Understanding trends in osteoporosis drug prescribing: implications for reducing futile biomedical research.

Introduction: Osteoporosis is a significant geriatric condition, considering its impact on fracture-related morbidity and mortality, particularly among older women. The interplay of clinical evidence, diagnostic tools availability, and broader societal attitudes toward aging and treatment efficacy affect medical attitude and prescribing behaviors. Using the example of osteoporosis in France and England, the study aims to unravel the intricacies of medical decision-making in geriatric care, offering insights into the evolving landscape of healthcare policy and practice, which in turn can help reduce futile biomedical research.

Durvalumab and tremelimumab in patients with advanced rare cancer: a multi-centre, non-blinded, open-label phase II basket trial.

Background: Dual inhibition of cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed death ligand 1 (PD-L1) has been shown to be an effective treatment strategy in many cancers. We sought to determine the objective response rate of combination durvalumab (D) plus tremelimumab (TM) in parallel cohorts of patients with carefully selected rare cancer types in which these agents had not previously been evaluated in phase II trials and for which there was clinical or biological rationale for dual immune checkpoint inhibitor therapy to be active.

Methods: We designed a multi-centre, non-blinded, open-label phase II basket trial with each of the following 8 rare cancers considered a separate phase II trial: salivary carcinoma, carcinoma of unknown primary (CUP) with tumour infiltrating lymphocytes and/or expressing PD-L1, mucosal melanoma, acral melanoma, osteosarcoma, undifferentiated pleomorphic sarcoma, clear cell carcinoma of the ovary (CCCO) or squamous cell carcinoma of the anal canal (SCCA).

Prediction of atrial and ventricular arrhythmias using multiple cardiovascular risk-factor polygenic risk scores.

Background: Atrial fibrillation (AF) prediction improves by combining clinical scores with a polygenic risk score (PRS) for AF (AF-PRS), but there are limited studies of PRS for ventricular arrhythmia (VA) prediction.

Objective: We assessed the value of including multiple PRS for cardiovascular risk factors (CV-PRS) for incident AF and VA prediction.

Methods: We used 158,733 individuals of European ancestry from UK Biobank to build 3 models for AF: CHARGE-AF (AF1), AF1 + AF-PRS (AF2), AF2 + CV-PRS (AF3).

Evaluating a Smart Textile Loneliness Monitoring System for Older People: Co-Design and Qualitative Focus Group Study.

Background: Previous studies have explored how sensor technologies can assist in in the detection, recognition, and prevention of subjective loneliness. These studies have shown a correlation between physiological and behavioral sensor data and the experience of loneliness. However, little research has been conducted on the design requirements from the perspective of older people and stakeholders in technology development.

How long is long enough? An international survey exploring practice variations on the recommended duration of maintenance therapy with PARP inhibitors in patients with platinum sensitive recurrent ovarian cancer and long-term outcomes.

Objective: There are no data, and thus no consensus, on the optimal duration of poly(ADP-ribose) polymerase (PARP) inhibitor maintenance therapy for exceptional responders (here defined as progression-free for 5 years or longer) with platinum sensitive recurrent ovarian cancer. The current licence is to continue PARP inhibitors until progression or toxicity; however, international practice varies considerably. The risks of late progression and late-onset myeloid malignancies, defined as occurring beyond 5 years of PARP inhibition, are unknown.

Qualitative exploration of the lived experiences of loneliness in later life to inform technology development.

Purpose: Loneliness is a negative emotional state which is common in later life. The accumulative effects of loneliness have a significant impact on the physical and mental health of older adults. We aim to qualitatively explore the experiences of loneliness in later life and identify relevant behaviours and indicators which will inform novel methods of loneliness detection and intervention.

Tissue-resident memory T cells in epicardial adipose tissue comprise transcriptionally distinct subsets that are modulated in atrial fibrillation.

Atrial fibrillation (AF) is the most common sustained arrhythmia and carries an increased risk of stroke and heart failure. Here we investigated how the immune infiltrate of human epicardial adipose tissue (EAT), which directly overlies the myocardium, contributes to AF. Flow cytometry analysis revealed an enrichment of tissue-resident memory T (T) cells in patients with AF.

Fine mapping of candidate effector genes for heart rate.

An elevated resting heart rate (RHR) is associated with increased cardiovascular mortality. Genome-wide association studies (GWAS) have identified > 350 loci. Uniquely, in this study we applied genetic fine-mapping leveraging tissue specific chromatin segmentation and colocalization analyses to identify causal variants and candidate effector genes for RHR.

The ric-8b protein (resistance to inhibitors of cholinesterase 8b) is key to preserving contractile function in the adult heart.

Resistance to inhibitors of cholinesterases (ric-8 proteins) are involved in modulating G-protein function, but little is known of their potential physiological importance in the heart. In the present study, we assessed the role of resistance to inhibitors of cholinesterase 8b (Ric-8b) in determining cardiac contractile function. We developed a murine model in which it was possible to conditionally delete ric-8b in cardiac tissue in the adult animal after the addition of tamoxifen.

Efficacy and safety of niraparib in patients aged 65 years and older with advanced ovarian cancer: Results from the PRIMA/ENGOT-OV26/GOG-3012 trial.

Objective: To evaluate the impact of age on the efficacy and safety of niraparib first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer with a complete/partial response to first-line platinum-based chemotherapy.

Methods: Post hoc analysis of the phase 3 PRIMA/ENGOT-OV26/GOG-3012 study (NCT02655016). Patients in the intent-to-treat population were categorized according to age at baseline (<65 years vs ≥65 years), and progression-free survival (PFS), safety, and health-related quality of life (HRQOL) were evaluated for each age subgroup (clinical cutoff date, May 17, 2019).

Identification and characterisation of functional K6.1-containing ATP-sensitive potassium channels in the cardiac ventricular sarcolemmal membrane.

Background And Purpose: The canonical K6.2/SUR2A ventricular K channel is highly ATP-sensitive and remains closed under normal physiological conditions. These channels activate only when prolonged metabolic compromise causes significant ATP depletion and then shortens the action potential to reduce contractile activity.

Targeting HER2-mutant metastatic cervical cancer with neratinib: Final results from the phase 2 SUMMIT basket trial.

Objective: HER2 mutations are associated with poor prognosis and are detected in 3-6% of cervical cancers. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, had activity in several HER2-mutant cancer types in the phase 2 SUMMIT basket study. We present updated and final results from the cervical cancer cohort of SUMMIT.

Transcriptional response of the heart to vagus nerve stimulation.

Heart failure is a major clinical problem, with treatments involving medication, devices, and emerging neuromodulation therapies such as vagus nerve stimulation (VNS). Considering the ongoing interest in using VNS to treat cardiovascular disease, it is important to understand the genetic and molecular changes developing in the heart in response to this form of autonomic neuromodulation. This experimental animal (rat) study investigated the immediate transcriptional response of the ventricular myocardium to selective stimulation of vagal efferent activity using an optogenetic approach.

Long-term association of ultra-short heart rate variability with cardiovascular events.

Heart rate variability (HRV) is a cardiac autonomic marker with predictive value in cardiac patients. Ultra-short HRV (usHRV) can be measured at scale using standard and wearable ECGs, but its association with cardiovascular events in the general population is undetermined. We aimed to validate usHRV measured using ≤ 15-s ECGs (using RMSSD, SDSD and PHF indices) and investigate its association with atrial fibrillation, major adverse cardiac events, stroke and mortality in individuals without cardiovascular disease.

Antitumor Activity and Safety of Dostarlimab Monotherapy in Patients With Mismatch Repair Deficient Solid Tumors: A Nonrandomized Controlled Trial.

Importance: Mismatch repair deficiency (dMMR) occurs in various cancers, and these tumors are attractive candidates for anti-programmed cell death 1 therapies, such as dostarlimab, a recently approved immune checkpoint inhibitor.

Objective: To assess the antitumor activity and safety of dostarlimab in patients with advanced or recurrent dMMR solid tumors.

Design, Setting, And Participants: The GARNET trial was a phase 1, open-label, single-group, multicenter study that began enrolling May 8, 2017.

Prognostic Significance of Different Ventricular Ectopic Burdens During Submaximal Exercise in Asymptomatic UK Biobank Subjects.

Background: The consequences of exercise-induced premature ventricular contractions (PVCs) in asymptomatic individuals remain unclear. This study aimed to assess the association between PVC burdens during submaximal exercise and major adverse cardiovascular events (MI/HF/LTVA: myocardial infarction [MI], heart failure [HF], and life-threatening ventricular arrhythmia [LTVA]), and all-cause mortality. Additional end points were MI, LTVA, HF, and cardiovascular mortality.

Hypoxia Promotes Atrial Tachyarrhythmias via Opening of ATP-Sensitive Potassium Channels.

Background: Hypoxia-ischemia predisposes to atrial arrhythmia. Atrial ATP-sensitive potassium channel (K) modulation during hypoxia has not been explored. We investigated the effects of hypoxia on atrial electrophysiology in mice with global deletion of K pore-forming subunits.

Survival and modelled cancer antigen-125 ELIMination rate constant K score in ovarian cancer patients in first-line before poly(ADP-ribose) polymerase inhibitor era: A Gynaecologic Cancer Intergroup meta-analysis.

Background: In patients with advanced ovarian cancer, the modelled CA-125 ELIMination rate constant K (KELIM) is an early indicator of the tumour intrinsic chemosensitivity. We assessed the prognostic and surrogate values of KELIM with respect to those of surgery outcome (based on post-operative residual lesions) in the Gynaecologic Cancer Intergroup (GCIG) individual patient data meta-analysis MAOV (Meta-Analysis in OVarian cancer) built before the emergence of poly(ADP-ribose) polymerase (PARP) inhibitors.

Methods: The dataset was split into learning and validation cohorts (ratio 1:2).

Immediate and sustained increases in the activity of vagal preganglionic neurons during exercise and after exercise training.

Aims: The brain controls the heart by dynamic recruitment and withdrawal of cardiac parasympathetic (vagal) and sympathetic activity. Autonomic control is essential for the development of cardiovascular responses during exercise, however, the patterns of changes in the activity of the two autonomic limbs, and their functional interactions in orchestrating physiological responses during exercise, are not fully understood. The aim of this study was to characterize changes in vagal parasympathetic drive in response to exercise and exercise training by directly recording the electrical activity of vagal preganglionic neurons in experimental animals (rats).