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Introduction: According to the World Health Organization (WHO), by 2050 at least 700 million people will need access to hearing care and hearing rehabilitation services. The search for cell or gene therapies has been intensifying, and stem cell therapy looks a promising candidate to support hearing regeneration and reduce these numbers. The aim of this study is to provide an overview of current advances in stem cell-based therapies for cochlear hair cell regeneration and the processes being developed for future applicability. Material and methods: Identification and review of all articles in the databases PubMed, Web of Science, and PLoS One using the terms stem cell, auditory hair cell regeneration, and mammalian during February 2023 and following the PRISMA guidelines. Results: 50 articles were obtained, published between 2003 and 2022 and were systematically analyzed. The current research quantity is limited and further studies are needed, particularly in human tissue. Conclusion: The simultaneous use of cell therapy and gene therapy may lead to more promising results. Moreover, advances in cochlear hair cell regeneration with stem cells suggest there is a realistic potential to make the technique a useful future therapy. [ABSTRACT FROM AUTHOR]

• Data from The French Cystic Fibrosis (CF) Registry and SNDS claims data were linked. • Healthcare resource use was lower before death than before lung transplantation (LT). • Some costs were lower before death than LT, particularly for CF treatments. • The study gathered key data on the total cost of LT in people with CF. We studied the health care resource utilization (HCRU) and associated costs in the year preceding LT in pwCF or death without LT, and we estimated the overall cost of LT. We performed a linkage between 2006 and 2017 data from the French CF Registry (FCFR) and the French health claims database (Système National des Données de Santé; SNDS). The HCRU and associated costs were described the year before LT or before death without LT, and two years after LT. Among the 7,671 patients included in the FCFR, 6,187 patients (80.7 %) were successfully matched to patients in the SNDS (males (m): 51.9 %, mean±SD age at the end of follow-up: 24.6 ± 13.6). Overall, 166 patients died without LT (m: 47.6 %, age at death: 30.4 ± 14.5) and 767 patients with primary LT (m: 48.2 %, age at transplantation: 28.0 ± 9.1) were identified. HCRU was lower among patients who died without receiving LT, with marked differences in the cost of hospital stays. The mean total cost per patient was €66,759 ± 38,249 in the year before death, €149,374 ± 62,678 in the year preceding LT, €63,919 ± 35,399 in the first year following LT, and €42,813 ± 39,967 in the second year of follow-up. Our results indicate that HCRU was two times lower in the year before death in non-transplant pwCF than in the year before LT, which may reflect inappropriate care of CF in patients who died without receiving LT. It also shows the cost associated with LT. [ABSTRACT FROM AUTHOR]

Since the first published report of experimental kidney transplantation in dogs in 1902, there were many experimental and clinical trials of organ transplantation, with many sacrifices. After the establishment of the surgical technique and the discovery of immunosuppressive drugs, transplantation became the definitive treatment strategy for patients with terminal organ failure. However, this is not a common therapy method due to the difficulty of solving the fundamental issues behind organ transplantation, including the shortage of donor graft, potential risks of transplant surgery and economic capability. The pre- and post-transplant management of recipients is another critical issue that may affect transplant outcome. Most liver transplant recipients experience post-transplant complications, including infection, acute/chronic rejection, metabolic syndrome and the recurrence of hepatocellular carcinoma. Therefore, the early prediction and diagnosis of these complications may improve overall and disease-free survival. Furthermore, how to induce operational tolerance is the key to achieving the ultimate goal of transplantation. In this review, we focus on liver transplantation, which is known to achieve operational tolerance in some circumstances, and the mechanical similarities and differences between liver transplant immunology and fetomaternal tolerance, autoimmunity or tumor immunity are discussed. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is a serious condition accompanied by severe adverse events that affect several aspects of the patient's life, such as motor, sensory, and functional impairment. Despite its severe consequences, definitive treatment for these injuries is still missing. Therefore, researchers have focused on developing treatment strategies aimed at ensuring full recovery post-SCI. Accordingly, attention has been drawn toward cellular therapy using mesenchymal stem cells. Considering their wide availability, decreased immunogenicity, wide expansion capacity, and impressive effectiveness in many therapeutic approaches, adipose-derived stem cell (ADSC) injections in SCI cases have been investigated and showed promising results. In this review, SCI pathophysiology and ADSC transplantation benefits are discussed independently, together with SCI animal models and adipose stem cell preparation and application techniques. The mechanisms of healing in an SCI post-ADSC injection, the outcomes of this therapeutic approach, and current clinical trials are also deliberated, in addition to the challenges and future perspectives, aiming to encourage further research in this field. [ABSTRACT FROM AUTHOR]

Simple Summary: Rhabdomyosarcoma of the extrahepatic and intrahepatic bile ducts is a rare location in children, and it poses a significant challenge for both oncologists and surgeons. Key elements of treatment where there are no clear guidelines include surgical treatment of RMS of the bile ducts, chemotherapy and radiotherapy. The authors wish to share the experience of a highly specialized center that has access to a wide range of therapeutic and treatment options, including the management approach and the outcomes achieved. We review cases treated at our center, discuss treatment approaches and outcomes and compare results with the existing literature and guidelines. Rhabdomyosarcoma (RMS) of the biliary tract is a rare tumor in children, constituting 0.5–0.8% of all pediatric RMS. Still, it is the most common malignancy in this location in children. Due to its rarity and location, it may cause diagnostic and treatment difficulties. Above all, there are no therapeutic guidelines specific for this tumor location. The aim of the study was to present an analysis of our experience with the treatment of children with biliary tract rhabdomyosarcoma (RMS) and discuss clinical recommendations for this specific location published in the literature. A retrospective analysis of medical records of eight children with biliary tree RMS treated in one center between 1996–2022 was performed. Records of eight children, five boys and three girls aged 2 yrs 6 mo to 16 yrs 9 mo (median—6 yrs) were analyzed. All patients presented with jaundice as the first symptom. In two patients, initial diagnosis of a tumor was established. For the remaining six, the primary diagnoses were as follows: choledochal cyst—one, malformation of the biliary ducts—one, choledocholithiasis—one, cholangitis—three. In four patients, the extrahepatic bile ducts were involved; in four patients, both the intrahepatic and extrahepatic bile ducts were involved. Embryonal RMS was diagnosed in seven patients (three botryoides type). Alveolar RMS was found in one patient. Biopsy (three surgical, four during endoscopic retrograde cholangiopancreatography (ERCP)) was performed in seven patients. One child underwent primary partial tumor resection (R2). Seven patients received neoadjuvant chemotherapy, followed by delayed resection in five, including liver transplantation in one (five were R0). Two patients did not undergo surgery. Radiotherapy was administered in four patients (two in first-line treatment, two at relapse/progression). Six patients (75%) are alive with no evidence of disease, with follow-up ranging from 1.2 yrs to 27 yrs (median 11 yrs. and 4 mo.). Two patients died from disease, 2 y 9 mo and 3 y 7 mo from diagnosis. Children presenting with obstructive jaundice should be evaluated for biliary tract RMS. The treatment strategy should include biopsy and preoperative chemotherapy, followed by tumor resection and radiotherapy for residual disease and in case of relapse. [ABSTRACT FROM AUTHOR]

Comprehensive infection prevention is crucial in transplantation, but current guidelines often lack comprehensive coverage. Transplantation patients are particularly susceptible to various infections, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), emerging and reemerging infections, in-hospital fungal infections, respiratory viral infections, and central line-associated bloodstream infection (CLABSI). These infections pose significant challenges and can lead to serious complications, and increased mortality rates in transplant recipients. Overall, preventing infections in transplantation patients requires a multidimensional approach, including strict adherence to infection control measures, surveillance programs, education and awareness campaigns, and tailored prevention strategies based on the specific risks and challenges faced by transplant recipients. In conclusion, the vital importance of infection prevention in transplant cases is emphasized. [ABSTRACT FROM AUTHOR]

Background Allogeneic hematopoietic stem cell transplant for myeloid neoplasms with increased fibrosis is uncommon; morphologic features posttransplant can be concerning for persistent disease. Methods In this retrospective study, we identified 22 patients transplanted for myeloproliferative neoplasms or chronic myelomonocytic leukemia with fibrosis at our institution, and reviewed slides from pretransplant and posttransplant bone marrow biopsies. Clinical features and results of molecular, chimerism, and cytogenetic studies were retrieved from the medical record. Results Pretransplant bone marrow biopsies commonly exhibited hypercellularity, atypical megakaryocytes, and reticulin fibrosis. At day 100, 36% of biopsies had reticulin grade >MF1 and 33% of those tested had positive molecular studies, with no significant associations between day 100 marrow characteristics and molecular profile or peripheral count recovery times. In the 1 year posttransplant biopsies (n = 12), 7 of 9 had negative molecular studies; of these, none had reticulin grade >MF1, 1 had trichrome 1+, 2 had atypical megakaryocytes, and 1 was hypercellular. Conclusions Supporting recent literature, our study indicates that persistent day 100 reticulin fibrosis/collagen deposition does not show an association with day 100 molecular status. Our study additionally provides data for 12 patients with 1 year posttransplant marrow biopsies, with the majority of those lacking either increased fibrosis or molecular evidence of persistent disease. [ABSTRACT FROM AUTHOR]

Organoids are small, self-organizing three-dimensional cell cultures that are derived from stem cells or primary organs. These cultures replicate the complexity of an organ, which cannot be achieved by single-cell culture systems. Organoids can be used in testing of new drugs instead of animals. Development and validation of organoids is thus important to reduce the reliance on animals for drug testing. In this review, we have discussed the developmental and regulatory aspects of organoids and highlighted their importance in drug development. We have first summarized different types of culture-based organoid systems such as submerged Matrigel, micro-fluidic 3D cultures, inducible pluripotent stem cells, and air-liquid interface cultures. These systems help us understand the intricate interplay between cells and their surrounding milieu for identifying functions of target receptors, soluble factors, and spatial interactions. Further, we have discussed the advances in humanized severe-combined immunodeficiency mouse models and their applications in the pharmacology of immune-oncology. Since regulatory aspects are important in using organoids for drug development, we have summarized FDA and EMA regulations on organoid research to support pre-clinical studies. Finally, we have included some unique studies highlighting the use of organoids in studying infectious diseases, cancer, and fundamental biology. These studies also exemplify the latest technological advances in organoid development resulting in improved efficiency. Overall, this review comprehensively summarizes the applications of organoids in early drug development during discovery and pre-clinical studies. [ABSTRACT FROM AUTHOR]

Racial disparities in pediatric kidney transplantation have been well described over the last two decades and include disparities in preemptive transplantation, waitlisting, time from activation to transplantation, living donation, and graft outcomes. Changes to the organ allocation system including the institution of Share 35 in 2005 and the Kidney Allocation System (KAS) of 2014 have resulted in resolution of some, but not all racial-ethnic disparities. Despite overall improvements in time from waitlist activation to transplant, disparities remain in preemptive transplantation, time to waitlisting, and living donor transplantation. Although improving under the KAS, racial disparities remain in graft survival as well. Racial disparity in kidney transplant access and graft survival is an international problem within pediatric nephrology. Although the racial group affected may differ, various minoritized pediatric groups across the world are affected by transplant disparities. Social determinants of health including financial access, language barriers, and the presence of a healthy living donor play a role in mediating these disparities. Further investigation is needed to better understand and intervene upon modifiable social, biological, and cultural factors driving the remaining disparity in transplant outcomes. [ABSTRACT FROM AUTHOR]

Background Kidney involvement is common in anti-neutrophil cytoplasm antibody–associated vasculitis (AAV) and the prognosis is determined by the severity of kidney damage. This study focused on long-term kidney outcomes, defining possible risk factors and comparing the performance of three different histological classifications to predict outcomes for patients with AAV. Methods The dataset included 848 patients with newly diagnosed AAV who participated in seven randomized controlled trials (RCTs) (1995–2012). Follow-up information was obtained from questionnaires sent to the principal investigators of the original RCTs. Results The cumulative incidence of end-stage kidney disease (ESKD) at 5 and 10 years was 17% and 22%, respectively. Patients who developed ESKD had reduced patient survival compared with those with preserved kidney function (hazard ratio 2.8, P  < .001). Comparing patients with AAV and kidney involvement with a matched general population, patients with AAV had poor survival outcomes, even in early stages of chronic kidney disease. The main cause of death was infection followed by cardiovascular disease in patients developing ESKD and malignancy in those who did not. Some 34% of patients with initial need for dialysis recovered kidney function after treatment. Thirty-five out of 175 in need of kidney replacement therapy (KRT) during follow-up received a kidney transplant with good outcome; there was 86% patient survival at 10 years. In the subcohort of 214 patients with available kidney biopsies, three scoring systems were tested: the Berden classification, the Renal Risk Score and the Mayo Clinic Score. The scores highlighted the importance of normal glomeruli and severe glomerulosclerosis on kidney survival (P  < .001 and P  = .001, respectively). The Renal Risk Score demonstrated a moderate prediction of kidney survival (area under the curve 0.79; standard error 0.03, 95% confidence interval 0.71–0.83). Conclusions Early diagnosis of AAV is extremely important. Even milder forms of kidney involvement have an impact on the prognosis. Patients in need of KRT had the lowest survival rates, but kidney transplantation has shown favorable outcomes for eligible AAV patients. The three histologic scoring systems were all identified as independent prognostic factors for kidney outcome. [ABSTRACT FROM AUTHOR]

Background: Posttransplant lymphoproliferative disorder (PTLD), a term that encompasses a wide array of malignancies that occur after transplant, can be one of the most devastating transplant complications. While there have been major advancements in care, especially after the landmark PTLD-1 trial in 2012, there is a paucity of information on hospitalizations for PTLD and the changes in hospitalizations over time. Methods: This retrospective cohort study used the National Inpatient Sample to identify hospitalizations for PTLD that occurred between 2009 and 2018. We extracted data for hospitalizations with a primary or secondary diagnosis of PTLD and examined a range of variables, including age, gender, race, hospital type, hospital location, and disposition status. We also collected data on hospital region, median household income, insurance status, and bed size. Results: There was a statistically significant increase in the number of hospitalizations from 2009 to 2019 and an increasing rate of hospitalizations over the study period. Hypertension, electrolyte imbalances, renal failure, and anemia were among the most common comorbidities. We found an increased mortality rate, but this was not statistically significant. Conclusion: Our study provides insight into the changes in hospitalizations for PTLD over nearly a decade, showing an increase in hospitalizations and reports of comorbidities. [ABSTRACT FROM AUTHOR]

Dr. Ron Jaffe, a renowned pediatric pathologist, was known for his exceptionalism, high standards, and compassion. Born in South Africa, he pursued a distinguished career in pathology, specializing in histiocytosis and solid-organ transplantation. Dr. Jaffe's legacy includes mentoring numerous trainees, contributing to over 250 publications, and playing a pivotal role in advancing the study of histiocytoses. His dedication to teaching and his witty sense of humor left a lasting impact on colleagues and friends in the field of pediatric pathology. [Extracted from the article]

Heart failure is one of the most important medical and social problems. Despite recent successes in the treatment of this disease, which have been achieved with guideline-recommended medical treatment, some patients become insensitive to the interventions. Refractoriness to treatment recommended by the guidelines means that patients cannot hope for symptom relief or prolongation of life. These individuals develop the phase of advanced heart failure and have the worst survival rates compared to other stages of chronic heart failure. In the absence of contraindications, heart transplantation is indicated for this group of patients. In the recent years, organ transplantation has been legalized and the work of cadaver donation institutions has been organized in Ukraine. These changes helped to significantly increase the annual number of heart transplantations in the country. The aim of the work is to systematize current knowledge about end-stage heart failure, to provide methods to timely diagnose advanced heart failure and indications for referral for heart transplantation. At least every tenth patient with heart failure may deteriorate to the advanced stage. The article details clinical trajectories of patients with heart failure, and a particular emphasis has been given to refractory patients in accordance with present guidelines and recommendations. The main pathophysiological links and corresponding clinical manifestations of advanced heart failure have been outlined. The problems of life expectancy prognosing and possible predictors of refractoriness to the treatment recommended by the guidelines have been discussed. Current diagnostic criteria for advanced heart failure have been specified, including physical, laboratory and imaging methods of examination. The principles of differential diagnosis, especially between symptomatic and advanced heart failure, have been considered. Triggers for referring patients to a heart transplant center have been detailed. Current guidelines for heart transplantation related to advanced heart failure have been given. Conclusions. Advanced heart failure is the progression of heart failure due to refractoriness to treatment. Diagnostic criteria for advanced heart failure have been developed relatively recently. This diagnosis requires an utmost understanding of pathophysiology and skills to examine cardiac patients using modern tools. Due to the extremely unfavorable prognosis, diagnosis of advanced heart failure is an absolute indication for referral to a heart transplant center. [ABSTRACT FROM AUTHOR]

Introduction: Regulations designed to protect children participating in clinical research often restrict the availability of research data necessary for the development of age-specific therapies and drug dosing. Few data exist on how children experience participation in clinical research, and studies investigating young children undergoing an intensive medical treatment are lacking. Methods: Mixed methods with semi-structured interviews and DISCO-RC questionnaires were used to explore young children's and their parents' experiences in clinical research participation during a kidney transplantation trajectory. Findings: Nine children and their parents were interviewed. Children's median age at kidney transplantation was 4 years (IQR 4,7); age at interview was 7 years (IQR 6,9). Thematic content analysis of interviews revealed that most children were unaware of having participated in a study. Both children and their parents frequently were unaware whether procedures were standard care or research related. The additional burden attributed to study participation varied from not at all to heavy in combination with intensive medical treatment. Positive experiences included kind healthcare professionals, effective distraction techniques, educational aspects, contributing to science and extra check-ups. Most reported negative experiences were conflicting communication, spending much time in the hospital, missing school and suboptimal planning. Venous puncture was stressful for all children, whereas the discomfort of other procedures varied. Conclusion: Pediatric clinical research design should focus on education and fun during research procedures, smart planning, consistent communication, close collaboration between clinical and research team and age appropriate distraction techniques. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Stem cell-derived islets (SC-islets) are being used as cell replacement therapy for insulin-dependent diabetes. Non-invasive long-term monitoring methods for SC-islet grafts, which are needed to detect misguided differentiation in vivo and to optimise their therapeutic effectiveness, are lacking. Positron emission tomography (PET) has been used to monitor transplanted primary islets. We therefore aimed to apply PET as a non-invasive monitoring method for SC-islet grafts. Methods: We implanted different doses of human SC-islets, SC-islets derived using an older protocol or a state-of-the-art protocol and SC-islets genetically rendered hyper- or hypoactive into mouse calf muscle to yield different kinds of grafts. We followed the grafts with PET using two tracers, glucagon-like peptide 1 receptor-binding [18F]F-dibenzocyclooctyne-exendin-4 ([18F]exendin) and the dopamine precursor 6-[18F]fluoro-l-3,4-dihydroxyphenylalanine ([18F]FDOPA), for 5 months, followed by histological assessment of graft size and composition. Additionally, we implanted a kidney subcapsular cohort with different SC-islet doses to assess the connection between C-peptide and stem cell-derived beta cell (SC-beta cell) mass. Results: Small but pure and large but impure grafts were derived from SC-islets. PET imaging allowed detection of SC-islet grafts even <1 mm3 in size, [18F]exendin having a better detection rate than [18F]FDOPA (69% vs 44%, <1 mm3; 96% vs 85%, >1 mm3). Graft volume quantified with [18F]exendin (r2=0.91) and [18F]FDOPA (r2=0.86) strongly correlated with actual graft volume. [18F]exendin PET delineated large cystic structures and its uptake correlated with graft SC-beta cell proportion (r2=0.68). The performance of neither tracer was affected by SC-islet graft hyper- or hypoactivity. C-peptide measurements under fasted or glucose-stimulated conditions did not correlate with SC-islet graft volume or SC-beta cell mass, with C-peptide under hypoglycaemia having a weak correlation with SC-beta cell mass (r2=0.52). Conclusions/interpretation: [18F]exendin and [18F]FDOPA PET enable non-invasive assessment of SC-islet graft size and aspects of graft composition. These methods could be leveraged for optimising SC-islet cell replacement therapy in diabetes. [ABSTRACT FROM AUTHOR]

Torque Teno Virus (TTV) is a non‐pathogenic anellovirus, highly prevalent in healthy populations. Variations in its viral load have been associated with states of diminished immunity, as occurs after organ transplantation. It is hypothesized that TTV‐load might be used as a diagnostic tool to guide prescription and dosing of immunosuppressive drugs. Not much is known about the effects of combined immunosuppressive drugs on TTV replication in renal transplantation. Belatacept was introduced to counter side‐effects of calcineurin inhibitors (CNI). It was never widely adopted, mainly because its association with increased risk of rejection. To investigate the differential effects of a regimen based on calcineurin inhibitors versus belatacept on TTV‐loads, we measured TTV‐levels in 105 patients from two randomized controlled trials in kidney transplant recipients (KTRs). We observed that time after transplantation was inversely related to TTV‐levels of patients that remained on a CNI‐containing regime, whereas this decline over time was diminished after conversion to belatacept. In addition, a correlation with tacrolimus‐trough levels and age were found. Our study is the first report on the impact of conversion from CNI to belatacept on TTV‐levels in KTR. In conclusion, the time‐related decline in TTV‐levels is mitigated after conversion from CNI to belatacept. [ABSTRACT FROM AUTHOR]

BACKGROUND: Ischemia-reperfusion injury (IRI) is a phenomenon that affects transplant survival. The aim of our study was to examine the effects of IRI in isogenic and allogeneic muscle and skin transplantation models exposed to prolonged warm ischemia. METHODS: Forty-eight Lewis rats and 16 Brown-Norway rats were used to create four groups: Isogenic Inguinal Flap Transplantation (IST), Isogenic Gastrocnemius Muscle Flap Transplantation (IMT), Allogeneic Inguinal Flap Transplantation (AST), and Allogeneic Gastrocnemius Muscle Flap Transplantation (AMT). Malonyldialdehyde (MDA) and superoxide dismutase (SOD) levels were measured on postoperative days 1, 7, 21, 35, 63, 100, and 120 in all groups. Donor-specific chimerism (DSC) in peripheral blood was evaluated in the allogeneic groups on postoperative days 7, 21, 35, 63, 100, and 120. The microRNA-21 and microRNA-205 levels were evaluated on postoperative days 1, 7, and 120 in all groups. At the end of the study, a histopathological examination was performed. RESULTS: A statistically significant difference was found between the groups in terms of MDA and SOD levels. DSC was detected in the AMT group. A significant increase in microRNA-205 was observed, especially in the AMT group. There was no significant difference in the number of functional muscle units between the muscle transplantation groups. CONCLUSION: The presence of DSC in the AMT group and the lack of a significant difference in the number of functional muscle units in the IMT and AMT groups are noteworthy findings. [ABSTRACT FROM AUTHOR]

Introduction: Heart transplantation is the standard treatment for severe heart failure. Graft preservation and infectious risk secondary to immunosuppressive drugs lead healthcare teams to offer nutritional advice to patients upon discharge from the hospital. However, no consensus or recommendation is available. Method: We conducted a study to review the practices in all 26 centers providing heart transplantation in French-speaking Europe. We requested and analyzed the written documents these centers provided to their patients. The same two dieticians categorized the highlighted pieces of advice into distinct, autonomous categories. Results: We identified 116 pieces of advice, categorized into three areas: dietary restrictions for immunosuppressant/food interaction; environmental and food preparation guidelines and prevention of foodborne infections; and healthy and active lifestyle recommendations. Except for advice on immunosuppressant/food interaction, over one-third of the centers suggest discontinuing advice within 2 years post-transplant. General dietary advice covers lipids, carbohydrates, protein, calcium, sodium, and fiber but offers limited guidance on fatty acids despite their importance in cardiovascular risk prevention. Conclusion: This study represents a pioneering exploration of the nutritional advice provided to patients following cardiac transplantation. It underscores the critical necessity of establishing consensus-based clinical guidelines in this domain. [ABSTRACT FROM AUTHOR]

Objective: To review the efficacy and safety of eculizumab for prevention and treatment of antibody-mediated rejection (AMR) in lung transplant recipients (LTRs). Data Sources: A literature search of PubMed and the Cochrane Controlled Trials Register (2007 to mid-October 2023) was performed using the following search terms: eculizumab, complement inhibitor, solid organ transplant, lung transplant, and AMR. Study Selection and Data Extraction: All relevant English-language studies were reviewed and considered. Data Synthesis: Eculizumab, a monoclonal antibody that binds complement protein C5 to inhibit its cleavage and subsequent generation of the membrane attack complex, is currently approved to treat paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, generalized myasthenia and neuromyelitis optica spectrum disorder. Given the role of antibodies directed against donor antigens that are produced by allospecific B-cells and plasma cells in AMR, eculizumab is being investigated for use within this indication. Three case reports have described the successful use of eculizumab for the prevention and treatment of AMR in LTRs. Given this lack of robust data, evidence for the use of eculizumab in other solid organ transplant recipients is of increased value. Early experiences from a single center's use of eculizumab in LTRs are also described. Relevance to Patient Care and Clinical Practice: Lung transplant is a recognized treatment for end-stage lung disease, though complications posttransplant can be associated with significant morbidity and mortality. While prevention and management of AMR remains a substantial challenge without comprehensive guidance from societal guidelines, recently published literature may be helpful to guide clinical practice using alternative treatment options. However, this remains an area of great clinical importance, given the impact of AMR on long-term allograft function. Conclusions: Optimizing use of current therapies, as well as identifying and advancing novel therapeutic modalities such as eculizumab, are vital for the improvement of AMR prevention and treatment in LTRs to extend long-term allograft function and survival. [ABSTRACT FROM AUTHOR]

The liver requires careful handling intra‐operatively owing to its vital functions and complexity. Traditional open hepatectomy, while standard, is invasive and requires long recovery periods. Laparoscopic hepatectomy is a less invasive option, with its own challenges. The rise of robotic surgery, such as the da Vinci® system, improves precision and control, addressing the limitations of conventional methods, but brings new concerns, such as costs and training. This review focuses on the latest advancements in robotic hepatectomy from 2022/23 articles, delving into topics like "robotic surgery in liver transplantation," "robotic hepatectomy for hilar cholangiocarcinoma," "robotic vascular reconstruction following hepatectomy," "robotic repeat hepatectomy," and "prospective trials in robotic hepatectomy." To retrieve articles, a focused literature search was conducted using PubMed for articles from 2022/23 with a 5‐year filter, excluding reviews. Initially, abstracts were screened, and relevant articles on robotic surgery were examined in full for inclusion in this review. Although all the above items are cutting‐edge, and many of the references are necessarily at the level of case reports, recent articles are still accompanied by surgical videos, which are useful to readers, especially surgeons who are considering imitating the procedures. In summary, we examined the recent advancements in robotic liver resection. The inclusion of videos that present new techniques aids in knowledge transfer. We anticipate the continued growth of this field of research. [ABSTRACT FROM AUTHOR]

Background: Situs inversus totalis is a rare congenital anomaly characterized by a mirror-image orientation of abdominal, and in some cases, thoracic organs. Here, we report our situs inversus totalis transplantation experience and further review liver transplantations in adult recipients and donors with situs inversus totalis. Case presentation: We describe three cases with situs inversus totalis. The first case was liver transplantation in a recipient (a 61-year-old Iranian man) with situs inversus totalis, the second was a liver transplantation from a donor (a 52-year-old Iranian woman) with situs inversus totalis, and finally, for the first time, a simultaneous pancreas and kidney transplantation in a recipient (a 26-year-old Iranian man) with situs inversus totalis. In patient one, hepatectomy could be performed according to the standard method and on the basis of preoperative studies. Hepatic vein and arterial anastomosis were performed as in every other patient without situs inversus totalis. To prevent biliary complications, a Roux-en-Y hepaticojejunostomy was performed. In patient two, implantation time, suprahepatic vein, portal vein, arterial, and biliary reconstruction could be done as in any other case without situs inversus totalis. Plication of the right-sided diaphragm and fixation of the falciform ligament was done for our patient. In patient three, systemic drainage was preferred to portal flow for establishing the outflow drainage of the pancreas compared with otherwise normal patients. Conclusion: Although situs inversus totalis is a rare condition, our reported techniques are suitable, considering advantages such as easier accessibility, more acceptable placement of the implanted organs regarding vascular variations, and the appropriate location of the allograft in the proximity of other organs. [ABSTRACT FROM AUTHOR]

BACKGROUND: The clinical application of human induced pluripotent stem cell--derived cardiomyocytes (CMs) for cardiac repair commenced with the epicardial delivery of engineered cardiac tissue; however, the feasibility of the direct delivery of human induced pluripotent stem cell--derived CMs into the cardiac muscle layer, which has reportedly induced electrical integration, is unclear because of concerns about poor engraftment of CMs and posttransplant arrhythmias. Thus, in this study, we prepared purified human induced pluripotent stem cell--derived cardiac spheroids (hiPSC-CSs) and investigated whether their direct injection could regenerate infarcted nonhuman primate hearts. METHODS: We performed 2 separate experiments to explore the appropriate number of human induced pluripotent stem cell--derived CMs. In the first experiment, 10 cynomolgus monkeys were subjected to myocardial infarction 2 weeks before transplantation and were designated as recipients of hiPSC-CSs containing 2107 CMs or the vehicle. The animals were euthanized 12 weeks after transplantation for histological analysis, and cardiac function and arrhythmia were monitored during the observational period. In the second study, we repeated the equivalent transplantation study using more CMs (6107 CMs). RESULTS: Recipients of hiPSC-CSs containing 2107 CMs showed limited CM grafts and transient increases in fractional shortening compared with those of the vehicle (fractional shortening at 4 weeks after transplantation [mean ± SD]: 26.2±2.1%; 19.3±1.8%; P<0.05), with a low incidence of posttransplant arrhythmia. Transplantation of increased dose of CMs resulted in significantly greater engraftment and long-term contractile benefits (fractional shortening at 12 weeks after transplantation: 22.5±1.0%; 16.6±1.1%; P<0.01, left ventricular ejection fraction at 12 weeks after transplantation: 49.0±1.4%; 36.3±2.9%; P<0.01). The incidence of posttransplant arrhythmia slightly increased in recipients of hiPSC-CSs containing 6107 CMs. [ABSTRACT FROM AUTHOR]

Tacrolimus, a calcineurin inhibitor, is a highly effective immunosuppressant used in solid organ transplantation (SOT). However, it is characterized by a narrow therapeutic range and high inter‐patient variability in pharmacokinetics. Standard weight‐based dosing followed by empiric dose titration is suboptimal in controlling drug concentrations, increasing risk of rejection or toxicity, particularly in the initial months post transplantation. This review explores the potential of combined pre‐transplant genotyping and pharmacokinetic (PK) modelling to improve tacrolimus dosing in paediatric SOT recipients. A systematic search of Medline, Embase and Cochrane databases identified studies published between March 2013 and March 2023 that investigated genotype‐ and PK model‐informed tacrolimus dosing in children post‐SOT. The Newcastle‐Ottawa Scale assessed study quality. Seven studies encompassing paediatric kidney, heart, liver and lung transplants reported using genotype and model‐informed dosing. A combination of clinical and genetic factors significantly impacts tacrolimus clearance and thus initial dose recommendation. Body size, transplant organ and co‐medications were consistently important, while either time post‐transplant or haematocrit emerged in some studies. Several models were identified, however, with limitations evident in some and with absence of evidence for their effectiveness in optimizing initial and subsequent dosing. This review highlights the development of PK models in paediatric SOT that integrate genotype and clinical covariates to personalize early tacrolimus dosing. While promising, prospective studies are needed to validate and confirm their effectiveness in improving time to therapeutic concentrations and reducing under‐ or overexposure. This approach has the potential to optimize tacrolimus therapy in paediatric SOT, thereby improving outcomes. [ABSTRACT FROM AUTHOR]

In 2016, the United Network for Organ Sharing revised its pediatric heart transplant (HT) allocation policy. This study sought to determine whether the 2016 revisions are associated with reduced waitlist mortality and capture patient-specific risks. Children listed for HT from 1999 to 2023 were identified using Organ Procurement and Transplantation Network data and grouped into 3 eras (era 1: 1999-2006; era 2: 2006-2016; era 3: 2016-2023) based on when the United Network for Organ Sharing implemented allocation changes. Fine-Gray competing risks modeling was used to identify factors associated with death or delisting for deterioration. Fixed-effects analysis was used to determine whether allocation changes were associated with mortality. Waitlist mortality declined 8 percentage points (PP) across eras (21%, 17%, and 13%, respectively; P < 0.01). At listing, era 3 children were less sick than era 1 children, with 6 PP less ECMO use (P < 0.01), 11 PP less ventilator use (P < 0.01), and 1 PP less dialysis use (P < 0.01). Ventricular assist device (VAD) use was 13 PP higher, and VAD mortality decreased 9 PP (P < 0.01). Non-White mortality declined 10 PP (P < 0.01). ABO-incompatible listings increased 27 PP, and blood group O infant mortality decreased 13 PP (P < 0.01). In multivariable analyses, the 2016 revisions were not associated with lower waitlist mortality, whereas VAD use (in era 3), ABO-incompatible transplant, improved patient selection, and narrowing racial disparities were. Match-run analyses demonstrated poor correlation between individual waitlist mortality risk and the match-run order. The 2016 allocation revisions were not independently associated with the decline in pediatric HT waitlist mortality. The 3-tier classification system fails to adequately capture patient-specific risks. A more flexible allocation system that accurately reflects patient-specific risks and considers transplant benefit is urgently needed. [ABSTRACT FROM AUTHOR]

Introduction: Peripheral blood stem cell (PBSC) donation is the primary procedure used to collect hematopoietic stem and progenitor cells (HSPCs) for hematopoietic stem cell transplantation. Single bouts of exercise transiently enrich peripheral blood with HSPCs and cytolytic natural killer cells (CD56dim), which are important in preventing post-transplant complications. To provide a rationale to investigate the utility of exercise in a PBSC donation setting (=3 h), this study aimed to establish whether interval cycling increased peripheral blood HSPC and CD56dim concentrations to a greater degree than continuous cycling. Methods: In a randomised crossover study design, eleven males (mean ± SD: age 25 ± 7 years) undertook bouts of moderate intensity continuous exercise [MICE, 30 min, 65%-70% maximum heart rate (HRmax)], high-volume high intensity interval exercise (HV-HIIE, 4 × 4 min, 80%-85% HRmax) and low-volume HIIE (LV-HIIE, 4 × 2 min, 90%-95% HRmax). The cumulative impact of each interval on circulating HSPC (CD34+CD45dimSSClow) and CD56dim concentrations (cells/µL), and the bone marrow homing potential of HSPCs (expression of CXCR-4 and VLA-4) were determined. Results: There was an increase in HSPC concentration after two intervals of LVHIIE (Rest: 1.84 ± 1.55 vs. Interval 2: 2.94 ± 1.34, P = 0.01) and three intervals of HV-HIIE only (Rest: 2.05 ± 0.86 vs. Interval 3: 2.51 ± 1.05, P = 0.04). The concentration of all leukocyte subsets increased after each trial, with this greatest for CD56dim NK cells, and in HIIE vs. MICE (LV-HIIE: 4.77 ± 2.82, HVHIIE: 4.65 ± 2.06, MICE: 2.44 ± 0.77, P < 0.0001). These patterns were observed for concentration, not frequency of CXCR-4+ and VLA-4+ HSPCs, which was unaltered. There was a marginal decrease in VLA-4, but not CXCR-4 expression on exercise-mobilised HSPCs after all trials (P < 0.0001). Discussion: The results of the present study indicate that HIIE caused a more marked increase in HSPC and CD56dim NK cell concentrations than MICE, with mobilised HSPCs maintaining their bone marrow homing phenotype. LV-HIIE evoked an increase in HSPC concentration after just 2 × 2-minute intervals. The feasibility and clinical utility of interval cycling in a PBSC donation context should therefore be evaluated. [ABSTRACT FROM AUTHOR]

Background: Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by diffuse, multifocal segmental narrowing of cerebral arteries and can result in ischaemic stroke. Causal factors, identified in 60% of cases, include immunosuppressant pharmacotherapy. The few reports following heart transplantation are almost all in Asian recipients. We report on a Caucasian Australian patient with immunotherapy induced RCVS post heart transplantation to highlight the state of knowledge of the condition and the treatment dilemma it poses. Case presentation: A 51-year-old female underwent orthotopic heart transplantation at our institution. Induction immunotherapy comprised basiliximab, mycophenolate mofetil and methylprednisolone. On day 6 post-transplantation the patient was transitioned to oral prednisolone and tacrolimus. On day 7 the patient began to experience bilateral, severe, transient occipital and temporal headaches. On day 9 tacrolimus dose was up-titrated. A non-contrast computed tomography brain (CTB) was normal. Endomyocardial biopsy on day 12 demonstrated moderate Acute Cellular Rejection (ACR), which was treated with intravenous methylprednisolone. That evening the patient experienced a 15-minute episode of expressive dysphasia. The following morning she became confused, aphasic, and demonstrated right sided neglect and right hemianopia. A CT cerebral perfusion scan demonstrated hypoperfusion in the left middle cerebral artery (MCA) territory and cerebral angiography revealed widespread, focal multi-segmental narrowing of the anterior and posterior circulations. A diagnosis of RCVS was made, and nimodipine was commenced. As both steroids and tacrolimus are potential triggers of RCVS, cyclosporin replaced tacrolimus and methylprednisolone dose was reduced. A further CTB demonstrated a large left MCA territory infarct with left M2 MCA occlusion. The patient made steady neurological improvement. She was discharged 34 days post-transplantation with mild residual right lower limb weakness and persistent visual field defect on verapamil, cyclosporine, everolimus, mycophenolate mofetil and prednisolone. Conclusion: Reversible cerebral vasoconstriction syndrome is rare after orthotopic heart transplantation. Until now, RCVS has been almost exclusively described in Asian recipients, and is typically caused by immunotherapy. The condition may lead to permanent neurological deficits, and in the absence of definitive treatments, early recognition and imaging based diagnosis is essential to provide the opportunity to remove the causal agent(s). Co-existent ACR, can pose unique treatment difficulties. [ABSTRACT FROM AUTHOR]

Posttransplant malignancies are an important complication of solid organ transplantation. Kidney transplant recipients are at particularly high risk of cancer development. The most relevant risk factors of carcinogenesis are the use of immunosuppressive agents and oncogenic viral infections. Additionally, immune dysregulation caused by these factors may predispose to various types of organ damage. Paraneoplastic glomerular diseases are one of the most interesting and understudied cancer manifestations. The appropriate diagnosis of paraneoplastic glomerular damage can be challenging in kidney transplant recipients, due to factors inherent to concomitant medication and common comorbidities. Recent advances in the field of molecular and clinical nephrology led to a significant improvement in our understanding of glomerular diseases and their more targeted treatment. On the other hand, introduction of novel anticancer drugs tremendously increased patients' survival, at the cost of kidney-related side effects. Our review aims to provide insights into diagnosis and treatment of paraneoplastic glomerular diseases, with a special attention to kidney transplant recipients. [ABSTRACT FROM AUTHOR]

Severe aplastic anemia (SAA) is a life-threatening bone marrow failure syndrome whose development can be triggered by environmental, autoimmune, and/or genetic factors. The latter comprises germ line pathogenic variants in genes that bring about habitually predisposing syndromes as well as immune deficiencies that do so only occasionally. One of these disorders is the autosomal dominant form of chronic mucocutaneous candidiasis (CMC), which is defined by germ line STAT1 gain-of-function (GOF) pathogenic variants. The resultant overexpression and constitutive activation of STAT1 dysregulate the Janus kinase/signal transducer and activator of transcription 1 (STAT) signaling pathway, which normally organizes the development and proper interaction of different components of the immunologic and hematopoietic system. Although SAA is an extremely rare complication in this disorder, it gained a more widespread interest when it became clear that the underlying causative pathomechanism may, in a similar fashion, also be instrumental in at least some of the idiopathic SAA cases. Based on these premises, we present herein what is the historically most likely first cord blood–transplanted SAA case in a CMC family with a documented STAT1 GOF pathogenic variant. In addition, we recapitulate the characteristics of the six CMC SAA cases that have been reported so far and discuss the significance of STAT1 GOF pathogenic variants and other STAT1 signaling derangements in the context of these specific types of bone marrow failure syndromes. Because a constitutively activated STAT1 signaling, be it driven by STAT1 GOF germ line pathogenic variants or any other pathogenic variant independent events, is apparently important for initiating and maintaining the SAA disease process, we propose to acknowledge that SAA is one of the definite disease manifestations in STAT1-mutated CMC cases. For the same reason, we deem it necessary to also incorporate molecular and functional analyses of STAT1 into the diagnostic work-up of SAA cases. [ABSTRACT FROM AUTHOR]

Axonopus compressus (Swartz) Beauv., a perennial herb in the Poaceae that has been introduced to a number of tropical and subtropical countries and regions, can serve as a lawn ground cover while its leaves can be developed as a bioenergy resource. It also displays some resistance to heavy metals, allowing it to be planted in areas and urban green spaces polluted by heavy metals. A. compressus is also used as a traditional Chinese medicine. This study is the first report on tissue culture of A. compressus. Stem explants induced shoot clusters on 6-benzyladenine (BA)-containing Murashige and Skoog (MS) medium, with 2.0 mg L–1 BA inducing a shoot proliferation coefficient (SPC) of 10.89 within 30 d, while MS medium containing 2.0 mg L–1 BA and 0.1 mg L–1 α-naphthaleneacetic acid (NAA) amplified SPC to 12.88 within 30 d. SPC on MS medium supplemented with kinetin (KIN) or thidiazuron (TDZ) was not as high as on medium with BA and never exceeded 3.57 within 30 d. A. compressus formed adventitious roots easily, within 15 d, most efficiently on ½MS medium supplemented with 0.1 to 0.5 mg L–1 IAA, NAA, or IBA, or even on auxin-free medium. Resulting plantlets displayed a high survival rate (> 98%) when transplanted to a substrate containing humus, or humus mixed with vermiculite or sand. Callus was also successfully induced from leaf sheaths on MS medium containing 1.0 mg L–1 2,4-dichlorophenoxyacetic acid, even more so when 1.15 g L–1l-proline was added. Induced callus was able to differentiate into adventitious shoots on MS medium with 0.1 to 0.5 mg L–1 KIN or BA. An efficient system of shoot proliferation, callus induction, and regeneration in A. compressus has been established. [ABSTRACT FROM AUTHOR]

Bartonella quintana is a louse-borne intracellular bacterium that remains a neglected cause of bacteremia, bacillary angiomatosis, and infective endocarditis among individuals experiencing poverty. In October 2023, Health Canada notified Canadian organ transplantation programs of an outbreak of donor-derived B quintana infection. From March to August 2023, 5 cases of donor-derived B quintana disease were acquired in Alberta, Canada, from 3 deceased donors who had experienced homelessness. Similar cases recently occurred in the United States. In this article, we discuss strategies to screen organ donors and monitor transplant recipients for B quintana infection using epidemiologic risk factors, physical examination signs, and laboratory diagnostic tests. We review the limitations of existing diagnostic tests for B quintana and describe how these problems may be magnified in the organ transplantation context. [ABSTRACT FROM AUTHOR]

Sources of autografts such as palmaris longus or plantaris are often limited or absent. We present our experience using a low donor-site morbidity method of harvesting strips of extensor carpi radialis brevis and longus (ECRB and ECRL) as free tendon autografts in upper extremity soft tissue reconstructions. Retrospective chart review identified five patients who received reconstructive upper extremity surgeries using ECRB and ECRL partial tendon autografts from January 2014 to October 2021 with at least a 12-month follow-up period. Mayo wrist scores were calculated to demonstrate clinical outcomes. All five patients (mean follow-up: 21 months) were able to return to regular activities while demonstrating improvements in 6- and 12-month postoperative Mayo wrist scores. There was minimal donor site morbidity and no ruptures of parent tendons following harvest. This study provides additional support for utilizing partial strips of ECRB and ECRL in repairing upper extremity tendon gap and ligament deformities. [ABSTRACT FROM AUTHOR]

OBJECTIVES Mechanical composite valve grafts (MCVGs) are the first-line therapy for aortic root replacement in young adults. Decellularized aortic homografts (DAH) present a promising novel alternative due to their lower thrombogenicity. We aimed to compare both treatment options regarding survival and valve-related adverse events. METHODS This study was designed as a single-centre retrospective cohort study including patients who underwent root replacement with MCVG or DAH between 2000 and 2022. Urgent or emergent procedures were excluded. RESULTS The study cohort included 289 patients (MCVG n  = 216, DAH n  = 73) with a mean age of 48.5 ± 12 years (MCVG 49 ± 12 years vs DAH 47 ± 11 years; P  = 0.23) and a median EuroScore II of 1.7% (1.2, 2.6). The 30-day mortality was 1% (n  = 3). Cumulative survival at 3 years was 99% for DAH and 94% for MCVG, respectively (P  = 0.15). Mean follow-up was 98.9 ± 72.7 months. Bleeding events (n  = 14, 6.5%) and thromboembolism (n  = 14, 6.5%) were only observed in the MCVG group (P  = 0.19 and 0.09, respectively). Four cases (5%) of moderate structural valve deterioration occurred, all in the DAH group (P  ≤ 0.001). The cumulative incidence of a composite end point of valve-related adverse events was significantly higher in the MCVG group (P  = 0.0295). CONCLUSIONS Aortic root replacement with MCVGs and decellularized aortic homografts showed low mortality in an elective setting. Patients in the homograft cohort demonstrated significantly higher freedom from valve-related adverse events. DAH present a promising treatment option for young patients requiring root replacement; however, data on long-term durability are needed. [ABSTRACT FROM AUTHOR]

OBJECTIVES Restrictive cardiomyopathy is rare and is generally associated with worse clinical outcomes compared to other cardiomyopathies. Ventricular assist device (VAD) support for these children is seldom applied and often hampered by the surgical difficulties. METHODS All paediatric (<19 years) patients with a restricted cardiomyopathy supported by a VAD from the EUROMACS database were included and compared to patients with a dilated cardiomyopathy (retrospective database analyses). Participating centres were retrospectively contacted to provide additional detailed echo and Swan Ganz measurements to analyse the effect of VAD support on pulmonary artery pressure and right ventricular function. RESULTS Forty-four paediatric VAD-supported patients diagnosed with restricted cardiomyopathy were included, with a median age at implantation of 5.0 years. Twenty-six of the 44 patient with a restricted cardiomyopathy survived to transplantation (59.1%), 16 died (36.4%) and 2 are still on ongoing VAD support (4.5%) after a median duration of support of 95.5 days (interquartile range 33.3–217.8). Transplantation probability after 1 and 2 years of VAD support in patients with a restricted cardiomyopathy were comparable to patients with a dilated cardiomyopathy (52.3% vs 51.4% and 59.5% vs 60.1%, P  = 0.868). However, mortality probability was higher in the restricted cardiomyopathy cohort (35.8% vs 17.0% and 35.8% vs 19.0%, P  = 0.005). Adverse event rates were high (cerebrovascular accident in 31.8%, pump thrombosis in 29.5%, major bleeding 25.0%, eventual biventricular support in 59.1%). In the atrially cannulated group, cerebrovascular accident and pump thrombosis occurred in twice as much patients (21.1% vs 40.0%, P  = 0.595 and 15.8% vs 40.0%, P  = 0.464; probably non-significant due to the small numbers). Pulmonary arterial pressures improved after implantation of a VAD, and 6 patients who were initially labelled as ineligible due to pulmonary hypertension could eventually be transplanted. CONCLUSIONS VAD support in children with a restricted cardiomyopathy is rarely performed. Mortality and adverse event rates are high. On the other hand, survival to cardiac transplantation was 59.1% with all patients surviving the 1st 30 days after cardiac transplantation. Pulmonary arterial pressures improved while on support, potentially making cardiac transplantation a viable option for previously ineligible children. [ABSTRACT FROM AUTHOR]

OBJECTIVES The use of ventricular assist devices (VADs) in children is increasing. However, absolute numbers in individual centres and countries remain small. Collaborative efforts such as the Paedi-European Registry for Patients with Mechanical Circulatory Support (EUROMACS) are therefore essential for combining international experience with paediatric VADs. Our goal was to present the results from the fourth Paedi-EUROMACS report. METHODS All paediatric (<19 years) patients from the EUROMACS database supported by a VAD were included. Patients were stratified into a congenital heart disease (CHD) group and a group with a non-congenital aetiology. End points included mortality, a transplant and recovery. Cox proportional hazard models were used to explore associated factors for mortality, cerebrovascular accident and pump thrombosis. RESULTS A total of 590 primary implants were included. The congenital group was significantly younger (2.5 vs 8.0 years, respectively, P  < 0.001) and was more commonly supported by a pulsatile flow device (73.5% vs 59.9%, P  < 0.001). Mortality was significantly higher in the congenital group (30.8% vs 20.4%, P  = 0.009) than in the non-congenital group. However, in multivariable analyses, CHD was not significantly associated with mortality [hazard ratio (HR) 1.285; confidence interval (CI) 0.8111–2.036, P  = 0.740]. Pump thrombosis was the most frequently reported adverse event (377 events in 132 patients; 0.925 events per patient-year) and was significantly associated with body surface area (HR 0.524, CI 0.333–0.823, P  = 0.005), CHD (HR 1.641, CI 1.054–2.555, P  = 0.028) and pulsatile flow support (HR 2.345, CI 1.406–3.910, P  = 0.001) in multivariable analyses. CONCLUSIONS This fourth Paedi-EUROMACS report highlights the increasing use of paediatric VADs. The patient populations with congenital and non-congenital aetiologies exhibit distinct characteristics and clinical outcomes. [ABSTRACT FROM AUTHOR]

Objective: To comprehensively summarize the existing evidence on the effectiveness of vaginal microbiota transplantation (VMT) in treating vaginal dysbiosis (VD) and bacterial vaginosis (BV). Methods: Following the PRISMA-ScR guidelines, a scoping review was conducted through October 10, 2023, using the databases PubMed, Embase, Scopus, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang, SinoMed, Weipu (VIP), ClinicalTrials.gov and the Chinese clinical trial registry. Results: A total of 12 studies were included, of which 7 were published (comprising 3 human and 4 animal studies), and 5 were ongoing registered trials (human). Of the published human studies involving 36 women, one focused on VD, and two investigated BV. These studies reported that VMT restored the Lactobacillus-dominated vaginal microbiota, alleviating symptoms. In animal studies with 145 female rats or mice, VMT was explored for one case of VD and three cases of BV, demonstrating a reduction in the expression of IL-1β and TNF-α. Additionally, two of the animal studies also indicated an increase in the number of Lactobacilli following VMT. The ongoing registered trials involved 556 women, with two focusing on VD and three targeting BV. Conclusions: VMT shows promise in restoring the Lactobacillus-dominated vaginal microbiota among women with VD or BV. Moreover, animal studies have indicated an increase in the number of Lactobacilli and a decrease in the expression of IL-1β and TNF-α following VMT. Ongoing registered trials are expected to provide comprehensive evidence regarding the efficacy of VMT. [ABSTRACT FROM AUTHOR]

Background: Methylmalonic Aciduria (MA) without homocystinuria (or isolated MA) is a group of rare inherited metabolic disorders which leads to the accumulation of methylmalonic acid (MMA), a toxic molecule that accumulates in blood, urine, and cerebrospinal fluid, causing acute and chronic complications including metabolic crises, acute kidney injury (AKI), and chronic kidney disease (CKD). Detailed Case Description: Herein, we report a case of a 39-year-old male with MA and stage IV CKD who experienced acute metabolic decompensation secondary to gastrointestinal infection. The patient underwent a single hemodialysis (HD) session to correct severe metabolic acidosis unresponsive to medical therapy and to rapidly remove MMA. The HD session resulted in prompt clinical improvement and shortening of hospitalization. Discussion: MMA accumulation in MA patients causes acute and life-threatening complications, such as metabolic decompensations, and long-term complications such as CKD, eventually leading to renal replacement therapy (RRT). Data reported in the literature show that, overall, all dialytic treatments (intermittent HD, continuous HD, peritoneal dialysis) are effective in MMA removal. HD, in particular, can be useful in the emergency setting to control metabolic crises, even with GFR > 15 mL/min. Kidney and/or liver transplantations are often needed in MA patients. While a solitary transplanted kidney can be rapidly affected by MMA exposure, with a decline in renal function even in the first year of follow-up, the combined liver–kidney transplantation showed better long-term results due to a combination of reduced MMA production along with increased urinary excretion. Conclusions: Early diagnosis, multidisciplinary management and preventive measures are pivotal in MA patients to avoid recurrent AKI episodes and, consequently, to slow down CKD progression. [ABSTRACT FROM AUTHOR]

Retinal degeneration (RD) is a leading cause of blindness worldwide and includes conditions such as retinitis pigmentosa (RP), age-related macular degeneration (AMD), and Stargardt's disease (STGD). These diseases result in the permanent loss of vision due to the progressive and irreversible degeneration of retinal cells, including photoreceptors (PR) and the retinal pigment epithelium (RPE). The adult human retina has limited abilities to regenerate and repair itself, making it challenging to achieve complete self-replenishment and functional repair of retinal cells. Currently, there is no effective clinical treatment for RD. Stem cell therapy, which involves transplanting exogenous stem cells such as retinal progenitor cells (RPCs), embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and mesenchymal stem cells (MSCs), or activating endogenous stem cells like Müller Glia (MG) cells, holds great promise for regenerating and repairing retinal cells in the treatment of RD. Several preclinical and clinical studies have shown the potential of stem cell-based therapies for RD. However, the clinical translation of these therapies for the reconstruction of substantial vision still faces significant challenges. This review provides a comprehensive overview of stem/progenitor cell-based therapy strategies for RD, summarizes recent advances in preclinical studies and clinical trials, and highlights the major challenges in using stem/progenitor cell-based therapies for RD. [ABSTRACT FROM AUTHOR]

Large osteochondral defects are a major challenge in orthopedics, for which osteochondral allograft (OCA) transplantation is nowadays considered as an option, especially in young patients. However, a major issue with OCA is the need for graft storage, which ensures adequate cartilage integrity over time. The aim of this study was to test how long a Ringer‐based storage solution can provide good graft quality after explantation and thus meet the requirements for OCA. For this purpose, human osteochondral allografts of the knee and ankle were analyzed. Live/Dead analysis was performed and glycosaminoglycan, as well as hydroxyproline content, were measured as crucial chondrocyte integrity factors. Furthermore, biomechanical tests focusing on stress relaxation and elastic compression modulus were performed. The critical value of 70% living chondrocytes, which corresponds to a number of 300 cells/mm², was reached after an average of 16 weeks of storage. In addition, a constant cell shrinkage was observed over time. The amount of glycosaminoglycan and hydroxyroline showed a slight and constant decrease over time, but no significant differences when compared from Day 0 to the values at Weeks 40–43. Biomechanical testing also revealed no significant differences at the different time points. Therefore, the results show that the Ringer‐based storage solution at 4°C is able to provide a chondrocyte survival of 70% until Week 16. This is comparable to previously published storage solutions. Therefore, the study contributes to the establishment of a Ringer‐based osteochondral allograft transplantation system for countries where medium‐based storage solution cannot be approved. [ABSTRACT FROM AUTHOR]

On 24 January 2023, Eurotransplant has introduced the virtual crossmatch for kidney and pancreas allocation as a better alternative for the physical Complement Dependent Cytotoxicity (CDC) crossmatches at the donor centre, which were associated with a longer cold ischaemia time and false positive reactions. For the time being, the physical CDC crossmatch at the recipient centre will remain in place as the final histocompatibility check. While Eurotransplant is certainly not the first organ allocation organisation to introduce virtual crossmatching, several novel aspects have been introduced, such as calculation of the virtual panel reactive antibody (vPRA) on 11 loci at the second‐field level in addition to the serological broad and split level, electronic HLA typing data transmission using Histoimmunogenetics Markup Language (HML) file format, and the actual virtual crossmatch based on ambiguous, second‐field HLA typing of the donor on all 11 loci. This short communication will focus on these novel aspects of the virtual crossmatch in Eurotransplant. [ABSTRACT FROM AUTHOR]

Background: An increasing number of pediatric solid organ transplant (SOT) recipients are surviving into adolescence and young adulthood. The transition from pediatric to adult‐oriented care occurs during a unique and vulnerable period. Methods: Presented here is a structured approach to healthcare transition (HCT) for adolescent and young adult SOT recipients aimed at optimizing independence in order to assist young patients with adherence, self‐management, and improved quality of life. Results: Close attention must be paid to neurocognitive development, mental well‐being, and social determinants of health. Conclusions: These efforts require a multidisciplinary team approach as well as collaboration between pediatric and adult providers in order to achieve these goals and patient longevity. [ABSTRACT FROM AUTHOR]

Damage to the central nervous system (CNS) often leads to irreversible neurological deficits, and there are currently few effective treatments available. However, recent advancements in regenerative medicine have identified CNS organoids as promising therapeutic options for addressing CNS injuries. These organoids, composed of various neurons and supporting cells, have shown potential for direct repair at injury sites. CNS organoids resemble the structure and function of actual brain tissue, which allows them to adapt and function well within the physiological environment when transplanted into injury sites. Research findings suggest that CNS organoids can replace damaged neurons, form new neural connections, and promote neural recovery. This review highlights the emerging benefits, evaluates preclinical transplantation outcomes, and explores future strategies for optimizing neuroregeneration using CNS organoids. With continued research and technological advancements, these organoids could provide new hope for patients suffering from neurological deficits. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a condition in the brain that is marked by a gradual and ongoing reduction in memory, thought, and the ability to perform simple tasks. AD has a poor prognosis but no cure yet. Therefore, the need for novel models to study its pathogenesis and therapeutic strategies is evident, as the brain poorly recovers after injury and neurodegenerative diseases and can neither replace dead neurons nor reinnervate target structures. Recently, mesenchymal stem cells (MSCs), particularly those from the human olfactory mucous membrane referred to as the olfactory ecto-MSCs (OE-MSCs), have emerged as a potential avenue to explore in modeling AD and developing therapeutics for the disease due to their lifelong regeneration potency and facile accessibility. This review provides a comprehensive summary of the current literature on isolating OE-MSCs and delves into whether they could be reliable models for studying AD pathogenesis. It also explores whether healthy individual-derived OE-MSCs could be therapeutic agents for the disease. Despite being a promising tool in modeling and developing therapies for AD, some significant issues remain, which are also discussed in the review. [ABSTRACT FROM AUTHOR]

Purpose: Kidney transplantation has a survival benefit for people with human immunodeficiency virus (HIV) and end‐stage kidney disease, however increased rates of rejection remain an issue. Questions remain regarding the impact of induction immunosuppression therapy and antiretroviral (ARV) choice on long‐term outcomes. Methods: We performed a multicenter retrospective analysis of outcomes in recipients with HIV who received kidneys from donors without HIV transplanted between 2004 and 2019. The association between induction and ARV regimens and long‐term outcomes including rejection, graft, and recipient survival over 5 years was investigated using Cox regression modeling. Results: Seventy‐eight kidney transplants (KT) performed in 77 recipients at five US transplant centers were included, with median follow up of 7.1 (4.3–10.7) years. Overall recipient and graft survival were 83% and 67%, respectively. Rejection occurred in 37% (29/78). Recipients with rejection were more likely to be younger, recipients of deceased donor organs, and Black. Receipt of rabbit anti‐thymocyte globulin (rATG) induction without protease‐inhibitor (PI)‐based ARVs was associated with 83% lower risk of rejection (adjusted hazard ratio (aHR) 0.17 (95% CI 0.05–0.63), p =.007) and a non‐statistically significantly lower risk of graft failure (aHR 0.18 (0.03–1.16), p =.07) when compared to those who received other induction and ARV combinations. Conclusions: In this multicenter retrospective study, we found a trend toward lower rejection and improved graft survival among those who received both rATG for induction and PI‐sparing ARVs. [ABSTRACT FROM AUTHOR]

The aim of our study was to determine whether granzyme B-expressing regulatory B cells (GZMB+ B cells) are enriched in the blood of transplant patients with renal graft tolerance. To achieve this goal, we analysed two single-cell RNA sequencing (scRNAseq) datasets: (1) peripheral blood mononuclear cells (PBMCs), including GZMB+ B cells from renal transplant patients, i.e., patients with stable graft function on conventional immunosuppressive treatment (STA, n = 3), drug-free tolerant patients (TOL, n = 3), and patients with antibody-mediated rejection (ABMR, n = 3), and (2) ex-vivo-induced GZMB+ B cells from these groups. In the patient PBMCs, we first showed that natural GZMB+ B cells were enriched in genes specific to Natural Killer (NK) cells (such as NKG7 and KLRD1) and regulatory B cells (such as GZMB, IL10, and CCL4). We performed a pseudotemporal trajectory analysis of natural GZMB+ B cells and showed that they were highly differentiated B cells with a trajectory that is very different from that of conventional memory B cells and linked to the transcription factor KLF13. By specifically analysing GZMB+ natural B cells in TOLs, we found that these cells had a very specific transcriptomic profile associated with a reduction in the expression of HLA molecules, apoptosis, and the inflammatory response (in general) in the blood and that this signature was conserved after ex vivo induction, with the induction of genes associated with migration processes, such as CCR7, CCL3, or CCL4. An analysis of receptor/ligand interactions between these GZMB+/− natural B cells and all of the immune cells present in PBMCs also demonstrated that GZMB+ B cells were the B cells that carried the most ligands and had the most interactions with other immune cells, particularly in tolerant patients. Finally, we showed that these GZMB+ B cells were able to infiltrate the graft under inflammatory conditions, thus suggesting that they can act in locations where immune events occur. [ABSTRACT FROM AUTHOR]

Background Advanced age has been widely identified as a risk factor for recurrent Clostridioides difficile infection (CDI), but most related studies were performed before the introduction of novel therapies. The aim of this study was to compare CDI characteristics and outcomes in patients over and under 80 years old with CDI and their outcomes in the era of new treatments. Methods This was a retrospective cohort study of patients diagnosed with CDI from January 2021 to December 2022 in an academic hospital. We compared recurrence and mortality at 12 weeks after the end of treatment. An extension of the Fine and Grey model adjusted for competing events was used to assess the effect of age on recurrence. Results Four hundred seventy-six patients were considered to have CDI (320 in patients <80 years and 156 in ≥80 years). CDI in older patients was more frequently healthcare-associated and was more severe. Although the Charlson index was almost identical between populations, comorbidities clearly differed. New treatments (bezlotoxumab, fidaxomicin and faecal microbiota transplantation) were more frequently used in older patients without statistical significance (41.3% vs. 33.4%, P  = .053). There were 69 (14.5%) recurrences, with no differences by age group after adjusting for competing events. Mortality was greater in the oldest (35.3%) than in the youngest (13.1%); P  < .001. Conclusions No differences in CDI recurrence rates were found between age groups. However, there was a high mortality rate in patients ≥80 years old, which emphasises the urgent need to improve the prevention and treatment of CDI in this group. [ABSTRACT FROM AUTHOR]

Purpose To review the composition, preparation, proposed mechanism of action, safety, efficacy, and current place in therapy of Rebyota (fecal microbiota, live-jslm). Summary As the first agent in a new class of drugs, live biotherapeutic products (LBPs), fecal microbiota, live-jslm offers another therapeutic approach for the prevention of recurrent Clostridioides difficile infection (rCDI). LBPs are given following antibiotic therapy for C. difficile to reintroduce certain bacteria present in the normal microbiome, as a means to reconstitute the microbiome of infected individuals. This review provides a summary of phase 2 and 3 clinical trials, product information, discussion of data limitations, and recommendations for place in therapy. High efficacy rates compared to placebo with sustained response up to 24 months after administration have been reported. The majority of adverse events identified were mild to moderate without significant safety signals. Conclusion Fecal microbiota, live-jslm has consistently been shown in randomized trials to be safe and effective in reducing rCDI. Its approval marks the culmination of decades of work to identify, characterize, and refine the intestinal microbiome to create pharmaceutical products. [ABSTRACT FROM AUTHOR]

We reviewed the cardiac surgical literature for 2023. PubMed displayed almost 34,000 hits for the search term "cardiac surgery AND 2023." We used a PRISMA approach for a results-oriented summary. Key manuscripts addressed the mid- and long-term effects of invasive treatment options in patient populations with coronary artery disease (CAD), comparing interventional therapy (percutaneous coronary intervention [PCI]) with surgery (coronary artery bypass graft [CABG]). The literature in 2023 again confirmed the excellent long-term outcomes of CABG compared with PCI in patients with left main stenosis, specifically in anatomically complex chronic CAD, but even in elderly patients, generating further support for an infarct-preventative effect as a prognostic mechanism of CABG. For aortic stenosis, a previous trend of an early advantage for transcatheter (transcatheter aortic valve implantation [TAVI]) and a later advantage for surgical (surgical aortic valve replacement) treatment was also re-confirmed by many studies. Only the Evolut Low Risk trial maintained an early advantage of TAVI over 4 years. In the mitral and tricuspid field, the number of interventional publications increased tremendously. A pattern emerges that clinical benefits are associated with repair quality, making residual regurgitation not irrelevant. While surgery is more invasive, it currently generates the highest repair rates and longest durability. For terminal heart failure treatment, donor pool expansion for transplantation and reducing adverse events in assist device therapy were issues in 2023. Finally, the aortic diameter related to adverse events and technical aspects of surgery dominated in aortic surgery. This article summarizes publications perceived as important by us. It cannot be complete nor free of individual interpretation, but provides up-to-date information for patient-specific decision-making. [ABSTRACT FROM AUTHOR]

Based on a voluntary registry, founded by the German Society for Thoracic and Cardiovascular Surgery (DGTHG) in 1980, a well-defined but limited dataset of all cardiac and vascular surgery procedures performed in 77 German heart surgery departments is reported annually. For the year 2023, a total of 168,841 procedures were submitted to the registry. Of these operations, 100,606 are defined as heart surgery procedures in a classical sense. The unadjusted in-hospital survival rate for the 28,996 isolated coronary artery bypass grafting procedures (relationship on-/off-pump 2.8:1) was 97.6%; 97.7% for the 39,859 isolated heart valve procedures (23,727 transcatheter interventions included); and 99.2% for 19,699 pacemaker/implantable cardioverter defibrillator procedures. Concerning short and long-term mechanical circulatory support, a total of 2,982 extracorporeal life support/extracorporeal membrane oxygenation implantations and 772 ventricular assist device implantations (left/right ventricular assist device, BVAD, total artificial heart) were reported. In 2023, 324 isolated heart transplantations, 248 isolated lung transplantations, and 2 combined heart–lung transplantations were performed. This annually updated registry of the DGTHG represents nonrisk adjusted voluntary public reporting and encompasses acute data for nearly all heart surgical procedures in Germany. It constitutes trends in heart medicine and represents a basis for quality management (e.g., benchmark) for all participating institutions. [ABSTRACT FROM AUTHOR]

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Recognizing the limitations of current therapies for Addison's disease, novel treatments that replicate dynamic physiologic corticosteroid secretion, under control of ACTH, are required. The aim of these experiments was to evaluate the feasibility of adrenocortical cell transplantation (ACT) in a large animal model, adapting methods successfully used for intracutaneous pancreatic islet cell transplantation, using a fully biodegradable temporizing matrix. Autologous porcine ACT was undertaken by bilateral adrenalectomy, cell isolation, culture, and intracutaneous injection into a skin site preprepared using a biodegradable temporizing matrix (BTM) foam. Hydrocortisone support was provided during adrenocortical cell engraftment and weaned as tolerated. Blood adrenocortical hormone concentrations were monitored, and the transplant site was examined at endpoint. Outcome measures included cellular histochemistry, systemic hormone production, and hydrocortisone independence. Transplanted adrenocortical cells showed a capability to survive and proliferate within the intracutaneous site and an ability to self-organize into discrete tissue organoids with features of the normal adrenal histologic architecture. Interpretation of systemic hormone levels was confounded by the identification of accessory adrenals and regenerative cortical tissue within the adrenal bed postmortem. Corticosteroids were unable to be completely ceased. ACT in a large animal model has not previously been attempted, yet it is an important step toward clinical translation. These results demonstrate rhe potential for ACT based on the development of adrenal organoids at the BTM site. However, the inability to achieve clinically relevant systemic hormone production suggests insufficient function, likely attributable to insufficient cells through delivered dose and subsequent proliferation. [ABSTRACT FROM AUTHOR]