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T cell exhaustion is a state of T cell dysfunction associated with expression of programmed death 1 (PD-1). Exhausted CD8+ T cells are maintained by self-renewing stem-like T cells that provide differentiated TIM3+ cells, a part of which possesses effector-like properties. PD-1–targeted therapies enhance T cell response by promoting differentiation of stem-like T cells toward TIM3+ cells, but the role of mTOR during T cell exhaustion remains elusive. Here, we showed that mTOR inhibition has distinct outcomes during the beginning of and after the establishment of chronic viral infection. Blocking mTOR during the T cell expansion phase enhanced the T cell response by causing accumulation of stem-like T cells, leading to improved efficacy of PD-1 immunotherapy; whereas, after exhaustion progressed, mTOR inhibition caused immunosuppression, characterized by decreased TIM3+ cells and increased viral load with minimal changes in stem-like T cells. Mechanistically, a cell-intrinsic mTOR signal was vital for differentiation of stem-like T cells into the TIM3+ state in the early and late phases of chronic infection as well as during PD-1 immunotherapy. Thus, PD-1 blockade worked after cessation of mTOR inhibition, but simultaneous treatment failed to induce functional TIM3+ cells, reducing efficacy of PD-1 immunotherapy. Our data demonstrate that mTOR regulates T cell exhaustion and have important implications for combination cancer therapies with PD-1 blockade.

Understanding disease burden and transmission dynamics in resource-limited, low-income countries like Nepal are often challenging due to inadequate surveillance systems. These issues are exacerbated by limited access to diagnostic and research facilities throughout the country. Nepal has one of the highest COVID-19 case rates (915 cases per 100,000 people) in South Asia, with densely-populated Kathmandu experiencing the highest number of cases. Swiftly identifying case clusters (hotspots) and introducing effective intervention programs is crucial to mounting an effective containment strategy. The rapid identification of circulating SARS-CoV-2 variants can also provide important information on viral evolution and epidemiology. Genomic-based environmental surveillance can help in the early detection of outbreaks before clinical cases are recognized and identify viral micro-diversity that can be used for designing real-time risk-based interventions. This research aimed to develop a genomic-based environmental surveillance system by detecting and characterizing SARS-CoV-2 in sewage samples of Kathmandu using portable next-generation DNA sequencing devices. Out of 22 sites in the Kathmandu Valley from June to August 2020, sewage samples from 16 (80%) sites had detectable SARS-CoV-2. A heatmap was created to visualize the presence of SARS-CoV-2 infection in the community based on viral load intensity and corresponding geospatial data. Further, 47 mutations were observed in the SARS-CoV-2 genome. Some detected mutations (n = 9, 22%) were novel at the time of data analysis and yet to be reported in the global database, with one indicating a frameshift deletion in the spike gene. SNP analysis revealed possibility of assessing circulating major/minor variant diversity on environmental samples based on key mutations. Our study demonstrated the feasibility of rapidly obtaining vital information on community transmission and disease dynamics of SARS-CoV-2 using genomic-based environmental surveillance.

Poultry (Gallus domesticus) farming plays an important role as an income generating enterprise in a developing country like Nepal, contributing more than 4% to the national Gross Domestic Product (GDP). Newcastle Disease (ND) is a major poultry disease affecting both commercial and backyard poultry production worldwide. There were more than 90 reported ND outbreaks in Nepal in 2018 with over 74,986 birds being affected. ND is responsible for over 7% of total poultry mortality in the country. Recent outbreaks of ND in 2021 affected many farms throughout Nepal and caused massive loss in poultry production. ND is caused by a single-stranded ribonucleic acid (RNA) virus that presents very similar clinical symptoms as Influenza A (commonly known as bird flu) adding much complexity to clinical disease identification and intervention. We conducted a nationwide ND and Influenza A (IA) prevalence study, collecting samples from representative commercial and backyard poultry farms from across the major poultry production hubs of Nepal. We used both serological and molecular assessments to determine disease exposure history and identification of strains of ND Virus (NDV). Of the 40 commercial farms tested, both NDV (n = 28, 70%) and IAV (n = 11, 27.5%) antibodies were detected in majority of the samples. In the backyard farms (n = 36), sero-prevalence of NDV and IAV were 17.5% (n = 7) and 7.5% (n = 3) respectively. Genotype II NDV was present in most of the commercial farms, which was likely due to live vaccine usage. We detected never reported Genotype I NDV in two backyard farm samples. Our investigation into 2021 ND outbreak implicated Genotype VII.2 NDV strain as the causative pathogen. Additionally, we developed a Tablet formulation of the thermostable I2-NDV vaccine (Ranigoldunga™) and assessed its efficacy on various (mixed) breeds of chicken (Gallus domesticus). Ranigoldunga™ demonstrated an overall efficacy >85% with a stability of 30 days at room temperature (25°C). The intraocularly administered vaccine was highly effective in preventing ND, including Genotype VII.2 NDV strain.

Background : Significant proportion of congenital heart surgery (CHS) children exhibit sepsis, but have negative blood culture and defined “culture negative sepsis (CNS).” Aims and Objectives : Retrospective analysis of CNS patients undergoing CHS. Material and Methods : 437 consecutive CHS children grouped as controls (antibiotic prophylaxis), CNS, and culture positive sepsis (CPS). Results : Incidences of CNS and CPS were 16% and 7%. Median mechanical ventilation (MV) in hours among CPS, CNS, and control was 116 (45–271), 63 (23–112), and 18 (6–28) (P < 0.001), respectively. Multivariable linear regression identified CPS (median ratio: 3.1 [2.3–4.1], P < 0.001), CNS (median ratio: 5.6 [3.7–8.4], P < 0.001), and weight (kg) (median ratio: 0.98 [0.96–0.99], P = 0.009) as associations of MV. Intensive care unit (ICU) stay (hours) was 192 (120–288) in CNS, 288 (156–444) in CPS, and 72 (48–120) in controls (P < 0.0001). Multivariable linear regression showed CNS (median ratio: 2.4 [2.0–2.9], P< 0.001) CPS (median ratio: 3.3 [2.5–4.4], P < 0.001), and weight (median ratio: 0.98 [0.97–0.99], P = 0.001) prolonging ICU stay. Mortality was 10.7%, 2.9% and 1.2% in CPS, CNS, and control (P = 0.03). Multivariable regression identified CPS an independent predictor of mortality with odds ratio 8.6 (1.7–44.9; P = 0.010). 11.26% patients in CNS and 79.3% in CPS received antibiotics for more than 10 d ays. Conclusion : Incidence of CNS was 16%; duration of MV and ICU stay and mortality was significantly less in CNS than CPS patients.

Transition metal oxide–based pseudocapacitors with various valence states are of particular interest in the field of energy storage due to their increased specific capacitance values. In particular, Copper cobaltite nanomaterials have attracted more research focus due to their multiple oxidation states in comparison to other transition metals. Spinel structures of metal oxides are of tremendous interest for energy storage applications. Mixed valence metal cations in spinel cobaltites (MCo2O4) offer more electronic conductivity and electrochemical activity than single–component oxides. Natural abundance, good electrical and thermal stability, environment–friendly nature, and low cost motivates researchers for carrying out an extensive study of such materials. In this study, binary composite CuCo2O4@Co3O4 was synthesized by facile hydrothermal method. FT–IR, XRD, FEG–SEM and XPS studies have established the successful formation of all the nanocomposites were used to primarily characterize the sample. XRD showed the existence of all the synthesized materials in crystalline form. Cyclic voltammetry (CV), Galvanostatic Charge–Discharge (GCD) and Electrochemical Impedance (EIS) measurements were recorded to examine the electrochemical characteristics. The comparative specific capacitance of the synthesized CuCo2O4@Co3O4 nanocomposite displayed 542.77 Fg−1 using Glassy Carbon (GCE) as the working electrode whereas it exhibited 683.72 Fg−1 at the same current density of 1 Ag−1 using Nickel foam as the electrode substrate. The composite electrode exhibited an excellent pseudocapacitive behaviour using 1 M Na2SO4 and 1 M KOH as electrolytes respectively for electrochemical measurements. Impedance analysis reveals capacitive nature of the synthesized materials. Furthermore, cyclic stability for CuCo2O4@Co3O4 nanocomposite was found to be 76% (GCE) upto 1000 cycles at 5 Ag−1 and 78% (Nickel foam) upto 3000 cycles at 5 Ag−1. Based on the study of the electrochemical performance, the synthesized transition metal oxide nanocomposite holds potency as an efficient electrode material for energy storage applications. [ABSTRACT FROM AUTHOR]

Background/Aim: Cigarette smoke has been shown to induce a phenotype in humans known as “acquired cystic fibrosis”. This occurs because the cystic fibrosis transmembrane conductance regulator (CFTR) functions are impaired systemically due to the deleterious effects of smoke components. Elucidation of cigarette smoke effects on the tracheal epithelium is important. The aim of this study was to develop an ex vivo sheep tracheal model to investigate tracheal ion function. In this model, the epithelial sodium channel (ENaC) is inhibited after exposure to cigarette smoke extract (CSE) as a proof of principle. Materials and Methods: Tracheas were isolated from healthy sheep and the tracheal epithelium was surgically excised. Tissues were mounted in Ussing chambers and the short circuit current (Isc) was measured after incubation with 5% CSE in PBS or PBS alone for 30 min. The function of ENaC was investigated by the addition of amiloride (10–5M) apically. Western blot analysis was performed to assess differences in ENaC quantity after CSE exposure. Some specimens were stained with H&E for detection of histological alterations. Results: The amiloride effect on normal epithelium led to a significant decrease in Isc [ΔI=33±5.92 μA/cm²; p<0.001 versus control experiments (ΔI=1.44±0.71 μA/cm²)]. After incubation with CSE, ENaC Isc was significantly reduced (ΔI=14.80±1.96 μA/cm²; p<0.001). No differences in αENaC expression were observed between CSE-exposed and normal tracheal epithelium. Histological images post CSE incubation revealed decreases in the height of the epithelium, with basal cell hyperplasia and loss of ciliated cells. Conclusion: Reduced ENaC inhibition by amiloride after CSE incubation could be due to alterations in the tracheal epithelium. [ABSTRACT FROM AUTHOR]

Introduction Minimally invasive surgery (MIS) has revolutionized the approach to surgical interventions in neonates with congenital malformations, offering distinct advantages over traditional open surgeries. Neonates born with congenital malformations often require surgical interventions early in life to correct or alleviate associated issues. Historically, these surgeries have predominantly been performed through open approaches, which pose significant challenges and risks in the delicate neonatal population. However, with advancements in medical technology and surgical techniques, minimally invasive surgery (MIS) has emerged as a promising alternative. Material and Methods A prospective observational study was conducted in a tertiary-care level neonatal intensive care unit (NICU) of the Pediatric Hospital. The following data were recorded: gestational age, birth weight, sex, diagnosis, associated malformations, age and weight at surgery, surgery duration, conversion to open surgery, intraoperative bleeding, intraoperative complications, pre- and post-operative arterial pressure of carbon dioxide (paCO2), postoperative morbidity surgery-related, type and duration of postoperative analgesia, postoperative mechanical ventilation duration, fasting time, postoperative hospitalization, and mortality surgery-related. Conclusion MIS represents a paradigm shift in the surgical management of neonates with congenital malformations, offering significant benefits in terms of reduced morbidity, faster recovery, and improved cosmetic outcomes. Continued advancements in technology and surgical techniques are likely to further enhance the applicability and effectiveness of MIS in this vulnerable patient population. [ABSTRACT FROM AUTHOR]

Background: Left atrium is not a simple passive transport chamber which transfers blood from the pulmonary circulation to the left ventricle. Left atrium has conduit, reservoir and pump functions and multiple variables have been developed to evaluate those functions. Aim of the study: It is comparison of LAFI to traditional echo parameters of Left atrium function in atrial fibrillation and diastolic dysfunction. Methods: This Prospective cross sectional study was conducted among the patients attending the Cardiology OPD with Atrial fibrillation and Diastolic dysfunction in Tertiary care centre, Chennai .The study was done for a period from Jan 2022 to Jan 2023.The study participants fulfilling the inclusion and the exclusion criteria were included in the study throughout the study period. The final attained sample is 75. After obtaining the Institutional Ethical Committee clearance, the study was started after obtaining patients informed consent. Baseline details of study participants like name, age, sex, residence. Anthropometric measurement like height and weight will be taken.Body mass index will be calculated. Echocardiography investigation will be done. After collecting the data it was entered in MS Excel Windows 10.Statistical analysis was done in SPSS 23..P value of <0.005 is considered to be statistically significant. Results: Age, sex, height, weight,Body mass index and Body surface are was found to be not statistically significant between the groups. There is a very weak correlation between LAVI & LAFI in atrial fibrillation group (r= 0.2). There is a strong correlation between A cm/s and LAFI, There is a strong correlation between AVTI and LAFI (r= 0.89). when LAFI <24.5 is set as cut off value, LAFI as a parameter to diagnose left atrial dysfunction has 100% sensitivity, 56%specificity, 53% positive predictive value, 100% negative predictive value. Conclusion: LAFI is low in chronic AF and Diastolic Dysfunction patients in our study. LAFI has high sensitivity and negative predictive value. LAFI is a rhythm independent Left atrium function marker. Thereby we conclude that LAFI is a comprehensive marker of left atrial structural and functional assessment. [ABSTRACT FROM AUTHOR]