Medication use and risk of reflux oesophagitis.

Objective: Reflux oesophagitis (RO) is one of the most common diseases encountered by gastroenterologists and primary care physicians. However, few epidemiological studies have investigated the association of medication use and RO. This study aimed to investigate the prevalence of RO and its risk factors, particularly with respect to medication use.

Clonal hematopoiesis-related mutant ASXL1 promotes atherosclerosis in mice via dysregulated innate immunity.

Certain somatic mutations provide a fitness advantage to hematopoietic stem cells and lead to clonal expansion of mutant blood cells, known as clonal hematopoiesis (CH). Among the most common CH mutations, ASXL1 mutations pose the highest risk for cardiovascular diseases (CVDs), yet the mechanisms by which they contribute to CVDs are unclear. Here we show that hematopoietic cells harboring C-terminally truncated ASXL1 mutant (ASXL1-MT) accelerate the development of atherosclerosis in Ldlr mice.

The future of inbound medical care as gauged from the foreigners undergoing complete medical examinations in Japan.

Complete medical examinations are a system of preventive medicine unique to Japan. In recent years, Japanese and foreigners have been aware of complete medical examinations. However, the extent to which this concept of comprehensive medical checkup is recognized in different counties is unknown.

Family Vulnerability Scale: validity evidence in primary health care.

Objective: Investigate evidence of validity of the Family Vulnerability Scale (EVFAM-BR) as an instrument to support population-based management in primary health care (PHC), in the scope of Health Care Planning (PAS).

Methods: This is a psychometric study to assess any additional evidence of the internal structure of EVFAM-BR using confirmatory factor analysis (CFA) and network analysis (NA). A preliminary version of the scale with 38 items was submitted to patients of PHC facilities that use the PAS methodology, distributed across the five regions of Brazil.

Specialized outpatient care for maternal and child health in PlanificaSUS areas.

Objective: To describe the organization of specialized outpatient clinics, according to the Secondary Outpatient Care Unit (SOCU) model according to the health care planning (HCP) methodology.

Methods: This is a descriptive and cross-sectional study, which used secondary data from the PlanificaSUS project. It was carried out in 16 outpatient clinics specialized in maternal and child care, distributed in the five Brazilian geographic regions.

Tuning the Reactivity of Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Activators for Optimal Efficacy.

Dimethyl fumarate is approved for the treatment of multiple sclerosis but is also associated with off-target activation of the niacin receptor. By using a tetrazolone or triazolone bioisostere approach to the fumarate and vinyl sulfone series of Nrf2 activators, we have optimized the electrophilicity of the double bond to tune the on-target Nrf2 activation with PK properties to achieve efficacy in animal models of multiple sclerosis. The study linked highly potent, highly electrophilic molecules to low plasma stability and, subsequently, limited efficacy.

Randomized Trial on the Effect of an Oral Spleen Tyrosine Kinase Inhibitor in the Treatment of IgA Nephropathy.

Introduction: We reported increased spleen tyrosine kinase (SYK) expression in kidney biopsies of patients with IgA nephropathy (IgAN) and that inhibition of SYK reduces inflammatory cytokines production from IgA stimulated mesangial cells.

Methods: This study was a double-blind, randomized, placebo-controlled phase 2 trial of fostamatinib (an oral SYK inhibitor) in 76 patients with IgAN. Patients were randomized to receive placebo, fostamatinib at 100 mg or 150 mg twice daily for 24 weeks on top of maximum tolerated dose of renin-angiotensin system inhibitors.

Family vulnerability scale: Evidence of content and internal structure validity.

Introduction: Territory view based on families' vulnerability strata allows identifying different health needs that can guide healthcare at primary care scope. Despite the availability of tools designed to measure family vulnerability, there is still a need for substantial validity evidence, which limits the use of these tools in a country showing multiple socioeconomic and cultural realities, such as Brazil. The primary objective of this study is to develop and gather evidence on the validity of the Family Vulnerability Scale for Brazil, commonly referred to as EVFAM-BR (in Portuguese).

Coronavirus disease 2019-associated thrombotic microangiopathy treated with plasma exchange and antihypertensive therapy in a patient with HIV: A case report with literature review.

Rationale: Coronavirus disease 2019 (COVID-19) is an infectious disease that often causes complications in multiple organs and thrombosis due to abnormal blood coagulation. This case report aimed to describe the clinical course of COVID-19-associated thrombotic microangiopathy (TMA) and reviewed the comprehensive information on TMA, thrombotic thrombocytopenic purpura (TTP), and atypical hemolytic uremic syndrome associated with COVID-19 in the past literature.

Patient Concerns: A 46-year-old Japanese man was diagnosed with human immunodeficiency virus infection 10 years ago and treated with antiretroviral therapy.

Caffeine-Supplemented Diet Prevents Fatigue-Like Behavior in Tumor-Bearing Mice.

Caffeine is a widely consumed stimulant, known for its positive effects on physical and mental performance. These effects are potentially beneficial for ameliorating cancer-related fatigue, which affects the quality of life of patients with cancer. This study aimed to determine the anti-fatigue and antitumor effects of caffeine in tumor-bearing mice.

Spatial, spatio-temporal, and origin-destination flow analyses of patients with severe acute respiratory syndrome hospitalized for COVID-19 in Southeastern Brazil, 2020-2021.

Brazil experienced one of the fastest increasing numbers of coronavirus disease (COVID-19) cases worldwide. The Sao Paulo State (SPS) reported a high incidence, particularly in Sao Paulo municipality. This study aimed to identify clusters of incidence and mortality of hospitalized patients with severe acute respiratory syndrome for COVID-19 in the SPS, in 2020-2021, and describe the origin flow pattern of the cases.

Regulation of bone homeostasis by MERTK and TYRO3.

The fine equilibrium of bone homeostasis is maintained by bone-forming osteoblasts and bone-resorbing osteoclasts. Here, we show that TAM receptors MERTK and TYRO3 exert reciprocal effects in osteoblast biology: Osteoblast-targeted deletion of MERTK promotes increased bone mass in healthy mice and mice with cancer-induced bone loss, whereas knockout of TYRO3 in osteoblasts shows the opposite phenotype. Functionally, the interaction of MERTK with its ligand PROS1 negatively regulates osteoblast differentiation via inducing the VAV2-RHOA-ROCK axis leading to increased cell contractility and motility while TYRO3 antagonizes this effect.

Syk Activation in Circulating and Tissue Innate Immune Cells in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

Objective: Syk is a cytoplasmic protein tyrosine kinase that plays a role in signaling via B cell and Fc receptors (FcR). FcR engagement and signaling via Syk is thought to be important in antineutrophil cytoplasm antibody (ANCA) IgG-mediated neutrophil activation. This study was undertaken to investigate the role of Syk in ANCA-induced myeloid cell activation and vasculitis pathogenesis.

Optimization of Pyrimidine Compounds as Potent JAK1 Inhibitors and the Discovery of R507 as a Clinical Candidate.

Janus kinases (JAK) play a critical role in JAK/signal transducer and activator of transcription (STAT) signaling pathways that mediate immune response and cell growth. From high-throughput screening (HTS) hit to lead optimization, a series of pyrimidine compounds has been discovered as potent JAK1 inhibitors with selectivity over JAK2. Cell-based assays were used as primary screening methods for evaluating potency and selectivity, the results were further assessed and confirmed by biochemical and additional cellular assays for lead molecules.

Utility of fluorescence imitating brightfield imaging microscopy for the diagnosis of feline chronic enteropathy.

Fluorescence imitating brightfield imaging (FIBI) is a novel microscopy method that allows for real-time, nondestructive, slide-free tissue imaging of fresh, formalin-fixed, or paraffin-embedded tissue. The nondestructive nature of the technology permits tissue preservation for downstream analyses. The objective of this observational study was to assess the utility of FIBI compared with conventional hematoxylin and eosin (H&E)-stained histology slides in feline gastrointestinal histopathology.

Coinfection with canine distemper virus and canine circovirus in a dog in Brazil.

Canine distemper virus (CDV) and canine circovirus (CanineCV) have been described worldwide in multi-systemic disease in dogs. Both agents may be occasionally associated with other viral pathogens, but reports of coinfection by CDV and CanineCV associated with disease are rare. In this article, we report a coinfection between CDV and CanineCV detected during an investigation of viral agents involved in multisystemic disease in dogs in Southern Brazil.

Bicyclic pyrimidine compounds as potent IRAK4 inhibitors.

Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role in transduction of IL-1R/TLR signaling which is responsible for innate immune response. From HTS campaign, bicyclic-pyrimidine compounds have been identified as potent IRAK4 inhibitors, exhibiting good potency in both IRAK4 biochemical and LPS induced IL-23 inhibition cell-based assays. The SAR efforts were focused on further improving on-target potency, reducing PAD activities of HTS hit molecule and improving in vivo PK profiles of early lead compounds.

Diagnosis of vaccination rooms in Brazilian primary health care centers taking part in the PlanificaSUS project, 2019.

Objective: To describe the diagnosis of vaccination rooms in primary healthcare centers in Brazil.

Methods: This was a cross-sectional study with secondary data of convenience sampling comprised of 25 rooms. Results of a checklist adapted from the Vaccine Room Supervision Tool of the National Immunization Program in 2019 regarding the dimensions 'general organization', 'general aspects', 'technical procedures', 'cold chain', 'information system', 'adverse events following vaccination', 'special immunobiological agents', 'epidemiological surveillance' and 'health education', were used.

Discovery of 5-Aryl-2,4-diaminopyrimidine Compounds as Potent and Selective IRAK4 Inhibitors.

IRAK4 kinase plays a key role in TLR/IL-1R signaling pathways that regulate innate immune responses, and if uncontrolled, it is responsible for various inflammatory disorders. By high-throughput screening (HTS) and hit-to-lead optimization, compounds with a 5-aryl-2,4-diaminopyrimidine core structure have been identified as potent IRAK4 inhibitors. A cocrystal structure of IRAK4 protein with an early lead molecule helped with understanding the structure-activity relationship and the design of the new compounds.

Inhibition of spleen tyrosine kinase decreases donor specific antibody levels in a rat model of sensitization.

Antibody mediated rejection is a major cause of renal allograft loss. Circulating preformed donor specific antibodies (DSA) can result as a consequence of blood transfusion, pregnancy or prior transplantation. Current treatment strategies are limited due to partial or transient efficacy, adverse side-effects or patient unsuitability.

Eliminating chronic myeloid leukemia stem cells by IRAK1/4 inhibitors.

Leukemia stem cells (LSCs) in chronic myeloid leukemia (CML) are quiescent, insensitive to BCR-ABL1 tyrosine kinase inhibitors (TKIs) and responsible for CML relapse. Therefore, eradicating quiescent CML LSCs is a major goal in CML therapy. Here, using a G marker (GM), we narrow down CML LSCs as GM- and CD27- double positive cells among the conventional CML LSCs.

COVID-19 in the state of São Paulo: the evolution of a pandemic.

Objectives: To retrospectively describe severe cases of hospitalized patients and deaths related to the COVID-19 epidemic in the state of São Paulo, starting from the date of the first record, with symptoms onset on 02/10/2020 up to 05/20/2021.

Methods: This is a descriptive study carried out using the Influenza Epidemiological Surveillance System (Sistema de Vigilância Epidemiológica da Gripe - SIVEP-Gripe) database. The rates of incidence, mortality, and accumulated incidence in the period were calculated, stratified by age group and Regional Health Department (RHD).

SARS-CoV-2 reinfection: report of two cases in Southeast Brazil.

From February 26, 2020 to March 11, 2021, coronavirus disease 2019 (COVID-19) pandemic resulted in 11,439,558 cases and 277,102 deaths in Brazil. Among them, 2,195,130 cases and 63,965 deaths occurred in Sao Paulo State, Southeast Brazil. The recent emergence and rise of new variants of SARS-CoV-2 is of concern because of their higher transmissibility and possible association with more severe disease.