age, 48.3 [15.7] years; 53.0% female), 1103 ASCVD events occurred during a median follow-up of 21.3 (IQR, 16.5-26.0) years. ApoB was positively associated with ASCVD events, especially in younger adults aged 18 to 39 years (adjusted HR [AHR] per-SD increase, 1.53; 95% CI, 1.30-1.79) vs those aged 40 years or older (AHR, 1.13; 95% CI, 1.06-1.20) (P < .001 for interaction). Lp(a) as a continuous variable was associated with a marginal increase in ASCVD in adults aged 40 years or older (AHR, 1.07; 95% CI, 1.00-1.16) but not in younger adults (AHR, 1.02; 95% CI, 0.87-1.19) (P = .61 for interaction). When dichotomized (>50 vs ≤50 mg/dL), Lp(a) was associated with ASCVD in adults aged 40 years or older (AHR range, 1.36; 95% CI, 1.13-1.64) but not in younger adults (AHR, 0.98; 95% CI, 0.66-1.45) (P = .42 for interaction). Adding apoB to 10-year ASCVD risk estimated by the PREVENT base equations was associated with improved risk reclassification in younger adults (continuous NRI, 0.67; 95% CI, 0.23-1.09) but not in those aged 40 years or older (continuous NRI, 0.16; 95% CI, -0.05 to 0.27). ApoB was also associated with improved 30-year risk reclassification in younger adults (continuous NRI, 0.47; 95% CI, 0.02-0.84). Dichotomized Lp(a), but not continuous Lp(a), was associated with improved 10-year NRI only in MESA (0.13; 95% CI, 0.03-0.24). In this cohort study of 10 519 adults, adding apoB to PREVENT-estimated ASCVD risks was associated with improved risk reclassification, particularly in younger adults. However, the clinical importance of these modest improvements remains uncertain. Show less

Functional decline may be an early indicator of dementia. This study examined the trajectories of frailty, grip strength, and gait speed over the 11 years prior to dementia, compared to matched individuals without dementia. A total of 1092 dementia cases were matched on age, sex and education to 4368 controls from a cohort of community-dwelling older adults recruited in Australia and the USA, aged 65 years or above at recruitment. Frailty was characterised by a deficit-accumulation index involving 67 items. Hand grip strength and gait speed were measured regularly by physical examination. Linear mixed-effects models estimated the backward trajectories of frailty, grip strength and gait speed before dementia, compared to controls. Secondary analyses were stratified by sex and ApoE ε4 carrier status. Higher frailty burden, with a steeper increase over time, was found in the years before dementia, compared to controls (P-interaction < .001). Hand grip strength and gait speed declined more rapidly in dementia cases than in controls (P-interaction < .001 for both). Differences between cases and controls became consistently significant four to six years prior to dementia (P-contrast < .001). An earlier divergence across all three measures was observed for females, and to a lesser extent in ApoE ε4 non-carriers. Functional decline occurs within the decade before dementia onset, with gait speed being the earliest indicator. These findings support the utility of functional measures as early markers of dementia risk, with potential implications for targeted monitoring and preventative strategies. Show less

Alzheimer's Disease (AD), the primary etiology of dementia, remains a considerable challenge owing to the limited availability of pharmacological interventions that effectively modify the course of the disease. This review evaluates CRISPR/Cas9 gene editing as a therapeutic strategy for AD, focusing on its capacity to target genetic drivers (e.g., APP, APOE, PSEN1/2, CD2AP) and modify disease pathology. CRISPR offers unprecedented precision in disrupting AD-associated pathogenic alleles, addressing the limitations of conventional Aβ/tau-targeted therapies that have failed in clinical trials. CRISPR corrects mutations in iPSC/organoid models, normalizing Aβ42/40 ratios and reducing tau hyperphosphorylation. Preclinical studies demonstrate reversal of amyloid accumulation and synaptic degeneration. Key challenges include off-target effects, blood-brain barrier (BBB) delivery limitations, and ethical concerns around permanent genome modifications. This study emphasizes that CRISPR/Cas9 holds transformative potential for AD therapy by targeting root genetic causes. Future success hinges on enhancing delivery systems (e.g., BBB-penetrant vectors) and integrating next-generation editors (base/prime editing) for clinical translation. Show less

Alzheimer's disease widely affects millions of people worldwide, accounting for 60% of dementia cases. Clinically classified by the presence of cognition impairment, pathophysiological representation includes deposited senile plaques, neurofibrillary tangles, and neuroinflammation. The pathogenesis of Alzheimer's disease (AD) remains multifaceted and is governed by multiple hypotheses. However, it undeniably involves amyloid-β (Aβ) accumulation and hyperphosphorylated tau (p-tau) pathology as the crucial events in disease initiation. Substantial evidence has correlated Vitamin D Show less

Alzheimer's disease (AD), a progressive neurodegenerative disorder, remains one of the greatest medical challenges because of its multifactorial nature. In recent years (2015-2025), benzothiazole-based compounds have gained increasing attention as promising scaffolds for the development of anti-Alzheimer agents. This comprehensive review focuses on the biological evaluation and structure-activity relationship (SAR) trends of benzothiazole derivatives targeting key enzymes and pathways implicated in AD. These include acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), β-secretase (BACE1), monoamine oxidase A and B (MAO-A, MAO-B), receptor-interacting protein kinase 1 (RIPK1), human DYRK1A (hDYRK1A), and human CLK1 (hCLK1). Benzothiazole hybrids with diverse heterocyclic frameworks have been explored, and SAR analysis suggests that the presence of electron-withdrawing substituents in the molecules significantly enhances their potency against Alzheimer's targets. Many of these compounds demonstrate strong in vitro activity, multitarget inhibition potential, and favorable interaction profiles in docking studies, highlighting their relevance as multitarget-directed ligands. This review consolidates data from the last decade to provide insights into the structural features contributing to anti-Alzheimer's activity and offers directions for the rational design of more selective, efficacious, and brain-penetrant benzothiazole derivatives. Future research should focus on optimizing pharmacokinetic properties, improving blood-brain barrier permeability, and validating in vivo efficacy of the designed molecules. Overall, benzothiazole remains a valuable and versatile scaffold in the ongoing search for effective therapeutics for AD. Show less

Alzheimer's disease (AD) is characterized by the gradual deterioration of cognitive functions, speech impairment, and memory loss. It can potentially be treated by targeting the beta-site amyloid precursor protein cleavage enzyme 1 (BACE1), which plays a key role in amyloid plaque formation, neurofibrillary tangles, and hyperphosphorylated tau protein. Current drugs have limitations in terms of safety, efficacy, and blood-brain barrier permeability. In view of this, this study was designed to determine the potential inhibitors of the BACE1 enzyme by virtual screening using a curated library of 415 natural products including terpenoids, phenolic compounds, and alkaloids from different medicinal plants. Based on the docking score and interaction analysis, 50 compounds were selected for the downstream analysis, such as ligand binding interactions, pharmacokinetics, druglikness and physicochemical parameters. Among the lead compounds, Palmatine (compound 45) and Berberine (compound 49), demonstrated optimal drug-likeness and blood-brain barrier permeability among the top compounds. 2-[(9Z,12Z)-heptadeca-9,12-dienyl]-6-hydroxybenzoic acid (compound 4) was inactive in most toxicity parameters. Pharmacophore analysis revealed that Palmatine and Berberine share similar features with the standard, highlighting their potential as effective compounds. Furthermore, structural chemistry analysis provided insights on their shared isoquinoline alkaloid framework, illustrating their structural similarities. Molecular dynamics simulations confirmed the stability of the Palmatine-BACE1 and Berberine-BACE1 complexes during a 50 ns production run. Overall, these findings highlighted the potential of Palmatine and Berberine as promising candidates for the experimental validation and the development of the drugs for the treatment of AD. Show less

Alzheimer's Disease (AD), a leading cause of dementia, is a known neurodegenerative disorder. Affecting millions of people worldwide, AD pathogenesis involves diverse risk factors such as lifestyle, environmental, and metabolic conditions that accelerate sporadic AD. Very recently, backed with substantial evidence, herpes simplex virus-1 (HSV-1) has been recognized as a potential causative factor that may play a pivotal role in sporadic AD. Latent virus is estimated to activate key underlying pathways, preferably Aβ and p-tau, to cause AD. Additionally, Antivirals such as Valacyclovir have emerged to impart a potential neuroprotective role in AD. Present research aimed to explore the neuroprotective role and mechanism of Valacyclovir in the streptozotocin-induced Alzheimer's disease model in rats. A single dose of 3 mg/kg ICV (intracerebroventricular) Streptozotocin (STZ) was administered to induce AD in rats. Two doses of Valacyclovir, i.e., 100 mg/kg and 150 mg/kg were evaluated with Donepezil 5 mg/kg as standard. Post 21 days of treatment, Valacyclovir demonstrated dose-dependent improvement in neurobehavioral parameters. Further, AD-specific parameters i.e. Aβ1-40 and Aβ1-42, p-tau, and BACE-1 were significantly (p < 0.001) reduced with parallel reduction in inflammatory (p < 0.001) and oxidative stress markers. Additionally, Valacyclovir also increased the levels of amyloid clearance enzymes i.e., neprilysin (NEP) (p < 0.001) and insulin-degrading enzyme (IDE) (p < 0.001). Results suggest promising neuroprotective action of valacyclovir via reducing Aβ-amyloid protein, p-Tau, BACE-1, as well as demonstrating anti-inflammatory and antioxidant activity. Show less

The statins remain the foundation of lipid management because they lower low-density lipoprotein cholesterol (LDL-C) and prevent cardiovascular events, and guidelines recommend stepwise intensification, often with ezetimibe first, when targets are not met or when intolerance limits dosing. This review introduces a mechanism-first, phenotype-guided framework that links add-on therapies to the dominant driver of residual risk, LDL-C, triglyceride-rich lipoproteins, elevated lipoprotein(a), or inherited dyslipidemia while integrating trial evidence with clinical practicality. Proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies remain the best-validated add-on for very high-risk patients. FOURIER and ODYSSEY OUTCOMES demonstrated event reduction with evolocumab or alirocumab on background statin therapy. For patients who cannot tolerate adequate statin doses, bempedoic acid provides liver-selective inhibition of adenosine triphosphate (ATP)-citrate lyase, and CLEAR Outcomes showed fewer major cardiovascular events in statin-intolerant populations. Inclisiran extends PCSK9 pathway suppression through hepatic small interfering RNA (siRNA) and enables durable LDL-C reduction with twice-yearly maintenance dosing, offering an adherence-oriented alternative while outcomes data mature. Angiopoietin-like protein 3 (ANGPTL3)-directed therapies (evinacumab and investigational RNAi agents such as zodasiran) lower atherogenic lipoproteins through largely LDL receptor independent biology. They expand options for refractory disease, including homozygous familial hypercholesterolemia. Apolipoprotein C-III (ApoC-III) inhibitors (olezarsen and plozasiran) drive large triglyceride reductions that can be decisive in severe hypertriglyceridemia and pancreatitis-prone syndromes. Next-generation cholesteryl ester transfer protein (CETP) inhibition (notably obicetrapib) has re-emerged as an oral strategy with substantial lipid effects as outcomes programs progress. High-dose eicosapentaenoic acid (EPA) (icosapent ethyl) has the clearest triglyceride-focused outcomes signal; REDUCE-IT showed significant ischemic event reduction in statin-treated patients with persistent hypertriglyceridemia. Early Show less

Elevated lipoprotein(a) [Lp(a)] is associated with a higher risk of atherosclerotic cardiovascular disease (ASCVD). Although Lp(a) is a genetically determined risk factor, the plasma proteomic features associated with Lp(a) and whether they provide information about ASCVD risk beyond Lp(a) concentration are not well characterized. We sought to identify plasma proteomic features associated with Lp(a) concentration and to evaluate whether an Lp(a)-associated proteomic signature is associated with ASCVD phenotypes in young, healthy adults. In the Coronary Artery Risk Development in Young Adults (CARDIA) study, we measured Year 7 Lp(a) and 184 cardiovascular proteins using the Olink proximity extension assay in 3,920 participants without prior coronary heart disease. Lp(a)-associated proteomic signatures were derived using LASSO regression in a split-sample design and tested for association with coronary artery calcification (CAC), incident CHD, and hs-CRP over 27 years of follow-up. External replication was performed in the UK Biobank (n=37,996). Lp(a) was associated with CAC (OR 1.23 [1.13-1.34]; p<0.0001) and incident CHD (HR 1.23 [1.07-1.41]; p=0.004). Lp(a) correlated with proteomic features reflecting immune activation, coagulation, and vascular dysfunction. A quantitative Lp(a) proteomic score was independently associated with incident CAC (standardized beta = 0.40, p<0.0001) and hs-CRP (standardized beta = 0.11, p = 0.00015) after adjustment for Lp(a) concentration. In the UK Biobank, a recalibrated Lp(a)-associated proteomic score was associated with CRP, incident CHD, and all-cause mortality. In young adults, Lp(a) is associated with distinct proteomic features that independently predict ASCVD phenotypes beyond Lp(a) concentration, generating hypotheses regarding biological pathways linked to Lp(a)-related cardiovascular risk. Show less

Lipoprotein(a) (Lp[a]) can refine atherosclerotic cardiovascular disease risk assessment and guide lipid-lowering therapy intensification (LLTI). However, the association between Lp(a) testing and LLTI across large health systems is not well characterized. Using Veterans Affairs electronic health record data, we conducted a retrospective cohort study of veterans undergoing lipid testing from January 1, 2017, to June 30, 2024. We first compared a 1:1 propensity-matched cohort with concurrent low-density lipoprotein cholesterol (LDL-C) and Lp(a) testing with those with LDL-C testing alone. We then compared veterans with elevated versus nonelevated Lp(a) (>50 versus <50 mg/dL). The primary outcome was LLTI within 12 months, defined as therapy initiation, dose escalation, or addition of another lipid-lowering agent. LDL-C goal attainment (<100 mg/dL primary prevention; <70 mg/dL secondary prevention) was assessed within 12 months. Multivariable logistic regression adjusted for sociodemographic and clinical factors. Among 6 941 840 veterans with LDL-C testing, 10 384 (0.1%) underwent Lp(a) testing. The propensity-matched cohort included 20 768 veterans (mean±SD age, 58.4±15.3 years; 12.4% women; 19.2% Black individuals). Elevated Lp(a) (>50 mg/dL) was present in 25% (n=2562). Lp(a) testing was associated with greater LLTI (odds ratio [OR], 2.11 [95% CI, 1.95-2.29]), LDL-C testing (OR, 1.27 [95% CI, 1.19-1.36]), and LDL-C goal attainment (OR, 1.22 [95% CI, 1.12-1.33]). Compared with Lp(a) <50 mg/dL, Lp(a) >50 mg/dL was associated with increased LLTI (OR, 1.73 [95% CI, 1.55-1.94]). Lp(a) >100 mg/dL was associated with lower LDL-C goal attainment (OR, 0.68 [95% CI, 0.56-0.84]). Lp(a) testing was associated with increased LLTI and LDL-C goal attainment. Elevated Lp(a) identified individuals more likely to undergo LLTI, suggesting testing may motivate preventive treatment optimization. Show less

Risk factor-weighted clinical likelihood (RF-CL) estimates the probability of obstructive coronary artery disease (CAD) in patients without known CAD. We examined whether adding lipoprotein(a) [Lp(a)] measurements to the RF-CL model improves predictions of obstructive CAD. In a derivation cohort (N = 4262; 54% male; mean age 58 years), the prevalence of obstructive CAD at invasive angiography with fractional flow reserve was assessed by Lp(a)-strata. On the basis of initial results, an Lp(a)-adjusted model (RF-CLLp(a)) was developed: RF-CL was multiplied by 1.5 in patients with elevated Lp(a) (≥125 nmol/L) and otherwise unchanged. Discrimination, calibration, and reclassification were compared. Findings were validated in an external validation cohort (N = 1595; 49% male; mean age 60 years) using a comparative endpoint; significant stenosis at invasive angiography or coronary computed tomography.In the derivation cohort, 473 patients (11.1%) had obstructive CAD; in the validation cohort, 206 patients (12.9%) had significant stenosis. The relative risk in patients with elevated Lp(a) was 1.51 [95% confidence interval (CI) 1.23-1.86] and 1.19 (95% CI 0.88-1.60) in the derivation and validation cohort, respectively. In the derivation cohort, the RF-CLLp(a) model showed a higher area under the receiver operating curve than the RF-CL model [0.743 (standard error 0.011) vs. 0.740 (0.013)] and better calibration in patients with elevated Lp(a). Reclassification from RF-CL to RF-CLLp(a) improved likelihood stratification in the derivation cohort but not in the validation cohort. Adding elevated Lp(a) as a risk factor to the RF-CL model improves accuracy of obstructive CAD in patients with high Lp(a). Show less

IntroductionPulmonary artery (PA) cannulation is emerging as a method for concurrent cardiac and respiratory failure, but limited data exists on how cannula positioning, particularly cannula tip angle, affects perfusion symmetry. Due to varying pulmonary bifurcation geometry between patients, ensuring even distribution of oxygen-saturated blood becomes critical. This computational fluid dynamics (CFD) study investigated the effects of cannula positioning and angles on oxygen delivery within the PA using 6 different configurations.MethodAn idealized PA geometry based on a CT scan was constructed including the 6 different cannula configurations: two straight (short and long) and four angled (5° and 10° toward either pulmonary branch). Simulations assumed laminar, steady-state flow at 6 L/min total (50% ECMO contribution). Oxygen transport was modeled as a passive scalar with 75% saturation from the heart and 100% from the cannula. Perfusion symmetry was quantified using the absolute difference in mean oxygen saturation (ΔSaO Show less

Deep brain stimulation (DBS) is an established therapy for motor symptom management in Parkinson's disease (PD), yet emerging evidence suggests that its effects may extend beyond functional circuit modulation to include cellular and molecular mechanisms with potential neuroprotective significance. This review synthesizes current evidence on the neuroprotective mechanisms of DBS, with an emphasis on preclinical and clinical studies that highlight its effects on neuronal survival, trophic support, oxidative stress, inflammation, synaptic plasticity, and network homeostasis. Preclinical data indicate that DBS reduces dopaminergic neuron degeneration, enhances brain-derived neurotrophic factor (BDNF) signaling, preserves mitochondrial function, attenuates neuroinflammation, and fosters synaptic remodeling. Clinical studies provide convergent, though less definitive, evidence from imaging, fluid biomarkers, and long-term outcomes supporting potential disease-modifying effects. These findings underscore a shift in the conceptualization of DBS from purely symptomatic relief toward modulation of underlying pathogenic processes. DBS holds promise as a neuroprotective therapy for PD, but critical gaps remain in validating these mechanisms in patients. Future directions include the development of biomarker-driven longitudinal studies, refinement of adaptive stimulation strategies, integration with adjunctive disease-modifying strategies, and exploration of personalized approaches based on molecular and network signatures. By bridging mechanistic understanding with translational innovation, DBS may evolve into a precision therapy capable of altering the progression trajectory of PD. Show less

To evaluate the diagnostic performance of APOA4, CEACAM1, CD147, DJ-1/PARK7, Gamma-synuclein, S100A1, and Stathmin-1 in urothelial carcinoma and establish optimal immunohistochemical cutoffs for their use as diagnostic markers. This cross-sectional study included 141 histologically confirmed urothelial carcinoma cases and controls. Immunohistochemical staining was optimized for each biomarker, and semiquantitative scoring was applied. Diagnostic validity was assessed using receiver operating characteristic (ROC) analysis, comparing sensitivity and specificity across several cutoffs and biomarker panels. Among seven biomarkers, APOA4, DJ-1/PARK7, Gamma-synuclein, and Stathmin-1 demonstrated high diagnostic accuracy (≥80% sensitivity and specificity). Using an Allred score ≤2 as a cutoff, the sensitivity/specificity were as follows: APOA4, 96%/100%; DJ-1/PARK7, 97%/94%; Gamma-synuclein, 98%/84%; and Stathmin-1, 98%/90%. A combined panel of these four biomarkers achieved near-perfect diagnostic performance, reaching almost 100% sensitivity and specificity. A biomarker panel comprising Stathmin-1, DJ-1/PARK7, Gamma-synuclein, and APOA4 reliably distinguished urothelial carcinoma from benign urothelium. These markers, when integrated with cytology, could enhance the diagnostic precision and reduce dependence on invasive cystoscopy. The proposed cutoffs (10%-20% positive cells or Allred score ≤2) offer clinically actionable threshold for histopathological practice. Show less

Apolipoprotein A-V (APOA5) is a critical regulator of circulating triglyceride (TG) levels. Its deletion leads to elevated plasma TG concentrations by altering the metabolism of VLDL particles in vivo. One way APOA5 exerts its effects is through the modulation of LPL activity, specifically by disrupting inhibitory interactions between LPL and angiopoietin-like proteins (ANGPTLs). However, the impact of APOA5 on VLDL composition and its potential to alter VLDL metabolism in other ways remains poorly understood. To address this, we investigated the influence of APOA5 on the VLDL proteome, LPL activation, and hepatic remnant uptake. Using VLDL from Apoa5 KO and WT mice, we found no evidence that APOA5 directly enhances LPL activity in purified or plasma systems. However, VLDL from Apoa5 KO mice was cleared significantly more slowly by cultured hepatocytes. VLDL proteomics experiments from two independent laboratories identified altered contents of 23 proteins involved in lipoprotein metabolism, inflammation, and immune response in Apoa5 KO VLDL, including reductions in APOE and serum amyloid A1. Remarkably, reintroduction of recombinant mouse APOA5 to the KO plasma partially restored the WT VLDL proteome, including APOE, and normalized VLDL uptake by hepatocytes without altering LPL lipolysis. These findings reveal that APOA5 influences hepatic clearance of VLDL remnants by modulating particle composition, particularly APOE content. This study expands the functional scope of APOA5 in TG metabolism and underscores its role in VLDL remodeling and remnant clearance, offering new insights with implications for understanding hypertriglyceridemia and its roles in inflammation and immune response. Show less

RNA interference (RNAi) therapy represents an evolving advancement in the management of dyslipidemia. One prominent form of RNAi therapy is small interfering RNA (siRNA), which has emerged as a promising therapeutic strategy. This study aims to critically analyze the efficacy and safety of siRNA in the treatment of dyslipidemia. PubMed, Scopus, and Web of Science servers were used to conduct a systematic search in compliance with the PRISMA guidelines. A total of 20 studies with 6651 participants were included in the analysis. The drugs used in the studies were. Inclisiran led to a notable 44.09% reduction in LDL and 37.5% in apolipoprotein levels among individuals with hypercholesterolemia. In hyperlipoproteinemia(a), therapies like Lepodisiran and Olpasiran achieved a 75.69% drop in apolipoproteins and 16.25% in LDL. For hypertriglyceridemia, agents such as ARO-APOC3 and Plozasiran showed over 50% reductions in both VLDL and triglycerides. In mixed hyperlipidemia and chylomicronemia, Plozasiran significantly reduced triglycerides by up to 79% and apolipoproteins by 87.5%. The 5 most common adverse effects reported were nasopharyngitis, diabetes mellitus (including new-onset diabetes mellitus and worsening diabetes mellitus), injection site adverse effects, back pain, and hypertension. In conclusion, the benefits of siRNA therapy in dyslipidemia management appear to outweigh its potential drawbacks, demonstrating promising efficacy and safety profiles. However, further research is necessary to fully understand its long-term effects and optimize its therapeutic potential. Show less

Promising evidence indicates that treating hearing loss with hearing aids (HAs) could reduce dementia risk. We extend this evidence by investigating the effect of HAs on plasma biomarkers of Alzheimer's disease and related dementias (ADRD). We emulated two target trials using observational data from Australian participants of the ASPREE study. Eligible participants had self-reported hearing problems, no past HA use, and were dementia-free. HA prescriptions and frequency of HA use were measured by questionnaire. Phosphorylated-tau181 (pTau181), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and amyloid-β (Aβ) 42/40 were measured after approximately 6-8 years. We estimated the effect of new HA prescription (first target trial) and the frequency of HA use (second target trial) using targeted maximum likelihood estimation, with multiple imputation for missing data. Across imputed datasets, a median of 2842 eligible individuals were included (mean age 75 years, 48% female), with a median of 735 receiving a new HA prescription. Among survivors, the estimated mean differences comparing HA prescription and no HA prescription were 1.8 pg/mL (95% CI: -0.6, 4.1), 0.1 pg/mL (-7.8, 8.0), -2.2 pg/mL (-14.5, 10.1), and -0.7 (-2.6, 1.2) for the concentrations of pTau181, NfL, GFAP, and (Aβ42 × 1000)/Aβ40, respectively. Mean differences did not differ substantially across levels of potential baseline effect modifiers, including APOE-ε4 genotype and cognition. In community-dwelling older people with hearing loss and no dementia, we found minimal effects of HA prescription and frequency of HA use on plasma ADRD biomarkers after a 7-year follow-up. Show less

Viral and neurodegenerative proteases, such as the cysteine protease and aspartyl protease, offer strategic targets in a multitarget therapeutic approach for Alzheimer's disease, especially when viral infection may exacerbate neurological degeneration. To establish a multitarget therapeutic for treating Alzheimer's disease, we chose β-secretase (BACE-1), an aspartyl protease, and the SARS-CoV-2 main protease (Mpro), a cysteine protease, as dual targets. In search of BACE-1 and M Show less

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, driven by the accumulation of amyloid-beta plaques and neurofibrillary tangles. It involves the dysfunction of key enzymes such as Acetylcholinesterase (AChE) and β-secretase (BACE1), making them critical targets for therapeutic intervention. In this study we investigated an in-house library of 820 secondary metabolites obtained from Ayurvedic plants against AChE and BACE1 with the aim to discover novel leads for AD. Virtual screening resulted in 15 ligands, mostly belonging to the ursane-type or dammarene-type triterpene saponins of Centella asiatica, reestablishing the potency of this plant in drug discovery against AD. The binding affinities were further verified by molecular dynamics (MD) simulation trajectories, including root mean square fluctuations (RMSF), root mean square deviation (RMSD), hydrogen bonding analysis, Coulomb interaction calculation, Lennard-Jones interactions, and the total interaction energy. Moreover, extensive Principal Component Analysis (PCA) and Gibbs free energy landscape were performed. Our results demonstrated three compounds, namely (S)-eriodictyol 7-O-(6-β-O-trans-p-coumaroyl)-β-d-glucopyranoside, sitoindoside-X and 1,5-di-o-caffeoyl quinic acid as more effective in treating AD due to their comparable drug-like properties. Drug-likeness, structural chemistry, pharmacophore, and ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) analysis support their potential for future drug development. To establish the effectiveness of these lead compounds against AD, additional experimental testing should be performed. Show less

The viability of cells and the integrity of the genome depend on the detection and repair of damaged DNA through intricate mechanisms. Cancer treatment employs chemotherapy or radiation therapy to eliminate neoplastic cells by causing substantial damage to their DNA. In many cases, improved DNA repair mechanisms lead to resistance to these medicines; therefore, it is essential to expand efforts to develop drugs that can sensitise cells to these treatments by inhibiting the DNA repair process. Multiple studies have demonstrated a correlation between the overexpression of Apurinic/Apyrimidinic Endonuclease (APE1), the primary mammalian enzyme responsible for excising apurinic or apyrimidinic sites in DNA, and the resistance of cells to cancer therapies; in contrast, APE1 downregulation increases cellular susceptibility to DNA-damaging agents. Thus, the effectiveness of existing therapies can be improved by promoting the targeted sensitization of cancer cells while protecting healthy cells. The current study aims to employ explainable artificial intelligence (XAI) to enhance the accuracy and reliability of machine learning models for the prediction of APE1 inhibitors. Various ML-based regression models are employed to predict the pIC50 value of different medicines. Bayesian optimization and the Permutation Feature Importance (PFI) approach are employed to determine the best hyperparameters of machine learning models and to discover the most significant features for recognizing drug candidates that target APE1 enzymes, respectively. To acquire comprehensive elucidations for the predictive models in our research, two XAI methodologies, namely SHAP and LIME, are used. The SHAP analysis reveals that the features 'C1SP2' and 'ASP-2' are essential in influencing the model's predictions. The SHAP values demonstrate variability for features such as 'maxHBint2' and 'GATS1s,' signifying that their impact is dependent on specific instances within the dataset. The LIME study corroborates these findings, demonstrating that 'C1SP2' and 'ASP-2' are the most significant positive contributors, whereas features like 'SHCHnX,' 'nHdCH2,' and 'GATS1s' result in a decrease in the predicted values. Due to the limited sample size of the APE1 dataset, direct training on this dataset posed challenges in model generalization and reliability. To overcome this limitation, the BACE-1 dataset is leveraged for model training, enabling the ML models to learn from a more extensive and diverse chemical space. Among the tested algorithms, XGBoost demonstrated superior predictive performance, achieving R Show less

Alzheimer's disease (AD) is marked by low neurotransmitter levels, inflammation, increased oxidative stress, and the aggregation of amyloid-β and tau proteins. The development of hybrid compounds acting as multi-target-directed ligands (MTDLs) is a novel and contemporary approach in Alzheimer's disease therapeutics. The objective of our current research focuses on identifying compounds with balanced, even moderate inhibition potential against multiple targets associated with cholinergic deficit and neuroinflammation. Inspired by our previous study, the thiazolidinedione-thiazole-based framework has been employed to design and synthesize a series of new hybrids. The inhibitory effects of the synthesized compounds on selected enzymes were investigated by employing in-vitro methods. The synergistic inhibition of acetylcholinesterase (AChE), monoamine oxidase-B (MAO-B), β-secretase (BACE-1), cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) by compound 49 is believed to have a more potent effect in treating Alzheimer's disease. Enzyme kinetic studies and their effect on substrate-enzyme interactions of the compounds with significant inhibitory potency for AChE and MAO-B were also investigated. Central nervous system (CNS) penetration was determined using in-vitro PAMPA assay. A neurotoxicity test on neuroblastoma cell lines (SH-SY5Y) showed that the compounds were non-toxic. Compound 49 showed an excellent neuroprotective effect by significantly reducing H Show less

Oral squamous cell carcinoma (OSCC) is a highly aggressive cancer with poor prognosis and limited response to conventional therapies. The fibroblast growth factor receptor 1 (FGFR1) has emerged as a pivotal molecular target among the oncogenic drivers of OSCC because of its critical role in tumor cell proliferation, migration, and chemoresistance. This research employed a comprehensive multi-tiered computational drug-discovery approach, integrating multi-class QSAR modeling, virtual screening, and molecular dynamics simulations, to identify novel small-molecule FGFR1 inhibitors with therapeutic potential for OSCC. The ChEMBL database was utilized to create a dataset of 3,222 distinct inhibitors, subsequently categorized into four bioactivity classes. Exploratory data analysis revealed that more potent compounds had a higher average molecular weight, an increased number of hydrogen bond acceptors, a higher count of rotatable bonds, and a higher. The ROS technique was employed on the training set to address the issue of dataset imbalance. We employed 10 distinct machine learning techniques to develop and assess multi-class QSAR models. These models explain how the chemical structures of substances connect to their biological functions mathematically. The Extra Trees (ET) classifier had the best performance, achieving a test set accuracy of 0.926 and MCC of 0.902. This made it the optimal model for our upcoming virtual screening. We employed the validated ET model to examine a repository of FDA-approved drugs and identified high-priority potential drugs. Molecular docking studies in the FGFR1 active site (PDB ID: 6MZW) followed by 200 ns molecular dynamics simulations demonstrated the stability of the top candidates. The study identified two significant lead compounds, CHEMBL155526361 and CHEMBL155529723, exhibiting robust binding affinities and strong interactions. This study provides a robust computational framework and remarkable molecular scaffolds for further preclinical investigation. This will expedite the search for innovative therapeutics for OSCC. The online version contains supplementary material available at 10.1186/s12885-025-15471-4. Show less

Pilocytic astrocytoma (PA) is a circumscribed low-grade glioma, typically defined by biphasic architecture, Rosenthal fibres, eosinophilic granular bodies, and MAPK pathway activation. However, PAs may sometimes display atypical morphologies, creating diagnostic dilemmas. DNA methylation profiling has emerged as a robust adjunct for resolving such ambiguity. We retrospectively analysed 68 gliomas with ambiguous histopathology. All underwent integrated work-up, including detailed histology, immunohistochemistry, fluorescence in situ hybridisation (FISH) for BRAF::KIAA Fusion, next-generation sequencing, transcriptomic profiling, and genome-wide DNA methylation profiling. Clinical and radiological data were reviewed with follow-up documentation. Out of 68 gliomas with ambiguous histopathological features, six cases were classified as pilocytic astrocytoma (PA) based on DNA methylation profiling. Ancillary molecular analyses revealed MAPK pathway alterations in all cases. The tumours occurred across cortical, midline, and infratentorial locations, exhibiting varied histomorphological appearances. Clinico-radiological correlation supported an indolent biological behavior, with all patients remaining alive and progression-free at 11-38 months of follow-up. Our findings emphasise the limitations of morphology-based diagnosis in histologically heterogeneous gliomas and demonstrate the critical role of DNA methylation profiling in establishing accurate classification. Adoption of integrated histological and molecular approaches is essential to avoid misclassification, prevent overtreatment, and improve prognostic assessment. Not applicable. Show less