Efficacy and safety clinical trial with efavirenz in patients diagnosed with adult Niemann-pick type C with cognitive impairment

Background:Niemann-Pick disease Type C (NPC) is a genetic, incurable, neurodegenerative disorder. This orphan disease is most frequently caused by mutations in the NPC1 protein, resulting in intralysossomal cholesterol accumulation. NPC1 is found in neuronal cell bodies, axon terminals and synaptosomes, suggesting it plays a role in lysosomal degradation pathway and in synaptic transmission. Neuronal function is especially vulnerable to NPC1 deficiency and synaptic changes seem a key element in disease development. Currently, Miglustat (Zavesca (R)) is the only approved treatment for NPC. However, preclinical evidence showed that low-dose Efavirenz reverted synaptic defects through pharmacological activation of the enzyme CYP46. Methods:This is a single-center, phase II clinical trial to evaluate the efficacy and safety of Efavirenz in addition to standard of care in patients diagnosed with adult or late juvenile-onset NPC with cognitive impairment. All enrolled patients will be treated orally with 25 mg/d of Efavirenz for 52 weeks (1 year). Secondary objectives include evaluating clinical (neurological and neuropsychological questionnaires) and biological (imaging and biochemical biomarkers) parameters. Discussion:NPC is still an unmet medical need. Although different therapeutic approaches are under study, this is the first clinical trial (to the best of our knowledge) studying the effects of Efavirenz in adult- and late-juvenile-onset NPC. Despite the small sample size and the single-arm design, we expect the results to show Efavirenz's capacity of activating the CYP46 enzyme to compensate for NPC1 deficiency and correct synaptic changes, therefore compensating cognitive and psychiatric changes in these patients. This study may provide direct benefit to enrolled patients in terms of slowing down the disease progression

Three double-dose reinforced hepatitis B revaccination scheme for patients with cirrhosis unresponsive to the standard regimen: an open-label randomised clinical trial

© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.[Objective] We aimed to compare the response rates between two different hepatitis B virus vaccination schedules for cirrhotic subjects who were non-responders to the first three 40 µg doses (month 0-1-2), and identify factors associated with the final response.[Design] A total of 120 cirrhotic patients (72.5% decompensated) were randomised at a 1:1 ratio to receive a single 40 µg booster vaccination at month 6 (classical arm) versus an additional round of three new 40 µg doses administered at monthly intervals (experimental arm). The main outcome was the rate of postvaccinal anti-hepatitis B surface antibodies levels ≥10 mIU/mL.[Results] Efficacy by ITT analysis was higher in the experimental arm (46.7%) than in the classical one (25%); OR 2.63, p=0.013. The experimental arm increased response rates compared with the classical one from 31% to 68% (OR 4.72; p=0.007), from 24.4% to 50% (OR 3.09; p=0.012) and from 24.4% to 53.8% (OR 3.62; p=0.007), in Child A, Model for End-Stage Liver Disease (MELD) <15 and MELD-Na<15 patients, respectively. Patients with more advanced liver disease did not benefit from the reinforced scheme. Both regimens showed similar safety profiles. Multivariable analysis showed that the experimental treatment was independently response associated when adjusted across three logistic regression models indicating equivalent cirrhosis severity.[Conclusion] For cirrhotic patients, the revaccination of non-responders to the first three dose cycle, with three additional 40 µg doses, achieved significantly better response rates to those obtained with an isolated 40 µg booster dose.[Trial registration number] NCT01884415.This study project was awarded competitive public funding for Independent Research from the Spanish Government Ministry of Health and Social Politics in 2011 via the Carlos III Health Institute (EC11-452). Javier Ampuero is supported by grants from the Carlos III Health Institute (GLD19/00100 and PI19/01404). IBiS was created as a partnership between the Junta of Andalusia Department of Health, the Department of Innovation, Science and Business of the Junta of Andalusia, the Andalusian Health Service, the University of Seville and the Spanish National Research Council.Peer reviewe

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Proceso asistencial integrado de esclerosis lateral amiotrófica

O proceso asistencial integrado da esclerose lateral amiotrófica, elaborouse co obxectivo de crear un proceso de traballo común en todas as áreas para facilitar a asistencia sanitaria ás persoas diagnosticadas desta enfermidade. Establécense actuacións como o asesoramento continuo, as consultas en acto único, a coordinación asistencial, tanto entre especialidades como coa atención primaria e a coordinación administrativa do sistema socio sanitario. Neste proceso participaron profesionais das diferentes áreas sanitarias especialistas en neuroloxía, endocrinoloxía, neumoloxía, psicoloxía clínica, rehabilitación, traballo social e hospitalización a domicilioEl proceso asistencial integrado de la esclerosis lateral amiotrófica, se elaboró con el objetivo de crear un proceso de trabajo común en todas las áreas para facilitar la asistencia sanitaria a las personas diagnosticadas de esta enfermedad. Se establecen actuaciones como el asesoramiento continuo, las consultas en acto único, la coordinación asistencial, tanto entre especialidades como con la atención primaria y la coordinación administrativa del sistema socio sanitario. En este proceso participaron profesionales de las diferentes áreas sanitarias especialistas en neurología, endocrinología, neumología, psicología clínica, rehabilitación, trabajo social y hospitalización a domicili

A global experiment on motivating social distancing during the COVID-19 pandemic

Finding communication strategies that effectively motivate social distancing continues to be a global public health priority during the COVID-19 pandemic. This cross-country, preregistered experiment (n = 25,718 from 89 countries) tested hypotheses concerning generalizable positive and negative outcomes of social distancing messages that promoted personal agency and reflective choices (i.e., an autonomy-supportive message) or were restrictive and shaming (i.e., a controlling message) compared with no message at all. Results partially supported experimental hypotheses in that the controlling message increased controlled motivation (a poorly internalized form of motivation relying on shame, guilt, and fear of social consequences) relative to no message. On the other hand, the autonomy-supportive message lowered feelings of defiance compared with the controlling message, but the controlling message did not differ from receiving no message at all. Unexpectedly, messages did not influence autonomous motivation (a highly internalized form of motivation relying on one’s core values) or behavioral intentions. Results supported hypothesized associations between people’s existing autonomous and controlled motivations and self-reported behavioral intentions to engage in social distancing. Controlled motivation was associated with more defiance and less long-term behavioral intention to engage in social distancing, whereas autonomous motivation was associated with less defiance and more short- and long-term intentions to social distance. Overall, this work highlights the potential harm of using shaming and pressuring language in public health communication, with implications for the current and future global health challenges

A multi-country test of brief reappraisal interventions on emotions during the COVID-19 pandemic.

The COVID-19 pandemic has increased negative emotions and decreased positive emotions globally. Left unchecked, these emotional changes might have a wide array of adverse impacts. To reduce negative emotions and increase positive emotions, we tested the effectiveness of reappraisal, an emotion-regulation strategy that modifies how one thinks about a situation. Participants from 87 countries and regions (n = 21,644) were randomly assigned to one of two brief reappraisal interventions (reconstrual or repurposing) or one of two control conditions (active or passive). Results revealed that both reappraisal interventions (vesus both control conditions) consistently reduced negative emotions and increased positive emotions across different measures. Reconstrual and repurposing interventions had similar effects. Importantly, planned exploratory analyses indicated that reappraisal interventions did not reduce intentions to practice preventive health behaviours. The findings demonstrate the viability of creating scalable, low-cost interventions for use around the world

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

Effects of a 12-week resistance and aerobic exercise program on muscular strength and quality of life in breast cancer survivors: Study protocol for the EFICAN randomized controlled trial.

The number of people living with the side effects of breast cancer treatment (eg, loss of muscular mass and muscular strength, upper-limb mobility and disability, lymphedema, cardiac toxicity, and reduced quality of life) is increasing yearly. These consequences can be improved through exercise, specially combining resistance and aerobic training. Previous exercise trials have not been consistent in applying training principles and standardized reporting, and this partly explains the variability in obtained results. The aim of this study is to assess the effect of a 12-week supervised resistance exercise program combined with home-based aerobic exercise, compared with home-based aerobic exercise only, on muscular strength and several aspects of health-related quality of life in breast cancer survivors. To maximize transparency, replicability, and clinical applicability, the intervention is described following the consensus on exercise reporting template. This study is a parallel-group randomized controlled trial in which 60 female breast cancer survivors, who have completed central treatments of the disease in the last 5 years, will be randomly assigned to either an experimental group that will perform a total of 24 progressive resistance training sessions for 12 weeks (ie, 2 weeks of individual training and 10 weeks of micro-group training) and will be requested to undertake 10,000 steps/d, or a control group that will be requested to undertake 10,000 steps/d, only. Outcomes will be evaluated at baseline and at week 12. Primary outcome measure is peak isometric muscular strength of the lower- and upper-body, assessed with several exercises through an electromechanical dynamometer. Secondary outcomes include cardiorespiratory fitness, upper-joint mobility and disability, health-related quality of life, cancer-related fatigue, depression, life satisfaction, and presence of lymphedema. This study aims to investigate the extent to which a 12-week supervised and progressive resistance exercise program, in addition to home-based aerobic physical activity, might improve muscular strength and health-related quality of life in breast cancer survivors. The comprehensive description of the intervention will likely contribute to enhancing exercise prescription in this population. ISRCTN14601208

How do women living with HIV experience menopause? Menopausal symptoms, anxiety and depression according to reproductive age in a multicenter cohort

CatedresBackground: To estimate the prevalence and severity of menopausal symptoms and anxiety/depression and to assess the differences according to menopausal status among women living with HIV aged 45-60 years from the cohort of Spanish HIV/AIDS Research Network (CoRIS). Methods: Women were interviewed by phone between September 2017 and December 2018 to determine whether they had experienced menopausal symptoms and anxiety/depression. The Menopause Rating Scale was used to evaluate the prevalence and severity of symptoms related to menopause in three subscales: somatic, psychologic and urogenital; and the 4-item Patient Health Questionnaire was used for anxiety/depression. Logistic regression models were used to estimate odds ratios (ORs) of association between menopausal status, and other potential risk factors, the presence and severity of somatic, psychological and urogenital symptoms and of anxiety/depression. Results: Of 251 women included, 137 (54.6%) were post-, 70 (27.9%) peri- and 44 (17.5%) pre-menopausal, respectively. Median age of onset menopause was 48 years (IQR 45-50). The proportions of pre-, peri- and post-menopausal women who had experienced any menopausal symptoms were 45.5%, 60.0% and 66.4%, respectively. Both peri- and post-menopause were associated with a higher likelihood of having somatic symptoms (aOR 3.01; 95% CI 1.38-6.55 and 2.63; 1.44-4.81, respectively), while post-menopause increased the likelihood of having psychological (2.16; 1.13-4.14) and urogenital symptoms (2.54; 1.42-4.85). By other hand, post-menopausal women had a statistically significant five-fold increase in the likelihood of presenting severe urogenital symptoms than pre-menopausal women (4.90; 1.74-13.84). No significant differences by menopausal status were found for anxiety/depression. Joint/muscle problems, exhaustion and sleeping disorders were the most commonly reported symptoms among all women. Differences in the prevalences of vaginal dryness (p = 0.002), joint/muscle complaints (p = 0.032), and sweating/flush (p = 0.032) were found among the three groups. Conclusions: Women living with HIV experienced a wide variety of menopausal symptoms, some of them initiated before women had any menstrual irregularity. We found a higher likelihood of somatic symptoms in peri- and post-menopausal women, while a higher likelihood of psychological and urogenital symptoms was found in post-menopausal women. Most somatic symptoms were of low or moderate severity, probably due to the good clinical and immunological situation of these women

Impact of COVID-19 confinement on eating behaviours across 16 European countries: The COVIDiet cross-national study

We aimed to evaluate the changes in eating behaviours of the adult population across 16 European countries due to the COVID-19 confinement and to evaluate whether these changes were somehow related to the severity of the containment measures applied in each country. An anonymous online self-reported questionnaire on socio-demographic characteristics, validated 14-items Mediterranean diet (MedDiet) Adherence Screener (MEDAS) as a reference of a healthy diet, eating and lifestyle behaviours prior to and during the COVID-19 confinement was used to collect data. The study included an adult population residing in 16 European countries at the time of the survey. Aggregated Stringency Index (SI) score, based on data from the Oxford COVID-19 Government Response Tracker, was calculated for each country at the time the questionnaire was distributed (range: 0–100). A total of 36,185 participants completed the questionnaire (77.6% female, 75.2% with high educational level and 42.7% aged between 21 and 35 years). In comparison to pre-confinement, a significantly higher adherence to the MedDiet during the confinement was observed across all countries (overall MEDAS score prior to- and during confinement: 5.23 ± 2.06 vs. 6.15 ± 2.06; p < 0.001), with the largest increase seen in Greece and North Macedonia. The highest adherence to MedDiet during confinement was found in Spain and Portugal (7.18 ± 1.84 and 7.34 ± 1.95, respectively). Stricter contingency restrictions seemed to lead to a significantly higher increase in the adherence to the MedDiet. The findings from this cross-sectional study could be used to inform current diet-related public health guidelines to ensure optimal nutrition is followed among the population, which in turn would help to alleviate the current public health crisis