Efficacy and safety of Mavacamten for symptomatic Hypertrophic cardiomyopathy - an updated Meta-Analysis of randomized controlled trials.

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disorder with risk of sudden cardiac death (SCD) in children and adolescents. Mavacamten, also referred to as MYK-461, a myosin inhibitor of cardiac myocytes is studied in symptomatic HCM. The safety and efficacy of this medication is not well studied in pooled meta-analysis. Online database search was performed from inception to September 2023. We selected randomized clinical trials that compared Mavacamten with placebo/guideline medical treatment for HCM. We studied safety outcomes (Serious adverse events (SAEs), treatment emergent adverse events (TEAs) and Atrial fibrillation). Functional status of patients was assessed as New York Heart Association (NYHA) Classification improvement of at least + 1 grade, Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) change from baseline). Relative risk ratios were used in randomized model using Review Manager Version 5.4 statistical software. A total of 4 RCTs comprising 503 patients were included in meta-analysis. On random effect model, we found that HCM patients that received Mavacamten had significant symptomatic improvement as depicted by improvement in NYHA class by at least + 1 grade (RR = 2.15; P < 0.0001) and KCCQ CSS score improvement (MD = 8.38; P < 0.00001) as compared to placebo arm. There was no statistically significant difference in SAEs (RR = 0.87; P = 0.69) and atrial fibrillation onset (RR = 0.80; P = 0.73) between HCM and placebo arm. The studies had low heterogeneity/publication bias. Mavacamten can improve symptoms in HCM patients, and can be additive to other alternative regimen in HCM patients with no statistical significance of risk of SAE or atrial fibrillation onset as compared to placebo.

The Embolization of the Segmental Branch of Hepatic Artery Pseudoaneurysm Following Endoscopic Retrograde Cholangiopancreatography: A Case Report.

Endoscopic retrograde cholangiopancreatography (ERCP) remains the main therapeutic modality towards the management of common bile duct (CBD) stones and dilatation of strictures. It also has varied diagnostic roles including brush biopsy. The procedure still is associated with side effects and increased morbidity and mortality. One side effect is bleeding. This may be associated with procedural trauma or bleeding following post-traumatic pseudoaneurysm delayed-onset bleeding. Although it may be argued that inflammation surrounding the biliary duct area and in particular the pancreas could also contribute to the delayed bleeding along the ampullary region, we present a case of delayed pseudoaneurysm bleeding that was successfully managed post-ERCP via interventional radiology-guided embolization.

Rising mortality related to cardiovascular disease and prostate cancer amongst older men across the United States.

OBJECTIVE: There is a significant association between cardiovascular diseases (CVD) and prostate cancer (PCa), leading to high mortality. This study evaluates the trends in mortality associated with CVDs and PCa among older (≥ 65 years) men in the United States (US). METHODS: This analysis utilized the Centers for Disease Control and Prevention's Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER). The analysis of Multiple Cause of Death Files was carried out from 1999 to 2019 to identify fatalities with CVD and PCa listed as either contributory or underlying causes of death. Crude and age-adjusted mortality rates (AAMRs) per 100,000 populations for variables such as year, race and ethnicity, and geographic regions were determined. To assess annual percent change (APC), a Joinpoint regression program was employed. RESULTS: Overall AAMR was 54.3 in 1999 and 34.6 in 2019. After a decline in AAMR from 1999 to 2015, an alarming rise in mortality was observed until 2019. Mortality rates were highest among Non-Hispanic (NH) Black and African American men (74.9). Geographically, the highest mortalities were witnessed in the West (46.4) and non-metropolitan areas (44.6). States with AAMRs ranking in the 90th percentile were Nebraska, California, North Dakota, the District of Columbia, and Mississippi. CONCLUSION: After decreasing death rates associated with CVD and PCa from 1999 to 2015, a reversal in the trend was observed from 2015 to 2019. Addressing this increase in death rates, especially among the vulnerable population, requires focused attention and targeted strategies to implement necessary safeguards in the upcoming years.

Systematic Review on the Worldwide Disparities in the Frequency and Results of Emergency Medical Services (EMS) and Response to Out-of-Hospital Cardiac Arrest (OHCA).

This systematic analysis aimed to analyze the key patterns and tendencies regarding bystander interventions, emergency medical service (EMS) systems, dispatcher support, regional and temporal differences, and the influence of national efforts on survival rates in out-of-hospital cardiac arrest (OHCA). The studies published between 2010 and 2024 examining outcomes of OHCA, interventions by bystanders, and variables linked to OHCA were included in this research. The inclusion process was done under Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), where publications (n = 24) from various geographical locations, including a wide range of research methodologies, were included for this research. The thematic analysis used for the data analysis shows that bystander cardiopulmonary resuscitation (CPR) enhances the chances of survival. The effectiveness of the EMS system, the assistance offered by dispatchers, and the inclusion of doctors in ambulance services are essential components in the management of OHCA. Regional and temporal variations highlight disparities in resuscitation protocols, emphasizing the need for adaptable approaches. Observations from statewide endeavors emphasize the impact of these activities in fostering a culture of prompt bystander intervention. This systematic review presents a comprehensive analysis of research conducted globally, providing a thorough insight into the variables that influence survival rates in instances of OHCA. The review recognizes the importance of bystander CPR and effective EMS services, while also bringing novel perspectives, such as gender disparities and geographical variations that contribute to the existing body of research. Despite possible variances in the studies and biases, the findings underscore the need for tailored therapies and ongoing research to optimize strategies for controlling OHCA and improving survival rates.

Silver incorporated SeTe nanoparticles with enhanced photothermal and photodynamic properties for synergistic effects on anti-bacterial activity and wound healing.

Bacteria invade the host's immune system, thereby inducing serious infections. Current treatments for bacterial infections mostly rely on single modalities, which cannot completely inhibit bacteria. This study evaluates the therapeutic potential of SeTe-Ag NPs, designed with excellent photo responsiveness, with a particular focus on their dual-action antibacterial effect and wound healing properties. SeTe-Ag NPs exhibited promising synergistic antibacterial effects due to their superior photothermal and photodynamic properties. The investigation records substantial zones of inhibition of bacteria, demonstrating potent antibacterial effect. Furthermore, upon the irradiation of near-infrared (NIR) light, SeTe-Ag NPs exhibit remarkable antibiofilm and wound-healing capabilities. Overall, this study shows the applications of NIR-active SeTe-Ag NPs, which serve as a versatile platform for biomedical applications.

Systemic Treatment with siRNA Targeting Gamma-Secretase Activating Protein Inhibits Amyloid-ß Accumulation in Alzheimer's Disease.

Amyloid-ß (Aß) peptide aggregation in the brain is a key factor in Alzheimer's disease. However, direct inhibition of ß-secretase or γ-secretase proves ineffective in reducing Aß accumulation and improving cognition in Alzheimer's. Recent findings suggest that inhibiting gamma-secretase activating protein (GSAP) can decrease Aß generation without affecting crucial γ-secretase substrates. Dimerization of Lep9R3LC (diLep9R3LC) was confirmed by Ellman's test. The peptide-small interfering RNA (siRNA) complex ratio, particle size, and surface charge were analyzed using electrophoretic mobility shift assay, and dynamic light scattering, respectively. In a 3xTg mice model of Alzheimer's disease, diLep9R3LC:siRNA complexes were intravenously administered twice a week for 8 weeks. Assessments included gene silencing, protein expression, and behavioral improvement using reverse transcription polymerase chain reaction, quantitative polymerase chain reaction, western blotting, Y-maze, and object recognition tests. The efficacy of Lep9R3LC dimerization was ~80% after a 3-d reaction by Ellman's test. In N2a cells, diLep9R3LC:siGSAP complexes achieved ~70% silencing at 48 h posttransfection. In 7-month-old male 3xTg mice, GSAP knockdown was ~30% in the cortex and ~50% in the hippocampus. The behavior improved in mice treated with diLep9R3LC:siGSAP complexes, showing a 60% increase in entries and an 80% increase object recognition. A novel dipeptide, diLep9R3LC, complexed with siRNA targeting GSAP (siGSAP), efficiently delivers siRNA to the mouse brain, targeting the hippocampus. The treatment inhibits Aß accumulation, reduces GSK-3ß-associated with tau hyperphosphorylation, and improves Alzheimer's behavior. Our findings highlight diLep9R3LC:siGSAP's potential for Alzheimer's and as a siRNA carrier for central nervous system-related diseases.

NIR light-activated nanocomposites combat biofilm formation and enhance antibacterial efficacy for improved wound healing.

Nanoparticle-based therapies are emerging as a pivotal frontier in biomedical research, showing their potential in combating infections and facilitating wound recovery. Herein, selenium-tellurium dopped copper oxide nanoparticles (SeTe-CuO NPs) with dual photodynamic and photothermal properties were synthesized, presenting an efficient strategy for combating bacterial infections. In vitro evaluations revealed robust antibacterial activity of SeTe-CuO NPs, achieving up to 99% eradication of bacteria and significant biofilm inhibition upon near-infrared (NIR) irradiation. Moreover, in vivo studies demonstrated accelerated wound closure upon treatment with NIR-activated SeTe-CuO NPs, demonstrating their efficacy in promoting wound healing. Furthermore, SeTe-CuO NPs exhibited rapid bacterial clearance within wounds, offering a promising solution for wound care. Overall, this versatile platform holds great promise for combating multidrug-resistant bacteria and advancing therapeutic interventions in wound management.

The brown algae: Sargassum binderi sonder bears potential nephroprotective activity in in-vivo experimental model.

OBJECTIVES: This study aimed to investigate the protective activity of brown seaweed, the ethanolic and water extracts of Sargassum binderi (S. binderi) were examined. Anticancer drug, cisplatin is normally used for the treatment of solid tumors that cause acute kidney damage after assemblage in the renal tubules. MATERIAL AND METHODS: It was an acute nephrotoxicity study, animals were divided into several groups randomly, cisplatin (7mg/kg i.p.) and normal saline were used as positive and negative control respectively. The S. bindari ethanolic and water extract were given orally in a dose of 200mg/kg for 5days. Various biomarkers were assessed to observe the nephroprotective potential, while antioxidant activities were investigated using reduced glutathione, catalase and malondialdehyde as oxidative stress. GCMS was performed to validate the presence of important therapeutic moieties. RESULTS: The current result justified that pretreatment with S. binderi inhibited the elevation of antioxidant parameters and also showed protection against lipid peroxidation, induced by cisplatin challenge. The overall impact was the nephroprotection, which has been revealed from the results. GCMS evaluation of hexanes fraction revealed the presence of therapeutically important compounds including heptasiloxane, 3,7,11,15-tetramethyl-2-hexadecen-1-ol, hexadecamethyl, cyclooctasiloxane, and hexadecamethyl. These compounds have been reported for their antioxidant, antibacterial, anticancer, and antifungal activities. CONCLUSION: S. binderi showed reno-protective effect by checking their well-known biochemical parameters probably due to the antioxidant activity as confirmed by the presence of compounds.

Genetic heterogeneity in epilepsy and comorbidities: insights from Pakistani families.

BACKGROUND: Epilepsy, a challenging neurological condition, is often present with comorbidities that significantly impact diagnosis and management. In the Pakistani population, where financial limitations and geographical challenges hinder access to advanced diagnostic methods, understanding the genetic underpinnings of epilepsy and its associated conditions becomes crucial. METHODS: This study investigated four distinct Pakistani families, each presenting with epilepsy and a spectrum of comorbidities, using a combination of whole exome sequencing (WES) and Sanger sequencing. The epileptic patients were prescribed multiple antiseizure medications (ASMs), yet their seizures persist, indicating the challenging nature of ASM-resistant epilepsy. RESULTS: Identified genetic variants contributed to a diverse range of clinical phenotypes. In the family 1, which presented with epilepsy, developmental delay (DD), sleep disturbance, and aggressive behavior, a homozygous splice site variant, c.1339-6 C > T, in the COL18A1 gene was detected. The family 2 exhibited epilepsy, intellectual disability (ID), DD, and anxiety phenotypes, a homozygous missense variant, c.344T > A (p. Val115Glu), in the UFSP2 gene was identified. In family 3, which displayed epilepsy, ataxia, ID, DD, and speech impediment, a novel homozygous frameshift variant, c.1926_1941del (p. Tyr643MetfsX2), in the ZFYVE26 gene was found. Lastly, family 4 was presented with epilepsy, ID, DD, deafness, drooling, speech impediment, hypotonia, and a weak cry. A homozygous missense variant, c.1208 C > A (p. Ala403Glu), in the ATP13A2 gene was identified. CONCLUSION: This study highlights the genetic heterogeneity in ASM-resistant epilepsy and comorbidities among Pakistani families, emphasizing the importance of genotype-phenotype correlation and the necessity for expanded genetic testing in complex clinical cases.

Primary leiomyosarcoma of thyroid with pulmonary metastasis: A diagnostic odyssey.

The presented primary thyroid leiomyosarcoma (TL) case report underscores the importance of recognizing and addressing the diagnostic challenges and management complexities associated with this exceedingly rare malignancy. Given the limited effective therapeutic strategies available, timely intervention, thorough diagnostics, and vigilant follow-up are paramount in managing such intricate tumors. Further research focusing on molecular-based treatment modalities is imperative to improve patient outcomes in cases of primary TL.

Frequency of Hypomagnesemia and Its Relationship With Severity Among Patients of Acute Ischemic Stroke Presenting to a Tertiary Care Hospital.

Objective The objective of this study was to assess the prevalence of hypomagnesemia and its association with the severity of acute ischemic stroke (AIS) in patients presenting at a tertiary care hospital. Methodology A total of 100 patients with AIS were included in the study. Demographic data, including age, gender, and severity of stroke, were collected. Serum magnesium levels were measured at admission, and the severity of stroke was classified as mild, moderate, or severe based on clinical criteria. The presence of hypomagnesemia was defined as a serum magnesium level below 1.8 mg/dL determined within 72 hours of onset of stroke. Statistical analysis was performed to assess the association between hypomagnesemia, stroke severity, age, and gender. Results The mean age of the patients with standard deviation was 65.45 ± 11.8 years, with the majority (38, 38%) aged 60-74 years. There were 53 (53%) male and 47 (47%) female patients. Hypomagnesemia was found in 35 (35%) patients, with an average magnesium level of 1.93 mg/dL and a standard deviation of 0.37 at admission. There was no statistically significant difference in the distribution of stroke severity (P = 0.779; P = 0.406) or hypomagnesemia (P = 0.287; P = 0.591) based on gender or age group, respectively. Stratification based on stroke severity showed that 16 (39%) patients with mild stroke, 10 (31.3%) with moderate stroke, and 9 (33.3%) with severe stroke had hypomagnesemia. The correlation between stroke severity and hypomagnesemia was weak (r = 0.099). Further, among hypomagnesemia patients, the majority were females aged 60-74 years. Conclusions This study found a weak positive relationship between the severity of AIS and the presence of hypomagnesemia. However, no statistically significant association was observed between gender or age group and stroke severity or hypomagnesemia. These findings suggest that further research is needed to understand the role of hypomagnesemia in AIS and its potential implications for patient management.

Radiology as a career among medical students of Pakistan: A cross-sectional study.

Radiology has become a fundamental constituent of the modern medicine. However, it has been observed that medical students in Pakistan often lack sufficient guidance and education in this field. This study aims to establish whether Pakistani medical students possess the requisite basic knowledge required in radiology and their attitude and perception toward radiology as a potential career path. This cross-sectional study conducted a survey among 530 medical students of Pakistan via a self-reported online questionnaire from August 01, 2021 to September 01, 2021. The data collected were analyzed using the SPSS software, along with logistic regression analyses to identify factors associated with interest in pursuing radiology as a career and possessing a comprehensive understanding of radiology among medical students. Of the 530 participants, 44.2% rated their understanding of radiology as "poor" with only 17% indicating interest to pursue a career in radiology. Logistic regression model showed significantly higher odds of radiology as a career among males (Crude odds ratio [COR] = 1.78, 95% confidence interval [CI] = 1.17-2.72, P = .007), medical students of Punjab (COR = 1.55, 95% CI = 1.01-2.40, P = .048), and those, who self-reported their knowledge of radiology as excellent (COR = 14.35, 95% CI = 5.13-40.12, P < .001). In contrast, medical students from Punjab (COR = 0.504, 95% CI = 0.344-0.737, P < .001) and second-year medical students (COR = 0.046, 95% CI = 0.019-0.107, P < .001) had lower odds of good knowledge. Our study suggests that the medical student's knowledge of radiology is deficient. Thus, it is advised that radiological societies work with medical school boards to integrate thorough and early radiology exposure into the undergraduate curriculum.

TriClip G4: A game-changer for tricuspid valve regurgitation treatment.

Tricuspid valve regurgitation, or TR, is a difficult-to-manage condition. In addition to EVOQUE, percutaneous annuloplasty, and surgical repair, the TriClip G4 system has been added to the interventional therapeutic choices for TR. Recently, the Food and Drug Administration (FDA) approved the use of the TriClip G4 device to treat patients with symptomatic, severe TR who have received optimal medication therapy but are at intermediate or higher risk of surgery. This review attempts to offer a thorough examination of the procedural features, learning curves, results of the device and compares the TriClip G4 system to other interventional therapies for TR. TriClip G4 has shown to have promising results in pivotal clinical trials, be cost-effective, and improve the quality of life of patients. Furthermore, it has its unique advantages against other conventional techniques and devices.

Healthcare workers' knowledge and risk perception regarding the first wave of COVID-19 in Khyber Pakhtunkhwa, Pakistan: an online cross-sectional survey.

Background: Increased COVID-19 transmission among the populace may be caused by healthcare workers (HCWs) who lack knowledge, awareness, and good preventive practices. Additionally, it may cause elevated stress levels, anxiety, poor medical judgement, and situational overestimation. Objectives: The present survey aimed to assess knowledge and risk perception regarding COVID-19 among HCWs in Khyber Pakhtunkhwa (KP), Pakistan. Methodology: A web-based online, pre-tested questionnaire comprising 26 items was circulated via social media in April 2020 amongst HCWs in major tertiary care facilities in KP. Results: The study's results, revealing both the commendable knowledge levels among HCWs about COVID-19 and their heightened risk perception, highlight the critical need for targeted interventions to address the potential impact on self-protective behaviour and mental health within this vital workforce. This insight is important for designing strategies that not only enhance HCWs' well-being but also ensure the continued effectiveness of healthcare delivery during pandemics. The percentage mean score (PMS) of COVID-19 knowledge was 85.14±10.82. Male HCWs and those with an age older than or equal to 32 years demonstrated a higher knowledge score (85.62±11.08; P=0.032 and 87.59±7.33, P=0.021, respectively). About 76% of HCWs feared contracting COVID-19. Nearly 82% of respondents were mentally preoccupied with the pandemic and also terrified of it. 'Of these, 81% were nurses, 87% had a job experience of 6-8 years and 54.45% were frontline workers. Feelings of panic and concern about the pandemic were found to be more in HCWs who were physicians above the age of 32, and who had 3-5 years of work experience. HCWs' overall risk perception was found to be significantly different between males (7.04±2.26) and females (8.01±1.97), job experience of 6-10 years (8.04±177) with 3-5 years and younger than or equal to 2 years job experience (7.18±2.43,6.93±2.22), respectively, and between frontline HCWs (7.50±2.10) and non-frontline HCWs (6.84±2.40). Conclusion: HCWs demonstrated good knowledge about COVID-19. As the risk perception of COVID-19 among HCWs is high, it can raise concerns about their self-protective behaviour, and mental health. These issues need to be addressed.

Nanozyme-based sensing of dopamine using cobalt-doped hydroxyapatite nanocomposite from waste bones.

Dopamine is one of the most important neurotransmitters and plays a crucial role in various neurological, renal, and cardiovascular systems. However, the abnormal levels of dopamine mainly point to Parkinson's, Alzheimer's, cardiovascular diseases, etc. Hydroxyapatite (HAp), owing to its catalytic nature, nanoporous structure, easy synthesis, and biocompatibility, is a promising matrix material. These characteristics make HAp a material of choice for doping metals such as cobalt. The synthesized cobalt-doped hydroxyapatite (Co-HAp) was used as a colorimetric sensing platform for dopamine. The successful synthesis of the platform was confirmed by characterization with FTIR, SEM, EDX, XRD, TGA, etc. The platform demonstrated intrinsic peroxidase-like activity in the presence of H2O2, resulting in the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB). The proposed sensor detected dopamine in a linear range of 0.9-35 µM, a limit of detection of 0.51 µM, limit of quantification of 1.7 µM, and an R2 of 0.993. The optimization of the proposed sensor was done with different parameters, such as the amount of mimic enzyme, H2O2, pH, TMB concentration, and time. The proposed sensor showed the best response at 5 mg of the mimic enzyme, pH 5, 12 mM TMB, and 8 mM H2O2, with a short response time of only 2 min. The fabricated platform was successfully applied to detect dopamine in physiological solutions.

The inhibitory effects of endophytic metabolites on glycated proteins under non-communicable disease conditions: A review.

Protein glycation in human body is closely linked to the onset/progression of diabetes associated complications. These glycated proteins are commonly known as advanced glycation end products (AGEs). Recent literature has also highlighted the involvement of AGEs in other non-communicable diseases (NCDs) such as cardiovascular, cancer, and Alzheimer's diseases and explored the impact of plant metabolites on AGEs formation. However, the significance of endophytic metabolites against AGEs has recently garnered attention but has not been thoroughly summarized thus far. Therefore, the objective of this review is to provide a comprehensive overview of the importance of endophytic metabolites in combating AGEs under NCDs conditions. Additionally, this review aims to elucidate the processes of AGEs formation, absorption, metabolism, and their harmful effects. Collectively, endophytic metabolites play a crucial role in modulating signaling pathways and enhancing the digestibility properties of gut microbiota (GM) by targeting on AGEs/RAGE (receptor for AGEs) axis. Furthermore, these metabolites exhibit anti-AGEs activities similar to those derived from host plants, but at a lower cost and higher production rate. The use of endophytes as a source of such metabolites offers a risk-free and sustainable approach that holds substantial potential for the treatment and management of NCDs.