A matched case-control study on polypharmacy and co-medications one year before drug treatment for Alzheimer's disease.

Background: Alzheimer's disease (AD) is the most prevalent form of dementia, characterized by amyloid-β plaques and neurofibrillary tangles. With an aging population, both AD and comorbidities are increasingly common. Managing comorbidities often requires multiple medications, leading to polypharmacy, defined as the concurrent use of five or more medications.

Identification and characterization of a human MORC2 DNA binding region that is required for gene silencing.

The eukaryotic microrchidia (MORC) protein family are DNA gyrase, Hsp90, histidine kinase, MutL (GHKL)-type ATPases involved in gene expression regulation and chromatin compaction. The molecular mechanisms underlying these activities are incompletely understood. Here, we studied the full-length human MORC2 protein biochemically.

Brain Hypertrophy in Patients With Mesial Temporal Lobe Epilepsy With Hippocampal Sclerosis and Its Clinical Correlates.

Background And Objectives: Mesial temporal lobe epilepsy (mTLE) is generally associated with focal brain atrophy, but little knowledge exists on possible disease-related hypertrophy of brain structures. We hypothesized that repeated seizures or adaptive plasticity may lead to focal brain hypertrophy and aimed to investigate associated clinical correlates.

Methods: In this cohort study, we included patients with mTLE undergoing detailed epilepsy evaluations and matched healthy volunteers (HVs) from 2 tertiary centers (discovery and validation cohorts).

The Imaging Database for Epilepsy And Surgery (IDEAS).

Objective: Magnetic resonance imaging (MRI) is a crucial tool for identifying brain abnormalities in a wide range of neurological disorders. In focal epilepsy, MRI is used to identify structural cerebral abnormalities. For covert lesions, machine learning and artificial intelligence (AI) algorithms may improve lesion detection if abnormalities are not evident on visual inspection.

Oxidative Stress in an African Ground Squirrel, a Case of Healthy Aging and Reproduction.

Oxidative stress plays a crucial role in mediating life-history processes, where it can compromise survival and reproduction through harmful alterations to DNA, lipids, and proteins. In this study, we investigated oxidative stress in Cape ground squirrels (), a longer-lived African ground squirrel species with a high reproductive skew and unique life history strategies. We measured oxidative stress as total antioxidant capacity (TAC), total oxidant status (TOS), and an oxidative stress index (OSI) in blood plasma from individuals of approximately known ages.

The Promise of AI for Image-Driven Medicine: Qualitative Interview Study of Radiologists' and Pathologists' Perspectives.

Background: Image-driven specialisms such as radiology and pathology are at the forefront of medical artificial intelligence (AI) innovation. Many believe that AI will lead to significant shifts in professional roles, so it is vital to investigate how professionals view the pending changes that AI innovation will initiate and incorporate their views in ongoing AI developments.

Objective: Our study aimed to gain insights into the perspectives and wishes of radiologists and pathologists regarding the promise of AI.

Making Pathologists Ready for the New Artificial Intelligence Era: Changes in Required Competencies.

In recent years, there has been an increasing interest in developing and using artificial intelligence (AI) models in pathology. Although pathologists generally have a positive attitude toward AI, they report a lack of knowledge and skills regarding how to use it in practice. Furthermore, it remains unclear what skills pathologists would require to use AI adequately and responsibly.

ARF alters PAF1 complex integrity to selectively repress oncogenic transcription programs upon p53 loss.

The polymerase associated factor 1 (PAF1) complex (PAF1c) promotes RNA polymerase II (RNA Pol II) transcription at the elongation step; however, how PAF1c transcription activity is selectively regulated during cell fate transitions remains poorly understood. Here, we reveal that the alternative reading frame (ARF) tumor suppressor operates at two levels to restrain PAF1c-dependent oncogenic transcriptional programs upon p53 loss in mouse cells. First, ARF assembles into homo-oligomers to bind the PAF1 subunit to promote PAF1c disassembly, consequently dampening PAF1c interaction with RNA Pol II and PAF1c-dependent transcription.

Comparative Effectiveness of Anti-Hyperlipidemic Drugs Monotherapy in Primary Prevention of Cardiovascular Disease.

Purpose: Anti-hyperlipidemic drug treatments are effective in reducing the risk of cardiovascular disease. In a long-term retrospective inception cohort study, we aimed to assess the real-world comparative effectiveness of anti-hyperlipidemic monotherapies for primary prevention of cardiovascular events.

Patients And Methods: Patients aged 18 years and older, who initiated primary prevention with anti-hyperlipidemic monotherapy, were selected from the University of Groningen IADB.

Measuring depressive symptoms among Latinos in the US: a psychometric evaluation of the CES-D Boston form.

Purpose: We present a psychometric evaluation of the Center for Epidemiologic Studies Depression Boston Form (CES-D-B) for use with different Latino subgroups as there is inconsistency regarding its performance across subgroups of Latinos, a large and rapidly growing cultural group in the United States.

Methods: We evaluated the reliability and structural validity of the scores generated by the CES-D-B using four distinct Latino samples residing in US: Mexicans, Venezuelans, Cubans, and "other Latinos" (total N = 1033). To further explore structural validity of CES-D-B scores, we conducted measurement invariance analyses across different countries of origin, gender groups, educational levels, and languages of assessment (English, Spanish).

Molecular landscape of the overlap between Alzheimer's disease and somatic insulin-related diseases.

Alzheimer's disease (AD) is a multifactorial disease with both genetic and environmental factors contributing to its etiology. Previous evidence has implicated disturbed insulin signaling as a key mechanism that plays a role in both neurodegenerative diseases such as AD and comorbid somatic diseases such as diabetes mellitus type 2 (DM2). In this study, we analysed available genome-wide association studies (GWASs) of AD and somatic insulin-related diseases and conditions (SID), i.

Design of a potent and selective dual JAK1/TYK2 inhibitor.

Janus kinase (JAK) inhibitors have gathered interest as treatments for several inflammatory and autoimmune diseases. The four first marketed inhibitors target JAK1, with varying selectivity towards other JAK family members, but none inhibit tyrosine kinase-2 (TYK2) at clinically relevant doses. TYK2 is required for the signaling of the interleukin (IL)-12 and IL-23 cytokines, which are key to the polarization of T1 and T17 cells, respectively; two cell subtypes that play major roles in inflammatory diseases.

Screening for Hypoglycaemia Risk and Medication Changes in Diabetes Patients Using Pharmacy Dispensing Data.

: To improve hypoglycaemia management in primary care, more insight is needed into the opportunities to screen for hypoglycaemia risk and subsequent treatment modification using routinely available data. Our primary aim was to assess the number of diabetes patients with an estimated high risk of hypoglycaemia and describe the treatment changes in these patients using pharmacy dispensing data. Additionally, our aim was to investigate patient characteristics associated with such treatment changes.

Complex structural variation is prevalent and highly pathogenic in pediatric solid tumors.

In pediatric cancer, structural variants (SVs) and copy-number alterations contribute to cancer initiation as well as progression, thereby aiding diagnosis and treatment stratification. Although suggested to be of importance, the prevalence and biological relevance of complex genomic rearrangements (CGRs) across pediatric solid tumors is largely unexplored. In a cohort of 120 primary tumors, we systematically characterized patterns of extrachromosomal DNA, chromoplexy, and chromothripsis across five pediatric solid cancer types.

Electrooxidative C(sp)-H Cyanation of Sparteine and Lupanine in Undivided Batch and Continuous-Flow Cells.

Sparteine is widely used as a chiral ligand in asymmetric synthesis, but methods for providing efficient access to functionalized sparteine derivatives are still limited. Herein, we describe an electrochemical α-cyanation of sparteine-type bis-quinolizidine alkaloids. This method features commercially available setups for batch and single-pass continuous flow conditions, enabling easy gram scale synthesis of valuable racemic and enantiopure products.

Pause Patrol: Negative Elongation Factor's Role in Promoter-Proximal Pausing and Beyond.

RNA polymerase (Pol) II is highly regulated to ensure appropriate gene expression. Early transcription elongation is associated with transient pausing of RNA Pol II in the promoter-proximal region. In multicellular organisms, this pausing is stabilized by the association of transcription elongation factors DRB-sensitivity inducing factor (DSIF) and Negative Elongation Factor (NELF).

The structural basis for RNA slicing by human Argonaute2.

Argonaute (AGO) proteins associate with guide RNAs to form complexes that slice transcripts that pair to the guide. This slicing drives post-transcriptional gene-silencing pathways that are essential for many eukaryotes and the basis for new clinical therapies. Despite this importance, structural information on eukaryotic AGOs in a fully paired, slicing-competent conformation-hypothesized to be intrinsically unstable-has been lacking.

Synaptic protein CSF levels relate to memory scores in individuals without dementia.

Introduction: We investigated how cerebrospinal fluid levels of synaptic proteins associate with memory function in normal cognition (CN) and mild cognitive impairment (MCI), and investigated the effect of amyloid positivity on these associations.

Methods: We included 242 CN (105(43%) abnormal amyloid), and 278 MCI individuals (183(66%) abnormal amyloid) from EMIF-AD MBD and ADNI. For 181 (EMIF-AD MBD) and 36 (ADNI) proteins with a synaptic annotation in SynGO, associations with word learning recall were analysed with linear models.

Feasibility and efficacy of a novel audiovisual tool to increase colorectal cancer screening among rural Appalachian Kentucky adults.

Introduction: Residents of Appalachian regions in Kentucky experience increased colorectal cancer (CRC) incidence and mortality. While population-based screening methods, such as fecal immunochemical tests (FITs), can reduce many screening barriers, written instructions to complete FIT can be challenging for some individuals. We developed a novel audiovisual tool ("talking card") to educate and motivate accurate FIT completion and assessed its feasibility, acceptability, and efficacy.