Defecatory dysfunction and other clinical variables are predictors of pessary discontinuation.

INTRODUCTION AND HYPOTHESIS: Pessaries provide first-line therapy for women with pelvic organ prolapse (POP) and stress urinary incontinence (SUI). The primary hypothesis was that defecatory dysfunction was associated with pessary discontinuation. METHODS: This was a retrospective cohort study of all women undergoing first pessary placement at one academic center from April 2014 to January 2017. Defecatory dysfunction was defined as the presence of constipation, rectal straining, rectal splinting, and/or incomplete defecation. Pessary discontinuation was defined as <1 year of pessary use and not using one at the most recent visit. Descriptive statistics; Person's chi-square, Fisher's exact, and Student's t test, and multivariate logistic regression analysis were used where appropriate. RESULTS: Charts of 1092 women were reviewed and 1071 were included. Mean age was 62 ± 15 years, mean body mass index (BMI) 28 ± 6 kg/m2, and mean parity 2 ± 1; 68% were Caucasian, 73% were menopausal, and 41% were sexually active. Reason for pessary use included POP (46%), SUI (24%), or both (30%). Overall pessary discontinuation rate was 77%; overall rate of defecatory dysfunction was 45%. In a logistic regression model, defecatory dysfunction in the form of incomplete defecation remained significantly associated with pessary discontinuation [odds ratio (OR) 3.29, 95% confidence interval (CI) 1.43-7.52]. Absence of bulge symptoms (OR 2.18, 95% CI 1.22-3.90), and younger age (OR 1.02, 95% CI 1.02-1.05) also remained significantly associated with pessary discontinuation. CONCLUSIONS: Pessary discontinuation was common, and defecatory dysfunction in the form of incomplete defecation had the strongest association with discontinuation. Understanding predictive factors of pessary discontinuation may help guide clinicians and patients when choosing treatment options for pelvic floor dysfunction.

In-Hospital and Postdischarge Mortality Among Patients With Acute Decompensated Heart Failure Hospitalizations Ending on the Weekend Versus Weekday: The ARIC Study Community Surveillance.

Background Hospital staffing is usually reduced on weekends, potentially impacting inpatient care and postdischarge coordination of care for patients with acute decompensated heart failure (ADHF). However, investigations of in-hospital mortality on the weekend versus weekday, and post-hospital outcomes of weekend versus weekday discharge are scarce. Methods and Results Hospitalizations for ADHF were sampled by stratified design from 4 US areas by the Community Surveillance component of the ARIC (Atherosclerosis Risk in Communities) study. ADHF was classified by a standardized computer algorithm and physician review of the medical records. Discharges or deaths on Saturday, Sunday, or national holidays were considered to occur on the "weekend." In-hospital mortality was compared between hospitalizations ending on a weekend versus weekday. Post-hospital (28-day) mortality was compared among patients discharged alive on a weekend versus weekday. From 2005 to 2014, 39 699 weighted ADHF hospitalizations were identified (19% terminating on a weekend). Demographics, comorbidities, length of stay, and guideline-directed therapies were similar for patients with hospitalizations ending on a weekend versus weekday. In-hospital death doubled on the weekend compared with weekday (12% versus 6%) and was not attenuated by adjustment for potential confounders (odds ratio, 2.37; 95% CI, 1.93-2.91). There was no association between weekend discharge and 28-day mortality among patients discharged alive. Conclusions The risk of in-hospital death among patients admitted with ADHF appears to be doubled on the weekends when hospital staffing is usually reduced. However, among patients discharged alive, hospital discharge on a weekend is not adversely associated with mortality.

Changing Natural History of HER2-Positive Breast Cancer Metastatic to the Brain in the Era of New Targeted Therapies.

BACKGROUND: Given the wide adoption of human epidermal growth factor receptor 2 (HER2)-targeted therapies for advanced HER2-positive breast cancer, we studied the natural history of patients with HER2-positive breast cancer brain metastases (BCBM) over time. PATIENTS AND METHODS: Patients with HER2-positive BCBM identified from a prospectively maintained database at the University of North Carolina were divided into 3 cohorts by year of BCBM diagnosis. Cohorts were selected by year of HER2-targeted therapy US Food and Drug Administration approval. Overall survival (OS), time to first metastasis, time to BCBM, and BCBM survival were estimated by the Kaplan-Meier method. Associations between OS after BCBM and clinical variables were assessed by Cox proportional hazards regression models. RESULTS: One hundred twenty-three patients were identified. Median age was 51 years, and 58% were white and 31% African American. OS from initial breast cancer diagnosis improved over time: 3.6 years (95% confidence interval [CI], 2.8-6.1) in the 1998-2007 cohort, 6.6 years (95% CI, 4.5-8.6) in the 2008-2012 cohort, and 7.6 years (95% CI, 4.4-9.6) in the 2013-2015 cohort (P = .05). While time from initial diagnosis to first metastasis did not differ (P = .12), time to BCBM increased over time (2.6 years [95% CI, 1.3-3.5] for 1998-2007; 2.6 years [95% CI, 2.1-4.3] for 2008-2012, and 3.3 years [95% CI, 2.2-6] for 2013-2015; P = .05). Although OS from BCBM did not significantly differ by cohort, patients who received HER2-targeted therapy after BCBM had a prolonged OS (2.1 years [95% CI, 1.6-2.6] vs. 0.65 years [95% CI, 0.4-1.3]; P = .001). CONCLUSION: OS from initial breast cancer diagnosis significantly improved over time for patients with HER2-positive breast cancer who develop BCBM, now exceeding 7 years; survival from BCBM diagnosis may now exceed 2 years.

Relation of Household Income to Incidence of Sudden Unexpected Death in Wake County, North Carolina.

The incidence of out-of-hospital sudden unexpected death (OHSUD) in a racially and socioeconomically diverse population has been inadequately studied. We collated all OHSUDs over a 24-month period among 18- to 64-year olds in Wake County, North Carolina, to investigate geographic and socioeconomic disparity in incidence of OHSUD. An electronic query of Wake County Emergency Medical Services (EMS) identified all EMS attended out-of-hospital deaths. After excluding trauma, expected deaths, and deaths occurring in non-free-living subjects, medical records and medical examiner's reports were reviewed by a committee of cardiologists to make the determination of OHSUD. Victims were geocoded to census tracts, and demographic and socioeconomic data were obtained from the 2014 American Community Survey and 2010 US Census. Incidence was examined by sociodemographic group with univariate analysis and multivariable regression. There were 397 OHSUDs, and 53% of census tracts had >1 event. The incidence of OHSUD was 64 of 100,000; 107 of 100,000 among blacks; and 60 of 100,000 among whites. Census tracts with >1 OHSUD had a higher population of blacks, a greater proportion unmarried, a lower median household income, and a greater proportion residing in a rural area. Only median household income remained a significant predictor of OHSUD after adjustment in multivariable analysis. Low median household income of a community portends a higher incidence of sudden death. In conclusion, interventions to reduce the incidence of sudden death need to be developed with these specific communities in mind.

Combined kinase inhibitors of MEK1/2 and either PI3K or PDGFR are efficacious in intracranial triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC), lacking expression of hormone and human epidermal growth factor receptor 2 receptors, is an aggressive subtype that frequently metastasizes to the brain and has no FDA-approved systemic therapies. Previous literature demonstrates mitogen-activated protein kinase kinase (MEK) pathway activation in TNBC brain metastases. Thus, we aimed to discover rational combinatorial therapies with MEK inhibition, hypothesizing that co-inhibition using clinically available brain-penetrant inhibitors would improve survival in preclinical models of TNBC brain metastases. METHODS: Using human-derived TNBC cell lines, synthetic lethal small interfering RNA kinase screens were evaluated with brain-penetrant inhibitors against MEK1/2 (selumetinib, AZD6244) or phosphatidylinositol-3 kinase (PI3K; buparlisib, BKM120). Mice bearing intracranial TNBC tumors (SUM149, MDA-MB-231Br, MDA-MB-468, or MDA-MB-436) were treated with MEK, PI3K, or platelet derived growth factor receptor (PDGFR; pazopanib) inhibitors alone or in combination. Tumors were analyzed by western blot and multiplexed kinase inhibitor beads/mass spectrometry to assess treatment effects. RESULTS: Screens identified MEK+PI3K and MEK+PDGFR inhibitors as tractable, rational combinations. Dual treatment of selumetinib with buparlisib or pazopanib was synergistic in TNBC cells in vitro. Both combinations improved survival in intracranial SUM149 and MDA-MB-231Br, but not MDA-MB-468 or MDA-MB-436. Treatments decreased mitogen-activated protein kinase (MAPK) and PI3K (Akt) signaling in sensitive (SUM149 and 231Br) but not resistant models (MDA-MB-468). Exploratory analysis of kinome reprogramming in SUM149 intracranial tumors after MEK ± PI3K inhibition demonstrates extensive kinome changes with treatment, especially in MAPK pathway members. CONCLUSIONS: Results demonstrate that rational combinations of the clinically available inhibitors selumetinib with buparlisib or pazopanib may prove to be promising therapeutic strategies for the treatment of some TNBC brain metastases. Additionally, effective combination treatments cause widespread alterations in kinase pathways, including targetable potential resistance drivers.

Estimated incidence and risk factors of sudden unexpected death.

OBJECTIVE: In this manuscript, we estimate the incidence and identify risk factors for sudden unexpected death in a socioeconomically and racially diverse population in one county in North Carolina. Estimates of the incidence and risk factors contributing to sudden death vary widely. The Sudden Unexpected Death in North Carolina (SUDDEN) project is a population-based investigation of the incidence and potential causes of sudden death. METHODS: From 3 March 2013 to 2 March 2014, all out-of-hospital deaths in Wake County, North Carolina, were screened to identify presumed sudden unexpected death among free-living residents between the ages of 18 and 64 years. Death certificate, public and medical records were reviewed and adjudicated to confirm sudden unexpected death cases. RESULTS: Following adjudication, 190 sudden unexpected deaths including 122 men and 68 women were identified. Estimated incidence was 32.1 per 100 000 person-years overall: 42.7 among men and 22.4 among women. The majority of victims were white, unmarried men over age 55 years, with unwitnessed deaths at home. Hypertension and dyslipidaemia were common in men and women. African-American women dying from sudden unexpected death were over-represented. Women who were under age 55 years with coronary disease accounted for over half of female participants with coronary artery disease. CONCLUSIONS: The overall estimated incidence of sudden unexpected death may account for approximately 10% of all deaths classified as 'natural'. Women have a lower estimated incidence of sudden unexpected death than men. However, we found no major differences in age or comorbidities between men and women. African-Americans and young women with coronary disease are at risk for sudden unexpected death.