Racial and Ethnic Disparities in Opioid Prescribing on Hospital Discharge Among Older Adults: A National Retrospective Cohort Study.

BACKGROUND: Disparities in opioid prescribing among racial and ethnic groups have been observed in outpatient and emergency department settings, but it is unknown whether similar disparities exist at discharge among hospitalized older adults. OBJECTIVE: To determine filled opioid prescription rates on hospital discharge by race/ethnicity among Medicare beneficiaries. DESIGN: Retrospective cohort study. PARTICIPANTS: Medicare beneficiaries 65 years or older discharged from hospital in 2016, without opioid fills in the 90 days prior to hospitalization (opioid-naïve). MAIN MEASURES: Race/ethnicity was categorized by the Research Triangle Institute (RTI), grouped as Asian/Pacific Islander, Black, Hispanic, other (American Indian/Alaska Native/unknown/other), and White. The primary outcome was an opioid prescription claim within 2 days of hospital discharge. The secondary outcome was total morphine milligram equivalents (MMEs) among adults with a filled opioid prescription. KEY RESULTS: Among 316,039 previously opioid-naïve beneficiaries (mean age, 76.8 years; 56.2% female), 49,131 (15.5%) filled an opioid prescription within 2 days of hospital discharge. After adjustment, Black beneficiaries were 6% less likely (relative risk [RR] 0.94, 95% CI 0.91-0.97) and Asian/Pacific Islander beneficiaries were 9% more likely (RR 1.09, 95% CI 1.03-1.14) to have filled an opioid prescription when compared to White beneficiaries. Among beneficiaries with a filled opioid prescription, mean total MMEs were lower among Black (356.9; adjusted difference - 4%, 95% CI - 7 to - 1%), Hispanic (327.0; adjusted difference - 7%, 95% CI - 10 to - 4%), and Asian/Pacific Islander (328.2; adjusted difference - 8%, 95% CI - 12 to - 4%) beneficiaries when compared to White beneficiaries (409.7). CONCLUSIONS AND RELEVANCE: Black older adults were less likely to fill a new opioid prescription after hospital discharge when compared to White older adults and received lower total MMEs. The factors contributing to these differential prescribing patterns should be investigated further.

Modifications of the readiness assessment for pragmatic trials tool for appropriate use with Indigenous populations.

BACKGROUND: Inequities in health access and outcomes exist between Indigenous and non-Indigenous populations. Embedded pragmatic randomized, controlled trials (ePCTs) can test the real-world effectiveness of health care interventions. Assessing readiness for ePCT, with tools such as the Readiness Assessment for Pragmatic Trials (RAPT) model, is an important component. Although equity must be explicitly incorporated in the design, testing, and widespread implementation of any health care intervention to achieve equity, RAPT does not explicitly consider equity. This study aimed to identify adaptions necessary for the application of the 'Readiness Assessment for Pragmatic Trials' (RAPT) tool in embedded pragmatic randomized, controlled trials (ePCTs) with Indigenous communities. METHODS: We surveyed and interviewed participants (researchers with experience in research involving Indigenous communities) over three phases (July-December 2022) in this mixed-methods study to explore the appropriateness and recommended adaptions of current RAPT domains and to identify new domains that would be appropriate to include. We thematically analyzed responses and used an iterative process to modify RAPT. RESULTS: The 21 participants identified that RAPT needed to be modified to strengthen readiness assessment in Indigenous research. In addition, five new domains were proposed to support Indigenous communities' power within the research processes: Indigenous Data Sovereignty; Acceptability - Indigenous Communities; Risk of Research; Research Team Experience; Established Partnership). We propose a modified tool, RAPT-Indigenous (RAPT-I) for use in research with Indigenous communities to increase the robustness and cultural appropriateness of readiness assessment for ePCT. In addition to producing a tool for use, it outlines a methodological approach to adopting research tools for use in and with Indigenous communities by drawing on the experience of researchers who are part of, and/or working with, Indigenous communities to undertake interventional research, as well as those with expertise in health equity, implementation science, and public health. CONCLUSION: RAPT-I has the potential to provide a useful framework for readiness assessment prior to ePCT in Indigenous communities. RAPT-I also has potential use by bodies charged with critically reviewing proposed pragmatic research including funding and ethics review boards.

Pragmatic Clinical Trials for Dementia Care: Experience from the First 5 Years of the IMPACT Collaboratory.

The IMPACT Collaboratory is a national infrastructure and resource dedicated to transforming dementia care in real-world environments for millions of Americans and their care partners, using embedded pragmatic clinical trials. This new approach of applied clinical research holds the promise of accelerating the science of dementia care, improving relevancy of interventions to real-world partners, promoting health equity, and closing the gaps between research, everyday clinical practice, and lived experiences of people living with dementia and their care partners.

Prostanoid receptors in hyperfiltration-mediated glomerular injury: Novel agonists and antagonists reveal opposing roles for EP2 and EP4 receptors.

Increased fluid-flow shear stress (FFSS) contributes to hyperfiltration-induced podocyte and glomerular injury resulting in progression of chronic kidney disease (CKD). We reported that increased FFSS in vitro and in vivo upregulates PGE2 receptor EP2 (but not EP4 expression), COX2-PGE2 -EP2 axis, and EP2-linked Akt-GSK3ß-ß-catenin signaling pathway in podocytes. To understand and use the disparities between PGE2 receptors, specific agonists, and antagonists of EP2 and EP4 were used to assess phosphorylation of Akt, GSK3ß and ß-catenin in podocytes using Western blotting, glomerular filtration barrier function using in vitro albumin permeability (Palb ) assay, and mitigation of hyperfiltration-induced injury in unilaterally nephrectomized (UNX) mice at 1 and 6 months. Results show an increase in Palb by PGE2 , EP2 agonist (EP2AGO ) and EP4 antagonist (EP4ANT ), but not by EP2 antagonist (EP2ANT ) or EP4 agonist (EP4AGO ). Pretreatment with EP2ANT blocked the effect of PGE2 or EP2AGO on Palb . Modulation of EP2 and EP4 also induced opposite effects on phosphorylation of Akt and ß-Catenin. Individual agonists or antagonists of EP2 or EP4 did not induce significant improvement in albuminuria in UNX mice. However, treatment with a combination EP2ANT + EP4AGO for 1 or 6 months caused a robust decrease in albuminuria. EP2ANT + EP4AGO combination did not impact adaptive hypertrophy or increased serum creatinine. Observed differences between expression of EP2 and EP4 on the glomerular barrier highlight these receptors as potential targets for intervention. Safe and effective mitigating effect of EP2ANT + EP4AGO presents a novel opportunity to delay the progression of hyperfiltration-associated CKD as seen in transplant donors.

Survival outcomes with warfarin compared with direct oral anticoagulants in cancer-associated venous thromboembolism in the United States: A population-based cohort study.

BACKGROUND: Direct oral anticoagulants (DOACs) have comparable efficacy with low-molecular-weight heparin (LMWH) for the treatment of cancer-associated venous thromboembolism (VTE). Whether there is a mortality benefit of DOACs compared with warfarin in the management of VTE in cancer is not established. METHODS AND FINDINGS: Utilizing the United States' Surveillance, Epidemiology, and End Results (SEER)-Medicare linked databases from 2012 through 2016, we analyzed overall survival in individuals diagnosed with a primary gastric, colorectal, pancreas, lung, ovarian, or brain cancer and VTE who received a prescription of DOAC or warfarin within 30 days of VTE diagnosis. Patients were matched 1:2 (DOAC to warfarin) through exact matching for cancer stage and propensity score matching for age, cancer site, cancer stage, and time interval from cancer to VTE diagnosis. The analysis identified 4,274 patients who received a DOAC or warfarin for the treatment of VTE within 30 days of cancer diagnosis (1,348 in DOAC group and 2,926 in warfarin group). Patients were of median age 75 years and 56% female. Within the DOAC group, 1,188 (88%) received rivaroxaban, and 160 (12%) received apixaban. With a median follow-up of 41 months, warfarin was associated with a statistically significantly higher overall survival compared to DOACs (median overall survival 12.0 months [95% confidence interval (CI): 10.9 to 13.5] versus 9.9 months [95% CI: 8.4 to 11.2]; hazard ratio (HR) 0.85; 95% CI: 0.78 to 0.91; p < 0.001). Observed differences in survival were consistent across subgroups of cancer sites, cancer stages, and type of VTE. The study limitations include retrospective design with potential for unaccounted confounders along with issues of generalizability beyond the cancer diagnoses studied. CONCLUSIONS: In this analysis of a population-based registry, warfarin was associated with prolonged overall survival compared to DOACs for treatment of cancer-associated VTE.

Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy.

BACKGROUND: B-cell anomalies play a role in the pathogenesis of membranous nephropathy. B-cell depletion with rituximab may therefore be noninferior to treatment with cyclosporine for inducing and maintaining a complete or partial remission of proteinuria in patients with this condition. METHODS: We randomly assigned patients who had membranous nephropathy, proteinuria of at least 5 g per 24 hours, and a quantified creatinine clearance of at least 40 ml per minute per 1.73 m2 of body-surface area and had been receiving angiotensin-system blockade for at least 3 months to receive intravenous rituximab (two infusions, 1000 mg each, administered 14 days apart; repeated at 6 months in case of partial response) or oral cyclosporine (starting at a dose of 3.5 mg per kilogram of body weight per day for 12 months). Patients were followed for 24 months. The primary outcome was a composite of complete or partial remission of proteinuria at 24 months. Laboratory variables and safety were also assessed. RESULTS: A total of 130 patients underwent randomization. At 12 months, 39 of 65 patients (60%) in the rituximab group and 34 of 65 (52%) in the cyclosporine group had a complete or partial remission (risk difference, 8 percentage points; 95% confidence interval [CI], -9 to 25; P = 0.004 for noninferiority). At 24 months, 39 patients (60%) in the rituximab group and 13 (20%) in the cyclosporine group had a complete or partial remission (risk difference, 40 percentage points; 95% CI, 25 to 55; P<0.001 for both noninferiority and superiority). Among patients in remission who tested positive for anti-phospholipase A2 receptor (PLA2R) antibodies, the decline in autoantibodies to anti-PLA2R was faster and of greater magnitude and duration in the rituximab group than in the cyclosporine group. Serious adverse events occurred in 11 patients (17%) in the rituximab group and in 20 (31%) in the cyclosporine group (P = 0.06). CONCLUSIONS: Rituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria at 12 months and was superior in maintaining proteinuria remission up to 24 months. (Funded by Genentech and the Fulk Family Foundation; MENTOR ClinicalTrials.gov number, NCT01180036.).

Association of Diagnosed Dementia with Post-discharge Mortality and Readmission Among Hospitalized Medicare Beneficiaries.

BACKGROUND: Patients with dementia are frequently hospitalized and may face barriers in post-discharge care. OBJECTIVE: To determine whether patients with dementia have an increased risk of adverse outcomes following discharge. DESIGN: Retrospective cohort study. SUBJECTS: Medicare beneficiaries hospitalized in 2016. MAIN MEASURES: Co-primary outcomes were mortality and readmission within 30 days of discharge. Multivariable logistic regression models were estimated to assess the risk of each outcome for patients with and without dementia accounting for demographics, comorbidities, frailty, hospitalization factors, and disposition. KEY RESULTS: The cohort included 1,089,109 hospitalizations of which 211,698 (19.3%) were of patients with diagnosed dementia (median (IQR) age 83 (76-89); 61.5% female) and 886,411 were of patients without dementia (median (IQR) age 76 (79-83); 55.0% female). At 30 days following discharge, 5.7% of patients with dementia had died compared to 3.1% of patients without dementia (adjusted odds ratio (aOR) 1.21; 95% CI 1.17 to 1.24). At 30 days following discharge, 17.7% of patients with dementia had been readmitted compared to 13.1% of patients without dementia (aOR 1.02; CI 1.002 to 1.04). Dementia was associated with an increased odds of readmission among patients discharged to the community (aOR 1.07, CI 1.05 to 1.09) but a decreased odds of readmission among patients discharge to nursing facilities (aOR 0.93, CI 0.90 to 0.95). Patients with dementia who were discharged to the community were more likely to be readmitted than those discharged to nursing facilities (18.9% vs 16.0%), and, when readmitted, were more likely to die during the readmission (20.7% vs 4.4%). CONCLUSIONS: Diagnosed dementia was associated with a substantially increased risk of mortality and a modestly increased risk of readmission within 30 days of discharge. Patients with dementia discharged to the community had particularly elevated risk of adverse outcomes indicating possible gaps in post-discharge services and caregiver support.

Guilt as an Influencer in End-of-Life Care Decisions for Nursing Home Residents With Advanced Dementia.

The concept of guilt has been studied in the context of caregivers of older adults with advanced dementia, usually describing the feelings a person has of placing a loved one in a long-term care facility; however, little research has been done to understand how nursing home staff and proxies for older adults with dementia describe guilt as a decision-influencer in end-of-life care. For the current study, private, semi-structured interviews were conducted with 158 nursing home staff and 44 proxies in 13 nursing homes across four demographic regions in the United States. Interviews were reviewed and analyzed for how the concept of guilt was perceived as a decision-influencer. Nursing home staff described guilt as an important influencer in why proxies make decisions about end-of-life care. Staff noted that proxies who felt guilty about their relationship with their loved one or lack of time spent at end-of-life tended to be more aggressive in care decisions, whereas no proxies mentioned guilt as an influencer in care decisions. Rather, proxies used language of obligation and commitment to describe why they make decisions. Findings highlight the disconnect between nursing home staff and proxies in what motivates proxies to make end-of-life decisions for loved ones. Nursing home staff should be aware of misconceptions about proxies and work to understand proxies' true rationale and motivations for making care decisions. [Journal of Gerontological Nursing, 48(1), 22-27.].

Relative risks of adverse events among older adults receiving opioids versus NSAIDs after hospital discharge: A nationwide cohort study.

BACKGROUND: Although analgesics are initiated on hospital discharge in millions of adults each year, studies quantifying the risks of opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) among older adults during this transition are limited. We sought to determine the incidence and risk of post-discharge adverse events among older adults with an opioid claim in the week after hospital discharge, compared to those with NSAID claims only. METHODS AND FINDINGS: We performed a retrospective cohort study using a national sample of Medicare beneficiaries age 65 and older, hospitalized in United States hospitals in 2016. We excluded beneficiaries admitted from or discharged to a facility. We derived a propensity score that included over 100 factors potentially related to the choice of analgesic, including demographics, diagnoses, surgeries, and medication coadministrations. Using 3:1 propensity matching, beneficiaries with an opioid claim in the week after hospital discharge (with or without NSAID claims) were matched to beneficiaries with an NSAID claim only. Primary outcomes included death, healthcare utilization (emergency department [ED] visits and rehospitalization), and a composite of known adverse effects of opioids or NSAIDs (fall/fracture, delirium, nausea/vomiting, complications of slowed colonic motility, acute renal failure, and gastritis/duodenitis) within 30 days of discharge. After propensity matching, there were 13,385 beneficiaries in the opioid cohort and 4,677 in the NSAID cohort (mean age: 74 years, 57% female). Beneficiaries receiving opioids had a higher incidence of death (1.8% versus 1.1%; relative risk [RR] 1.7 [1.3 to 2.3], p < 0.001, number needed to harm [NNH] 125), healthcare utilization (19.0% versus 17.4%; RR 1.1 [1.02 to 1.2], p = 0.02, NNH 59), and any potential adverse effect (25.2% versus 21.3%; RR 1.2 [1.1 to 1.3], p < 0.001, NNH 26), compared to those with an NSAID claim only. Specifically, they had higher relative risk of fall/fracture (4.5% versus 3.4%; RR 1.3 [1.1 to 1.6], p = 0.002), nausea/vomiting (9.2% versus 7.3%; RR 1.3 [1.1 to 1.4], p < 0.001), and slowed colonic motility (8.0% versus 6.2%; RR 1.3 [1.1 to 1.4], p < 0.001). Risks of delirium, acute renal failure, and gastritis/duodenitis did not differ between groups. The main limitation of our study is the observational nature of the data and possibility of residual confounding. CONCLUSIONS: Older adults filling an opioid prescription in the week after hospital discharge were at higher risk for mortality and other post-discharge adverse outcomes compared to those filling an NSAID prescription only.

Upregulated proteoglycan-related signaling pathways in fluid flow shear stress-treated podocytes.

The ultrafiltrate flow over the major processes and cell body generates fluid flow shear stress (FFSS) on podocytes. Hyperfiltration-associated increase in FFSS can lead to podocyte injury and detachment. Previously, we showed that FFSS-induced upregulation of the cyclooxygenase 2 (COX2)-PGE2-prostaglandin E receptor 2 (EP2) axis in podocytes activates Akt-glycogen synthase kinase-3ß-ß-catenin and MAPK/ERK signaling in response to FFSS. Integrative MultiOmics Pathway Resolution (IMPRes) is a new bioinformatic tool that enables simultaneous time-series analysis of more than two groups to identify pathways and molecular connections. In the present study, we used previously characterized COX2 [prostaglandin-endoperoxide synthase 2 (Ptgs2)], EP2 (Ptger2), and ß1-catenin (Ctnnb1) as "seed genes" from an array data set of four groups analyzed over a time course. The 3 seed genes shared 7 pathways and 50 genes of 14 pathways and 89 genes identified by IMPRes. A composite of signaling pathways highlighted the temporal molecular connections during mechanotransduction signaling in FFSS-treated podocytes. We investigated the "proteoglycans in cancer" and "galactose metabolism" pathways predicted by IMPRes. A custom-designed PCR array validated 60.7% of the genes predicted by IMPRes analysis, including genes for the above-named pathways. Further validation using Western blot analysis showed increased expression of phosho-Erbb2, phospho-mammalian target of rapamycin (mTOR), CD44, and hexokinase II (Hk2); decreased total Erbb2, galactose mutarotase (Galm), and ß-1,4-galactosyltransferase 1 (B4galt1); and unchanged total mTOR and AKT3. These findings corroborate our previously reported results. This study demonstrates the potential of the IMPRes method to identify novel pathways. Identifying the "proteoglycans in cancer" and "galactose metabolism" pathways has generated a lead to study the significance of FFSS-induced glycocalyx remodeling and possible detachment of podocytes from the glomerular matrix.

Predicting Mortality and Adverse Outcomes: Comparing the Frailty Index to General Prognostic Indices.

BACKGROUND: Mortality prediction models are useful to guide clinical decision-making based on prognosis. The frailty index, which allows prognostication and personalized care planning, has not been directly compared with validated prognostic models. OBJECTIVE: To compare the discrimination of mortality, disability, falls, and hospitalization between a frailty index and validated prognostic indices. DESIGN: Secondary Analysis of the National Health and Aging Trends Study. PARTICIPANTS: Seven thousand thirty-three Medicare beneficiaries 65 years or older. MEASUREMENTS: We measured a deficit-accumulation frailty index, Schonberg index, and Lee index at the 2011 baseline assessment. Primary outcome was mortality at 5 years. Secondary outcomes were decline in activities of daily living (ADL), decline in instrumental activities of daily living (IADL), fall, and hospitalization at 1 year. We used C-statistics to compare discrimination between indices, adjusting for age and sex. RESULTS: The study population included 4146 (44.8%) with age ≥ 75 years, with a median frailty index of 0.15 (interquartile range 0.09-0.25). A total of 1385 participants died (14.7%) and 2386 (35.2%) were lost to follow-up. Frailty, Schonberg, and Lee indices predicted mortality similarly: C-statistics (95% confidence interval) were 0.78 (0.77-0.80) for frailty index; 0.79 (0.78-0.81) for Schonberg index; and 0.78 (0.77-0.80) for Lee index. The frailty index had higher C-statistics for decline in ADL function (frailty index, 0.80 [0.78-0.83]; Schonberg, 0.74 [0.72-0.76]; Lee, 0.74 [0.71-0.77]) and falls (frailty index, 0.66 [0.65-0.68]; Schonberg, 0.61 [0.58-0.63]; Lee, 0.61 [0.59-0.63]). C-statistics were similar for decline in IADL function (frailty index, 0.61 [0.59-0.63]; Schonberg, 0.60 [0.59-0.62]; Lee, 0.60 [0.58-0.62]) and hospitalizations (frailty index, 0.68 [0.66-0.70]; Schonberg, 0.68 [0.66-0.69]; Lee, 0.65 [0.63-0.67]). CONCLUSIONS: A deficit-accumulation frailty index performs as well as prognostic indices for mortality prediction, and better predicts ADL disability and falls in community-dwelling older adults. Frailty assessment offers a unifying approach to risk stratification for key health outcomes relevant to older adults.

Urinary prostaglandin E2 is a biomarker of early adaptive hyperfiltration in solitary functioning kidney.

INTRODUCTION: Hyperfiltration is a major contributor to progression of chronic kidney disease (CKD) in diabetes, obesity and in individuals with solitary functioning kidney (SFK). We have proposed hyperfiltration-induced injury as a continuum of overlapping glomerular changes caused by increased biomechanical forces namely, fluid flow shear stress (FFSS) and tensile stress. We have shown that FFSS is elevated in animals with SFK and, it upregulates prostaglandin E2 (PGE2), cyclooxygenase-2 and PGE2 receptor EP2 in cultured podocytes and in uninephrectomized mice. We conceptualized urinary PGE2 as a biomarker of early effects of hyperfiltration-induced injury preceding microalbuminuria in individuals with SFK. We studied children with SFK to validate our hypothesis. METHODS: Urine samples from children with SFK and controls were analyzed for PGE2, albumin (glomerular injury biomarker) and epidermal growth factor (EGF, tubular injury biomarker). Age, gender, and Z-scores for height, weight, BMI, and blood pressure were obtained. RESULTS: Children with SFK were comparable to controls except for lower BMI Z-scores. The median values were elevated in SFK compared to control for urine PGE2 [9.1 (n = 57) vs. 5.7 (n = 72), p = 0.009] ng/mgCr and albumin [7.6 (n = 40) vs. 7.0 (n = 41), p = 0.085] µg/mgCr, but not for EGF [20098 (n = 44) vs. 18637 (n = 44), p = 0.746] pg/mgCr. Significant increase in urinary PGE2 (p = 0.024) and albumin (p = 0.019) but not EGF (p = 0.412) was observed using additional regression modeling. These three urinary analytes were independent of each other. CONCLUSION: Increased urinary PGE2 from elevated SNGFR and consequently increased FFSS during early stage of CKD precedes overt microalbuminuria and is a biomarker for early hyperfiltration-induced injury in individuals with SFK.

Effects of Social Disparities on Management and Surgical Outcomes for Patients with Secondary Hyperparathyroidism.

INTRODUCTION: Nearly 80% of chronic renal failure patients have secondary hyperparathyroidism. Cinacalcet is used to lower parathyroid hormone; however, it is expensive and has side effects. When secondary hyperparathyroidism is resistant to medication or medications are inaccessible, parathyroidectomy is performed. Race and socioeconomic status influence access to care and surgical outcomes. We sought to evaluate the effect of race and socioeconomic status on parathyroidectomy rate as well as surgical outcomes of patients with secondary hyperparathyroidism. METHODS: We undertook cross-sectional analysis of adults diagnosed with secondary hyperparathyroidism in the USA between 2012 and 2014, using the National Inpatient Sample. Univariate and multivariate analyses were used to determine associations between social disparities, likelihood to undergo parathyroidectomy, and surgical outcomes. RESULTS: Between 2012 and 2014, a national estimate of 724,170 hospitalizations were identified where patients had a diagnosis of secondary hyperparathyroidism. Operative rate was 0.67%. By socioeconomic status, differences in rates of surgery in the poorest compared to the richest were not significant (0.74% vs. 0.55%, OR 1.08, p = 0.5). African-American patients had higher rates of parathyroidectomy compared to Caucasians (1 vs. 0.74%, OR 1.49, p < 0.001). African-American patients also had a trend toward more complications and greater length of stay. CONCLUSIONS: According to a large administrative dataset, parathyroidectomy for secondary hyperparathyroidism is seldom used in the USA. African-American patients have higher rates of surgical management. Surgical outcomes may be affected by race. Clinicians treating secondary hyperparathyroidism should be aware of existing disparities within their health system.

Meeting the World Health Organization Maternal Antenatal Care Guidelines Is Associated with Improved Early and Middle Childhood Cognition in Ethiopia.

OBJECTIVE: To assess the association between meeting the World Health Organization (WHO) maternal antenatal care attendance guidelines and early and middle childhood cognition among impoverished Ethiopian children. STUDY DESIGN: A total of 1914 impoverished Ethiopian children from the Young Lives longitudinal cohort study were included. Childhood cognition was assessed via the Cognitive Development Assessment (CDA) and Peabody Picture Vocabulary Test (PPVT) at ages 4-5 years; PPVT, Early Grade Reading Assessment (EGRA), and Math Test at ages 7-8 years; and PPVT, Math Test, and Reading Test at ages 11-12 years. Linear regression models were used to examine the association between maternal antenatal care attendance and childhood academic achievement test scores. RESULTS: In the univariable analysis, children of mothers who received the WHO recommended 4+ antenatal care visits or received the WHO recommended first antenatal care visit during the first trimester scored higher on all academic achievement tests. In the multivariable analysis, children of mothers who received 4+ antenatal care visits scored significantly higher on the CDA at ages 4-5 years and Math Test at ages 7-8 years. Children of mothers who received antenatal care in the first trimester scored higher on the CDA at ages 4-5 years and Math Test scores at ages 11-12 years. Children of mothers who received both antenatal care in the first trimester and 4+ antenatal care visits scored significantly higher on the CDA at ages 4-5 years and Math Test at both ages 7-8 and 11-12 years. CONCLUSIONS: Children of mothers who received the WHO recommended number and timing of antenatal care visits had significantly higher academic achievement scores across multiple domains during early and middle childhood. Promotion of antenatal care visit attendance may improve cognition through middle childhood.

Relationship between Race/Ethnicity and Hysterectomy Outcomes for Benign Gynecologic Conditions.

STUDY OBJECTIVE: To examine the association between race/ethnicity, route of hysterectomy, and risk of inpatient surgical complications. DESIGN: Cross-sectional analysis (Canadian Task Force classification III). SETTING: Inpatient hospitals in the United States. PATIENTS AND INTERVENTIONS: There were 114 719 women aged 18 and older from the Nationwide Inpatient Sample who underwent an elective hysterectomy for benign indications using International Classification of Diseases codes. MEASUREMENTS AND MAIN RESULTS: Multivariable logistic regression was performed to examine the association between race/ethnicity and route of hysterectomy and surgical complications, after adjusting for patient characteristics, clinical factors, and hospital characteristics. Analyses were weighted to provide national estimates of prevalence. The rate of minimally invasive hysterectomy was 55.0% in white women, 28.6% in black women, 50.1% in Hispanic women, and 45.6% in other race/ethnic categories. Compared with white women, black women had a .55 odds (95% confidence interval, .52-.59) of undergoing minimally invasive hysterectomy, after adjusting for patient, clinical, and hospital characteristics. This finding remained consistent across quartiles of median household income of residence, primary payer, and diagnosis of myomas. Among women who had an elective hysterectomy, 6091 experienced a complication, representing an estimated 30 455 women nationwide. The rate of surgical complications was 5.3% in white women, 5.9% in black women, 4.6% in Hispanic women, and 5.1% in women of other racial/ethnic groups. There was no difference in odds of experiencing a surgical complication between white and black women (odds ratio, 1.03; 95% confidence interval, .93-1.13) after adjusting for patient, clinical, and hospital characteristics. This finding remained consistent across quartiles of median household income of residence, primary payer, and route of hysterectomy. CONCLUSION: Among women undergoing an elective hysterectomy, black women were less likely to receive minimally invasive hysterectomy compared with white women. However, the rate of inpatient surgical complications did not vary significantly by race/ethnicity. Further research is encouraged to identify and address the influential factors behind the disparity in minimally invasive hysterectomy use among black women in the United States.

Mechanotransduction signaling in podocytes from fluid flow shear stress.

Recently, we and others have found that hyperfiltration-associated increase in biomechanical forces, namely, tensile stress and fluid flow shear stress (FFSS), can directly and distinctly alter podocyte structure and function. The ultrafiltrate flow over the major processes and cell body generates FFSS to podocytes. Our previous work suggests that the cyclooxygenase-2 (COX-2)-PGE2-PGE2 receptor 2 (EP2) axis plays an important role in mechanoperception of FFSS in podocytes. To address mechanotransduction of the perceived stimulus through EP2, cultured podocytes were exposed to FFSS (2 dyn/cm2) for 2 h. Total RNA from cells at the end of FFSS treatment, 2-h post-FFSS, and 24-h post-FFSS was used for whole exon array analysis. Differentially regulated genes ( P < 0.01) were analyzed using bioinformatics tools Enrichr and Ingenuity Pathway Analysis to predict pathways/molecules. Candidate pathways were validated using Western blot analysis and then further confirmed to be resulting from a direct effect of PGE2 on podocytes. Results show that FFSS-induced mechanotransduction as well as exogenous PGE2 activate the Akt-GSK3ß-ß-catenin (Ser552) and MAPK/ERK but not the cAMP-PKA signal transduction cascades. These pathways are reportedly associated with FFSS-induced and EP2-mediated signaling in other epithelial cells as well. The current regimen for treating hyperfiltration-mediated injury largely depends on targeting the renin-angiotensin-aldosterone system. The present study identifies specific transduction mechanisms and provides novel information on the direct effect of FFSS on podocytes. These results suggest that targeting EP2-mediated signaling pathways holds therapeutic significance for delaying progression of chronic kidney disease secondary to hyperfiltration.

Role of biomechanical forces in hyperfiltration-mediated glomerular injury in congenital anomalies of the kidney and urinary tract.

Congenital anomalies of the kidney and urinary tract (CAKUT) including solitary kidney constitute the main cause of progressive chronic kidney disease (CKD) in children. Children born with CAKUT develop signs of CKD only during adolescence and do not respond to renin-angiotensin-aldosterone system blockers. Early cellular changes underlying CKD progression to end-stage renal disease by early adulthood are not well understood. The mechanism of maladaptive hyperfiltration that occurs from loss of functional nephrons, including solitary kidney, is not clear. We re-examine the phenomenon of hyperfiltration in the context of biomechanical forces with special reference to glomerular podocytes. Capillary stretch exerts tensile stress on podocytes through the glomerular basement membrane. The flow of ultrafiltrate over the cell surface directly causes fluid flow shear stress (FFSS) on podocytes. FFSS on the podocyte surface increases 1.5- to 2-fold in animal models of solitary kidney and its effect on podocytes is a subject of ongoing research. Podocytes (i) are mechanosensitive to tensile and shear forces, (ii) use prostaglandin E2, angiotensin-II or nitric oxide for mechanoperception and (iii) use specific signaling pathways for mechanotransduction. We discuss (i) the nature of and differences in cellular responses to biomechanical forces, (ii) methods to study biomechanical forces and (iii) effects of biomechanical forces on podocytes and glomeruli. Future studies on FFSS will likely identify novel targets for strategies for early intervention to complement and strengthen the current regimen for treating children with CAKUT.

Hyperfiltration-associated biomechanical forces in glomerular injury and response: Potential role for eicosanoids.

Hyperfiltration is a well-known risk factor in progressive loss of renal function in chronic kidney disease (CKD) secondary to various diseases. A reduced number of functional nephrons due to congenital or acquired cause(s) results in hyperfiltration in the remnant kidney. Hyperfiltration-associated increase in biomechanical forces, namely pressure-induced tensile stress and fluid flow-induced shear stress (FFSS) determine cellular injury and response. We believe the current treatment of CKD yields limited success because it largely attenuates pressure-induced tensile stress changes but not the effect of FFSS on podocytes. Studies on glomerular podocytes, tubular epithelial cells and bone osteocytes provide evidence for a significant role of COX-2 generated PGE2 and its receptors in response to tensile stress and FFSS. Preliminary observations show increased urinary PGE2 in children born with a solitary kidney. FFSS-induced COX2-PGE2-EP2 signaling provides an opportunity to identify targets and, for developing novel agents to complement currently available treatment.

Accounting for individualized competing mortality risks in estimating postmenopausal breast cancer risk.

PURPOSE: Accurate risk assessment is necessary for decision-making around breast cancer prevention. We aimed to develop a breast cancer prediction model for postmenopausal women that would take into account their individualized competing risk of non-breast cancer death. METHODS: We included 73,066 women who completed the 2004 Nurses' Health Study (NHS) questionnaire (all ≥57 years) and followed participants until May 2014. We considered 17 breast cancer risk factors (health behaviors, demographics, family history, reproductive factors) and 7 risk factors for non-breast cancer death (comorbidities, functional dependency) and mammography use. We used competing risk regression to identify factors independently associated with breast cancer. We validated the final model by examining calibration (expected-to-observed ratio of breast cancer incidence, E/O) and discrimination (c-statistic) using 74,887 subjects from the Women's Health Initiative Extension Study (WHI-ES; all were ≥55 years and followed for 5 years). RESULTS: Within 5 years, 1.8 % of NHS participants were diagnosed with breast cancer (vs. 2.0 % in WHI-ES, p = 0.02), and 6.6 % experienced non-breast cancer death (vs. 5.2 % in WHI-ES, p < 0.001). Using a model selection procedure which incorporated the Akaike Information Criterion, c-statistic, statistical significance, and clinical judgement, our final model included 9 breast cancer risk factors, 5 comorbidities, functional dependency, and mammography use. The model's c-statistic was 0.61 (95 % CI [0.60-0.63]) in NHS and 0.57 (0.55-0.58) in WHI-ES. On average, our model under predicted breast cancer in WHI-ES (E/O 0.92 [0.88-0.97]). CONCLUSIONS: We developed a novel prediction model that factors in postmenopausal women's individualized competing risks of non-breast cancer death when estimating breast cancer risk.