Baricitinib with cyclosporine eliminates acute graft rejection in fully mismatched skin and heart transplant models.

Solid organ transplant represents a potentially lifesaving procedure for patients suffering from end-stage heart, lung, liver, and kidney failure. However, rejection remains a significant source of morbidity and immunosuppressive medications have significant toxicities. Janus kinase (JAK) inhibitors are effective immunosuppressants in autoimmune diseases and graft versus host disease after allogeneic hematopoietic cell transplantation.

A Case of Sudden-Onset Flaccid Paralysis In a Previously Healthy Person.

Flaccid paralysis is a neurological syndrome characterized by weakness and paralysis of the limbs, followed by reduced muscle tone. Common causes of flaccid paralysis include blockage of the anterior spinal artery, trauma to the spinal cord, cancer, arterial disease, or thrombosis. A potential differential diagnosis in a 35-year-old male presenting with sudden-onset flaccid paralysis with no history of trauma is hypokalemic periodic paralysis.

Conserved transcription factors promote cell fate stability and restrict reprogramming potential in differentiated cells.

Defining the mechanisms safeguarding cell fate identity in differentiated cells is crucial to improve 1) - our understanding of how differentiation is maintained in healthy tissues or altered in a disease state, and 2) - our ability to use cell fate reprogramming for regenerative purposes. Here, using a genome-wide transcription factor screen followed by validation steps in a variety of reprogramming assays (cardiac, neural and iPSC in fibroblasts and endothelial cells), we identified a set of four transcription factors (ATF7IP, JUNB, SP7, and ZNF207 [AJSZ]) that robustly opposes cell fate reprogramming in both lineage and cell type independent manners. Mechanistically, our integrated multi-omics approach (ChIP, ATAC and RNA-seq) revealed that AJSZ oppose cell fate reprogramming by 1) - maintaining chromatin enriched for reprogramming TF motifs in a closed state and 2) - downregulating genes required for reprogramming.

A deep learning platform to assess drug proarrhythmia risk.

Drug safety initiatives have endorsed human iPSC-derived cardiomyocytes (hiPSC-CMs) as an in vitro model for predicting drug-induced cardiac arrhythmia. However, the extent to which human-defined features of in vitro arrhythmia predict actual clinical risk has been much debated. Here, we trained a convolutional neural network classifier (CNN) to learn features of in vitro action potential recordings of hiPSC-CMs that are associated with lethal Torsade de Pointes arrhythmia.

Pediatric acute liver failure: An experience of a pediatric intensive care unit from resource limited settings.

Introduction: Pediatric acute liver failure is a rare and serious disease. Though liver transplantation is considered as the established treatment option for patients who are unlikely to recover with medical management, however, with the advancement of medical care there has been an increase in spontaneous regeneration of liver, obviating the need for liver transplantation. We identified the etiologies, outcome and prognostic factors of acute liver failure and the validity of the existing liver transplantation criteria to predict the outcome of pediatric acute liver failure.

Effect of the of 10-valent pneumococcal conjugate vaccine in Nepal 4 years after introduction: an observational cohort study.

Background: In Nepal, Streptococcus pneumoniae (pneumococcus) is a common cause of bacterial pneumonia in children, and is a major health concern. There are few data on the effect of vaccination on the disease or colonisation with pneumococci in the nasopharynx of children in this setting. The 10-valent pneumococcal conjugate vaccine (PCV10) was introduced into the routine infant immunisation schedule in Nepal in 2015.

Reengineering Ponatinib to Minimize Cardiovascular Toxicity.

Unlabelled: Small molecule tyrosine kinase inhibitors (TKI) have revolutionized cancer treatment and greatly improved patient survival. However, life-threatening cardiotoxicity of many TKIs has become a major concern. Ponatinib (ICLUSIG) was developed as an inhibitor of the BCR-ABL oncogene and is among the most cardiotoxic of TKIs.

A fatal outbreak of neonatal sepsis caused by mcr-10-carrying Enterobacter kobei in a tertiary care hospital in Nepal.

Background: Enterobacter kobei is an emerging cause of outbreak of nosocomial infections in neonatal intensive care units (NICUs). Between July and September 2016, a NICU in a tertiary care hospital of Nepal observed an abrupt increase in the number of neonatal sepsis cases caused by Enterobacter spp. infecting 11 out of 23 admitted neonates, five of whom died of an exacerbated sepsis.

Risk factors for the development of neonatal sepsis in a neonatal intensive care unit of a tertiary care hospital of Nepal.

Background: Sepsis is an overwhelming and life-threatening response to bacteria in bloodstream and a major cause of neonatal morbidity and mortality. Understanding the etiology and potential risk factors for neonatal sepsis is urgently required, particularly in low-income countries where burden of infection is high and its epidemiology is poorly understood.

Methods: A prospective observational cohort study was conducted between April 2016 and October 2017 in a level three NICU at a tertiary care hospital in Nepal to determine the bacterial etiology and potential risk factors for neonatal sepsis.

Unfolded Protein Response as a Compensatory Mechanism and Potential Therapeutic Target in PLN R14del Cardiomyopathy.

Background: Phospholamban (PLN) is a critical regulator of calcium cycling and contractility in the heart. The loss of arginine at position 14 in PLN (R14del) is associated with dilated cardiomyopathy with a high prevalence of ventricular arrhythmias. How the R14 deletion causes dilated cardiomyopathy is poorly understood, and there are no disease-specific therapies.

Metabolic Maturation Media Improve Physiological Function of Human iPSC-Derived Cardiomyocytes.

Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have enormous potential for the study of human cardiac disorders. However, their physiological immaturity severely limits their utility as a model system and their adoption for drug discovery. Here, we describe maturation media designed to provide oxidative substrates adapted to the metabolic needs of human iPSC (hiPSC)-CMs.

Prevalence of Kawasaki Disease in a Tertiary Care Hospital: A Descriptive Cross-sectional Study.

Introduction: Kawasaki disease is an acute vasculitis of unknown etiology. The epidemiological data available for Nepal remains insufficient. In Nepal, Kawasaki disease has only been reported in cases of brief reports, leaving the true disease burden unknown.

The State of Remote Sensing Capabilities of Cascading Hazards over High Mountain Asia.

Cascading hazard processes refer to a primary trigger such as heavy rainfall, seismic activity, or snow melt, followed by a chain or web of consequences that can cause subsequent hazards influenced by a complex array of preconditions and vulnerabilities. These interact in multiple ways and can have tremendous impacts on populations proximate to or downstream of these initial triggers. High Mountain Asia (HMA) is extremely vulnerable to cascading hazard processes given the tectonic, geomorphologic, and climatic setting of the region, particularly as it relates to glacial lakes.

Transcendental meditation and hypothalamic-pituitary-adrenal axis functioning: a pilot, randomized controlled trial with young adults.

Transcendental meditation (TM) is effective in alleviating stress and anxiety and promoting well-being. While the underlying biological mechanisms of TM are not yet fully explored, the hypothalamic-pituitary-adrenal (HPA) axis represents an index providing important clues embodying the stress system cascade. In this pilot study, young adults were randomly assigned to TM training followed by 8 weeks of meditation practice or a wait-list control condition.

Inhibition of Marburg Virus RNA Synthesis by a Synthetic Anti-VP35 Antibody.

Marburg virus causes sporadic outbreaks of severe hemorrhagic fever with high case fatality rates. Approved, effective, and safe therapeutic or prophylactic countermeasures are lacking. To address this, we used phage display to engineer a synthetic antibody, sFab H3, which binds the Marburg virus VP35 protein (mVP35).

Bacterial Contamination on Latrine Surfaces in Community and Household Latrines in Kathmandu, Nepal.

A lack of sanitation infrastructure is a major contributor to the global burden of diarrheal disease, particularly in low-income countries. Access to basic sanitation was identified as part of the 2015 United Nations Sustainable Development Goals. However, current definitions of "basic" sanitation infrastructure exclude community or shared sanitation, due to concerns around safety, equity, and cleanliness.

Practice and lived experience of menstrual exiles (Chhaupadi) among adolescent girls in far-western Nepal.

Background: Menstrual exile, also known as Chhaupadi, is a tradition of "untouchability" in far-western Nepal. Forbidden from touching other people and objects, women and girls are required to live away from the community, typically in a livestock shed, during menstruation. We assessed the lived experiences of Chhaupadi among Nepalese adolescent girls in the far-western Achham district of Nepal, observed the safety and sanitation of their living spaces during Chhaupadi, and assessed the perceptions of local adult stakeholders towards the practice of Chhaupadi.

Depression, malnutrition, and health-related quality of life among Nepali older patients.

Background: Little is known about the health, nutrition, and quality of life of the aging population in Nepal. Consequently, we aimed to assess the nutritional status, depression and health-related quality of life (HRQOL) of Nepali older patients and evaluate the associated factors. Furthermore, a secondary aim was to investigate the proposed mediation-moderation models between depression, nutrition, and HRQOL.

MRI Is a DNA Damage Response Adaptor during Classical Non-homologous End Joining.

The modulator of retrovirus infection (MRI or CYREN) is a 30-kDa protein with a conserved N-terminal Ku-binding motif (KBM) and a C-terminal XLF-like motif (XLM). We show that MRI is intrinsically disordered and interacts with many DNA damage response (DDR) proteins, including the kinases ataxia telangiectasia mutated (ATM) and DNA-PKcs and the classical non-homologous end joining (cNHEJ) factors Ku70, Ku80, XRCC4, XLF, PAXX, and XRCC4. MRI forms large multimeric complexes that depend on its N and C termini and localizes to DNA double-strand breaks (DSBs), where it promotes the retention of DDR factors.

Intravenous Ketamine for Adolescents with Treatment-Resistant Depression: An Open-Label Study.

Background: Novel interventions for treatment-resistant depression (TRD) in adolescents are urgently needed. Ketamine has been studied in adults with TRD, but little information is available for adolescents. This study investigated efficacy and tolerability of intravenous ketamine in adolescents with TRD, and explored clinical response predictors.

Handwashing Practices in Neonatal Intensive Care Unit, Paediatric Intensive Care Unit and Neonatal Nurseries in Patan Hospital.

Background: Hand hygiene has been identified as the single most important factor in minimising hospital acquired infections. However, compliance of handwashing guidelines has remained low. The aim of this study was to study the handwashing practices in the Paediatric and Neonatal intensive care units and Neonatal nurseries in Patan Hospital, and secondly to re-evaluate the improvement on compliance of handwashing guidelines after intervention.

Occurrence of Pharmaceuticals in Calgary's Wastewater and Related Surface Water.

The influents/effluents from Calgary's water resource recovery facilities and the surface water were analyzed for pharmaceuticals in the present study. The median concentrations in the effluents for the 15 targeted pharmaceuticals were within the range of 0.006 to 3.

Genome sequencing of an extended series of NDM-producing Klebsiella pneumoniae isolates from neonatal infections in a Nepali hospital characterizes the extent of community- versus hospital-associated transmission in an endemic setting.

NDM-producing Klebsiella pneumoniae strains represent major clinical and infection control challenges, particularly in resource-limited settings with high rates of antimicrobial resistance. Determining whether transmission occurs at a gene, plasmid, or bacterial strain level and within hospital and/or the community has implications for monitoring and controlling spread. Whole-genome sequencing (WGS) is the highest-resolution typing method available for transmission epidemiology.

Clinical and ultrasonographic measurement of liver size in normal children.

Objectives: To measure the normal range of dimensions of liver in children of various age groups and to compare the liver measurement obtained by palpation-percussion, auscultation and ultrasonography.

Methods: This was a cross-sectional comparative study in which 500 normal (weight for height between ± 2 SD of WHO standards for children aged less than 5 y and BMI between ± 2 SD of WHO standards for children aged more than 5 y) children (0-15 y) divided in 5 age groups (100 in each age group). Subjects were enroled from normal hospital delivery neonates, children visiting immunization and well baby clinics, children visiting outpatient and inpatient department with minor illnesses and healthy school children.