Stochastic demethylation and redundant epigenetic suppressive mechanisms generate highly heterogeneous responses to pharmacological DNA methyltransferase inhibition.

Background: Despite promising preclinical studies, the application of DNA methyltransferase inhibitors in treating patients with solid cancers has thus far produced only modest outcomes. The presence of intratumoral heterogeneity in response to DNA methyltransferase inhibitors could significantly influence clinical efficacy, yet our understanding of the single-cell response to these drugs in solid tumors remains very limited.

Methods: In this study, we used cancer/testis antigen genes as a model for methylation-dependent gene expression to examine the activity of DNA methyltransferase inhibitors and their potential synergistic effect with histone deacetylase inhibitors at the single-cancer cell level.

RapA opens the RNA polymerase clamp to disrupt post-termination complexes and prevent cytotoxic R-loop formation.

Following transcript release during intrinsic termination, Escherichia coli RNA polymerase (RNAP) often remains associated with DNA in a post-termination complex (PTC). RNAPs in PTCs are removed from the DNA by the SWI2/SNF2 adenosine triphosphatase (ATPase) RapA. Here we determined PTC structures on negatively supercoiled DNA and with RapA engaged to dislodge the PTC.

Feasibility and acceptability for LION, a fully remote, randomized clinical trial within the VA for light therapy to improve sleep in Veterans with and without TBI: An MTBI2 sponsored protocol.

Sleep-wake disturbances frequently present in Veterans with mild traumatic brain injury (mTBI). These TBI-related sleep impairments confer significant burden and commonly exacerbate other functional impairments. Therapies to improve sleep following mTBI are limited and studies in Veterans are even more scarce.

Diabetes Mellitus Is Not a Risk Factor for Difficult Intubation Among Critically Ill Adults: A Secondary Analysis of Multicenter Trials.

Objectives: Diabetes mellitus has been associated with greater difficulty of tracheal intubation in the operating room. This relationship has not been examined for tracheal intubation of critically ill adults. We examined whether diabetes mellitus was independently associated with the time from induction of anesthesia to intubation of the trachea among critically ill adults.

Clinical Presentation of Adults with Traumatic Orthopedic Injuries Enrolled in a Multisite Psychosocial Trial.

Objectives: Traumatic orthopedic injuries are a top cause of hospital visits in the U.S. The Toolkit for Optimal Recovery (TOR) is a brief mind-body intervention that targets catastrophic thinking and pain anxiety following orthopedic injury.

Dementia Care Specialists Perspectives of Diagnosis and Early Psychosocial Care: A Qualitative Analysis of Focus Groups in Two Large Academic Medical Centers.

Background And Objective: Alzheimer's disease and related dementias (ADRDs) are progressive conditions that substantially impact individuals and families. Timely diagnosis and early support are critical for long-term adjustment. However, current dementia care models do not meet needs of patients and families.

Pain catastrophizing and pain anxiety mediate changes in physical function in a mind-body intervention for adults with traumatic orthopedic injuries.

Traumatic orthopedic injuries are common and frequently associated with persistent pain, disability, and emotional distress. Risk factors of persistent pain and disability include pain catastrophizing and pain anxiety, though most interventions for orthopedic injuries are primarily biomedical (eg, surgeries, pharmacology, physiotherapy/exercise). The Toolkit for Optimal Recovery (TOR) is a brief, live video mind-body program designed to directly target pain catastrophizing and anxiety in patients with recent traumatic orthopedic injury to prevent persistent disability.

Volumetric imaging and computation to explore contractile function in zebrafish hearts.

Despite advancements in cardiovascular engineering, heart diseases remain a leading cause of mortality. The limited understanding of the underlying mechanisms of cardiac dysfunction at the cellular level restricts the development of effective screening and therapeutic methods. To address this, we have developed a framework that incorporates light field detection and individual cell tracking to capture real-time volumetric data in zebrafish hearts, which share structural and electrical similarities with the human heart and generate 120 to 180 beats per minute.

Patient and staff perspectives on pain treatment experiences in a community clinic serving under-resourced older adults.

Aims: Chronic pain affects up to 37.8% of older adults with higher prevalence among those in under-resourced communities. While there are many treatments for chronic pain, there are complexities to treating under-resourced older adults in community clinics, including multimorbidity, barriers to treatment access, and varying degrees of openness to different treatment approaches.

Using the Socioecological Model to Understand Medical Staff and Older Adult Patients' Experience with Chronic Pain: A Qualitative Study in an Underserved Community Setting.

Purpose: Chronic pain is highly prevalent and disabling for older adults, particularly those from underserved communities. However, there is an absence of research on how contextual (eg, community/societal) factors interact with pain for these patients. Informed by the socio-ecological model, this study aimed to elucidate the individual, interpersonal, community, and societal factors associated with chronic pain from the perceptions of older adult patients and medical staff in a community clinic.

Socio-ecological barriers to behavior change-oriented dementia prevention: a qualitative study of healthcare professionals' perspectives.

Objectives: This qualitative study aimed to: (1) identify socio-ecological barriers to behavior change-oriented dementia (AD/ADRD) prevention from the perspectives of healthcare professionals, and (2) propose strategies to address these barriers during a clinical trial for an AD/ADRD prevention program ().

Method: Multidisciplinary healthcare professionals involved in geriatric care ( = 26, experience > 17 years) from diverse clinics within a medical center participated in focus groups. Using the Socio-Ecological Model (SEM), 5 focus groups were conducted to identify individual, interpersonal, institutional, community, and societal barriers.

A Mindfulness-Based Lifestyle Intervention for Dementia Risk Reduction: Protocol for the My Healthy Brain Feasibility Randomized Controlled Trial.

Background: Lifestyle behavior change and mindfulness have direct and synergistic effects on cognitive functioning and may prevent Alzheimer disease and Alzheimer disease-related dementias (AD/ADRD). We are iteratively developing and testing My Healthy Brain (MHB), the first mindfulness-based lifestyle group program targeting AD/ADRD risk factors in older adults with subjective cognitive decline. Our pilot studies (National Institutes of Health [NIH] stage 1A) have shown that MHB is feasible, acceptable, and associated with improvement in lifestyle behavior and cognitive outcomes.

Within-person relationships between catastrophizing and pain intensity during a mind-body intervention to prevent persistent pain and disability after acute traumatic orthopedic injury.

Interventions aimed at preventing chronic pain after acute traumatic injury have significant potential to reduce healthcare expenditures and improve quality of life for millions of individuals. Given recent development of such interventions, limited research has examined mechanisms of change using repeated measures (e.g.

Characterization of human melanoma skin cancer models: A step towards model-based melanoma research.

Advancing 3D in vitro human tissue models is crucial for biomedical research and drug development to address the ethical and biological limitations of animal testing. Recently, 3D skin models have proven to be effective for studying serious skin conditions, such as melanoma. For these advanced models to be applicable in preclinical studies, thorough characterization is essential to understand their applicability and limitations.

ENIGMA-Meditation: Worldwide consortium for neuroscientific investigations of meditation practices.

Meditation is a family of ancient and contemporary contemplative mind-body practices that can modulate psychological processes, awareness, and mental states. Over the last 40 years, clinical science has manualised meditation practices and designed various meditation interventions (MIs), that have shown therapeutic efficacy for disorders including depression, pain, addiction, and anxiety. Over the past decade, neuroimaging has examined the neuroscientific basis of meditation practices, effects, states, and outcomes for clinical and non-clinical populations.

Artificial intelligence-based morphologic classification and molecular characterization of neuroblastic tumors from digital histopathology.

A deep learning model using attention-based multiple instance learning (aMIL) and self-supervised learning (SSL) was developed to perform pathologic classification of neuroblastic tumors and assess MYCN-amplification status using H&E-stained whole slide images from the largest reported cohort to date. The model showed promising performance in identifying diagnostic category, grade, mitosis-karyorrhexis index (MKI), and MYCN-amplification with validation on an external test dataset, suggesting potential for AI-assisted neuroblastoma classification.

"Pushed to Their Limits": Health Care Provider Perspectives on Barriers and Facilitators to Implementing a Mind-Body and Activity Program for Older Adults With Chronic Pain in a Community Clinic for the Underserved.

Older adults from underserved backgrounds experience chronic pain at a rate of 60% to 75%. Pharmacological treatments have limited efficacy and involve considerable risks. Mind-body interventions hold promise to improve pain outcomes but are typically not implemented in community clinics in which they are needed most, thus contributing to health disparities in chronic pain treatment.

Acetabular Fracture and Triradiate Cartilage Injury in an Adolescent After a Motorcycle Crash: A Case Report.

The acetabular triradiate cartilage is the main structure that determines the development of the acetabulum. Furthermore, the paucity of data in the literature and lack of consensus amongst physicians following diagnosis regarding whether to treat these fractures operatively or non-operatively places the physician with a challenging choice. Here, we report a case of a 13-year-old boy who suffered a triradiate cartilage fracture from a high-energy motorcycle crash and presented with a displaced, left T-type acetabulum fracture.

APOE 𝜀4-related blood-brain barrier breakdown is associated with microstructural abnormalities.

Introduction: Blood-brain barrier (BBB) dysfunction occurs in Alzheimer's disease (AD). Yet, the stage at which it appears along the AD time course and whether it contributes to neurodegeneration remain unclear.

Methods: Older adults (61 to 90 years) from cognitively normal (CN) to mildly cognitively impaired (CI), enriched for APOE 𝜀4 and amyloid positivity, underwent dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and diffusion MRI to measure BBB permeability and brain microstructure.

Memory-related brain potentials for visual objects in early AD show impairment and compensatory mechanisms.

Impaired episodic memory is the primary feature of early Alzheimer's disease (AD), but not all memories are equally affected. Patients with AD and amnestic Mild Cognitive Impairment (aMCI) remember pictures better than words, to a greater extent than healthy elderly. We investigated neural mechanisms for visual object recognition in 30 patients (14 AD, 16 aMCI) and 36 cognitively unimpaired healthy (19 in the "preclinical" stage of AD).

A Validation Study of the Mindfulness-Based Interventions Teaching Assessment Criteria for Assessing Mindfulness-Based Intervention Teacher Skill: Inter-Rater Reliability and Predictive Validity.

Background: Prior data suggests the Mindfulness-Based Interventions: (MBI) Teaching Assessment Criteria (MBI:TAC) has good inter-rater reliability, but many raters knew teacher experience level.

Objective: We sought to further evaluate the MBI-TAC's inter-rater reliability and obtain preliminary data on predictive validity.

Methods: We videorecorded 21 MBSR teachers from academic and community settings.