Discovery of PF-07265028, A Selective Small Molecule Inhibitor of Hematopoietic Progenitor Kinase 1 (HPK1) for the Treatment of Cancer.

Hematopoietic progenitor kinase 1 (HPK1/MAP4K1) represents a high interest target for the treatment of cancer through an immune-mediated mechanism. Herein we present highlights of the drug discovery campaign within the lactam/azalactam series of inhibitors that yielded a small molecule (, PF-07265028), which was advanced to a phase 1 clinical trial (NCT05233436). Key components of the discovery effort included optimization of potency through mitigation of ligand strain as guided by the use of cocrystal structures, mitigation of ADME liabilities (plasma instability and fraction metabolism by CYP2D6), and optimization of kinase selectivity, particularly over immune-modulating kinases with high homology to HPK1.

Effects of physical activity on menopausal symptoms, psychosomatic factors and well-being among working women in England: A path analysis.

Background: Research to date suggests that physical activity (PA) can buffer menopausal symptoms and support well-being, but there is limited evidence on the link between PA and menopausal symptoms in the United Kingdom, and no study has assessed how PA affects well-being through menopausal symptoms and three psychosomatic factors (i.e. depression, anxiety and stress).

Professional Male Soccer Players' Perspectives of the Nutrition Culture Within an English Premier League Football Club: A Qualitative Exploration Using Bourdieu's Concepts of Habitus, Capital and Field.

Background And Aim: Professional soccer players' self-reported dietary intakes often do not meet recommended sport nutrition guidelines. Although behaviour change models have previously explored barriers and enablers to nutritional adherence, the cultural factors influencing players' nutritional habits also warrant investigation. Accordingly, we aimed to explore players' perceptions of the nutrition culture within the professional soccer environment.

Use of Patient-Reported Outcomes in Risk Prediction Model Development to Support Cancer Care Delivery: A Scoping Review.

Purpose: The integration of patient-reported outcomes (PROs) into electronic health records (EHRs) has enabled systematic collection of symptom data to manage post-treatment symptoms. The use and integration of PRO data into routine care are associated with overall treatment success, adherence, and satisfaction. Clinical trials have demonstrated the prognostic value of PROs including physical function and global health status in predicting survival.

Changes in hospital-supported substance use services across US nonprofit hospitals, 2015-2021.

Substance use remains a timely and important community need to understand and address. Nonprofit hospitals are in a unique position to identify needs and develop programs in response to substance use challenges in their communities. To better understand how nonprofit hospitals do this, we collected data from community health needs assessments and their corresponding implementation strategy (IS) to address these needs for a 20% random sample of hospitals in each state of the United States over 2 periods (2015-2018 and 2019-2021).

Revealing the Novel Role of Purinergic Receptor P2X4 in Phagocytic Uptake After Ischemic Stroke.

Background: Purinergic receptor P2X4 (P2X4R), highly expressed on microglia and macrophages, is activated by ATP released from damaged cells and linked to poststroke inflammation. Previous studies showed that short-term P2X4R inhibition reduces inflammation and promotes long term recovery, but the mechanism underlying P2X4R and inflammation remains unclear. We hypothesized that P2X4R absence or pharmacological blockade can enhance macrophage phagocytic function by alleviating excessive inflammation after stroke.

Interactions of depression, anxiety, and sleep quality with menopausal symptoms on job satisfaction among middle-aged health workers in England: a STROBE-based analysis.

Background: This study examined the association between menopausal symptoms and job satisfaction, and ascertained whether three psychosomatic factors (e.g., anxiety, depression, and sleep quality) interact with menopausal symptoms on job satisfaction.

A Patient and Public Engagement Project to Inform Dementia Care in a UK Hospital Trust.

Introduction: The increasing prevalence of dementia in the United Kingdom presents significant challenges for healthcare, with projections estimating over a million affected individuals by 2025, costing the NHS £6.3 billion annually. Hospital admissions among dementia patients are common, occupying about 25% of UK hospital beds and leading to prolonged stays and diminished health outcomes.

Preoperative imaging of colorectal liver metastases: what the radiologist and the multidisciplinary team need to know.

The management of patients with colorectal liver metastases (CRLM) has transformed over the past 2 decades. Advances in surgical techniques, systemic therapies, and local treatments have resulted in a paradigm shift. Disease that would once have been considered terminal is now frequently treated aggressively with both a disease-free and overall survival benefit.

2-Substituted (N)-Methanocarba A Adenosine Receptor Agonists: In Silico, In Vitro, and In Vivo Characterization.

2-Arylethynyl (N)-methanocarba adenosine 5'-methylamides are selective A adenosine receptor (AR) agonists containing a preestablished receptor-preferred pseudoribose conformation. Here, we compare analogues having bulky 2-substitution, either containing or lacking an ethynyl spacer between adenine and a cyclic group. 2-Aryl compounds -, , , , , , , , , and , lacking a spacer, had human (h) AAR values of 2-30 nM, and others displayed lower affinity.

A retrospective comparison of IgE-mediated cow's milk protein allergy management strategies in pediatric cohorts.

Background: Complete avoidance of milk is the usual management for IgE-mediated cow's milk protein allergy (CMPA). A baked milk ladder is a method of dietary advancement therapy in IgE-mediated CMPA in Ireland, while in Spain, avoidance of milk awaiting natural tolerance acquisition through an oral food challenge (OFC) is employed. The aim of this study was to evaluate the use of dietary advancement therapy using a milk ladder compared with complete avoidance of milk for managing IgE-mediated CMPA.

Exploring the application and significance of case study research in nursing.

Background: Case study research (CSR) has gained popularity across disciplines due to its ability to provide detailed insights into specific phenomena.

Aim: To explore the philosophy and methodology of CSR, drawing from notable authors who have contributed to its development.

Discussion: This article discusses the characteristics of CSR in terms of design and method in both quantitative and qualitative approaches.

Barriers and Facilitators to Establishing Partnerships for Substance Use Disorder Care Transitions Between Safety-Net Hospitals and Community-Based Organizations.

Background: The effectiveness of hospital-based transitional opioid programs (TOPs), which aim to connect patients with substance use disorders (SUD) to ongoing treatment in the community following initiation of medication for opioid use disorder (MOUD) treatment in the hospital, hinges on successful patient transitions. These transitions are enabled by strong partnerships between hospitals and community-based organizations (CBOs). However, no prior study has specifically examined barriers and facilitators to establishing SUD care transition partnerships between hospitals and CBOs.

Ohio Presents Opportunities For Understanding Hospital Alignment With Public Health Agencies On Community Health Assessments.

Multisector collaboration is critical for improving population health. Improving alignment between nonprofit hospitals and local health departments is one promising approach to achieving health improvement, and a number of states are exploring policies to facilitate such collaboration. Using public documents, we evaluated the alignment between Ohio nonprofit hospitals and local health departments in the community health needs they identify and those they prioritize.

New insights about community benefit evaluation: Using the Community Health Implementation Evaluation Framework to assess what hospitals are measuring.

Background: Nonprofit hospitals are required to conduct community health needs assessments (CHNA) every 3 years and develop corresponding implementation plans. Implemented strategies must address the identified community needs and be evaluated for impact.

Purpose: Using the Community Health Implementation Evaluation Framework (CHIEF), we assessed whether and how nonprofit hospitals are evaluating the impact of their CHNA-informed community benefit initiatives.

A national overview of nonprofit hospital community benefit programs to address the social determinants of health.

Decades of research have solidified the crucial role that social determinants of health (SDOH) play in shaping health outcomes, yet strategies to address these upstream factors remain elusive. The aim of this study was to understand the extent to which US nonprofit hospitals invest in SDOH at either the community or individual patient level and to provide examples of programs in each area. We analyzed data from a national dataset of 613 hospital community health needs assessments and corresponding implementation strategies.

Public perceptions of US for-profit, nonprofit, and public hospitals.

Nonprofit hospitals have been criticized for behaving like for-profit hospitals. One prominent defense of nonprofit hospitals is contract failure theory, which suggests that nonprofits are important in markets defined by information asymmetries. Unlike for-profits, nonprofit hospitals' inability to distribute profits may provide patients with an important assurance that they will not be exploited in the course of receiving care.

What is the optimum post treatment surveillance imaging protocol for low-grade appendiceal mucinous neoplasms and pseudomyxoma peritoneii?

Appendiceal mucinous neoplasms are rare and can be associated with the development of disseminated peritoneal disease known as pseudomyxoma peritonei (PMP). Mucinous tumours identified on appendicectomy are therefore followed up to assess for recurrence and the development of PMP. In addition, individuals who initially present with PMP and are treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) are followed up to assess for recurrence.

Dietary Advancement Therapy Using Milk and Egg Ladders Among Children With a History of Anaphylaxis.

Background: Anaphylaxis has been increasing in recent years, with common triggers in infants being milk and eggs. Currently, the mainstay of treatment for milk and/or egg allergy is strict avoidance. Recently, new therapies have emerged including stepwise introduction of allergens via a ladder approach.

National Overview of Nonprofit Hospitals' Community Benefit Programs to Address Housing.

Background: Housing is a critical social determinant of health that can be addressed through hospital-supported community benefit programming.

Objectives: To explore the prevalence of hospital-based programs that address housing-related needs, categorize the specific actions taken to address housing, and determine organizational and community-level factors associated with investing in housing.

Research Design: This retrospective, cross-sectional study examined a nationally representative dataset of administrative documents from nonprofit hospitals that addressed social determinants of health in their federally mandated community benefit implementation plans.