Cardiovascular, Kidney Failure, and All-Cause Mortality Events in Patients with Focal Segmental Glomerulosclerosis in a U.S. Real-World Database.

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) leads to proteinuria and progressive decline in glomerular filtration rate which correlates with kidney failure and increased cardiovascular risk. The purpose of this study was to estimate the effects of proteinuria on kidney failure status/all-cause mortality and cardiovascular disease events/all-cause mortality, as well as the relationship between progression to kidney failure and occurrence of cardiovascular disease/mortality events among adult patients (≥18 years old) with FSGS. METHODS: This was an observational, retrospective cohort study utilizing Optum® de-identified Market Clarity Data and proprietary Natural Language Processing (NLP) data. The study period was from January 1, 2007 through March 31, 2021, with patients in the overall cohort being identified from July 1, 2007 through March 31, 2021. The index date was the first FSGS ICD-10 diagnosis code or FSGS-related NLP term within the identification period. RESULTS: Elevated proteinuria >1.5 g/g and ≥3.5 g/g increased risk for kidney failure/all-cause mortality (adjusted hazard ratio [95% CI]: 2.34 [1.99-2.74] and 2.44 [2.09-2.84], respectively) and cardiovascular disease/all-cause mortality (adjusted hazard ratio [95% CI]: 2.11 [1.38-3.22] and 2.27 [1.44-3.58], respectively). Progression to kidney failure was also associated with a higher risk of cardiovascular disease/all-cause mortality (adjusted hazard ratio [95% CI]: 3.04 [2.66-3.48]. CONCLUSIONS: A significant proportion of FSGS patients experience kidney failure and cardiovascular disease events. Elevated proteinuria and progression to kidney failure were associated with a higher risk of cardiovascular disease/all-cause mortality events, and, elevated pre-kidney failure proteinuria was associated with progression to kidney failure/all-cause mortality events. Treatments that meaningfully reduce proteinuria and slow the decline in glomerular filtration rate have the potential to reduce the risk of cardiovascular disease, kidney failure and early mortality in patients with FSGS.

Impact of Proteinuria and Kidney Function Decline on Health Care Costs and Resource Utilization in Adults With IgA Nephropathy in the United States: A Retrospective Analysis.

Rationale & Objective: Among patients with IgA nephropathy (IgAN), proteinuria and decline in kidney function may be associated with increased economic burden. This study aimed to provide current information on the epidemiology and economic burden of IgAN in the United States. Study Design: Retrospective cohort study. Setting & Study Population: Overall, 9,984 patients in the Optum's Market Clarity database identified by the presence of at least 2 natural language processing-derived IgAN signs and disease and symptoms terms; 813 with linked claims data included in a health care resource utilization/cost subcohort. Predictor: High-risk proteinuria (≥1 g/d), chronic kidney disease (CKD) stage. Outcomes: Standardized prevalence, health care resource utilization, costs. Analytical Approach: Descriptive statistics for categorical and continuous variables. Direct standardization for prevalence estimation. Generalized linear models for health care resource utilization/costs, reported as per-patient-per-month (PPPM) costs in 2020 US dollars. Results: The estimated standardized US prevalence of IgAN (2016-2020) was 329.0 per 1,000,000 persons. High-risk proteinuria (≥1 vs <1 g/d) was associated with a higher mean PPPM number of outpatient visits (3.49 vs 1.74; P = 0.01) and pharmacy claims (3.79 vs 2.41; P = 0.01), contributing to higher mean total costs PPPM ($3,732 vs $1,457; P = 0.01). Furthermore, higher CKD stage was also associated with higher health care resource utilization (number of outpatient visits PPPM, number of pharmacy claims PPPM, proportion of patients with inpatient visits and emergency department visits; P < 0.001) and mean total cost PPPM (from $2,111 CKD stage 1 to $10,703 CKD stage 5/kidney failure; P < 0.001). Limitations: Generalizability outside of the catchment group for the database, missing data/errors inherent in retrospective database studies, relatively small sample size, use of Optum Market Clarity standardized pricing algorithms, exclusion of out-of-pocket costs. Conclusions: Health care resource utilization and costs were higher for IgAN patients with high-risk proteinuria and worsening kidney function. Treatments that reduce proteinuria and slow CKD disease progression may reduce the economic burden associated with IgAN. Plain-Language Summary: Immunoglobulin A nephropathy (IgAN) is a rare kidney disease. Over time, the kidneys may leak protein into the urine (proteinuria). IgAN can lead to kidney failure. Because IgAN is rare, it is hard to know how many people have it. This study used electronic health records to estimate the number of patients with IgAN in the United States, describe the characteristics of patients, and understand their treatments and the costs. The number of patients with IgAN increased between 2016 and 2020. The researchers think this is because doctors learned more about IgAN. Patients with severe disease used more health care resources and had higher costs. The authors believe treatments that slow kidney damage may reduce the cost of treating IgAN.

Humanistic and Economic Burden of IgA Nephropathy: Systematic Literature Reviews and Narrative Synthesis.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is a progressive inflammatory kidney disease requiring long-term treatment to reduce the risk of progression to kidney failure. Here, we present two systematic literature reviews (SLRs) to identify and summarize literature reporting the humanistic and economic burden of IgAN. METHODS: Electronic literature databases (Ovid Embase, PubMed, and Cochrane) were searched for relevant literature on 29 November 2021, supplemented with gray literature searches. Studies reporting any health-related quality of life (HRQoL) or health state utility outcomes in IgAN patients were included in the humanistic impact SLR, and studies reporting the costs and healthcare resource utilization associated with or economic models of IgAN disease management were included in the economic burden SLR. Narrative synthesis was used to discuss the heterogeneous studies included in the SLRs. Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and Cochrane guidelines were followed, and all included studies were assessed for risk of bias using the Center for Evidence-Based Management tool for Critical Appraisal of a Survey or the Drummond Checklist. RESULTS: A total of 876 and 1122 references were identified from electronic and gray literature searches for humanistic and economic burden, respectively. Three studies reporting humanistic impact and five studies reporting economic burden met criteria for inclusion in these SLRs. The included humanistic studies reported patient preferences in the USA and China, HRQoL for patients with IgAN in Poland, and impact of exercise on HRQoL for patients with IgAN in China. The five economic studies reported costs of IgAN treatment in Canada, Italy, and China, along with two economic models from Japan. DISCUSSION: Current literature suggests IgAN is associated with substantial humanistic and economic burdens. However, these SLRs demonstrate the paucity of research conducted to specifically describe the humanistic or economic burden of IgAN and highlight the need for further research.

QALYs and ambulatory status: societal preferences for healthcare decision making.

BACKGROUND: This research aimed to review the theoretical and methodological aspects of the quality-adjusted life year (QALY) which give rise to potential for bias against certain patient populations, including those with problems with walking or an inability to walk (ambulatory disabilities), when health technology assessment decisions rely on QALY gain to show cost-effectiveness. Societal preferences for treating ambulatory versus non-ambulatory patients were also investigated. METHODS: We reviewed published literature to identify information on theoretical underpinnings of the QALY, measurement of utilities for QALY assessment, and empirical evidence of societal preferences for the treatment of ambulatory and non-ambulatory patients. RESULTS AND DISCUSSION: Health states which represent mobility impairment and the inability to walk receive low valuation from general public preferences. Non-ambulatory patients, for example those with advanced neuromuscular disease, have lower utilities determined by standardized preference-based measurement (PBM) tools. Any treatment that increases survival but could not restore ambulation would result in lower lifetime QALY gains for non-ambulatory versus ambulatory patients. Treatments could therefore potentially be deemed less cost-effective, or not cost-effective at all for this patient population.Empirical research indicates a societal preference for equal treatment of patients regardless of ambulatory status. The main limitation of our review was the non-systematic approach to evidence search and review, however, given the broad scope of content required to meet the aims of the review, we believe that the targeted approach was appropriate. The evidence presented in this article highlights the need for alternatives to strict QALY-based approaches to prevent avoidable health inequities when determining cost-effectiveness of healthcare interventions for non-ambulatory populations against fixed cost-effectiveness thresholds. An alternative metric, the Equal Value of Life Years Gained (evLYG), has been proposed as a supplementary measure for use alongside the QALY for its potential to alleviate bias against disabled patient populations during the assessment of healthcare treatments.

Mortality and guideline-directed medical therapy in real-world heart failure patients with reduced ejection fraction.

OBJECTIVE: To estimate the prevalence of guideline-directed medical therapy (GDMT) in commercially insured US patients with heart failure with reduced ejection fraction (HFrEF) and examine the effect of GDMT on all-cause mortality. GDMT for HFrEF includes pharmacologic therapies such as ß-blockers (BB), angiotensin-converting enzyme inhibitors (ACE-I), angiotensin receptor blockers (ARB), angiotensin receptor-neprilysin (ARNI), mineralocorticoid receptor antagonists (MRA), and sodium-glucose cotransporter inhibitors to reduce morbidity and mortality. METHODS: Patients in the Optum Integrated File from 2007 to 2019Q3, ≥18 years, with history of HFrEF, were identified. Patients prescribed both a BB and either an ACE-I, ARB, or ARNI during 6-month post-diagnosis were assigned to the GDMT cohort. All others were assigned to the not on GDMT cohort. The GDMT cohort was further classified by those patients with a record of prescription fills for both classes of medications concurrently (GDMT concurrent medication fills). Mortality at 2 years was assessed with a Cox regression model accounting for baseline demographics, comorbidities, and diuretic use. RESULTS: This study identified 14 880 HFrEF patients, of which 70% had a record of GDMT, and 57% had a record of concurrent prescriptions. Patients in the not on GDMT cohort had 29% increased risk of mortality versus GDMT (hazard ratio 1.29; 95% CI (1.19-1.40); p < .0001). As a sensitivity analysis, the effect of patients not on GDMT compared to GDMT with concurrent medication fills was more pronounced, with a 37% increased mortality risk. CONCLUSION: In a real-world population of HFrEF patients, inadequate GDMT confers a 29% excess mortality risk over the 2-year follow-up.

Healthcare utilization and guideline-directed medical therapy in heart failure patients with reduced ejection fraction.

Aim: This study examines the effect of guideline-directed medical therapy (GDMT) on healthcare utilization in patients with heart failure with reduced ejection fraction from Optum® Integrated File from 1 January 2007 to 30 June 2020. Materials & methods: Patients with both a beta blocker and either an ACE inhibitor (ACE-I), angiotensin receptor blocker (ARB) or angiotensin receptor neprilysin inhibitor were assigned to the GDMT cohort. All others were not on GDMT. Results: Estimated annual all cause hospitalizations and emergency department visits per 100 patients was 29% (80 vs 62 patients) and 26% higher (54 vs 43 patients; p < 0.0001) and annualized hospital days were longer (1.88 vs 1.64; p = 0.0020) for patients not on GDMT. Conclusion: In a real-world population, heart failure with reduced ejection fraction, patients not optimally managed on GDMT had higher annualized healthcare utilization when compared with patients on GDMT.

Comparison of Survival in Patients With Clinically Significant Tricuspid Regurgitation With and Without Heart Failure (From the Optum Integrated File).

This study aimed to quantify survival rates for patients with tricuspid regurgitation (TR) using real-world data. Several clinical conditions are associated with TR, including heart failure (HF), other valve disease (OVD), right-sided heart disease (RSHD), and others that impact mortality. Optum data from January 1, 2007, through December 31, 2018 included patients age ≥18 years with TR and 12 months of continuous health plan enrollment before TR. Exclusion criteria were end-stage renal disease or known/primary organ pathology. Cohorts were created hierarchically: (1) TR with HF; (2) TR with OVD (no HF); (3) TR with RSHD only (no OVD or HF); (4) TR only. Survival was estimated using a Cox hazard model with an interaction term for TR severity and adjusted for patient demographics and Elixhauser co-morbidities. A total of 33,686 met study inclusion (1) TR with HF (26.6%); (2) TR with OVD (36.7%); (3) TR with RSHD only (17.1%); (4) TR only (19.6%). TR patients (regardless of severity) with HF, OVD or RSHD had an increased risk of mortality compared with patients with TR alone. TR severity was also significantly associated (hazard ratio = 1.33; p = 0.0002) with an increased risk of all-cause mortality. In conclusion, TR severity is significantly associated with an increased risk of all-cause mortality, independent of associated conditions including HF, OVD, or RSHD. In patients with severe TR, the mortality risk is most pronounced for patients who had RSHD without HF or OVD before their TR diagnosis.

Healthcare utilization in clinically significant tricuspid regurgitation patients with and without heart failure.

Aim: This study evaluated how the presence of right-sided heart disease (RSHD), other valve disease (OVD) and heart failure (HF) impacts healthcare utilization in patients with tricuspid valve disease (tricuspid regurgitation [TR]). Materials & methods: Of the 33,686 patients with TR: 6618 (19.6%) had TR-only; 8952 (26.6%) had TR with HF; 12,367 (36.7%) had TR with OVD but no HF; and 5749 (17.1%) had TR with RSHD only. Results: The presence of RSHD, OVD or HF in patients with TR was independently associated with increased annualized hospitalizations, hospital days and costs relative to patients with TR alone. Conclusion: All three co-morbidities were associated with increased healthcare utilization, with HF showing the greatest impact across all measures.

Impact of mitral regurgitation on cardiovascular hospitalization and death in newly diagnosed heart failure patients.

AIMS: Heart failure (HF) carries a poor prognosis, and the impact of concomitant mitral regurgitation (MR) is not well understood. This analysis aimed to estimate the incremental effect of MR in patients newly diagnosed with HF. METHODS AND RESULTS: Data from the IBM® MarketScan® Research Databases were analysed. Included patients had at least one inpatient or two outpatient HF claims. A 6 month post-period after HF index was used to capture MR diagnosis and severity. HF patients were separated into three cohorts: without MR (no MR), not clinically significant MR (nsMR), and significant MR (sMR). Time-to-event analyses were modelled to estimate the clinical burden of disease. The primary outcome was a composite endpoint of death or cardiovascular (CV)-related admission. Secondary outcomes were death and CV hospitalization alone. All models controlled for baseline demographics and co-morbidities. Patients with sMR were at significantly higher risk of either death or CV admission compared with patients with no MR [hazard ratio (HR) 1.26; 95% confidence interval (CI) 1.15-1.39]. When evaluating death alone, patients with sMR had significantly higher risk of death (HR 1.24; 95% CI 1.08-1.43) compared with patients with no MR. When evaluating CV admission alone, patients with MR were at higher risk of hospital admission vs. patients with no MR, and the magnitude was dependent upon the MR severity: sMR (HR 1.55; 95% CI 1.38-1.74) and nsMR (HR 1.23; 95% CI 1.08-1.40). CONCLUSIONS: Evidence of MR in retrospective claims significantly increases the clinical burden of incident HF patients. Time to death and CV hospitalizations are increased when MR is clinically significant.

The economic impact of clinically significant tricuspid regurgitation in a large, administrative claims database.

Aim: This study aimed to quantify the healthcare burden of clinically significant tricuspid regurgitation (TR) in patients with and without heart failure (HF).Materials and Methods: Data were from the IBM MarketScan Research Databases from October 2011 to September 2016. Eligible patients met the following inclusion criteria: age ≥18 with a TR diagnosis, 12 months pre (baseline), and 6 months post (landmark) medical enrollment. The landmark period was used to categorize TR severity, defined as a record of pulmonary hypertension with ascites, lower extremity edema or hepatic insufficiency, or tricuspid valve surgery. Cohorts were defined based on TR etiology and severity: (1) no HF and no clinically significant TR; (2) HF with no clinically significant TR; (3) no HF with clinically significant TR; and (4) HF with clinically significant TR. Outcomes of interest were all-cause hospitalizations, hospital days, and expenditures. Multivariable models were fit for each of the annualized outcomes and adjusted for patient demographics, comorbidities, and other concomitant valve diseases.Results: There were 92,994 patients eligible for analysis. Patients with no HF and no clinically significant TR had the annualized healthcare burden of 0.20 all-cause hospitalizations (approximately one inpatient hospitalization every 5 years), 1.07 hospital days, and $17,478 in expenditures. The presence of clinically significant TR, alone or with HF, significantly increased healthcare utilization and expenditures. For patients with no HF with clinically significant TR, the annualized economic burden increased to 0.41 all-cause hospitalizations, 3.13 hospital days, and $29,985 in expenditures. For patients with HF and clinically significant TR, the annualized economic burden was even greater with 0.59 all-cause hospitalizations, 4.31 hospital days, and $42,255 in expenditures.Conclusion: The presence of clinically significant TR is associated with an increase in healthcare utilization and expenditures, irrespective of the presence of HF.

Twelve-month healthcare utilization and expenditures in Medicare fee-for-service patients with clinically significant mitral regurgitation.

Aim: This study sought to quantify the healthcare burden of Medicare patients with clinically significant mitral regurgitation (sMR). Materials & methods: Proxy definitions were used for sMR, including MR surgery, atrial fibrillation, pulmonary hypertension or >2 echocardiograms. Results: In this study, 11,173 patients had significant degenerative MR (sDMR); 25,402 had significant functional MR (sFMR); and 12,232 had significant uncharacterized MR (sUMR). Patients with sFMR (18,880) were more likely to be hospitalized and present to the emergency department compared with patients with sDMR (9,795) or sUMR (10,587). Annual healthcare expenditures for sMR patients were: US$29,328 for sFMR; US$17,112 for sUMR; and US$12,870 for sDMR. Conclusion: Novel therapeutic interventions merit further evaluation to reduce the substantial healthcare burden of sMR in the Medicare population.

The Economic Impact of Mitral Regurgitation on Patients With Medically Managed Heart Failure.

The objective of this study was to quantify the financial healthcare burden of mitral regurgitation (MR) on medically managed heart failure (HF) patients. Data from the Truven Health MarketScan Commercial Claims and Medicare Supplemental Databases were analyzed. Included patients had a minimum of 1 inpatient or 2 outpatient claims for HF with a 6-month preperiod (baseline). A 6-month postperiod (landmark) after HF index was used to capture MR diagnosis and severity. Following the landmark period, patients had to have 12 months of continuous medical and prescription drug plan enrollment with at least 2 records of HF medication refills. A therapeutic intensity score was calculated based on HF medication usage. Medically managed HF patients were separated into 3 cohorts: without MR (no MR), insignificant MR (iMR), and significant MR (sMR). Healthcare utilization and all-cause expenditures were modeled to quantify the burden of MR. All models controlled for baseline demographics, co-morbid conditions, and HF therapeutic intensity. Medically managed incident HF patients with sMR had significantly more hospital days (1.91 vs 1.72 days; p = 0.0096) and annual expenditures ($23,988 vs $21,530; p < 0.0001) compared with no MR patients. No differences were identified when comparing iMR and no MR. When evaluating HF admissions, sMR patients had an estimated 50% greater HF admissions rate (0.036 vs 0.024; p < 0.0001) compared with no MR patients. Additionally, HF admits for iMR were 23% more than those with no MR (0.029 vs 0.024; p = 0.0064). In conclusion, evidence of MR in retrospective claims significantly increases the healthcare impact of medically managed HF patients. Both utilization and financial burden is more pronounced when MR is clinically significant.

Rapid and efficient synthesis of a novel cholinergic muscarinic M1 receptor positive allosteric modulator using flash chemistry.

Continuous flow-flash synthesis of a 2-bromobenzaldehyde derivative 18 as a key intermediate of a novel cholinergic muscarinic M1 positive allosteric modulator 1 bearing an isoindolin-1-one ring system as a pharmacophore has been achieved using flow microreactors through selective I/Li exchange of 1-bromo-2-iodobenzene derivative 17 with BuLi and subsequent formylation at -40 °C of the highly reactive 2-bromophenyllithium intermediate using DMF, which is difficult to achieve by a conventional batch process due to the conversion of the highly reactive 2-bromophenyllithium intermediate into benzyne even at -78 °C. Late-stage cyclization to give the isoindolin-1-one ring system, through reductive amination of 18 followed by palladium-catalyzed carbonylation with carbon monoxide and intramolecular cyclization, efficiently afforded 1 for its further research and development.

The healthcare burden of disease progression in medicare patients with functional mitral regurgitation.

Objective: This retrospective database analysis estimated the incremental effect that disease progression from non-clinically significant functional mitral regurgitation (nsFMR) to clinically significant FMR (sFMR) has on clinical outcomes and costs. Methods: Medicare Fee for Service beneficiaries with nsFMR were examined, defined as those with a heart failure diagnosis prior to MR. Patients were classified as ischemic if there was a history of: CAD, AMI, PCI, or CABG. The primary outcome was time to sFMR, defined as pulmonary hypertension, atrial fibrillation, mitral valve surgery, serial echocardiography, or death, using a Cox hazard regression model. Annualized hospitalizations, inpatient hospital days, and healthcare expenditures were also modeled. Results: Patients with IHD had higher risk (Hazard Ratio = 1.22 [1.14-1.30]) for disease progression compared to patients without. The progression cohort had significantly more annual inpatient hospitalizations (non-IHD = 1.32; IHD = 1.40) than the non-progression cohort (non-IHD = 0.36; IHD = 0.34), and significantly more annual inpatient hospital days (non-IHD = 13.07; IHD = 13.52) than the non-progression cohort (non-IHD = 2.29; with IHD = 2.08). The progression cohort had over 3.5-times higher costs vs the non-progression cohort, independent of IHD (non-IHD = $12,798 vs $46,784; IHD = $12,582 vs $49,348). Conclusion: Treating FMR patients earlier in their clinical trajectory may prevent disease progression and reduce high rates of healthcare utilization and expenditures.

Recurrent Cardiogenic Shock Associated with Cannabis Use: Report of a Case and Review of the Literature.

BACKGROUND: The United States has recently undergone increases in the legalization and use of marijuana. There have been previous reports on the association of cannabis use and myocardial dysfunction, however, few on the association with acute stress cardiomyopathy and cardiogenic shock. CASE REPORT: This is a case of a 58-year-old female with a history of inhaled cannabis use, no history of diabetes, and no known history of cardiac disease, that illustrates an association between cannabis use and the recurrent development of stress cardiomyopathy and cardiogenic shock. A review of medical records was performed from two hospitalizations and subsequent outpatient follow-up for similar presentations 6 years apart and review of literature regarding cannabis use and its association with cardiac dysfunction. In separate hospitalizations, the patient presented with clinical findings of cardiogenic shock, severe left ventricular dysfunction with morphologic features of stress cardiomyopathy, and normal coronary angiography. Laboratory results included elevated cardiac biomarkers and urine tetrahydrocannabinol levels > 300 ng/mL. The patient required intensive cardiovascular support, but recovered with normal cardiac function after each event. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: As use of cannabis becomes more prevalent, it will be important for physicians to recognize the potential association of cannabis use and acute myocardial dysfunction, and how early treatment may contribute to salutary outcomes.

Systematic reviews of economic burden and health-related quality of life in patients with acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is a rare hematologic malignancy largely affecting older adults. Comorbidities may compromise fitness and eligibility for high-intensity chemotherapy (HIC). This study presents the results of two systematic reviews (SRs) assessing (1) the impact of AML and current treatments on health-related quality of life (HRQoL), and (2) the economic burden and cost drivers of AML in patients who are ineligible for HIC. METHODS: Electronic searches (MEDLINE, EMBASE, EconLit, Cochrane library) were supplemented with manual searching of conference, utility, and HTA databases. All studies reporting HRQoL or economic data for patients with AML who were ineligible for HIC were included. RESULTS: The HRQoL SR included ten studies. Patients with AML have lower baseline HRQoL than other cancer patients or the general population, and those receiving lower intensity treatment have lower HRQoL than those eligible for HIC. Low baseline HRQoL predicts poor outcomes, and treatment had variable effects on HRQoL. The economic burden SR included nine studies. Medical costs varied widely, reflecting the heterogeneity of AML. Hospitalization is a key cost driver in AML treatment but was largely not considered in cost studies. Medical resource utilization comprised drug acquisition, drug administration, disease monitoring tests, transfusions, adverse event management, supportive care/monitoring costs and terminal care. CONCLUSION: As new drugs emerge that extend survival, assessment of HRQoL will be important to evaluate the quality of that survival. Cost data, driven by transfusions and hospitalization, will be important to evaluate the economic value of new treatments.

Percutaneous Repair of Postoperative Mitral Regurgitation After Left Ventricular Assist Device Implant.

Mitral regurgitation commonly improves after implantation of a left ventricular assist device without concomitant valvular repair owing to the mechanical unloading of the left ventricle. However, the development (or persistence) of significant mitral regurgitation after implantation of a left ventricular assist device is associated with adverse clinical events. We present a case of a left ventricular assist device patient who successfully underwent a percutaneous MitraClip procedure for repair of persistent late postoperative mitral insufficiency with demonstrable clinical and hemodynamic improvement.

Identification of a novel K311 ubiquitination site critical for androgen receptor transcriptional activity.

The androgen receptor (AR) is the main driver of prostate cancer (PC) development and progression, and the primary therapeutic target in PC. To date, two functional ubiquitination sites have been identified on AR, both located in its C-terminal ligand binding domain (LBD). Recent reports highlight the emergence of AR splice variants lacking the LBD that can arise during disease progression and contribute to castrate resistance. Here, we report a novel N-terminal ubiquitination site at lysine 311. Ubiquitination of this site plays a role in AR stability and is critical for its transcriptional activity. Inactivation of this site causes AR to accumulate on chromatin and inactivates its transcriptional function as a consequence of inability to bind to p300. Additionally, mutation at lysine 311 affects cellular transcriptome altering the expression of genes involved in chromatin organization, signaling, adhesion, motility, development and metabolism. Even though this site is present in clinically relevant AR-variants it can only be ubiquitinated in cells when AR retains LBD suggesting a role for AR C-terminus in E2/E3 substrate recognition. We report that as a consequence AR variants lacking the LBD cannot be ubiquitinated in the cellular environment and their protein turnover must be regulated via an alternate pathway.

A Case Series of Biventricular Circulatory Support Using Two Ventricular Assist Devices: A Novel Operative Approach.

Increased use of continuous-flow left ventricular assist devices (LVADs) to treat advanced heart failure has heightened concern for right ventricular failure after LVAD implantation, which is associated with increased morbidity and mortality. Biventricular support is required in up to 30% of LVAD recipients. Currently, no durable long-term right ventricular assist device (RVAD) has been approved other than the Syncardia (Tucson, AZ) total artificial heart. A recent publication reported the placement of continuous flow LVAD in the heavily trabeculated right ventricle; however, this orientation may jeopardize both assist device and right ventricle function. We describe three cases of right-sided mechanical circulatory support with durable RVAD implanted in the right atrium, allowing long-term support with fewer anatomic limitations as compared with right ventricular cannulation.