A phase 1 study in healthy volunteers to investigate the safety, tolerability, and pharmacokinetics of VIR-2482: a monoclonal antibody for the prevention of severe influenza A illness.

The objective of this study was to evaluate the safety, tolerability, pharmacokinetics (PK), and immunogenicity of VIR-2482 in healthy adult subjects. A phase 1, first-in-human, randomized, double-blind, placebo-controlled dose-escalation study was conducted. One hundred participants were allocated to four cohorts (60 mg, 300 mg, 1,200 mg, and 1,800 mg). In each cohort, participants were randomized in a 4:1 ratio (active:placebo) to receive either VIR-2482 or volume-matched placebo by gluteal intramuscular injection. Participants remained at the investigative site under observation for 48 h, and adverse events (AEs) were collected for 56 days. PK and immunogenicity were measured up to 52 weeks post-dose. VIR-2482 was well tolerated at all doses studied. The overall incidence of AEs was comparable between VIR-2482 (68.8%) and placebo (85.0%). Nineteen VIR-2482 (23.8%) and six placebo (30.0%) recipients had Grade 1 or 2 AEs that were considered to be related to the study intervention. There were no treatment-related serious AEs. Injection-site reactions (ISRs) were reported in six (7.5%) VIR-2482 recipients, while no such reactions were reported among the placebo recipients. All ISRs were Grade 1, and there was no relationship with the dose. Median VIR-2482 serum elimination half-life ranged from 56.7 to 70.6 days across cohorts. The serum area under the curve and Cmax were dose-proportional. Nasopharyngeal VIR-2482 concentrations were approximately 2%-5% of serum levels and were less than dose-proportional. The incidence of immunogenicity across all cohorts was 1.3%. Overall, the safety, tolerability, and pharmacokinetic profile of VIR-2482 at doses up to 1,800 mg supported its further investigation as a long-acting antibody for the prevention of influenza A illness. This study has been registered at ClinicalTrials.gov under identifier NCT04033406.

Achieving efficacy in subjects with sustained pegvaliase-neutralizing antibody responses.

Pegvaliase (Palynziq®) is an enzyme substitution therapy using PEGylated recombinant Anabaena variabilis phenylalanine ammonia lyase (PAL) to reduce blood phenylalanine (Phe) levels in adults with phenylketonuria (PKU). In Phase 3 clinical studies, all subjects treated with pegvaliase developed anti-drug antibodies. To specifically evaluate pegvaliase-neutralizing antibodies (NAbs) and assess impact on pegvaliase efficacy, a novel hybrid ligand-binding/tandem mass spectrometry NAb assay was developed. Analysis of Phase 3 study samples revealed that pegvaliase NAb titers developed during early treatment (≤6 months after treatment initiation), and then plateaued and persisted in the majority of subjects during late treatment (>6 months). Subjects with the lowest/undetectable NAb titers had relatively high plasma pegvaliase concentrations and experienced the most rapid decline in blood Phe concentrations at relatively low pegvaliase dose concentrations. In contrast, subjects with higher NAb titers generally had lower plasma pegvaliase concentrations on similar low doses, with little change in blood Phe concentrations. However, with additional time on treatment and individualized dose titration, the majority of subjects achieved substantial and sustained blood Phe reduction, including those with higher NAb titers. Moreover, after maturation of the anti-pegvaliase immune response, NAb titers were stable over time and did not rise in response to dose increases; thus, subjects did not require additional dose increases to maintain reduction in blood Phe.

An evaluation of training of teachers in medical education in four medical schools of Nepal.

Effective teaching is a concern of all teachers. Therefore, regular teachers' training is emphasized globally. B. P. Koirala Institute of Health Sciences (BPKIHS), a health science deemed university situated in eastern region of Nepal has an established Medical Education unit which attempts to improve teaching-learning skills by training faculty members through organizing regular medical education training programs. The aim of the present study was to assess the effectiveness of 3-day training workshop on "Teaching-learning methodology and Evaluation" held in four different medical colleges of Nepal. The workshop was targeted at middle and entry level of health profession teachers who had not been previously exposed to any teacher's training program. The various components, such as teaching-learning principles, writing educational objectives, organizing and sequencing education materials, teaching-learning methods, microteaching and assessment techniques, were incorporated in the workshop. A team of resource persons from BPKIHS were involved in all the four medical institutions. The collection data had two categories of responses: (1) a questionnaire survey of participants at the beginning and end of the workshop to determine their gain in knowledge and (2) a semi-structured questionnaire survey of participants at the end of workshop to evaluate their perception on usefulness of the workshop. The later category had items with three-point likert scale (very useful, useful and not useful) and responses to open-ended questions/ statements to document participants general views. The response was entered into a spreadsheet and analyzed using SPSS. The result showed that all participants (n = 92) improved their scores after attending the workshop (p < 0.001). Majority of respondents expressed that the teaching-learning methods, media, microteaching and evaluation techniques were useful in teaching-learning. The workshop was perceived as an acceptable way of acquiring teaching-learning skills but 39.4% participants expressed that the duration of the workshop was too short. The overall impression about trainers was very positive. Therefore, regular organization of such workshops with addition of new advances in medical education would be highly beneficial to improve teaching learning skill of medical teachers.

Comparative study of cerebrospinal fluid adenosine deaminase activity in patients with meningitis.

Cerebrospinal fluid (CSF) adenosine deaminase (ADA) activity in tubercular meningitis (TBM) patients (n=20), non-tubercular meningitis (NTBM) patients (n=10) and non-tubercular non-meningitis (NTBNM) cases (n=15) were measured by the method based on Berthlot's reaction. The mean CSF ADA activity in TBM (13.62 +/- 8.45 IU/L) was found to be significantly higher as compared to NTBM (6.51 +/- 2.41 IU/ L, p<0.001) and NTBNM (2.35 +/- 1.16 IU/L, p<0.0001) respectively. The sensitivity and specificity of CSF ADA activity was 85.0% and 88.0% respectively at cut-off value of 6.97 IU/L to diagnose tubercular meningitis. The specificity and sensitivity of CSF ADA for TBM was found to be 85.0% and 70.0% as compared to NTBM and 85.0% and 100.0% as compared to NTBNM. We propose that estimation of that ADA activity in CSF of TBM patients, using a cut off value 6.97 IU/L can diagnose differentially tubercular meningitis. Since, most developing countries have the dubious distinction of having higher prevalence and incidence of tubeculosis and lack of well equipped laboratory services for proper diagnosis of tubercular meningitis, measurement of CSF ADA activity can be a better and reliable approach for the rapid diagnosis and management of tubercular meningitis vis a vis other types of meningitis.

Assessment of proteinuria as a marker of nephropathy in type 2 diabetes mellitus.

This is a cross sectional hospital based study carried out at Om Hospital and Research Center Kathmandu, Nepal. In the study, 200 diabetic patients attending the hospital were taken as the subjects and we evaluated the urinary albumin excretion and other biochemical parameters (such as creatinine, total cholesterol, HDL cholesterol, LDL cholesterol), blood pressure and body mass index (BMI). Among these 200 patients with type 2 diabetes mellitus (DM), 52.0% were having high blood pressure. The proteinuria was present in 23.0% of the overall subjects but when it is categorized in hypertensive and non-hypertensive group, 30.7% of the diabetic patients with hypertension were having proteinuria. It has been found that males were having higher prevalence ofproteinuria (53.8%) than female (17.6%). There was significant difference in systolic blood pressure, diastolic blood pressure in nephropathy and without nephropathy group. Thus the nephropathy or the incidence of proteinuria was associated with obesity, high diastolic blood pressure and male sex. These data suggest that control of diabetes; hypertension should decrease the risk for proteinuria thus decreasing end stage renal disease (ESRD) and mortality from ESRD.