Cold acclimation with shivering improves metabolic health in adults with overweight or obesity.

Cold acclimation increases insulin sensitivity, and some level of muscle contraction appears to be needed for provoking this effect. Here 15 men and (postmenopausal) women with overweight or obesity, the majority of whom had impaired glucose tolerance, were intermittently exposed to cold to induce 1 h of shivering per day over 10 days. We determined the effect of cold acclimation with shivering on overnight fasted oral glucose tolerance (primary outcome) and on skeletal muscle glucose transporter 4 translocation (secondary outcome).

The association between the 'at risk of developing undernutrition' category of the Short Nutritional Assessment Questionnaire 65+ and incident undernutrition in community-dwelling older adults.

Background & Aims: Screening tools like the Short Nutritional Assessment Questionnaire 65+ (SNAQ) have been developed for the early recognition of undernutrition in older adults. The SNAQ screens for being undernourished (red), being 'at risk of developing undernutrition' (i.e.

The novel adrenergic agonist ATR-127 targets skeletal muscle and brown adipose tissue to tackle diabesity and steatohepatitis.

Objective: Simultaneous activation of β2- and β3-adrenoceptors (ARs) improves whole-body metabolism via beneficial effects in skeletal muscle and brown adipose tissue (BAT). Nevertheless, high-efficacy agonists simultaneously targeting these receptors whilst limiting activation of β1-ARs - and thus inducing cardiovascular complications - are currently non-existent. Therefore, we here developed and evaluated the therapeutic potential of a novel β2-and β3-AR, named ATR-127, for the treatment of obesity and its associated metabolic perturbations in preclinical models.

Impact of Pain and Neuropsychiatric Symptoms on Activities in Nursing Home Residents (COSMOS Trial).

Objective: This study aims to identify whether pain and dementia-related behavior are associated with different types of activities in nursing home residents, controlled for dementia severity.

Design: Cross-sectional baseline data from the multicomponent cluster randomized controlled COSMOS trial (acronym for Communication, Systematic pain treatment, Medication review, Organization of activities, and Safety).

Setting And Participants: A total of 723 patients from 33 Norwegian nursing homes with 67 units (clusters).

Harzianic acid exerts antimicrobial activity against Gram-positive bacteria and targets the cell membrane.

The thermophilic fungus is a saprobe that is commonly isolated from soil. Here, we identified a Gram-positive bacteria-selective antimicrobial secondary metabolite from this fungal species, harzianic acid (HA). Using strain 168 combined with dynamic bacterial morphology imaging, we found that HA targeted the cell membrane.

Development and external validation of a clinical prediction model for predicting quality of recovery up to 1 week after surgery.

The Quality of Recovery Score-40 (QoR-40) has been increasingly used for assessing recovery after patients undergoing surgery. However, a prediction model estimating quality of recovery is lacking. The aim of the present study was to develop and externally validate a clinical prediction model that predicts quality of recovery up to one week after surgery.

Development of novel β-adrenergic receptor agonists for the stimulation of glucose uptake - The importance of chirality and ring size of cyclic amines.

β-Adrenergic receptor (βAR) agonists have been reported to stimulate glucose uptake (GU) by skeletal muscle cells and are therefore highly interesting as a possible treatment for type 2 diabetes (T2D). The chirality of compounds often has a great impact on the activity of βAR agonists, although this has thus far not been investigated for GU. Here we report the GU for a selection of synthesized acyclic and cyclic β-hydroxy-3-fluorophenethylamines.

Drug interaction potential of high-dose rifampicin in patients with pulmonary tuberculosis.

Accumulating evidence supports the use of higher doses of rifampicin for tuberculosis (TB) treatment. Rifampicin is a potent inducer of metabolic enzymes and drug transporters, resulting in clinically relevant drug interactions. To assess the drug interaction potential of higher doses of rifampicin, we compared the effect of high-dose rifampicin (40 mg/kg daily, RIF40) and standard-dose rifampicin (10 mg/kg daily, RIF10) on the activities of major cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp).

Modeling the Impact of a Highly Potent Plasmodium falciparum Transmission-Blocking Monoclonal Antibody in Areas of Seasonal Malaria Transmission.

Transmission-blocking interventions can play an important role in combating malaria worldwide. Recently, a highly potent Plasmodium falciparum transmission-blocking monoclonal antibody (TB31F) was demonstrated to be safe and efficacious in malaria-naive volunteers. Here we predict the potential public health impact of large-scale implementation of TB31F alongside existing interventions.

Physiological and molecular mechanisms of cold-induced improvements in glucose homeostasis in humans beyond brown adipose tissue.

Exposure to low ambient temperatures has previously been demonstrated to markedly improve glucose homeostasis in both rodents and humans. Although the brown adipose tissue is key in mediating these beneficial effects in rodents, its contribution appears more limited in humans. Hence, the exact tissues and underlying mechanisms that mediate cold-induced improvements in glucose homeostasis in humans remain to be fully established.

Effect of β2-agonist treatment on insulin-stimulated peripheral glucose disposal in healthy men in a randomised placebo-controlled trial.

β-agonist treatment improves skeletal muscle glucose uptake and whole-body glucose homeostasis in rodents, likely via mTORC2-mediated signalling. However, human data on this topic is virtually absent. We here investigate the effects of two-weeks treatment with the β-agonist clenbuterol (40 µg/day) on glucose control as well as energy- and substrate metabolism in healthy young men (age: 18-30 years, BMI: 20-25 kg/m) in a randomised, placebo-controlled, double-blinded, cross-over study (ClinicalTrials.

Sex-specific newborn screening for X-linked adrenoleukodystrophy.

Males with X-linked adrenoleukodystrophy (ALD) are at high risk for developing adrenal insufficiency and/or progressive leukodystrophy (cerebral ALD) at an early age. Pathogenic variants in ABCD1 result in elevated levels of very long-chain fatty acids (VLCFA), including C26:0-lysophosphatidylcholine (C26:0-LPC). Newborn screening for ALD enables prospective monitoring and timely therapeutic intervention, thereby preventing irreversible damage and saving lives.

Model-Predicted Impact of ECG Monitoring Strategies During Bedaquiline Treatment.

Background: The M2 metabolite of bedaquiline causes QT-interval prolongation, making electrocardiogram (ECG) monitoring of patients receiving bedaquiline for drug-resistant tuberculosis necessary. The objective of this study was to determine the relationship between M2 exposure and Fridericia-corrected QT (QTcF)-interval prolongation and to explore suitable ECG monitoring strategies for 6-month bedaquiline treatment.

Methods: Data from the PROBeX study, a prospective observational cohort study, were used to characterize the relationship between M2 exposure and QTcF.

Physical Activity in People With Dementia Living in Long-Term Care Facilities and the Connection With Environmental Factors and Behavior.

This study is conducted in order to gain a better understanding of the relationship between physical activity and agitated behavior among older people with dementia, and physical activity and characteristics of long-term care wards. Data were collected among people with dementia living in long-term care facilities (N = 76) by conducting observations at the wards and distributing questionnaires among professional caregivers. The results show that participants are largely inactive (82.

Survival outcomes of patients with muscle-invasive bladder cancer according to pathological response at radical cystectomy with or without neo-adjuvant chemotherapy: a case-control matching study.

Objectives: To assess survival of patients with muscle-invasive bladder cancer (MIBC) who underwent radical cystectomy (RC) with or without neo-adjuvant chemotherapy (NAC) according to the pathological response at RC.

Methods: 965 patients with MIBC (cT2-4aN0M0) who underwent RC with or without NAC were analyzed. Among the collected data were comorbidity, clinical and pathological tumor stage, tumor grade, nodal status (y)pN, and OS.

Safety, tolerability, and Plasmodium falciparum transmission-reducing activity of monoclonal antibody TB31F: a single-centre, open-label, first-in-human, dose-escalation, phase 1 trial in healthy malaria-naive adults.

Background: Malaria elimination requires interruption of the highly efficient transmission of Plasmodium parasites by mosquitoes. TB31F is a humanised monoclonal antibody that binds the gamete surface protein Pfs48/45 and inhibits fertilisation, thereby preventing further parasite development in the mosquito midgut and onward transmission. We aimed to evaluate the safety and efficacy of TB31F in malaria-naive participants.

Three weeks of time-restricted eating improves glucose homeostasis in adults with type 2 diabetes but does not improve insulin sensitivity: a randomised crossover trial.

Aims/hypothesis: Time-restricted eating (TRE) is suggested to improve metabolic health by limiting food intake to a defined time window, thereby prolonging the overnight fast. This prolonged fast is expected to lead to a more pronounced depletion of hepatic glycogen stores overnight and might improve insulin sensitivity due to an increased need to replenish nutrient storage. Previous studies showed beneficial metabolic effects of 6-8 h TRE regimens in healthy, overweight adults under controlled conditions.

Pharmacogenetics of Between-Individual Variability in Plasma Clearance of Bedaquiline and Clofazimine in South Africa.

Background: Plasma bedaquiline clearance is reportedly more rapid with African ancestry. Our objective was to determine whether genetic polymorphisms explained between-individual variability in plasma clearance of bedaquiline, its M2 metabolite, and clofazimine in a cohort of patients treated for drug-resistant tuberculosis in South Africa.

Methods: Plasma clearance was estimated with nonlinear mixed-effects modeling.

The dosimetric and clinical advantages of the GTV-CTV-PTV margins reduction by 6 mm in head and neck squamous cell carcinoma: Significant acute and late toxicity reduction.

Purpose: We aim to identify the dosimetric and clinical impact of reducing the total GTV-CTV-PTV margins in head-and-neck squamous cell carcinoma (HNSCC) treated with definitive (chemo)radiation.

Materials And Methods: The acute and late toxicity and outcomes of 155 consecutive patients treated between February 2017 and March 2019 with GTV-CTV-PTV margins of 9 mm were compared to those of 155 consecutive patients treated with total margin of 15 mm margin, before April 2015. All patients were treated with VMAT with daily-image guidance using CBCT.

Optimized Loading Dose Strategies for Bedaquiline When Restarting Interrupted Drug-Resistant Tuberculosis Treatment.

Interruption of treatment is common in drug-resistant tuberculosis patients. Bedaquiline has a long terminal half-life; therefore, restarting after an interruption without a loading dose could increase the risk of suboptimal treatment outcome and resistance development. We aimed to identify the most suitable loading dose strategies for bedaquiline restart after an interruption.

Improving predictive CTV segmentation on CT and CBCT for cervical cancer by diffeomorphic registration of a prior.

Purpose: Automatic cervix-uterus segmentation of the clinical target volume (CTV) on CT and cone-beam CT (CBCT) scans is challenged by the limited visibility and the non-anatomical definition of certain border regions. We study the potential performance gain of convolutional neural networks by regulating the segmentation predictions as diffeomorphic deformations of a segmentation prior.

Materials And Methods: We introduce a 3D convolutional neural network that segments the target scan by joint voxel-wise classification and the registration of a given prior.

Updating Clinical Prediction Models: An Illustrative Case Study.

The performance of clinical prediction models tends to deteriorate over time. Researchers often develop a new prediction if an existing model performs poorly at external validation. Model updating is an efficient technique and promising alternative to the de novo development of clinical prediction models.

Prediction of pathological response following neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer: the PRE-PREVENCYS trial.

Background: The recommended treatment for patients with non-metastatic muscle-invasive bladder cancer (MIBC) is neoadjuvant chemotherapy (NAC) and radical cystectomy (RC). Following NAC, 20-40% of patients experience a complete pathological response (pCR) in the RC specimen and these patients have excellent long-term overall survival. Subject to debate is, however, whether patients with a pCR to NAC benefit from RC, which is a major surgical procedure with substantial morbidity, and if these patients might be candidates for close surveillance instead.