Enhanced Costimulation Blockade With αCD154, αCD2, and αCD28 to Promote Heart Allograft Tolerance in Nonhuman Primates.

Background: Long-term renal allograft acceptance has been achieved in macaques using a transient mixed hematopoetic chimerism protocol, but similar regimens have proven unsuccessful in heart allograft recipients unless a kidney transplant was performed simultaneously. Here, we test whether a modified protocol based on targeting CD154, CD2, and CD28 is sufficient to prolong heart allograft acceptance or promote the expansion of regulatory T cells.

Methods: Eight macaques underwent heterotopic allo-heart transplantation from major histocompatibility complex-mismatched donors.

Early Renal Outcomes Following Heart Transplantation Using Organs Procured After Circulatory Death.

Background: Transplantation using hearts obtained through donation after circulatory death (DCD) is increasing, but data on recipient renal outcomes are limited.

Methods And Results: Patients at a single institution who underwent heart transplantation using organs procured through DCD or donation after brain death (DBD) from April 2016 to August 2022 were included in this retrospective cohort study. Hemodynamic measures were collected via right heart catheterization performed 1 week after transplantation.

Extended survival of 9- and 10-gene-edited pig heart xenografts with ischemia minimization and CD154 costimulation blockade-based immunosuppression.

Background: Xenotransplantation has made significant advances recently using pigs genetically engineered to remove carbohydrate antigens, either alone or with addition of various human complement, coagulation, and anti-inflammatory ''transgenes''. Here we evaluated results associated with gene-edited (GE) pig hearts transplanted in baboons using an established costimulation-based immunosuppressive regimen and a cold-perfused graft preservation technique.

Methods: Eight baboons received heterotopic abdominal heart transplants from 3-GE (GalKO.

Novel Imaging Technologies for Accurate Assessment of Cardiac Allograft Performance.

Purpose Of The Review: The current lack of objective and quantitative assessment techniques to determine cardiac graft relative viability results in risk-averse decision-making, which negatively impact the utilization of cardiac grafts. The purpose of this review is to highlight the current deficiencies in cardiac allograft assessment before focusing on novel cardiac assessment techniques that exploit conventional and emerging imaging modalities, including ultrasound, magnetic resonance, and spectroscopy.

Recent Findings: Extensive work is ongoing by the scientific community to identify improved objective metrics and tools for cardiac graft assessment, with the goal to safely increasing the number and proportion of hearts accepted for transplantation.

Research opportunities and ethical considerations for heart and lung xenotransplantation research: A report from the National Heart, Lung, and Blood Institute workshop.

Xenotransplantation offers the potential to meet the critical need for heart and lung transplantation presently constrained by the current human donor organ supply. Much was learned over the past decades regarding gene editing to prevent the immune activation and inflammation that cause early organ injury, and strategies for maintenance of immunosuppression to promote longer-term xenograft survival. However, many scientific questions remain regarding further requirements for genetic modification of donor organs, appropriate contexts for xenotransplantation research (including nonhuman primates, recently deceased humans, and living human recipients), and risk of xenozoonotic disease transmission.

Pediatric Cardiac Xenotransplantation: Recommendations for the Ethical Design of Clinical Trials.

For children with complex congenital heart problems, cardiac allotransplantation is sometimes the best therapeutic option. However, availability of hearts for pediatric patients is limited, resulting in a long and growing waitlist, and a high mortality rate while waiting. Cardiac xenotransplantation has been proposed as one therapeutic alternative for neonates and infants, either in lieu of allotransplantation or as a bridge until an allograft becomes available.

NSAID use in orthopedic surgery: A review of current evidence and clinical practice guidelines.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a valuable class of medications for orthopedic surgeons and often play a pivotal role in pain control. However, there are many common stipulations resulting in avoidance of its use in the treatment of musculoskeletal disease. This review summarizes the mechanism of action of NSAIDs as well as provides an overview of commonly used NSAIDs and the differences between them.

Antibody-mediated rejection in xenotransplantation: Can it be prevented or reversed?

Antibody-mediated rejection (AMR) is the commonest cause of failure of a pig graft after transplantation into an immunosuppressed nonhuman primate (NHP). The incidence of AMR compared to acute cellular rejection is much higher in xenotransplantation (46% vs. 7%) than in allotransplantation (3% vs.

Increased human complement pathway regulatory protein gene dose is associated with increased endothelial expression and prolonged survival during ex-vivo perfusion of GTKO pig lungs with human blood.

Introduction: Expression of human complement pathway regulatory proteins (hCPRP's) such as CD46 or CD55 has been associated with improved survival of pig organ xenografts in multiple different models. Here we evaluate the hypothesis that an increased human CD46 gene dose, through homozygosity or additional expression of a second hCPRP, is associated with increased protein expression and with improved protection from injury when GTKO lung xenografts are perfused with human blood.

Methods: Twenty three GTKO lungs heterozygous for human CD46 (GTKO.

Recruited macrophages elicit atrial fibrillation.

Atrial fibrillation disrupts contraction of the atria, leading to stroke and heart failure. We deciphered how immune and stromal cells contribute to atrial fibrillation. Single-cell transcriptomes from human atria documented inflammatory monocyte and macrophage expansion in atrial fibrillation.

Dominant follicle growth patterns and associated endocrine dynamics in anovulatory and ovulatory waves in women.

Growth patterns and associated endocrine profiles were compared between dominant anovulatory (ADF) and ovulatory follicles (OvF) developing from different waves within and between menstrual cycles in women. Follicular mapping profiles of 49 healthy women of reproductive age and blood samples were obtained every 1-3 days. Sixty-three dominant follicles were classified into wave 1 (W1ADF; n = 8) and wave 2 (W2ADF; n = 6) anovulatory follicles and wave 2 (W2OvF; n = 33) and wave 3 (W3OvF; n = 16) ovulatory follicles.

A novel system for rapid conversion of Gardner embryo grades to linear scale numeric variables.

Research Question: Can Gardner embryo grades be converted to numeric interval variables to improve the incorporation of embryo grading in statistical analyses?

Design: An equation that can be used to convert Gardner embryo grades to regular interval scale variables was developed: the numerical embryo quality scoring index (NEQsi). The NEQsi system was then validated with a retrospective chart analysis assessing IVF cycles (n = 1711) conducted at a single Canadian fertility centre between 2014 and 2022. Gardner embryo grades on file were assigned using EmbryoScope and converted to NEQsi scores.

TNX-1500, a crystallizable fragment-modified anti-CD154 antibody, prolongs nonhuman primate cardiac allograft survival.

Blockade of the CD40/CD154 T cell costimulation pathway is a promising approach to supplement or replace current clinical immunosuppression in solid organ transplantation. We evaluated the tolerability and activity of a novel humanized anti-CD154 monoclonal antibody, TNX-1500 (TNX), in a nonhuman primate heterotopic cardiac allogeneic (allo) transplant model. TNX-1500 contains a rupluzimab fragment antigen-binding region and an immunoglobin G4 crystallizable fragment region engineered to reduce binding to the crystallizable fragment gamma receptor IIa and associated risks of thrombosis.

A randomized double-blind controlled proof-of-concept study of alanyl-glutamine for reduction of post-myomectomy adhesions.

Study Objective: To test the hypothesis that intraperitoneal instillation of a single bolus dose of l-alanyl-l-glutamine (AG) will reduce the incidence, extent and/or severity of adhesions following myomectomy and establish preliminary safety and tolerability of AG in humans.

Design: Phase 1,2 Randomized, double-blind, placebo-controlled study (DBRCT).

Setting: Tertiary care gynecology surgical centre.

TNX-1500, a crystallizable fragment-modified anti-CD154 antibody, prolongs nonhuman primate renal allograft survival.

The blockade of the CD154-CD40 pathway with anti-CD154 monoclonal antibody has been a promising immunomodulatory approach to prevent allograft rejection. However, clinical trials of immunoglobulin G1 antibodies targeting this pathway revealed thrombogenic properties, which were subsequently shown to be mediated by crystallizable fragment (Fc)-gamma receptor IIa-dependent platelet activation. To prevent thromboembolic complications, an immunoglobulin G4 anti-CD154 monoclonal antibody, TNX-1500, which retains the fragment antigen binding region of ruplizumab (humanized 5c8, BG9588), was modified by protein engineering to decrease Fc binding to Fc-gamma receptor IIa while retaining certain other effector functions and pharmacokinetics comparable with natural antibodies.

Guidelines and principles for the care of the cardiothoracic transplant patient in the intensive care unit.

Heart and lung transplant recipients require care provided by clinicians from multiple different specialties, each contributing unique expertise and perspective. The period the patient spends in the intensive care unit is one of the most critical times in the perioperative trajectory. Various organizational models of intensive care exist, including those led by intensivists, surgeons, transplant cardiologists, and pulmonologists.

Milestones on the path to clinical pig organ xenotransplantation.

Progress in pig organ xenotransplantation has been made largely through (1) genetic engineering of the organ-source pig to protect its tissues from the human innate immune response, and (2) development of an immunosuppressive regimen based on blockade of the CD40/CD154 costimulation pathway to prevent the adaptive immune response. In the 1980s, after transplantation into nonhuman primates (NHPs), wild-type (genetically unmodified) pig organs were rejected within minutes or hours. In the 1990s, organs from pigs expressing a human complement-regulatory protein (CD55) transplanted into NHPs receiving intensive conventional immunosuppressive therapy functioned for days or weeks.

Future of Lung Transplantation: Xenotransplantation and Bioengineering Lungs.

Xenotransplantation promises to alleviate the issue of donor organ shortages and to decrease waiting times for transplantation. Recent advances in genetic engineering have allowed for the creation of pigs with up to 16 genetic modifications. Several combinations of genetic modifications have been associated with extended graft survival and life-supporting function in experimental heart and kidney xenotransplants.

Identification of prescription opioid misuse and abuse behaviors and risk factors in chronic pain patients using the Prescription Opioid Misuse and Abuse Questionnaire (POMAQ).

Objectives: To identify patient risk factors associated with prescription opioid misuse and abuse as well as groupings of misuse and abuse behaviors as measured by the Prescription Opioid Misuse and Abuse Questionnaire (POMAQ).

Methods: Adults with chronic pain requiring long-term treatment with opioids completed the POMAQ and other study questionnaires. Latent class analysis (LCA) was used to examine underlying subgroups exhibiting particular risk profiles.

Ethics and Theoretical Issues in Kidney Xenotransplantation.

Xenotransplantation has seen recent global interest peak as a result of several clinical xenotransplants being performed in decedents and a live cardiac recipient. However, underpinning these latest transplants have been decades of invested scientific research programs that have been developing the ideal donor source animals to avoid the overwhelming hyperacute xenograft rejection seen using nongenetically modified animal organs, tissues, and cells. However, this also needs to be undertaken along with the development of safe and efficacious xenotransplantation technologies, immunosuppression, monitoring, disease screening, patient selection, societal education, and acceptance.