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Abstract Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a protein crucial for cellular stress response and survival, particularly in the nervous and cardiovascular systems. Unlike traditional neurotrophic factors, MANF primarily regulates endoplasmic reticulum (ER) stress and protects cells by reducing ER stress-induced apoptosis. MANF operates both inside and outside cells, influencing key pathways like JAK/STAT and NF-κB to enhance cell survival during stress. Beyond its neuroprotective role, MANF is also vital in cardiovascular protection, mitigating damage by reducing inflammation and maintaining cellular function. Elevated MANF levels have been observed in patients experiencing myocardial infarction and murine models of ischemia–reperfusion (I/R) injury, highlighting its importance in these conditions. Overexpression of MANF in cardiomyocytes reduces ER-stress-induced cell death, while its depletion worsens this effect. Treatment with recombinant MANF (rMANF) has been shown to improve cardiac function in mice with I/R injury by decreasing infarct size and inflammation. Research also indicates that alterations in the α1-helix region of MANF can impact its structure, expression, secretion, and overall function. Given its protective effects and involvement in critical signaling pathways, MANF is being explored as a potential therapeutic target for ER stress-related diseases, including neurodegenerative disorders and cardiovascular conditions like myocardial I/R injury.

Abstract Ischemia with non-obstructive coronary artery (INOCA) is a common cause of hospital admissions, leading to negative outcomes and reduced quality of life. Central to its pathophysiology is endothelial dysfunction, which contributes to myocardial ischemia despite the absence of significant coronary artery blockage. Addressing endothelial dysfunction is essential in managing INOCA to alleviate symptoms and prevent cardiovascular events. Recent studies have identified diabetes mellitus (DM) as a significant factor exacerbating INOCA complications by promoting endothelial impairment and coronary microvascular dysfunction. MicroRNAs (miRNAs) have emerged as potential biomarkers and therapeutic targets in various biological processes, including endothelial dysfunction and cardiovascular diseases. However, research on miRNA biomarkers in INOCA patients is sparse. In this study, we examined a panel of circulating miRNAs involved in the regulation of endothelial function in INOCA patients with and without DM. We analyzed miRNA expression using RT-qPCR in a cohort of consecutive INOCA patients undergoing percutaneous coronary intervention. We detected a significant dysregulation of miR-363-5p and miR-92a-3p in INOCA patients with DM compared to those without DM, indicating their role as biomarkers for predicting and monitoring endothelial dysfunction in INOCA patients with DM.

Key Clinical Message Immune checkpoint inhibitors can rarely lead to occurrence of myositis, myocarditis, and myasthenia gravis (MG). Early recognition and multidisciplinary management are crucial for optimal outcomes. Vigilance for overlapping toxicities is essential in patients receiving combination immunotherapy. Abstract The use of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, but it is associated with immune‐related adverse events (IRAEs) affecting various organ systems. The simultaneous occurrence of MG, myocarditis, and myositis highlights the complex nature of IRAEs. Early recognition and comprehensive multidisciplinary management are crucial for optimal patient outcomes. We present a unique case report of a 76‐year‐old male patient with advanced melanoma who developed concurrent myositis, myocarditis, and MG while receiving combination immunotherapy with Nivolumab and Ipilimumab. This case underscores the significance of recognizing and addressing the “Terrible Triad” of IRAEs in patients receiving ICIs. Healthcare providers should maintain a high index of suspicion for overlapping toxicities and promptly initiate appropriate interventions.

The need to address antimicrobial resistance (AMR) through a One Health (OH) approach is now well recognized. There is, however, limited guidance on how AMR surveillance should be implemented across sectors to generate meaningful AMR and AMU data for decision-making. Using a sympatric approach to cross-sector sample collection, Nepal adopted the WHO extended-spectrum beta-lactamase (ESBL)–producing Escherichia coli (E. coli) Tricycle Project as a step toward OH surveillance for assessing the prevalence of ESBL-producing E. coli across human, veterinary, and environment sectors. This involved a three-stage approach: identification of human hotspots (Stage 1) and sample collection sites for poultry (Stage 2) and wastewater (Stage 3). A total of 53 blood cultures from patients with bloodstream infections (BSIs), 100 stool samples from healthy pregnant women, 220 poultry ceca from slaughterhouses and live markets, and 48 wastewater samples were processed for bacterial culture and analyzed for the presence of ESBL-producing E. coli. The prevalence of ESBL-producing E. coli among isolated E. coli was the highest in wastewater samples (91%) followed by human BSIs (49%), poultry (38.6%), and fecal carriage isolates from healthy pregnant females (15%). A statistically significant association was seen in the prevalence of multidrug resistance among ESBL producers (52%) and nonproducers (26%). ESBL-producing E. coli was detected in all wastewater samples tested except for the upstream river. The findings of the study showed a high prevalence of ESBL-producing E. coli in samples from all three sectors and provided baseline data based upon which strategies for the safe disposal of communal and hospital waste, integrated AMR surveillance, and control strategies could be planned and implemented.

IntroductionIn the context of collective efforts taken in Japan to control the spread of COVID-19, the state of emergency and social distancing have caused a negative impact on the mental health of all residents, including foreign communities in Japan. This study aimed to evaluate the level of anxiety and its associated factors among non-Japanese residents residing in Japan during the COVID-19 pandemic.MethodsA web-based survey in 13 languages was conducted among non-Japanese residents living in Japan during the COVID-19 situation. The State-Trait Anxiety Inventory assessed the level of anxiety-State (STAI-S) scores prorated from its six-item version. The multivariable logistic regression using the Akaike Information Criterion (AIC) method was performed to identify the associated factors of anxiety among participants.ResultsFrom January to March 2021, we collected 392 responses. A total of 357 valid responses were analyzed. 54.6% of participants suffered from clinically significant anxiety (CSA). In multivariable logistic model analysis, the CSA status or the high level of anxiety was associated with three factors, including having troubles/difficulties in learning or working, decreased sleep duration, and decreased overall physical health (pConclusionOur study suggests several possible risk factors of anxiety among non-Japanese residents living in Japan undergoing the COVID-19 pandemic, including the troubles or difficulties in learning or working, the decrease in sleep duration, and the decrease in overall physical health.

Abstract L-Arginine (L-Arg), is a semi-essential amino acid involved in the formation of nitric oxide. The functional relevance of L-Arg in diabetes mellitus has been evaluated both in animal models and in human subjects. In the literature there are several lines of evidence indicating that L-Arg has beneficial effects in diabetes and numerous studies advocate its administration to attenuate glucose intolerance in diabetic patients. Here we present a comprehensive overview of the main studies exploring the effects of L-Arg in diabetes, including preclinical and clinical reports on this topic.

Key Clinical Message The pelvic and peritoneal hydatidosis occurs mostly after the traumatic rupture or surgical spillage of Echinococcus from liver or spleen. The treatment is surgical aiming to eradicate local disease, preventing complications, and reducing recurrences. Abstract We report a unique case of a 26‐year‐old male who presented with acute urinary retention and abdominal distention. Later, CT‐urography revealed peritoneal and pelvic hydatidosis behind this presentation, which was managed surgically.

Key Clinical Message Granulomatosis with polyangiitis (GPA), formerly known as Wegener's granulomatosis, is a necrotizing vasculitis characterized by small‐to‐medium‐sized vessel involvement and the presence of antineutrophil cytoplasmic antibodies (ANCA). We present a case of a 26‐year‐old Asian woman who was transferred to our center from a nearby hospital, where she presented with shortness of breath, tested positive for COVID‐19, and was being managed for COVID‐19 pneumonia. She also had hemoptysis, skin lesions, and left foot numbness. Serological markers and VATS‐guided lung biopsy confirmed the diagnosis. Treatment with methylprednisolone and rituximab led to stabilization, despite complications of subcutaneous emphysema and lower extremity neuropathic symptoms. Early recognition and appropriate management of GPA are crucial for optimal outcomes.

Introduction: Tracheoesophageal fistula (TEF) is a condition with an abnormal connection between the trachea and the esophagus. Type H, which is a fistula without atresia of the esophagus, accounts for only 4% of all TEF. It manifests as cyanosis, choking during breastfeeding, abdominal distention, and recurrent lung infections. It is frequently overlooked in infancy because the clinical picture is non-specific. A tracheal bronchus, also known as “pig bronchus”, is a bronchus that comes off the trachea before the carina, and has a prevalence of 1.5–2% in children. Case presentation: We present a term neonate who developed cyanosis shortly after birth while being breastfed. The patient's clinical status deteriorated and required endotracheal intubation. She subsequently developed severe abdominal distension which was suspicious for a TEF. A contrast esophagogram confirmed the diagnosis. A contrast-enhanced CT (CECT) showed a right tracheal bronchus and also confirmed the TEF. A right thoracotomy was done to ligate the TEF, and the tracheal bronchus was left unrepaired. The patient was discharged after an uneventful recovery. Conclusion: Neonates that exhibit cyanosis and respiratory distress during breastfeeding should be evaluated for a TEF. If found, the treatment is surgical ligation. There is no need to do any surgical treatment of a tracheal bronchus, unless there are clinical complications.

Introduction: Stunting refers to low height for age, resulting from chronic undernutrition, often linked to poor socio-economic conditions, maternal health, infant care, and nutrition. It hinders children's physical and cognitive development. In Nepal, over half of children under five suffer from malnutrition. Despite efforts, stunting remains high but has decreased from 57% in 1996 to 25% in 2022. The aim of the study was to find out the prevalence of stunting among children aged 6 to 59 months visiting the outpatient Department of Pediatrics in a tertiary care centre. Methods: A descriptive cross-sectional study was conducted among children aged 6 to 59 months visiting the outpatient Department of Pediatrics in a tertiary care centre after obtaining ethical approval from the Institutional Review Committee from 27 April 2023 to 15 July 2023. Anthropometric measurements were taken. World health organization standard growth charts for Z score was used appropriately for the completed age in months and gender of the child. A pre-designed questionnaire was used for face-to-face interviews. Convenience sampling method was used. The point estimate was calculated at a 95% Confidence Interval. Results: Among 320 children, 46 (14.38%) (10.54-18.22, 95% Confidence Interval) children had stunting. Among those 46 children with stunting, 20 (43.47%) had severe stunting. Conclusions: The prevalence of stunting among children aged 6 to 59 months was found to be lower than other studies done in similar settings.

Abstract Omega 3 polyunsaturated fatty acids (n-3 PUFA) are known to have beneficial effects on cardiovascular and metabolic health. However, whether different sources of n-3 PUFA, for instance fatty fish vs vegetable oils, could elicit different effects on glucose and lipid metabolism, remains to be determined. Herein we examine recent findings showing that while a plant-based n-3 PUFA supplementation for six months can reduce fasting blood glucose, marine-based n-3 PUFA can instead reduce serum levels of triglycerides. We also discuss the potential molecular mechanisms that could underlie these different effects on the regulation of glycolipid metabolism.

Abstract Restenosis, defined as the re-narrowing of an arterial lumen after revascularization, represents an increasingly important issue in clinical practice. Indeed, as the number of stent placements has risen to an estimate that exceeds 3 million annually worldwide, revascularization procedures have become much more common. Several investigators have demonstrated that vessels in patients with diabetes mellitus have an increased risk restenosis. Here we present a systematic overview of the effects of diabetes on in-stent restenosis. Current classification and updated epidemiology of restenosis are discussed, alongside the main mechanisms underlying the pathophysiology of this event. Then, we summarize the clinical presentation of restenosis, emphasizing the importance of glycemic control in diabetic patients. Indeed, in diabetic patients who underwent revascularization procedures a proper glycemic control remains imperative.

In this comprehensive review, we examine the main preclinical and clinical investigations assessing the effects of different forms of choline supplementation currently available, including choline alfoscerate (C8H20NO6P), also known as alpha-glycerophosphocholine (α-GPC, or GPC), choline bitartrate, lecithin, and citicoline, which are cholinergic compounds and precursors of acetylcholine. Extensively used as food supplements, they have been shown to represent an effective strategy for boosting memory and enhancing cognitive function.

Xanthogranulomatous cholecystitis (XGC) is a rare benign chronic inflammatory disease of the gallbladder that often presents as cholecystitis and can mimic gallbladder carcinoma. Distinguishing XGC from gallbladder cancer preoperatively is challenging. We present a case of a 62-year-old male who presented with features of carcinoma gallbladder in the CECT abdomen and MRCP. Intraoperatively, there was a mass in the gallbladder and extension into the adjacent structures with involvement of the hepatic artery, 1st part of the duodenum, portal vein, and hepatic flexure of the colon, and thus a palliative cholecystectomy was done. The histopathological report came out as XCG. The case aims to outline the clinical presentation of XGC and differentiate it from carcinoma gallbladder.

Surfactant therapy has been the mainstay of treatment in preterm neonates with respiratory distress syndrome. Delivery of surfactant through endotracheal intubation has been the commonly used technique. Intubation requires expertise and is associated with complications. In addition, there is also an increased future risk of chronic lung disease. Newer techniques of surfactant delivery abating the need of intubation have been reported. One such minimally invasive technique is surfactant administration through a supraglottic airway device. In this report, we describe the delivery of surfactants using this technique.

Emerging evidence has shown that microRNAs (miRNAs) play critical role in the pathogenesis of several disorders. In the present minireview, we focus our attention on the functional role of a specific miRNA, namely miR-34a, in the pathophysiology of frailty and diabetes mellitus. Based on the current literature, we speculate that this miRNA may serve as a potential biomarker of frailty in diabetic older adults. Additionally, its actions on oxidative stress might represent a druggable target to obtain new potentials treatments.

BACKGROUND: Prediabetes has garnered increasing attention due to its association with cardiovascular conditions, especially hypertension, which heightens the risk of prefrailty and frailty among older individuals. METHODS: We screened elders with prefrail hypertension from March 2021 to January 2023. We assessed the correlation linking cognitive dysfunction (Montreal Cognitive Assessment score), insulin resistance (triglyceride-to-glucose index), and physical impairment (5-meter gait speed). Then, we measured the risk of developing frailty after a 1-year follow-up period, adjusting the outcome using multivariable Cox regression analysis. We also investigated the impact of administering 500 mg of metformin once daily to a subset of frail subjects for an additional 6 months. RESULTS: We assessed the relationship between the triglyceride-to-glucose index and the Montreal Cognitive Assessment score, observing a significant correlation (r, 0.880; P<0.0001). Similarly, we analyzed the association between the triglycerideto-glucose index and 5-meter gait speed, uncovering a significant link between insulin resistance and physical impairment (r, 0.809; P<0.0001). Prediabetes was found to significantly (P<0.0001) elevate the risk of frailty development compared with individuals without prediabetes by the end of the 1-year follow-up, a finding confirmed via multivariable analysis with Cox regression. Furthermore, among the subgroup of subjects who developed frailty, those who received metformin exhibited a significant decrease in frailty levels (P<0.0001). CONCLUSIONS: Insulin resistance and prediabetes play substantial roles in the development of cognitive and physical impairments, highlighting their importance in managing hypertension, even before the onset of frank diabetes. Metformin, a well-established drug for the treatment of diabetes, has shown favorable effects in mitigating frailty. [ABSTRACT FROM AUTHOR]

Abstract Post-translational modification of proteins, such as tyrosine phosphorylation, plays a major role in driving the oncogenic activity of oncogenes. WAVE3 (WASF3), an adaptor and actin cytoskeleton remodeling protein, contributes to cell migration, cancer cell invasion, and metastasis. WAVE3 plays a vital role in the progression and metastasis of triple negative breast cancer (TNBC), in part through the regulation of cancer stem cells (CSCs). Several studies have shown that WAVE3 tyrosine phosphorylation is required for its oncogenic activity. Moreover, our recent study showed that the proline rich domain (PRD) of WAVE3 is required for maintenance of the CSC niche in breast cancer by regulating the nuclear translocation of the CSC-specific nuclear transcription factor YB1. Here, we show that the PRD domain of WAVE3 and its phosphorylation are essential for driving the oncogenic activity of WAVE3. We show that phosphorylation of WAVE3 PRD is essential for migration and invasion of breast cancer cells in vitro, as well as tumor growth and metastasis in vivo. Mechanistically, we show that phosphorylation of the WAVE3 PRD is essential for interaction between WAVE3 and YB1. Loss of PRD phosphorylation inhibits such interaction and the YB1-mediated activation of expression of CSC markers, as well as the WAVE3 mediated activation of EMT. Together, our study identifies a novel role of WAVE3 and its PRD domain in the regulation of the invasion metastasis cascade in BC that is independent of the known function of WAVE3 as an actin cytoskeleton remodeling protein through the WAVE regulatory complex (WRC).

Cognitive impairment is a prevailing event in hypertensive patients and in frail older adults. Endothelial dysfunction has been shown to underlie both hypertension and cognitive dysfunction. Our hypothesis is that L-Arginine, which is known to ameliorate endothelial dysfunction, could counteract cognitive impairment in a high-risk population of hypertensive frail older adults. We designed a clinical trial to verify the effects of 4-weeks oral supplementation of L-Arginine on global cognitive function of hypertensive frail older patients. The study was successfully completed by 35 frail hypertensive elderly patients assigned to L-Arginine and 37 assigned to placebo. At follow-up, we found a significant difference in the Montreal Cognitive Assessment (MoCA) test score between the L-Arginine treated group and placebo (p: 0.0178). Moreover, we demonstrated that L-Arginine significantly attenuates Angiotensin II-induced mitochondrial oxidative stress in human endothelial cells. In conclusion, our findings indicate for the first time that oral L-Arginine supplementation significantly improves cognitive impairment in frail hypertensive older adults.Clinical Trial Registrationwww.ClinicalTrials.gov, identifier: NCT04962841.

After an ischemic injury, the heart undergoes a complex process of structural and functional remodeling that involves several steps, including inflammatory and fibrotic responses. In this review, we are focusing on the contribution of microRNAs in the regulation of inflammation and fibrosis after myocardial infarction. We summarize the most updated studies exploring the interactions between microRNAs and key regulators of inflammation and fibroblast activation and we discuss the recent discoveries, including clinical applications, in these rapidly advancing fields.

Background: With rise in prevalence of conventional risk factors like diabetes, hypertension, smoking, dyslipidemia and obesity the incidence of coronary artery disease in young patients have increased in the recent decades even in developing world. There have been multiple studies done in Nepal studying the angiographic profile of coronary disease in general population. However, only few studies has been done till date on the angiographic profile in the young population in our country. Aims and Objectives: In this study, we aim to determine the angiographic profile of young patient ≤ 40 years in a tertiary care centre of Nepal. Materials and Methods: A retrospective analytic study was done in Shahid Gangalal National Heart Centre from January 2019 to December 2019. Individuals of both genders with age ≤ 40 years who underwent coronary angiography were included. Results: Total 109 patients were included. Out of 109, 89 were male and 20 were female. The mean age for male was 35.55 ± 4.31 and for female was 38.55 ± 1.90 (P = 0.003). Among 61 (55.96%) patients who had significant coronary artery disease, 33 patients (30.27%) with single vessel disease, 15 patients (13.76%) had double vessel disease, and 13 patients (11.92%) had triple vessel disease. Left anterior descending (LAD) artery was found to be most frequently involved in all patterns of Coronary artery disease (CAD). Smoking was the most common coronary risk factor present in 29.3% of patients followed by hypertension, family history of premature CAD and diabetes in 14.6%, 7.5% and 5.5% of patients respectively. Overall, the prevalence of smoking was more in males (31.4%) than in females (20%). Conclusion: Single vessel disease (SVD) was most prevalent in young patients with significant CAD. LAD is the most commonly involved coronary artery followed by Right coronary artery (RCA) and Left Circumflex (LCX).

Sortilin is a glycoprotein mainly known for its role as a trafficking molecule directing proteins to specific secretory or endocytic compartments of the cell. Its actual contribution to essential hypertension has remained hitherto elusive. Combining top-notch in vivo, ex vivo, and in vitro approaches to clinical investigations, Di Pietro et al. explored the signaling pathway evoked by sortilin in endothelial cells and report on such exploration in this issue of the JCI. The researchers identified circulating sortilin as a biomarker associated with high blood pressure. Mechanistically, they demonstrate that sortilin altered sphingolipid/ceramide homeostasis, initiating a signaling cascade that, from sphingosine-1-phosphate (S1P), leads to the augmented production of reactive oxygen species. Herein, we discuss the main implications of these findings, and we anticipate some of the potential avenues of investigation prompted by this discovery, which could eventually lead to treatments for cardiometabolic disorders.

MicroRNAs (miRs) are small non-coding RNAs that modulate the expression of several target genes. Fibroblast growth factor binding protein 1 (FGFBP1) has been associated with endothelial dysfunction at the level of the blood–brain barrier (BBB). However, the underlying mechanisms are mostly unknown and there are no studies investigating the relationship between miRs and FGFBP1. Thus, the overarching aim of the present study was to identify and validate which miR can specifically target FGFBP1 in human brain microvascular endothelial cells, which represent the best in vitro model of the BBB. We were able to identify and validate miR-4432 as a fundamental modulator of FGFBP1 and we demonstrated that miR-4432 significantly reduces mitochondrial oxidative stress, a well-established pathophysiological hallmark of hypertension.

Oxidative stress and endothelial dysfunction have been shown to play crucial roles in the pathophysiology of COVID-19 (coronavirus disease 2019). On these grounds, we sought to investigate the impact of COVID-19 on lipid peroxidation and ferroptosis in human endothelial cells. We hypothesized that oxidative stress and lipid peroxidation induced by COVID-19 in endothelial cells could be linked to the disease outcome. Thus, we collected serum from COVID-19 patients on hospital admission, and we incubated these sera with human endothelial cells, comparing the effects on the generation of reactive oxygen species (ROS) and lipid peroxidation between patients who survived and patients who did not survive. We found that the serum from non-survivors significantly increased lipid peroxidation. Moreover, serum from non-survivors markedly regulated the expression levels of the main markers of ferroptosis, including GPX4, SLC7A11, FTH1, and SAT1, a response that was rescued by silencing TNFR1 on endothelial cells. Taken together, our data indicate that serum from patients who did not survive COVID-19 triggers lipid peroxidation in human endothelial cells.

Introduction: Nepal is one of the countries which has been hit hard by the COVID-19 pandemic and has resulted in high morbidity and mortality across all age groups including neonates. There has been a paucity of studies regarding maternal to neonatal COVID-19 transmission and the published studies also have a poor sample size to reach any definite conclusion. Hence this study was carried out to see the clinical profiles of neonates born to COVID-19 mothers. Methods: It was a descriptive cross-sectional study. The study was conducted at a tertiary care centre over the period of one year from April 2020 to March 2021 after taking ethical clearance from the Institutional Review Committee with reference number drs2105211526. Convenient sampling was done. All neonates born to COVID-19 positive mothers who were diagnosed by a real-time polymerase chain reaction of the nasopharyngeal swab during the time of delivery were included in the study. Data analysis was done using Statistical Package for Social Sciences 20 using appropriate tools. Results: A total of 105 babies born to COVID-19 positive mothers who were tested for COVID-19 infection were included in the study. Ten (9.5%) (3.89-15.10 at 95% Confidence Interval) of neonates born to COVID-19 positive mothers were positive for the COVID-19 virus. All the neonates born to COVID-19 positive mothers were discharged home except one case who had other comorbidities. Fever was present in four (40%) of COVID-19 positive neonates. Conclusions: There is a possibility of vertical transmission of coronavirus in neonates although the outcome is favourable.