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As we enter the third year of the new adult heart allocation policy, we are faced with the new challenges of the COVID-19 pandemic. In 2020, new listings (adult and pediatric) decreased slightly, with 4000 new listings in 2020, compared with 4087 in 2019; however, the number of adult heart transplants performed continued to increase, to 3715 in 2020. The number of pediatric heart transplants declined from 509 in 2019 to 465 in 2020. One-year and six-month posttransplant mortality rates in adult recipients have increased slightly since 2015 but have not significantly changed over the past decade. Overall, posttransplant mortality rates for adult recipients were 7.4% at six months and 9.4% at one year for transplants in 2019, 14.0% at three years for transplants in 2017, and 19.1% at five years for transplants in 2015. Although shorter-term posttransplant mortality rates have slightly increased, there has been a steady downward trend in longer-term mortality. Mortality rates for pediatric recipients were 5.7% at six months and 8.1% at one year for transplants in 2019, 11.6% at three years for transplants in 2017, and 15.2% at five years for transplants in 2015.

Background: Clinical pharmacists play pivotal roles in multidisciplinary heart failure (HF) teams through the management of HF pharmacotherapy, but no study has examined the economic impact of HF ambulatory clinical pharmacists in an advanced HF clinic. Objective: The objective of the study was to evaluate the economic impact of HF ambulatory clinical pharmacist interventions in an advanced HF clinic using a cost-benefit analysis. Methods: This prospective observational study detailed HF ambulatory clinical pharmacist interventions over 6 months in an advanced HF clinic in a single-center tertiary teaching hospital. The economic impact of the interventions was estimated based on the indirect cost savings with pharmacist interventions and direct cost savings recommendations. A cost-benefit analysis was performed to assess the cost of delivering the interventions compared with the benefits generated by clinical pharmacists. Results were reported as a benefit-cost ratio and net benefits. Results: HF ambulatory clinical pharmacists made a total of 2,361 provider-accepted interventions over 6 months. Overall, the 3 most common intervention types were medication reconciliation (28.7%), dose change (20.8%), and addition of medication (12.3%). Anticoagulation (21.2%) was the most common intervened class of medication, followed by sodium-glucose cotransporter-2 inhibitor (12.3%) and angiotensin receptor neprilysin inhibitor (9.2%). The total net benefits were $55,553.24 over 6 months and the benefit-cost ratio was 1.55. Conclusion and Relevance: The addition of cardiology clinical pharmacists to an advanced HF clinic may be financially justified and cost-beneficial.

Background: Racial disparities in access to advanced therapies for heart failure (HF) patients are well documented, although the reasons remain uncertain. We sought to determine the association of race on utilization of ventricular assist device (VAD) and transplant among patients with access to care at VAD centers and if patient preferences impact the effect. Methods: We performed an observational cohort study of ambulatory chronic systolic HF patients with high-risk features and no contraindication to VAD enrolled at 21 VAD centers and followed for 2 years in the REVIVAL study (Registry Evaluation of Vital Information for VADs in Ambulatory Life). We used competing events cause-specific proportional hazard methodology with multiple imputation for missing data. The primary outcomes were (1) VAD/transplant and (2) death. The exposures of interest included race (Black or White), additional demographics, captured social determinants of health, clinician-assessed HF severity, patient-reported quality of life, preference for VAD, and desire for therapies. Results: The study included 377 participants, of whom 100 (26.5%) identified as Black. VAD or transplant was performed in 11 (11%) Black and 62 (22%) White participants, although death occurred in 18 (18%) Black and 36 (13%) White participants. Black race was associated with reduced utilization of VAD and transplant (adjusted hazard ratio, 0.45 [95% CI, 0.23–0.85]) without an increase in death. Preferences for VAD or life-sustaining therapies were similar by race and did not explain racial disparities. Conclusions: Among patients receiving care by advanced HF cardiologists at VAD centers, there is less utilization of VAD and transplant for Black patients even after adjusting for HF severity, quality of life, and social determinants of health, despite similar care preferences. This residual inequity may be a consequence of structural racism and discrimination or provider bias impacting decision-making. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01369407.

Health literacy is associated with heart failure (HF) care and outcomes. Online resources offer important educational materials for patients seeking access to heart transplantation but tend to be complex and potentially ineffective for non-English speakers and those with low reading levels. The purpose of this study was to evaluate both the readability of patient-level information posted on United States heart transplant center websites and the availability of non-English resources.We performed a review of patient-facing information on websites of U.S. heart transplant centers identified through the United Network for Organ Sharing in August 2022. Written English text was extracted and assessed for readability by using the Fry Graph Readability score. Websites were additionally evaluated for non-English language text and translator tools. Standard ANOVA analysis was used to compare readability levels across transplant regions. The median Fry readability level to understand a piece of text for all regions was 15, which is equivalent to a college-junior reading level (range: 7-17, 7th grade to postgraduate level). There was no statistical difference in median Fry readability levels among regions (P = 0.16). Of the 139 eligible heart transplant center websites, only 56.1% (78/139) had non-English resources available for patients. Regions 5 (75% [15/20]) and 6 (75% [3/4]) had the highest percentage of non-English resources, and region 2 had the lowest (38% [6/16]).Heart transplant center online resources are inadequate, and many do not provide translations of the English language. Additional work is needed to standardize heart-transplant patient information for a diverse U.S.

Chemotherapy extravasation can lead to serious patient harm in patients with cancer. For nurses who administer vesicant chemotherapy, extravasation is a primary concern. Regardless of nurse experience level and despite prevention strategies, extravasations occur. Literature related to nurse management of chemotherapy extravasation beyond initial treatment is lacking, and no descriptors are available for a formalized process. Communication gaps and a lack of standardized follow-up within a 1400-bed, quaternary care academic medical institution contributes to challenges in care continuity when patients transition between hospital and ambulatory settings. With chemotherapy extravasation, the site does not immediately exhibit signs of tissue injury, leading to a false sense of security. As a result, tissue damage can be significant by the time the patient returns for his or her regular appointment. Two oncology clinical nurse specialists (CNSs) recognized an opportunity to bridge the gap and overcome the challenges by addressing patient needs postextravasation. Between 2015 and 2016, a formal consult process was designed, approved, and implemented to observe, manage, and make recommendations for timely care and follow-up. Since implementation of the process, the oncology CNSs have received multiple requests for consultations. Nursing staff report increased comfort levels with this process in place. A formalized process for managing chemotherapy extravasations increases patient safety and patient and nurse satisfaction.

International audience; The role of brain dystrophin in muscular dystrophy: Implications for clinical care and translational research, Hoofddorp, the Netherlands, November 29 th-December 1 st 2019

The 2022 American College of Cardiology/American Heart Association/Heart Failure Society of America (AHA/ACC/HFSA) Guideline for the Management of Heart Failure replaces the 2013 ACCF/AHA Guideline for the Management of Heart Failure and the 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure. The 2022 guideline is intended to provide patient-centric recommendations for clinicians to prevent, diagnose and manage patients with heart failure.A comprehensive literature search was conducted from May 2020 to December 2020, encompassing studies, reviews and other evidence conducted in human subjects that were published in English from MEDLINE (PubMed), EMBASE, the Cochrane Collaboration, the Agency for Healthcare Research and Quality, and other relevant databases. Additional relevant clinical trials and research studies published through September 2021 were also considered. This guideline was harmonized with other American Heart Association/American College of Cardiology guidelines published through December 2021.Heart failure remains a leading cause of morbidity and mortality globally. The 2022 heart failure guideline provides recommendations based on contemporary evidence for the treatment of these patients. The recommendations present an evidence-based approach to managing patients with heart failure, with the intent to improve quality of care and align with patients' interests. Many recommendations from the earlier heart failure guidelines have been updated with new evidence, and new recommendations have been created when supported by published data. Value statements are provided for certain treatments that have high-quality published economic analyses.

BackgroundThroughout US history, chronic and infectious diseases have severely impacted minority communities due to lack of accessibility to quality healthcare, accurate information, and underlying racism. These fault lines in the care of minority communities in the US have been further exposed by the rise of COVID-19 pandemic. This study examined the factors associated with COVID-19 vaccine hesitancy among African American and Latinx communities in Eastern Pennsylvania (PA).MethodsSurvey data was collected in July 2021 in Philadelphia, Scranton, Wilkes-Barre, and Hazleton, PA. The 203 participants (38.7% Black, 27.5% Latinx) completed the 28-question survey of COVID-19 vaccination attitudes in either English or Spanish.ResultsOut of a total of 181 participants that met inclusion criteria of completed surveys, results indicate that 63.5% (n=115) were acceptant of the COVID-19 vaccine whereas the remainder 36.5% (n=66) were hesitant. Binary logistic regression results showed that age, concern for vaccine efficacy, race, knowledge on the vaccine, and belief that the COVID-19 virus is serious significantly influenced COVID vaccine hesitancy. Minorities were more likely to be hesitant toward vaccination (OR: 2.77, 95% CI: 1.13, 6.79) than non-Hispanic whites. Those who believed the COVID vaccine was ineffective (OR: 8.29, 95% CI: 3.78,18.2), and that the virus is not serious (OR: 8.28, 95% CI: 1.11, 61.8) showed the greatest odds of hesitancy.ConclusionsContributing factors of vaccine hesitancy in minority communities were age, concern for vaccine efficacy, and education. Understanding and addressing the barriers to COVID-19 vaccination in minority groups is essential to decreasing transmission and controlling this pandemic.

Sacubitril/valsartan is an angiotensin receptor/neprilysin inhibitor that the Food and Drug Administration has indicated to reduce the risk of cardiovascular hospitalization and death in patients with left ventricular ejection fraction below normal and with no specified ejection-fraction cut-off. However, clinically significant patient groups were excluded or minimally represented in sacubitril/valsartan's pivotal clinical trials. Clinicians often encounter scenarios in which a sacubitril/valsartan off-label use may be beneficial, but limited resources are available to evaluate the efficacy and safety in these patients. This state-of-the-art review describes contemporary literature for sacubitril/valsartan Food and Drug Administration off-label indications to help clinicians assess its appropriateness in these selected, clinically important groups of patients: those with acute decompensated heart failure, acute coronary syndrome, peripartum cardiomyopathy, chemotherapy-induced cardiomyopathy, adult congenital heart disease, cardiomyopathy in dialysis patients, right ventricular failure, or durable left ventricular assist device.

Introduction: In 2018, a new heart allocation policy was implemented to promote uniform access to transplantation by mandating sharing of donor hearts over larger geographic areas rather than by location within a given Donation Service Area (DSA). The long-term impact of this policy on sharing across DSAs is unknown. Methods: Using data from the Scientific Registry of Transplant Recipients, we assessed the association between the new policy and organ sharing at the level of each DSA. We included adult, single-organ heart transplants performed in the mainland US between Oct 1, 2015 and Dec 31, 2020. For each DSA, we evaluated the proportion of donor hearts imported from another DSA, the proportion exported, and their log-transformed ratio (sharing ratio). We performed multivariable regression with heteroscedasticity to evaluate the association between policy period and sharing ratio, adjusting for deaths per DSA population, household income and urbanicity. Results: The new policy was associated with increased importation and exportation of donor hearts across DSAs (Figure). The mean import proportion increased from 0.31 (95% CI: 0.27 to 0.36) to 0.74 (95% CI: 0.71 to 0.78) and the mean export proportion from 0.36 (95% CI: 0.31 to 0.40) to 0.75 (95% CI: 0.71 to 0.79) after the policy change. In addition, the mean sharing ratio of import:export shifted from 1.22 (95% CI: 0.91 to 1.53) to 1.01 (95% CI: 0.96 to 1.07) suggesting more balance across DSAs. The variance of the log-transformed sharing ratio was negatively associated with the new policy (β = -1.55; 95% CI, -1.82 to -1.27; P < .001), indicating a 79% drop in the variation of the sharing ratio and more uniform access. Deaths per DSA population was associated with the log-transformed sharing ratio while household income and urbanicity were not. Conclusion: The new policy is associated with more balanced sharing of hearts. The broader impact on waitlist survival and post-transplant outcomes remains unknown.

Purpose of review Black patients with heart failure in the United States are underrepresented in clinical trials relative to their overrepresentation in the heart failure population and in adverse heart failure outcomes. We aim to evaluate historical trends in this space and highlight recent developments. Recent findings Multiple landmark heart failure trials published since 2019 have underrepresented Black patients, though several discussed this lack of representation as limitations. A review of large heart failure clinical trials from 2001 to 2016 found persistent underrepresentation of Black patients without significant change over time. Trials enrolling from North America exclusively had more proportional representation, enrolling an average of 31.6% Black participants. Summary There is a shrinking proportion of Black patients in pivotal heart failure trials despite a higher prevalence of disease and associated adverse outcomes. There is increasing awareness of these disparities within the heart failure community, potentially leading to improved representation in future studies.

A bimodal prosthetic ankle-foot system has been developed to support the demands of both walking mobility and standing balance. Using a novel hydraulic locking mechanism, this system provides a curved effective rocker shape for walking and a flat effective rocker shape for standing and swaying on non-level surfaces. To date, the hydraulic cylinder sub-assembly has been cycle tested to 1.2 million cycles. Future testing with lower-limb prosthesis users is planned, which will reveal the extent to which this new hydraulic ankle-foot design improves standing balance on both level and non-level surfaces. The capacity for an automatic switching algorithm, designed to appropriately detect and switch between modes as users transition between walking and standing tasks, will also be evaluated.

Background and purpose We aimed to identify and develop novel, selective muscarinic M1 receptor agonists as potential therapeutic agents for the symptomatic treatment of Alzheimer's disease. Experimental approach We developed and utilized a novel M1 receptor occupancy assay to drive a structure activity relationship in a relevant brain region while simultaneously tracking drug levels in plasma and brain to optimize for central penetration. Functional activity was tracked in relevant native in vitro assays allowing translational (rat-human) benchmarking of structure-activity relationship molecules to clinical comparators. Key results Using this paradigm, we identified a series of M1 receptor selective molecules displaying desirable in vitro and in vivo properties and optimized key features, such as central penetration while maintaining selectivity and a partial agonist profile. From these compounds, we selected spiropiperidine 1 (SPP1). In vitro, SPP1 is a potent, partial agonist of cortical and hippocampal M1 receptors with activity conserved across species. SPP1 displays high functional selectivity for M1 receptors over native M2 and M3 receptor anti-targets and over a panel of other targets. Assessment of central target engagement by receptor occupancy reveals SPP1 significantly and dose-dependently occupies rodent cortical M1 receptors. Conclusions and implications We report the discovery of SPP1, a novel, functionally selective, brain penetrant partial orthosteric agonist at M1 receptors, identified by a novel receptor occupancy assay. SPP1 is amenable to in vitro and in vivo study and provides a valuable research tool to further probe the role of M1 receptors in physiology and disease.

Improving the portability of diagnostic medicine is crucial for alleviating global access-to-care deficiencies. This requires not only designing devices that are small and lightweight, but also autonomous and independent of electricity. Here, we present a strategy for conducting automated multistep diagnostic assays using chemically generated, passively regulated heat. Ligation and polymerization reagents for rolling circle amplification of nucleic acids are separated by meltable phase-change partitions, thus replacing precise manual reagent additions with automated partition melting. To actuate these barriers and individually initiate the various steps of the reaction, field ration heaters exothermically generate heat in a thermos, whereas fatty acids embedded in a carbonaceous matrix passively buffer the temperature around their melting points. Achieving multistage temperature profiles extend the capability of instrument-free diagnostic devices and improve the portability of reaction automation systems built around phase-change partitions.

Background: The blood and marrow transplant (BMT) unit at Cleveland Clinic had an increased rate of central line associated bloodstream infections (CLABSIs) in 2020 for allogeneic transplant admissions from an expected average of 1 per month to 4 in August of 2020. We aimed to reduce the number of CLABSIs in allogeneic BMT patients during their transplant admission to an average of 1 per month. Patients and Methods: We formed a multidisciplinary team with nursing, advanced practice providers (APPs), infection prevention, fellows, residents, BMT staff, and Taussig quality improvement staff. We underwent training through the SolVE (Solutions for Value Enhancement) program, with biweekly meetings for training and coaching sessions to help design and support the quality improvement project. Results: We performed an initial data review of CLABSIs from January 2020 until September 2020 with a total of 13 cases identified. 53% of cases were female, 76% of patients were neutropenic, 53% of patients had mucositis, 61% of patients had diarrhea and 7% of patients had graft versus host disease. Patients had the following underlying diagnoses: myelodysplastic syndrome (4), acute myeloid leukemia (3), acute lymphoblastic leukemia (4) and diffuse large B-cell lymphoma (1). Central line data revealed that all lines were placed at Cleveland Clinic. 76% of lines were removed after identification of infection, 46% of lines had signs of infection or malfunction. Microbiologic data culture revealed that 7 cases were Pseudomonas aeruginosa, 3 Staphylococcus epidermidis, 1 vancomycin-resistant Enterococcus faecalis, 1 Streptococcus mitis and 1 Stenotrophomonas maltophilia. To build our process map we performed a Gemba walk where we observed central line use and access on the BMT unit. We conducted a root cause analysis and identified the following factors as drivers of the rise in CLABSIs: severe immunocompromised state, pre-existing infections, long duration of line present, frequent access, excessive line manipulation, and poor hand hygiene. The changes that were implemented on the unit included: retraining of all nurses on central line care, central line care being added as a topic to the annual competency review, site and tubing checks were to be performed at the time of bedside handoff at shift change, increasing Shine Audits to 40 per week from 10 on average and deep clean of nursing unit by EVS following outbreak of pseudomonas. Following the above interventions, we decided to form a CLABSI review meeting to review each CLABSI in real time and to be able to have a longitudinal comprehensive data collection of factors contributing to each case. These meetings involve nursing, infection prevention, APPs, and physicians directly involved with the patient's care. Data is stored in Redcap and includes patient factors (admission date, conditioning regimen, type of transplant, disease data), line factors (placement date, location, infection date, line removal date), microbiologic data (organism, reason for culture collection), personnel factors, maintenance/environmental factors and space for other comments. Data is presented at regular quality meetings with the section chair to develop further quality improvement projects. Initially the reduction of CLABSI rates did not reach our objective: we had 5 CLABSIs from January to February 2021. However, in the following months (March to June, 2021) we were able to reach our objective of 0-1 CLABSI's per month. Conclusion We continue to work as a team to reduce the number of infections in the BMT unit. Next steps include continuing CLABSI review meetings, discussions with ICU to better understand indications and process of blood culture collections, discussion with infectious disease for input on other strategies for CLABSI reduction and examining central line processes in other institutions. Disclosures Sobecks: CareDX: Membership on an entity's Board of Directors or advisory committees.

Objective: (1) Develop a standardized approach to quantitatively measure residual limb skin health. (2) Report reference residual limb skin health values in people with transtibial and transfemoral amputation. Approach: Residual limb health outcomes in individuals with transtibial (n = 5) and transfemoral (n = 5) amputation were compared to able-limb controls (n = 4) using noninvasive imaging (hyperspectral imaging and laser speckle flowmetry) and probe-based approaches (laser doppler flowmetry, transcutaneous oxygen, transepidermal water loss, surface electrical capacitance). Results: A standardized methodology that employs noninvasive imaging and probe-based approaches to measure residual limb skin health are described. Compared to able-limb controls, individuals with transtibial and transfemoral amputation have significantly lower transcutaneous oxygen tension, higher transepidermal water loss, and higher surface electrical capacitance in the residual limb. Innovation: Residual limb health as a critica...

Objective: Prosthetic sockets are custom made for each amputee, yet there are no quantitative tools to determine the appropriateness of socket fit. Ensuring a proper socket fit can have significant effects on the health of residual limb soft tissues and overall function and acceptance of the prosthetic limb. Previous work found that elevated vacuum pressure data can detect movement between the residual limb and the prosthetic socket; however, the correlation between the two was specific to each user. The overall objective of this work is to determine the relationship between elevated vacuum pressure deviations and prosthetic socket fit. Approach: A tension compression machine was used to apply repeated controlled forces onto a residual limb model with sockets of different internal volume. Results: The vacuum pressure-displacement relationship was dependent on socket fit. The vacuum pressure data were sensitive enough to detect differences of 1.5% global volume and can likely detect differences even smaller. Limb motion was reduced as surface area of contact between the limb model and socket was maximized. Innovation: The results suggest that elevated vacuum pressure data provide information to quantify socket fit. Conclusions: This study provides evidence that the use of elevated vacuum pressure data may provide a method for prosthetists to quantify and monitor socket fit. Future studies should investigate the relationship between socket fit, limb motion, and limb health to define optimal socket fit parameters.

Purpose: This study aimed to investigate the influence of display window setting on technologist performance detecting subtle but clinically relevant artifacts in daily computed tomography (CT) quality control (dQC) images. Methods: Fifty three sets of dQC images were retrospectively selected, including 30 sets without artifacts, and 23 with subtle but clinically relevant artifacts. They were randomized and shown to six CT technologists (two new and four experienced). Each technologist reviewed all images in each of two sessions, one with a display window width (WW) of 100 HU, which is currently recommended by the American College of Radiology, and the other with a narrow WW of 40 HU, both at a window level of 0 HU. For each case, technologists rated the presence of image artifacts based on a five point scale. The area under the receiver operating characteristic curve (AUC) was used to evaluate the artifact detection performance. Results: At a WW of 100 HU, the AUC (95% confidence interval) was 0.658 (0.576, 0.740), 0.532 (0.429, 0.635), and 0.616 (0.543, 0.619) for the experienced, new, and all technologists, respectively. At a WW of 40 HU, the AUC was 0.768 (0.687, 0.850), 0.546 (0.433, 0.658), and 0.694 (0.619, 0.769), respectively. The performance significantly improved at WW of 40 HU for experienced technologists (p = 0.009) and for all technologists (p = 0.040). Conclusions: Use of a narrow display WW significantly improved technologists’ performance in dQC for detecting subtle but clinically relevant artifacts as compared to that using a 100 HU display WW.

A remarkable aspect of enzyme evolution is the portability of catalytic mechanisms for fundamentally different chemical reactions. For example, aspartyl proteases, which contain two active site carboxylic acid groups, catalyze the hydrolysis of amide bonds, while glycosyltransferases (and glycosyl hydrolases), which often also contain two active site carboxylates, have evolved to form (or break) glycosidic bonds. However, neither catalyst exhibits cross-reactivity in the intracellular environment. The large, macromolecular architectures of these biocatalysts tailor their active sites to their precise, divergent functions. The analogous portability of a small-molecule catalyst for truly orthogonal chemical reactivity is rare. Herein, we report aspartic acid containing peptides that can be directed to different sectors of a substrate for which the danger of cross-reactivity looms large. A transiently formed aspartyl peracid catalyst can participate either as an electrophilic oxidant to catalyze alkene epoxidation or as a nucleophilic oxidant to mediate the Baeyer–Villiger oxidation (BVO) of ketones. We show in this study that an appended peptide sequence can dictate the mode of reactivity for this conserved catalytic functional group within a substrate that has the potential to undergo both alkene epoxidation and BVO; in both cases the additional aspects of chemical selectivity (regio- and stereoselectivity) are high. This sequence-dependent tuning of a common catalytic moiety for functional group selective reactions constitutes a biomimetic strategy that may impact late-stage diversification of complex polyfunctional molecules., The sequence of an aspartyl peptide catalyst can dictate functional group selectivity within a complex substrate, wherein a transient peracid acts as either an electrophile or a nucleophile, catalyzing orthogonal chemical reactions.

Improving the portability of diagnostic medicine is crucial to alleviating global access-to-care deficiencies. This requires not only designing devices that are small and lightweight but also autonomous and independent of electricity. Here, we present a strategy for conducting automated multi-step diagnostic assays using chemically generated, passively regulated heat. Ligation and polymerization reagents for Rolling Circle Amplification of nucleic acids are separated by melt-able phase-change partitions, thus replacing precise manual reagent additions with automated partition melting. To actuate these barriers and individually initiate the various steps of the reaction, field ration heaters exothermically generate heat in a thermos while fatty acids embedded in a carbonaceous matrix passively buffer the temperature around their melting points. Achieving multi-stage temperature profiles extends the capability of instrument-free diagnostic devices and improves the portability of reaction automation systems built around phase-change partitions.

BACKGROUND AND PURPOSE: We aimed to identify and develop novel, selective muscarinic M(1) receptor agonists as potential therapeutic agents for the symptomatic treatment of Alzheimer's disease. EXPERIMENTAL APPROACH: We developed and utilized a novel M(1) receptor occupancy assay to drive a structure activity relationship in a relevant brain region while simultaneously tracking drug levels in plasma and brain to optimize for central penetration. Functional activity was tracked in relevant native in vitro assays allowing translational (rat–human) benchmarking of structure–activity relationship molecules to clinical comparators. KEY RESULTS: Using this paradigm, we identified a series of M(1) receptor selective molecules displaying desirable in vitro and in vivo properties and optimized key features, such as central penetration while maintaining selectivity and a partial agonist profile. From these compounds, we selected spiropiperidine 1 (SPP1). In vitro, SPP1 is a potent, partial agonist of cortical and hippocampal M(1) receptors with activity conserved across species. SPP1 displays high functional selectivity for M(1) receptors over native M(2) and M(3) receptor anti‐targets and over a panel of other targets. Assessment of central target engagement by receptor occupancy reveals SPP1 significantly and dose‐dependently occupies rodent cortical M(1) receptors. CONCLUSIONS AND IMPLICATIONS: We report the discovery of SPP1, a novel, functionally selective, brain penetrant partial orthosteric agonist at M(1) receptors, identified by a novel receptor occupancy assay. SPP1 is amenable to in vitro and in vivo study and provides a valuable research tool to further probe the role of M(1) receptors in physiology and disease.

As the number of candidates listed for heart transplant continues to rise, it is encouraging that the number of heart transplants also continues to rise steadily each year. Evaluation of waitlist activity demonstrates a growing number of adult candidates removed from the list due to undergoing transplant, but also growing numbers of adult candidates added to the list over the past 3 years. In 2014, 2679 heart transplants were performed, an increase of 28.4% since 2003, and the number of people living with a transplanted heart continued to increase. The number of new pediatric candidates added to the heart transplant waiting list increased to 593 in 2014. The number of pediatric heart transplants performed each year increased from 293 in 2003 to 410 in 2014. Almost 60% of pediatric candidates waiting on December 31, 2014, had been waiting for less than 1 year, compared with 43.0% in 2004. Among pediatric patients who underwent transplant in 2008-2012, overall cumulative incidence of death at 1, 3, and 5 years was 9.2%, 14.7%, and 18.3%, respectively.

Heart failure is a leading cause of death in adults in America. African Americans have a higher prevalence of heart failure, possibly due to hypertension. While guideline-directed therapy for heart failure is recommended for all adults, understanding of specific mechanisms leading to heart failure in African Americans may provide an avenue for development of tailored therapies and subsequently better outcomes.

In the search for improved symptomatic treatment options for neurodegenerative and neuropsychiatric diseases, muscarinic acetylcholine M1 receptors (M1 mAChRs) have received significant attention. Drug development efforts have identified a number of novel ligands, some of which have advanced to the clinic. However, a significant issue for progressing these therapeutics is the lack of robust, translatable, and validated biomarkers. One valuable approach to assessing target engagement is to use positron emission tomography (PET) tracers. In this study we describe the pharmacological characterization of a selective M1 agonist amenable for in vivo tracer studies. We used a novel direct binding assay to identify nonradiolabeled ligands, including LSN3172176, with the favorable characteristics required for a PET tracer. In vitro functional and radioligand binding experiments revealed that LSN3172176 was a potent partial agonist (EC(50) 2.4–7.0 nM, E(max) 43%–73%), displaying binding selectivity for M1 mAChRs (K(d) = 1.5 nM) that was conserved across species (native tissue K(d) = 1.02, 2.66, 8, and 1.03 at mouse, rat, monkey, and human, respectively). Overall selectivity of LSN3172176 appeared to be a product of potency and stabilization of the high-affinity state of the M1 receptor, relative to other mAChR subtypes (M1 > M2, M4, M5 > M3). In vivo, use of wild-type and mAChR knockout mice further supported the M1-preferring selectivity profile of LSN3172176 for the M1 receptor (78% reduction in cortical occupancy in M1 KO mice). These findings support the development of LSN3172176 as a potential PET tracer for assessment of M1 mAChR target engagement in the clinic and to further elucidate the function of M1 mAChRs in health and disease.