Specific cultural traits of the precarity of older Latinos living alone with cognitive impairment in the San Francisco Bay Area.

Objectives: Latinos are about twice as likely to develop cognitive impairment. Culturally, filial support and familismo are expected within Latino families. Yet approximately twenty percent of Latinos live alone in the United States.

Witnessing inter-parental violence in childhood and help-seeking behaviours in violence against women in Peru.

Background: Violence against women (VAW) severely impacts their physical and mental health. In some cultures, women can normalize certain types of violence if they were linked to home models in childhood and, eventually, do not seek for help in adulthood. We aimed to determine, in Peruvian women, (1) the association between witnessing violence in their family of origin and VAW experienced in adulthood, (2) the extent to which women who have experienced VAW seek some help, and (3) identify VAW prevalence by Peruvian region.

Incorporating an intersectional gender approach to improve access to maternal and child health screening services.

Background: In the Americas, the Pan American Health Organization (PAHO) has promoted initiatives that aim at the elimination of mother-to-child transmitted diseases for over two decades. Although Guatemala has assumed the commitment to improve access and coverage of reproductive and perinatal services, the goals have not yet been reached. Often, the implementation of these efforts is hampered by complexities rooted in social, cultural, and environmental intersections.

Adoption of community-based strategies for sustainable vector control and prevention.

Community engagement strategies provide tools for sustainable vector-borne disease control. A previous cluster randomized control trial engaged nine intervention communities in seven participatory activities to promote management of the domestic and peri-domestic environment to reduce risk factors for vector-borne Chagas disease. This study aims to assess the adoption of this innovative community-based strategy, which included chickens' management, indoor cleaning practices, and domestic rodent infestation control, using concepts from the Diffusion of Innovations Theory.

Perceptions of the Role of Living Alone in Providing Services to Patients With Cognitive Impairment.

Importance: The potential role of living alone in either facilitating or hampering access to and use of services for older adults with cognitive impairment is largely unknown. Specifically, it is critical to understand directly from health care and social services professionals how living alone creates barriers to the access and use of supportive health care and social services for racially and ethnically diverse patients with cognitive impairment.

Objective: To identify the potential role of living alone in the access and use of health care and social services for diverse patients with cognitive impairment by investigating professionals' perceptions of caring for such patients who live alone in comparison with counterparts living with others.

The Effects of the COVID-19 Pandemic on the Lived Experience of Diverse Older Adults Living Alone With Cognitive Impairment.

Background And Objectives: Even before the COVID-19 pandemic, older adults with cognitive impairment living alone (an estimated 4.3 million individuals in the United States) were at high risk for negative health outcomes. There is an urgent need to learn how this population is managing during the pandemic.

Understanding Pharmacokinetic Disconnect in Preclinical Species for 4-Aminoquinolines: Consequences of Low Permeability and High P-glycoprotein Efflux Ratio on Rat and Dog Oral Pharmacokinetics.

Receptor Interacting Protein 2 (RIP2) kinase inhibitors have been reported for therapeutic opportunities in inflammatory bowel diseases such as Ulcerative Colitis and Crohn's disease. During lead optimization, team identified 4-aminoquinoline series and several compounds from this series were investigated in rat and dog pharmacokinetic studies. While compounds such as GSKA and GSKB demonstrated acceptable pharmacokinetics in rat and dog, further progression of these compounds was halted due to adverse findings in advanced safety studies.

Correction to Identification of Quinoline-Based RIP2 Kinase Inhibitors with an Improved Therapeutic Index to the hERG Ion Channel.

[This corrects the article DOI: 10.1021/acsmedchemlett.8b00344.

Discovery of a First-in-Class Receptor Interacting Protein 2 (RIP2) Kinase Specific Clinical Candidate, 2-((4-(Benzo[]thiazol-5-ylamino)-6-(-butylsulfonyl)quinazolin-7-yl)oxy)ethyl Dihydrogen Phosphate, for the Treatment of Inflammatory Diseases.

RIP2 kinase has been identified as a key signal transduction partner in the NOD2 pathway contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP2 kinase or its signaling partners on the NOD2 pathway that are suitable for advancement into the clinic have yet to be described. Herein, we report our discovery and profile of the prodrug clinical compound, inhibitor , currently in phase 1 clinical studies.

Identification of a RIP1 Kinase Inhibitor Clinical Candidate (GSK3145095) for the Treatment of Pancreatic Cancer.

RIP1 regulates cell death and inflammation and is believed to play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases and cancer. While small-molecule inhibitors of RIP1 kinase have been advanced to the clinic for inflammatory diseases and CNS indications, RIP1 inhibitors for oncology indications have yet to be described. Herein we report on the discovery and profile of GSK3145095 (compound ).

Haploidentical transplantation outcomes are comparable with those obtained with identical human leukocyte antigen allogeneic transplantation in Chilean patients with benign and malignant hemopathies.

Introduction: Patients with benign or malignant blood disorders, who require allogeneic stem cell transplantation and lack an identical human leukocyte antigen HLA identicalHL sibling donor, could be transplanted with hematopoietic stem cells from unrelated adult or umbilical cord donors. However, in our country, both approaches are costly and time-consuming options.

Methods: Over the last few years, haploidentical modalities have been investigated as an alternative donor source, showing similar results to those obtained with identical HLA donors.

Discovery and Lead-Optimization of 4,5-Dihydropyrazoles as Mono-Kinase Selective, Orally Bioavailable and Efficacious Inhibitors of Receptor Interacting Protein 1 (RIP1) Kinase.

RIP1 kinase regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including inflammatory and neurological diseases. Currently, RIP1 kinase inhibitors have advanced into early clinical trials for evaluation in inflammatory diseases such as psoriasis, rheumatoid arthritis, and ulcerative colitis and neurological diseases such as amyotrophic lateral sclerosis and Alzheimer's disease. In this paper, we report on the design of potent and highly selective dihydropyrazole (DHP) RIP1 kinase inhibitors starting from a high-throughput screen and the lead-optimization of this series from a lead with minimal rat oral exposure to the identification of dihydropyrazole 77 with good pharmacokinetic profiles in multiple species.

Identification of Quinoline-Based RIP2 Kinase Inhibitors with an Improved Therapeutic Index to the hERG Ion Channel.

RIP2 kinase was recently identified as a therapeutic target for a variety of autoimmune diseases. We have reported previously a selective 4-aminoquinoline-based RIP2 inhibitor and demonstrated its effectiveness in blocking downstream NOD2 signaling in cellular models, rodent in vivo models, and human ex vivo disease models. While this tool compound was valuable in validating the biological pathway, it suffered from activity at the hERG ion channel and a poor PK/PD profile thereby limiting progression of this analog.

Identification of an antibody-based immunoassay for measuring direct target binding of RIPK1 inhibitors in cells and tissues.

Therapies that suppress RIPK1 kinase activity are emerging as promising therapeutic agents for the treatment of multiple inflammatory disorders. The ability to directly measure drug binding of a RIPK1 inhibitor to its target is critical for providing insight into pharmacokinetics, pharmacodynamics, safety and clinical efficacy, especially for a first-in-class small-molecule inhibitor where the mechanism has yet to be explored. Here, we report a novel method for measuring drug binding to RIPK1 protein in cells and tissues.

Discovery of a First-in-Class Receptor Interacting Protein 1 (RIP1) Kinase Specific Clinical Candidate (GSK2982772) for the Treatment of Inflammatory Diseases.

RIP1 regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP1 kinase that are suitable for advancement into the clinic have yet to be described. Herein, we report our lead optimization of a benzoxazepinone hit from a DNA-encoded library and the discovery and profile of clinical candidate GSK2982772 (compound 5), currently in phase 2a clinical studies for psoriasis, rheumatoid arthritis, and ulcerative colitis.

The Identification and Pharmacological Characterization of 6-(tert-Butylsulfonyl)-N-(5-fluoro-1H-indazol-3-yl)quinolin-4-amine (GSK583), a Highly Potent and Selective Inhibitor of RIP2 Kinase.

RIP2 kinase is a central component of the innate immune system and enables downstream signaling following activation of the pattern recognition receptors NOD1 and NOD2, leading to the production of inflammatory cytokines. Recently, several inhibitors of RIP2 kinase have been disclosed that have contributed to the fundamental understanding of the role of RIP2 in this pathway. However, because they lack either broad kinase selectivity or strong affinity for RIP2, these tools have only limited utility to assess the role of RIP2 in complex environments.

Molecular profiling of experimental endometriosis identified gene expression patterns in common with human disease.

Objective: To validate a rat model of endometriosis using complimentary DNA (cDNA) microarrays by identifying common gene expression patterns between experimental and natural disease.

Design: Autotransplantation rat model.

Setting: Medical school department.

Molecular profiling of a rat model of colitis: validation of known inflammatory genes and identification of novel disease-associated targets.

Background: Inflammatory bowel disease (IBD) is a disease of unknown etiology characterized by acute and chronic relapsing inflammation. The most suitable animal model for studying this disease is still under debate. Microarray transcript profiling has the potential to illuminate the molecular processes that are involved in both the human condition and animal models.

Identification of molecular markers for endometriosis in blood lymphocytes by using deoxyribonucleic acid microarrays.

Objective: To identify molecular biomarkers for endometriosis in peripheral blood lymphocytes by using DNA microarrays.

Design: Case-control.

Setting: Multicenter academic research programs.

Cloning and molecular characterization of a cDNA from Blomia tropicalis homologous to dust mite group 3 allergens (trypsin-like proteases).

Background: Exposure to the house dust mite Blomia tropicalis is increasingly being implicated as a major risk factor for asthma exacerbations in sensitized individuals. The objective of this study is to clone and characterize B. Tropicalis allergens in order to better define their role in allergic asthma.

Meeting the Critical Shortage of Speech-Language Pathologists to Serve the Public Schools-Collaborative Rewards.

This article presents a collaborative approach to providing graduate education to speech-language pathologists who are employed in public school districts. A partnership called the Central Florida Speech-Language Consortium was established among the University of Central Florida, 10 Central Florida school districts, and community agencies to address the issue of the critical shortage of speech-language pathologists in the public schools. The consortium program provided bachelor-level speech-language pathologists in the public schools the opportunity to obtain a master's degree while they continued to work in the schools.