Background Insomnia symptoms are common in older adults. While observational studies suggest physical activity (PA) timing affects health outcomes, its effect on sleep remains unclear. We compared morning versus evening PA effects on insomnia severity and sleep quality in older adults with insomnia symptoms. Methods Eligible participants were aged 60–80 years with (sub)clinical insomnia (Insomnia Severity Index [ISI] score ≥10). In a randomized cross-over trial, participants engaged in coached PA in the morning (10:00–11:00) or evening (19:30–20:30) for 14 days each. ISI scores were assessed post-intervention. Objective sleep parameters—duration, latency, efficiency, and timing—were assessed with a Withings Sleep Analyzer under the mattress. Subjective sleep quality was reported daily via smartphone app. Salivary dim light melatonin onset (DLMO) was measured on the final day of each intervention. Results Sleep data was available from 31 participants (mean age 69.8 years ± 5; 64.5% women). Although ISI improved after all intervention periods compared to baseline (estimated marginal mean ISI baseline: 14.44 points, inactive period: 12.37 points, active morning: 11.87 points, active evening: 12.35 points), there was no evidence for a difference in ISI between the active evening and active morning period (β 0.55, 95%CI -0.80, 1.91). compared to the active evening period, sleep midpoint occurred earlier during the active morning period (4:13 vs. 3:54 a.m. respectively, β 0.31 min, 95%CI 0.14, 0.48). No differences were observed in subjective sleep quality or DLMO. Conclusions While morning vs. evening PA timing did not impact most sleep quality measures, it influenced sleep timing. Larger studies are needed to define optimal and personalized PA timing for improving sleep.
OBJECTIVES:This study aimed to investigate the efficacy and safety of filgotinib, a JAK1 preferential inhibitor, in patients with axial spondyloarthritis (axSpA). METHODS:The phase 3 OLINGUITO trial comprises 2 international, randomised, double-blind, placebo (PBO)-controlled studies. Patients with an established diagnosis of radiographic (r) or nonradiographic (nr) axSpA and an inadequate response/intolerance to ≥2 nonsteroidal anti-inflammatory drugs were randomised 1:1 to filgotinib 200 mg or PBO once daily through week (W) 16 (double-blind period; stratified by high-sensitivity C-reactive protein [hs-CRP] level and prior biologic disease-modifying antirheumatic drug [bDMARD] use). After W16, patients received open-label filgotinib 200 mg through W52; patients ≥65 years and/or with prespecified risk factors received response-based dosing (100 or 200 mg). The primary (Assessment of SpondyloArthritis international Society ≥40% response [ASAS40 response]) and secondary efficacy endpoints were assessed at W16. Efficacy and safety were assessed through W52. RESULTS:At W16, the primary endpoint was met in both studies (ASAS40 response rates: r = axSpA [n = 258], 39.5% filgotinib vs 20.9% PBO [P = .001]; nr-axSpA [n = 237], 34.5% vs 17.8% [P = .003], respectively). ASAS40 improvements, irrespective of hs-CRP level/prior bDMARD use, were observed as early as W1. For secondary endpoints, significant improvements were seen in Axial Spondyloarthritis Disease Activity Score and Spondyloarthritis Research Consortium of Canada magnetic resonance imaging sacroiliac joint inflammation in both studies, and in Bath Ankylosing Spondylitis Functional Index and Ankylosing Spondylitis Quality of Life Questionnaire in patients with r-axSpA. Improvements with filgotinib were maintained/increased further through W52. Overall, 2 cases of myocardial infarction (PBO: n = 1; PBO-filgotinib: n = 1), 3 of herpes zoster (PBO-filgotinib), and 4 of malignancies (excluding nonmelanoma skin cancer; filgotinib: n = 3; PBO-filgotinib: n = 1) occurred. CONCLUSIONS:Across the whole spectrum of axSpA, filgotinib provided rapid and significant patient-relevant improvements in axSpA signs and symptoms and was well tolerated.
CORT118335 (miricorilant) is a selective glucocorticoid receptor (GR) modulator (SGRM) that is currently being evaluated in clinical trials for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD), based on strong efficacy in mouse models. We reveal gene-specific GR modulation by CORT118335 in the mouse liver. In cell-based models, we evaluated the biological activity of CORT118335 metabolites. Metabolite CORT118335-P9a showed potent GR agonism, while metabolite CORT118335-P9b was largely inactive. CORT118335-P9a concentrations in the mouse liver were very low, and therefore neither metabolite is likely to contribute to the beneficial effects of CORT118335 in vivo. We investigated various aspects of CORT118335 activity in reducing lipid levels in the mouse liver using a model of short-term high-fat diet feeding. Daily administration of CORT118335 appeared to lower hepatic triglyceride rapidly within several days after treatment initiation, specifically in male mice, and these effects were reversed after 7 days of treatment discontinuation. No synergy was observed between the lipid-lowering effects of CORT118335 and the TRβ agonist VK2809 or the PPARγ agonist pioglitazone. At a dose of 6 mg/kg/day, CORT118335 induced evident transcriptional effects with modest lowering of hepatic triglyceride levels, while higher doses induced a more pronounced lipid lowering but less ongoing transcriptional activity for hepatic lipid metabolism genes. Altogether we substantiate the potential of selective GR modulation using CORT118335 as a lipid-lowering strategy in MASLD and highlight the complexity of SGRM-mediated hepatic lipid lowering.
Objectives Understanding patients’ values, wishes, and needs (VWN) is essential to guiding appropriate palliative care in home and hospital settings, thereby optimizing quality of life. This study aims to gain insight into the expectations and experiences of patients with advanced gynecological cancer in the palliative phase regarding clinicians' attention to their VWN throughout the illness trajectory. Methods A qualitative study grounded in an interpretivist–constructivist approach was conducted from March 2024 to October 2024. Patients with advanced gynecological cancer were recruited from outpatient clinics at two hospitals in the Netherlands, using purposive sampling to achieve variation in age, diagnosis, and time since diagnosis. Data were collected through semi-structured interviews and analyzed using reflexive thematic analysis. Results Twenty-one patients (aged 39–86) participated; most were diagnosed with ovarian cancer (N = 17). Three key needs shaped patients' ability to express and discuss their VWN: 1) feeling recognized as a person, 2) being involved in the decision-making process in accordance with their preferences, and 3) receiving help and guidance in navigating the complex healthcare system. Participants hesitated to share non-physical issues, perceiving communication as primarily focused on the illness and medical treatment. Conclusion The findings highlight the importance of dialogues that create space for patients to express and discuss their VWN related to both the illness and broader aspects of living with advanced cancer, tailored to their individual preferences and need for support in navigating care. The way clinicians time and structure conversations is among the important factors shaping these opportunities. Practice implications A systematic approach can support continuous attention to VWN throughout the illness trajectory, thereby guiding appropriate palliative care and optimizing quality of life. This approach requires explicit agreements on which clinician explores and monitors VWN, when this should occur, and how this is documented and transferred between settings.
The 16th Acromegaly Consensus Conference in September 2024 updated recommendations on diagnosis and treatment of acromegaly comorbidities. Since the 2020 acromegaly comorbidity management guideline was published, new evidence has emerged on novel and known comorbidities and new treatment approaches. Forty-three experts in the management of acromegaly reviewed the current literature and assessed changes in clinical practice standards and management. Current outcome goals were considered and updated, with a focus on the impact of current and emerging treatments of these comorbidities. Participants assessed factors that determine pharmacological choices, as well as use of specific agents in the management of the most relevant acromegaly comorbidities. We present consensus recommendations highlighting optimization of evidence-based acromegaly comorbidities management.
