Perceived fear of COVID-19 and its associated factors among Nepalese older adults in eastern Nepal : a cross-sectional study

Coronavirus disease 2019 (COVID-19) has affected all age groups worldwide, but older adults have been affected greatly with an increased risk of severe illness and mortality. Nepal is struggling with the COVID-19 pandemic. The normal life of older adults, one of the vulnerable populations to COVID-19 infection, has been primarily impacted. The current evidence shows that the COVID-19 virus strains are deadly, and non-compliance to standard protocols can have serious consequences, increasing fear among older adults. This study assessed the perceived fear of COVID-19 and associated factors among older adults in eastern Nepal. Methods A cross-sectional study was conducted between July and September 2020 among 847 older adults (?60 years) residing in three districts of eastern Nepal. Perceived fear of COVID-19 was measured using the seven-item Fear of COVID-19 Scale (FCV-19S). Multivariate logistic regression identified the factors associated with COVID-19 fear. Results The mean score of the FCV-19S was 18.1 (SD = 5.2), and a sizeable proportion of older adults, ranging between 12%-34%, agreed with the seven items of the fear scale. Increasing age, Dalit ethnicity, remoteness to the health facility, and being concerned or overwhelmed with the COVID-19 were associated with greater fear of COVID-19. In contrast, preexisting health conditions were inversely associated with fear. Conclusion Greater fear of the COVID-19 among the older adults in eastern Nepal suggests that during unprecedented times such as the current pandemic, the psychological needs of older adults should be prioritized. Establishing and integrating community-level mental health support as a part of the COVID-19 preparedness and response plan might help to combat COVID-19 fear among them

Nitric oxide-mediated posttranslational modifications control neurotransmitter release by modulating complexin farnesylation and enhancing its clamping ability.

Nitric oxide (NO) regulates neuronal function and thus is critical for tuning neuronal communication. Mechanisms by which NO modulates protein function and interaction include posttranslational modifications (PTMs) such as S-nitrosylation. Importantly, cross signaling between S-nitrosylation and prenylation can have major regulatory potential. However, the exact protein targets and resulting changes in function remain elusive. Here, we interrogated the role of NO-dependent PTMs and farnesylation in synaptic transmission. We found that NO compromises synaptic function at the Drosophila neuromuscular junction (NMJ) in a cGMP-independent manner. NO suppressed release and reduced the size of available vesicle pools, which was reversed by glutathione (GSH) and occluded by genetic up-regulation of GSH-generating and de-nitrosylating glutamate-cysteine-ligase and S-nitroso-glutathione reductase activities. Enhanced nitrergic activity led to S-nitrosylation of the fusion-clamp protein complexin (cpx) and altered its membrane association and interactions with active zone (AZ) and soluble N-ethyl-maleimide-sensitive fusion protein Attachment Protein Receptor (SNARE) proteins. Furthermore, genetic and pharmacological suppression of farnesylation and a nitrosylation mimetic mutant of cpx induced identical physiological and localization phenotypes as caused by NO. Together, our data provide evidence for a novel physiological nitrergic molecular switch involving S-nitrosylation, which reversibly suppresses farnesylation and thereby enhances the net-clamping function of cpx. These data illustrate a new mechanistic signaling pathway by which regulation of farnesylation can fine-tune synaptic release

A randomized, phase II study of sequential belimumab and rituximab in primary Sjögren's syndrome

BACKGROUND: Primary Sjögren’s syndrome (pSS) is characterized by B cell hyperactivity and elevated B-lymphocyte stimulator (BLyS). Anti-BLyS treatment (e.g., belimumab) increases peripheral memory B cells; decreases naive, activated, and plasma B cell subsets; and increases stringency on B cell selection during reconstitution. Anti-CD20 therapeutics (e.g., rituximab) bind and deplete CD20-expressing B cells in circulation but are less effective in depleting tissue-resident CD20(+) B cells. Combined, these 2 mechanisms may achieve synergistic effects. METHODS: This 68-week, phase II, double-blind study (GSK study 201842) randomized 86 adult patients with active pSS to 1 of 4 arms: placebo, s.c. belimumab, i.v. rituximab, or sequential belimumab + rituximab. RESULTS: Overall, 60 patients completed treatment and follow-up until week 68. The incidence of adverse events (AEs) and drug-related AEs was similar across groups. Infections/infestations were the most common AEs, and no serious infections of special interest occurred. Near-complete depletion of minor salivary gland CD20(+) B cells and a greater and more sustained depletion of peripheral CD19(+) B cells were observed with belimumab + rituximab versus monotherapies. With belimumab + rituximab, reconstitution of peripheral B cells occurred, but it was delayed compared with rituximab. At week 68, mean (± standard error) total EULAR Sjögren’s syndrome disease activity index scores decreased from 11.0 (1.17) at baseline to 5.0 (1.27) for belimumab + rituximab and 10.4 (1.36) to 8.6 (1.57) for placebo. CONCLUSION: The safety profile of belimumab + rituximab in pSS was consistent with the monotherapies. Belimumab + rituximab induced enhanced salivary gland B cell depletion relative to the monotherapies, potentially leading to improved clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02631538. FUNDING: Funding was provided by GSK

Discrepancy between radiological and pathological size of renal masses

<p>Abstract</p> <p>Background</p> <p>Tumor size is a critical variable in staging for renal cell carcinoma. Clinicians rely on radiological estimates of pathological tumor size to guide patient counseling regarding prognosis, choice of treatment strategy and entry into clinical trials. If there is a discrepancy between radiological and pathological measurements of renal tumor size, this could have implications for clinical practice. Our study aimed to compare the radiological size of solid renal tumors on computed tomography (CT) to the pathological size in an Australian population.</p> <p>Methods</p> <p>We identified 157 patients in the Westmead Renal Tumor Database, for whom data was available for both radiological tumor size on CT and pathological tumor size. The paired Student's <it>t</it>-test was used to compare the mean radiological tumor size and the mean pathological tumor size. Statistical significance was defined as <it>P </it>< 0.05. We also identified all cases in which post-operative down-staging or up-staging occurred due to discrepancy between radiological and pathological tumor sizes. Additionally, we examined the relationship between Fuhrman grade and radiological tumor size and pathological T stage.</p> <p>Results</p> <p>Overall, the mean radiological tumor size on CT was 58.3 mm and the mean pathological size was 55.2 mm. On average, CT overestimated pathological size by 3.1 mm (<it>P </it>= 0.012). CT overestimated pathological tumor size in 92 (58.6%) patients, underestimated in 44 (28.0%) patients and equaled pathological size in 21 (31.4%) patients. Among the 122 patients with pT1 or pT2 tumors, there was a discrepancy between clinical and pathological staging in 35 (29%) patients. Of these, 21 (17%) patients were down-staged post-operatively and 14 (11.5%) were up-staged. Fuhrman grade correlated positively with radiological tumor size (<it>P </it>= 0.039) and pathological tumor stage (<it>P </it>= 0.003).</p> <p>Conclusions</p> <p>There was a statistically significant but small difference (3.1 mm) between mean radiological and mean pathological tumor size, but this is of uncertain clinical significance. For some patients, the difference leads to a discrepancy between clinical and pathological staging, which may have implications for pre-operative patient counseling regarding prognosis and management.</p

Development of a Patient-Centred, Psychosocial Support Intervention for Multi-Drug-Resistant Tuberculosis (MDR-TB) Care in Nepal

Multi-drug-resistant tuberculosis (MDR-TB) poses a major threat to public health worldwide, particularly in low-income countries. The current long (20 month) and arduous treatment regime uses powerful drugs with side-effects that include mental ill-health. It has a high loss-to-follow-up (25%) and higher case fatality and lower cure-rates than those with drug sensitive tuberculosis (TB). While some national TB programmes provide small financial allowances to patients, other aspects of psychosocial ill-health, including iatrogenic ones, are not routinely assessed or addressed. We aimed to develop an intervention to improve psycho-social well-being for MDR-TB patients in Nepal. To do this we conducted qualitative work with MDR-TB patients, health professionals and the National TB programme (NTP) in Nepal. We conducted semi-structured interviews (SSIs) with 15 patients (10 men and 5 women, aged 21 to 68), four family members and three frontline health workers. In addition, three focus groups were held with MDR-TB patients and three with their family members. We conducted a series of meetings and workshops with key stakeholders to design the intervention, working closely with the NTP to enable government ownership. Our findings highlight the negative impacts of MDR-TB treatment on mental health, with greater impacts felt among those with limited social and financial support, predominantly married women. Michie et al's (2011) framework for behaviour change proved helpful in identifying corresponding practice- and policy-level changes. The findings from this study emphasise the need for tailored psycho-social support. Recent work on simple psychological support packages for the general population can usefully be adapted for use with people with MDR-TB

Interpretative and predictive modelling of Joint European Torus collisionality scans

Transport modelling of Joint European Torus (JET) dimensionless collisionality scaling experiments in various operational scenarios is presented. Interpretative simulations at a fixed radial position are combined with predictive JETTO simulations of temperatures and densities, using the TGLF transport model. The model includes electromagnetic effects and collisions as well as □(→┬E ) X □(→┬B ) shear in Miller geometry. Focus is on particle transport and the role of the neutral beam injection (NBI) particle source for the density peaking. The experimental 3-point collisionality scans include L-mode, and H-mode (D and H and higher beta D plasma) plasmas in a total of 12 discharges. Experimental results presented in (Tala et al 2017 44th EPS Conf.) indicate that for the H-mode scans, the NBI particle source plays an important role for the density peaking, whereas for the L-mode scan, the influence of the particle source is small. In general, both the interpretative and predictive transport simulations support the experimental conclusions on the role of the NBI particle source for the 12 JET discharges

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Strength of Drug–Polymer Interactions: Implications for Crystallization in Dispersions

We investigated the influence of the strength of drug–polymer interactions on the crystallization behavior of a model drug in amorphous solid dispersions (ASDs). Ketoconazole ASDs were prepared with each poly­(acrylic acid), poly­(2-hydroxyethyl methacrylate), and polyvinylpyrrolidone. Over a wide temperature range in the supercooled region, the α-relaxation time was obtained, which provided a measure of molecular mobility. Isothermal crystallization studies were performed in the same temperature interval using either a synchrotron (for low levels of crystallinity) or a laboratory X-ray (for crystallization kinetics) source. The stronger the drug–polymer interaction, the longer was the delay in crystallization onset time, indicating an increase in physical stability. Stronger drug–polymer interactions also translated to a decrease in the magnitude of the crystallization rate constant. In amorphous ketoconazole as well as in the dispersions, the coupling coefficient, a measure of the extent of coupling between relaxation and crystallization times was ∼0.5. This value was unaffected by the strength of drug–polymer interactions. On the basis of these results, the crystallization times in ASDs were predicted at temperatures very close to <i>T</i>_g, using the coupling coefficient experimentally determined for amorphous ketoconazole. The predicted and experimental crystallization times were in good agreement, indicating the usefulness of the model

Complex involvement of pertussis toxin-sensitive G proteins in the regulation of type 1 alpha metabotropic glutamate receptor signaling in baby hamster kidney cells

Previously, we demonstrated that the coupling of the metabotropic glutamate receptor mGlu1 alpha to phosphoinositide hydrolysis is enhanced by pertussis toxin (PTX) in stably transfected baby hamster kidney cells (BHK). Here, we show that the PTX effect on agonist-stimulated [H-3]inositol phosphate accumulation can be resolved into two components: an immediate increase in agonist potency, and a more slowly developing increase in the magnitude of the response observed at maximally effective agonist concentrations. Using G(q)/(11)alpha- and G(i/o)alpha-selective antibodies to immunoprecipitate [S-35]guanosine-5'-O-(3-thio)triphosphate-bound G alpha proteins, we also show that agonist stimulation of mGlu1a in BHK membranes increases specific [S-35]guanosine-5'-O-(3-thio)triphosphate binding to both G(q/11) and G(i/o) proteins. Preincubation of BHK-mGlu1 alpha with L-glutamate (300 mu M) results in a progressive loss (60% in 30 min) of L-quisqualate-induced [H-3]inositol phosphate accumulation (without a change in potency), providing evidence for agonist-induced receptor desensitization. Although such desensitization of mGlu receptor signaling was mimicked by a phorbol ester, agonist-induced phosphorylation of the receptor was not observed and protein kinase C inhibition by Ro 31-8220 did not prevent L-glutamate-mediated desensitization. In contrast, PTX treatment of the cells almost completely prevented L-glutamate-mediated desensitization. Together, these data provide evidence for a multifunctional coupling of mGlu1a to different types of G proteins, including PTX-sensitive G(i)-type G proteins. The latter are involved in the negative control of phospholipase C activity while also influencing the rate of desensitization of the mGlu1 alpha receptor

Comparative evaluation demineralized freeze dried bone allograft with and without platelet rich fibrin in intrabony defects: A clinical and radiographical study

Background and Objectives: The study was designed to evaluate the clinical and radiological effectiveness of demineralized freeze dried bone allograft with and without platelet rich fibrin in intrabony defects. Materials and Methods: twelve patients with 2 intrabony defects were recruited for the study. The two defects in each patient were randomly assigned to receive either DFDBA (site A) or DFDBA with PRF (site B). Soft tissue measurements and radiographs were taken at baseline, 3, 6 and 9 months. Results: The results indicated that probing depths were reduced by 3.08 ± 1.16 mm at site A and 3.33 ± 1.72 mm at site B.&nbsp; Site A resulted in 2.42 ± 1.24mm attachment gain, while site B had a 3.17 ± 1.40 mm gain in attachment Site A. Defects displayed 2.00mm bone fill. Site B defects showed 3.00 mm bone fill. Both treatments provided soft and hard tissue improvement when compared to baseline. No statistical significance was noted between the two groups. Conclusion: The Clinical evaluation is suggestive of the fact that both DFDBA and PRF are biocompatible with the tissues