Synthesis and Structural Characterization of Novel Trihalo-sulfone Inhibitors of WNK1.

With No lysine (K) [WNK] kinases are structurally unique serine/threonine protein kinases that have therapeutic potential for blood pressure regulation and cancer. A novel class of trihalo-sulfone compounds was identified by high-throughput screening. Trihalo-sulfone emerged as an effective inhibitor of WNK1 with an IC value of 1.

Addressing childcare as a barrier to healthcare access through community partnerships in a large public health system.

Objective: In our public health system, a survey of reproductive-aged women identified lack of childcare as the most common reason for missing or delaying healthcare. Community-based organisations (CBOs) in our county identified a similar need, so we partnered to develop a hospital-based childcare centre for patients to use during appointments.

Methods: In a large academic public health system, a partnership with a non-profit childcare CBO was formed to address lack of childcare as a barrier to accessing healthcare.

Exposure to umbilical cord management approaches and death or neurodevelopmental impairment at 22-26 months' corrected age after extremely preterm birth.

Objective: To compare death or severe neurodevelopmental impairment (NDI) at 22-26 months' corrected age (CA) among extremely preterm infants following exposure to different forms of umbilical cord management.

Design: Retrospective study.

Setting: National Institute of Child Health and Human Development Neonatal Research Network registry.

Vonoprazan Versus Lansoprazole for Healing and Maintenance of Healing of Erosive Esophagitis: A Randomized Trial.

Background & Aims: For decades, proton pump inhibitors (PPIs) have been the mainstay of treatment for erosive esophagitis. The potassium-competitive acid blocker vonoprazan provides more potent acid inhibition than PPIs, but data on its efficacy for erosive esophagitis are limited.

Methods: Adults with erosive esophagitis were randomized to once-daily vonoprazan, 20 mg, or lansoprazole, 30 mg, for up to 8 weeks.

Dorsal medulla surface texture: Differentiating neuromyelitis optica spectrum disorder from multiple sclerosis.

Background And Purpose: The timely and accurate diagnosis of neuromyelitis optica spectrum disorder (NMOSD) is essential and exposure to multiple sclerosis (MS) disease-modifying therapies may result in permanent neurological disability.

Methods: Standardized 3-Tesla 3-dimensional brain MRI studies were retrospectively studied from people with NMOSD, MS, other CNS neurological diseases, and healthy control subjects. Comparisons of surface texture characteristics at the area postrema involving absolute introverted planar triangle counts, representing more complex and concave tissue topography, along with the spatial dissemination pattern of these triangles were performed cross-sectionally and longitudinally.

Acute Hepatitis B Virus Infection in North American Adults.

Background & Aims: Acute hepatitis B virus (aHBV) is thought to be self-limited with clearance of hepatitis B surface antigen (HBsAg) within 6 months. There are limited reports of the presenting features and outcomes of adults with symptomatic aHBV in the United States.

Methods: Demographics, clinical features, and 12-month outcomes of patients with adjudicated aHBV were captured prospectively and compared with a contemporaneous cohort of chronic HBV (cHBV) patients enrolled in the Hepatitis B Research Network.

Incidence and Progression of Fibrotic Lung Disease in an At-Risk Cohort.

Relatives of patients with familial interstitial pneumonia (FIP) are at increased risk for pulmonary fibrosis and develop preclinical pulmonary fibrosis (PrePF). We defined the incidence and progression of new-onset PrePF and its relationship to survival among first-degree relatives of families with FIP. This is a cohort study of family members with FIP who were initially screened with a health questionnaire and chest high-resolution computed tomography (HRCT) scan, and approximately 4 years later, the evaluation was repeated.

Emerging hormonal agents for the treatment of prostate cancer.

Introduction: Prostate cancer is the most common solid organ malignancy in men in the United States. Until recently, treatment options for men with metastatic disease were limited and patients faced poor outcomes with minimal alternatives. The landscape of prostate cancer treatment has transformed and taken shape over the last 20 years with novel hormonal and non-hormonal therapeutics that have demonstrated significant improvement in survival.

Development of a biomarker to monitor target engagement after treatment with dihydroorotate dehydrogenase inhibitors.

Dihydroorotate dehydrogenase (DHODH) catalyzes a key step in pyrimidine biosynthesis and has recently been validated as a therapeutic target for malaria through clinical studies on the triazolopyrimidine-based Plasmodium DHODH inhibitor DSM265. Selective toxicity towards Plasmodium species could be achieved because malaria parasites lack pyrimidine salvage pathways, and DSM265 selectively inhibits Plasmodium DHODH over the human enzyme. However, while DSM265 does not inhibit human DHODH, it inhibits DHODH from several preclinical species, including mice, suggesting that toxicity could result from on-target DHODH inhibition in those species.

Alterations in sorting and secretion of hepatic apoA5 induce hypertriglyceridemia due to short-term use of olanzapine.

Long-term use of olanzapine, an antipsychotic drug, induces hypertriglyceridemia, resulting in a higher risk of cardiovascular disease. However, the effects and underlying mechanisms of short-term use of olanzapine on circulating triglyceride levels remain poorly understood. Here, the role of apolipoprotein A5 (apoA5), a regulator of triglyceride metabolism, was investigated in olanzapine-induced hypertriglyceridemia.

SAGES safe cholecystectomy modules improve practicing surgeons' judgment: results of a randomized, controlled trial.

Background: Despite the advantages of laparoscopic cholecystectomy, major bile duct injury (BDI) rates during this operation remain unacceptably high. In October 2018, SAGES released the Safe Cholecystectomy modules, which define specific strategies to minimize the risk of BDI. This study aims to investigate whether this curriculum can change the knowledge and behaviors of surgeons in practice.

The More the Better, Only in the Longer Term: A Cluster Randomized Controlled Trial to Evaluate a Compound Intervention Among Mainland Chinese Immigrants in Hong Kong.

Barriers to adaptation faced by mainland Chinese immigrants to Hong Kong can be reduced by improving two targets of adaptation: information about negotiating their new environment and psychological well-being. We developed and evaluated a Compound intervention to address these two domains simultaneously and compared its effects to two separate interventions exclusively targeting either information about Hong Kong or psychological well-being. This cluster randomized controlled trial assigned 251 immigrants to an information provision arm (IP, n = 84) targeting knowledge and adaptation difficulties, a psychological well-being enhancement arm (WBE, n = 80) targeting resilience and mental health, or a Compound arm (i.

Outcomes of patients with acute liver failure listed for liver transplantation: A multicenter prospective cohort analysis.

Liver transplantation (LT) is a life-saving treatment for patients with acute liver failure (ALF). Currently, there are few detailed data regarding long-term outcomes after LT for ALF. We combined prospective data from the Acute Liver Failure Study Group (ALFSG) Registry with those of the Scientific Registry of Transplant Recipients (SRTR) to assess outcomes among consecutive patients with ALF listed for LT.

Interstitial fluid streaming in deep tissue induced by ultrasound momentum transfer for accelerating nanoagent transport and controlling its distribution.

This study aims to theoretically investigate the dynamics of ultrasound-induced interstitial fluid streaming and tissue recovery after ultrasound exposure for potentially accelerating nanoagent transport and controlling its distribution in tissue.Starting from fundamental equations, the dynamics of ultrasound-induced interstitial fluid streaming and tissue relaxation after an ultrasound exposure were modeled, derived and simulated. Also, both ultrasound-induced mechanical and thermal effects were considered in the models.

Sustained inhibition of NPY/AgRP neuronal activity by FGF1.

In rodent models of type 2 diabetes (T2D), central administration of FGF1 normalizes elevated blood glucose levels in a manner that is sustained for weeks or months. Increased activity of NPY/AgRP neurons in the hypothalamic arcuate nucleus (ARC) is implicated in the pathogenesis of hyperglycemia in these animals, and the ARC is a key brain area for the antidiabetic action of FGF1. We therefore sought to determine whether FGF1 inhibits NPY/AgRP neurons and, if so, whether this inhibitory effect is sufficiently durable to offer a feasible explanation for sustained diabetes remission induced by central administration of FGF1.

Risk Factors for Antibiotic Resistant Urinary Pathogens in Patients Discharged From the Emergency Department.

Urinary tract infections (UTIs) are one of the most common indications for antimicrobial use in the emergency department (ED). Appropriate empiric selection is crucial to ensure optimal care while limiting broad-spectrum antibiotic use. The primary objective of this study was to evaluate the relationship between patient-specific risk factors and drug resistant urinary pathogens in patients discharged from the ED and followed by Emergency Medicine Pharmacists (EMPs).

A Randomized Controlled Trial of Mobile Health Intervention in Patients With Heart Failure and Diabetes.

Background: Mobile health (mHealth) platforms can affect health behaviors but have not been rigorously tested in randomized trials.

Objectives: We sought to evaluate the effectiveness of a pragmatic mHealth intervention in patients with heart failure (HF) and diabetes (DM).

Methods: We conducted a multicenter randomized trial in 187 patients with both HF and DM to assess an mHealth intervention to improve physical activity and medication adherence compared to usual care.

Development of entrustable professional activities for regional anesthesia and pain medicine fellowship training.

Introduction: The Accreditation Council for Graduate Medical Education (ACGME) offers descriptions of competencies and milestones but does not provide standardized assessments to track trainee competency. Entrustable professional activities (EPAs) and special assessments (SAs) are emerging methods to assess the level of competency obtained by regional anesthesiology and acute pain medicine (RAAPM) fellows.

Methods: A panel of RAAPM physicians with experience in education and competency assessment and one medical student were recruited to participate in a modified Delphi method with iterative rounds to reach consensus on: a list of EPAs, SAs, and procedural skills; detailed definitions for each EPA and SA; a mapping of the EPAs and SAs to the ACGME milestones; and a target level of entrustment for graduating US RAAPM fellows for each EPA and procedural skill.

Patient journey in erosive oesophagitis: real-world perspectives from US physicians and patients.

Objective: Management of erosive oesophagitis (EE) remains suboptimal, with many patients experiencing incomplete healing, ongoing symptoms, and relapse despite proton pump inhibitor (PPI) treatment. The Study of Acid-Related Disorders investigated patient burden of individuals with EE in a real-world setting.

Design: US gastroenterologists (GIs) or family physicians (FPs)/general practitioners (GPs) treating patients with EE completed a physician survey and enrolled up to four patients with EE for a patient survey, with prespecified data extracted from medical records.

Inhibition of NLRP3-mediated crosstalk between hepatocytes and liver macrophages by geniposidic acid alleviates cholestatic liver inflammatory injury.

The excessive accumulation of bile acids (BA) in hepatocytes can trigger inflammatory response and recruit macrophages, thereby accelerating cholestatic liver injury. The crosstalk between hepatocytes and macrophages has been recently implicated in the pathogenesis of cholestasis; however, the underlying mechanisms remain unclear. Here, we demonstrated that BA initiate NLRP3 inflammasome activation in hepatocytes to release proinflammatory cytokines and promote the communication between hepatocytes and macrophages, thus enhancing liver inflammation in an NLRP3-dependent manner.