Drug Development.

Background: Alzheimer's disease (AD) trials report a high screening failure rate (potentially eligible trial candidates who do not meet inclusion/exclusion criteria during screening) due to multiple factors including stringent eligibility criteria. Here, we report the main reasons for screening failure in the 12-week screening phase of the ongoing evoke (NCT04777396) and evoke+ (NCT04777409) trials of semaglutide in early AD.

Method: Key inclusion criteria were age 55-85 years; mild cognitive impairment due to AD (Clinical Dementia Rating [CDR] global score of 0.

Drug Development.

Background: Convergent evidence indicates that deficits in the endosomal recycling pathway underlies pathogenesis of Alzheimer's disease (AD). SORL1 encodes the retromer-associated receptor SORLA that plays an essential role in recycling of AD-associated cargos such as the amyloid precursor protein and the glutamatergic AMPA receptor. Importantly, loss of function pathogenic SORL1 variants are associated with AD.

Drug Development.

Background: Phase 3 randomized clinical trials within Alzheimer's Disease (AD) typically last over 18 months. Post-baseline participants can use additional treatment for Alzheimer's disease, potentially impacting the cognitive ability as evaluated by the primary endpoint. Consequently, this could overestimate or underestimate the treatment effect, depending on the distribution of usage between treatment arms.

Drug Development.

Background: Differences in patient characteristics across geographical regions may result in heterogeneity in clinical trial populations. evoke (NCT04777396) and evoke+ (NCT04777409) are two phase 3, multinational, randomised trials investigating semaglutide versus placebo in individuals with mild cognitive impairment or mild dementia due to Alzheimer's disease (AD) (early AD). We present baseline characteristics across the geographical regions in evoke/evoke+.

Drug Development.

Background: evoke and evoke+ are phase 3, randomized, placebo-controlled trials currently investigating the glucagon-like peptide-1 receptor agonist semaglutide as disease-modifying therapy (DMT) in persons with early Alzheimer's disease (AD). How the evoke and evoke+ trial populations compare with other phase 3 programs for DMTs in early AD has not been described.

Method: We compare the inclusion/exclusion criteria and baseline characteristics of the evoke/evoke+ trial populations with those of Clarity AD (lecanemab) and TRAILBLAZER-ALZ-2 (donanemab): two recent phase 3 trials assessing anti-amyloid monoclonal antibodies in persons with early AD.

Drug Development.

Alzheimer's disease (AD) is a complex disease that is often accompanied by a range of comorbidities, such as cardiovascular disease, diabetes, and depression. These comorbidities can impact the progression of AD and can complicate treatment strategies. Targeting comorbidities in Alzheimer's disease and developing combination therapies are emerging areas of research.

Drug Development.

Background: Evidence suggests glucagon-like peptide 1 receptor agonists (GLP-1RAs) may have therapeutic potential in Alzheimer's disease (AD). Cumulative evidence has indicated a potential reduction in cognitive decline in people with AD, while real-world evidence has shown decreased dementia risk in patients with type 2 diabetes. Non-clinical data reveal that GLP-1RAs impact neuroinflammation and other biological processes believed to be involved in AD pathophysiology, including effects on central and peripheral immune cells.

Exploring the association between familial hemiplegic migraine genes (, and ) with migraine and epilepsy: A UK Biobank exome-wide association study.

Background: Familial hemiplegic migraine (FHM) types 1-3 are associated with protein-altering genetic variants in , and , respectively. These genes have also been linked to epilepsy. Previous studies primarily focused on phenotypes, examining genetic variants in individuals with characteristic FHM symptoms.

Sex-specific temporal trends in incidence and prevalence of chronic kidney disease: a Danish population-based cohort study.

Background: Rates of chronic kidney disease (CKD) may change with ageing populations, rising metabolic and cardiovascular disease prevalence, increasing CKD awareness and new treatments. We examined sex-specific temporal trends in CKD incidence and prevalence from 2011 through 2021.

Methods: We conducted a population-based cohort study among adults residing in the North and Central Denmark Regions (population ∼1.

-associated autosomal dominant tubulointerstitial kidney disease: prevalence in kidney failure of undetermined aetiology and clinical insights from Danish families.

Background: Frameshift variants in the variable number tandem repeat region of () cause autosomal dominant tubulointerstitial kidney disease (ADTKD-) but are challenging to detect. We investigated the prevalence in patients with kidney failure of undetermined aetiology and compared Danish families with ADTKD-.

Methods: We recruited patients with suspected kidney failure of undetermined aetiology at ≤50 years and excluded those with a clear-cut clinical or histopathological kidney diagnoses or established genetic kidney diseases identified thorough medical record review.

An overview of approaches for assessing the environmental sustainability of diets - a scoping review for Nordic Nutrition Recommendations 2023.

Assessing the environmental impacts of food, food systems and diets is highly complex due to the multitude of processes involved, the uncertainty in assessment models, the variability in production systems and the large range of products available. No single assessment method alone can provide a complete evidence base. The increasing number of Life Cycle Assessment and food system analyses, and more recently the integration of planetary boundaries offer insights from which we can draw some robust high-level conclusions, whilst recognising there is a need for more detailed analysis to capture the inherent nuances of more location and context-specific situations.

Fragmented markets for older antibiotics and child formulations, Denmark, Norway, Sweden.

Antibiotic resistance is one of the most urgent threats to public health. The development of antibiotic resistance can be reduced by the use of narrow-spectrum antibiotics that target specific bacteria, meaning that fewer non-harmful bacteria are killed and other harmful bacteria are not exposed to selection pressure. However, many narrow-spectrum antibiotics were introduced decades ago and therefore lack regulatory documentation in line with current standards.

Impact of TCF7L2 rs7903146 on clinical presentation and risk of complications in patients with type 2 diabetes.

Aims: TCF7L2 rs7903146 is the most impactful single genetic risk variant for type 2 diabetes. However, its role on disease progression, complications and mortality among people with type 2 diabetes at diagnosis remains unclear.

Materials And Methods: We assessed the per allele impact of the rs7903146 T-allele on clinical characteristics and complication risk in 9231 individuals with type 2 diabetes at diagnosis and over a 10-year follow-up period.

Identifying clusters of raters with a common notion of diagnosing erosive tooth wear: a step towards improving the accuracy of diagnostic procedures.

Background: Heterogeneous results are to be expected when multiple raters diagnose whether the dentine of a tooth with erosive tooth wear (ETW) is exposed or not. Identification of notions (fundamental concepts and understanding) about the diagnostic problem shared by groups of raters can be helpful to develop guidelines and to optimize teaching and calibration procedures. We aim to illustrate how clusters of raters with a common notion can be identified and how first insights about the notions can be obtained.

Development of a non-specialist worker delivered psychological intervention to address alcohol use disorders and psychological distress among conflict-affected populations in Uganda and Ukraine.

Background: Despite the significant burden of alcohol use disorders (AUD), there is a large treatment gap, especially in settings and populations affected by armed conflict. A key barrier to care is the lack of contextually relevant interventions and adequately skilled human resources to deliver them. This paper describes the systematic development of the CHANGE intervention, a potentially scalable psychological intervention for people with co-existing AUD and psychological distress in conflict-affected populations, delivered by non-specialist workers (NSWs).

evoke and evoke+: design of two large-scale, double-blind, placebo-controlled, phase 3 studies evaluating efficacy, safety, and tolerability of semaglutide in early-stage symptomatic Alzheimer's disease.

Background: Disease-modifying therapies targeting the diverse pathophysiology of Alzheimer's disease (AD), including neuroinflammation, represent potentially important and novel approaches. The glucagon-like peptide-1 receptor agonist semaglutide is approved for the treatment of type 2 diabetes and obesity and has an established safety profile. Semaglutide may have a disease-modifying, neuroprotective effect in AD through multimodal mechanisms including neuroinflammatory, vascular, and other AD-related processes.

Development of a PROM to measure patient-centredness in chronic care consultations in primary care.

Introduction: Validated patient-reported outcome measures (PROMs) are crucial for assessing patients' experiences in the healthcare system. Both clinically and theoretically, patient-centered consultations are essential in patient-care, and are often suggested as the optimal strategy in caring for patients with multimorbidity.

Aim: To either identify or develop and validate a patient-reported outcome measure (PROM) to assess patient-centredness in consultations for patients with multimorbidity in general practice.

Public health economic modelling in evaluations of salt and/or alcohol policies: a systematic scoping review.

Background: Public health economic modelling is an approach capable of managing the intricacies involved in evaluating interventions without direct observational evidence. It is used to estimate potential long-term health benefits and cost outcomes. The aim of this review was to determine the scope of health economic models in the evaluation of salt and/or alcohol interventions globally, to provide an overview of the literature and the modelling methods and structures used.

The TRIPOD-LLM reporting guideline for studies using large language models.

Large language models (LLMs) are rapidly being adopted in healthcare, necessitating standardized reporting guidelines. We present transparent reporting of a multivariable model for individual prognosis or diagnosis (TRIPOD)-LLM, an extension of the TRIPOD + artificial intelligence statement, addressing the unique challenges of LLMs in biomedical applications. TRIPOD-LLM provides a comprehensive checklist of 19 main items and 50 subitems, covering key aspects from title to discussion.

Saturation genome editing-based clinical classification of BRCA2 variants.

Sequencing-based genetic tests have uncovered a vast array of BRCA2 sequence variants. Owing to limited clinical, familial and epidemiological data, thousands of variants are considered to be variants of uncertain significance (VUS). Here we have utilized CRISPR-Cas9-based saturation genome editing in a humanized mouse embryonic stem cell line to determine the functional effect of VUS.

Dynamic transitions of initiator binding coordinate the replication of the two chromosomes in Vibrio cholerae.

The replication of the two chromosomes in the pathogenic bacterium Vibrio cholerae is coordinated by the binding of initiator protein RctB to a checkpoint sequence, crtS. Replication of crtS on the primary chromosome (Chr1) triggers replication of the secondary chromosome (Chr2), but the details are poorly understood. Here, we analyze RctB binding patterns in the V.

Structural basis of THC analog activity at the Cannabinoid 1 receptor.

Tetrahydrocannabinol (THC) is the principal psychoactive compound derived from the cannabis plant Cannabis sativa and approved for emetic conditions, appetite stimulation and sleep apnea relief. THC's psychoactive actions are mediated primarily by the cannabinoid receptor CB. Here, we determine the cryo-EM structure of HU210, a THC analog and widely used tool compound, bound to CB and its primary transducer, G.

Therapeutic Potential of Agmatine in Essential Tremor Through Regulation of Lingo-1 and Inflammatory Pathways.

Purpose: Essential tremor (ET) is a prevalent movement disorder, yet current therapeutic options remain limited. Emerging evidence implicates leucine-rich repeat and immunoglobulin-like domain-containing protein (Lingo-1) and neuroinflammation in the pathophysiology of ET. This study aimed to investigate whether agmatine, a biogenic amine neuromodulator attenuates tremors and modulates the expression of Lingo-1 and proinflammatory markers in a rodent model of ET.

Unsymmetric triazine-based triglucoside detergents for membrane protein stability.

Membrane proteins play a crucial role in a variety of biological processes and are key targets for pharmaceutical development. Structural studies of membrane proteins provide molecular insights into the mechanisms of these processes and are essential for effective drug discovery. Historically, these studies have relied on solubilization of the target protein using detergents, but conventional detergents often fail to maintain the stability of challenging membrane proteins.