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Supplementary Figure 3 from Alterations of the HBP1 Transcriptional Repressor Are Associated with Invasive Breast Cancer

Invasive breast cancer has a high risk of recurrence to incurable disease and needs improved prognostic and therapeutic tools. Our work combines clinical and molecular analyses to show that the transcriptional repressor HBP1 may be a new target for invasive breast cancer. Previous work indicated that HBP1 regulated proliferation and senescence and inhibited Wnt signaling. Two of these functions have been associated with invasive breast cancer. In 76 breast tumors, we identified 10 HBP1 mutations/variants that were associated with fully invasive breast cancer. In a separate analysis, we found that a subset of invasive breast cancer specimens also had reduced HBP1 mRNA levels. These clinical correlations suggested that mutation or reduction of HBP1 occurs in invasive breast cancer and that HBP1 might regulate the proliferation and invasiveness of this breast cancer type. Analysis of the HBP1 mutants showed they were functionally defective for suppressing Wnt signaling. To test the consequences of reduced HBP1 levels, we used RNA interference to knock down HBP1 and observed increased Wnt signaling, tumorigenic proliferation, and invasiveness in cell and animal breast cancer models. Lastly, statistical analysis of a breast cancer patient database linked reduced HBP1 expression to breast cancer recurrence. In considering two-gene criteria for relapse potential, reduced expression of HBP1 and SFRP1, which is another Wnt inhibitor that was recently linked to invasive breast cancer, strikingly correlated with recurrence. Together, these data indicate that HBP1 may be a molecularly and clinically relevant regulator of breast cancer transitions that eventually lead to poor prognosis. [Cancer Res 2007;67(13):6136–45]

Supplementary Figure 2 from Alterations of the HBP1 Transcriptional Repressor Are Associated with Invasive Breast Cancer

Supplementary Figure 1 from Alterations of the HBP1 Transcriptional Repressor Are Associated with Invasive Breast Cancer

Supplementary Table 1 from Alterations of the HBP1 Transcriptional Repressor Are Associated with Invasive Breast Cancer

Background Elevated pulmonary vascular resistance (PVR) is common in patients with advanced heart failure. PVR generally improves after left ventricular assist device (LVAD) implantation, but the rate of decrease has not been quantified and the patient characteristics most strongly associated with this improvement are unknown. Methods and Results We analyzed 1581 patients from the Interagency Registry for Mechanically Assisted Circulatory Support registry who received a primary continuous-flow LVAD, had a baseline PVR of ≥3 Wood units (WU), and had PVR measured at least once postoperatively. Multivariable linear mixed effects modeling was used to evaluate independent associations between postoperative PVR and patient characteristics. PVR decreased by 1.53 WU (95% confidence interval [CI] 1.27–1.79 WU) per month in the first 3 months postoperatively, and by 0.066 WU (95% CI 0.060–0.070 WU) per month thereafter. Severe mitral regurgitation at any time during follow-up was associated with a 1.29 WU (95% CI 1.05–1.52 WU) higher PVR relative to absence of mitral regurgitation at that time. In a cross-sectional analysis, 15%–25% of patients had persistently elevated PVR of ≥3 WU at any given time within 36 months after LVAD implantation. Conclusion The PVR tends to decrease rapidly early after implantation, and only more gradually thereafter. Residual mitral regurgitation may be an important contributor to elevated postoperative PVR. Future research is needed to understand the implications of elevated PVR after LVAD implantation and the optimal strategies for prevention and treatment.

BACKGROUND The proportion of live births by cesarean delivery (CD) in China is significant, with some, particularly rural, provinces reporting up to 62.5%. The No Pain Labor & Delivery-Global Health Initiative (NPLD-GHI) was established to improve obstetric and neonatal outcomes in China, including through a reduction of CD through educational efforts. The purpose of this study was to determine whether a reduction in CD at a rural Chinese hospital occurred after NPLD-GHI. We hypothesized that a reduction in CD trend would be observed. METHODS The NPLD-GHI program visited the Weixian Renmin Hospital, Hebei Province, China, from June 15 to 21, 2014. The educational intervention included problem-based learning, bedside teaching, simulation drill training, and multidisciplinary debriefings. An interrupted time-series analysis using segmented logistic regression models was performed on data collected between June 1, 2013 and May 31, 2015 to assess whether the level and/or trend over time in the proportion of CD births would decline after the program intervention. The primary outcome was monthly proportion of CD births. Secondary outcomes included neonatal intensive care unit (NICU) admissions and extended NICU length of stay, neonatal antibiotic and intubation use, and labor epidural analgesia use. RESULTS Following NPLD-GHI, there was a level decrease in CD with an estimated odds ratio (95% confidence interval [CI]) of 0.87 (0.78-0.98), P = .017, with odds (95% CI) of monthly CD reduction an estimated 3% (1-5; P < .001), more in the post- versus preintervention periods. For labor epidural analgesia, there was a level increase (estimated odds ratio [95% CI] of 1.76 [1.48-2.09]; P < .001) and a slope decrease (estimated odds ratio [95% CI] of 0.94 [0.92-0.97]; P < .001). NICU admissions did not have a level change (estimated odds ratio [95% CI] of 0.99 [0.87-1.12]; P = .835), but the odds (95% CI) of monthly reduction in NICU admission was estimated 9% (7-11; P < .001), greater in post- versus preintervention. Neonatal intubation level and slope changes were not statistically significant. For neonatal antibiotic administration, while the level change was not statistically significant, there was a decrease in the slope with an odds (95% CI) of monthly reduction estimated 6% (3-9; P < .001), greater post- versus preintervention. CONCLUSIONS In a large, rural Chinese hospital, live births by CD were lower following NPLD-GHI and associated with increased use of labor epidural analgesia. We also found decreasing NICU admissions. International-based educational programs can significantly alter practices associated with maternal and neonatal outcomes.

Identifying patients who are likely to transfer from peritoneal dialysis (PD) to hemodialysis (HD) before transition could improve their subsequent care. This study developed a prediction tool for transition from PD to HD.Retrospective cohort study.Adults initiating PD between January 2008 and December 2011, followed up through June 2015, for whom data were available in the US Renal Data System (USRDS).Clinical characteristics at PD initiation and peritonitis claims.Transfer to HD, with the competing outcomes of death and kidney transplantation.Outcomes were ascertained from USRDS treatment history files. Subdistribution hazards (competing-risk) models were fit using clinical characteristics at PD initiation. A nomogram was developed to classify patient risk at 1, 2, 3, and 4 years. These data were used to generate quartiles of HD transfer risk; this quartile score was incorporated into a cause-specific hazards model that additionally included a time-dependent variable for peritonitis.29,573 incident PD patients were followed up for a median of 21.6 (interquartile range, 9.0-42.3) months, during which 41.2% transferred to HD, 25.9% died, 17.1% underwent kidney transplantation, and the rest were followed up to the study end in June 2015. Claims for peritonitis were present in 11,733 (40.2%) patients. The proportion of patients still receiving PD decreased to 50% at 22.6 months and 14.2% at 5 years. Peritonitis was associated with a higher rate of HD transfer (HR, 1.82; 95% CI, 1.76-1.89; P 0.001), as were higher quartile scores of HD transfer risk (HRs of 1.31 [95% CI, 1.25-1.37), 1.51 [95% CI, 1.45-1.58], and 1.78 [95% CI, 1.71-1.86] for quartiles 2, 3, and 4 compared to quartile 1 [P 0.001 for all]).Observational data, reliant on the Medical Evidence Report and Medicare claims.A large majority of the patients who initiated renal replacement therapy with PD discontinued this modality within 5 years. Transfer to HD was the most common outcome. Patient characteristics and comorbid diseases influenced the probability of HD transfer, death, and transplantation, as did episodes of peritonitis.

Background During cancer operations, the cancer itself is often hard to delineate—buried beneath healthy tissue and lacking discernable differences from the surrounding healthy organ. Long-wave infrared, or thermal, imaging poses a unique solution to this problem, allowing for the real-time label-free visualization of temperature deviations within the depth of tissues. The current study evaluated this technology for intraoperative cancer detection. Methods In this diagnostic study, patients with gastrointestinal, hepatobiliary, and renal cancers underwent long-wave infrared imaging of the malignancy during routine operations. Results It was found that 74% were clearly identifiable as hypothermic anomalies. The average temperature difference was 2.4°C (range 0.7 to 5.0) relative to the surrounding tissue. Cancers as deep as 3.3 cm from the surgical surface were visualized. Yet, 79% of the images had clinically relevant false positive signals [median 3 per image (range 0 to 10)] establishing an accuracy of 47%. Analysis suggests that the degree of temperature difference was primarily determined by features within the cancer and not peritumoral changes in the surrounding tissue. Conclusion These findings provide important information on the unexpected hypothermal properties of intra-abdominal cancers, directions for future use of intraoperative long-wave infrared imaging, and new knowledge about the in vivo thermal energy expenditure of cancers and peritumoral tissue.

Background Neutropenia is a serious complication following heart transplantation (OHT); however, risk factors for its development and its association with outcomes is not well described. We sought to study the prevalence of neutropenia, risk factors associated with its development, and its impact on infection, rejection, and survival. Methods A retrospective single-center analysis of adult OHT recipients from July 2004 to December 2017 was performed. Demographic, laboratory, medication, infection, rejection, and survival data were collected for 1 year post-OHT. Baseline laboratory measurements were collected within the 24 hours before OHT. Neutropenia was defined as absolute neutrophil count ≤1000 cells/mm3. Cox proportional hazards models explored associations with time to first neutropenia. Associations between neutropenia, analyzed as a time-dependent covariate, with secondary outcomes of time to infection, rejection, or death were also examined. Results Of 278 OHT recipients, 84 (30%) developed neutropenia at a median of 142 days (range 81-228) after transplant. Factors independently associated with increased risk of neutropenia included lower baseline WBC (HR 1.12; 95% CI 1.11-1.24), pre-OHT ventricular assist device (1.63; 1.00-2.66), high-risk CMV serostatus [donor positive, recipient negative] (1.86; 1.19-2.88), and having a previous CMV infection (4.07; 3.92-13.7). Conclusions Neutropenia is a fairly common occurrence after adult OHT. CMV infection was associated with subsequent neutropenia, however, no statistically significant differences in outcomes were found between neutropenic and non-neutropenic patients in this small study. It remains to be determined in future studies if medication changes in response to neutropenia would impact patient outcomes.

Background Despite well-defined criteria for use of antibiotics in patients presenting with mild to moderate Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD), their overuse is widespread. We hypothesized that following implementation of a molecular multiplex respiratory viral panel (RVP), AECOPD patients with viral infections would be more easily identified, limiting antibiotic use in this population. The primary objective of our study was to investigate if availability of the RVP decreased antibiotic prescription at discharge among patients with AECOPD. Methods This is a single center, retrospective, before (pre-RVP) - after (post-RVP) study of patients admitted to a tertiary medical center from January 2013 to March 2016. The primary outcome was antibiotic prescription at discharge. Groups were compared using univariable and multivariable logistic-regression. Results A total of 232 patient-episodes were identified, 133 following RVP introduction. Mean age was 68.1 (pre-RVP) and 68.3 (post-RVP) years respectively (p = 0.88). Patients in pre-RVP group were similar to the post-RVP group with respect to gender (p = 0.54), proportion of patients with BMI

Peritoneal lesions are common findings during operative abdominal cancer staging. The decision to perform biopsy is made subjectively by the surgeon, a practice the authors hypothesized to be imprecise. This study aimed to describe optical characteristics differentiating benign peritoneal lesions from peritoneal metastases. The study evaluated laparoscopic images of 87 consecutive peritoneal lesions biopsied during staging laparoscopies for gastrointestinal malignancies from 2014 to 2017. A blinded survey assessing these lesions was completed by 10 oncologic surgeons. Three senior investigators categorized optical features of the lesions. Computer-aided digital image processing and machine learning was used to classify the lesions. Of the 87 lesions, 28 (32%) were metastases. On expert survey, surgeons on the average misidentified 36 ± 19% of metastases. Multivariate analysis identified degree of nodularity, border transition, and degree of transparency as independent predictors of metastases (each p

OBJECTIVE: Approximately 84 million people in the US have pre-diabetes, but only a fraction of them receive proven effective therapies to prevent type 2 diabetes. We estimated the value of prioritizing individuals at highest risk of progression to diabetes for treatment, compared to non-targeted treatment of individuals meeting inclusion criteria for the Diabetes Prevention Program (DPP). METHODS: Using microsimulation to project outcomes in the DPP trial population, we compared two interventions to usual care: (1) lifestyle modification and (2) metformin administration. For each intervention, we compared targeted and non-targeted strategies, assuming either limited or unlimited program capacity. We modeled the individualized risk of developing diabetes and projected diabetic outcomes to yield lifetime costs and quality-adjusted life expectancy, from which we estimated net monetary benefits (NMB) for both lifestyle and metformin versus usual care. RESULTS: Compared to usual care, lifestyle modification conferred positive benefits and reduced lifetime costs for all eligible individuals. Metformin’s NMB was negative for the lowest population risk quintile. By avoiding use when costs outweighed benefits, targeted administration of metformin conferred a benefit of $500 per person. If only 20% of the population could receive treatment, when prioritizing individuals based on diabetes risk, rather than treating a 20% random sample, the difference in NMB ranged from $14,000 to $20,000 per person. CONCLUSIONS: Targeting active diabetes prevention to patients at highest risk could improve health outcomes and reduce costs compared to providing the same intervention to a similar number of patients with pre-diabetes without targeted selection.

Purpose We examined the role of obesity and intraoperative red blood cell (RBC) and platelet transfusion in early allograft dysfunction (EAD) following liver transplantation (LT). Methods This is a retrospective analysis of 239 adult deceased-donor LT recipients over a 10-year period. EAD was defined by Olthoff’s criteria. Data collection included donor (D) and recipient (R) age, body mass index (BMI) ≥ 35 kg/m2, diabetes mellitus, allograft macrosteatosis, and intraoperative (RBC) and platelet administration. We employed logistic regression to evaluate associations of these factors with EAD. Results are presented as odds ratios (OR) and 95% confidence intervals (CI) with corresponding P values. A P ≤ .05 was considered statistically significant. Results EAD occurred in 85 recipients (36%). Macrosteatosis data were available for 199 donors. In the multivariate analyses, BMI-D ≥ 35 kg/m2 increased the odds of developing EAD by 156% in the entire cohort (OR 2.56, 95% CI 1.09-6.01) and by 187% in recipients with macrosteatosis data (n = 199, OR 2.87, 95% CI 1.15-7.15). Each unit of RBCs increased the odds for EAD by 8% (OR 1.08, 95% CI 1.02-1.14) and, for the subgroup of 238 recipients with macrosteatosis data, by 9% (OR 1.09, 95% CI 1.02-1.16). Conclusion We found a significant independent association of donor obesity and intraoperative RBC transfusion with EAD but no such association for platelet administration, MELD score, age, recipient obesity, and diabetes.

Background and Purpose: In patients with cryptogenic stroke and patent foramen ovale (PFO), the Risk of Paradoxical Embolism (RoPE) Score has been proposed as a method to estimate a patient-specific “PFO-attributable fraction”—the probability that a documented PFO is causally-related to the stroke, rather than an incidental finding. The objective of this research is to examine the relationship between this RoPE-estimated PFO-attributable fraction and the effect of closure in 3 randomized trials. Methods: We pooled data from the CLOSURE-I (Evaluation of the STARFlex Septal Closure System in Patients With a Stroke and/or Transient Ischemic Attack due to Presumed Paradoxical Embolism through a Patent Foramen Ovale), RESPECT (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment), and PC (Clinical Trial Comparing Percutaneous Closure of Patent Foramen Ovale [PFO] Using the Amplatzer PFO Occluder With Medical Treatment in Patients With Cryptogenic Embolism) trials. We examine the treatment effect of closure in high RoPE score (≥7) versus low RoPE score ( Results: In the low RoPE score group (P =0.56) compared with 0.30 versus 1.03 (hazard ratio, 0.31 [0.11–0.85] P =0.02) in the high RoPE score group (≥7, n=1221); treatment-by-RoPE score group interaction, P =0.12. The RoPE score estimated attributable fraction anticipated the relative risk reduction across all levels of the RoPE score, in both the 3-trial ( r =0.95, P r =0.92, P Conclusions: The RoPE score estimated attributable fraction is highly correlated to the relative risk reduction of device versus medical therapy. This observation suggests the RoPE score identifies patients with cryptogenic stroke who are likely to have a PFO that is pathogenic rather than incidental.

Objective:To quantify diet-related burdens of cardiometabolic diseases (CMD) by country, age and sex in Latin America and the Caribbean (LAC).Design:Intakes of eleven key dietary factors were obtained from the Global Dietary Database Consortium. Aetiologic effects of dietary factors on CMD outcomes were obtained from meta-analyses. We combined these inputs with cause-specific mortality data to compute country-, age- and sex-specific absolute and proportional CMD mortality of eleven dietary factors in 1990 and 2010.Setting:Thirty-two countries in LAC.Participants:Adults aged 25 years and older.Results:In 2010, an estimated 513 371 (95 % uncertainty interval (UI) 423 286–547 841; 53·8 %) cardiometabolic deaths were related to suboptimal diet. Largest diet-related CMD burdens were related to low intake of nuts/seeds (109 831 deaths (95 % UI 71 920–121 079); 11·5 %), low fruit intake (106 285 deaths (95 % UI 94 904–112 320); 11·1 %) and high processed meat consumption (89 381 deaths (95 % UI 82 984–97 196); 9·4 %). Among countries, highest CMD burdens (deaths per million adults) attributable to diet were in Trinidad and Tobago (1779) and Guyana (1700) and the lowest were in Peru (492) and The Bahamas (504). Between 1990 and 2010, greatest decline (35 %) in diet-attributable CMD mortality was related to greater consumption of fruit, while greatest increase (7·2 %) was related to increased intakes of sugar-sweetened beverages.Conclusions:Suboptimal intakes of commonly consumed foods were associated with substantial CMD mortality in LAC with significant heterogeneity across countries. Improved access to healthful foods, such as nuts and fruits, and limits in availability of unhealthful factors, such as processed foods, would reduce diet-related burdens of CMD in LAC.

Background Recurrent cytomegalovirus (CMV) disease in solid organ transplant recipients frequently occurs despite effective antiviral therapy. We previously demonstrated that patients with lymphopenia before liver transplantation are more likely to develop posttransplant infectious complications including CMV. The aim of this study was to explore absolute lymphocyte count (ALC) as a predictor of relapse following treatment for CMV disease. Methods We performed a retrospective cohort study of heart, liver, and kidney transplant recipients treated for an episode of CMV disease. Our primary outcome was time to relapse of CMV within 6 months. Data on potential predictors of relapse including ALC were collected at the time of CMV treatment completion. Univariate and multivariate hazard ratios (HRs) were calculated with a Cox model. Multiple imputation was used to complete the data. Results Relapse occurred in 33 of 170 participants (19.4%). Mean ALC in relapse-free patients was 1.08 ± 0.69 vs 0.73 ± 0.42 × 103 cells/μL in those who relapsed, corresponding to an unadjusted hazard ratio of 1.11 (95% confidence interval, 1.03-1.21; P = .009, n = 133) for every decrease of 100 cells/μL. After adjusting for potential confounders, the association between ALC and relapse remained significant (HR, 1.11 [1.03-1.20]; P = .009). Conclusions Low ALC at the time of CMV treatment completion was a strong independent predictor for recurrent CMV disease. This finding is biologically plausible given the known importance of T-cell immunity in maintaining CMV latency. Future studies should consider this inexpensive, readily available marker of host immunity.

Though serum iron has been known to be associated with an increased risk of infection, hepcidin, the major regulator of iron metabolism, has never been systematically explored in this setting. Finding early biomarkers of infection, such as hepcidin, could help identify patients in whom early empiric antimicrobial therapy would be beneficial. We prospectively enrolled consecutive patients (n = 128) undergoing first-time, single-organ orthotopic liver transplantation (OLT) without known iron overload disorders at 2 academic hospitals in Boston from August 2009 to November 2012. Cox regression compared the associations between different iron markers and the development of first infection at least 1 week after OLT; 47 (37%) patients developed a primary outcome of infection at least 1 week after OLT and 1 patient died. After adjusting for perioperative bleeding complications, number of hospital days, and hepatic artery thrombosis, changes in iron markers were associated with the development of infection post-OLT including increasing ferritin (hazard ratio [HR], 1.51; 95% confidence interval [CI], 1.12-2.05), rising ferritin slope (HR, 1.10; 95% CI, 1.03-1.17), and increasing hepcidin (HR, 1.43; 95% CI, 1.05-1.93). A decreasing iron (HR, 1.76; 95% CI, 1.20-2.57) and a decreasing iron slope (HR, 4.21; 95% CI, 2.51-7.06) were also associated with subsequent infections. In conclusion, hepcidin and other serum iron markers and their slope patterns or their combination are associated with infection in vulnerable patient populations. Liver Transplantation 23 1541-1552 2017 AASLD.

Introduction Central venous catheters (CVC) increase risks associated with hemodialysis (HD), but may be necessary until an arteriovenous fistula (AVF) or graft (AVG) is achieved. The impact of vascular imaging on achievement of working AVF and AVG has not been firmly established. Methods Retrospective cohort of patients initiating HD with CVC in 2010–2011, classified by exposure to venography or Doppler vein mapping, and followed through December 31, 2012. Standard and time-dependent Cox models were used to determine hazard ratios (HRs) of death, working AVF, and any AVF or AVG. Logistic regression was used to assess the association of preoperative imaging with successful AVF or AVG among 18,883 individuals who had surgery. Models were adjusted for clinical and demographic factors. Findings Among 33,918 patients followed for a median of 404 days, 39.1% had imaging and 55.7% had surgery. Working AVF or AVG were achieved in 40.6%; 46.2% died. Compared to nonimaged patients, imaged patients were more likely to achieve working AVF (HR = 1.45 [95% confidence interval [CI] 1.36, 1.55], P 0.001), and less likely to die (HR = 0.88 [0.83-0.94], P

Extracorporeal membrane oxygenation (ECMO) use is perceived to cause thrombocytopenia (T), but the role of non-ECMO factors in the development of T remains unclear. We sought to evaluate the incidence and factors associated with severe T (platelet count ≤ 50,000/μl) in adults with severe acute respiratory distress syndrome (ARDS) managed with or without ECMO. The ECMO (n = 32) versus the non-ECMO (n = 53) groups had a similar baseline platelet count (214,000 vs. 179,000/μl), Acute Physiology and Chronic Health Evaluation (APACHE) II score (p = 0.13), unfractionated heparin (UFH) exposure (p = 0.62), and severe T incidence (25 vs. 19%, p = 0.5). Although the APACHE II score (p = 0.01), presence of liver failure (p = 0.08), and platelet transfusion (p = 0.0009) were different between the severe T (18/85 [21%]) and non-severe T groups (67/85 [79%]), the incidence of septic shock (p = 0.64), heparin infusion use (p = 0.41), exposure to non-heparin T-causing medications (p = 0.77) and ECMO use (p = 0.5) were not. An adjusted multivariate linear regression model revealed that only the APACHE II score was independently associated with the development of severe T (p = 0.01) but use of ECMO was not (p = 0.32) ECMO use may not affect the incidence of severe T among adults with severe ARDS. Larger studies that are prospective in nature are required to confirm this finding.

Introduction Benign fasciculations are common. Despite the favorable prognosis of benign fasciculation syndrome (BFS), patients are often anxious about their symptoms. In this study, we prospectively followed 35 patients with BFS over a 24-month period. Methods We conducted serial questionnaires to assess anxiety, associated symptoms, and duration. Results 71.4% of patients were men, and 34.4% were employed in the medical field. Most reported anxiety, but only 14% were anxious as measured by the Zung self-rating anxiety scale. Fasciculations were most common in the calves and persisted in 93% of patients. Anxiety levels did not change over time. Associated symptoms (subjective weakness, sensory symptoms, and cramps) were common and resolved to varying degrees. No patients developed motor neuron disease. Discussion BFS is a benign disorder that usually persists over time. Commonly associated symptoms include subjective weakness, sensory symptoms, and cramps. BFS is usually not associated with pathologic anxiety. Muscle Nerve 58:852-854, 2018.

Introduction:Shared patient–clinician decision-making is central to choosing between medical treatments. Decision support tools can have an important role to play in these decisions. We developed a decision support tool for deciding between nonsurgical treatment and surgical total knee replacement for patients with severe knee osteoarthritis. The tool aims to provide likely outcomes of alternative treatments based on predictive models using patient-specific characteristics. To make those models relevant to patients with knee osteoarthritis and their clinicians, we involved patients, family members, patient advocates, clinicians, and researchers as stakeholders in creating the models.Methods:Stakeholders were recruited through local arthritis research, advocacy, and clinical organizations. After being provided with brief methodological education sessions, stakeholder views were solicited through quarterly patient or clinician stakeholder panel meetings and incorporated into all aspects of the project.Results:Participating in each aspect of the research from determining the outcomes of interest to providing input on the design of the user interface displaying outcome predications, 86% (12/14) of stakeholders remained engaged throughout the project. Stakeholder engagement ensured that the prediction models that form the basis of the Knee Osteoarthritis Mathematical Equipoise Tool and its user interface were relevant for patient–clinician shared decision-making.Conclusions:Methodological research has the opportunity to benefit from stakeholder engagement by ensuring that the perspectives of those most impacted by the results are involved in study design and conduct. While additional planning and investments in maintaining stakeholder knowledge and trust may be needed, they are offset by the valuable insights gained.

Background:To identify potential participants for clinical trials, electronic health records (EHRs) are searched at potential sites. As an alternative, we investigated using medical devices used for real-time diagnostic decisions for trial enrollment.Methods:To project cohorts for a trial in acute coronary syndromes (ACS), we used electrocardiograph-based algorithms that identify ACS or ST elevation myocardial infarction (STEMI) that prompt clinicians to offer patients trial enrollment. We searched six hospitals’ electrocardiograph systems for electrocardiograms (ECGs) meeting the planned trial’s enrollment criterion: ECGs with STEMI or > 75% probability of ACS by the acute cardiac ischemia time-insensitive predictive instrument (ACI-TIPI). We revised the ACI-TIPI regression to require only data directly from the electrocardiograph, the e-ACI-TIPI using the same data used for the original ACI-TIPI (development set n = 3,453; test set n = 2,315). We also tested both on data from emergency department electrocardiographs from across the US (n = 8,556). We then used ACI-TIPI and e-ACI-TIPI to identify potential cohorts for the ACS trial and compared performance to cohorts from EHR data at the hospitals.Results:Receiver-operating characteristic (ROC) curve areas on the test set were excellent, 0.89 for ACI-TIPI and 0.84 for the e-ACI-TIPI, as was calibration. On the national electrocardiographic database, ROC areas were 0.78 and 0.69, respectively, and with very good calibration. When tested for detection of patients with > 75% ACS probability, both electrocardiograph-based methods identified eligible patients well, and better than did EHRs.Conclusion:Using data from medical devices such as electrocardiographs may provide accurate projections of available cohorts for clinical trials.

Background:To enhance enrollment into randomized clinical trials (RCTs), we proposed electronic health record-based clinical decision support for patient–clinician shared decision-making about care and RCT enrollment, based on “mathematical equipoise.”Objectives:As an example, we created the Knee Osteoarthritis Mathematical Equipoise Tool (KOMET) to determine the presence of patient-specific equipoise between treatments for the choice between total knee replacement (TKR) and nonsurgical treatment of advanced knee osteoarthritis.Methods:With input from patients and clinicians about important pain and physical function treatment outcomes, we created a database from non-RCT sources of knee osteoarthritis outcomes. We then developed multivariable linear regression models that predict 1-year individual-patient knee pain and physical function outcomes for TKR and for nonsurgical treatment. These predictions allowed detecting mathematical equipoise between these two options for patients eligible for TKR. Decision support software was developed to graphically illustrate, for a given patient, the degree of overlap of pain and functional outcomes between the treatments and was pilot tested for usability, responsiveness, and as support for shared decision-making.Results:The KOMET predictive regression model for knee pain had four patient-specific variables, and an r2 value of 0.32, and the model for physical functioning included six patient-specific variables, and an r2 of 0.34. These models were incorporated into prototype KOMET decision support software and pilot tested in clinics, and were generally well received.Conclusions:Use of predictive models and mathematical equipoise may help discern patient-specific equipoise to support shared decision-making for selecting between alternative treatments and considering enrollment into an RCT.

Eating behaviors such as eating fast and ignoring internal satiety cues are associated with overweight/obesity, and may be influenced by environmental factors. This study examined changes in those behaviors, and associations between those behaviors and BMI, cardiometabolic biomarkers, and diet quality in military recruits before and during initial military training (IMT), an environment wherein access to food is restricted. Eating rate and reliance on internal satiety cues were self-reported, and BMI, body fat, cardiometabolic biomarkers, and diet quality were measured in 1389 Army, Air Force and Marine recruits (45% female, mean ± SEM BMI = 24.1 ± 0.1 kg/m2) before and after IMT. Pre-IMT, habitually eating fast relative to slowly was associated with a 1.1 ± 0.3 kg/m2 higher BMI (P

BACKGROUND: Olfactory maturation is essential for successful oral feeding. Previous studies have suggested that olfactory stimulation with maternal breast milk may expedite oral feeding skills in the premature infant; however, the optimal developmental window to utilize this intervention and sex-specific responses to stimuli are largely unknown. OBJECTIVES: To determine individual responses to olfactory stimulation with mother's own milk (MOM) on feeding outcomes in premature newborns. MATERIALS AND METHODS: Infants born between 28 0/7 and 33 6/7 weeks' gestation (n = 36) were randomized to receive either MOM or water (sham) stimulus during the learning process of oral feeding. Clinical and feeding outcomes were recorded. Statistical analyses examined the effect of stimulation with MOM on feeding outcomes stratified for age and sex. RESULTS: Overall, there was no significant difference between sham infants compared with MOM infants in mean postmenstrual age of full oral feeds (sham: 35 5/7 versus MOM 36 0/7; p = 0.37). However, when stratified by gestational age (GA), infants born

Objectives To evaluate salivary biomarkers that elucidate the molecular mechanisms by which in utero opioid exposure exerts sex-specific effects on select hypothalamic and reward genes driving hyperphagia, a hallmark symptom of infants suffering from neonatal opioid withdrawal syndrome (NOWS). Study design We prospectively collected saliva from 50 newborns born at ≥34 weeks of gestational age with prenatal opioid exposure and 50 sex- and gestational age-matched infants without exposure. Saliva underwent transcriptomic analysis for 4 select genes involved in homeostatic and hedonic feeding regulation (neuropeptide Y2 receptor [NPY2R], proopiomelanocortin [POMC], leptin receptor [LEPR], dopamine type 2 receptor [DRD2]). Normalized gene expression data were stratified based on sex and correlated with feeding volume on day of life 7 and length of stay in infants with NOWS requiring pharmacotherapy. Results Expression of DRD2, a hedonistic/reward regulator, was significantly higher in male newborns compared with female newborns with NOWS (Δ threshold cycle 10.8 ± 3.8 vs 13.9 ± 3.7, P = .01). In NOWS requiring pharmacotherapy expression of leptin receptor, an appetite suppressor, was higher in male subjects than female subjects (Δ threshold cycle 8.4 ± 2.5 vs 12.4 ± 5.1, P = .05), DRD2 expression significantly correlated with intake volume on day of life 7 (r = 0.58, P = .02), and expression of NPY2R, an appetite regulator, negatively correlated with length of stay (r = −0.24, P = .05). Conclusions Prenatal opioid exposure exerts sex-dependent effects on hypothalamic feeding regulatory genes with clinical correlations. Neonatal salivary gene expression analyses may predict hyperphagia, severity of withdrawal state, and length of stay in infants with NOWS.

Aim “Early” withdrawal of life support therapies (eWLST) within the first 3 calendar days after resuscitation from cardiac arrest (CA) is discouraged. We evaluated a prospective multicenter registry of patients admitted to hospitals after resuscitation from CA to determine predictors of eWLST and estimate its impact on outcomes. Methods CA survivors enrolled from 2012–2017 in the International Cardiac Arrest Registry (INTCAR) were included. We developed a propensity score for eWLST and matched a cohort with similar probabilities of eWLST who received ongoing care. The incidence of good outcome (Cerebral Performance Category of 1 or 2) was measured across deciles of eWLST in the matched cohort. Results 2688 patients from 24 hospitals were included. Median ischemic time was 20 (IQR 11, 30) minutes, and 1148 (43%) had an initial shockable rhythm. Withdrawal of life support occurred in 1162 (43%) cases, with 459 (17%) classified as eWLST. Older age, initial non-shockable rhythm, increased ischemic time, shock on admission, out-of-hospital arrest, and admission in the United States were each independently associated with eWLST. All patients with eWLST died, while the matched cohort, good outcome occurred in 21% of patients. 19% of patients within the eWLST group were predicted to have a good outcome, had eWLST not occurred. Conclusions Early withdrawal of life support occurs frequently after cardiac arrest. Although the mortality of patients matched to those with eWLST was high, these data showed excess mortality with eWLST.

Background Patients with heart failure with reduced ejection fraction (HFrEF) and elevated pulmonary vascular resistance (PVR) are at risk increased for poor outcomes and may be ineligible for heart transplantation (HT). Left ventricular assist device (LVAD) therapy can lower PVR for certain patients, but it is difficult to identify these patients preoperatively. Methods Using the INTERMACS registry, we developed a clinical prediction model to predict the likelihood of PVR normalization (≤ 3 WU) or HT within 1 year of LVAD implant among patients with baseline PVR > 3 WU. Backwards stepwise selection was used to select variables from 14 candidate predictors and logistic regression was used to estimate model coefficients. Model performance was summarized using measures of discrimination (c-statistic) and calibration (Harrel's EAVG). Internal validation was performed using bootstrap resampling over 200 iterations to generate an average calibration slope, which was used to uniformly shrink all model coefficients to generate the final model. Results There were 2209 patients available for analysis. Median preoperative PVR was 4.26 WU (IQR 3.54-5.54 WU) and the median time from LVAD implant to postoperative PVR assessment was 3 months. 1596 patients (72%) experienced PVR normalization or were transplanted within 1 year. 412 (19%) patients died and 201 (9%) were alive with persistently elevated PVR at 1 year. Final model coefficients are shown in the Table. Important predictors included older age (OR 0.72 per 10 years), severe baseline mitral regurgitation (MR) (OR 2.49 vs no MR), and increased baseline pulmonary capillary wedge pressure (PCWP) (OR 1.24 per 5 mmHg increase). The model c-statistic was 0.66 and EAVG was 0.004. Conclusion Among patients with elevated PVR, preoperative patient characteristics such as severe MR and elevated PCWP are able to predict the likelihood of PVR normalization or HT within 1 year of LVAD implantation. These findings can help to inform decision making and frame patient expectations regarding anticipated improvements in pulmonary vascular disease following LVAD surgery. Future studies are needed to investigate potential management strategies to increase the likelihood of PVR normalization with LVAD support.

The IMMEDIATE Trial of emergency medical service use of intravenous glucose–insulin–potassium (GIK) very early in acute coronary syndromes (ACS) showed benefit for the composite outcome of cardiac arrest or in-hospital mortality. This analysis of IMMEDIATE Trial data sought to develop a predictive model to help clinicians identify patients at highest risk for this outcome and most likely to benefit from GIK. Multivariable logistic regression was used to develop a predictive model for the composite endpoint cardiac arrest or in-hospital mortality using the 460 participants in the placebo arm of the IMMEDIATE Trial. The final model had four variables: advanced age, low systolic blood pressure, ST elevation in the presenting electrocardiogram, and duration of time since ischemic symptom onset. Predictive performance was good, with a C statistic of 0.75, as was its calibration. Stratifying patients into three risk categories based on the models predictions, there was an absolute risk reduction of 8.6% with GIK in the high-risk tertile, corresponding to 12 patients needed to treat to prevent one bad outcome. The corresponding values for the low-risk tertile were 0.8% and 125, respectively. The multivariable predictive model developed identified patients with very early ACS at high risk of cardiac arrest or death. Using this model could assist treating those with greatest potential benefit from GIK.

Hodgkin lymphoma post-transplant lymphoproliferative disorder (HL-PTLD) is an uncommon PTLD with unclear prognosis and differences between HL-PTLD and immunocompetent HL are not well defined. Patient characteristics were compared among 192 patients with HL-PTLD from the Scientific Registry of Transplant Recipients and 13,847 HL patients in SEER (HL-SEER). Overall survival (OS) and disease-specific survival (DSS) were compared after exact matching. Additionally, multivariable analyses were used to identify prognostic markers of survival and associations between treatment and survival. Median time from transplant to HL-PTLD diagnosis was 88 months. When compared with HL-SEER, patients with HL-PTLD were older (median age, 52 vs. 36 years, P = 0.001), more likely male (73% vs. 54%, P

Background The comparative effectiveness of percutaneous closure of patent foramen ovale (PFO) plus medical therapy versus medical therapy alone for cryptogenic stroke is uncertain. Objectives The authors performed the first pooled analysis of individual participant data from completed randomized trials comparing PFO closure versus medical therapy in patients with cryptogenic stroke. Methods The analysis included data on 2 devices (STARFlex [umbrella occluder] [NMT Medical, Inc., Boston, Massachusetts] and Amplatzer PFO Occluder [disc occluder] [AGA Medical/St. Jude Medical, St. Paul, Minnesota]) evaluated in 3 trials. The primary composite outcome was stroke, transient ischemic attack, or death; the secondary outcome was stroke. We used log-rank tests and unadjusted and covariate-adjusted Cox regression models to compare device closure versus medical therapy. Results Among 2,303 patients, closure was not significantly associated with the primary composite outcome. The difference became significant after covariate adjustment (hazard ratio [HR]: 0.68; p = 0.049). For the outcome of stroke, all comparisons were statistically significant, with unadjusted and adjusted HRs of 0.58 (p = 0.043) and 0.58 (p = 0.044), respectively. In analyses limited to the 2 disc occluder device trials, the effect of closure was not significant for the composite outcome, but was for the stroke outcome (unadjusted HR: 0.39; p = 0.013). Subgroup analyses did not identify significant heterogeneity of treatment effects. Atrial fibrillation was more common among closure patients. Conclusions Among patients with PFO and cryptogenic stroke, closure reduced recurrent stroke and had a statistically significant effect on the composite of stroke, transient ischemic attack, and death in adjusted but not unadjusted analyses.

To compare the efficacy and safety of scheduled low-dose haloperidol versus placebo for the prevention of delirium (Intensive Care Delirium Screening Checklist ≥ 4) administered to critically ill adults with subsyndromal delirium (Intensive Care Delirium Screening Checklist = 1-3).Randomized, double-blind, placebo-controlled trial.Three 10-bed ICUs (two medical and one surgical) at an academic medical center in the United States.Sixty-eight mechanically ventilated patients with subsyndromal delirium without complicating neurologic conditions, cardiac surgery, or requiring deep sedation.Patients were randomly assigned to receive IV haloperidol 1 mg or placebo every 6 hours until delirium occurred (Intensive Care Delirium Screening Checklist ≥ 4 with psychiatric confirmation), 10 days of therapy had elapsed, or ICU discharge.Baseline characteristics were similar between the haloperidol (n = 34) and placebo (n = 34) groups. A similar number of patients given haloperidol (12/34 [35%]) and placebo (8/34 [23%]) developed delirium (p = 0.29). Haloperidol use reduced the hours per study day spent agitated (Sedation Agitation Scale ≥ 5) (p = 0.008), but it did not influence the proportion of 12-hour ICU shifts patients spent alive without coma (Sedation Agitation Scale ≤ 2) or delirium (p = 0.36), the time to first delirium occurrence (p = 0.22), nor delirium duration (p = 0.26). Days of mechanical ventilation (p = 0.80), ICU mortality (p = 0.55), and ICU patient disposition (p = 0.22) were similar in the two groups. The proportion of patients who developed corrected QT-interval prolongation (p = 0.16), extrapyramidal symptoms (p = 0.31), excessive sedation (p = 0.31), or new-onset hypotension (p = 1.0) that resulted in study drug discontinuation was comparable between the two groups.Low-dose scheduled haloperidol, initiated early in the ICU stay, does not prevent delirium and has little therapeutic advantage in mechanically ventilated, critically ill adults with subsyndromal delirium.

Purpose Neutropenia is a serious complication following heart transplantation (OHT) however risk factors for its development and its association with outcomes is not well described. We sought to study the prevalence of neutropenia, risk factors associated with its development and its impact on infection, rejection and survival. Methods A retrospective single center analysis of adult OHT recipients from July 2004 to December 2017 was performed. Demographic, laboratory, medication, infection, rejection and survival data were collected for 1 year post-OHT. Baseline lab measurements were collected within the 24 hours before OHT. Neutropenia was defined as absolute neutrophil count ≤ 1000 mm3. Cox proportional hazards models explored associations with time to first neutropenia. Associations of neutropenia, analyzed as a time-dependent covariate, with secondary outcomes of time to infection, rejection or death were also examined. Results Of 278 OHT recipients, 84 (30%) developed neutropenia within a median of 142 days (81-228 days) after transplant. More than half (56%) of those with neutropenia were treated with GCSF. Most infections were CMV disease whether they occurred before (14/22, 64%) or after (8/9, 89%) neutropenia or in the absence of neutropenia (20/40, 50%). Factors associated with increased risk of neutropenia are in Table 1. Neutropenia was not significantly associated with secondary outcomes of infection (N=9), rejection (N=10) or death (N=4), however numbers were small. Conclusion Neutropenia is a fairly common occurrence after adult OHT. Infection was associated with subsequent neutropenia, however no statistically significant differences in outcomes (infection, rejection, death) were found between neutropenic and non-neutropenic patients in this small study. It remains to be determined if medication changes in response to neutropenia impact patient outcomes. Supported by an unrestricted grant by Merck, NIH CTSA award: UL1TR002544 and Tupper Research Fund at Tufts Medical Center.

Anthracycline agents can cause cardiotoxicity. We used multivariable risk prediction models to identify a subset of patients with breast cancer at high risk of cardiotoxicity, for whom the harms of anthracycline chemotherapy may balance or exceed the benefits.A clinical prediction model for anthracycline cardiotoxicity was created in 967 patients with human epidermal growth factor receptor-negative breast cancer treated with doxorubicin in the ECOG-ACRIN study E5103. Cardiotoxicity was defined as left ventricular ejection fraction (LVEF) decline of ≥ 10% to 50% and/or a centrally adjudicated clinical heart failure diagnosis. Patient-specific incremental absolute benefit of anthracyclines (compared with non-anthracycline taxane chemotherapy) was estimated using the PREDICT model to assess breast cancer mortality risk.Of the 967 women who initiated therapy, 51 (5.3%) developed cardiotoxicity (12 with clinical heart failure). In a multivariate model, increasing age (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.01-1.08), higher body mass index (OR, 1.06; 95% CI, 1.02-1.10), and lower baseline LVEF (OR, 0.93; 95% CI, 0.89-0.98) at baseline were significantly associated with cardiotoxicity. The concordance statistic of the risk model was 0.70 (95% CI, 0.63-0.77). In patients with low anticipated treatment benefit (n = 176) from the addition of anthracycline (2% absolute risk difference of breast cancer mortality at 10 years), 16 (9%) of 176 had a10% risk of cardiotoxicity and 61 (35%) of 176 had a 5% to 10% risk of cardiotoxicity at 1 year.Older age, higher body mass index, and lower baseline LVEF were associated with increased risk of cardiotoxicity. We identified a subgroup with low predicted absolute benefit of anthracyclines but with high predicted risk of cardiotoxicity. Additional studies are needed incorporating long-term cardiac outcomes and cardiotoxicity model external validation prior to implementation in routine clinical practice.

Benign fasciculations are common. Despite the favorable prognosis of benign fasciculation syndrome (BFS), patients are often anxious about their symptoms. In this study, we prospectively followed 35 patients with BFS over a 24-month period.We conducted serial questionnaires to assess anxiety, associated symptoms, and duration.71.4% of patients were men, and 34.4% were employed in the medical field. Most reported anxiety, but only 14% were anxious as measured by the Zung self-rating anxiety scale. Fasciculations were most common in the calves and persisted in 93% of patients. Anxiety levels did not change over time. Associated symptoms (subjective weakness, sensory symptoms, and cramps) were common and resolved to varying degrees. No patients developed motor neuron disease.BFS is a benign disorder that usually persists over time. Commonly associated symptoms include subjective weakness, sensory symptoms, and cramps. BFS is usually not associated with pathologic anxiety. Muscle Nerve 58:852-854, 2018.

Background Heart failure clinical practice guidelines recommend applying validated clinical predictive models ( CPM s) to support decision making. While CPM s are now widely available, the generalizability of heart failure CPM s is largely unknown. Methods and Results We identified CPM s derived in North America that predict mortality for patients with acute heart failure and validated these models in different world regions to assess performance in a contemporary international clinical trial (N=4133) of patients with acute heart failure treated with guideline‐directed medical therapy. We performed independent external validations of 3 CPM s predicting in‐hospital mortality, 60‐day mortality, and 1‐year mortality, respectively. CPM discrimination decreased in all regional validation cohorts. The median change in area under the receiver operating curve was −0.09 (range −0.05 to −0.23). Regional calibration was highly variable (90th percentile of absolute difference between smoothed observed and predicted values range 50%). Calibration remained poor after global recalibrations; however, region‐specific recalibration procedures significantly improved regional performance (recalibrated 90th percentile of absolute difference range Conclusions Acute heart failure CPM discrimination and calibration vary substantially across different world regions; region‐specific (as opposed to global) recalibration techniques are needed to improve CPM calibration.

Background: To investigate preimplant risk factors associated with early right ventricular assist device (RVAD) use in patients undergoing continuous-flow left ventricular assist device (LVAD) surgery. Methods and Results: Patients in the Interagency Registry for Mechanically Assisted Circulatory Support who underwent primary continuous-flow–LVAD surgery were examined for concurrent or subsequent RVAD implantation within 14 days of LVAD. Risk factors for RVAD implantation and the combined end point of RVAD or death within 14 days of LVAD were assessed with stepwise logistic regression. We compared survival between patients with and without RVAD using Kaplan–Meier method and Cox proportional hazards modeling. Of 9976 patients undergoing continuous-flow–LVAD implantation, 386 patients (3.9%) required an RVAD within 14 days of LVAD surgery. Preimplant characteristics associated with RVAD use included interagency registry for mechanically assisted circulatory support patient profiles 1 and 2, the need for preoperative extracorporeal membrane oxygenation or renal replacement therapy, severe preimplant tricuspid regurgitation, history of cardiac surgery, and concomitant procedures other than tricuspid valve repair at the time of LVAD. Hemodynamic determinants included elevated right atrial pressure, reduced pulmonary artery pulse pressure, and reduced stroke volume. The final model demonstrated good performance for both RVAD implant (area under the curve, 0.78) and the combined end point of RVAD or death within 14 days (area under the curve, 0.73). Compared with patients receiving an isolated LVAD, patients requiring RVAD had decreased 1- and 6-month survival: 78.1% versus 95.8% and 63.6% versus 87.9%, respectively ( P Conclusions: The need for RVAD implantation after LVAD is associated with indices of global illness severity, markers of end-organ dysfunction, and profiles of hemodynamic instability.

Background: The role of adiponectin in patients with acute coronary syndromes is incompletely defined. This study investigated adiponectin levels in patients with acute coronary syndromes and the association between adiponectin and 30-day infarct size and 1-year clinical outcomes. Methods: Retrospective analysis of 120 participants with acute coronary syndromes enrolled in the Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency care Trial. Blood levels were tested three times within 24 h of onset of ischaemic symptoms. Infarct size was measured at 30 days. The 1-year clinical outcome was the composite of all-cause mortality or hospitalization for heart failure. Results: Using linear mixed models, log adiponectin levels decreased by −0.005 µg/mL per hour ( p = 0.035). After stratifying the analysis by gender, there was no decrease in log adiponectin in men; however, levels decreased by −0.01 µg/mL per hour in women ( p = 0.02). Results of multivariable regression models showed no association between log adiponectin and infarct size ( β = −1.1, p = 0.64). Log adiponectin levels did not predict 1-year outcomes using Cox-proportional hazard models. Conclusion: There was a small decrease in plasma adiponectin shortly after symptoms of ischaemia, more noticeable in women. No relationship was found between adiponectin and infarct size or clinical outcomes. This adds to evidence showing no clear association between adiponectin and adverse outcomes in patients with acute coronary syndromes.

Background: Since Food and Drug Administration’s approval of the HeartMate II left ventricular assist device (LVAD) as destination therapy, the number of hospitals offering LVAD therapy has grown rapidly. A rising number are performed at centers without internal transplant programs. We sought to determine whether outcomes after destination therapy LVAD implantation are similar at transplant and nontransplant centers. Methods and Results: Adult recipients of a primary, continuous-flow LVAD as destination therapy between January 2012 and March 2014 from the Interagency Registry for Mechanically Assisted Circulatory Support were included. Subjects were classified by implanting center as transplant (n=3323) or nontransplant (n=260). Center volume before 2012 was categorized as Conclusions: In a large, modern cohort of destination therapy LVAD recipients, outcomes after implantation were similar at transplant and nontransplant centers.

Introduction: The Risk of Paradoxical Embolism (RoPE) Score can disaggregate patients with cryptogenic stroke (CS) and patent foramen ovale (PFO) into those who are more likely to have a pathogenic PFO (high RoPE score) than an incidental PFO (low RoPE score). Those with higher RoPE scores have a lower risk of recurrent stroke and different recurrence predictors compared to those with low RoPE scores. Hypotheses: Patients with high RoPE scores benefit more from PFO closure than patients with low RoPE scores. Patients with high RoPE scores and risk factors for recurrence should benefit even more. Methods: The RoPE score was created from a database of CS patients with known PFO status to estimate stratum-specific PFO-attributable fraction and recurrence rates. Variables that predict stroke recurrence in high RoPE score groups (atrial septal aneurysm, history of stroke/TIA prior to index event) were added – the “RoPE Recurrence Score.” Using pooled individual patient data from all 3 RCTs of PFO closure vs. medical therapy (ITT populations; stroke outcome) we tested the ability of the scores to predict the heterogeneity of response to assigned treatment. Results: The mean RoPE score was significantly higher (6.8 vs. 6.3) with smaller variance (Stdev 1.5 vs. 1.9) in the pooled RCT population than in the original RoPE cohort (p Conclusion: As expected, the HR favoring closure trended lower in the high RoPE score group in the RCTs but missed statistical significance. The RoPE Recurrence score did not improve the prediction. This may be due to the narrow distribution of relatively high RoPE scores amongst RCT patients and so a low power to detect heterogeneity of treatment effect. Given that PFO closure can only prevent PFO-related recurrences, the treatment effect may also have been obscured by including recurrent strokes with non-PFO-related mechanisms.

Low blood levels of 25-hydroxyvitamin D (25OHD) have been associated with cardiometabolic disease but results are inconsistent. The objective of the study was to investigate the association of 25OHD with metabolic syndrome in a population at increased risk for diabetes.Using baseline data from the placebo and lifestyle intervention arms of the Diabetes Prevention Program (N=2000), multivariable logistic regression models were used to estimate the odds of prevalent metabolic syndrome and each of its individual components across 25OHD tertiles. Multivariable linear regression was used to estimate the adjusted mean difference of insulin secretion and sensitivity across the same 25OHD tertiles. In participants free of metabolic syndrome at baseline (N=546), incident metabolic syndrome in the first 2 years of follow-up was assessed using discrete-time proportional hazards regression to test its association with 25OHD concentration.After multivariate adjustment, participants in the highest tertile of 25OHD had lower odds of prevalent metabolic syndrome (odds ratio=0.62; 95% confidence interval (CI)=0.45-0.84), smaller waist circumference, higher high-density lipoprotein and lower fasting plasma glucose compared with participants in the lowest tertile of 25OHD. Higher plasma 25OHD concentration was associated with greater insulin sensitivity and lower insulin secretion. After multivariate adjustment, there was a nonsignificant lower risk of metabolic syndrome in the highest tertile of 25OHD (hazard ratio=0.79; 95% CI=0.48-1.32) compared with the lowest tertile.In a population at increased risk for diabetes, higher plasma 25OHD concentration was inversely associated with prevalent metabolic syndrome and nonsignificantly with incident metabolic syndrome.