Intranasal Carbetocin Reduces Hyperphagia, Anxiousness, and Distress in Prader-Willi Syndrome: CARE-PWS Phase 3 Trial.

CONTEXT: Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by endocrine and neuropsychiatric problems including hyperphagia, anxiousness, and distress. Intranasal carbetocin, an oxytocin analog, was investigated as a selective oxytocin replacement therapy. OBJECTIVE: To evaluate safety and efficacy of intranasal carbetocin in PWS. DESIGN: Randomized, double-blind, placebo-controlled phase 3 trial with long-term follow-up. SETTING: Twenty-four ambulatory clinics at academic medical centers. PARTICIPANTS: A total of 130 participants with PWS aged 7 to 18 years. INTERVENTIONS: Participants were randomized to 9.6 mg/dose carbetocin, 3.2 mg/dose carbetocin, or placebo 3 times daily during an 8-week placebo-controlled period (PCP). During a subsequent 56-week long-term follow-up period, placebo participants were randomly assigned to 9.6 mg or 3.2 mg carbetocin, with carbetocin participants continuing at their previous dose. MAIN OUTCOME MEASURES: Primary endpoints assessed change in hyperphagia (Hyperphagia Questionnaire for Clinical Trials [HQ-CT]) and obsessive-compulsive symptoms (Children's Yale-Brown Obsessive-Compulsive Scale [CY-BOCS]) during the PCP for 9.6 mg vs placebo, and the first secondary endpoints assessed these same outcomes for 3.2 mg vs placebo. Additional secondary endpoints included assessments of anxiousness and distress behaviors (PWS Anxiousness and Distress Behaviors Questionnaire [PADQ]) and clinical global impression of change (CGI-C). RESULTS: Because of onset of the COVID-19 pandemic, enrollment was stopped prematurely. The primary endpoints showed numeric improvements in both HQ-CT and CY-BOCS which were not statistically significant; however, the 3.2-mg arm showed nominally significant improvements in HQ-CT, PADQ, and CGI-C scores vs placebo. Improvements were sustained in the long-term follow-up period. The most common adverse event during the PCP was mild to moderate flushing. CONCLUSIONS: Carbetocin was well tolerated, and the 3.2-mg dose was associated with clinically meaningful improvements in hyperphagia and anxiousness and distress behaviors in participants with PWS. CLINICAL TRIALS REGISTRATION NUMBER: NCT03649477.

Impact of preoperative versus postoperative dialysis on left ventricular assist device outcomes: An analysis from the Society of Thoracic Surgeons Interagency Registry for Mechanically Assisted Circulatory Support database.

Objective: Chronic kidney disease and renal failure are common in patients being considered for left ventricular assist device support. We sought to evaluate the outcomes of patients undergoing left ventricular assist device implantation with preoperative dialysis and those with new-onset postoperative renal failure requiring dialysis. Methods: All patients (n = 14,090) undergoing primary left ventricular assist device implantation who were listed in the Interagency Registry for Mechanically Assisted Circulatory Support database (2014-2019) were evaluated. Landmark analysis then stratified patients alive at 1 month by preoperative dialysis and at 1 month postoperatively, preoperative dialysis only, postoperative dialysis only, and no dialysis. Results: Of 14,090 patients undergoing left ventricular assist device implantation, patients on dialysis (400%, 3%) preoperatively had significantly higher mortality at 1 month (18% vs 6%, P < .0001). However, of patients on preoperative dialysis, 131 (32.8%) no longer required dialysis at 1 month postoperatively and had long-term survival similar to patients who never required dialysis (no dialysis vs recovered, P = .13). Long-term survival was significantly worse in patients with persistent dialysis and new dialysis at 1 month postoperatively (P < .0001). Time to first stroke, major nondevice infection, any bleeding event, and gastrointestinal bleeding were all worse in patients on preoperative or postoperative dialysis (all P < .0001). Device infection, malfunction, or thrombosis was not associated with dialysis status (P > .05). Negative predictors of recovery include biventricular assist device (odds ratio, 0.20) and inotropes 1 week postimplant (odds ratio, 0.19). Conclusions: Preoperative renal failure is associated with 3 times higher mortality and worse morbidity in patients receiving a left ventricular assist device. However, one-third of patients with preoperative dialysis will recover renal function postimplant with similar long-term survival and quality of life as those without dialysis.

Right Heart Failure Following Left Ventricular Device Implantation: Natural History, Risk Factors, and Outcomes: An Analysis of the STS INTERMACS Database.

BACKGROUND: Our current understanding of right heart failure (RHF) post-left ventricular assist device (LVAD) is lacking. Recently, a new Interagency Registry for Mechanically Assisted Circulatory Support definition of RHF was introduced. Based on this definition, we investigated natural history, risk factors, and outcomes of post-LVAD RHF. METHODS: Patients implanted with continuous flow LVAD between June 2, 2014, and June 30, 2016 and registered in the Interagency Registry for Mechanically Assisted Circulatory Support/Society of Thoracic Surgeons Database were included. RHF incidence and predictors, and survival after RHF were assessed. The manifestations of RHF which were separately analyzed were elevated central venous pressure, peripheral edema, ascites, and use of inotropes. RESULTS: Among 5537 LVAD recipients (mean 57±13 years, 49% destination therapy, support 18.9 months) prevalence of 1-month RHF was 24%. Of these, RHF persisted at 12 months in 5.3%. In contrast, de novo RHF, first identified at 3 months, occurred in 5.1% and persisted at 12 months in 17% of these, and at 6 months occurred in 4.8% and persisted at 12 months in 25%. Higher preimplant blood urea nitrogen (ORs,1.03-1.09 per 5 mg/dL increase; P<0.0001), previous tricuspid valve repair/replacement (ORs, 2.01-10.09; P<0.001), severely depressed right ventricular systolic function (ORs,1.17-2.20; P=0.004); and centrifugal versus axial LVAD (ORs,1.15-1.78; P=0.001) represented risk factors for RHC incidence at 3 months. Patients with persistent RHF at 3 months had the lowest 2-year survival (57%) while patients with de novo RHF or RHF which resolved by 3 months had more favorable survival outcomes (75% and 78% at 2 years, respectively; P<0.001). CONCLUSIONS: RHF at 1 or 3 months post-LVAD was a common and frequently transient condition, which, if resolved, was associated with relatively favorable prognosis. Conversely, de novo, late RHF post-LVAD (>6 months) was more frequently a persistent disorder and associated with increased mortality. The 1-, 3-, and 6-month time points may be used for RHF assessment and risk stratification in LVAD recipients.

STS INTERMACS Database: The Key to Conduct Single-Arm Trials in Advanced Heart Failure Patients.

BACKGROUND: Safe introduction of novel mechanical circulatory support (MCS) devices into clinical practice is a challenging process. Single-arm trials using a control arm from existing database is an effective alternative that could be applied for regulatory approval. This study analyzes the capability of the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) database to establish objective performance criteria and select patient population that could be used for future single-arm MCS trials. METHODS: Patients with INTERMACS profiles IM1-2 and IM3-5, who underwent implantation of isolated left ventricular assist devices between 2014 and 2017, were included. Both cohorts were further stratified into shock and nonshock groups using surrogate markers of shock (extracorporeal membrane oxygenation, temporary ventricular assist device, vasopressor infusions). Survival, transplantation rates, adverse events, 6-minute walk test, and quality-of-life measures were obtained for all 4 groups at 6 and 12 months. RESULTS: Total of 7907 patients were divided into IM1-2 (n = 3909), IM3-5 (n = 3998), shock (n = 3469), and nonshock (n = 3040) groups. Recategorization occurred in 11% of patients from the IM3-5 group into the shock group. Overall, patients in the shock group had similar outcomes to the IM1-2 group (1-year survival: 86% vs 85%; P = .74). Patients in the nonshock group also had similar outcomes to the IM3-5 (1-year survival: 90% vs 90%; P = .43). CONCLUSIONS: The INTERMACS database can successfully establish objective performance criteria and concurrent control group for single-arm trials that could be used to support regulatory approval of new, less invasive MCS. INTERMACS data allow reliable comparisons of outcomes and adverse events.

Long-term survival on LVAD support: Device complications and end-organ dysfunction limit long-term success.

BACKGROUND: Preoperative variables can predict short term left ventricular assist device (LVAD) survival, but predictors of extended survival remain insufficiently characterized. METHOD: Patients undergoing LVAD implant (2012-2018) in the Intermacs registry were grouped according to time on support: short-term (<1 year, n = 7,483), mid-term (MT, 1-3 years, n = 5,976) and long-term (LT, ≥3 years, n = 3,015). Landmarked hazard analyses (adjusted hazard ratio, HR) were performed to identify correlates of survival after 1 and 3 years of support. RESULTS: After surviving 1 year of support, additional LVAD survival was less likely in older (HR 1.15 per decade), Caucasian (HR 1.22) and unmarried (HR 1.16) patients (p < 0.05). After 3 years of support, only 3 preoperative characteristics (age, race, and history of bypass surgery, p < 0.05) correlated with extended survival. Postoperative events most negatively influenced achieving LT survival. In those alive at 1 year or 3 years, the occurrence of postoperative renal (creatinine HR MT = 1.09; LT HR = 1.10 per mg/dl) and hepatic dysfunction (AST HR MT = 1.29; LT HR = 1.34 per 100 IU), stroke (MT HR = 1.24; LT HR = 1.42), infection (MT HR = 1.13; LT HR = 1.10), and/or device malfunction (MT HR = 1.22; LT HR = 1.46) reduced extended survival (all p ≤ 0.03). CONCLUSIONS: Success with LVAD therapy hinges on achieving long term survival in more recipients. After 1 year, extended survival is heavily constrained by the occurrence of adverse events and postoperative end-organ dysfunction. The growth of destination therapy intent mandates that future LVAD studies be designed with follow up sufficient for capturing outcomes beyond 24 months.

Evolution of Late Right Heart Failure With Left Ventricular Assist Devices and Association With Outcomes.

BACKGROUND: A revised definition of right heart failure (RHF) for the Society of Thoracic Surgeons Intermacs database of left ventricular assist devices (LVADs) was introduced in June 2014. OBJECTIVES: The purpose of this study was to determine the prevalence and severity of RHF over time and the association of RHF status at 3 months with 12-month outcomes after LVAD. METHODS: All patients in Society of Thoracic Surgeons Intermacs with follow-up and supported at least 3 months with a continuous flow LVAD implanted between June 2, 2014 and March 31, 2017 without a simultaneous RVAD. RHF was defined as both documentation and manifestations of elevated central venous pressures. RESULTS: There were 6,118 patients included with an incidence of RHF at 3, 6, and 12 months postimplant categorized as mild in 5%, 6%, and 6% and moderate in 5%, 3%, and 3%, respectively. For those with no RHF at 3 months, there was a low incidence of subsequent RHF at 6 and 12 months. The lack of RHF at 3 months, compared with mild and moderate RHF, was associated with a lower 12-month cumulative incidence of mortality (6.9% vs 16.7% vs 28.1%; P < 0.0001) and a lower 12-month cumulative incidence of stroke (7.4% vs 9.5% vs 11.0%; P = 0.0095), gastrointestinal bleeding (14.8% vs 24.2% vs 23.6%; P < 0.0001), and rehospitalization (65.2% vs 73.2% vs 71.2%; P < 0.0001). CONCLUSIONS: In patients surviving 3 months with LVAD support alone, mild or moderate RHF occurred in nearly 1 of 10 patients at 12 months. Patients with late RHF had worse survival and a higher cumulative incidence of major adverse events.

Impact of thoracotomy approach on right ventricular failure and length of stay in left ventricular assist device implants: an intermacs registry analysis.

INTRODUCTION: Traditionally, implantation of Left Ventricular Assist Devices (LVADs) is performed via median sternotomy. Recently, less invasive thoracotomy approaches are growing in popularity as they involve less surgical trauma, potentially less bleeding, and may preserve right ventricular function. We hypothesized implantation of LVADs via thoracotomy has less perioperative right ventricular failure (RVF) and shorter postoperative length of stay (LOS). METHODS: Continuous flow LVAD implants from Intermacs between February 6, 2014 - December 31, 2018 were identified. Patients implanted via thoracotomy were propensity matched in a 1:1 ratio with patients implanted via sternotomy. Outcomes were compared between sternotomy and thoracotomy approach and by device type (axial, centrifugal-flow with hybrid levitation (CF-HL), centrifugal-flow with full magnetic levitation devices (CF-FML)). The primary outcome was time to first moderate or severe RVF. Secondary outcomes included survival and LOS. RESULTS: Overall 978 thoracotomy patients were matched with 978 sternotomy patients. Over the study period, 242 thoracotomy patients and 219 sternotomy patients developed RVF with no significant difference in time to first moderate to severe RVF by surgical approach overall (p = 0.27) or within CF-HL (p = 0.36) or CF-FML devices (p = 0.25). Survival did not differ by implant technique (150 deaths in thoracotomy group, 154 deaths in sternotomy group; p = 0.58). However, sternotomy approach was associated with a significantly shorter LOS (17 Vs 18 days, p = 0.009). CONCLUSION: As compared to sternotomy, implantation of continuous flow LVADs via thoracotomy approach does not reduce moderate to severe RVF or improve survival but does reduce post-operative LOS. Device type did not influence outcomes and most centers did a small volume of thoracotomy implants.

Growing Up Fast: Managing Autism Spectrum Disorder and Precocious Puberty.

CASE: John is a 4-year-old boy with autism spectrum disorder (ASD) and developmental delay who presented with concerns about increasing aggressive behavior at a follow-up visit with his developmental-behavioral pediatrician. Diagnosis of ASD was made via Diagnostic and Statistical Manual of Mental Disorders, 5th version criteria at initial evaluation at 34 months. Medical history at that time was pertinent for rapid linear growth since the age of 1 and recent pubic hair growth and penile enlargement. Family history was significant for early puberty in a maternal uncle and 4 distant maternal relatives. Standardized testing included administration of the Childhood Autism Rating Scale 2-Standard, which was consistent with severe symptoms of ASD, and the Mullen Scales of Early Learning, which indicated moderate delay in fine motor skills and expressive language and severe delay in receptive language and visual receptive skills.At initial assessment, John's parents also reported a pattern of aggressive behavior, which included frequent hitting of other children at childcare, consistently forceful play with peers and family members, and nightly tantrums with hitting and throwing at bedtime. Triggers of aggressive behavior included other children taking his toys, transition away from preferred activities, and being told "no."John was concurrently evaluated by a pediatric endocrinologist at 34 months. At that assessment, his height Z-score was +2.5, and he had Tanner 2 pubic hair, Tanner 3 genitalia, and 6 cc testicular volumes. Radiograph of the hand revealed a bone age of 6 years (+7.8 S.D.). Laboratory studies revealed a markedly elevated testosterone level and low gonadotropin (luteinizing hormone [LH] and follicle-stimulating hormone) levels and a normal dehydroepiandrosterone sulfate, suggestive of peripheral precocious puberty. Targeted genetic testing with sequencing of the LHCGR gene revealed a heterozygous D578G mutation resulting in the rare condition Familial Male-Limited Precocious Puberty (FMPP), characterized by constitutive activation of the LH receptor. FMPP, also referred to as testotoxicosis, was attributed as the cause of John's peripheral precocious puberty.By the age of 4, John's height Z-score was +3.1, his genitalia larger, and his bone age 10 years (+10.3 S.D.). His parents elected to start off-label therapy with bicalutamide (a nonsteroidal antiandrogen) and anastrazole (an aromatase inhibitor), recommended by the endocrinologist. Unexpectedly, as John's hyperandrogenism was treated, John's family reported intensified aggression toward other children and adults, especially at school, in addition to multiple daily instances of biting when upset. What is your next step in John's treatment of his challenging behavior? REFERENCE: 1. Shenker A, Laue L, Kosugi S, et al. A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty. Nature. 1993;365:652-654.

Quantifying the impact from stroke during support with continuous flow ventricular assist devices: An STS INTERMACS analysis.

INTRODUCTION: Adverse events, especially strokes, during the implantation of continuous flow durable left ventricular assist devices (LVADs) remain the major barriers to greater application among patients with ambulatory advanced heart failure. METHODS: Between June 2014 and June 2017, a total of 9,489 patients in the Society of Thoracic Surgeons Interagency Registry for Mechanically Assisted Circulatory Support database received 10,285 continuous flow LVADs, with follow-up through June 2018. RESULTS: During the follow-up period, 1,515 (16%) patients suffered 1 or more strokes, with a nearly equal frequency of ischemic and hemorrhagic etiology. The risk of stroke was about 4% in the first month, 9% during the first 6 months, and 14% in the first year. By multivariable hazard function analysis, the major risk factors identified in the early phase were LVAD centrifugal flow device and concomitant cardiac surgery, whereas in the constant phase (longer term), a history of repeated non-compliance was most associated with a stroke event. Using a modulated renewal model, the occurrence of an ischemic and especially a hemorrhagic stroke dominated as risk factors for subsequent mortality. Six-month survival after an ischemic stroke was 70%, and after a hemorrhagic stroke, it was <50%. Disabling stroke as judged by Modified Rankin Score was associated with significantly worse survival at 1 and 2 years compared with strokes with mild or no early disability. CONCLUSIONS: This study confirms the 20% incidence of stroke over the first 2 years with axial flow and hybrid (magnetic and hydrodynamic) levitated centrifugal flow pumps. This study suggests a major increase in 1- and 2-year mortality among those with an initial disabling vs non-disabling stroke. To better understand the impact of strokes after implantation and the effect of prevention and intervention strategies, we need more complete Modified Rankin Scores and quality of life data during the stroke recovery period.

The Society of Thoracic Surgeons Intermacs 2019 Annual Report: The Changing Landscape of Devices and Indications.

BACKGROUND: The field of mechanical circulatory support has been impacted by the approval of new continuous-flow left ventricular assist devices (LVADs) and changes to the United States heart allocation system. METHODS: Primary isolated continuous-flow LVAD implants in The Society of Thoracic Surgeons Intermacs registry from January 2014 through September 2019 were evaluated. Survival and freedom from major adverse events were compared between axial-flow, centrifugal-flow with hybrid levitation (CF-HL), and centrifugal-flow with full magnetic levitation (CF-FML) devices. RESULTS: Of 2603 devices implanted in 2014, 1824 (70.1%) were axial flow and 1213 (46.6%) were destination therapy (DT); through September 2019, 1752 devices were implanted, but only 37 (2.1%) were axial flow and 1230 (70.2%) were DT. Implants were performed in 13,016 patients between 2014 and 2018. Patients receiving implants in 2017-2018 compared with 2014-2016 were more likely to be at Intermacs profile 1 (17.1% vs 14.3%, P < .001) and to have preimplant temporary mechanical circulatory support (34.8% vs 29.3%, P < .001). Overall survival and freedom from major adverse events were higher with CF-FML devices. In multivariable analysis of survival between CF-HL and CF-FML, device type was not a significant early hazard, but the use of CF-HL devices had a late hazard ratio for death of 3.01 (P < .001). CONCLUSIONS: Over the past 5 years, centrifugal-flow LVADs have become the dominant technology and DT the most common implant strategy. While outcomes with CF-FML devices are promising, comparisons with other devices from nonrandomized registry studies should be made with caution.

Care Pathways in a Suicide Crisis Assessment Nurse (SCAN) service.

AIM: The Suicide Crisis Assessment Nurse service has been developed as a Primary Care suicide intervention over the last decade. The current study aimed to describe the demographic details of users of this nurse led service, and to evaluate subsequent care pathways following this intervention. METHODS: This study was conducted using a retrospective file review with a cross-sectional observational design investigating demographic details of service users and care pathways in a Suicide Crisis Assessment Nurse service within a defined catchment area of Ireland between June 2015 and May 2017. RESULTS: The majority of referrals were managed in Primary Care following Suicide Crisis Assessment Nurse intervention. There was an increase in Primary Care management pathway in the second year of the service which was independent of age and gender. CONCLUSION: There was an increase in referrals to the service over time, and the majority of presentations were managed in primary care following Suicide Crisis Assessment Nurse intervention. The study suggests that primary care interventions for suicidal crises merit further research.

Biventricular Support With Intracorporeal, Continuous Flow, Centrifugal Ventricular Assist Devices.

BACKGROUND: The incidence of right ventricular dysfunction requiring right ventricular assist device after left ventricular assist device placement has been reported between 10% to 30%. The mortality rate is higher compared with patients who require left ventricular assist device only; the most effective and safest biventricular assist device remains unknown. We aimed to determine the survival outcomes and frequency of adverse events in patients with two durable, intracorporeal, continuous flow centrifugal pumps for support. METHODS: Between November 2012 and June 2015, 38 patients were identified from INTERMACS received durable, intracorporeal continuous flow centrifugal pumps for biventricular support. Pediatric patients were excluded. Mean age was 47 years, and 74% of patients were male. The common primary diagnoses in this cohort were dilated myopathy, idiopathic (37%) and ischemic (16%). RESULTS: Nineteen participating centers implanted devices in 38 patients; 11 patients died with device in place, 9 patients received a heart transplant, and 18 were alive on support with the right ventricular assist device in place. Survival outcomes were 68% at 6 months and 62% at 12 months. The left ventricular assist device was placed in the left ventricle apex in 91% of cases, and in 9%, the location was not specified. The right ventricular assist device was placed in the right ventricle in 50%, right atrium in 37%, and not specified in 13%. The adverse events included infection 50%, bleeding 44%, respiratory failure 31.6%, and malfunction 26.3%; neurologic dysfunction 26.3%; renal dysfunction 18.4%; and arrhythmia 18.4%. CONCLUSIONS: The use of durable, intracorporeal, continuous flow centrifugal pumps for management of advanced biventricular heart failure is associated with high morbidity and mortality. Further investigation of this device configuration is warranted.

Concomitant mitral valve procedures in patients undergoing implantation of continuous-flow left ventricular assist devices: An INTERMACS database analysis.

BACKGROUND: Management of existing mitral valve (MV) disease in patients undergoing left ventricular assist device (LVAD) implantation remains controversial. METHODS: Among continuous-flow LVAD patients with moderate to severe mitral regurgitation entered into the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) database between April 2008 and March 2014 (n = 4,930), outcomes were compared between patients who underwent MV repair (MVr, n = 252), MV replacement (MVR, n = 11) and no MV procedure (no MVP, n = 4,667). Impact on survival was analyzed by stratified actuarial and hazard function multivariable methodology. Post-operative functional capacity and quality of life were assessed. RESULTS: Patients who underwent MVPs had higher pre-operative pulmonary vascular resistance (3.6 ± 2.9 vs 2.9 ± 2.6 Wood units; p = 0.0006) and higher pulmonary artery systolic pressures (55.1 ± 13.8 vs 51.5 ± 14.0 mm Hg; p = 0.0003). Two-year survival was 76% for patients with concomitant MVr, 57% for those with MVR and 71% for those with no MVP (p = 0.15). By multivariable analysis, neither MVr nor MVR affected early or late survival. Although improvements in post-operative functional status as evaluated by 6-minute walk distances were comparable across groups, visual analog score assessments of quality of life suggested a benefit of concomitant MVPs at 1-year post-implant (79.00 ± 1.73 vs 74.45 ± 0.51; p = 0.03), with fewer re-admissions observed for MVP patients (p < 0.0001). CONCLUSIONS: Concomitant MVPs are not associated with increased survival overall. However, MVPs are associated with benefits in terms of reduced hospital re-admission and improved quality of life in select patients.

Causes and Consequences of Missing Health-Related Quality of Life Assessments in Patients Who Undergo Mechanical Circulatory Support Implantation: Insights From INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support).

BACKGROUND: Missing health-related quality of life (HRQOL) data in longitudinal studies can reduce precision and power and bias results. Using INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support), we sought to identify factors associated with missing HRQOL data, examine the impact of these factors on estimated HRQOL assuming missing at random missingness, and perform sensitivity analyses to examine missing not at random (MNAR) missingness because of illness severity. METHODS AND RESULTS: INTERMACS patients (n=3248) with a preimplantation profile of 1 (critical cardiogenic shock) or 2 (progressive decline) were assessed with the EQ-5D-3L visual analog scale and Kansas City Cardiomyopathy Questionnaire-12 summary scores pre-implantation and 3 months postoperatively. Mean and median observed and missing at random-imputed HRQOL scores were calculated, followed by sensitivity analyses. Independent factors associated with HRQOL scores and missing HRQOL assessments were determined using multivariable regression. Independent factors associated with preimplantation and 3-month HRQOL scores, and with the likelihood of missing HRQOL assessments, revealed few correlates of HRQOL and missing assessments (R2 range, 4.7%-11.9%). For patients with INTERMACS profiles 1 and 2 and INTERMACS profile 1 alone, missing at random-imputed mean and median HRQOL scores were similar to observed scores, before and 3 months after implantation, whereas MNAR-imputed mean scores were lower (≥5 points) at baseline but not at 3 months. CONCLUSIONS: We recommend use of sensitivity analyses using an MNAR imputation strategy for longitudinal studies when missingness is attributable to illness severity. Conduct of MNAR sensitivity analyses may be less critical after mechanical circulatory support implant, when there are likely fewer MNAR data.

Outcomes of Restrictive and Hypertrophic Cardiomyopathies After LVAD: An INTERMACS Analysis.

BACKGROUND: Patients with restrictive (RCM) and hypertrophic (HCM) cardiomyopathies are felt to be a difficult population to treat with left ventricular assist device (LVAD) therapy. Scarce data exist on outcomes of continuous-flow (CF) LVAD support in these challenging patient cohorts. METHODS: The Interagency Registry for Mechanically Assisted Circulatory Support Registry was queried for all patients with RCM (n = 94) and HCM (n = 104) who underwent CF LVAD implantation between March 2008 and March 2014. Survival, adverse event rates, baseline demographics, echocardiography parameters, and competing outcomes were compared with patients with dilated cardiomyopathy (DCM) (n = 8749). RESULTS: Left ventricular size was smaller and baseline EF was higher in RCM and HCM compared with DCM patients. Nonetheless, these parameters were not completely normal in the RCM and HCM groups, suggesting that most of these patients exhibited features of a DCM and represented a mixed phenotype. In these specific patient populations, survival up to 4 years was not different among the 3 groups (log rank 0.25) and competing outcomes at 1 year were similar. In the subgroup of patients with very small ventricles (ie, < 5.0 cm), survival was far inferior. Finally, overall rates of right ventricular assist device requirement, hemolysis, pump dysfunction, and cardiac arrhythmias were similar among the 3 groups. CONCLUSION: Relatively few patients with HCM and RCM undergo CF LVAD implantation, and most that do display some features of a DCM. Overall survival and adverse event profiles of these patients were similar to traditional DCM patients; however, in those with very small ventricles, survival was inferior.

Eighth annual INTERMACS report: Special focus on framing the impact of adverse events.

BACKGROUND: The Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) database now includes >20,000 patients from >180 hospitals. METHODS: The eighth annual report of INTERMACS updates the first decade of patient enrollment. RESULTS: In the current era, >95% of implants are continuous flow devices. Overall survival continues to remain >80% at 1 year and 70% at 2 years. Review of major adverse events shows minimal advantage for patients with ambulatory heart failure pre-implant. Stroke, major infection, and continued inotrope requirement during the first 3 months have a major effect on subsequent survival. CONCLUSIONS: Greater application of durable devices to patients with ambulatory heart failure will mandate more effective neutralization or prevention of major adverse events.

Effects of MetAP2 inhibition on hyperphagia and body weight in Prader-Willi syndrome: A randomized, double-blind, placebo-controlled trial.

AIMS: There are no treatments for the extreme hyperphagia and obesity in Prader-Willi syndrome (PWS). The bestPWS clinical trial assessed the efficacy, safety and tolerability of the methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib. MATERIALS AND METHODS: Participants with PWS (12-65 years old) were randomly assigned (1:1:1) to biweekly placebo, 1.8 mg beloranib or 2.4 mg beloranib injection for 26 weeks at 15 US sites. Co-primary endpoints were the changes in hyperphagia [measured by Hyperphagia Questionnaire for Clinical Trials (HQ-CT); possible score 0-36] and weight by intention-to-treat. ClinicalTrials.gov registration: NCT02179151. RESULTS: One-hundred and seven participants were included in the intention-to-treat analysis: placebo (n = 34); 1.8 mg beloranib (n = 36); or 2.4 mg beloranib (n = 37). Improvement (reduction) in HQ-CT total score was greater in the 1.8 mg (mean difference -6.3, 95% CI -9.6 to -3.0; P = .0003) and 2.4 mg beloranib groups (-7.0, 95% CI -10.5 to -3.6; P = .0001) vs placebo. Compared with placebo, weight change was greater with 1.8 mg (mean difference - 8.2%, 95% CI -10.8 to -5.6; P < .0001) and 2.4 mg beloranib (-9.5%, 95% CI -12.1 to -6.8; P < .0001). Injection site bruising was the most frequent adverse event with beloranib. Dosing was stopped early due to an imbalance in venous thrombotic events in beloranib-treated participants (2 fatal events of pulmonary embolism and 2 events of deep vein thrombosis) compared with placebo. CONCLUSIONS: MetAP2 inhibition with beloranib produced statistically significant and clinically meaningful improvements in hyperphagia-related behaviours and weight loss in participants with PWS. Although investigation of beloranib has ceased, inhibition of MetAP2 is a novel mechanism for treating hyperphagia and obesity.

Incorporating Antiracism Coursework into a Cultural Competency Curriculum.

Creating a socially conscious educational environment is an imperative if health care practitioners are to have a significant impact on health inequities. The effects of practitioner bias, prejudice, and discrimination on health and health outcomes have been well documented in the literature. Individuals being trained to provide health care will be entering into an increasingly diverse world and must be equipped with the appropriate knowledge and skills in order to meet the needs of those seeking their care. Cultural competency training in medical education has evolved over the past 15 years since the Institute of Medicine's 2002 report, Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care. As research on the effectiveness of this training has emerged, several authors have called for the integration of antiracism training into the cultural competency curriculum, but few have found effective ways of doing so. This article describes the approach of one midwifery program in order to inform clinical education programs across the spectrum of health care practitioners.

Age and gender differences and factors related to change in health-related quality of life from before to 6 months after left ventricular assist device implantation: Findings from Interagency Registry for Mechanically Assisted Circulatory Support.

BACKGROUND: Gaps in the literature exist regarding health-related quality of life (HRQOL) early after left ventricular assist device (LVAD) surgery. The purposes of our study were to describe HRQOL over time, by age and gender, and identify risk factors for poor HRQOL early after LVAD implant. METHODS: Patients (n = 7,353) from the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) database received a continuous-flow LVAD as a primary implant at 133 United States hospitals. Of these, 5,640 patients had pre-LVAD HRQOL data, 3,353 patients had 6-month post-LVAD HRQOL data, and 2,748 patients had data at both times. HRQOL was measured using the EQ-5D-3L (Euro-Qol) instrument. Data were collected pre-implant and 3 and 6 months post-operatively. Statistical analyses included chi-square test, t-test, Pearson correlation coefficients, and multiple regression analysis. RESULTS: Overall HRQOL and dimensions of HRQOL improved from before to 6 months after device implant when examined by age and gender. However, younger patients and women reported significantly more problems regarding all dimensions before implant and significantly more problems regarding pain/discomfort and anxiety/depression at 3 and 6 months after implant. An increase in overall HRQOL from before to 6 months after implant was related to pre-implant INTERMACS Level 1. Factors related to a decrease in HRQOL from before to 6 months after implant were listed for heart transplant before surgery, comorbidities, better preoperative HRQOL, adverse events within 6 months after implant, bridge to transplant moderately likely and unlikely, and New York Heart Association Functional Classification IV at 6 months after LVAD (R(2) = 41%). CONCLUSIONS: Overall HRQOL and dimensions of HRQOL improve in sub-groups of patients from before to 6 months after surgery, although differences in improvement exist. Adverse events are risk factors for decreased HRQOL across time and support the ongoing need to improve device technology with the aim of reducing adverse events.

Endocrine Effects of Inhaled Corticosteroids in Children.

Inhaled corticosteroids (ICSs) are widely used as first-line treatment for various chronic respiratory illnesses. Advances in devices and formulations have reduced their local adverse effects. However, as delivery of ICSs to the lungs improves, the systemic absorption increases, and an adverse effect profile similar to, although milder than, oral corticosteroids has emerged. The most serious potential adverse effect is adrenal insufficiency, which can be life threatening. Adrenal insufficiency occurs most in patients taking the highest doses of ICSs but is reported with moderate or even low doses as well. Our recommendations include greater vigilance in testing adrenal function than current standard practice. In patients with diabetes mellitus (types 1 and 2), an increase in glucose levels is likely, and diabetes medication adjustment may be needed when initiating or increasing ICSs. The risk of linear growth attenuation and adverse effects on bone mineral density is generally low but should be considered in the face of additional risk factors. On behalf of the Pediatric Endocrine Society Drugs and Therapeutics Committee, we present a review of the endocrine adverse effects of ICSs in children and offer recommendations relating to testing and referral. Limited data in particular realms diminish the strength of certain recommendations, and clinical judgment continues to be paramount.