Rilzabrutinib, an Oral BTK Inhibitor, in Immune Thrombocytopenia.

BACKGROUND: Rilzabrutinib, an oral, reversible covalent inhibitor of Bruton's tyrosine kinase, may increase platelet counts in patients with immune thrombocytopenia by means of dual mechanisms of action: decreased macrophage (Fcγ receptor)-mediated platelet destruction and reduced production of pathogenic autoantibodies. METHODS: In an international, adaptive, open-label, dose-finding, phase 1-2 clinical trial, we evaluated rilzabrutinib therapy in previously treated patients with immune thrombocytopenia. We used intrapatient dose escalation of oral rilzabrutinib over a period of 24 weeks; the lowest starting dose was 200 mg once daily, with higher starting doses of 400 mg once daily, 300 mg twice daily, and 400 mg twice daily. The primary end points were safety and platelet response (defined as at least two consecutive platelet counts of ≥50×103 per cubic millimeter and an increase from baseline of ≥20×103 per cubic millimeter without the use of rescue medication). RESULTS: Sixty patients were enrolled. At baseline, the median platelet count was 15×103 per cubic millimeter, the median duration of disease was 6.3 years, and patients had received a median of four different immune thrombocytopenia therapies previously. All the treatment-related adverse events were of grade 1 or 2 and transient. There were no treatment-related bleeding or thrombotic events of grade 2 or higher. At a median of 167.5 days (range, 4 to 293) of treatment, 24 of 60 patients (40%) overall and 18 of the 45 patients (40%) who had started rilzabrutinib treatment at the highest dose met the primary end point of platelet response. The median time to the first platelet count of at least 50×103 per cubic millimeter was 11.5 days. Among patients with a primary platelet response, the mean percentage of weeks with a platelet count of at least 50×103 per cubic millimeter was 65%. CONCLUSIONS: Rilzabrutinib was active and associated with only low-level toxic effects at all dose levels. The dose of 400 mg twice daily was identified as the dose for further testing. Overall, rilzabrutinib showed a rapid and durable clinical activity that improved with length of treatment. (Funded by Sanofi; ClinicalTrials.gov number, NCT03395210; EudraCT number, 2017-004012-19.).

Exosomal LINC00355 promotes the malignant progression of gastric cancer through histone deacetylase HDAC3-mediated TP53INP1 transcriptional inhibition.

AIMS: Exosomes are a subpopulation of extracellular vesicles (EV) derived from multivesicular body (MVB) that transmit various cellular molecular constituents, including long noncoding RNAs (lncRNAs), to promote intercellular communication. Our aim was to investigate the function and mechanism of exosomal LINC00355 in gastric cancer cells. MAIN METHODS: Exosomal levels of LINC00355 in GC patients and healthy controls were measured by RT-qPCR. The effects of exosomal LINC00355 on GC cell viability, proliferation, migration and invasion were evaluated by CCK8, colony formation, Transwell and wound healing assays. The expression levels of Ki67 in xenograft tumor tissues were confirmed by immunohistochemistry assay, and apoptosis was analyzed by TUNEL apoptosis assay. Western blotting was used to monitor protein expression. RNA immunoprecipitation and RNA pulldown were performed to detect the interaction between LINC00355 and HDAC3. Chromatin immunoprecipitation was used to assess the interaction of HDAC3 with the TP53INP1 promoter. KEY FINDINGS: Exosomal LINC00355 levels were higher in plasma from gastric cancer patients than in plasma from healthy volunteers. Exosomal LINC00355 promoted the proliferation, migration and invasion of gastric cancer cell lines. RNA sequence analysis demonstrated that LINC00355 knockdown downregulated histone deacetylase HDAC3 and upregulated TP53INP1. Mechanistic investigation indicated that exosomal LINC00355 interacted with HDAC3 to suppress TP53INP1 transcription, which promoted epithelial-mesenchymal transition (EMT). SIGNIFICANCE: Exosomal LINC00355 plays a pivotal role in regulating EMT to induce the malignant progression of GC. Exosomal LINC00355 could be a promising biomarker in the early diagnosis and prognosis of GC.

Electrolyte intake and nonpharmacologic blood pressure control.

PURPOSE: To characterize relationships between sodium and potassium intakes and blood pressure control. METHODS: We analyzed repeated 24-hour diet recalls and 24-hour urine assays from 873 elderly participants with established hypertension in a 3-year clinical trial of lifestyle interventions. Pooled estimates of electrolyte intakes were developed using hierarchical measurement error models and related to nonpharmacologic blood pressure control. RESULTS: Relative decreases in sodium and increases in potassium intakes each had graded relationships with better blood pressure control. After adjustment for measurement error, a 100 mmol/24-hour decrease in sodium intake was associated with an odds ratio of 2.93 [95% confidence interval: 1.83, 4.64] for maintaining nonpharmacologic blood pressure control throughout follow-up. A 50 mmol/24-hour increase in potassium intake was associated with an odds ratio of 2.00 [1.12, 3.55]. These relationships were independent of each other and of baseline levels of intakes. Blood pressure control was most strongly associated with sodium intake for participants with lower systolic blood pressures and longer duration of hypertension, and with potassium for those with elevated diastolic blood pressures. CONCLUSIONS: Sodium and potassium intakes exert independent graded influences on nonpharmacologic blood pressure control. Correlated measurement error may spuriously introduce a dependency among these relationships.

Measuring patients' trust in their primary care providers.

Existing scales to measure trust in physicians have differing content and limited testing. To improve on these measures, a detailed conceptual model was constructed and a large item pool (n = 78) was generated following a detailed conceptual model and expert review. After pilot testing, the best-performing items were validated with a random national sample (n = 959) and a regional sample of HMO members (n =1,199). Various psychometric tests produced a 10-item unidimensional scale consistent with most aspects of the conceptual model. Compared with previous scales, the Wake Forest physician trust scale has a somewhat improved combination of internal consistency, variability, and discriminability. The scale is more strongly correlated with satisfaction, desire to remain with a physician, willingness to recommend to friends, and not seeking second opinions; it is less correlated with insurer trust, membership in managed care, and choice of physician. Correlations are equivalent with lack of disputes, length of relationship, and number of visits [corrected].

Development of a scale to measure patients' trust in health insurers.

OBJECTIVE: To develop a scale to measure patients' trust in health insurers, including public and private insurers and both indemnity and managed care. A scale was developed based on our conceptual model of insurer trust. The scale was analyzed for its factor structure, internal consistency, construct validity, and other psychometric properties. DATA SOURCES/STUDY SETTING: The scale was developed and validated on a random national sample (n = 410) of subjects with any type of insurance and further validated and used in a regional random sample of members of an HMO in North Carolina (n = 1152). STUDY DESIGN: Factor analysis was used to uncover the underlying dimensions of the scale. Internal consistency was assessed by Cronbach's alpha. Construct validity was established by Pearson or Spearman correlations and t tests. DATA COLLECTION: Data were collected via telephone interviews. PRINCIPAL FINDINGS: The 11-item scale has good internal consistency (alpha = 0.92/ 0.89) and response variability (range = 11-55, M = 36.5/37.0, SD = 7.8/7.0). Insurer trust is a unidimensional construct and is related to trust in physicians, satisfaction with care and with insurer, having enough choice in selecting health insurer, no prior disputes with health insurer, type of insurer, and desire to remain with insurer. CONCLUSIONS: Trust in health insurers can be validly and reliably measured. Additional studies are required to learn more about what factors affect insurer trust and whether differences and changes in insurer trust affect actual behaviors and other outcomes of interest.

Baseline health-related quality of life in postmenopausal women with coronary heart disease: the Estrogen Replacement and Atherosclerosis (ERA) trial.

OBJECTIVES: This study examined the baseline health-related quality of life (HRQL) of 301 postmenopausal women with heart disease enrolled in the Estrogen Replacement and Atherosclerosis (ERA) trial. METHODS: The primary measure of HRQL was the Medical Outcomes Study Short Form-36 (MOS SF-36). The SF-36 was augmented with secondary assessments, including measures of depressive symptoms, life satisfaction, urinary incontinence, sleep disturbance, and physical symptoms. Multiple regression analyses were used to test hypotheses regarding the contribution of positive (social support) and negative (social strain) aspects of social relations after accounting for other correlates of HRQL and heart disease. RESULTS: Results indicate that social support was positively associated with better functioning for all measured outcomes (all p < 0.05) except symptom frequency and severity. Social strain was negatively associated with HRQL functioning (all p < 0.05) except overall physical functioning, sleep disturbance, and urinary incontinence. In addition, several comorbid conditions were negatively associated with HRQL outcomes. In particular, chest pain was significantly associated with worse functioning on all HRQL outcomes except urinary incontinence. CONCLUSIONS: These data suggest that both clinical status variables (particularly chest pain) and the psychosocial context (represented by dimensions of relationship quality) influenced HRQL in this cohort. Thus, interventions that combine medical treatments with psychosocially based interventions may be most effective for women at risk for impaired HRQL.

Asthma in older adults: observations from the epidemiology and natural history of asthma: outcomes and treatment regimens (TENOR) study.

BACKGROUND: The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) was a 3-year, multicenter, observational study of 4,756 patients 6 years or older with severe or difficult-to-treat asthma by physician evaluation. More than 280 pulmonologist and allergist sites across the United States participated. OBJECTIVE: To compare health care utilization (HCU), medication use, asthma control, and quality of life (QoL) in older (> or =65 years; n = 566) and younger (18-64 years; n = 2,912) adult patients in TENOR. METHODS: Patients had to be under a physician's care for at least 1 year and have high medication use or HCU in the past year. Heavy smokers (> or =30 pack-years) and patients with cystic fibrosis were excluded. RESULTS: Although older patients in TENOR had worse lung function as measured by decreased percent predicted forced expiratory volume in 1 second (FEV1) (P < .001), they had significantly lower HCU compared with younger patients. They also had higher use of inhaled corticosteroids and better QoL than younger patients. Older patients reported fewer problems controlling their asthma (P < .001) but reported worse communication with their physicians (P = .02). CONCLUSIONS: Older patients in TENOR appeared to do better than younger patients, despite having worse lung function. Older patients in TENOR may have received more aggressive care than older asthmatic patients in other studies, based on a higher use of inhaled and oral corticosteroids. Whether differences in treatment or disease influenced other physiologic or inflammatory outcomes that contribute to the disconnect between HCU and FEV1 awaits further study.

Total serum IgE levels in a large cohort of patients with severe or difficult-to-treat asthma.

BACKGROUND: Limited data are available on levels of IgE in large cohorts of patients with severe or difficult-to-treat asthma. OBJECTIVE: To examine IgE levels and disease in patients from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study. METHODS: From January 2001 to October 2001, 4,923 patients were screened for inclusion in the study. Of these, 4,756 patients 6 years or older with severe or difficult-to-treat asthma were enrolled and completed a baseline study visit. Total serum IgE levels were measured at the baseline visit and are summarized by geometric means. RESULTS: The mean total IgE level of the population is 106.6 IU/mL (95% confidence interval, 101.5-112.0 IU/mL). Children (6-12 years old) and adolescents (13-17 years old) have higher mean IgE levels than adults (> or =18 years old) (P < .001). Males have a higher mean IgE level than females (P < .001). IgE levels are higher among nonwhite patients than white patients (P < .001). Current smokers have higher IgE levels than past smokers or never smokers (P < .001). Among children, patients with severe asthma have a higher mean IgE level (280.2 IU/mL) than patients with moderate (145.8 IU/mL) or mild (137.8 IU/mL) asthma (P < .001). Among adults, patients with childhood-onset asthma have higher IgE levels (124.3 IU/mL [n = 1,348]) than patients with adult-onset asthma (65.7 IU/mL [n = 1,956]) (P < .001). CONCLUSION: In patients with severe or difficult-to-treat asthma from the TENOR study, higher total IgE levels were observed in males, children, smokers, nonwhite racial/ethnic groups, and adults with childhood-onset disease. In addition, IgE levels are associated with asthma severity among younger patients.

Correlates of sleep behavior among hemodialysis patients. The kidney outcomes prediction and evaluation (KOPE) study.

BACKGROUND: Given the importance of sleep to overall physical and mental well-being, we sought to identify the correlates of seven sleep disturbances in a cross-sectional study of a biracial population of male and female patients treated with hemodialysis. METHODS: Univariate and multivariate analyses of a cohort study of adult patients with end-stage renal disease. Demographic, psychosocial, clinical, and health and physical functioning variables were included. RESULTS: Waking up during the night (57%) and waking up too early (55%) were the most commonly reported sleep problems. Multivariate analyses consistently indicated that levels of pain, depressive symptoms, and physical functioning were consistently associated with the seven sleep disturbances. CONCLUSION: Sleep disturbances are common in patients with end-stage renal disease. Physical and mental well-being were consistently related to the seven sleep disturbances.

Design and baseline characteristics of the epidemiology and natural history of asthma: Outcomes and Treatment Regimens (TENOR) study: a large cohort of patients with severe or difficult-to-treat asthma.

BACKGROUND: Patients with severe and difficult-to-treat asthma represent a small percentage of asthma patients, yet they account for much of the morbidity, mortality, and cost of disease. The goal of The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study is to better understand the natural history of asthma in these patients. OBJECTIVE: To describe the methods and baseline characteristics of the TENOR study cohort. METHODS: The TENOR study is a 3-year, multicenter, observational study of patients with severe or difficult-to-treat asthma. From January through October 2001, more than 400 US pulmonologists and allergists enrolled patients. Patients 6 years or older who were considered to have severe or difficult-to-treat asthma by their physicians were eligible. Patients have been receiving care for 1 year or more, have a smoking history of 30 pack-years or less, and have current high medication or health care utilization in the past year. Data are collected semiannually. RESULTS: A total of 4,756 patients enrolled and completed a baseline visit. Overall, 73% of the TENOR study patients are adults, 10% are adolescents, and 16% are children. According to physician evaluation, 48% of patients have severe asthma, 48% have moderate asthma, 3% have mild asthma, and 96% have difficult-to-treat asthma. Severe asthmatic patients have the highest health care utilization in the past 3 months (P < .001). CONCLUSIONS: The TENOR study is the largest cohort of patients with severe or difficult-to-treat asthma. Although patients are equally divided into moderate or severe asthma categories, most are considered difficult-to-treat. The TENOR study highlights the lack of control in moderate-to-severe asthma and provides a unique opportunity to examine factors related to health outcomes in this understudied population.