Evaluation of Cereblon-Directing Warheads for the Development of Orally Bioavailable PROTACs.

PROTACs usually occupy physicochemical space outside the one defined by classical drug-like molecules, which often presents considerable challenges in their optimization and development for oral administration. We have previously reported phenyl glutarimide (PG)-based BET PROTAC SJ995973, with improved overall degradation and antiproliferative activities compared to its direct thalidomide-based analogue dBET1, but similarly poor pharmacokinetic profile. To further demonstrate the PG utility, we describe here optimization efforts that led to the discovery of an orally bioavailable BET-PROTAC SJ44236 (), and results of a comprehensive comparative study with analogues containing alternative CRBN-directing warheads.

Promotes Antioxidant Gene Expression and Mitochondrial Oxidative Respiration in Experimental Autoimmune Encephalomyelitis.

(L.) Urban (family Apiaceae) () is a traditional botanical medicine used in aging and dementia. Water extracts of (CAW) have been used to treat neuropsychiatric symptoms in related animal models and are associated with increases in antioxidant response element (ARE) genes and improvements in mitochondrial respiratory function and neuronal health.

The Intramolecular Self-Assembly of Statistical Copolymers in Aqueous Solution to Form Anisotropic Single-Chain Nanoparticles with Tunable Aspect Ratio.

Natural single-chain nanoparticles (SCNPs) such as proteins have inspired research into the formation and application of synthetic SCNPs. Although the latter can mimic general aspects of the self-assembly behavior of their biological counterparts, these systems remain relatively understudied. In this respect, a systematic series of amphiphilic statistical copolymers (ASC) of different molecular weights, with a hydrophilic comonomer (methacrylic acid) and varying hydrophobic comonomer to encompass methacrylates of different hydrophobicity, are synthesized.

Risk and Prognosis of Hamstring Injuries in the National Football League: A 12-Year Review.

Background: Hamstring injuries can have a significant burden on a professional football player's career and performance. One in 4 players will suffer a lower extremity strain in their career, with the hamstring being the most common. These injuries are often fraught with extended periods of recovery and reinjury rates varying between 16% and 38%.

Time delay and evidence profiles forming clinical recommendations of US surgical society guidelines.

Introduction: Surgical society guidelines facilitate implementation of up-to-date, evidence-based care, but concerns regarding the contemporality and quality of evidence can hinder adherence. We aimed to evaluate the time gap between evidence publication and their inclusion within clinical guidelines-the publication-to-guideline delay-and characterize the quality of evidence within contemporary surgical society guidelines.

Study Design: This cross-sectional study analyzed guidelines published by U.

Multiple sclerosis disease-modifying therapy use in the department of veteran affairs and Medicare: A comparative analysis.

Background: High-cost disease-modifying therapies (DMT) for multiple sclerosis (MS) have created affordability challenges for people with MS (PwMS) and payers. The Department of Veterans Affairs (VA) is the largest integrated healthcare system in the US and uses a variety of approaches to manage utilization and cost of MS DMT. The objective of this paper is to compare national utilization trends in the VA to the US Medicare program, another large federal public healthcare program.

Use of qPCR to monitor 2,4-dinitroanisole degrading bacteria in water and soil slurry cultures.

Unlabelled: Prediction and process monitoring during natural attenuation, bioremediation, and biotreatment require effective strategies for detection and enumeration of the responsible bacteria. The use of 2,4-dinitroanisole (DNAN) as a component of insensitive munitions leads to environmental contamination of firing ranges and manufacturing waste streams. Nocardioides sp.

An Exploratory Study of Capacity Assessment in Medical Practice in Ireland.

The current legal test for capacity under the common law is a functional test. It determines whether a person can make a particular decision at a particular time; it focuses on retained abilities rather than on presumed deficits - in order to promote patient autonomy in decision-making. International evidence suggests however that the test is not well understood and consequently not being correctly applied in practice by a range of medical professionals.

The impact of the current medico-legal and regulatory culture in Ireland on the decision of graduate entry medical school students to pursue a career in obstetrics and gynecology.

Objectives: Medico-legal and regulatory culture has a significant impact on medical practitioners, including the decision of graduates to enter high-risk specialties. This study explores the impact of the current medico-legal and regulatory culture in Ireland on the decision of graduate entry medical students to enter one high risk specialty, obstetrics and gynecology.

Study Design: We conducted a survey of 146 final-year, graduate-entry medical students pre- and post- a 6-week rotation in obstetrics and gynecology in Ireland.

Controlled dual drug release from adhesive electrospun patches for prevention and treatment of alveolar osteitis.

Approximately one in five individuals experience alveolar osteitis (AO) following wisdom tooth extraction. AO is characterised by loss of the blood clot from the tooth extraction socket leading to infection and pain, resulting in repeated hospital visits that impose a substantial burden on healthcare systems. Current treatments are sub-optimal; to address this we developed a novel drug-loaded mucoadhesive patch composed of dual electrospun polyvinyl pyrrolidone/Eudragit RS100 (PVP/RS100) and poly(N-isopropylacrylamide) (PNIPAM) fibres protected by a poly(ε-caprolactone) (PCL) backing layer.

Resident-Applicant Buddy Program Increases Applicant Interest and Program Transparency.

Objective: Resident-Applicant Buddy Programs (RABPs) are a new initiative designed to improve resident recruitment. This study aims to evaluate the impact and perceived value of RABPs and to identify areas for improvement for future recruitment cycles.

Design: Anonymous online survey study of RABP participants with mixed-methods approach to evaluate participants' experience and perceived impact of the program.

Differential diagnosis of autism, attachment disorders, complex post-traumatic stress disorder and emotionally unstable personality disorder: A Delphi study.

Individuals diagnosed with autism, attachment disorders, emotionally unstable personality disorder (EUPD) or complex post-traumatic stress disorder (CPTSD) can present with similar features. This renders differential and accurate diagnosis of these conditions difficult, leading to diagnostic overshadowing and misdiagnosis. The purpose of this study was to explore professionals' perspectives on the differential diagnosis of autism, attachment disorders and CPTSD in young people; and of autism, CPTSD and EUPD in adults.

Areal specializations in the morpho-electric and transcriptomic properties of primate layer 5 extratelencephalic projection neurons.

Large-scale analysis of single-cell gene expression has revealed transcriptomically defined cell subclasses present throughout the primate neocortex with gene expression profiles that differ depending upon neocortical region. Here, we test whether the interareal differences in gene expression translate to regional specializations in the physiology and morphology of infragranular glutamatergic neurons by performing Patch-seq experiments in brain slices from the temporal cortex (TCx) and motor cortex (MCx) of the macaque. We confirm that transcriptomically defined extratelencephalically projecting neurons of layer 5 (L5 ET neurons) include retrogradely labeled corticospinal neurons in the MCx and find multiple physiological properties and ion channel genes that distinguish L5 ET from non-ET neurons in both areas.

The use of an online learning module to improve knowledge for prevention of back pain and injury in industrial workers.

Back pain is a significant public health problem that accounts for a high percentage of morbidity and disability worldwide. Low back pain is a frequent cause of missed workdays and job-specific disability and is associated with poor outcomes for employees and employers. An online learning module that focused on normal anatomy of the spine, common pathophysiologic diagnosis or findings that may contribute to back pain, and techniques for back pain reduction was created for employees at risk due to the nature of their labor-intensive jobs.

Discovery of the 1-naphthylamine biodegradation pathway reveals a broad-substrate-spectrum enzyme catalyzing 1-naphthylamine glutamylation.

1-Naphthylamine (1NA), which is harmful to human and aquatic animals, has been used widely in the manufacturing of dyes, pesticides, and rubber antioxidants. Nevertheless, little is known about its environmental behavior and no bacteria have been reported to use it as the growth substrate. Herein, we describe a pathway for 1NA degradation in the isolate sp.

Ethnoracial Differences in Social Determinants of Health and Acute Mental Health Symptoms Among Adults Hospitalized After Emergency Care.

Research has established relationships between social determinants of health (SDOH) and mental health, with mixed findings on which ethnoracial groups are most vulnerable to deleterious outcomes. The current study examines ethnoracial differences in SDOH and their associations with acute mental health symptoms among patients hospitalized after emergency care. Using data collected in a multi-site study of 1,318 diverse adults admitted to inpatient units, we performed analyses using linear regression models.

Approaches to improving mental healthcare for autistic people: systematic review.

Background: Autistic people have a high likelihood of developing mental health difficulties but a low chance of receiving effective mental healthcare. Therefore, there is a need to identify and examine strategies to improve mental healthcare for autistic people.

Aims: To identify strategies that have been implemented to improve access, experiences of care and mental health outcomes for autistic adults, and to examine evidence on their acceptability, feasibility and effectiveness.

Comparative Analysis of Frailty Scores for Predicting Adverse Outcomes in Hip Fracture Patients: Insights from the United States National Inpatient Sample.

The aim of the current investigation was to compare the ability of several frailty scores to predict adverse outcomes in hip fracture patients. All adult patients (18 years or older) who suffered a hip fracture due to a fall and underwent surgical fixation were extracted from the 2019 National Inpatient Sample (NIS) Database. A combination of logistic regression and bootstrapping was used to compare the predictive ability of the Orthopedic Frailty Score (OFS), the Nottingham Hip Fracture Score (NHFS), the 11-factor modified Frailty Index (11-mFI) and 5-factor (5-mFI) modified Frailty Index, as well as the Johns Hopkins Frailty Indicator.

A Systematic Review of the Assessment of ICD-11 Complex Post-Traumatic Stress Disorder (CPTSD) in Young People and Adults.

Complex post-traumatic stress disorder (CPTSD) was introduced in the International Classification of Diseases (ICD) 11 in 2013 to simplify diagnosis and increase clinical utility. Given the recent ICD-11 conceptualisation, there is no standard approach for its assessment, and a review of research is necessary. This systematic review focuses on ICD-11 CPTSD assessment in young people aged 7 to 17 and adults aged 18 and above, examining measures, differentiating features and clinical considerations.

Serratus anterior plane block improves pain and incentive spirometry volumes in trauma patients with multiple rib fractures: a prospective cohort study.

Background: Rib fractures are common injuries associated with considerable morbidity, long-term disability, and mortality. Early, adequate analgesia is important to mitigate complications such as pneumonia and respiratory failure. Regional anesthesia has been proposed for rib fracture pain control due to its superior side effect profile compared with systemic analgesia.