Occupational Stress Among Middle-Aged Professionals in India.

Background: Professional world nowadays is very competitive, and surviving the cutthroat competition while sustaining work-related stress and pressure is an important task for employees. Professionals are required to meet daily and monthly objectives and may encounter work-related stressors. Purpose: The study aims to explore occupational stress among middle-aged professionals in the age range of 45-60 years from the marketing, banking, and teaching sectors. Methods: A total sample of 180 consented middle-aged professionals in the age range of 45-60 years from the banking, teaching, and marketing sectors were included in the study using a purposive and snowball sampling technique. Professionals having serious medical or psychiatric conditions and undergoing treatment for the same were excluded. The Occupational Stress Index was administered to assess different types of occupational stressors. The statistical analysis was done using the Statistical Package for Social Sciences version 20 software. A descriptive analysis and a one-way analysis of variance (ANOVA) were used to get meaningful results. Results: Results revealed that 40% of the middle-aged professionals reported experiencing minimal levels of occupational stress, followed by 32.2% experiencing moderate levels and 27.8% experiencing high levels of occupational stress. Additionally, it was found that a significantly higher percentage (91.6%) of banking professionals reported low levels of occupational stress compared to their counterparts. Eighty percent of marketing professionals reported experiencing high levels of occupational stress, whereas a majority (73.3%) of teaching professionals reported moderate levels of occupational stress. Conclusion: Occupational stress with different severity levels is found to be common among middle-aged professionals, which is a risk factor to develop mental health problems and affects well-being. Large-scale primary and secondary interventions are required to manage stress and facilitate professional growth and development in India.

Diversity of CFTR variants across ancestries characterized using 454,727 UK biobank whole exome sequences.

BACKGROUND: Limited understanding of the diversity of variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene across ancestries hampers efforts to advance molecular diagnosis of cystic fibrosis (CF). The consequences pose a risk of delayed diagnoses and subsequently worsened health outcomes for patients. Therefore, characterizing the spectrum of CFTR variants across ancestries is critical for revolutionizing molecular diagnoses of CF. METHODS: We analyzed 454,727 UK Biobank (UKBB) whole-exome sequences to characterize the diversity of CFTR variants across ancestries. Using the PanUKBB classification, the participants were assigned into six major groups: African (AFR), American/American Admixed (AMR), Central South Asia (CSA), East Asian (EAS), European (EUR), and Middle East (MID). We segregated ancestry-specific CFTR variants, including those that are CF-causing or clinically relevant. The ages of certain CF-causing variants were determined and analyzed for selective pressure effects, and curated phenotype analysis was performed for participants with clinically relevant CFTR genotypes. RESULTS: We detected over 4000 CFTR variants, including novel ancestry-specific variants, across six ancestries. Europeans had the most unique CFTR variants [n = 2212], while the American group had the least unique variants [n = 23]. F508del was the most prevalent CF-causing variant found in all ancestries, except in EAS, where V520F was the most prevalent. Common EAS variants such as 3600G > A, V456A, and V520, which appeared approximately 270, 215, and 338 generations ago, respectively, did not show evidence of selective pressure. Sixteen participants had two CF-causing variants, with two being diagnosed with CF. We found 154 participants harboring a CF-causing and varying clinical consequences (VCC) variant. Phenotype analysis performed for participants with multiple clinically relevant variants returned significant associations with CF and its pulmonary phenotypes [Bonferroni-adjusted p < 0.05]. CONCLUSIONS: We leveraged the UKBB database to comprehensively characterize the broad spectrum of CFTR variants across ancestries. The detection of over 4000 CFTR variants, including several ancestry-specific and uncharacterized CFTR variants, warrants the need for further characterization of their functional and clinical relevance. Overall, the presentation of classical CF phenotypes seen in non-CF diagnosed participants with more than one CF-causing variant indicates that they may benefit from current CFTR modulator therapies.

Phase 1 study of safety, pharmacokinetics, and antiviral activity of SARS-CoV-2 neutralizing monoclonal antibody ABBV-47D11 in patients with COVID-19.

ABBV-47D11 is a neutralizing monoclonal antibody that targets a mutationally conserved hydrophobic pocket distal to the ACE2 binding site of SARS-CoV-2. This first-in-human safety, pharmacokinetics, and antiviral pharmacodynamic assessment in patients with COVID-19 provide an initial evaluation of this antibody that may allow further development. This multicenter, randomized, double-blind, and placebo-controlled single ascending dose study of ABBV-47D11 (180, 600, or 2400 mg) as an intravenous infusion, was in hospitalized and non-hospitalized (confined) adults with mild to moderate COVID-19. Primary outcomes were grade 3 or higher study drug-related adverse events and infusion-related reactions. Secondary outcomes were pharmacokinetic parameters and concentration-time profiles to Day 29, immunogenicity (anti-drug antibodies), and antiviral activity (change in RT-PCR viral load) from baseline to Days 15 and 29. ABBV-47D11 single doses up to 2400 mg were safe and tolerated and no safety signals were identified. The pharmacokinetics of ABBV-47D11 were linear and showed dose-proportional increases in serum concentrations with ascending doses. The exploratory anti-SARS-CoV-2 activity revealed a reduction of viral load at and above the 600 mg dose of ABBV-47D11 regardless of patient demographics and baseline characteristics, however; because of the high inter-individual variability and small sample size a statistical significance was not reached. There is potential for anti-SARS-CoV-2 activity with ABBV-47D11 doses of 600 mg or higher, which could be evaluated in future clinical trials designed and powered to assess viral load reductions and clinical benefit.

Mental health promotion for elderly populations in World Health Organization South-East Asia Region: Needs and resource gaps.

The accelerated population growth of the elderly (individuals aged 60 years or more) across the globe has many indications, including changes in demography, health, the psycho-social milieu, and economic security. This transition has given rise to varied challenges; significant changes have been observed in regard to developing strategies for health care systems across the globe. The World Health Organization (WHO) is also engaging in initiatives and mediating processes. Furthermore, advocacy is being conducted regarding a shift toward the salutogenic model from the pathogenic model. The concept behind this move was to shift from disablement to enablement and from illness to wellness, with the notion of mental health promotion (MHP) being promoted. This article attempts to discuss the MHP of elderly individuals, with special reference to the need to disseminate knowledge and awareness in the community by utilizing the resources of the health sector available in the WHO South-East Asia Region countries. We have tried to present the current knowledge gap by exploring the existing infrastructure, human resources, and financial resources. There is much to do to promote the mental health of the elderly, but inadequate facilities are available. Based on available resources, a roadmap for MHP in elderly individuals is discussed.

Linkage of resistance-associated substitutions in GT1 sofosbuvir + NS5A inhibitor failures treated with glecaprevir/pibrentasvir.

BACKGROUND & AIMS: Retreatment with glecaprevir/pibrentasvir (G/P) resulted in a rate of sustained virologic response 12 weeks after treatment completion (SVR12) of >90% in HCV genotype 1 (GT1) patients who previously failed a regimen of sofosbuvir plus an NS5A inhibitor (NS5Ai). This study investigated the prevalence and impact of baseline NS3 and NS5A resistance-associated substitutions (RASs) on the efficacy of G/P in prior GT1 sofosbuvir+NS5Ai failures and the persistence of treatment-emergent RASs. METHODS: Longitudinal samples from 177 patients enrolled in a phase IIIb, randomized pragmatic clinical trial were analyzed. Patients without cirrhosis were randomized to 12 or 16 weeks of G/P, and patients with compensated cirrhosis were randomized to G/P and ribavirin for 12 weeks or G/P for 16 weeks. Linkage of RAS was identified using Primer-ID next-generation sequencing at a 15% cut-off. RESULTS: Of 177 patients, 169 (95.5%) were PI-naïve. All 33 GT1b-infected patients achieved SVR12. In GT1a-infected patients, baseline NS5A RASs were prevalent (74.5%, 105/141) but NS3 RASs were uncommon. Baseline NS3 RASs had no impact on G/P efficacy and patients with baseline NS5A RASs showed a numerically but not statistically significantly lower SVR12 rate compared to those without NS5A RASs (89% vs. 97%). SVR12 was achieved in 34 of 35 (97%) patients without NS5A baseline substitution, and 53 of 57 (93%), 35 of 40 (88%), 5 of 8 (63%) with single, double-linked, and triple-linked NS5A substitutions, respectively. Among 13 patients with virologic failure, 4 acquired treatment-emergent NS3 RASs and 10 acquired NS5A RASs. CONCLUSION: Baseline NS5A RASs were highly prevalent. The presence of an increasing number of linked NS5A RASs in GT1a showed a trend in decreasing SVR12 rates, although no specific NS5A RASs or their linkage pattern were associated with lower SVR12 rates. LAY SUMMARY: Direct-acting antivirals have revolutionized the treatment of chronic hepatitis C infection, but treatment failure occurs in some patients. Retreatment of patients who previously failed a regimen consisting of sofosbuvir and an NS5A inhibitor with a regimen of glecaprevir and pibrentasvir (G/P) is >90% effective. Herein, we analyzed samples from these patients and showed that retreatment efficacy with G/P is lower in patients with double- or triple-linked NS5A resistance mutations than in patients with single or no NS5A resistance mutations. CLINICAL TRIAL NUMBER: NCT03092375.

Pharmacokinetics, Safety, and Efficacy of Glecaprevir/Pibrentasvir in Children With Chronic HCV: Part 2 of the DORA Study.

BACKGROUND AND AIMS: Glecaprevir/pibrentasvir (GLE/PIB) has shown high efficacy and safety in chronic HCV-infected adults and adolescents; data in children were limited. DORA part 2 is a phase 2/3, nonrandomized, open-label study evaluating the pharmacokinetics, efficacy, and safety of a pediatric formulation of GLE and PIB in children ages 3 to < 12 years. APPROACH AND RESULTS: Children with chronic HCV infection, genotype 1-6, with or without compensated cirrhosis, were divided into three cohorts by age-cohort 2 (9 to < 12 years), cohort 3 (6 to < 9 years), and cohort 4 (3 to < 6 years)-and given weight-based doses of GLE and PIB for 8, 12, or 16 weeks. Primary endpoints were sustained virologic response at posttreatment week 12 (SVR12) and steady-state exposure; secondary endpoints were rates of persistent viremia, relapse, and reinfection. Safety and laboratory abnormalities were assessed. Final pediatric dosages determined to be efficacious were 250 mg GLE + 100 mg PIB (in children weighing ≥ 30 to < 45 kg), 200 mg GLE + 80 mg PIB (≥ 20 to < 30 kg), and 150 mg GLE + 60 mg PIB (12 to < 20 kg). Of 80 participants enrolled and dosed, 96% (77/80) achieved SVR12. One participant, on the initial dose ratio, relapsed by posttreatment week 4; no participants had virologic failures on the final dose ratio of GLE 50 mg/PIB 20 mg. Two nonresponders prematurely discontinued the study. Most adverse events (AEs) were mild; no drug-related serious AEs occurred. Pharmacokinetic exposures were comparable to those of adults. CONCLUSIONS: A pediatric formulation of GLE/PIB was highly efficacious and well tolerated in chronic HCV-infected children 3 to < 12 years old.

Glecaprevir-pibrentasvir to treat chronic hepatitis C virus infection in Asia: two multicentre, phase 3 studies- a randomised, double-blind study (VOYAGE-1) and an open-label, single-arm study (VOYAGE-2).

BACKGROUND: Glecaprevir-pibrentasvir results in high rates of sustained virological response in patients with chronic hepatitis C virus (HCV) genotype 1-6 infection. Data for glecaprevir-pibrentasvir in non-Japanese Asian patients have been minimal. The aim of these studies was to assess the efficacy and safety of glecaprevir-pibrentasvir in treatment-naive and treatment-experienced Asian patients with chronic HCV genotype 1-6 infection without cirrhosis (VOYAGE-1) and with compensated cirrhosis (VOYAGE-2). METHODS: We did two phase 3 studies in treatment-naive and treatment-experienced patients with chronic HCV genotype 1-6 infection. VOYAGE-1 was a randomised, double-blind, placebo-controlled study that recruited patients without cirrhosis at 47 sites across China, South Korea, and Singapore. Randomisation was 2:1 with a fixed block size of three and stratified by geographical region and HCV genotype. Investigators, study site personnel, the study sponsor, and patients were masked to treatment allocation. VOYAGE-2 was a single-arm, open-label study that recruited patients with compensated cirrhosis at 34 sites across China and South Korea. Glecaprevir (300 mg) and pibrentasvir (120 mg) or placebo (VOYAGE-1, 2:1 ratio), administered as three tablets daily, was given for 8 weeks in patients without cirrhosis and for 12 weeks in those with cirrhosis (and for 16 weeks in treatment-experienced patients with genotype 3). The primary efficacy endpoint was the proportion of patients with a sustained virological response, defined as HCV RNA below the lower limit of quantification 12 weeks after the last dose of glecaprevir-pibrentasvir. We analysed efficacy and safety in all patients who received at least one dose of the study drug. These trials are registered with ClinicalTrials.gov, NCT03222583 (VOYAGE-1) and NCT03235349 (VOYAGE-2); both trials have been completed. This Article reports the results of the primary analysis for each study, undertaken when all patients who received glecaprevir-pibrentasvir (during the double-blind period in VOYAGE-1) had been followed up for 12 weeks following their last dose of study drug. Data from the double-blind period for placebo patients in VOYAGE-1 are also summarised. FINDINGS: Between Oct 4, 2017, and April 20, 2018, 546 patients with chronic HCV without cirrhosis were randomly assigned to treatment (363 to glecaprevir-pibrentasvir, 183 to placebo) in VOYAGE-1. One patient withdrew consent and did not receive treatment with glecaprevir-pibrentasvir. 352 of 362 patients who received glecaprevir-pibrentasvir achieved SVR12 (97·2% [95% CI 95·5-98·9]). Of 160 patients with compensated cirrhosis who were enrolled in VOYAGE-2 between Sept 29, 2017, and June 14, 2018, 159 of 160 achieved SVR12 (99·4%, 95% CI 98·2-100·0). 20 patients with HCV genotype 3b across both trials received glecaprevir-pibrentasvir; six of these patients were among the 11 patients who did not achieve SVR12. Upper respiratory tract infection was the most common adverse event (35 [10%] of 362 receiving glecaprevir-pibrentasvir and 18 [10%] of 183 receiving placebo in VOYAGE-1; 19 [12%] of 160 in VOYAGE-2). For patients receiving glecaprevir-pibrentasvir, serious adverse events occurred in three (<1%) of 362 patients in VOYAGE-1 and five (3%) of 160 patients in VOYAGE-2. Grade 3-4 adverse events in patients receiving glecaprevir-pibrentasvir occurred in five (1%) of 362 patients in VOYAGE-1 and six (4%) of 160 patients in VOYAGE-2; each type of event was experienced by at most one patient within a study. One patient with cirrhosis discontinued study drug because of an adverse event. INTERPRETATION: Glecaprevir-pibrentasvir showed high efficacy and an acceptable safety profile in these studies although responses were less common in the few patients with HCV genotype 3b. The results support the use of glecaprevir-pibrentasvir in these Asian populations. FUNDING: AbbVie.

Usefulness of clock-drawing test in Indian older adults with diabetes mellitus.

BACKGROUND: Clock-drawing test (CDT) is a simple, quick, and bedside cognitive screening test which measures different cognitive domains but has some limitations. The aim of this study was to examine the usefulness of CDT for Indian older adult based on a part of an ICMR-funded research project, New Delhi, India. MATERIALS AND METHODS: Sample comprised seventy participants (38 controls and 32 cases) aged 60 years and above included according to the inclusion/exclusion criteria in a consecutive series. Participants, who gave written informed consent, residing permanently in the area of Chowk, Lucknow, constituted the study sample. Semistructured sociodemographic details and medical history pro forma, socioeconomic status scale, General Health Questionnaire-12 (GHQ-12), CDT, and Hindi cognitive screening test (HCST) were administered. Biochemical investigations were carried out, and blood glucose level (fasting ≤100 mg/dl and postprandial ≤140 mg/dl) was considered for having diabetes mellitus (DM). The participants were categorized into two groups: (1) case: participants with DM only and (2) control: participants without discernible abnormality of physical illness and GHQ negative. Data were analyzed using percentages, t-test, the Chi-square test, sensitivity, and specificity. RESULTS: About 71.05% participants in control and 81.25% in the case group have cognitive impairment on CDT. Significantly higher illiterates (P < 0.05) were found to be significantly more cognitively impaired on HCST. CDT has a high level of sensitivity (0.71) and low specificity (0.23) when compared with HCST. CONCLUSION: CDT had screening bias to Indian older adults as a higher number of literates (almost double) and illiterates (four times) were found to be cognitively impaired compared to on HCST. Usefulness of CDT to screen Indian older adults for cognitive impairment is debatable.

Ombitasvir, paritaprevir, and ritonavir with peginterferon-α2a plus ribavirin in treatment-experienced patients with chronic hepatitis C virus genotype 1 infection.

BACKGROUND: This international, phase 2, open-label, multicenter study (ClinicalTrials.gov Identifier: NCT01609933) was conducted to evaluate the safety and efficacy of an enhanced regimen consisting of the direct-acting antivirals (DAAs) ombitasvir, paritaprevir, and ritonavir administered for 24 weeks, combined with pegylated interferon-α2a plus ribavirin (pegIFN-α2a/RBV) for 48 weeks, in patients with chronic hepatitis C virus (HCV) genotype 1 infection who had experienced virologic failure with a prior DAA regimen. This study was undertaken at a time when options were limited for the retreatment of patients who had failed prior DAA therapy. METHODS AND RESULTS: Thirty-two patients were enrolled; the majority were male (78%) and White (94%), and the median age was 54.5 years. Twelve weeks after the last dose of study drug, sustained virologic response was achieved in 81.3% of patients. Five patients prematurely discontinued the study drugs and one patient relapsed. Safety and tolerability were similar to prior studies of pegIFN-α2a/RBV alone. CONCLUSION: Given the availability of highly efficacious DAA regimens that are both IFN- and RBV-free, this regimen is no longer relevant in today's HCV treatment landscape.

Hepatitis C virus genetic diversity by geographic region within genotype 1-6 subtypes among patients treated with glecaprevir and pibrentasvir.

Hepatitis C virus (HCV) is genetically diverse and includes 7 genotypes and 67 confirmed subtypes, and the global distribution of each HCV genotype (GT) varies by geographic region. In this report, we utilized a large dataset of NS3/4A and NS5A sequences isolated from 2348 HCV GT1-6-infected patients treated with the regimen containing glecaprevir/pibrentasvir (GLE/PIB) to assess genetic diversity within HCV subtypes by geographic region using phylogenetic analyses, and evaluated the prevalence of baseline amino acid polymorphisms in NS3 and NS5A by region/country and phylogenetic cluster. Among 2348 NS3/4A and NS5A sequences, phylogenetic analysis identified 6 genotypes and 44 subtypes, including 3 GT1, 8 GT2, 3 GT3, 13 GT4, 1 GT5, and 16 GT6 subtypes. Phylogenetic analysis of HCV subtype 1a confirmed the presence of two clades, which differed by geographic region distribution and NS3 Q80K prevalence. We detected phylogenetic clustering by country in HCV subtypes 1a, 1b, 2a, 2b, and 5a, suggesting that genetically distinct virus lineages are circulating in different countries. In addition, two clades were detected in HCV GT4a and GT6e, and NS5A amino acid polymorphisms were differentially distributed between the 2 clades in each subtype. The prevalence of NS3 and NS5A baseline polymorphisms varied substantially by genotype and subtype; therefore, we also determined the activity of GLE or PIB against replicons containing NS3/4A or NS5A from HCV GT1-6 clinical samples representing 6 genotypes and 21 subtypes overall. GLE and PIB retained activity against the majority of HCV replicons containing NS3/4A or NS5A from HCV GT1-6 clinical samples, with a median EC50 of 0.29 nM for GLE and 1.1 pM for PIB in a transient replicon assay. The data presented in this report expands the available data on HCV epidemiology, subtype diversity by geographic region, and NS3 and NS5A baseline polymorphism prevalence.

Pooled Resistance Analysis in Patients with Hepatitis C Virus Genotype 1 to 6 Infection Treated with Glecaprevir-Pibrentasvir in Phase 2 and 3 Clinical Trials.

Over 2,200 patients infected with hepatitis C virus (HCV) genotypes (GT) 1 to 6, with or without cirrhosis, who were treatment naive or experienced to interferon, ribavirin, and/or sofosbuvir were treated with glecaprevir/pibrentasvir for 8, 12, or 16 weeks in eight registrational phase 2 and 3 clinical studies. High rates of sustained virologic response at 12 weeks postdosing (SVR12) were achieved with a <1% virologic failure (VF) rate. The prevalence of baseline polymorphisms (BPs) in NS3 at amino acid position 155 or 168 was low (<3%) in patients infected with GT1, GT2, GT3, GT4, and GT6, while 41.9% of the GT5-infected patients had NS3-D168E; BPs were not detected at position 156 in NS3. The prevalence of NS5A-BPs was high across genotypes, driven by common polymorphisms at amino acid position 30 or 31 in GT2, 58 in GT4, and 28 in GT6. The prevalence of NS5A T/Y93 polymorphisms was 5.5% in GT1, 4.9% in GT3, and 12.5% in GT6. Consistent with the activity of glecaprevir and pibrentasvir against most amino acid polymorphisms in vitro, BPs in NS3 and/or NS5A did not have an impact on treatment outcome for patients infected with GT1 to GT6, with the exception of treatment-experienced GT3-infected patients treated for 12 weeks, for whom a 16-week regimen of glecaprevir/pibrentasvir was required to achieve SVR12 rates of ≥95%. Among the 22 patients experiencing VF, treatment-emergent substitutions were detected in NS3 in 50% of patients and in NS5A in 82% of patients, frequently as a combination of substitutions that conferred resistance to glecaprevir and/or pibrentasvir. The glecaprevir/pibrentasvir regimen, when the recommended durations are used, allows for a pan-genotypic treatment option without the need for baseline resistance testing.

Resistance Analysis of a 3-Day Monotherapy Study with Glecaprevir or Pibrentasvir in Patients with Chronic Hepatitis C Virus Genotype 1 Infection.

Glecaprevir (an NS3/4A protease inhibitor) and pibrentasvir (an NS5A inhibitor) are potent and pangenotypic hepatitis C virus (HCV) direct-acting antivirals. This report describes the baseline polymorphisms and treatment-emergent substitutions in NS3 or NS5A detected in samples from HCV genotype 1-infected patients receiving 3-day monotherapy of glecaprevir or pibrentasvir, respectively. None of the NS3 polymorphisms detected in the 47 baseline samples collected prior to glecaprevir monotherapy conferred reduced susceptibility to glecaprevir. The NS3 A156T substitution, which conferred resistance to glecaprevir but had low replication efficiency, emerged in one genotype 1a-infected patient among the 35 patients with available post-baseline sequence data. Baseline NS5A polymorphisms were detected in 12 of 40 patients prior to pibrentasvir monotherapy; most polymorphisms were single-position NS5A amino acid substitutions that did not confer resistance to pibrentasvir. Among the 19 patients with available post-baseline NS5A sequence data, 3 had treatment-emergent NS5A substitutions during pibrentasvir monotherapy. All treatment-emergent NS5A substitutions were linked multiple-position, almost exclusively double-position, substitutions that conferred resistance to pibrentasvir. Replicons engineered with these double-position substitutions had low replication efficiency. In conclusion, resistance-conferring substitutions emerged in a small number of genotype 1-infected patients during glecaprevir or pibrentasvir monotherapy; unlike other NS5A inhibitors, pibrentasvir did not select single-position NS5A substitutions during monotherapy.

Prevalence of Psychiatric Illness among Residents of Old Age Homes in Northern India.

CONTEXT: There are many factors which compelled older adults to live in old age homes (OAHs) and vulnerable to psychological problems. Studies reported high prevalence of mental health problems (20%-60%) among elderlies of OAHs. Therefore, the study was conducted to explore prevalence of psychiatric illness (PI) among residents of OAHs of Northern India. SETTINGS AND DESIGN: The present study was conducted in OAHs of Districts Bareilly, Lucknow, Varanasi, Dehradun, and Haridwar, using cross-sectional descriptive study method. Sample Size were 306 (male - 98 [32.5%] and female n = 208 [68%]) residing in OAHs selected by means of purposive sampling. SUBJECTS AND METHODS: Inclusion criteria: (a) older adults aged 60 years and above residing in OAHs and able to communicate. (b) Staying in OAHs for 6 months or more. (c) Able to understand comprehends and reply to questions and (d) Giving written informed consent. Exclusion criteria: (a) Residents who declined/not interested to participate in the study. (b) Residents having any sensory impairment/physical health problem which can impede the interview. Research tools were (i) a semi-structured pro forma, (ii) Hindi Mental Status Examination, (iii) Survey psychiatric assessment schedule, and (iv) Schedules for clinical assessment in neuropsychiatry-based clinical interview for diagnosis of PIs according to International Classification of Disease 10. STATISTICAL ANALYSIS USED: The quantitative data obtained was analyzed by means of frequency tables. RESULTS: The results show overall prevalence of PI is 43% among residents of OAHs. The prevalence of PI was found to be higher among females compared to males. Depression was the most common among the residents of OAHs. CONCLUSIONS: There is an urgent need of trained professionals to provide professional help for highly prevalent psychiatric disorders among residents of OAHs.

Efficacy and Safety of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir ± Ribavirin for HCV in Brazilian Adults with Advanced Fibrosis.

INTRODUCTION AND AIM: Approximately 650,000 people in Brazil have chronic hepatitis C virus (HCV) infection. We evaluated the safety and efficacy of ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) plus dasabuvir (DSV) with/without ribavirin (RBV) in an openlabel multicenter phase 3b trial in treatment-naive or interferon (IFN) treatment-experienced Brazilian patients with advanced hepatic fibrosis (METAVIR F3/4) and HCV genotype (GT) 1 infection. MATERIAL AND METHODS: All patients received coformulated OBV/PTV/r daily + DSV twice daily (3-DAA). GT1a-infected patients received 3-DAA plus RBV for 12 weeks, except for prior pegIFN/RBV nonresponders with cirrhosis who were treated for 24 weeks. GT1b-infected patients received 3-DAA alone (F3) or in combination with RBV (F4) for 12 weeks. The primary endpoint was sustained virologic response (HCV RNA < 15 IU/mL) at post-treatment Week 12 (SVR12). RESULTS: The study enrolled 222 patients, 214 achieved an SVR12 (96.4%; 95% CI, 93.1-98.2%), one GT1a-infected patient experienced virologic breakthrough, six (5 GT1a) relapsed, and one was lost to follow-up. SVR12 was achieved in 111/ 112 (99.1%) GT1b-infected patients, including 42/43 (97.7%) noncirrhotic, and 69/69 (100%) cirrhotic patients; and in 103/110 (93.6%) GT1a-infected patients, including 44/46 (95.7%) noncirrhotic and 59/64 (92.2%) cirrhotic patients. Overall there was a low rate of serious adverse events (n = 6, 2.7%). One patient experienced a treatment-related serious adverse event and one patient discontinued treatment because of an adverse event. DISCUSSION: The results confirm that the 3-DAA regimen with/without RBV is well tolerated and had a favorable safety profile and is efficacious in GT1-infected patients with advanced fibrosis (METAVIR F3/4).

Resistance characterization of hepatitis C virus genotype 2 from Japanese patients treated with ombitasvir and paritaprevir/ritonavir.

Treatment of HCV genotype (GT) 2-infected Japanese patients with paritaprevir (NS3/4A inhibitor boosted with ritonavir) and ombitasvir (NS5A inhibitor) without ribavirin for 12 weeks in the phase 2 study M12-536, and with ribavirin for 16 weeks in phase 3 study GIFT II resulted in SVR rates of 72.2% to 91.5%. Overall, 11 out of 125 patients with GT2a and 37 out of 79 patients with GT2b infection experienced virologic failure. The prevalence of baseline polymorphisms in NS3 and NS5A and their the impact on treatment outcome, as well as the development of viral resistance in GT2-infected patients experiencing virologic failure were evaluated by HCV NS3 and NS5A population and clonal sequence analyses. Baseline polymorphisms in NS3 that confer resistance to paritaprevir were rare in both GT2a- and GT2b-infected patients, while baseline polymorphisms in NS5A that confer resistance to ombitasvir were detected in 11.2% and 14.1% of the GT2a- and GT2b-infected patients, respectively. There was no significant impact of baseline polymorphisms on treatment outcome in Japanese patients. The most common treatment-emergent substitutions at the time of virologic failure occurred at amino acid positions 168 in NS3 and 28 in NS5A in both GT2a- and GT2b-infected patients. Although there was a higher rate of virologic failure in patients with GT2b infection, the resistance analyses presented in this report support the conclusion that testing for baseline resistance-associated polymorphisms is not warranted for HCV GT2-infected patients treated with a regimen of ombitasvir/paritaprevir/ritonavir + ribavirin for 16 weeks.

Integrated Resistance Analysis of CERTAIN-1 and CERTAIN-2 Studies in Hepatitis C Virus-Infected Patients Receiving Glecaprevir and Pibrentasvir in Japan.

Glecaprevir and pibrentasvir are hepatitis C virus (HCV) pangenotypic inhibitors targeting NS3/4A protease and NS5A, respectively. This once-daily, fixed-dose combination regimen demonstrated high sustained virologic response 12 weeks postdosing (SVR12) rates in CERTAIN-1 and CERTAIN-2 studies in Japanese HCV-infected patients, with a low virologic failure rate (1.2%). There were no virologic failures among direct-acting antiviral (DAA)-treatment-naive genotype 1a (GT1a) (n = 4)-, GT1b (n = 128)-, and GT2 (n = 97)-infected noncirrhotic patients treated for 8 weeks or among GT1b (n = 38)- or GT2 (n = 20)-infected patients with compensated cirrhosis treated for 12 weeks. Two of 33 DAA-experienced and 2 of 12 GT3-infected patients treated for 12 weeks experienced virologic failure. Pooled resistance analysis, grouped by HCV subtype, treatment duration, prior treatment experience, and cirrhosis status, was conducted. Among DAA-naive GT1b-infected patients, the baseline prevalence of NS3-D168E was 1.2%, that of NS5A-L31M was 3.6%, and that of NS5A-Y93H was 17.6%. Baseline polymorphisms in NS3 or NS5A were less prevalent in GT2, with the exception of the common L/M31 polymorphism in NS5A. Among DAA-experienced GT1b-infected patients (30/32 daclatasvir plus asunaprevir-experienced patients), the baseline prevalence of NS3-D168E/T/V was 48.4%, that of NS5A-L31F/I/M/V was 81.3%, that of the NS5A P32deletion was 6.3%, and that of NS5A-Y93H was 59.4%. Common baseline polymorphisms in NS3 and/or NS5A had no impact on treatment outcomes in GT1- and GT2-infected patients; the impact on GT3-infected patients could not be assessed due to the enrollment of patients infected with diverse subtypes and the limited number of patients. The glecaprevir-pibrentasvir combination regimen allows a simplified treatment option without the need for HCV subtyping or baseline resistance testing for DAA-naive GT1- or GT2-infected patients. (The CERTAIN-1 and CERTAIN-2 studies have been registered at ClinicalTrials.gov under identifiers NCT02707952 and NCT02723084, respectively.).

In Vitro Antiviral Activity and Resistance Profile of the Next-Generation Hepatitis C Virus NS3/4A Protease Inhibitor Glecaprevir.

Glecaprevir (formerly ABT-493) is a novel hepatitis C virus (HCV) NS3/4A protease inhibitor (PI) with pangenotypic activity. It inhibited the enzymatic activity of purified NS3/4A proteases from HCV genotypes 1 to 6 in vitro (half-maximal [50%] inhibitory concentration = 3.5 to 11.3 nM) and the replication of stable HCV subgenomic replicons containing proteases from genotypes 1 to 6 (50% effective concentration [EC50] = 0.21 to 4.6 nM). Glecaprevir had a median EC50 of 0.30 nM (range, 0.05 to 3.8 nM) for HCV replicons containing proteases from 40 samples from patients infected with HCV genotypes 1 to 5. Importantly, glecaprevir was active against the protease from genotype 3, the most-difficult-to-treat HCV genotype, in both enzymatic and replicon assays demonstrating comparable activity against the other HCV genotypes. In drug-resistant colony selection studies, glecaprevir generally selected substitutions at NS3 amino acid position A156 in replicons containing proteases from genotypes 1a, 1b, 2a, 2b, 3a, and 4a and substitutions at position D/Q168 in replicons containing proteases from genotypes 3a, 5a, and 6a. Although the substitutions A156T and A156V in NS3 of genotype 1 reduced susceptibility to glecaprevir, replicons with these substitutions demonstrated a low replication efficiency in vitro Glecaprevir is active against HCV with most of the common NS3 amino acid substitutions that are associated with reduced susceptibility to other currently approved HCV PIs, including those at positions 155 and 168. Combination of glecaprevir with HCV inhibitors with other mechanisms of action resulted in additive or synergistic antiviral activity. In summary, glecaprevir is a next-generation HCV PI with potent pangenotypic activity and a high barrier to the development of resistance.

Crystal structure of full-length Zika virus NS5 protein reveals a conformation similar to Japanese encephalitis virus NS5.

The rapid spread of the recent Zika virus (ZIKV) epidemic across various countries in the American continent poses a major health hazard for the unborn fetuses of pregnant women. To date, there is no effective medical intervention. The nonstructural protein 5 of Zika virus (ZIKV-NS5) is critical for ZIKV replication through the 5'-RNA capping and RNA polymerase activities present in its N-terminal methyltransferase (MTase) and C-terminal RNA-dependent RNA polymerase (RdRp) domains, respectively. The crystal structure of the full-length ZIKV-NS5 protein has been determined at 3.05 Šresolution from a crystal belonging to space group P21212 and containing two protein molecules in the asymmetric unit. The structure is similar to that reported for the NS5 protein from Japanese encephalitis virus and suggests opportunities for structure-based drug design targeting either its MTase or RdRp domain.

In Vitro Antiviral Activity and Resistance Profile of the Next-Generation Hepatitis C Virus NS5A Inhibitor Pibrentasvir.

Pibrentasvir (ABT-530) is a novel and pan-genotypic hepatitis C virus (HCV) NS5A inhibitor with 50% effective concentration (EC50) values ranging from 1.4 to 5.0 pM against HCV replicons containing NS5A from genotypes 1 to 6. Pibrentasvir demonstrated similar activity against a panel of chimeric replicons containing HCV NS5A of genotypes 1 to 6 from clinical samples. Resistance selection studies were conducted using HCV replicon cells with NS5A from genotype 1a, 1b, 2a, 2b, 3a, 4a, 5a, or 6a at a concentration of pibrentasvir that was 10- or 100-fold over its EC50 for the respective replicon. With pibrentasvir at 10-fold over the respective EC50, only a small number of colonies (0.00015 to 0.0065% of input cells) with resistance-associated amino acid substitutions were selected in replicons containing genotype 1a, 2a, or 3a NS5A, and no viable colonies were selected in replicons containing NS5A from other genotypes. With pibrentasvir at 100-fold over the respective EC50, very few colonies (0.0002% of input cells) were selected by pibrentasvir in genotype 1a replicon cells while no colonies were selected in other replicons. Pibrentasvir is active against common resistance-conferring substitutions in HCV genotypes 1 to 6 that were identified for other NS5A inhibitors, including those at key amino acid positions 28, 30, 31, or 93. The combination of pibrentasvir with HCV inhibitors of other classes produced synergistic inhibition of HCV replication. In summary, pibrentasvir is a next-generation HCV NS5A inhibitor with potent and pan-genotypic activity, and it maintains activity against common amino acid substitutions of HCV genotypes 1 to 6 that are known to confer resistance to currently approved NS5A inhibitors.

Caregiver Burden and Quality of Life of Key Caregivers of Patients with Dementia.

BACKGROUND: Dementia is the most devastating cognitive disorder of the elderly and needs extra attention to care. Therefore, this study was conducted to identify the caregiver burden of dementia key caregivers and their Quality of Life (QOL). MATERIALS AND METHODS: Sample consisted of purposively selected 24 dementia key caregivers fulfilling the inclusion criteria from the in-patient of the Department of Geriatric Mental Health, King George's Medical University, Lucknow, Uttar Pradesh, India. Zarit Burden Interview and World Health Organization QOL-BREF were administered. Mean, standard deviation, t-test, Chi-square with Yate's correction were used to analyze the data. RESULTS: All key caregivers felt mild to moderate level of burden. Gender-wise significant difference was found on burden area of expectation (P < 0.05). Mean scores on physical, psychological, social relationship, and environmental QOL were found to be on lower side. A negative correlation was found between burden and QOL. CONCLUSION: Professional help and supportive psychotherapy can be provided to the key caregivers of dementia patients to reduce their burden, strengthen the coping skill and thus improve their QOL.