Donor utilization in heart transplant with donation after circulatory death in the United States.

Heart transplantation using donation after circulatory death (DCD) was recently adopted in the United States. This study aimed to characterize organ yield from adult (≥18 years) DCD heart donors in the United States using the United Network for Organ Sharing registry. The registry does not identify potential donors who do not progress to circulatory death, and only those who progressed to death were included for analysis. Outcomes included organ recovery from the donor operating room and organ utilization for transplant. Multiple logistic regression was used to identify predictors of heart recovery and utilization. Among 558 DCD procurements, recovery occurred in 89.6%, and 92.5% of recovered hearts were utilized for transplant. Of 506 DCD procurements with available data, 65.0% were classified as direct procurement and perfusion and 35.0% were classified as normothermic regional perfusion (NRP). Logistic regression identified that NRP, shorter agonal time, younger donor age, and highest volume of organ procurement organizations were independently associated with increased odds for heart recovery. NRP independently predicted heart utilization after recovery. DCD heart utilization in the United States is satisfactory and consistent with international experience. NRP procurements have a higher yield for DCD heart transplantation compared with direct procurement and perfusion, which may reflect differences in donor assessment and acceptance criteria.

Trends and Outcomes of Combined Heart-Kidney and Heart-Lung Transplantation Over the Past Two Decades.

INTRODUCTION: Combined heart-kidney transplantation (HKTx) and combined heart-lung transplantation (HLTx) remain the definitive therapy for patients with end-stage heart failure with concomitant end-stage renal or lung failure. We sought to study trends and outcomes of HKTx and HLTx over the last two decades. METHODS: The United Network for Organ Sharing registry was used to identify all adult patients (aged >18 y) who underwent HKTx and HLTx between 2001 and 2021. Patients were divided into 5-y groups by the year of transplantation (2001-2006, 2007-2011, 2012-2016, and 2017-2021). Primary outcome was 1-y posttransplantation mortality. Kaplan-Meier and multivariable Cox proportional hazards models were used for unadjusted and risk-adjusted survival analyses, respectively. RESULTS: A total of 2301 HKTx and 567 HLTx patients were included. Between 2001 and 2021, HKTx volume increased from 25 to 344 patients (P < 0.001) and centers performing HKTx increased from 19 to 76 (P < 0.001). On unadjusted analysis, 1-y survival after HKTx improved from 86.7% in 2001-2006 to 89.0% in 2017-2021 (log-rank, P = 0.005). On risk-adjusted analysis, the hazard ratio of 1-y mortality for 2017-2021 was 0.62 (0.39-1.00, P = 0.048) compared with that for 2001-2006. Between 2001 and 2021, HLTx volume increased from 21 to 43 patients (P < 0.001) and centers performing HLTx increased from 12 to 20 (P = 0.047). On unadjusted analysis, 1-y survival after HLTx improved from 68.9% in 2001-2006 to 83.9% in 2017-2021 (log-rank, P = 0.600). On risk-adjusted analysis, the hazard ratio of 1-y mortality for 2017-2021 was 0.37 (0.21-0.67, P = 0.001) compared with that for 2001-2006. CONCLUSIONS: Over the last two decades, HKTx volume substantially increased and HLTx experienced resurgent growth. One-year survival persistently improved for both procedures, especially over the past 5 y.

Heart Transplantation for Adults With Congenital Heart Disease Can Be Performed at Adult or Pediatric Hospitals With Comparable Outcomes.

INTRODUCTION: The goal of this study was to evaluate the relationship between hospital-related factors and hospital type on outcomes of heart transplantation for patients with adult congenital heart disease (ACHD). METHODS: Patients with ACHD who underwent heart transplant between 2010 and 2021 were identified using the United Network for Organ Sharing data registry. The primary outcome was post-transplant mortality. Kaplan-Meier unadjusted survival curves were compared using the log-rank test. Multivariable Cox proportional hazard models were used for risk-adjustment in evaluating the independent effect of hospital type on post-transplant mortality. RESULTS: Of 70 centers, 54 (77.1%) adult centers performed 415 (87.0%) heart transplants and 16 (22.9%) pediatric centers performed 62 (13.0%) heart transplants. Patients transplanted at pediatric centers were younger, had lower creatinine levels, and had lower body mass index. The unadjusted 1-y and 5-y survival was comparable in pediatric versus adult centers, respectively: 93.4% versus 86.6% (log-rank P = 0.16) and 87.4% versus 73.9% (log-rank P = 0.06). These findings persisted after risk-adjustment. One-year mortality hazard ratio for pediatric hospitals: 0.64 (0.22-1.89, P = 0.416) and 5-y mortality hazard ratio for pediatric hospitals: 0.53 (0.21-1.33, P = 0.175). Rates of acute rejection, postoperative stroke, and new-onset postoperative dialysis were also comparable. CONCLUSIONS: Heart transplantation for patients with ACHD can be performed safely in adult centers. The majority of heart transplant for ACHD in the United States are performed at adult hospitals. However, further research is needed to delineate the impact of individual surgeon characteristics and hospital-related factors on outcomes.

Prevention and treatment of SHIVAD8 infection in rhesus macaques by a potent d-peptide HIV entry inhibitor.

Cholesterol-PIE12-trimer (CPT31) is a potent d-peptide HIV entry inhibitor that targets the highly conserved gp41 N-peptide pocket region. CPT31 exhibited strong inhibitory breadth against diverse panels of primary virus isolates. In a simian-HIV chimeric virus AD8 (SHIVAD8) macaque model, CPT31 prevented infection from a single high-dose rectal challenge. In chronically infected animals, CPT31 monotherapy rapidly reduced viral load by ∼2 logs before rebound occurred due to the emergence of drug resistance. In chronically infected animals with viremia initially controlled by combination antiretroviral therapy (cART), CPT31 monotherapy prevented viral rebound after discontinuation of cART. These data establish CPT31 as a promising candidate for HIV prevention and treatment.

Risk of recipient age on 1-year mortality after simultaneous heart-lung transplantation.

BACKGROUND: Heart-lung transplantation (HLTx) is relatively uncommon, and there is a paucity of literature to suggest an age at which older recipients may be exposed to excess risk for mortality. This analysis aimed to identify a threshold of age that predicts adverse outcomes after HLTx. METHODS: The United Network of Organ Sharing registry was used to identify adult patients undergoing HLTx from 2005 to 2021. The primary outcome was 1-year mortality. Threshold regression was used to identify the threshold at which age impacts 1-year mortality. Kaplan-Meier analysis was used to model survival, and Cox proportional hazards modeling was used for risk-adjustment. RESULTS: We identified 453 patients undergoing HLTx. Threshold analysis identified that the risk for 1-year mortality was significantly elevated beyond an age of 58 years, and 47 (10.38%) patients were older than this threshold. On Kaplan-Meier analysis, 1-year survival was significantly lower in patients > 58 years compared to younger recipients (64.7% vs. 82.0%, p = .007). After risk adjustment, the hazard ratio for 1-year mortality in recipients older than 58 years was 2.27 (95% confidence interval [1.21-4.28], p = .011). CONCLUSION: A threshold for recipient age of 58 years of age may avoid excess 1-year mortality after HLTx. However, patients older than this threshold demonstrate acceptable early and midterm survival, and the majority survive to 1 year. Advanced age should be considered in patient selection for HLTx, but may not be a contraindication for candidacy particularly in the absence of other risk factors.

Pharmacokinetic and Chemical Synthesis Optimization of a Potent d-Peptide HIV Entry Inhibitor Suitable for Extended-Release Delivery.

Peptides often suffer from short in vivo half-lives due to proteolysis and renal clearance that limit their therapeutic potential in many indications, necessitating pharmacokinetic (PK) enhancement. d-Peptides, composed of mirror-image d-amino acids, overcome proteolytic degradation but are still vulnerable to renal filtration due to their small size. If renal filtration could be slowed, d-peptides would be promising therapeutic agents for infrequent dosing, such as in extended-release depots. Here, we tether a diverse set of PK-enhancing cargoes to our potent, protease-resistant d-peptide HIV entry inhibitor, PIE12-trimer. This inhibitor panel provides an opportunity to evaluate the PK impact of the cargoes independently of proteolysis. While all the PK-enhancing strategies (PEGylation, acylation, alkylation, and cholesterol conjugation) improved in vivo half-life, cholesterol conjugation of PIE12-trimer dramatically improves both antiviral potency and half-life in rats, making it our lead anti-HIV drug candidate. We designed its chemical synthesis for large-scale production (CPT31) and demonstrated that the PK profile in cynomolgous monkeys supports future development of monthly or less frequent depot dosing in humans. CPT31 could address an urgent need in both HIV prevention and treatment.

On the stability of parainfluenza virus 5 F proteins.

The crystal structure of the F protein (prefusion form) of the paramyxovirus parainfluenza virus 5 (PIV5) WR isolate was determined. We investigated the basis by which point mutations affect fusion in PIV5 isolates W3A and WR, which differ by two residues in the F ectodomain. The P22 stabilizing site acts through a local conformational change and a hydrophobic pocket interaction, whereas the S443 destabilizing site appears sensitive to both conformational effects and amino acid charge/polarity changes.

Probing the functions of the paramyxovirus glycoproteins F and HN with a panel of synthetic antibodies.

Paramyxoviruses are enveloped negative-strand RNA viruses that are significant human and animal pathogens. Most paramyxoviruses infect host cells via the concerted action of a tetrameric attachment protein (variously called HN, H, or G) that binds either sialic acid or protein receptors on target cells and a trimeric fusion protein (F) that merges the viral envelope with the plasma membrane at neutral pH. F initially folds to a metastable prefusion conformation that becomes activated via a cleavage event during cellular trafficking. Upon receptor binding, the attachment protein, which consists of a globular head anchored to the membrane via a helical tetrameric stalk, triggers a major conformation change in F which results in fusion of virus and host cell membranes. We recently proposed a model for F activation in which the attachment protein head domains move following receptor binding to expose HN stalk residues critical for triggering F. To test the model in the context of wild-type viral glycoproteins, we used a restricted-diversity combinatorial Fab library and phage display to rapidly generate synthetic antibodies (sAbs) against multiple domains of the paramyxovirus parainfluenza 5 (PIV5) pre- and postfusion F and HN. As predicted by the model, sAbs that bind to the critical F-triggering region of the HN stalk do not disrupt receptor binding or neuraminidase (NA) activity but are potent inhibitors of fusion. An inhibitory prefusion F-specific sAb recognized a quaternary antigenic site and may inhibit fusion by preventing F refolding or by blocking the F-HN interaction. Importance: The paramyxovirus family of negative-strand RNA viruses cause significant disease in humans and animals. The viruses bind to cells via their receptor binding protein and then enter cells by fusion of their envelope with the host cell plasma membrane, a process mediated by a metastable viral fusion (F) protein. To understand the steps in viral membrane fusion, a library of synthetic antibodies to F protein and the receptor binding protein was generated in bacteriophage. These antibodies bound to different regions of the F protein and the receptor binding protein, and the location of antibody binding affected different processes in viral entry into cells.

Structure of the parainfluenza virus 5 (PIV5) hemagglutinin-neuraminidase (HN) ectodomain.

Paramyxoviruses cause a wide variety of human and animal diseases. They infect host cells using the coordinated action of two surface glycoproteins, the receptor binding protein (HN, H, or G) and the fusion protein (F). HN binds sialic acid on host cells (hemagglutinin activity) and hydrolyzes these receptors during viral egress (neuraminidase activity, NA). Additionally, receptor binding is thought to induce a conformational change in HN that subsequently triggers major refolding in homotypic F, resulting in fusion of virus and target cell membranes. HN is an oligomeric type II transmembrane protein with a short cytoplasmic domain and a large ectodomain comprising a long helical stalk and large globular head domain containing the enzymatic functions (NA domain). Extensive biochemical characterization has revealed that HN-stalk residues determine F specificity and activation. However, the F/HN interaction and the mechanisms whereby receptor binding regulates F activation are poorly defined. Recently, a structure of Newcastle disease virus (NDV) HN ectodomain revealed the heads (NA domains) in a "4-heads-down" conformation whereby two of the heads form a symmetrical interaction with two sides of the stalk. The interface includes stalk residues implicated in triggering F, and the heads sterically shield these residues from interaction with F (at least on two sides). Here we report the x-ray crystal structure of parainfluenza virus 5 (PIV5) HN ectodomain in a "2-heads-up/2-heads-down" conformation where two heads (covalent dimers) are in the "down position," forming a similar interface as observed in the NDV HN ectodomain structure, and two heads are in an "up position." The structure supports a model in which the heads of HN transition from down to up upon receptor binding thereby releasing steric constraints and facilitating the interaction between critical HN-stalk residues and F.

Fusion activation by a headless parainfluenza virus 5 hemagglutinin-neuraminidase stalk suggests a modular mechanism for triggering.

The Paramyxoviridae family of enveloped viruses enters cells through the concerted action of two viral glycoproteins. The receptor-binding protein, hemagglutinin-neuraminidase (HN), H, or G, binds its cellular receptor and activates the fusion protein, F, which, through an extensive refolding event, brings viral and cellular membranes together, mediating virus-cell fusion. However, the underlying mechanism of F activation on receptor engagement remains unclear. Current hypotheses propose conformational changes in HN, H, or G propagating from the receptor-binding site in the HN, H, or G globular head to the F-interacting stalk region. We provide evidence that the receptor-binding globular head domain of the paramyxovirus parainfluenza virus 5 HN protein is entirely dispensable for F activation. Considering together the crystal structures of HN from different paramyxoviruses, varying energy requirements for fusion activation, F activation involving the parainfluenza virus 5 HN stalk domain, and properties of a chimeric paramyxovirus HN protein, we propose a simple model for the activation of paramyxovirus fusion.

Structure of the cleavage-activated prefusion form of the parainfluenza virus 5 fusion protein.

The paramyxovirus parainfluenza virus 5 (PIV5) enters cells by fusion of the viral envelope with the plasma membrane through the concerted action of the fusion (F) protein and the receptor binding protein hemagglutinin-neuraminidase. The F protein folds initially to form a trimeric metastable prefusion form that is triggered to undergo large-scale irreversible conformational changes to form the trimeric postfusion conformation. It is thought that F refolding couples the energy released with membrane fusion. The F protein is synthesized as a precursor (F0) that must be cleaved by a host protease to form a biologically active molecule, F1,F2. Cleavage of F protein is a prerequisite for fusion and virus infectivity. Cleavage creates a new N terminus on F1 that contains a hydrophobic region, known as the FP, which intercalates target membranes during F protein refolding. The crystal structure of the soluble ectodomain of the uncleaved form of PIV5 F is known; here we report the crystal structure of the cleavage-activated prefusion form of PIV5 F. The structure shows minimal movement of the residues adjacent to the protease cleavage site. Most of the hydrophobic FP residues are buried in the uncleaved F protein, and only F103 at the newly created N terminus becomes more solvent-accessible after cleavage. The conformational freedom of the charged arginine residues that compose the protease recognition site increases on cleavage of F protein.

Impact of institutional variables on centre performance in long-term survival after heart transplant.

OBJECTIVES: The gold standard metric for centre-level performance in orthotopic heart transplantation (OHT) is 1-year post-OHT survival. However, it is unclear whether centre performance at 1 year is predictive of longer-term outcomes. This study evaluated factors impacting longer-term centre-level performance in OHT. METHODS: Patients who underwent OHT in the USA between 2010 and 2021 were identified using the United Network of Organ Sharing data registry. The primary outcome was 5-year survival conditional on 1-year survival following OHT. Multivariable Cox proportional hazard models assessed the impact of centre-level 1-year survival rates on 5-year survival rates. Mixed-effect models were used to evaluate between-centre variability in outcomes. RESULTS: Centre-level risk-adjusted 5-year mortality conditional on 1-year survival was not associated with centre-level 1-year survival rates [hazard ratio: 0.99 (0.97-1.01, P = 0.198)]. Predictors of 5-year mortality conditional on 1-year survival included black recipient race, pre-OHT serum creatinine, diabetes and donor age. In mixed-effect modelling, there was substantial variability between centres in 5-year mortality rates conditional on 1-year survival, a finding that persisted after controlling for recipient, donor and institutional factors (P < 0.001). In a crude analysis using Kaplan-Meier, the 5-year survival conditional on 1-year survival was: low volume: 86.5%, intermediate volume: 87.5%, high volume: 86.7% (log-rank P = 0.52). These measured variables only accounted for 21.4% of the between-centre variability in 5-year mortality conditional on 1-year survival. CONCLUSIONS: Centre-level risk-adjusted 1-year outcomes do not correlate with outcomes in the 1- to 5-year period following OHT. Further research is needed to determine what unmeasured centre-level factors contribute to longer-term outcomes in OHT.

Prediction of coronary artery bypass graft outcomes using a single surgical note: An artificial intelligence-based prediction model study.

BACKGROUND: Healthcare providers currently calculate risk of the composite outcome of morbidity or mortality associated with a coronary artery bypass grafting (CABG) surgery through manual input of variables into a logistic regression-based risk calculator. This study indicates that automated artificial intelligence (AI)-based techniques can instead calculate risk. Specifically, we present novel numerical embedding techniques that enable NLP (natural language processing) models to achieve higher performance than the risk calculator using a single preoperative surgical note. METHODS: The most recent preoperative surgical consult notes of 1,738 patients who received an isolated CABG from July 1, 2014 to November 1, 2022 at a single institution were analyzed. The primary outcome was the Society of Thoracic Surgeons defined composite outcome of morbidity or mortality (MM). We tested three numerical-embedding techniques on the widely used TextCNN classification model: 1a) Basic embedding, treat numbers as word tokens; 1b) Basic embedding with a dataloader that Replaces out-of-context (ROOC) numbers with a tag, where context is defined as within a number of tokens of specified keywords; 2) ScaleNum, an embedding technique that scales in-context numbers via a learned sigmoid-linear-log function; and 3) AttnToNum, a ScaleNum-derivative that updates the ScaleNum embeddings via multi-headed attention applied to local context. Predictive performance was measured via area under the receiver operating characteristic curve (AUC) on holdout sets from 10 random-split experiments. For eXplainable-AI (X-AI), we calculate SHapley Additive exPlanation (SHAP) values at an ngram resolution (SHAP-N). While the analyses focus on TextCNN, we execute an analogous performance pipeline with a long short-term memory (LSTM) model to test if the numerical embedding advantage is robust to model architecture. RESULTS: A total of 567 (32.6%) patients had MM following CABG. The embedding performances are as follows with the TextCNN architecture: 1a) Basic, mean AUC 0.788 [95% CI (confidence interval): 0.768-0.809]; 1b) ROOC, 0.801 [CI: 0.788-0.815]; 2) ScaleNum, 0.808 [CI: 0.785-0.821]; and 3) AttnToNum, 0.821 [CI: 0.806-0.834]. The LSTM architecture produced a similar trend. Permutation tests indicate that AttnToNum outperforms the other embedding techniques, though not statistically significant verse ScaleNum (p-value of .07). SHAP-N analyses indicate that the model learns to associate low blood urine nitrate (BUN) and creatinine values with survival. A correlation analysis of the attention-updated numerical embeddings indicates that AttnToNum learns to incorporate both number magnitude and local context to derive semantic similarities. CONCLUSION: This research presents both quantitative and clinical novel contributions. Quantitatively, we contribute two new embedding techniques: AttnToNum and ScaleNum. Both can embed strictly positive and bounded numerical values, and both surpass basic embeddings in predictive performance. The results suggest AttnToNum outperforms ScaleNum. With regards to clinical research, we show that AI methods can predict outcomes after CABG using a single preoperative note at a performance that matches or surpasses the current risk calculator. These findings reveal the potential role of NLP in automated registry reporting and quality improvement.

Variability of Maximum Glottal Angle on Clinical Sniff Task Differs in Patients With Functional and Organic Laryngeal Pathologies Compared to Healthy Controls.

OBJECTIVES: Practitioners rely heavily on flexible endoscopic visualization of the true vocal folds during a repeated "sniff-ee" maneuver to assess vocal fold mobility. However, the human eye lacks the temporal and spatial precision required to accurately gauge fine differences in maximal glottal angle. This study compared differences in maximal glottal angle variables during "sniff-ee" maneuvers across patients with various voice and laryngeal breathing disorders. METHODS: We retrospectively measured glottal angle from flexible laryngoscopy examinations in six groups of patients with voice and upper airway disorders: laryngeal dystonia/essential tremor (LD/ET), vocal fold lesions, vocal fold atrophy, paradoxical vocal fold motion disorder (PVFMD), muscle tension dysphonia (MTD), and healthy controls. Maximum glottal angle (GAMAX) and average glottal angle (GAAVG) were calculated during three serial "sniff-ee" maneuvers for all participants. Individual disorder groups (MTD, PVFMD, LD/ET, atrophy, and lesion) and broader disorder types (functional and organic) were compared to healthy controls using simple linear regression analyses. RESULTS: No significant difference in either GAMAX or GAAVG was found between controls and the disorder subgroups or broader disorder type (function and organic). However, there were statistically significant differences in the variability of GAMAX in both PVFMD (6.2° more variability; P < 0.001) and LD/ET (5.8° more variability; P < 0.001) compared to healthy controls. CONCLUSION: Patients diagnosed with LD/ET and PVFMD both demonstrated significantly more variability in their GAMAX compared to healthy controls, suggesting that movement consistency or coordination may be relatively compromised in these patient groups. Further research is warranted to investigate the sensitivity and specificity of glottal angle variability in diagnosing PVFMD and LD in clinical or research settings. LEVEL OF EVIDENCE: 4 SHORT SUMMARY: Laryngeal examinations from five patient groups were compared to those from healthy controls. Patients with paradoxical vocal fold motion disorder and laryngeal movement disorders exhibited significantly greater variability of glottal angle during sniff maneuver compared to healthy controls.

Risk Factors for 1-Year Mortality After Heart Transplant in Obese Patients Bridged With an LVAD.

BACKGROUND: Heart transplantation is relatively contraindicated in morbidly obese patients because of increased morbidity and mortality. This study identified risk factors for post-heart transplantation mortality in obese patients with a left ventricular assist device (LVAD). METHODS: The United Network for Organ Sharing database was used to identify patients with a body mass index ≥35 kg/m2 who had a durable LVAD at the time of isolated heart transplantation between 2010 and 2021. The primary outcome was post-heart transplantation 1-year mortality. Multivariable Cox regression modeling was used to identify significant risk factors for 1-year mortality. Receiver-operating characteristic analyses were performed to identify optimal thresholds for continuous variables associated with the primary outcome. Patients were stratified by the number of risk factors, and Kaplan-Meier analysis was used to compare survival. RESULTS: A total of 1222 obese patients were bridged to heart transplantation with a durable LVAD. Six risk factors were identified as significantly associated with 1-year post-heart transplantation mortality: recipient age >62.5 years, body mass index >36.6 kg/m2, bilirubin level >0.95 mg/dL, cold ischemic time >3.7 hours, recipient-donor sex mismatch, and pretransplantation mechanical ventilation. The distribution of cumulative risk factors was as follows: 8.6% with 0, 30.6% with 1, 37.0% with 2, and 23.8% patients with ≥3 risk factors. The 1-year survival rate decreased significantly from 96.0% in those patients with 0 risk factors to 77.6% in those with 3 or more risk factors. CONCLUSIONS: These data provide a useful guide for risk stratification and patient selection in obese LVAD candidates being considered for heart transplantation.

Changes in heart transplant outcomes of elderly patients in the new allocation era.

OBJECTIVE: Studies demonstrate that heart transplantation can be performed safely in septuagenarians. We evaluate the outcomes of septuagenarians undergoing heart transplantation after the US heart allocation change in 2018. METHODS: The United Network for Organ Sharing registry was used to identify heart transplant recipients aged 70 years or more between 2010 and 2021. Primary outcomes were 90-day and 1-year mortality. Kaplan-Meier, multivariable Cox proportional hazards, and accelerated failure time models were used for unadjusted and risk-adjusted analyses. RESULTS: A total of 27,403 patients underwent heart transplantation, with 1059 (3.9%) aged 70 years or more. Patients aged 70 years or more increased from 3.7% before 2018 to 4.5% after 2018 (P = .003). Patients aged 70 years or more before 2018 had comparable 90-day and 1-year survivals relative to patients aged less than 70 years (90 days: 93.8% vs 94.2%, log-rank P = .650; 1 year: 89.4% vs 91.1%, log-rank P = .130). After 2018, septuagenarians had lower 90-day and 1-year survivals (90 days: 91.4% vs 95.0%, log-rank P = .021; 1 year: 86.5% vs 90.9%, log-rank P = .018). Risk-adjusted analysis showed comparable 90-day mortality (hazard ratio, 1.29; 0.94-1.76, P = .110) but worse 1-year mortality (hazard ratio, 1.32; 1.03-1.68, P = .028) before policy change. After policy change, both 90-day and 1-year mortalities were higher (90 days: HR, 1.99; 1.23-3.22, P = .005; 1 year: hazard ratio, 1.71; 1.14-2.56, P = .010). An accelerated failure time model showed comparable 90-day (0.42; 0.16-1.44; P = .088) and 1-year (0.48; 0.18-1.26; P = .133) survival postallocation change. CONCLUSIONS: Septuagenarians comprise a greater proportion of heart transplant recipients after the allocation change, and their post-transplant outcomes relative to younger recipients have worsened.

Self-Reported Stress, Trauma, and Prevalence of Laryngoresponders in the General Population.

INTRODUCTION: It has been proposed that some individuals are "laryngoresponders" (LRs) in that their stress manifests in the laryngeal region and laryngeal functions (e.g., voice and breathing). Preliminary data support the notion that LRs might differ from nonlaryngoresponders (NLRs) in their self-reported past trauma and recent stress. The purpose of this study was to establish the point prevalence of self-identified LRs in the general population. METHOD: Using a web-based questionnaire, participants reported up to 13 stress-vulnerable bodily regions and described symptom nature and severity for each region. At the end of the questionnaire, they were explicitly prompted to report whether their laryngeal region or its functions were affected by stress. Participants were categorized a posteriori as Unprompted LRs, Prompted LRs, Inconsistent LRs, or NLRs. We compared LR and NLR groups on the Perceived Stress Scale (PSS-10) and the Childhood Trauma Questionnaire (CTQ-SF). We also redistributed the survey to a subset of participants to establish grouping reliability. RESULTS: A total of 1,217 adults responded to the survey, and 995 provided complete data sets. Of those, 15.7% were classified as Unprompted LRs, 26.7% as Prompted LRs, 3% as Inconsistent LRs, and 54.6% as NLRs. Unprompted LRs demonstrated significantly higher/worse PSS-10 and CTQ-SF scores than all other groups. Reliability of LR classification was moderate upon follow-up, κ = .62, 95% confidence interval [0.47, 0.77]. CONCLUSIONS: Unprompted LRs described their symptoms in ways that were indistinguishable from patients with functional voice disorders (e.g., throat clenches, voice gets tired easily, lose my voice, voice gets hoarse). The method of self-report solicitation impacted the resulting response. Specifically, the report of larynx-related symptoms differed substantially depending on whether or not the participants were directly prompted to consider the larynx and its related functions.

Intrinsic Laryngeal Muscle Activity During Subvocalization.

PURPOSE: Subvocalization, the low-grade activity of speech articulator muscles while thinking or reading, may mediate phonological representations of verbal material. However, no literature exists that directly measures whether intrinsic laryngeal muscles (ILMs) are active during subvocalization. The possibility of ILM activation during subvocalization has implications for establishing appropriate baselines when experimental conditions involve linguistic features. METHOD: In two separate studies, forty-five cisgender women completed one or two silentsil tasks (two in the first study, Experiments 1a and 1b, and one in the second, Experiment 2). Fine wire electromyography was used to directly measure ILM activity during an at-rest baseline and silent tasks used to determine whether subvocalization occurred (referred to hereafter as "subvocalization tasks"). Other muscles were measured via surface electromyography: submental muscle in Experiments 1a and 1b, anterior tibialis in Experiment 2, and upper trapezius in all experiments. RESULTS: Interrupted time-series analysis was used to directly measure changes in ILM activity from baseline to the subvocalization tasks. A paired two tailed t-test was used to measure mean differences in ILM activity across conditions for each participant. Some individuals displayed statistically significant increases from baseline during subvocalization tasks, whereas others displayed decreases. Cohen's d was used to calculate the effect size for each muscle across the three subvocalization conditions. Of the 21 muscles measured across three experiments, five yielded a small mean effect size, and the effect sizes for the remaining 16 muscles were negligible. At a group level, only the right cricothyroid showed statistically significant changes (Experiment 1b). CONCLUSION: The ILM responses during subvocalization vary in both magnitude and direction. Most but not all changes can be described as negligible. For future studies of ILM activity during conditions that involve linguistic processing, investigators should consider the idiosyncratic variation during subvocalization when determining the most appropriate baseline task.

Outcomes of Combined Heart-Kidney Transplantation in Older Recipients.

Objectives: The upper limit of recipient age for combined heart-kidney transplantation (HKT) remains controversial. This study evaluated the outcomes of HKT in patients aged ≥65 years. Methods: The United Network of Organ Sharing (UNOS) was used to identify patients undergoing HKT from 2005 to 2021. Patients were stratified by age at transplantation: <65 and ≥ 65 years. The primary outcome was one-year mortality. Secondary outcomes included 90-day and 5-year mortality, postoperative new-onset dialysis, postoperative stroke, acute rejection prior to discharge, and rejection within one-year of HKT. Survival was compared using Kaplan-Meier analysis, and risk adjustment for mortality was performed using Cox proportional hazards modeling. Results: HKT in recipients aged ≥65 significantly increased from 5.6% of all recipients in 2005 to 23.7% in 2021 (p=0.002). Of 2,022 HKT patients in the study period, 372 (18.40%) were aged ≥65. Older recipients were more likely to be male and white, and fewer required dialysis prior to HKT. There were no differences between cohorts in unadjusted 90-day, 1-year, or 5-year survival in Kaplan-Meier analysis. These findings persisted after risk-adjustment, with an adjusted hazard for one-year mortality for age ≥65 of 0.91 (95% CI (0.63-1.29), p=0.572). As a continuous variable, increasing age was not associated with one-year mortality (HR 1.01 (95% CI (1.00-1.02), p=0.236) per year). Patients aged ≥65 more frequently required new-onset dialysis prior to discharge (11.56% vs. 7.82%, p=0.051). Stroke and rejection rates were comparable. Conclusion: Combined HKT is increasing in older recipients, and advanced age ≥65 should not preclude HKT.

Outcomes of Over 1000 Heart Transplants Using Hepatitis C-Positive Donors in the Modern Era.

BACKGROUND: Advances in hepatitis C virus (HCV) treatment and the ongoing opioid epidemic have made HCV-positive donors increasingly available for heart transplantation (HT). This analysis reports outcomes of over 1000 HCV-positive HTs in the United States in the modern era. METHODS: The United Network of Organ Sharing registry was used to identify HTs between 2015 and 2021. Recipients were grouped by donor HCV status and by nucleic acid amplification test (NAT) positivity. The primary outcome was 1-year mortality, and secondary outcomes included 3-year mortality. A subanalysis compared HCV-positive HT outcomes between NAT-positive and NAT-negative donors. Risk adjustment was performed using Cox regression. Kaplan-Meier analysis was used to estimate survival. RESULTS: The frequency of HCV-positive HT increased from 0.12% of HTs in 2015 to 12.9% in 2021 (P < .001). Of 16,648 HTs, 1170 (7.0%) used an organ from an HCV-positive donor. Recipients of HCV-positive organs were more likely to be HCV seropositive, older, and White. Unadjusted 1- and 3-year survival rates were not significantly different between recipients of HCV-negative and HCV-positive organs. After risk adjustment HCV-positive donor status was not associated with an elevated risk for 1-year (hazard ratio, 0.92; 95% CI, 0.71-1.19; P = .518) or 3-year mortality. Among HCV-positive HTs 772 (61.7%) were NAT positive. After risk adjustment NAT positivity did not impact 1-year mortality. CONCLUSIONS: The proportion of HCV-positive HTs has increased over 100-fold in recent years. This analysis of the US experience demonstrates that recipients of HCV-positive hearts, including those that are NAT positive, have acceptable outcomes with similar early to midterm survival as recipients of HCV-negative organs.