Engagement Among Diverse Patient Backgrounds in a Remote Symptom Monitoring Program.

PURPOSE: Previous randomized controlled trials have demonstrated benefit from remote symptom monitoring (RSM) with electronic patient-reported outcomes. However, the racial diversity of enrolled patients was low and did not reflect the real-world racial proportions for individuals with cancer. METHODS: This secondary, cross-sectional analysis evaluated engagement of patients with cancer in a RSM program. Patient-reported race was grouped as Black, Other, or White. Patient address was used to map patient residence to determine rurality using Rural-Urban Commuting Area Codes and neighborhood disadvantage using Area Deprivation Index. Key outcomes included (1) being approached for RSM enrollment, (2) declining enrollment, (3) adherence with RSM via continuous completion of symptom surveys, and (4) withdrawal from RSM participation. Risk ratios (RR) and 95% CI were estimated from modified Poisson models with robust SEs. RESULTS: Between May 2021 and May 2023, 883 patients were approached to participate, of which 56 (6%) declined RSM. Of those who enrolled in RSM, a total of 27% of patients were Black or African American and 67% were White. In adjusted models, all patient population subgroups of interest had similar likelihoods of being approached for RSM participation; however, Black or African American patients were more than 3× more likely to decline participation than White participants (RR, 3.09 [95% CI, 1.73 to 5.53]). Patients living in more disadvantaged neighborhoods were less likely to decline (RR, 0.49 [95% CI, 0.24 to 1.02]), but less likely to adhere to surveys (RR, 0.81 [95% CI, 0.68 to 0.97]). All patient populations had a similar likelihood of withdrawing. CONCLUSION: Black patients and individuals living in more disadvantaged neighborhoods are at risk for lower engagement in RSM. Further work is needed to identify and overcome barriers to equitable participation.

Understanding the financial cost of cancer clinical trial participation.

BACKGROUND: Though financial hardship is a well-documented adverse effect of standard-of-care cancer treatment, little is known about out-of-pocket costs and their impact on patients participating in cancer clinical trials. This study explored the financial effects of cancer clinical trial participation. METHODS: This cross-sectional analysis used survey data collected in December 2022 and May 2023 from individuals with cancer previously served by Patient Advocate Foundation, a nonprofit organization providing social needs navigation and financial assistance to US adults with a chronic illness. Surveys included questions on cancer clinical trial participation, trial-related financial hardship, and sociodemographic data. Descriptive and bivariate analyses were conducted using Cramer's V to estimate the in-sample magnitude of association. Associations between trial-related financial hardship and sociodemographics were estimated using adjusted relative risks (aRR) and corresponding 95% confidence intervals (CI) from modified Poisson regression models with robust standard errors. RESULTS: Of 650 survey respondents, 18% (N = 118) reported ever participating in a cancer clinical trial. Of those, 47% (n = 55) reported financial hardship as a result of their trial participation. Respondents reporting trial-related financial hardship were more often unemployed or disabled (58% vs. 43%; V = 0.15), Medicare enrolled (53% vs. 40%; V = 0.15), and traveled >1 h to their cancer provider (45% vs. 17%; V = 0.33) compared to respondents reporting no hardship. Respondents who experienced trial-related financial hardship most often reported expenses from travel (reported by 71% of respondents), medical bills (58%), dining out (40%), or housing needs (40%). Modeling results indicated that respondents traveling >1 h vs. ≤30 min to their cancer provider had a 2.2× higher risk of financial hardship, even after adjusting for respondent race, income, employment, and insurance status (aRR = 2.2, 95% CI 1.3-3.8). Most respondents (53%) reported needing $200-$1000 per month to compensate for trial-related expenses. Over half (51%) of respondents reported less willingness to participate in future clinical trials due to incurred financial hardship. Notably, of patients who did not participate in a cancer clinical trial (n = 532), 13% declined participation due to cost. CONCLUSION: Cancer clinical trial-related financial hardship, most often stemming from travel expenses, affected almost half of trial-enrolled patients. Interventions are needed to reduce adverse financial participation effects and potentially improve cancer clinical trial participation.

Changing Strategy Between Bridge to Transplant and Destination LVAD Therapy After the First 3 Months: Analysis of the STS-INTERMACS Database.

BACKGROUND: Left ventricular assist devices (LVADs) have been implanted as bridge to transplantation (BTT), bridge to candidacy (BTC) or destination therapy (DT) on the basis of relative and absolute contraindications to transplantation. Multiple factors may lead to changes in the strategy of support after LVAD implantation. METHODS: Based on INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) 2012-2020 data, 11,262 patients survived to 3 months on continuous-flow LVADs with intent of BTT or DT. Preimplant characteristics and early events post-LVAD were analyzed in relation to changes in BTT or DT strategy during the next 12 months. RESULTS: Among 3216 BTT patients at 3 months, later transplant delisting or death without transplant occurred in 536 (16.7%) and was more common with age, profiles 1-2, renal dysfunction, and independently for prior cardiac surgery (HR 1.25, 95% CI 1.04-1.51; P = 0.02). Post-LVAD events of infections, gastrointestinal bleeding, stroke, and right heart failure as defined by inotropic therapy, predicted delisting and death, as did in-hospital location at 3 months (HR 1.67, 95% CI 1.20-2.33; P = 0.0024). Of 8046 patients surviving to 3 months with the intent of destination therapy, 750 (9.3%) subsequently underwent listing or transplantation, often with initial histories of acute HF (HR 1.70, 95% CI 1.27-2.27; P = 0.0012) or malnutrition-cachexia (1.73, 95% CI 1.14-2.63; P = 0.0099). Multiple gastrointestinal bleeding events (≥ 4) with LVAD increased transition from BTT to DT (HR 4.22, 95% CI 1.46-12.275; P = 0.0078) but also from DT to BTT (HR 5.17, 95% CI 1.92-13.9; P = 0.0011). CONCLUSIONS: Implant strategies change over time in relation to preimplant characteristics and adverse events post implant. Preimplant recognition of factors predicting later change in implant strategy will refine initial triage, whereas further reduction of post-LVAD complications will expand options, including eventual consideration of heart transplantation.

Primary or Delayed Repair for Complete Atrioventricular Septal Defect, Tetralogy of Fallot, and Ventricular Septal Defect: Relationship to Country Economic Status.

OBJECTIVE: Primary repair in the first six months of life is routine for tetralogy of Fallot, complete atrioventricular septal defect, and ventricular septal defect in high-income countries. The objective of this analysis was to understand the utilization and outcomes of palliative and reparative procedures in high versus middle-income countries. METHODS: The World Database of Pediatric and Congenital Heart Surgery identified patients who underwent surgery for: tetralogy of Fallot, complete atrioventricular septal defect, and ventricular septal defect. Patients were categorized as undergoing primary repair, repair after prior palliation, or palliation only. Country economic status was categorized as lower middle, upper middle, and high, defined by the World Bank. Multiple logistic regression models were utilized to identify independent predictors of hospital mortality. RESULTS: Economic categories included high (n = 571, 5.3%), upper middle (n = 5,342, 50%), and lower middle (n = 4,793, 49.7%). The proportion of patients and median age with primary repair were: tetralogy of Fallot, 88.6%, 17.7 months; complete atrioventricular septal defect, 83.4%, 7.7 months; and ventricular septal defect, 97.1%, ten months. Age at repair was younger in high income countries (P < .0001). Overall mortality after repair was lowest in high income countries. Risk factors for hospital mortality included prematurity, genetic syndromes, and urgent or emergent operations (all P < .05). CONCLUSIONS: Primary repair was selected in >90% of patients, but definitive repair was delayed in lower and upper middle income countries compared with high-income countries. Repair after prior palliation versus primary repair was not a risk factor for hospital mortality. Initial palliation continues to have a small but important role in the management of these three specific congenital heart defects.

Hospital Mortality and Adverse Events Following Repair of Congenital Heart Defects in Developing Countries.

BACKGROUND: Mortality associated with the correction of congenital heart disease has decreased to approximately 2% in developed countries and major adverse events are uncommon. Outcomes in developing countries are less well defined. The World Database for Pediatric and Congenital Heart Surgery was utilized to compare mortality and adverse events in developed and developing countries. METHODS: A total of 16,040 primary procedures were identified over a two-year period. Centers that submitted procedures were dichotomized to low/middle income (LMI) and high income (HI) by the Gross National Income per capita categorization. Mortality was defined as any death following the primary procedure to discharge or 90 days inpatient. Multiple logistic regression models were utilized to identify independent predictors of mortality. RESULTS: Of the total number of procedures analyzed, 83% (n = 13,294) were from LMI centers. Among all centers, the mean age at operation was 2.2 years, with 36% (n = 5,743) less than six months; 85% (n = 11,307) of procedures were STAT I/II for LMI centers compared with 77% (n = 2127) for HI centers (P < .0001). Overall mortality across the cohort was 2.27%. There was a statistical difference in mortality between HI centers (0.55%) versus LMI centers (2.64%) (P < .0001). After adjustment for other risk factors, the risk of death remained significantly higher in LMI centers (odds ratio: 2.36, 95% confidence interval: 1.707-3.27). CONCLUSION: Although surgical expertise has increased across the globe, there remains a disparity with some outcomes associated with the correction of congenital heart disease between developing and developed countries. Further studies are needed to identify specific opportunities for improvement.

The World Society for Pediatric and Congenital Heart Surgery: 2021 Update of the World Database for Pediatric and Congenital Heart Surgery.

BACKGROUND: The World Database for Pediatric and Congenital Heart Surgery (WDPCHS), sponsored by the World Society for Pediatric and Congenital Heart Surgery (WSPCHS), provides complex programmatic outcomes analyses for all members of the WSPCHS. METHODS: The Data center, currently at Kirklin Institute for Research in Surgical Outcomes (KIRSO), University of Alabama, Birmingham (USA), provides biannual reports to all active members of the database. This report presents a descriptive analysis of these procedures submitted from January 1, 2017 to December 31, 2020. RESULTS: A total of 37,386 procedures were submitted with an overall mortality of 4.3%. The majority of submissions were from Asian countries. The majority of cases submitted from these countries were of Society of Thoracic Surgeons (STS)-European Association for Cardio-Thoracic Surgery (STAT) Mortality Categories I and II. CONCLUSIONS: The WSPCHS accomplished one of its missions in 2017 when the WDPCHS began accepting data from pediatric and congenital heart surgery programs across the globe. In doing so, it became one of the first organizations to create a platform for the exchange of knowledge and experience, regardless of the socioeconomic status of the particular program or country.

Generalizability of Trial Data to Real-World Practice: An Analysis of The Society of Thoracic Surgeons Intermacs Database.

BACKGROUND: Although the current wide-scale adoption of the HeartMate 3 left ventricular assist device can be attributed to favorable clinical trial outcomes, restrictive clinical trial eligibility criteria may result in lack of generalizability to real-world populations. We assessed the generalizability of left ventricular assist device clinical trial outcomes and evaluated the prognostic value of specific inclusion and exclusion criteria. METHODS: The Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Therapy With HeartMate 3 (MOMENTUM 3) eligibility criteria were applied to patients identified in The Society of Thoracic Surgeons Interagency Registry for Mechanically Assisted Circulatory Support (Intermacs) who underwent HeartMate 3 implantation (n = 4610) between August 2017 and March 2020. Patients were categorized as trial-eligible or trial-ineligible and by number of ineligibility criteria. The effect of trial eligibility on mortality was estimated using Cox models. RESULTS: Indications for HeartMate 3 implant included destination therapy (n = 2827, 61%), bridge to candidacy (n = 969, 21%), and bridge to transplant (n = 702, 15%). A total of 1941 recipients (42%) were trial-ineligible, with 1245 (27%) meeting one ineligibility criterion, 470 (10%) meeting two, and 226 (5%) meeting three or more. Estimated 1-year mortality for trial-ineligible recipients was higher than for trial-eligible recipients (17% ± 1% vs 10% ± 1%, P < .001). Compared with trial-eligible patients, 1-year mortality was incrementally higher for patients meeting one ineligibility criterion (15% ± 1%), two criteria (16% ± 2%), and three or more criteria (30% ± 3%). Thrombocytopenia and elevated creatinine, bilirubin, and international normalized ratio in trial-ineligible patients were independently associated with increased mortality. CONCLUSIONS: Despite differences in mortality, both trial-eligible and trial-ineligible HeartMate 3 recipients had excellent outcomes in real-world practice, suggesting future trial eligibility criteria could be expanded.

Progression to Transplant Under the New Heart Allocation System: The Society of Thoracic Surgeons Intermacs Database.

BACKGROUND: Under the new heart allocation policy patients needing durable left ventricular assist devices receive lower priority on the transplant list. We sought to identify predictors of successful heart transplant after durable device implant as a means to inform patient care in the current era. METHODS: All patients (N = 25,164) undergoing primary durable left ventricular device implant in The Society of Thoracic Surgeons Intermacs database (2010-2019) were evaluated. Patients identified as bridge to transplant (BTT; n = 5242) or bridge to candidacy (n = 6248) were analyzed with the endpoint of transplant before (n = 10,588) and after (n = 902) the change in the heart allocation system on October 18, 2018. Multivariable hazard modeling was used to assess risk-adjusted time to event associations. RESULTS: Of 11,490 patients, 45.5% progressed to transplant (BTT, 53.0%; bridge to candidacy, 36.6%), most by 14 months after left ventricular assist device implant. Under the new allocation system progression to transplant was significantly lower at 14 months (18.6% vs 34.8%, P < .001). Factors associated with successful BTT before the allocation change included BTT status, white race, and married. Under the new allocation system BTT status (hazard ratio, 1.79; 95% confidence interval, 1.19-2.69; P < .0054) remained a positive predictor, whereas blood type O (hazard ratio, 0.43; 95% confidence interval, 0.28-0.65; P < .0001) remained a negative predictor. CONCLUSIONS: Despite having priority in the previous allocation system, less than half of BTT and bridge to candidacy patients progressed to transplant. Under the current system these numbers are further reduced. Heart teams should consider the implications of longer wait times for a durable left ventricular assist device when determining the optimal bridging strategy.

A prediction model for postoperative urinary retention after thoracic surgery.

Background: Urinary retention remains a frequent postoperative complication, associated with patient discomfort and delayed discharge following general thoracic surgery (GTS). We aimed to develop and prospectively validate a predictive model of postoperative urinary retention (POUR) among GTS patients. Methods: We retrospectively developed a predictive model using data from the Society of Thoracic Surgeons GTS Database at our institution. The patient study cohort included adults undergoing elective in-patient surgical procedures without a history of renal failure or Foley catheter on entry to the recovery suite (August 2013 to March 2017). Multivariable logistic regression models identified factors associated with urinary retention, and a nomogram to aid medical decision making was developed. The predictive model was validated in a cohort of GTS patients between April 2017 and November 2018 using receiver operating characteristic (ROC) analysis. Results: The predictive model was developed from 1484 GTS patients, 284 of whom (19%) experienced postoperative urinary retention within 24 hours of the operation. Risk factors for POUR included older age, male sex, higher preoperative creatinine, chronic obstructive pulmonary disease, primary diagnosis, primary procedure, and use of postoperative patient-controlled analgesia. A logistic nomogram for estimating the risk of POUR was created and validated in 646 patients, 65 of whom (10%) had urinary retention. The ROC curves of development and validation models had similar favorable c-statistics (0.77 vs 0.72; P > .05). Conclusions: Postoperative urinary retention occurs in nearly 20% of patients undergoing major GTS. Using a validated predictive model may help by targeting certain patients with prophylactic measures to prevent this complication.

Cardiac Surgery and Postoperative Renal Allograft Failure.

BACKGROUND: Although cardiac surgery among renal allograft recipients is relatively safe, less is known about the impact of cardiac surgery on the functioning renal allograft. This study assessed postoperative renal failure among renal transplant recipients undergoing cardiac surgery. METHODS: The study population was identified by matching medical record numbers from the United Network for Organ Sharing Kidney Transplant Database to a cardiovascular surgery database and The Society of Thoracic Surgeons Adult Cardiac Surgery Database for the authors' institution from January 1992 through August 2018. RESULTS: One hundred seventy-nine renal transplant recipients with a functioning allograft underwent cardiac surgery a mean of 6.4 ± 5.6 years after renal transplantation. Thirty (17.6%) of the 170 patients either died or had allograft failure during the first postoperative year. Receiver-operating characteristics curve analysis using Cox regression demonstrated an optimal cutoff point for preoperative serum creatinine predicting postoperative allograft loss is 1.9 mg/dL (hazard ratio 3; 95% confidence interval, 1.5 to 6.9) with a model C statistic of 0.642. CONCLUSIONS: The current study affirms findings in the literature that cardiac surgery in renal transplant recipients carries acceptable perioperative morbidity and mortality. Renal transplant recipients who underwent cardiac surgery had a constant hazard of renal allograft loss similar to that of the general transplant population. A preoperative serum creatinine value greater than 1.9 mg/dL increases the risk for long-term renal allograft loss after cardiac surgery.

Surgical Management of Heterotaxy Syndrome: Current Challenges and Opportunities.

INTRODUCTION: Heterotaxy syndrome presents a unique challenge in surgical management, even in the current era. We hypothesized that certain anatomic subsets merit novel strategies. METHODS: We analyzed morphologic details, surgeries, comorbidities, subsequent admissions, and survival using Kaplan-Meier methods and multivariable risk models from a single-institution experience of 103 consecutive patients with heterotaxy who underwent cardiac surgery between January 1, 1990, and May 31, 2016. RESULTS: Of the 103 patients (50 males and 53 females), 31 had left atrial isomerism, 64 had right atrial isomerism (RAI), and 8 patients' isomerism was indeterminate (IND), with first cardiac operation at a mean 1.0 year (standard deviation ±3.0 years) of age. Kaplan-Meier overall survival estimate was 83.1% at six months, 77.8% at one year, 65.9% at five years, and 52.1% at ten years. Survival was particularly low among RAI following repair of total anomalous pulmonary venous connection (TAPVC) at first operation, with one- and five-year survival of 57% and 46%, respectively. By multivariable analysis, the only risk factor for death during the early phase (hazard model) was repair of TAPVC at the first cardiac operation (hazard ratio [HR]: 4.4, P = .01), and risk factors during the longer term constant phase were atrioventricular valve (AVV) regurgitation (HR: 4.2, P < .01), male gender (HR: 3.7, P < .01), and two-ventricle repair (HR: 3.0, P = .02). Patients with heterotaxy undergoing the Fontan procedure had excellent subsequent survival (85% at ten years). CONCLUSIONS: This analysis of over 100 patients with heterotaxy identified TAPVC requiring initial repair as the major risk factor for early death and important AVV regurgitation as the major risk factor in the longer term. Survival with RAI and early repair of TAPVC were poor, with one-year mortality exceeding 40%. Patients with single ventricle completing the Fontan operation enjoyed outstanding ten-year survival (85%). Initial management of RAI requiring early repair of TAPVC remains challenging. For this high-risk subset, alternative strategies such as early referral for cardiac transplantation evaluation warrant consideration.

Prevalence of Activity Limitations and Association with Multimorbidity Among US Adults 50 to 64 Years Old.

BACKGROUND: Functional limitations may be more common in middle-aged adults than previously recognized. However, there are few published data on the prevalence of activity limitations, and their association with multimorbidity, among adults 50 to 64 years old. OBJECTIVE: To describe the prevalence of activity limitations and the association with multimorbidity in middle-aged adults. DESIGN: Cross-sectional analysis of US population-based National Health and Nutrition Examination Survey (NHANES) 2011-2016. PARTICIPANTS: The total number of community-dwelling NHANES participants aged 50-64 years old is 4217. MAIN MEASURES: Chronic conditions included hypertension, high cholesterol, diabetes mellitus, obesity, chronic kidney disease, cancer, stroke, coronary heart disease, heart failure, chronic obstructive pulmonary disease/asthma, arthritis, and depression. Activity limitations were defined as any difficulty within each of four International Classification of Functioning (ICF) domains: functional limitations (kneeling, carrying, standing, sitting, reaching, grasping, pulling), mobility (walking » mile, climbing 10 steps), basic activities of daily living (BADLs; walking, transferring, eating, dressing), and instrumental activities of daily living (IADLs; finances, chores, cooking). We calculated prevalence ratios for activity limitations using generalized estimating equations. KEY RESULTS: The prevalence of functional limitations, mobility limitations, BADL difficulty, and IADL difficulty was 34%, 11%, 15%, and 17%, respectively. Seventy-two percent of participants had two or more chronic conditions; 23% had two, 18% had three, 15% had four, and 16% had five or more. Multivariable adjusted prevalence ratios (95% CI) for functional limitations among those with 2, 3, 4, and 5 or more chronic conditions, compared with 0-1 conditions, were 1.94 (1.43-2.63), 2.50 (1.93-3.23), 3.26 (2.48-4.27), and 4.54 (3.48-5.93), respectively (p trend < 0.001). Larger prevalence ratios at a higher number of chronic conditions were present for mobility limitations, BADL difficulty, and IADL difficulty. CONCLUSIONS: Problems with function are not limited to older adults and multimorbidity may be helpful for identifying middle-aged adults with a high prevalence of activity limitations.

Racial Differences in Maintaining Optimal Health Behaviors Into Middle Age.

INTRODUCTION: Earlier development of cardiovascular disease risk factors in blacks versus whites may result from differences in maintaining health behaviors. Age-specific racial differences in maintaining health behaviors from ages 18 to 50 years were determined. METHODS: In 1985-1986, the population-based Coronary Artery Risk Development in Young Adults study enrolled 5,115 participants aged 18-30 years. In 2017, a total of 2,485 blacks and 2,407 whites with one or more optimal health behaviors at baseline who attended one or more of seven follow-up exams over 25 years (i.e., through 2010-2011) were analyzed. The primary outcome, maintaining four or more optimal health behaviors, included BMI <25; never smoking; ≥150 minutes/week of moderate to vigorous physical activity; no/moderate alcohol intake (women/men: zero to seven/zero to 14 drinks per week); and Dietary Approaches to Stop Hypertension diet adherence score ≥15 (i.e., baseline highest quartile). Hazard ratios comparing blacks with whites for maintaining optimal health behaviors were calculated among participants with each optimal behavior at baseline. RESULTS: From ages 18 to 50 years, 2.6% of blacks and 9.2% of whites maintained four or more optimal health behaviors (for optimal BMI: 16.0% and 30.1%, smoking status: 74.6% and 78.4%, physical activity: 17.7% and 21.4%, alcohol intake: 68.4% and 64.6%, diet adherence: 3.9% and 10.3%, respectively). The multivariable adjusted hazard ratio comparing blacks with whites was 0.63 (95% CI=0.56, 0.72) for maintaining four or more optimal health behaviors (for optimal BMI: 0.82 [95% CI=0.66, 1.01], smoking status: 0.57 [95% CI=0.52, 0.62], physical activity: 0.83 [95% CI=0.75, 0.91], alcohol intake: 1.19 [95% CI=1.03, 1.37], diet adherence: 0.71 [95% CI=0.61, 0.82]). CONCLUSIONS: Fewer blacks than whites maintained four or more optimal health behaviors until age 50 years, but maintenance was low among both races.

Trends in Statin Use Among US Adults With Chronic Kidney Disease, 1999-2014.

Background The 2013 American College of Cardiology/American Heart Association cholesterol guidelines recognize cardiovascular disease and diabetes mellitus but not chronic kidney disease ( CKD ) as high-risk conditions warranting statin therapy. Statin use may be lower for adults with CKD compared with adults with conditions that have guideline indications for statin use. Methods and Results We analyzed data from the National Health and Nutrition Examination Surveys from 1999-2002 through 2011-2014 to determine trends in the percentage of US adults ≥20 years of age with and without CKD taking statins. CKD was defined by an estimated glomerular filtration rate <60 mL/min per 1.73m2 or albumin-to-creatinine ratio ≥30 mg/g. Statin use was identified through a medication inventory. Between 1999-2002 and 2011-2014, the percentage of adults taking statins increased from 17.6% to 35.7% among those with CKD and from 6.8% to 14.7% among those without CKD . After multivariable adjustment, adults with CKD were not more likely to be taking statins compared with those without CKD (prevalence ratio, 1.01; 95% CI] 0.96-1.08). Among adults without a history of cardiovascular disease, those with CKD but not diabetes mellitus were less likely to be taking statins compared with those with diabetes mellitus but not CKD (prevalence ratio, 0.54; 95% CI , 0.44-0.66). Among adults with a history of cardiovascular disease, there was no difference in statin use between those with CKD but not diabetes mellitus versus those with diabetes mellitus but not CKD (prevalence ratio, 0.95; 95% CI , 0.79-1.15). Conclusions CKD does not appear to be a major stimulus for statin use among US adults.

Cardiovascular Health and Healthcare Utilization and Expenditures Among Medicare Beneficiaries: The REasons for Geographic And Racial Differences in Stroke (REGARDS) Study.

BACKGROUND: Better cardiovascular health is associated with lower cardiovascular disease risk. METHODS AND RESULTS: We determined the association between cardiovascular health and healthcare utilization and expenditures in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. We included 6262 participants ≥65 years with Medicare fee-for-service coverage for the year after their baseline study visit in 2003-2007. Cardiovascular health at baseline was assessed using the American Heart Association's Life's Simple 7 (LS7) metric, which includes 7 factors: cigarette smoking, physical activity, diet, body mass index, blood pressure, cholesterol, and glucose. Healthcare utilization and expenditures were ascertained using Medicare claims in the year following baseline. Overall, 17.2%, 31.1%, 29.0%, 16.4% and 6.4% of participants had 0 to 1, 2, 3, 4, and 5 to 7 ideal LS7 factors, respectively. The multivariable-adjusted relative risk (95% confidence interval [CI]) for having any inpatient and outpatient encounters comparing participants with 5 to 7 versus 0 to 1 ideal LS7 factors were 0.55 (0.39, 0.76) and 1.00 (0.98, 1.02), respectively. Among participants with 0 to 1 and 5 to 7 ideal LS7 factors, mean inpatient expenditures were $3995 and $1250, respectively, mean outpatient expenditures were $5166 and $2853, respectively, and mean total expenditures were $9147 and $4111, respectively. After multivariable adjustment, the mean (95% CI) cost difference comparing participants with 5 to 7 versus 0 to 1 ideal LS7 factors was -$2551 (-$3667, -$1435) for inpatient, -$2410 (-$3089, -$1731) for outpatient, and -$5016 (-$6577, -$3454) for total expenditures. CONCLUSIONS: Better cardiovascular health is associated with lower risk for inpatient encounters and lower inpatient and outpatient healthcare expenditures.

Characteristics and prognosis of acute myocardial infarction by discharge diagnosis: the Reasons for Geographic and Racial Differences in Stroke study.

PURPOSE: To compare the characteristics and prognosis of acute myocardial infarctions (AMIs) that were not the primary reason for hospitalization, and thus not primary discharge diagnosis, to AMIs that were the primary reason for hospitalization. METHODS: Primary discharge diagnoses for Reasons for Geographic and Racial Differences in Stroke study participants (black and white men and women age ≥45 years) with adjudicated AMIs were categorized as "AMI" or "other". Cox models were used to compare mortality up to 5 years post-AMI between primary discharge diagnoses of AMI and other. RESULTS: Of 871 AMIs, primary discharge diagnosis was not AMI in 550 (63%). When primary discharge diagnosis was not AMI, average troponin elevations were smaller and heart failure was more common. Adjusted for participant and hospitalization characteristics, all-cause, coronary heart disease, and cardiovascular disease mortality after AMI were similar between groups (hazard ratios [95% confidence intervals]: 1.08 [0.80-1.47]; 1.29 [0.76-2.18]; and 0.86 [0.58-1.27], respectively). CONCLUSIONS: Studies limited to individuals with primary discharge diagnosis of AMI may underestimate the burden of AMI and exclude a group with elevated risk of all-cause, coronary heart disease, and cardiovascular disease mortality.

The role of prolactin receptor in GH signaling in breast cancer cells.

GH and prolactin (PRL) are structurally related hormones that exert important effects in disparate target tissues. Their receptors (GHR and PRLR) reside in the cytokine receptor superfamily and share signaling pathways. In humans, GH binds both GHR and PRLR, whereas PRL binds only PRLR. Both hormones and their receptors may be relevant in certain human and rodent cancers, including breast cancer. GH and PRL promote signaling in human T47D breast cancer cells that express both GHR and PRLR. Furthermore, GHR and PRLR associate in a fashion augmented acutely by GH, even though GH primarily activates PRLR, rather than GHR, in these cells. To better understand PRLR's impact, we examined the effects of PRLR knockdown on GHR availability and GH sensitivity in T47D cells. T47D-ShPRLR cells, in which PRLR expression was reduced by stable short hairpin RNA (shRNA) expression, were compared with T47D-SCR control cells. PRLR knockdown decreased the rate of GHR proteolytic turnover, yielding GHR protein increase and ensuing sensitization of these cells to GHR signaling events including phosphorylation of GHR, Janus kinase 2, and signal transducer and activator of transcription 5 (STAT5). Unlike in T47D-SCR cells, acute GH signaling in T47D-ShPRLR cells was not blocked by the PRLR antagonist G129R but was inhibited by the GHR-specific antagonist, anti-GHR(ext-mAb). Thus, GH's use of GHR rather than PRLR was manifested when PRLR was reduced. In contrast to acute effects, GH incubation for 2 h or longer yielded diminished STAT5 phosphorylation in T47D-ShPRLR cells compared with T47D-SCR, a finding perhaps explained by markedly greater GH-induced GHR down-regulation in cells with diminished PRLR. However, when stimulated with repeated 1-h pulses of GH separated by 3-h washout periods to more faithfully mimic physiological GH pulsatility, T47D-ShPRLR cells exhibited greater transactivation of a STAT5-responsive luciferase reporter than did T47D-SCR cells. Our data suggest that PRLR's presence meaningfully affects GHR use in breast cancer cells.

Excretion of anti-angiogenic proteins in patients with chronic allograft dysfunction.

BACKGROUND: We have recently documented the appearance of an anti-angiogenic peptide, endorepellin, in the urine of patients with chronic allograft dysfunction (CAD). METHODS: Here, we analyzed using enzyme-linked immunosorbent assay the excretion of anti-angiogenic peptides endostatin, pigment epithelium-derived factor (PEDF) and Kruppel-like factor-2 (KLF-2), in healthy individuals, patients with stable graft function and patients with various degrees of CAD. RESULTS: In healthy subjects and patients with CAD-0, endostatin, PEDF and KLF-2 excretions were at the level of detection. In contrast, there were significant differences between the patients with CAD-3 and CAD-0, CAD-1 and healthy controls for endostatin and CAD-0 versus CAD-3 for PEDF, but no differences in KLF-2 excretion. Receiver operating characteristic (ROC) curve analyses demonstrated a highly discriminative profile for all three biomarkers: the combination of these parameters offered 83% sensitivity and 90% specificity in distinguishing CAD-0 from CAD-1-3. The quality of these potential biomarkers of CAD was, however, highest in discriminating CAD status in biopsy-proven cases and dropped when CAD-0 was diagnosed based on clinical criteria. CONCLUSIONS: In conclusion, these findings indicate the diagnostic potential of urinary detection of endostatin, PEDF and to lesser degree KLF-2 and suggest a mechanistic role played by anti-angiogenic substances in the developing vasculopathy and vascular rarefaction in patients with CAD.

A CK2-dependent mechanism for activation of the JAK-STAT signaling pathway.

JAK-STAT signaling is involved in the regulation of cell survival, proliferation, and differentiation. JAK tyrosine kinases can be transiently activated by cytokines or growth factors in normal cells, whereas they become constitutively activated as a result of mutations that affect their function in tumors. Specifically, the JAK2V617F mutation is present in the majority of patients with myeloproliferative disorders (MPDs) and is implicated in the pathogenesis of these diseases. In the present study, we report that the kinase CK2 is a novel interaction partner of JAKs and is essential for JAK-STAT activation. We demonstrate that cytokine-induced activation of JAKs and STATs and the expression of suppressor of cytokine signaling 3 (SOCS-3), a downstream target, are inhibited by CK2 small interfering RNAs or pharmacologic inhibitors. Endogenous CK2 is associated with JAK2 and JAK1 and phosphorylates JAK2 in vitro. To extend these findings, we demonstrate that CK2 interacts with JAK2V617F and that CK2 inhibitors suppress JAK2V617F autophosphorylation and downstream signaling in HEL92.1.7 cells (HEL) and primary cells from polycythemia vera (PV) patients. Furthermore, CK2 inhibitors potently induce apoptosis of HEL cells and PV cells. Our data provide evidence for novel cross-talk between CK2 and JAK-STAT signaling, with implications for therapeutic intervention in JAK2V617F-positive MPDs.

Growth hormone receptor targeting to lipid rafts requires extracellular subdomain 2.

GH receptor (GHR) is a single membrane-spanning glycoprotein dimer that binds GH in its extracellular domain (ECD). GH activates the GHR intracellular domain (ICD)-associated tyrosine kinase, JAK2, which causes intracellular signaling. We previously found that plasma membrane (PM)-associated GHR was dramatically enriched in the lipid raft (LR) component of the membrane and that localization of GHR within PM regions may regulate GH signaling by influencing the profile of pathway activation. In this study, we examined determinants of LR localization of the GHR using a reconstitution system which lacks endogenous JAK2 and GHR. By non-detergent extraction and multistep fractionation, we found that GHR was highly enriched in the LR fraction independent of JAK2 expression. Various GHR mutants were examined in transfectants harboring JAK2. LR concentration was observed for a GHR in which the native transmembrane domain (TMD) is replaced by that of the unrelated LDL receptor and for a GHR that lacks its ICD. Thus, LR association requires neither the TMD nor the ICD. Similarly, a GHR that lacks the ECD, except for the membrane-proximal ECD stem region, was only minimally LR-concentrated. Mutants with internal stem deletions in the context of the full-length receptor were LR-concentrated similar to the wild-type. A GHR lacking ECD subdomain 1 reached the PM and was LR-concentrated, while one lacking ECD subdomain 2, also reached the PM, but was not LR-concentrated. These data suggest LR targeting resides in ECD subdomain 2, a region relatively uninvolved in GH binding.