Force-Based Neuromodulation.

Technologies for neuromodulation have rapidly developed in the past decade with a particular emphasis on creating noninvasive tools with high spatial and temporal precision. The existence of such tools is critical in the advancement of our understanding of neural circuitry and its influence on behavior and neurological disease. Existing technologies have employed various modalities, such as light, electrical, and magnetic fields, to interface with neural activity. While each method offers unique advantages, many struggle with modulating activity with high spatiotemporal precision without the need for invasive tools. One modality of interest for neuromodulation has been the use of mechanical force. Mechanical force encapsulates a broad range of techniques, ranging from mechanical waves delivered via focused ultrasound (FUS) to torque applied to the cell membrane.Mechanical force can be delivered to the tissue in two forms. The first form is the delivery of a mechanical force through focused ultrasound. Energy delivery facilitated by FUS has been the foundation for many neuromodulation techniques, owing to its precision and penetration depth. FUS possesses the potential to penetrate deeply (∼centimeters) into tissue while maintaining relatively precise spatial resolution, although there exists a trade-off between the penetration depth and spatial resolution. FUS may work synergistically with ultrasound-responsive nanotransducers or devices to produce a secondary energy, such as light, heat, or an electric field, in the target region. This layered technology, first enabled by noninvasive FUS, overcomes the need for bulky invasive implants and also often improves the spatiotemporal precision of light, heat, electrical fields, or other techniques alone. Conversely, the second form of mechanical force modulation is the generation of mechanical force from other modalities, such as light or magnetic fields, for neuromodulation via mechanosensitive proteins. This approach localizes the mechanical force at the cellular level, enhancing the precision of the original energy delivery. Direct interaction of mechanical force with tissue presents translational potential in its ability to interface with endogenous mechanosensitive proteins without the need for transgenes.In this Account, we categorize force-mediated neuromodulation into two categories: 1) methods where mechanical force is the primary stimulus and 2) methods where mechanical force is generated as a secondary stimulus in response to other modalities. We summarize the general design principles and current progress of each respective approach. We identify the key advantages of the limitations of each technology, particularly noting features in spatiotemporal precision, the need for transgene delivery, and the potential outlook. Finally, we highlight recent technologies that leverage mechanical force for enhanced spatiotemporal precision and advanced applications.

Socioeconomic Disparities and the Prevalence of Antimicrobial Resistance.

BACKGROUND: The increased prevalence of antimicrobial resistant (AMR) infections is a significant global health threat, resulting in increased morbidity, mortality, and costs. The drivers of AMR are complex and potentially impacted by socioeconomic factors. We investigated the relationships between geographic and socioeconomic factors and AMR. METHODS: We collected select patient bacterial culture results from 2015 to 2020 from electronic health records (EHR) of two expansive healthcare systems within the Dallas-Fort Worth, TX (DFW) metropolitan area. Among individuals with EHR records who resided in the four most populus counties in DFW, culture data were aggregated. Case counts for each organism studied were standardized per 1,000 persons per area population. Using residential addresses, the cultures were geocoded and linked to socioeconomic index values. Spatial autocorrelation tests identified geographic clusters of high and low AMR organism prevalence and correlations with established socioeconomic indices. RESULTS: We found significant clusters of AMR organisms in areas with high levels of deprivation, as measured by the Area Deprivation Index (ADI). We found a significant spatial autocorrelation between ADI and the prevalence of AMR organisms, particularly for AmpC and MRSA with 14% and 13%, respectively, of the variability in prevalence rates being attributable to their relationship with the ADI values of the neighboring locations. CONCLUSIONS: We found that areas with a high ADI are more likely to have higher rates of AMR organisms. Interventions that improve socioeconomic factors such as poverty, unemployment, decreased access to healthcare, crowding, and sanitation in these areas of high prevalence may reduce the spread of AMR.

Regulation of the swimming kinematics of lampreys Petromyzon marinus across changes in viscosity.

The bodies of most swimming fishes are very flexible and deform as result of both external fluid dynamic forces and internal musculoskeletal forces. If fluid forces change, the body motion will also change unless the fish senses the change and alters its muscle activity to compensate. Lampreys and other fishes have mechanosensory cells in their spinal cords that allow them to sense how their body is bending. We hypothesized that lampreys (Petromyzon marinus) actively regulate body curvature to maintain a fairly constant swimming waveform even as swimming speed and fluid dynamic forces change. To test this hypothesis, we measured the steady swimming kinematics of lampreys swimming in normal water, and water in which the viscosity was increased by 10 or 20 times by adding methylcellulose. Increasing the viscosity over this range increases the drag coefficient, potentially increasing fluid forces up to 40%. Previous computational results suggested that if lampreys did not compensate for these forces, the swimming speed would drop by about 52%, the amplitude would drop by 39%, and posterior body curvature would increase by about 31%, while tail beat frequency would remain the same. Five juvenile sea lampreys were filmed swimming through still water, and midlines were digitized using standard techniques. Although swimming speed dropped by 44% from 1× to 10× viscosity, amplitude only decreased by 4%, and curvature increased by 7%, a much smaller change than the amount we estimated if there was no compensation. To examine the waveform overall, we performed a complex orthogonal decomposition and found that the first mode of the swimming waveform (the primary swimming pattern) did not change substantially, even at 20× viscosity. Thus, it appears that lampreys are compensating, at least partially, for the changes in viscosity, which in turn suggests that sensory feedback is involved in regulating the body waveform.

Pyrogallol impairs staphylococcal biofilm formation via induction of bacterial oxidative stress.

AIMS: To examine the effect of the phenolic compound pyrogallol on staphylococcal biofilm formation. METHODS AND RESULTS: In crystal violet biofilm assays, pyrogallol-reduced biofilm formation in Staphylococcus epidermidis ATCC 35984, Staph. epidermidis NRRL-B41021, Staphylococcus aureus USA300, and Staph. aureus Newman, without significantly impairing bacterial viability. Pyrogallol-mediated impairment of biofilm formation was likely due to induction of bacterial oxidative stress, as its effect was greater in catalase-deficient versus WT Staph. aureus, and biofilm production was rescued by exogenous catalase. The effect of pyrogallol on staphylococcal biofilm formation mirrored that of the known oxidant hydrogen peroxide, which also reduced biofilm formation in a dose-dependent manner. CONCLUSIONS: Pyrogallol reduces biofilm formation in S. aureus and Staph. epidermidis in a mechanism involving induction of bacterial oxidative stress.

Guidance for Timely and Appropriate Referral of Patients With Advanced Heart Failure: A Scientific Statement From the American Heart Association.

Among the estimated 6.2 million Americans living with heart failure (HF), ≈5%/y may progress to advanced, or stage D, disease. Advanced HF has a high morbidity and mortality, such that early recognition of this condition is important to optimize care. Delayed referral or lack of referral in patients who are likely to derive benefit from an advanced HF evaluation can have important adverse consequences for patients and their families. A 2-step process can be used by practitioners when considering referral of a patient with advanced HF for consideration of advanced therapies, focused on recognizing the clinical clues associated with stage D HF and assessing potential benefits of referral to an advanced HF center. Although patients are often referred to an advanced HF center to undergo evaluation for advanced therapies such as heart transplantation or implantation of a left ventricular assist device, there are other reasons to refer, including access to the infrastructure and multidisciplinary team of the advanced HF center that offers a broad range of expertise. The intent of this statement is to provide a framework for practitioners and health systems to help identify and refer patients with HF who are most likely to derive benefit from referral to an advanced HF center.

The influence of heart failure on clinical and economic outcomes among older adults ≥75 years of age with acute myocardial infarction.

BACKGROUND: We aimed to evaluate the influence of heart failure (HF) on clinical and economic outcomes among older adults ≥75 years of age during their acute myocardial infarction (AMI) admission in large population-based study from the United States. We also evaluated the clinical characteristics associated with the presence of HF and the predictors of mortality, healthcare utilization, and cost among older adults with AMI. METHODS: From January 1, 2000, to December 31, 2016, AMI admission was identified using the primary diagnosis and concomitant HF was identified using any non-primary diagnoses in the Premier Healthcare Database. RESULTS: Of the 468,654 patients examined, 42,946 (9%) had concomitant HF during their AMI admission. These patients were older, more often female, and were more likely to be White. Patients with concomitant HF were more likely to be frail than non-HF patients (59% vs 15%, P < .001). The mean (SD) Elixhauser comorbidity index was 2.6 (2.5) vs 0.4 (1.1), P < .001 in the AMI with HF vs AMI only group. The use of percutaneous coronary intervention in those with AMI and HF was lower than those with AMI only (15% vs 31%, P < .001). The overall mortality rate for those with HF was 12%, the median [IQR] hospital length of stay was 5 [3,9] days, and only 25% of patients were discharged home. A higher proportion of patients were discharged to rehabilitation or hospice if they had AMI and HF (Rehabilitation: 33% vs 20%, P < .001; Hospice: 5% vs 3%, P < .001). The mean unadjusted cost of an AMI hospitalization in patients with concomitant HF was lower ($12,411 ± $14,860) than in those without HF ($15,828 ± $19,330). After adjusting for age, gender, race, hypertension, frailty, revascularization strategy, and death, the average cost of hospitalization attributed to concomitant HF was +$1,075 (95% CI +876 to $1,274) when compared to AMI patients without HF. CONCLUSION: In patients ≥75 years of age, AMI with concomitant HF carries higher risk of death, but at ages ≥85 years, the risk difference diminishes due to other competing risks. HF was also associated with longer hospital length of stay and higher likelihood of referral to hospice and rehabilitation facilities when compared to older patients without HF. Care for these older adults is associated with increased hospitalization costs. Measures to identify HF in older adults during their AMI admission are necessary to optimize health outcomes, care delivery, and costs.

A Randomized Controlled Trial of Mobile Health Intervention in Patients With Heart Failure and Diabetes.

BACKGROUND: Mobile health (mHealth) platforms can affect health behaviors but have not been rigorously tested in randomized trials. OBJECTIVES: We sought to evaluate the effectiveness of a pragmatic mHealth intervention in patients with heart failure (HF) and diabetes (DM). METHODS: We conducted a multicenter randomized trial in 187 patients with both HF and DM to assess an mHealth intervention to improve physical activity and medication adherence compared to usual care. The primary endpoint was change in mean daily step count from baseline through 3 months. Other outcomes included medication adherence, health-related quality of life and metabolomic profiling. RESULTS: The mHealth group had an increase in daily step count of 151 steps/day at 3 months, whereas the usual-care group had a decline of 162 steps/day (least squares mean between-group difference = 313 steps/day; 95% CI: 8 619; P = 0.044). Medication adherence, measured using the Voils Adherence Questionnaire, did not change from baseline to 3 months (LS-mean change -0.08 in mHealth vs -0.15 in usual care; P = 0.47). The mHealth group had an improvement in Kansas City Cardiomyopathy Questionnaire Overall Summary Score compared to the usual-care group (LS-mean difference = 5.5 points, 95% CI: 1.4, 9.6; P = 0.009). Thirteen metabolites, primarily medium- and long-chain acylcarnitines, changed differently between treatment groups from baseline to 3 months (P < 0.05). CONCLUSIONS: In patients with HF and DM, a 3-month mHealth intervention significantly improved daily physical activity, health-related quality of life and metabolomic markers of cardiovascular health but not medication adherence. CONDENSED ABSTRACT: Heart failure (HF) and diabetes (DM) have overlapping biological and behavioral risk factors. We conducted a multicenter randomized, clinical trial in 187 patients with both HF (regardless of ejection fraction) and DM to assess whether an mHealth intervention could improve physical activity and medication adherence. The mHealth group had an increase in mean daily step count and quality of life but not in medication adherence. Medium- and long-chain acylcarnitines changed differently in treatment groups from baseline to 3 months (P < 0.05). These data have important implications for designing effective lifestyle interventions in HF and DM.

Health System-Level Performance in Prescribing Guideline-Directed Medical Therapy for Patients With Heart Failure With Reduced Ejection Fraction: Results From the CONNECT-HF Trial.

BACKGROUND: Health system-level interventions to improve use of guideline-directed medical therapy (GDMT) often fail in the acute care setting. We sought to identify factors associated with high performance in adoption of GDMT among health systems in CONNECT-HF. METHODS AND RESULTS: Site-level composite quality scores were calculated at discharge and last follow-up. Site performance was defined as the average change in score from baseline to last follow-up and analyzed by performance tertile using a mixed-effects model with baseline performance as a fixed effect and site as a random effect. Among 150 randomized sites, the mean 12-month improvement in GDMT was 1.8% (-26.4% to 60.0%). Achievement of 50% or more of the target dose for angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor-neprilysin inhibitors, and beta-blockers at 12 months was modest, even at the highest performing sites (median 29.6% [23%, 41%] and 41.2% [29%, 50%]). Sites achieving higher GDMT scores had care teams that included social workers and pharmacists, as well as patients who were able to afford medications and access medication lists in the electronic health record. CONCLUSIONS: Substantial gaps in site-level use of GDMT were found, even among the highest performing sites. The failure of hospital-level interventions to improve quality metrics suggests that a team-based approach to care and improved patient access to medications are needed for postdischarge success.

Effect of a Hospital and Postdischarge Quality Improvement Intervention on Clinical Outcomes and Quality of Care for Patients With Heart Failure With Reduced Ejection Fraction: The CONNECT-HF Randomized Clinical Trial.

Importance: Adoption of guideline-directed medical therapy for patients with heart failure is variable. Interventions to improve guideline-directed medical therapy have failed to consistently achieve target metrics, and limited data exist to inform efforts to improve heart failure quality of care. Objective: To evaluate the effect of a hospital and postdischarge quality improvement intervention compared with usual care on heart failure outcomes and care. Design, Setting, and Participants: This cluster randomized clinical trial was conducted at 161 US hospitals and included 5647 patients (2675 intervention vs 2972 usual care) followed up after a hospital discharge for acute heart failure with reduced ejection fraction (HFrEF). The trial was performed from 2017 to 2020, and the date of final follow-up was August 31, 2020. Interventions: Hospitals (n = 82) randomized to a hospital and postdischarge quality improvement intervention received regular education of clinicians by a trained group of heart failure and quality improvement experts and audit and feedback on heart failure process measures (eg, use of guideline-directed medical therapy for HFrEF) and outcomes. Hospitals (n = 79) randomized to usual care received access to a generalized heart failure education website. Main Outcomes and Measures: The coprimary outcomes were a composite of first heart failure rehospitalization or all-cause mortality and change in an opportunity-based composite score for heart failure quality (percentage of recommendations followed). Results: Among 5647 patients (mean age, 63 years; 33% women; 38% Black; 87% chronic heart failure; 49% recent heart failure hospitalization), vital status was known for 5636 (99.8%). Heart failure rehospitalization or all-cause mortality occurred in 38.6% in the intervention group vs 39.2% in usual care (adjusted hazard ratio, 0.92 [95% CI, 0.81 to 1.05). The baseline quality-of-care score was 42.1% vs 45.5%, respectively, and the change from baseline to follow-up was 2.3% vs -1.0% (difference, 3.3% [95% CI, -0.8% to 7.3%]), with no significant difference between the 2 groups in the odds of achieving a higher composite quality score at last follow-up (adjusted odds ratio, 1.06 [95% CI, 0.93 to 1.21]). Conclusions and Relevance: Among patients with HFrEF in hospitals randomized to a hospital and postdischarge quality improvement intervention vs usual care, there was no significant difference in time to first heart failure rehospitalization or death, or in change in a composite heart failure quality-of-care score. Trial Registration: ClinicalTrials.gov Identifier: NCT03035474.

Heart Failure End Points in Cardiovascular Outcome Trials of Sodium Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes Mellitus: A Critical Evaluation of Clinical and Regulatory Issues.

Following regulatory guidance set forth in 2008 by the US Food and Drug Administration for new drugs for type 2 diabetes mellitus, many large randomized, controlled trials have been conducted with the primary goal of assessing the safety of antihyperglycemic medications on the primary end point of major adverse cardiovascular events, defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Heart failure (HF) was not specifically mentioned in the US Food and Drug Administration guidance and therefore it was not a focus of these studies when planned. Several trials subsequently showed the impact of antihyperglycemic drugs on HF outcomes, which were not originally specified as the primary end point of the trials. The most impressive finding has been the substantial and consistent risk reduction in HF hospitalization seen across 4 trials of sodium glucose cotransporter 2 inhibitors. However, to date, these results have not led to regulatory approval of any of these drugs for a HF indication or a recommendation for use by US HF guidelines. It is therefore important to explore to what extent persuasive treatment effects on nonprimary end points can be used to support regulatory claims and guideline recommendations. This topic was discussed by researchers, clinicians, industry sponsors, regulators, and representatives from professional societies, who convened on the US Food and Drug Administration campus on March 6, 2019. This report summarizes these discussions and the key takeaway messages from this meeting.

Care Optimization Through Patient and Hospital Engagement Clinical Trial for Heart Failure: Rationale and design of CONNECT-HF.

Many therapies have been shown to improve outcomes for patients with heart failure (HF) in controlled settings, but there are limited data available to inform best practices for hospital and post-discharge quality improvement initiatives. The CONNECT-HF study is a prospective, cluster-randomized trial of 161 hospitals in the United States with a 2×2 factorial design. The study is designed to assess the effect of a hospital and post-discharge quality improvement intervention compared with usual care (primary objective) on HF outcomes and quality-of-care, as well as to evaluate the effect of hospitals implementing a patient-level digital intervention compared with usual care (secondary objective). The hospital and post-discharge intervention includes audit and feedback on HF clinical process measures and outcomes for patients with HF with reduced ejection fraction (HFrEF) paired with education to sites and clinicians by a trained, nationally representative group of HF and quality improvement experts. The patient-level digital intervention is an optional ancillary study and includes a mobile application and behavioral tools that are intended to facilitate improved use of guideline-directed recommendations for self-monitoring and self-management of activity and medications for HFrEF. The effects of the interventions will be measured through an opportunity-based composite score on quality and time-to-first HF readmission or death among patients with HFrEF who present to study hospitals with acute HF and who consent to participate. The CONNECT-HF study is evaluating approaches for implementing HF guideline recommendations into practice and is one of the largest HF implementation science trials performed to date.

Long-term remission in an adult heart transplant recipient with advanced Burkitt's lymphoma post-transplant lymphoproliferative disorder after anthracycline-free chemotherapy: A case report and literature review.

Incidence of Burkitt's lymphoma post-transplant lymphoproliferative disorder (BL-PTLD) in solid organ transplant (SOT) recipients in 1.4%-1.6% with unknown cure rate. We report a case of Epstein-Barr virus (EBV) positive, late-onset BL-PTLD in a 24-year-old EBV donor positive/recipient negative female. This is the first reported case of advanced BL-PTLD post-heart transplant in an adult. This is also the first reported case of treatment of advanced BL-PTLD in a heart transplant recipient with a combined chemotherapy regimen without anthracyclines to avoid cardiotoxicity. The patient received 6 cycles of R-COEP (rituximab with cyclophosphamide, vincristine, etoposide, prednisone) over 6 months and subsequently 3 cycles of high-dose methotrexate (MTX) over 3 months for CNS prophylaxis. She remains without evidence of disease at 19 months post-treatment. This case demonstrates that an anthracycline-free regimen can be the therapy option for patients with BL-PTLD after heart transplantation.

Transmission of Eastern Equine Encephalitis Virus From an Organ Donor to 3 Transplant Recipients.

BACKGROUND: In fall 2017, 3 solid organ transplant (SOT) recipients from a common donor developed encephalitis within 1 week of transplantation, prompting suspicion of transplant-transmitted infection. Eastern equine encephalitis virus (EEEV) infection was identified during testing of endomyocardial tissue from the heart recipient. METHODS: We reviewed medical records of the organ donor and transplant recipients and tested serum, whole blood, cerebrospinal fluid, and tissue from the donor and recipients for evidence of EEEV infection by multiple assays. We investigated blood transfusion as a possible source of organ donor infection by testing remaining components and serum specimens from blood donors. We reviewed data from the pretransplant organ donor evaluation and local EEEV surveillance. RESULTS: We found laboratory evidence of recent EEEV infection in all organ recipients and the common donor. Serum collected from the organ donor upon hospital admission tested negative, but subsequent samples obtained prior to organ recovery were positive for EEEV RNA. There was no evidence of EEEV infection among donors of the 8 blood products transfused into the organ donor or in products derived from these donations. Veterinary and mosquito surveillance showed recent EEEV activity in counties nearby the organ donor's county of residence. Neuroinvasive EEEV infection directly contributed to the death of 1 organ recipient and likely contributed to death in another. CONCLUSIONS: Our investigation demonstrated EEEV transmission through SOT. Mosquito-borne transmission of EEEV to the organ donor was the likely source of infection. Clinicians should be aware of EEEV as a cause of transplant-associated encephalitis.

Utilizing mobile technologies to improve physical activity and medication adherence in patients with heart failure and diabetes mellitus: Rationale and design of the TARGET-HF-DM Trial.

Heart failure (HF) and diabetes mellitus (DM) are major public health issues that place significant burden on patients and health care systems. Patients with both HF and DM are at higher risk of adverse cardiovascular and HF outcomes than those with either disease in isolation. Different antihyperglycemic medications (even within the same medication class) have conflicting results of benefit or harm in patients with established and incident HF. Recent data highlight the importance of a renewed focus on optimal pharmacotherapy for this population with DM and HF (or at risk for HF). Both HF and DM require major lifestyle modification for optimal management, in terms of both optimizing health behaviors (eg, physical activity, diet) and adherence to complex medical and self-care regimens. Mobile health (mHealth) technologies (eg, apps, wearables) are widely available in the community and may play a role in optimizing the health status of patients; however, there is limited and conflicting information on whether such technologies are actually beneficial in at-risk populations. In this article, we summarize current strategies, including mobile health interventions, to improve physical activity levels, drug adherence, and outcomes in patients with DM, HF, or both and describe the design and rationale for the Technologies to improve drug Adherence and Reinforce Guideline based Exercise Targets in patients with heart Failure and Diabetes Mellitus trial, which is designed to test the efficacy of using mHealth technology to improve health behaviors and outcomes in this high-risk population.

Worsening renal function during decongestion among patients hospitalized for heart failure: Findings from the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial.

INTRODUCTION: Worsening renal function (WRF) can occur throughout a hospitalization for acute heart failure (HF). However, decongestion can be measured in different ways and the prognostic implications of WRF in the setting of different measures of decongestion are unclear. METHODS: Patients (N = 433) from the ESCAPE were classified by measures of decongestion during hospitalization: hemodynamic (right atrial pressure ≤8 mmHg and/or wedge pressure ≤15 mmHg at discharge), clinical (≤1 sign of congestion at discharge), hemoconcentration (any increase in hemoglobin) and estimated plasma volume using the Hakim formula (5% reduction in plasma volume). WRF was defined as creatinine increase ≥0.3 mg/dl during hospitalization. The association between WRF and 180-day all-cause death was assessed. RESULTS: Successful decongestion was observed in 124 (60%) patients by hemodynamics, 204 (49%) by clinical exam, 173 (47%) by hemoconcentration, and 165 (45%) by plasma volume. There was no agreement between the hemodynamic assessment and other decongestion measures in up to 43% of cases. Persistent congestion with concomitant WRF at discharge was associated with worse outcomes compared to patients without congestion and WRF. Among patients decongested at discharge, in-hospital WRF was not significantly associated with 180-day all-cause death, when using hemodynamic, clinical or estimated plasma volume as measures of decongestion (P > .05 for all markers). CONCLUSIONS: In patients hospitalized for HF, although there was disagreement across common measures of decongestion, in-hospital WRF was not associated with increased hazard of all-cause mortality among patients successfully decongested at discharge.

Trends and outcomes of cardiac transplantation from donors dying of drug intoxication.

BACKGROUND: Deaths from drug intoxication have increased in the United States but outcomes of recipients of orthotopic heart transplantation (OHT) from these donors are not well characterized. METHODS: We performed a retrospective analysis of the United Network for Organ Sharing's STAR database between January 2000 and March 2014 and assessed mortality and retransplantation using adjusted Cox models by mechanism of donor death. RESULTS: Of the 31,660 OHTs from 2000 to 2014, 1233 (3.9%) were from drug intoxication. These donors were more likely to be female, white, with greater tobacco use and higher BMI compared to donors who died of other mechanisms. Drug intoxication accounted for 1.1% of OHT donors in 2000 and 6.2% in March 2014. No significant difference was observed in 10-year mortality (adjusted hazard ratio [HR], 95% confidence interval [CI]: 0.99, 0.87-1.13), 10-year retransplantation (adjusted HR 0.84, 0.49-1.41) or 1-year and 3-year rehospitalization with other mechanisms of death compared to drug intoxication. CONCLUSION: There has been a large increase in OHT donors who die of drug intoxication in the United States. OHT outcomes from these donors are similar to those dying from other mechanisms. These data have important implications for donor selection in context of the ongoing opioid epidemic.

Clinical Significance of Early Fluid and Weight Change During Acute Heart Failure Hospitalization.

AIMS: To explore the association of changes in weight and fluid during treatment for acute heart failure (AHF) with clinical endpoints. METHODS AND RESULTS: Weight and net fluid changes recorded at 72-96 hours in 708 AHF patients enrolled in Diuretic Optimization Strategy Evaluation in Acute Decompensated Heart Failure, Cardiorenal Rescue Study in Acute Decompensated Heart Failure, and Renal Optimization Strategies Evaluation in Acute Heart Failure studies were compared with freedom from congestion at 72-96 hours and a composite endpoint of death, rehospitalization, and unplanned hospital visit at 60 days. Weight loss was concordant with net fluid loss in 55%, discordant and less than expected for fluid loss in 34%, and paradoxically discordant or more than expected for fluid loss in 11% of patients. Weight loss, but not fluid loss, was associated with freedom from congestion (odds ratio per 1-kg weight loss = 1.11 [1.03-1.19]) and a nominal reduction in the composite endpoint (hazard ratio per 1-kg weight loss = 0.98 [0.95-1.00]). Outcomes were similar in patients with concordant and discordant weight-fluid loss. CONCLUSION: During treatment for AHF, early changes in weight may be more useful for identifying response to therapy and for predicting outcomes than net fluid output. Nearly one-half of patients receiving decongestive therapies demonstrate discordant changes in weight and fluid; however, discordance was not associated with outcomes.

Unanswered Questions in Contemporary Heart Failure.

OBJECTIVE: The epidemiology of heart failure (HF) is changing. This study aimed to describe questions that arise during the routine care of HF patients that are unanswered by the current literature and describe how the type and focus of these questions has changed over time. METHODS: Investigators from the National Heart, Lung, and Blood Institute-sponsored Heart Failure Apprentice Network collected and categorized questions from 5 academic hospitals over 12 months. A total of 174 unanswered questions were collected and analyzed. RESULTS: Compared with 2004, there were more unanswered questions about "whether" to use therapies and fewer about "how" to use therapies. There were fewer questions about what therapeutic targets, therapy adjustment, and combination therapies. There were more questions about whether or how to stop therapies and how to add therapies back. Newly prominent topics, not observed in 2004, including novel therapeutics, refractory ventricular tachycardia, right heart failure, and nutrition/frailty, accounted for 24% of questions. CONCLUSIONS: Compared with 2004, there are fewer unanswered questions about how to use, adjust, and combine therapies. There were more unanswered questions about whether and how to stop therapies. Almost 25% of unanswered questions dealt with topics indicative of more advanced disease which were not observed in 2004.