Host functions used by hepatitis B virus to complete its life cycle: Implications for developing host-targeting agents to treat chronic hepatitis B

Similar to other mammalian viruses, the life cycle of hepatitis B virus (HBV) is heavily dependent upon and regulated by cellular (host) functions. These cellular functions can be generally placed in to two categories: (a) intrinsic host restriction factors and innate defenses, which must be evaded or repressed by the virus; and (b) gene products that provide functions necessary for the virus to complete its life cycle. Some of these functions may apply to all viruses, but some may be specific to HBV. In certain cases, the virus may depend upon the host function much more than does the host itself. Knowing which host functions regulate the different steps of a virus' life cycle, can lead to new antiviral targets and help in developing novel treatment strategies, in addition to improving a fundamental understanding of viral pathogenesis. Therefore, in this review we will discuss known host factors which influence key steps of HBV life cycle, and further elucidate therapeutic interventions targeting host-HBV interactions

Antimicrobial Resistance Patterns and Plasmid Profiles of Methicillin Resistant Staphylococcus aureus Isolated from Clinical Samples

Methicillin-resistant Staphylococcus aureus (MRSA), showing resistance to several antibiotics is a global health problem associated with considerable mortality and morbidity. Antibiotic susceptibility test is a commonly used method to characterize MRSA in epidemiologic studies. Additionally, plasmid profile has been reported to be useful in tracing the epidemiology of antibiotic resistance. This research was conducted to determine the antimicrobial resistance patterns and plasmid profiles of MRSA isolated from clinical samples at KIST Medical College, Imadol, Kathmandu, Nepal. All the clinical specimens sent to the laboratory were processed by standard microbiological techniques and antibiotic susceptibility testing was done by the modified Kirby Bauer disc diffusion method. Further, plasmid profiling was done by Alkaline-lysis method. A total of 27 (38.02%) MRSA were isolated from 71 S. aureus positive samples. MRSA showed the highest resistance towards penicillin (92.60%) and ampicillin (92.60%). In contrast, high levels of sensitivity were shown towards vancomycin (85.19%) and tetracycline (85.19%). Out of 27 MRSA positive samples, single plasmids were isolated from only 6 (22.22%) MRSA isolates. Antibiograms alone are inadequate to accomplish the characterization of MRSA during epidemiological studies. However, plasmid profile analysis in conjunction with the antibiotic susceptibility pattern is valuable in the epidemiological investigation of MRSA, and for reducing MRSA prevalence and treatment cost

Evaluation of wheat (Triticum aestivum L.) genotypes for spot blotch (Bipolaris sorokiniana Sacc) resistance in terai condition of Nepal

Spot blotch caused by Bipolaris sorokiniana is a major disease of wheat in warm and humid regions of Nepal. The fungus has a worldwide distribution but as a pathogen, it is the most aggressive under the conditions of high relative humidity and temperature associated with the low fertility of soils in Nepal. The yield loss due to the disease is very significant in Nepal. This experiment was conducted to identify the genotypes having a good level of resistance against spot blotch. The experiment set was received from CIMMYT comprises 52 genotypes and arranged in alpha lattice design with two replications in 2017/18 at National Wheat Research Program, Bhairahawa, Nepal, and Regional Agricultural Research Station, Parwanipur, Bara, Nepal. Each plot size was 8 rows of 2 meters long. Three times disease scoring was done in the double-digit method and calculated the Area under the disease progress curve (AUDPC). Other data were analyzed by using R software (4.2.2). Heading days, days to maturity, plant height, number of grains per spike (NGPS), number of tillers per meter square (NTPM), mean AUDPC, thousand-grain weight (TGW), and grain yield were found highly significant. The genotype 8HLBSN47 was found the highest yielder (4996kg/ha) with a 304 mean AUDPC value. Seventeen genotypes (15.3%) found the lowest mean AUDPC, Penultimate leaf AUDPC, Flag leaf AUDPC, and the highest number of tillers per square meter, number of grains per spike, thousand-grain weight, and grain yield

Accuracy of bedside index for severity in acute pancreatitis ‘BISAP’ score in predicting outcome of acute pancreatitis

Introduction: Early identification of severe acute pancreatitis is of paramount importance in the management and for improving outcomes. Bedside index for severity in acute pancreatitis (BISAP) is a simple and accurate score for stratification in acute pancreatitis. This study was conducted to find out the accuracy of BISAP score in predicting outcomes of acute pancreatitis in local population. Method: We prospectively analyzed 96 patients with acute pancreatitis from February 2019 to December 2019. Revised Atlanta classification was used to stratify mild, moderately severe and severe pancreatitis. BISAP score was calculated within 24 hours of admission. Accuracy was measured by area under receiver operating curve (AUC). Result: Out of 96 patients, alcohol related acute pancreatitis accounted for 74.7%. There were 63.2% of mild AP, 37.3% of moderately severe AP, 9.4% of severe AP and 15.8 % of pancreatic necrosis. The AUC for moderately severe AP, severe AP and pancreatic necrosis were 0.77 (CI 0.68-0.87), 0.95 (CI 0.90-0.99) and 0.87 (CI 0.79-0.96) respectively. The statistically significant BISAP cut off for diagnosing sever AP was≥3, and ≥2 for moderately sever AP and pancreatic necrosis. There was positive correlation between revised Atlanta severity of acute pancreatitis and length of hospital stay (r=0.41). Mortality was 3.3 % which was seen in BISAP score 3 or above. Conclusion: BISAP is a simple predictive model in identifying patient at a risk of developing different severity of pancreatitis and its outcome in our population

Implementing Diagnostic Imaging Services in a Rural Setting of Extreme Poverty: Five Years of X-ray and Ultrasound Service Delivery in Achham, Nepal

Introduction: Diagnostic radiology services are severely lacking in many rural settings and the implementation of these services poses complex challenges. The purpose of this paper is to describe the implementation of diagnostic radiology services at a district-level hospital in Achham, a rural district in Nepal. Methods and Materials: We conducted a retrospective review of the implementation of diagnostic radiology services. We compiled a list of implementation challenges and proposed solutions based on an internal review of historical data, hospital records, and the experiences of hospital staff members. We used a seven-domain analytic framework to structure our discussion of these challenges. Results: We documented the first five years of challenges faced and lessons learned by the non-profit organization Possible while implementing and providing diagnostic radiology services for the first time in a remote location. Additionally, we documented the uptake of these services through the first five years of operations. During this time, the number of X-rays performed increased 271%, while ultrasounds increased 258%. The main challenges included educating the community about the appropriate use of these services, recruiting trained providers, and coordinating referral care and consultations for higher-level diagnostics and treatment. Finally, investments in training providers and technicians, as well as investments in infrastructure, primarily the installation of solar panels to maintain a power supply, were critical to sustaining services. Discussion: This experience demonstrates that reliable and sustained services can be deployed even in extremely remote areas and identifies challenges that other implementers may face in similar program implementation

Knowledge of Cardiopulmonary Resuscitation Among Interns Working at Kathmandu Medical College

Background: Cardiac arrest is a substantial public health problem estimated to account for 15-20% of all death. Cardiac arrest is one of the most common emergencies within the emergency department leading to serious and life threatening results which can be managed if medical and paramedical personnel working in the emergency department have adequate knowledge about cardiopulmonary resuscitation (CPR) and if they are well trained to administer it effectively.  Objective: To assess the knowledge, attitude and practice regarding CPR amongst interns in tertiary medical center of Nepal and comprehend the depth of knowledge about CPR and practice regarding defibrillation used during CPR. Methodology: This is a cross-sectional study carried out in Kathmandu Medical College Teaching Hospital  using a semi structured pretested questionnaire. We requested interns to answer the questionnaire, which included 25 questions to assess the knowledge of  BLS. Similarly, subjects were inquired about  the  attitude level questionnaire by the researcher and scoring was done accordingly.  We analyzed the statistics through frequency, percentage, mean and mean percentw. Results:  Out of 150 interns , regarding knowledge, on an average 11.71 questions were correctly answered. Highest score of 22 was scored by five participants and lowest of 5 scored by seven participants. Eleven questions were rightly answered by more than 50%. All the participants  agreed that resuscitation training need to  be added in the curriculum . . Conclusion: The present study identified the  attitude score was good however, knowledge score of BLS  was poor among medical interns.  BLS training should be the part of the MBBS curriculum to solve this very critical issue. The unconsolidated knowledge about resuscitation among the  interns is not adequate. This study  emphasizes the necessity for standardized systemic resuscitation program in the undergraduate curriculum and effort should be made to introduce an appropriate, efficient and effective course design

Transaminitis among Patients with Dengue Fever Visiting a Tertiary Care Centre

Introduction: Transaminitis is a condition where serum aspartate transaminase and alanine transaminase increase indicating liver dysfunction. One such disease where liver involvement might be observed is dengue, which is a mosquito-borne viral infection. The aim of the study was to find out the prevalence of transaminitis among patients with dengue fever in a tertiary care centre. Methods: A descriptive cross-sectional study was conducted in a tertiary care centre from 1 November 2022 to 31 March 2023 after obtaining ethical approval from the Institutional Review Committee. Informed written consent was taken before collecting the data. A rapid immunochromatography test was used to confirm dengue infection. Serum aspartate transaminase and alanine transaminase were measured through routine Reitman and Frankel’s enzymatic method. Dengue-confirmed patients from the medical outpatient department, fever clinic, and medical ward of the centre were included in the study. Patients with known prior liver diseases or any other chronic diseases, pregnancy, and patients in the hospice unit were excluded. Convenience sampling method was used. The point estimate was calculated at a 95% Confidence Interval. Results: Among 442 dengue infected patients, the prevalence of transaminitis was 188 (42.53%) (37.92-47.13, 95% Confidence Interval). The highest frequency of dengue positive was observed among the 18-35 years age group, which was 97 (51.59%) with male predominance 134 (71.27%). Conclusions: The prevalence of transaminitis among patients with dengue fever in a tertiary care centre was found to be lower than other studies done in similar settings

Bacteriological Etiology and Antibiotics Susceptibility Pattern in Blood Samples from the Patients Attending Emergency Department of a Tertiary Care Hospital, Nepal

Background: Bacteriological aetiology and its culture sensitivity pattern is an important parameter for evaluating antibiotic use in Emergency Department. Blood-stream infections cause significant morbidity and mortality, increase in length of hospital stay and increased cost of care. Frequent inappropriate antibiotic use contributes to emergence of drug-resistant bacteria pathogens. Objectives: The objective of this study was to identify likely etiologic agents’ and antibiotic sensitivity profile of bacteria from blood stream infection in Emergency Department of Patan Hospital. Methodology: The study was conducted at tertiary care hospital from July to August 2014  blood culture was done and  antibiotic susceptibility test was performed following Kirby Bauer disc diffusion technique and growth and sensitivity pattern of organisms isolated were analyzed.   Results: There were 282 blood culture sent from the Emergency Department. The most common bacterial isolates were Enterobacter species. Second most common bacteria were Streptococcus pneumoniae.  Enterobacter species was more sensitive to Chloramphenicol, Amikacin and Gentamycin. While Streptococcus pneumoniae was sensitive to most of the antibiotics, we also found that 65.3% bacterial isolates were resistant to Cephalosporin. Conclusion:  Contaminated blood samples were found higher therefore, emphasis should be given in reducing the contamination. Proper cleaning of skin with antiseptic and guidelines to draw blood for culture should be familiarized and strictly followed while drawing the blood and others from Emergency Department of Patan Hospital.  

Structure Guided Design of Potent and Selective Ponatinib-Based Hybrid Inhibitors for RIPK1

SummaryRIPK1 and RIPK3, two closely related RIPK family members, have emerged as important regulators of pathologic cell death and inflammation. In the current work, we report that the Bcr-Abl inhibitor and anti-leukemia agent ponatinib is also a first-in-class dual inhibitor of RIPK1 and RIPK3. Ponatinib potently inhibited multiple paradigms of RIPK1- and RIPK3-dependent cell death and inflammatory tumor necrosis factor alpha (TNF-α) gene transcription. We further describe design strategies that utilize the ponatinib scaffold to develop two classes of inhibitors (CS and PN series), each with greatly improved selectivity for RIPK1. In particular, we detail the development of PN10, a highly potent and selective “hybrid” RIPK1 inhibitor, capturing the best properties of two different allosteric RIPK1 inhibitors, ponatinib and necrostatin-1. Finally, we show that RIPK1 inhibitors from both classes are powerful blockers of TNF-induced injury in vivo. Altogether, these findings outline promising candidate molecules and design approaches for targeting RIPK1- and RIPK3-driven inflammatory pathologies