Cardiac afferent signals can facilitate visual dominance in binocular rivalry.

Sensory signals from the body's visceral organs (e.g. the heart) can robustly influence the perception of exteroceptive sensations. This interoceptive-exteroceptive interaction has been argued to underlie self-awareness by situating one's perceptual awareness of exteroceptive stimuli in the context of one's internal state, but studies probing cardiac influences on visual awareness have yielded conflicting findings. In this study, we presented separate grating stimuli to each of subjects' eyes as in a classic binocular rivalry paradigm - measuring the duration for which each stimulus dominates in perception. However, we caused the gratings to 'pulse' at specific times relative to subjects' real-time electrocardiogram, manipulating whether pulses occurred during cardiac systole, when baroreceptors signal to the brain that the heart has contracted, or in diastole when baroreceptors are silent. The influential 'Baroreceptor Hypothesis' predicts the effect of baroreceptive input on visual perception should be uniformly suppressive. In contrast, we observed that dominance durations increased for systole-entrained stimuli, inconsistent with the Baroreceptor Hypothesis. Furthermore, we show that this cardiac-dependent rivalry effect is preserved in subjects who are at-chance discriminating between systole-entrained and diastole-presented stimuli in a separate interoceptive awareness task, suggesting that our results are not dependent on conscious access to heartbeat sensations.

Transcatheter Aortic Valve Implantation by Valve Type in Women With Small Annuli: Results From the SMART Randomized Clinical Trial.

Importance: Historically, women with aortic stenosis have experienced worse outcomes and inadequate recognition compared to men, being both underdiagnosed and undertreated, while also facing underrepresentation in clinical trials. Objective: To determine whether women with small aortic annuli undergoing transcatheter aortic valve replacement have better clinical and hemodynamic outcomes with a self-expanding valve (SEV) or balloon-expandable valve (BEV). Design, Setting, Participants: The Small Annuli Randomized to Evolut or SAPIEN Trial (SMART) was a large-scale randomized clinical trial focusing on patients with small aortic annuli undergoing transcatheter aortic valve replacement, randomized to receive SEVs or BEVs and included 716 patients treated at 83 centers in Canada, Europe, Israel, and the US from April 2021 to October 2022. This prespecified secondary analysis reports clinical and hemodynamic findings for all 621 women enrolled in SMART. Data for this report were analyzed from February to April 2024. Interventions: Transcatheter aortic valve replacement with an SEV or a BEV. Main Outcomes and Measures: The composite coprimary clinical end point comprised death, disabling stroke, or heart failure-related rehospitalization. The coprimary valve function end point was the incidence of bioprosthetic valve dysfunction, both assessed through 12 months. Secondary end points included the incidence of moderate or severe prosthesis-patient mismatch. Results: A total of 621 women (mean [SD] age, 80.2 [6.2] years; 312 randomized to the SEV group and 309 to the BEV group) were included in the present analysis. At 12 months, there were no significant differences in the coprimary clinical end point between the SEV and BEV groups (9.4% vs 11.8%, absolute risk difference -2.3%; 95% CI -7.2 to 2.5, P = .35). However, SEV implantation was associated with less bioprosthetic valve dysfunction (8.4% vs 41.8%; absolute risk difference, -33.4%; 95% CI, -40.4 to -26.4; P < .001). SEV implantation resulted in lower aortic valve gradients and larger effective orifice areas at 30 days and 12 months and less mild or greater aortic regurgitation at 12 months compared to BEV implantation. Prosthesis-patient mismatch was significantly lower with SEVs, regardless of the definition used and adjustment for body mass index. Use of SEVs was associated with better quality of life outcomes as assessed by the Valve Academic Research Consortium-3 ordinal quality of life measure. Conclusions and Relevance: Among women with severe symptomatic aortic stenosis and small aortic annuli undergoing transcatheter aortic valve replacement, the use of SEVs, compared to BEVs, resulted in similar clinical outcomes and a markedly reduced incidence of bioprosthetic valve dysfunction through 12 months, including a lower risk of prosthesis-patient mismatch and better 12-month quality of life. Trial Registration: ClinicalTrials.gov Identifier: NCT04722250.

Arterial Properties and Ventricular-Arterial Interactions in Severe Aortic Stenosis: Impact on Prognosis.

BACKGROUND: Systemic arterial properties contribute to clinical heterogeneity and outcomes in degenerative calcific aortic stenosis (AS). Lumped parameters of afterload have previously been associated with adverse left ventricular remodeling, mortality, and poor exercise tolerance in this population, but most studies did not assess pulsatile aortic pressure-flow relations, the gold standard method for assessing arterial load. Moreover, arterial compliance is highly dependent on non-pulsatile (mean) arterial pressure, which influences prognosis in this population. METHODS: We retrospectively studied 135 patients with severe AS with same-day catheterization and echocardiogram. Invasive aortic pressures and echocardiographic flow waveforms were used to assess pressure-flow and pressure-volume relations using Windkessel modeling and wave separation analyses. We used Cox regression to assess the relationship between pulsatile load and time to death and heart failure hospital admission (DHFA). RESULTS: Total arterial compliance accounting for pressure-dependence (PD-TAC) was independently predictive of all-cause mortality (HR=0.80, 95%CI=0.66-0.97; p=0.023) and DHFA (HR=0.70; 95%CI=0.50-0.97; p=0.031) even after adjustment for age, race, gender, BMI, and comorbidities, while other arterial parameters were not. CONCLUSIONS: In patients with severe AS, pressure-dependent arterial compliance predicts adverse outcomes, while traditional pulsatile arterial load measures do not. Our findings suggest that methods accounting for pressure load on the arterial wall are advantageous in this population in which lower mean pressure can result from severe stenosis and ventricular dysfunction.

Trigeminal Trophic Syndrome With Herpetic Keratitis.

PURPOSE: The aim of this study was to report a rare observation of trigeminal trophic syndrome presenting with concurrent herpetic keratitis. METHODS: This study was a case report. RESULTS: A 42-year-old male with a remote history of a motor vehicle accident, traumatic brain injury, extensive facial reconstructive surgery, and traumatic optic neuropathy presented with left periorbital swelling. He was found to have extensive periorbital and total hypoesthesia in the cranial nerve V1 distribution and partial hypoesthesia in the V2 distribution. Corneal findings were highly suspicious for herpes simplex keratitis or zoster ophthalmicus. The patient was diagnosed with herpetic epithelial and stromal keratitis with periorbital ulceration secondary to Trigeminal trophic syndrome. The patient was treated broad spectrum intravenous antibiotics, intravenous acyclovir, and topical antibiotics. He was treated with topical steroids upon closure of epithelial defect. Upon discharge, the patient's vision improved from hand-motion to 20/30 at near. The patient was later fit with a custom thermoplastic facial mask to minimize further selfinjurious behavior. CONCLUSIONS: To our knowledge, this is the first report of trigeminal trophic syndrome presenting with concurrent herpetic keratitis. Successful treatment requires a multidisciplinary approach to provide the patient insight and create protective equipment.

Non-Operative Management of Uncomplicated Appendicitis in Children: Can Patients Be Discharged From the Emergency Department?

INTRODUCTION: Non-operative management of uncomplicated appendicitis in children is a safe alternative to laparoscopic appendectomy. The purpose of this study is to determine the feasibility of nonoperative outpatient management of uncomplicated appendicitis in pediatric patients. METHODS: A standardized pathway for non-operative outpatient management of uncomplicated appendicitis in children (NOMA-C) was implemented in a university pediatric surgery practice starting October 2021. Those who met criteria would be considered for discharge from the emergency department (ED) with oral antibiotics and close followup over the following year. A quality improvement project started concurrently to monitor patients for recurrent symptoms of appendicitis. RESULTS: A total of 121 patients were diagnosed with acute appendicitis during the study period (October 2021 to April 2023). Forty-five children (38%) met criteria for the NOMA-C protocol, and 11 patients/families chose appendectomy. Of the 34 patients who pursued nonoperative management, 14 patients were admitted to the hospital and 20 patients were discharged from the ED. Total time in the ED/hospital was significantly shorter for patients discharged from the ED (7 hours versus 23 hours; p<0.001). At one year follow up only 4 (12%) had undergone appendectomy. There were no adverse events for patients who underwent nonoperative management. CONCLUSION: A protocol offering non-operative management of appendicitis with an option for outpatient management was feasible and safe. Outpatient management was associated with shorter ED/hospital stays than those admitted. Future studies should evaluate whether this protocol can be adopted by EDs without pediatric surgery services to avoid the need for transfer.

Tumor-Associated Carbohydrate Antigen 19-9 (CA 19-9), a Promising Target for Antibody-Based Detection, Diagnosis, and Immunotherapy of Cancer.

Carbohydrate antigen 19-9 (CA 19-9) also known as sialyl Lewis A is a tetrasaccharide overexpressed on a wide range of cancerous cells, which has been detected at elevated levels in sera of patients with various types of malignancies, most prominently pancreatic ductal adenocarcinoma. After its identification in 1979, multiple studies have highlighted the significant roles of CA 19-9 in cancer progression, including facilitating extravasation and eventually metastases, proliferation of cancer cells, and suppression of the immune system. Therefore, CA 19-9 has been considered an attractive target for cancer diagnosis, prognosis, and therapy. This review discusses the synthesis of CA 19-9 antigen, elicitation of antibodies through vaccination, development of anti-CA 19-9 monoclonal antibodies, and their applications as imaging tracers and therapeutics for a variety of CA 19-9-positive cancer.

QuickPic AAC: An AI-Based Application to Enable Just-in-Time Generation of Topic-Specific Displays for Persons Who Are Minimally Speaking.

As artificial intelligence (AI) makes significant headway in various arenas, the field of speech-language pathology is at the precipice of experiencing a transformative shift towards automation. This study introduces QuickPic AAC, an AI-driven application designed to generate topic-specific displays from photographs in a "just-in-time" manner. Using QuickPic AAC, this study aimed to (a) determine which of two AI algorithms (NLG-AAC and GPT-3.5) results in greater specificity of vocabulary (i.e., percentage of vocabulary kept/deleted by clinician relative to vocabulary generated by QuickPic AAC; percentage of vocabulary modified); and to (b) evaluate perceived usability of QuickPic AAC among practicing speech-language pathologists. Results revealed that the GPT-3.5 algorithm consistently resulted in greater specificity of vocabulary and that speech-language pathologists expressed high user satisfaction for the QuickPic AAC application. These results support continued study of the implementation of QuickPic AAC in clinical practice and demonstrate the possibility of utilizing topic-specific displays as just-in-time supports.

Metacognition bridges experiences and beliefs in sense of agency.

Cognitive scientists differentiate the "minimal self" - subjective experiences of agency and ownership in our sensorimotor interactions with the world - from declarative beliefs about the self that are sustained over time. However, it remains an open question how individual sensory experiences of agency are integrated into the belief ofbeing an agent.We administered a sensorimotor task to measure subjects' (n = 195) propensity to classify stimuli as self-caused and metacognitive monitoring of such judgements, and we compared these behavioral metrics to declarative beliefs about their agency. Subjects who were less sensitive to control cues also reported more negative agency beliefs, though positive beliefs were not clearly correlated with any sensorimotor measure. Importantly, this relationship between first-order sensitivity and declarative beliefs essentially disappears when controlling for metacognitive sensitivity. Results suggest agency beliefs are not related directly to the propensity to make positive agency judgements but are connected through introspective access.

Six Years of Quality Improvement in Pectus Excavatum Repair: Implementation of Intercostal Nerve Cryoablation and ERAS Protocols for Patients Undergoing Nuss Procedure.

BACKGROUND: The Nuss procedure for pectus excavatum is associated with prolonged hospitalizations due to pain. We evaluated implementation of intercostal nerve cryoablation and enhanced recovery after surgery (ERAS) protocols on outcomes of Nuss procedures performed over six years at a single institution. METHODS: This retrospective cohort study included patients who underwent Nuss procedure from 10/2017 to 09/2023. Patients received epidurals prior to 06/2019, cryoablation from 06/2019 to 07/2021, and ERAS with cryoablation and intraoperative methadone administration after 07/2021. We used multivariable linear regression to evaluate length of stay (LOS), inpatient morphine milligram equivalents (MMEs), and discharge opioids. We assessed the balancing measures of operative time, postoperative pain scores, and complications. RESULTS: We identified 62 patients; 15 who received epidurals, 18 cryoablation, and 29 cryoablation with ERAS. Cryoablation was associated with a 62.3% (p < 0.001) decrease in length of stay, an 86.6% (p < 0.001) decrease in inpatient MMEs, and a 72.9% (p < 0.001) decrease in discharge opioids. Cryoablation was additionally associated with 24.5% (p = 0.02) longer operative times and 46.4% (p = 0.04) higher postoperative day one pain scores. Subsequent implementation of an ERAS protocol was associated with a further 82.8% (p = 0.04) decrease in discharge opioids and a 25.0% (p = 0.04) decrease in postoperative day one pain scores. CONCLUSIONS: Over six years of quality improvement efforts, we found the implementation of cryoablation and ERAS protocols to be associated with a significant decrease in length of stay and opioid exposures. Protocolized pain management and cryoablation may work synergistically to improve outcomes without compromising patient experience. LEVEL OF EVIDENCE: Level III - Retrospective comparative study.

Strategies for Achieving Better Cognitive Health in Individuals with Schizophrenia Spectrum: A Focus on the Canadian Landscape: Stratégies pour atteindre une meilleure santé cognitive chez les personnes souffrant du spectre de la schizophrénie : un regard sur le paysage canadien.

BACKGROUND: Schizophrenia spectrum disorders (SSDs) are a group of psychiatric disorders characterized by positive and negative symptoms as well as cognitive impairment that can significantly affect daily functioning. METHOD: We reviewed evidence-based strategies for improving cognitive function in patients with SSDs, focusing on the Canadian landscape. RESULTS: Although antipsychotic medications can address the positive symptoms of SSDs, cognitive symptoms often persist, causing functional impairment and reduced quality of life. Moreover, cognitive function in patients with SSDs is infrequently assessed in clinical practice, and evidence-based recommendations for addressing cognitive impairment in people living with schizophrenia are limited. While cognitive remediation (CR) can improve several domains of cognitive function, most individuals with SSDs are currently not offered such an intervention. While the development of implementation strategies for CR is underway, available and emerging pharmacological treatments may help overcome the limited capacity for psychosocial approaches. Furthermore, combining pharmacological with non-pharmacological interventions may improve outcomes compared to pharmacotherapy or CR alone. CONCLUSION: This review highlights the challenges and discusses the potential solutions related to the assessment and management of cognitive impairment to help mental health-care practitioners better manage cognitive impairment and improve daily functioning in individuals with SSDs.

Improving Thinking Skills in People With Schizophrenia: A Focus on CanadaPlain Language SummarySchizophrenia spectrum disorders (SSDs) are mental health conditions that can cause a mix of symptoms making everyday life difficult for people. For example, some people might experience positive symptoms like seeing and hearing things that are not there, having false believes, or feeling suspicious. Others might experience negative symptoms like isolating from social interactions, having trouble showing emotion, or finding it hard to connect with others. Finally, they might also have trouble with thinking skills, like paying attention, planning and organizing, remembering things, or understanding social cues. While some medicines can help with some of the symptoms, they often do not help with improving thinking skills. In addition, these thinking problems are not checked often enough in patients with SSDs. In fact, there are not many proven ways to help with these issues. One method that can help with thinking skills is called cognitive remediation (CR), but it is not offered to most people with SSDs. There are ongoing efforts to make CR more available. It is also possible that CR may be combined with new medicines to make it work better than using just one treatment. This article looks at ways to improve thinking skills in people with SSDs, with a focus on what is happening in Canada. We present the challenges and possible solutions for checking and managing thinking problems, to help health-care workers better care for people with SSDs.

ROR2 Regulates Cellular Plasticity in Pancreatic Neoplasia and Adenocarcinoma.

Cellular plasticity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) starting from the conversion of normal cells into precancerous lesions, to the progression of carcinoma subtypes associated with aggressiveness and therapeutic response. We discovered that normal acinar cell differentiation, maintained by the transcription factor Pdx1, suppresses a broad gastric cell identity that is maintained in metaplasia, neoplasia, and the classical subtype of PDAC in mouse and human. We have identified the receptor tyrosine kinase Ror2 as marker of a gastric metaplasia-like identity in pancreas neoplasms. Ablation of Ror2 in a mouse model of pancreatic tumorigenesis promoted a switch to a gastric pit cell identity that largely persisted through progression to the classical subtype of PDAC. In both human and mouse pancreatic cancer, ROR2 activity continued to antagonize the gastric pit cell identity, strongly promoting an epithelial to mesenchymal transition, conferring resistance to KRAS inhibition, and vulnerability to AKT inhibition.

Secreted antigen A peptidoglycan hydrolase is essential for Enterococcus faecium cell separation and priming of immune checkpoint inhibitor therapy.

Enterococcus faecium is a microbiota species in humans that can modulate host immunity (Griffin and Hang, 2022), but has also acquired antibiotic resistance and is a major cause of hospital-associated infections (Van Tyne and Gilmore, 2014). Notably, diverse strains of E. faecium produce SagA, a highly conserved peptidoglycan hydrolase that is sufficient to promote intestinal immunity (Rangan et al., 2016; Pedicord et al., 2016; Kim et al., 2019) and immune checkpoint inhibitor antitumor activity (Griffin et al., 2021). However, the functions of SagA in E. faecium were unknown. Here, we report that deletion of sagA impaired E. faecium growth and resulted in bulged and clustered enterococci due to defective peptidoglycan cleavage and cell separation. Moreover, ΔsagA showed increased antibiotic sensitivity, yielded lower levels of active muropeptides, displayed reduced activation of the peptidoglycan pattern-recognition receptor NOD2, and failed to promote cancer immunotherapy. Importantly, the plasmid-based expression of SagA, but not its catalytically inactive mutant, restored ΔsagA growth, production of active muropeptides, and NOD2 activation. SagA is, therefore, essential for E. faecium growth, stress resistance, and activation of host immunity.

Patient- and family-reported experiences of their treating teams in early psychosis services in Chennai, India and Montreal, Canada.

BACKGROUND: Cross-cultural psychosis research has mostly focused on outcomes, rather than patient and family experiences. Therefore, our aim was to examine differences in patients' and families' experiences of their treating teams in early intervention services for psychosis in Chennai, India [low- and middle-income country] and Montreal, Canada [high-income country]. METHODS: Patients (165 in Chennai, 128 in Montreal) and their families (135 in Chennai, 110 in Montreal) completed Show me you care, a patient- and family-reported experience measure, after Months 3, 12, and 24 in treatment. The measure assesses the extent to which patients and families view treating teams as being supportive. A linear mixed model with longitudinal data from patient and family dyads was used to test the effect of site (Chennai, Montreal), stakeholder (patient, family), and time on Show me you care scores. This was followed by separate linear mixed effect models for patients and families with age and gender, as well as symptom severity and functioning as time-varying covariates. RESULTS: As hypothesized, Chennai patients and families reported more supportive behaviours from their treating teams (ß=4.04; ß= 9, respectively) than did Montreal patients (Intercept =49.6) and families (Intercept=42.45). Higher symptom severity over follow-up was associated with patients reporting lower supportive behaviours from treating teams. Higher levels of positive symptoms (but lower levels of negative symptoms) over follow-up were associated with families reporting lower supportive behaviours from treating teams. There was no effect of time, age, gender and functioning. CONCLUSIONS: The levels to which treating teams are perceived as supportive may reflect culturally shaped attitudes (e.g., warmer attitudes towards healthcare providers in India vis-à-vis Canada) and actual differences in how supportive treating teams are, which too may be culturally shaped. Being expected to be more involved in treatment, Chennai families may receive more attention and support, which may further reinforce their involvement. Across contexts, those who improve over follow-up may see their treating teams more positively.

Levothyroxine may not adequately prepare hypothyroid women for controlled ovarian hyperstimulation.

BACKGROUND: Thyroid axis dysregulation during controlled ovarian hyperstimulation (COH) is more pronounced in hypothyroid-treated women. Whether or not this leads to compromised thyroid hormone levels within the ovarian follicular fluid is not known. AIMS: To determine whether ovarian follicular thyroid hormone levels are compromised in adequately replaced hypothyroid women undergoing controlled ovarian hyperstimulation (COH), and/or influence cycle/pregnancy outcomes. MATERIALS AND METHODS: Prospective cohort study involving 46 euthyroid (anti-thyroid peroxidase antibody negative) and 16 levothyroxine-replaced women with baseline thyroid-stimulating hormone (TSH) <2.5 mIU/L attending their first COH cycle. Follicular fluid TSH, free triiodothyronine (T3) and free thyroxine (T4) were recorded at oocyte pick-up. Serum levels were measured at: (i) baseline; (ii) human chorionic gonadotropin trigger day; and (iii) cycle conclusion. The number of mature oocytes retrieved, fertilisation, early pregnancy loss and live birth rates were compared. RESULTS: Median serum TSH levels were similar at baseline (1.76 vs 1.24 mIU/L, P = 0.053), but free T3 levels were lower (4.5 vs 4.8 pmol/L, P = 0.029) in levothyroxine-replaced compared to euthyroid women, with serum TSH levels increasing across ovarian stimulation (P = 0.006) into pregnancy testing (P = 0.030). Follicular fluid free T3 levels were lower in levothyroxine-replaced women (median 4.3 vs 4.6 pmol/L, P = 0.032). Fertilisation rates were lower (52% vs 71%, P = 0.043) in women requiring levothyroxine replacement, but numbers of mature oocytes retrieved, early pregnancy loss and live births did not differ. CONCLUSION: Adequately replaced hypothyroid women achieve lower ovarian follicular fluid free T3 levels and poorer fertilisation rates compared to euthyroid women undergoing COH. Optimising T3 levels may be pivotal in improving COH outcomes in hypothyroid women.

Patent Foramen Ovale Closure in Older Patients With Stroke: Patient Selection for Trial Feasibility.

BACKGROUND AND OBJECTIVES: Whether patent foramen ovale (PFO) closure benefits older patients with PFO and cryptogenic stroke is unknown because randomized controlled trials (RCTs) have predominantly enrolled patients younger than 60 years of age. Our objective was to estimate anticipated effects of PFO closure in older patients to predict the numbers needed to plan an RCT. METHODS: Effectiveness estimates are derived from major observational studies (Risk of Paradoxical Embolism [RoPE] Study and Oxford Vascular Study, together referred to as the "RoPE-Ox" database) and all 6 major RCTs (Systematic, Collaborative, PFO Closure Evaluation [SCOPE] Consortium). To estimate stroke recurrence risk, observed outcomes were calculated for patients older than 60 years in the age-inclusive observational databases (n = 549). To estimate the reduction in the rate of recurrent stroke associated with PFO closure vs medical therapy based on the RoPE score and the presence of high-risk PFO features, a Cox proportional hazards regression model was developed on the RCT data in the SCOPE database (n = 3,740). These estimates were used to calculate sample sizes required for a future RCT. RESULTS: Five-year risk of stroke recurrence using Kaplan-Meier estimates was 13.7 (95% CI 10.5-17.9) overall, 14.9% (95% CI 10.2-21.6) in those with high-risk PFO features. Predicted relative reduction in the event rate with PFO closure was 12.9% overall, 48.8% in those with a high-risk PFO feature. Using these estimates, enrolling all older patients with cryptogenic stroke and PFO would require much larger samples than those used for prior PFO closure trials, but selectively enrolling patients with high-risk PFO features would require totals of 630 patients for 90% power and 471 patients for 80% power, with an average of 5 years of follow-up. DISCUSSION: Based on our projections, anticipated effect sizes in older patients with high-risk features make a trial in these subjects feasible. With lengthening life expectancy in almost all regions of the world, the utility of PFO closure in older adults is increasingly important to explore.

Left and right ventricular longitudinal systolic function following aortic valve replacement in the PARTNER 2 trial and registry.

AIMS: Evaluation of left and right ventricular (RV) longitudinal systolic function may enhance risk stratification following aortic valve replacement (AVR). The study objective was to evaluate the changes in left and RV longitudinal systolic function and RV-pulmonary artery (RV-PA) coupling from baseline to 30 days and 1 year after AVR. METHODS AND RESULTS: Left ventricular (LV) longitudinal strain (LS), tricuspid annulus plane systolic excursion (TAPSE), and RV-PA coupling were evaluated in patients from the PARTNER 2A surgical AVR (SAVR) arm (n = 985) and from the PARTNER 2 SAPIEN 3 registry (n = 719). TAPSE and RV-PA coupling decreased significantly following SAVR, but remained stable following TAVR. Lower LV LS, TAPSE, or RV-PA coupling at baseline was associated with increased risk of the composite of death, hospitalization, and stroke at 5 years [adjusted hazard ratios (HRs) for LV LS < 15%: 1.24, 95% confidence interval (CI) 1.05-1.45, P = 0.001; TAPSE < 14 mm: 1.44, 95% CI 1.21-1.73, P < 0.001; RV-PA coupling < 0.55 mm/mmHg: 1.32, 95% CI 1.07-1.63, P = 0.011]. Reduced TAPSE at baseline was the most powerful predictor of the composite endpoint at 5 years. Patients with LV ejection fraction <50% at baseline had increased risk of the primary endpoint with SAVR (HR: 1.34, 95% CI 1.08-1.68, P = 0.009) but not with TAVR (HR: 1.12, 95% CI 0.88-1.42). Lower RV-PA coupling at 30 days showed the strongest association with cardiac mortality. CONCLUSION: SAVR but not TAVR was associated with a marked deterioration in RV longitudinal systolic function and RV-PA coupling. Lower TAPSE and RV-PA coupling at 30 days were associated with inferior clinical outcomes at 5 years. In patients with LVEF < 50%, TAVR was associated with superior 5-year outcomes.

Angiogenic Gene Therapy for Refractory Angina: Results of the EXACT Phase 2 Trial.

BACKGROUND: XC001 is a novel adenoviral-5 vector designed to express multiple isoforms of VEGF (vascular endothelial growth factor) and more safely and potently induce angiogenesis. The EXACT trial (Epicardial Delivery of XC001 Gene Therapy for Refractory Angina Coronary Treatment) assessed the safety and preliminary efficacy of XC001 in patients with no option refractory angina. METHODS: In this single-arm, multicenter, open-label trial, 32 patients with no option refractory angina received a single treatment of XC001 (1×1011 viral particles) via transepicardial delivery. RESULTS: There were no severe adverse events attributed to the study drug. Twenty expected severe adverse events in 13 patients were related to the surgical procedure. Total exercise duration increased from a mean±SD of 359.9±105.55 seconds at baseline to 448.2±168.45 (3 months), 449.2±175.9 (6 months), and 477.6±174.7 (12 months; +88.3 [95% CI, 37.1-139.5], +84.5 [95% CI, 34.1-134.9], and +115.5 [95% CI, 59.1-171.9]). Total myocardial perfusion deficit on positron emission tomography imaging decreased by 10.2% (95% CI, -3.1% to 23.5%), 14.3% (95% CI, 2.8%-25.7%), and 10.2% (95% CI, -0.8% to -21.2%). Angina frequency decreased from a mean±SD 12.2±12.5 episodes to 5.2±7.2 (3 months), 5.1±7.8 (6 months), and 2.7±4.8 (12 months), with an average decrease of 7.7 (95% CI, 4.1-11.3), 6.6 (95% CI, 3.5-9.7), and 8.8 (4.6-13.0) episodes at 3, 6, and 12 months. Angina class improved in 81% of participants at 6 months. CONCLUSIONS: XC001 administered via transepicardial delivery is safe and generally well tolerated. Exploratory improvements in total exercise duration, ischemic burden, and subjective measures support a biologic effect sustained to 12 months, warranting further investigation. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04125732.