Transplantation Group Research Articles

Effects of Nighttime Procurement and Transplantation on Outcomes Following Heart Transplantation.

This study evaluates the effects of nighttime procurement and transplantation on outcomes following heart transplantation. The UNOS registry was queried to analyze adult recipients who underwent isolated orthotopic heart transplantation between January 1, 2010, and September 30, 2022. The cohort was stratified into daytime (4 am-8 pm) and nighttime (8 pm-4 am) transplant groups. The primary outcome was 1-year survival. Propensity score-matching was performed. Risk adjustment was performed using multivariable Cox regression. Restricted cubic spline was used to model the association between the time of transplantation and the likelihood of 1-year mortality. Sub-analysis was performed to evaluate the impact of nighttime procurement. Altogether 30 426 recipients were analyzed, where 10 807 recipients (35.5%) underwent nighttime transplantation. The nighttime recipients had reduced 1-year post-transplant survival compared to the daytime recipients (90.6%vs. 91.5%, p = 0.019), and this lower survival persisted in the propensity score-matched comparison. After adjusting for established predictors for post-transplant mortality, nighttime transplantation continued to have a significantly increased risk of 1-year mortality (hazard ratio [HR] 1.12, 95% confidence interval [CI] 1.03-1.21, p = 0.005). The spline model demonstrated increased odds of 1-year mortality between 5 pm and 4 am, with the highest odds at 11 pm (odds ratio [OR] 1.25, 95% CI 1.07-1.47), compared to the reference transplantation time of 7 am. When assessing the impact of procurement timing, nighttime procurement negatively impacted 1-year post-transplant survival among the daytime recipients. This study demonstrates the adverse impact of nighttime heart procurement and transplantation on early post-transplant survival. With emerging organ perfusion and thermal protection systems, additional studies are warranted to assess the safety of extending the heart preservation period to optimize the timing of transplantation.

P-400. Surgical Site Infections among Heart Transplant, Lung Transplant, and VAD Inserted Patients

Abstract Background Surgical site infections (SSI) after heart and lung transplantation and implantation of Ventricular Assist Devices (VAD) confer significant morbidity. Despite this, many sites do not perform routine surveillance of this population. Considering the paucity of available data, this retrospective chart review evaluated the incidence, risk factors, associated microorganisms, and outcomes associated with surgical site infection by type of transplant received. Methods This review was conducted at a tertiary care hospital in Edmonton, Alberta. All patients who received a heart or lung transplant or VAD insertion between July 1, 2022, and December 31, 2023, that had at least 90 days of follow-up were included. Information collected included data on transplant/VAD insertion, age, sex, presence of SSI, microorganisms associated with infection, length of stay, and outcome. Other data collected included receipt of antibiotic prophylaxis, admission to hospital in the six months prior to transplant, and surgery in the six months prior to transplant. Results A total of 219 patients were included in the review (double lung transplant = 104, heart transplant = 38 and VAD insertion = 77) SSI rate was found to be higher in the VAD insertion group (16%), compared to lung (12.5%) or heart transplant (7.8%) recipients. Post-transplant hospital stay was longer in lung transplant (17-131; median 55) and heart transplant recipients (81-115; median 112) who developed SSI, compared to their counterparts who did not develop SSI (12-197; median 32 and 13-120; median 20 respectively). Coagulase-negative staphylococcus aureus was found to be the most common pathogen among all three groups of transplants that developed surgical site infections (SSIs). However, Cutibacterium acne was also frequently isolated in VAD recipients, while Yeast, E. fecalis and E. feceium were commonly found to be responsible for lung transplant SSIs. Conclusion Rates of SSI after heart and lung transplantation and VAD insertion are high and result in significant morbidity. The choice of antibiotic prophylaxis may need to be individualized in this patient population given prior antibiotic exposure, hospitalization, and risk of more resistant pathogens. Disclosures All Authors: No reported disclosures

381. Transplantation of Maternal Intestinal Flora to the Newborn After Elective Cesarean Section - A Randomized Controlled Trial (SECFLOR)

Abstract Background Normal microbial colonization process from the mother to the newborn is disrupted by birth by caesarean section (CS). We assess, whether in CS-delivered infants, the intestinal microbiome could be successfully and safely normalized by postnatal oral transfer of maternal fecal microbiome (FMT). In this double-blinded randomized controlled trial started in autumn 2019, we assess the difference in heterogeneity of the intestinal microbiome between the two groups from birth to 24 months of age. The randomization code was opened in March 2024 when last transplanted child turned one year of age. Primary outcome measures are assessed from samples collected at 3 months of age. Methods 90 healthy pregnant women scheduled for elective CS were recruited. After screening and randomization, within two hours of delivery, 31 newborns were given 3.5 mg of the transplant from their own mothers or placebo mixed in mother’s milk. The children are followed for 24 months. Stool and blood samples from the child and mother are collected during the follow up and analyzed for changes in microbiome heterogeneity between the groups and to assess, for example, immunological changes associated with the transfer. Results All mothers were asymptomatic, no prescribed courses of antibiotics or travelling history outside the European Union region within three months of screening. 38 had positive findings in screening tests. 31 infants were included in the study of whom 15 received the transplant and 16 placebo. 3 adverse events were reported in the transplant group: one infant had thrombocytopenia at the age of two days, which normalized within one week. One infant was diagnosed with bilateral grade one intraventricular hemorrhage at the age of two weeks. One infant was treated for transient tachypnea of the newborn after receiving the transplant. None of the adverse events were considered related to the transplant. Conclusion In our proof-of-concept study we previously demonstrated the effectiveness and safety of our protocol. The immunology and microbiota samples (fecal and blood) of our first-of-a-kind randomized controlled trial are being analyzed and first results will be available in September 2024. Disclosures All Authors: No reported disclosures

GDF11 restores the impaired function of EPCs-MA by promoting autophagy: GDF11 ameliorates endothelial progenitor cell aging by promoting autophagy

Abstract Objective Our study aimed to assess the effects of Growth and differentiation factor 11 (GDF11) on the function of endothelial progenitor cells in middle-age individuals (EPCs-MA) isolated from mouse bone marrow and to explore the mechanistic relationship between GDF11 and age-related ALP impairment. Methods Bone marrow-derived EPCs were isolated, culture and GDF11 treatment. In vivo, the mice model of myocardial ischemia (MI) was induced by permanent ligation of the left anterior descending coronary artery (LAD) and mice were randomly divided into MI group and EPCs transplantation group (EPCs-Y, EPCs-MA, EPCs-MA/GDF11). The positive effect of GDF11 treatment of EPCs-MA on MI was verified by echocardiography and the average ratio of fibrotic area to left ventricular (LV) area. In vitro, the effect of GDF11 on ameliorating EPCs aging by promoting autophagy was confirmed by transwell assay, immunofluorescence staining, characterization of EPCs ultrastructure through transmission electron microscope (TEM), lysosome imaging and Western blot. Result Our findings demonstrate that GDF11 enhances the migration capacity of EPCs-MA and improves recovery of impaired cardiac function after myocardial infarction (MI) in mice, with EPCs isolated from young mice (EPCs-Y) as controls. Moreover, GDF11 restored functional phenotypes of EPCs-MA to levels akin to EPCs-Y, promoting the expression of CD31, endogenous NO synthase, and the restoration of von Willebrand factor (vWF) and CDH5 expression patterns, as well as the formation of Weibel-Palade bodies—key organelles for storage and secretion in endothelial cells and EPCs. Furthermore, GDF11 significantly enhanced the autophagic clearance capability of EPCs-MA by promoting ALP. Conclusions Our results suggest that GDF11 ameliorates cardiac function impairment by restoring the activities of EPCs from aging mice through enhanced ALP. These findings suggest that GDF11 may hold therapeutic potential for improving aging-related conditions associated with declined autophagy.

Effects of rumen fluid transplantation on the fecal flora of yaks

IntroductionThere are few studies on the effect of rumen fluid transplantation on the fecal flora of yaks. Yak fecal flora is closely related to their health. This study aimed to evaluate the effects of rumen fluid transplantation on growth performance and fecal flora indicators.MethodsTwenty 6-month healthy male yaks (weight: 57.20 ± 7.80 kg) were selected from grazing yaks in an alpine meadow pasture at an altitude of approximately 3,400 m. They were then transferred to a farm and randomly divided into a control group (CON; n = 10) and a rumen fluid transplantation group (RT; n = 10). Separate single-pen rearing was performed in two pens using the same rearing environment and feeding method, and all yaks were earmarked for identification. In addition, 10 yaks that had been adapted to stall fattening feed in 1 month were selected as the rumen fluid donor group to provide fresh rumen fluid. Ruminal fluid transplantation trials were conducted on the 1st, 3rd, and 5th weeks. Overall, 1 L of ruminal fluid was transplanted to each yak in the RT and CON groups. The formal trial then began with both groups fed the same diet. After this, yak feed intake was recorded daily; yaks were weighed on days 1, 30, and 60 of the formal trial; and yak feces were collected directly from the ground on days 1, 4, 7, 14, 30, and 60 to compare the microbial composition of the feces using 16S rRNA sequencing data.ResultsThe results showed that rumen fluid transplantation significantly increased the alpha diversity of fecal microflora (P < 0.05), and on day 30 of the experiment, both the operational taxonomic unit (OTU) and Shannon index were significantly higher in the RT group than the CON group (P < 0.05). In the principal coordinate analysis (PCoA) plot, the intestinal flora of the RT group was significantly different (P < 0.05) on days 1–7 but not significantly different after day 14. In contrast, the intestinal flora of the CON group was significantly different (P < 0.05) on days 1–14 but not significantly different after day 30. Compared with the CON group, the relative abundance of Firmicutes in the RT group was significantly lower on days 1, 4, 7, and 14 (P < 0.05); the relative abundance of Bacteroidetes in the RT group was significantly higher on days 1, 4, 14, and 30 and significantly lower on day 7 (P < 0.05); the relative abundance of Tenericutes in the RT group was significantly higher on day 30 (P < 0.05); the relative abundance of Actinobacteria in the RT group was significantly higher on day 60 (P < 0.05); the relative abundance of Ruminococcaceae_UCG-005 in the RT group was significantly lower on days 4, 7, 14, and 60 (P < 0.05); the relative abundance of Unidentified in the RT group was significantly higher on days 1, 4, and 7 days (P < 0.05); and the relative abundance of Rikenellaceae_RC9_gut_group, Bacteroides, and Christensenellaceae_R-7_group in the RT group was significantly higher on day 1 (P < 0.05). Moreover, Actinobacteria was positively correlated with ADG and negatively correlated with DMI; Tenericutes was positively correlated with weight and negatively correlated with F/G. Metabolism of terpenes and polyketones, metabolism of other amino acids, and energy metabolism were higher in the RT group than in the CON group. LEfSe analysis showed that 32 species were more abundant in the RT group and 11 in the CON group. In conclusion, our findings suggest that rumen fluid transplantation improved the stability of the intestinal tract of yaks, improved the immunity of yaks, and reduced the occurrence of intestinal diseases; rumen fluid transplantation remodeled the structure of the intestinal flora, shortened the time of remodeling the intestinal flora of yaks during the transition period, and accelerated yak adaptation to digest housed rations, reducing the DMI. The findings of this study provide new insights into yak microbial community transplantation and a reference for improving feed efficiency in the yak industry.

Hospice Referral Rate Disparities of American Indian/Alaska Native Kidney Transplant Recipients with End-Stage Kidney Disease: A Retrospective Cohort Analysis.

American Indian/Alaska Native (AI/AN) persons disproportionately suffer from end-stage kidney disease caused by diabetes (ESKD-D). Kidney transplant is the most desirable option to treating ESKD-D, but remains unattainable for many AI/AN persons, especially in rural South Dakota (SD). Additionally, palliative and hospice care options for AI/AN with any serious illness in SD are largely inaccessible. Moreover, receiving kidney transplant potentially affects hospice referral because of the desire to prolong transplant function. Therefore, the purpose of this study was to compare hospice use rates among AI/AN and non-Hispanic White (NHW) persons with ESKD-D prior to death and determine if differences in referral rates are present for those with and without a prior kidney transplant. Retrospective cohort analysis of United States Renal Data System data from 2000-2021. Data for persons with hospice care, transplant status, place of death, and race were analyzed using chi-squared tests with Yates' continuity correction and the Cochran-Mantel-Haenszel test. AI/AN persons with ESKD-D were less likely to receive hospice care prior to death compared to NHW persons in both transplant (P < 0.001) and non-transplant (P < 0.001) groups. When comparing transplant and non-transplant groups by hospice use, persons with no previous transplant were more likely to receive hospice care prior to death (P < 0.001). These results confirm the assumptions of significant differences in hospice care use among AI/AN vs NHW who have ESKD-D, including differences between those with a prior transplant. There is a need to expand palliative/hospice care services for persons with a prior kidney transplant.

The Diurnal Variation in Mitochondrial Gene in Human Type 2 Diabetic Mesenchymal Stem Cell Grafts.

The application of regenerative therapy through stem cell transplantation has emerged as a promising avenue for the treatment of diabetes mellitus (DM). Transplanted tissue homeostasis is affected by disturbances in the clock genes of stem cells. The aim of this study is to investigate the diurnal variation in mitochondrial genes and function after transplantation of adipose-derived mesenchymal stem cells (T2DM-ADSCs) from type 2 diabetic patients into immunodeficient mice. Diurnal variation in mitochondrial genes was assessed by next-generation sequencing. As a result, the diurnal variation in mitochondrial genes showing troughs at ZT10 and ZT22 was observed in the group transplanted with adipose-derived mesenchymal stem cells derived from healthy individuals (N-ADSC). On the other hand, in the group transplanted with T2DM-ADSCs, diurnal variation indicative of troughs was observed at ZT18, with a large phase and amplitude deviation between the two groups. To evaluate the diurnal variation in mitochondrial function, we quantified mitochondrial DNA copy number using the Human mtDNA Monitoring Primer Set, measured mitochondrial membrane potential using JC-1, and evaluated mitophagy staining. The results showed a diurnal variation in mitochondrial DNA copy number, mitophagy, mitochondrial membrane potential, and NF-kB signaling in the N-ADSC transplant group. In contrast, no diurnal variation was observed in T2DM-ADSC transplants. The diurnal variation in mitochondrial function revealed in this study may be a new marker for the efficiency of T2DM-ADSC transplantation.

Disease-specific complaints among multiple myeloma patients treated with chemotherapy, autotransplantation and supportive therapy in Poland: a cross-sectional study

Due to its course, multiple myeloma may negatively affect the functioning of patients. Different treatment methods are also associated with patients’ varying perception of their health condition. The purpose of this study is to determine the disease-specific complaints among multiple myeloma patients during selected treatment methods—chemotherapy, autologous hematopoietic stem cell transplantation, and supportive therapy. The study group included 246 patients (98 in the chemotherapy group, of which 87 in the autologous hematopoietic stem cell transplantation group and 61 in the supportive therapy group). The study was conducted between August 2020 and December 2021 with the EORTC QLQ-MY20 questionnaire. According to the study results, patients treated with chemotherapy had the highest degree of disease symptom severity and side effects of treatment as well as the lowest assessment of their perspectives for the future. Patients who received supportive treatment had the lowest degree of disease symptom severity and side effects of treatment, and also assessed their body image and future perspectives the highest. Women assessed their future perspectives significantly lower than men. The severity of disease symptoms experienced by patients increases with age.

Mitochondrial transplantation normalizes transcriptomic and proteomic shift associated with ischemia reperfusion injury in neonatal hearts donated after circulatory death

Heart transplantation remains the ultimate treatment strategy for neonates and children with medically refractory end-stage heart failure and utilization of donors after circulatory death (DCD) can expand th donor pool. We have previously shown that mitochondrial transplantation preserves myocardial function and viability in neonatal swine DCD hearts to levels similar to that observed in donation after brain death (DBD). Herein, we sought to investigate the transcriptomic and proteomic pathways implicated in these phenotypic changes using ex situ perfused swine hearts. Pathway analysis showed that ATP binding, voltage-gated K channel activity involved in cardiac cell muscle contraction and ribosomal RNA biogenesis were upregulated in the mitochondrial transplantation group, while mitochondria were the predicted source. Promotion of ribosome biogenesis and downregulation of apoptosis were the overlapping mechanisms between transcriptomic and proteomic alterations. Moreover, we showed that mitochondrial transplantation modulates ischemic transcriptomic and proteomic profiles to that of non-ischemia through the mitochondria. Replication of these findings in human in vivo experiments is warranted.

Prevalence of aortoiliac aneurysms in solid organ transplant recipients using the National Inpatient Sample database.

Single-center studies have suggested that solid organ transplant recipients are at increased risk for arterial aneurysms. Moreover, they describe a more aggressive natural history with increased rates of expansion and rupture. In this exploratory analysis, we aimed to assess the frequency of arterial aneurysms in solid organ transplant recipients using a large-scale national database. We queried the National Inpatient Sample dataset from 2016 to 2020 using International Classification of Disease, Tenth Revision, Clinical Modification codes to identify patients with solid organ transplants. We calculated the prevalence of aortoiliac aneurysms by organ transplant type and performed one:one propensity score matching to compare aneurysm rates between transplant recipients and nontransplant patients. Additionally, we used a multivariable model to determine whether the observed aneurysm frequency was due to the transplant intervention or attributable to variable baseline characteristics of the groups. A retrospective analysis of the National Inpatient Sample database identified 34,920,964 nontransplant patients and 34,288 transplant recipients. Among the transplant cohort, kidney transplant recipients made up the largest group at 57.5%. The median age of the transplant group was 55years, with a predominance of male patients and a low smoking rate of 2.19%. The overall frequency of aortoiliac aneurysms in the transplant population was 0.48%. Specifically, the prevalence of thoracic aortic aneurysms, abdominal aortic aneurysms, and iliac artery aneurysms was 0.2%, 0.19%, and 0.06%, respectively. Thoracic organ transplant recipients had a higher frequency of aortoiliac aneurysms compared with those with abdominal organ transplants. The frequencies of aortoiliac aneurysms were 0.81% in heart transplant recipients, 1.37% in single lung recipients, 0.91% in double lung recipients, 0.42% in liver recipients, and 0.42% in kidney recipients. Additionally, the frequency of abdominal aortic aneurysms was 0.42% in heart transplant recipients and 0.51% in single lung transplant recipients. As transplant patient survival continues to improve, monitoring for comorbid conditions will become increasingly important. Given the limited availability of organs and importance of post-transplant care, the observed prevalence of aortoiliac aneurysms in heart, lung, and liver transplant recipients highlights the need for enhanced screening and surveillance. Further studies are required to better understand the rates of aneurysm expansion and rupture in solid organ transplant recipients.

Correlation between obstructive sleep apnea and serum markers HIF-1, IL-6 and iNOS after lung transplantation.

To analyze the correlation between obstructive sleep apnea (OSA) and hypoxia-inducible factor (HIF)-1, interleukin (IL)-6 and inducible nitric oxide synthase (iNOS) in patients complicated with OSA after lung transplantation. To identify serum markers of OSA after lung transplantation. We retrospectively selected patients who planned to undergo lung transplantation between 2018 and 2020, including 25 without OSA before lung transplantation (group A), 20 with OSA after lung transplantation (group B), and 15 patients without OSA after lung transplantation (group C). Sleep monitoring was performed, general information collection and hematological samples were collected. HIF-1, IL-6 and iNOS were detected by ELISA. Group B were older [59.2 ± 10.1 (B) vs. 49.8 ± 15.1 (A), 58.2 ± 3.3 (C), yrs.], had a bigger neck circumference [38.1 ± 4.7 (B) vs. 34.6 ± 4.2 (A),35.7 ± 4.2 (C), cm], and a greater abdominal circumference [88.2 ± 12.5 (B) vs. 76.2 ± 7.9 (A), 82.5 ± 6.5 (C), cm] compared with Groups A and C (P < 0.05). iNOS in group B (4784.8 ± 1365.2 (B) vs. 1925.2 ± 1868.5 (A), 2838.7 ± 3015.5 (C), pg/mL) was significantly increased compared to groups A and C (P < 0.05). iNOS was positively correlated with AHI. iNOS is significantly increased in OSA after lung transplantation, and maybe an important indicator of OSA.

The Safety and Late Hemodynamics of Donor Cardiac Undersizing in Heart Transplantation.

Predicted heart mass ratio (PHMr) has become the standard donor-recipient size matching method in heart transplantation. While utilization of small PHMr hearts is associated with increased one-year mortality, the underlying mechanisms and time horizon of mortality remain uncertain. A single institution analysis of isolated heart transplant recipients (01/2019-7/2022) was performed (N=334). Patients were stratified by PHMr: undersized (<0.86) (n=106), matched (0.86-1.15) (n=175), and oversized (>1.15) (n=53). Survival within PHMr groups was further stratified: complex transplant group (preoperative LVAD, adult congenital, or preoperative ECMO) and non-complex transplant group (all others). Donor and recipient variables were similar. However, undersized patients were more likely to have a durable LVAD (P=0.022). While postoperative PGD and inotrope score were similar between groups, there was a trend toward increased postoperative dialysis need with undersized hearts (P=0.056). Overall, thirty-day (P=0.012) and one-year survival (P=0.002) was significantly worse in the undersized group compared to matched or oversized groups. However, on subset analysis, these differences only remained among the complex transplant recipients (P=0.013), but not the non-complex transplant recipients (P=0.428). Median mixed venous oxygen saturations at serial time-points were maintained between 65-70% in all heart size groups, with cardiac indices between 2.4-2.8 LPM/m2. Small PHMr hearts are associated with increased one-year mortality, driven by complex transplant operations. Recipients who received undersized PHMr hearts from non-complex transplant operations had a similar hemodynamic profile and survival as those who received matched and oversized hearts. Small PHMr hearts may be selectively safe for transplantation.

Chinese guidelines for minimally invasive donor hepatectomy in living donor liver transplantation (2024 edition).

Minimally invasive surgeries are increasingly central to modern medicine, particularly in liver transplantation. These techniques, which offer reduced trauma, precise operations, minimal bleeding, and swift recovery, are, however, unevenly adopted across China. Only a limited number of centers routinely perform minimally invasive donor hepatectomies, indicating a significant imbalance in the development and application of these advanced procedures. Additionally, there lacks a set of standardized guidelines that are tailored to meet China's unique healthcare challenges and conditions. In August 2023, the Branch of Organ Transplant of Chinese Medical Association and the Branch of Organ Transplant Physicians of Chinese Medical Doctor Association convened a group of national liver transplantation experts to establish a guideline development committee. This committee conducted a thorough review of relevant literature, evaluated existing guidelines and consensus, and assessed factors such as the evidence base, patient preferences, and the cost-effectiveness of interventions within China. After multiple rounds of discussions, both online and offline, the committee finalized the guidelines. This collaborative effort led to the creation of the "Chinese guidelines for minimally invasive donor hepatectomy in living donor liver transplantation (2024 edition)". These guidelines address crucial aspects such as the safety and advantages of minimally invasive surgery for living donor liver transplantation, donor selection criteria, anesthesia strategies, surgical technical details, and learning curves associated with these procedures, resulting in a comprehensive set of 26 recommendations. The formulation of these guidelines represents a significant advancement towards standardizing minimally invasive liver transplantation surgeries in China. They are designed to enhance outcomes for both donors and recipients by synthesizing expert consensus with contemporary research and clinical practices. Moreover, they serve as a crucial reference for surgeons and medical institutions, promoting the refinement and adoption of minimally invasive surgical techniques in liver transplantation.

Perturbed Microbial Ecology in Neuromyelitis Optica Spectrum Disorder: Evidence from the Gut Microbiome and Fecal Metabolome

BackgroundNeuromyelitis optica spectrum disorder (NMOSD) is a central nervous system inflammatory demyelinating immune-mediated ailment, which is influenced by genetic, epigenetic, and environmental elements. The escalating incidence of NMOSD in recent years implies alterations in environmental risk factors. Recent research has established a correlation between gut microbiomes and the development of NMOSD. MethodsMetagenomic shotgun sequencing and gas chromatography-mass spectrometry (GC-MS) were employed to assess alterations of the structure and function in the fecal microbiome, as well as levels of short-chain fatty acids (SCFAs) in fecal and blood samples, among individuals with neuromyelitis optica spectrum disorder (NMOSD) during the acute phase (n=25), the remission phase (n=11), and a group of healthy controls (HCs) (n = 24). We further explored the correlation between gut microbiota and the pathogenesis of NMOSD through fecal microbiota transplantation (FMT). The gut microbiome from human donors diagnosed with NMOSD or HCs was transplanted into germ-free mice, followed by an analysis of the alterations in the structure and functionality of the transplanted mice's gut microbiome. Additionally, the impact of microbiome transfer on the immunity and spinal cord of germ-free mice was assessed through various techniques, including ELISA, flow cytometry, western blot, histopathology, and transcriptome sequencing. Results(1) At the taxonomic levels of genus and species, there were significant differences in the α-diversity of the microbiome between HCs and NMOSD patients in the acute phase, with NMOSD patients having higher species diversity. (2) In the acute phase, the gut microbiota of NMOSD patients was characterized by Ruminococcaceae_unclassified, Campylobacter, Parabacteroides, Lactobacillus, Akkermansia, Streptococcus oralis, Clostridium leptum, Clostridium asparagiforme, Firmicutes bacterium CAG 238, and Lactobacillus fermentum. (3) The relative abundances of Coprobacter, Turicimonas, Gemmiger, Enterobacter, Roseburia sp.CAG 471, Veillonella tobetsuensis, Proteobacteria bacterium CAG 139, Ruminococcus bicirculans, Lactococcus lactis, Flavonifractor plautii, and Streptococcus cristatus were notably lower in patients experiencing remission compared to NMOSD patients in the acute phase, On the other hand, the relative abundances of Flavonifractor (P = 0.049) and Clostridium aldenense (P = 0.049) were significantly higher. Following medication, the gut microbiome distribution in NMOSD patients during remission closely resembled that of healthy controls (HCs). (4) Compared with HCs, acetate levels in the feces of patients with NMOSD in the acute phase were significantly lower. (5) In addition, we transplanted feces from NMOSD patients into germ-free mice and revealed a significant increase in the levels of IL-6, IL-17A, and IL-23 in the blood of mice belonging to the NMOSD fecal transplantation (NFMT) group. Additionally, the IL-10 level exhibited a significant reduction. Moreover, the proportion of Th17 cells displayed a significant increase, while the proportion of Treg cells exhibited a significant decrease in the spleens of NFMT mice. ConclusionPatients in the acute phase of neuromyelitis optica spectrum disorder (NMOSD) exhibited imbalances in their gut microbiota and a deficiency in short-chain fatty acids (SCFAs). Following drug treatment, the composition of intestinal microbes in NMOSD patients during the remission phase closely resembled that of the healthy control population. The FMT experiment provided evidence of the significant association between intestinal flora and the pathogenesis of NMOSD. Consequently, investigating gut microbiota and identifying novel microbial markers hold promise for the diagnosis and treatment of NMOSD patients.

Post-transplant relapse in pediatric acute lymphoblastic leukemia in the era of CAR-T cell therapy. A multicenter analysis of Grupo Español de Trasplante Hematopoyetico y Terapia Celular (GETH-TC) Pediatric Committee.

BackgroundThe management of relapsed acute lymphoblastic leukemia (ALL) after hematopoietic stem cell transplantation (HSCT) has evolved significantly. Initially, treatment options were limited to palliative care, salvage chemotherapy, and second HSCT. Currently, the focus has shifted to innovative immunotherapies, particularly CAR T-cell therapy. ObjectivesThis study aims to: 1. Analyze outcomes after relapse following HSCT and identify prognostic factors associated with prolonged survival. 2. To evaluate and compare treatment strategies, including immunotherapy (e.g., CAR T-cell therapy) and second HSCT after achieving a new remission, or both treatments in high-risk cases. Study designThis retrospective, multicenter study will evaluate the outcomes of HSCT relapse in pediatric ALL patients. Key endpoints include disease-free survival (DFS), relapse rate, and NRM. We enrolled 73 children with ALL who relapsed after HSCT in 10 hospitals of the Pediatric Committee of the Spanish Group of Transplantation (GETH-TC) between 2013 and 2021. Among them, 56 patients (77%) had B-cell ALL and 17 (23%) had T-cell ALL. ResultsThe median time to relapse was 6 months after the first HSCT. CAR-T cell therapy was administered to 31 patients, all of whom achieved complete remission with negative MRD. However, two patients died prematurely due to cytokine release syndrome (CRS), resulting in a NRM of 7±4%. Sixteen patients relapsed after CAR-T therapy with a cumulative incidence (CI) of 65±11%. Seven of these patients subsequently underwent a second HSCT. The only significant prognostic factor for DFS was the MRD level prior to CAR-T therapy: DFS was 20±8% with MRD ≥3% compared to 100% with MRD <3% (p=0.002). At a median follow-up of 17 months after CAR-T therapy, DFS was 28±10% and overall survival (OS) was 40±10%. Second allogeneic HSCT was performed in 23 patients, including 7 who had previously received CAR-T therapy. Three patients died from NRM (CI: 19±10%). Eight patients relapsed after the second HSCT (CI: 52±13%), of which 2 were successfully treated with CAR-T therapy. At a median follow-up of 33 months after the second HSCT, DFS was 29±11% and OS was 32±10%. Of 17 patients with T-cell ALL, only 2 survived after a second HSCT with a DFS of 12±9%. Of the 73 patients, 20 are alive with a median follow-up of 4 years (DFS: 20±5%). Time to relapse after HSCT was the strongest predictor of outcome; no patient who relapsed within 6 months after the first HSCT survived. There was a trend towards worse DFS in patients who developed chronic GVHD during the first transplant, with 8 out of 9 relapsing despite rescue therapy (p<0.07). ConclusionsChildren with relapsed ALL after HSCT have a substantial chance of long-term survival if relapse occurs more than 6 months after the first transplant and if chronic GVHD was not present. The treatment paradigm has shifted to immunotherapy, including monoclonal antibodies and CAR-T therapy. The role of bridging to a second allogeneic HSCT after CAR-T therapy to improve long-term survival remains a subject of ongoing debate.

Interventional effect of bone marrow mesenchymal stem cell transplantation with different doses of X-ray irradiation induced hepatic injury in mice

Objective: To investigate the interventional effect of bone marrow mesenchymal stem cell (BMMSC) transplantation with different doses of X-ray irradiation induced hepatic injury in mice. Methods: Eighteen female C57BL/6J mice were randomly divided into 0, 2, and 3 Gy irradiation groups and 0, 2, and 3 Gy transplantation groups. The irradiation group was used as the control and injected with an equal volume of culture medium. The mice in the transplantation group were irradiated with different doses of X-ray irradiation, and BMMSCs were intravenously infused into the bone marrow. The mice were sacrificed for sampling at the end of the 21st day. Mice body weight changes were recorded daily. The changes in the content of peripheral blood lymphocytes, red blood cells, platelets, and hemoglobin were detected by an automatic blood tester. The morphological changes in mice liver tissues were observed by hematoxylin-eosin staining. The serum activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were detected by a biochemical analyzer. The reduced glutathione contents in liver tissue were detected by the microplate method. The malondialdehyde content in liver tissue was detected by thiobarbituric acid. The content of total superoxide dismutase (T-SOD) in liver tissue was detected by the hydroxylamine method. The expression of the F4/80 protein in liver tissue was detected by the immunohistochemistry method. The protein expression of nuclear transcription factor erythroid 2 related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) in liver tissue was determined by the western blotting method. The mRNA expression of NLRP3, IL-6, and Nrf2 in liver tissue was detected by a real-time quantitative polymerase chain reaction. The multiple-group comparisons were analyzed by factorial analysis of variance. The inter-group comparisons were analyzed by the LSD method for statistical analysis. Results: The contents of peripheral blood lymphocytes, erythrocytes, platelets, and hemoglobin were significantly decreased in the 3 Gy irradiation group than the 0 Gy irradiation group (P<0.05), while the activities of serum ALT and AST were significantly increased (P<0.05). The malondialdehyde content, F4/80 protein expression level, nucleotide-binding domain and leucine-rich repeats, nucleotide oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3), and interleukin 6 mRNA expression levels were significantly increased in liver tissue, while the contents of T-SOD and glutathione, Nrf2 and HO-1 protein expression levels, and Nrf2 mRNA expression level in liver tissue were significantly decreased (P<0.05). The contents of peripheral blood lymphocytes, red blood cells, platelets, and hemoglobin were significantly increased in the 3 Gy transplantation group than the 3 Gy irradiation group (P<0.05), while the activities of serum ALT and AST were significantly decreased (P<0.05). The malondialdehyde content, F4/80 protein expression level, NLRP3 and interleukin-6 mRNA expression levels in liver tissue were significantly decreased (P<0.05), while the content of T-SOD and glutathione, Nrf2 and HO-1 protein expression levels, and Nrf2 mRNA expression level in liver tissue were significantly increased (P<0.05). Conclusion: X-ray irradiation at a dose of 3 Gy can induce liver oxidative damage in mice. BMMSC transplantation can improve X-ray irradiation-induced liver oxidative damage in mice, and its mechanism of action may be related to the regulation of the Nrf2/HO-1 pathway.

The safety of indocyanine green in patients with advanced chronic kidney disease or kidney transplantation – a scoping review

Near-infrared fluorescence imaging with indocyanine green (ICG) is increasingly being used in the field of image-guided surgery. Although ICG is considered non-nephrotoxic in current literature, caution is advised for the use of ICG in patients with advanced chronic kidney disease (CKD), including kidney transplant recipients. Therefore, a scoping review was performed to assess the safety of ICG in patients with advanced CKD or a renal allograft. This scoping review was guided by the PRISMA-ScR (Preferred Reporting Items for Systematic reviews and Meta-analyses extension for Scoping Reviews). Web of Science, PubMed, and Embase were searched for articles and abstracts in which ICG was administered in patients with CKD or a renal allograft. The extracted data included the incidence of adverse events, kidney function after injection of ICG, preservation of transplant function, and type of other possible complications. The initial search resulted in 635 records of which nineteen studies were found eligible for the review. ICG was used for multiple purposes but never specifically as an objective to investigate possible nephrotoxicity. No adverse events were reported in the transplant group (n=250) or the CKD group (n= 74). Despite ICG-injection, preservation of transplant function after transplantation surgery was 94% in 198 patients, and no increase in possible ICG-related other complications was reported. This scoping review found no evidence that ICG increases the risk of adverse events in patients with CKD, including kidney transplant recipients. Therefore, the administration of ICG should not be withheld from these patients.

Abstract 4138721: Outcomes of Coronary Revascularization in Patients with Contemporaneous Abdominal Organ Transplant

Background: Clinical evaluation surrounding liver and kidney transplantation may reveal obstructive coronary artery disease (CAD). However, little is known about outcomes after revascularization in this population. Our aim was to examine coronary artery bypass grafting (CABG) and percutaneous intervention (PCI) in peri-transplant patients compared to the general CABG/PCI populations. Methods: We conducted a matched retrospective cohort study between 2014-2022 at a single academic center. Matching was done by optimal full matching of a logistic regression-based propensity score adjusting for age, chronic kidney disease, diabetes, tobacco use, chronic lung disease, hypertension, prior myocardial infarction, and valvular disease. Covariate balance was assessed as standardized mean difference &lt;0.2. The primary outcome was a composite of in-hospital death, stroke, and myocardial infarction, and a key secondary outcome was incident arrhythmia. Results: The study population comprised 2655 patients: 24 CABG/transplant (median age, 64 [IQR, 59-66]; 4 female [17%]), 1037 CABG/non-transplant (age, 66 [59-73]; 190 female [18%]), 27 PCI/transplant (age, 62 [IQR, 55-67]; 6 female [22%]), and 1567 PCI/non-transplant (age, 70 [IQR, 60-78]; 399 female [25%]). CABG/PCI preceded transplant by a median 321/324 days, respectively, and followed transplant by a median 461/36 days, respectively. For the primary outcome in CABG patients, there were no events in the transplant group and an estimated potential outcome in 6.5% of the matched non-transplant group (marginal RR, &lt;0.001; p&lt;0.001). For the primary outcome in PCI patients, there were no events in the transplant group and an estimated potential outcome in 2.4% of the matched non-transplant group (marginal RR, &lt;0.001; p&lt;0.001). For incident arrhythmia in CABG patients, the estimated potential outcome was 12% and 17.5% in the transplant and matched non-transplant groups, respectively (marginal RR, 0.98; 95% CI, 0.37-2.6; p=0.97). For incident arrhythmia in PCI patients, the estimated potential outcome was &lt;0.001% and 3.6% in the transplant and matched non-transplant groups, respectively (marginal RR, 0.89; 95% CI, 0.12-6.5; p=0.91). Conclusions: Patients with contemporaneous abdominal organ transplant undergoing coronary revascularization suffered no in-hospital mortality, stroke, or myocardial infarction, and were not at greater risk of incident arrhythmia than similar non-transplant patients.

Abstract 4124354: Transplantation of vascularized cardiac microtissue derived from human iPS cells improves impaired electrical conduction capacity in a porcine myocardial injury model

Background: To realize efficient regenerative medicine using human iPS cell (hiPSC)-derived cardiac tissue, it is necessary to achieve electrical synchronization between the graft and the host heart and to improve conduction disturbances in the impaired heart. In this study, we aimed to demonstrate that the transplantation of hiPSC-derived vascularized cardiac tissue can improve these conduction disturbances using a porcine myocardial injury model. Methods: We prepared cell sheet-shaped vascularized cardiac microtissue (VCM) by seeding cardiomyocytes, endothelial cells, and vascular mural cells differentiated from hiPSCs onto temperature-responsive culture plates and thickening them using dynamic rocking culture. We induced myocardial injury (MI) via epicardial cryoablation in immunosuppressed crown minipigs and transplanted the VCMs immediately after MI induction, covering the cryoinjury-induced MI area. The pigs underwent epicardial electroanatomic mapping under sinus rhythm and epicardial pacing, both immediately before and one week after MI induction, while using amiodarone. Differences in myocardial voltages and conduction velocities were assessed between VCM and sham groups (N=3 in each group). After electroanatomic analysis, the hearts were harvested and subjected to histological examination. Results: One week after MI induction, mean voltages at the MI site decreased in both groups during sinus rhythm, remote site pacing, and combined remote and MI site pacing (11.05 to 1.74 mV, 14.26 to 3.44 mV, and 15.61 to 3.67 mV, respectively, in the VCM group; and 8.72 to 2.70 mV, 19.64 to 3.64 mV, and 14.66 to 1.96 mV, respectively, in the Sham group). Mean voltages at the remote site also decreased in both groups during the same conditions (12.57 to 4.53 mV, 10.61 to 3.38 mV, and 19.56 to 5.85 mV, respectively, in the VCM group; and 8.75 to 6.03 mV, 14.15 to 5.79 mV, and 13.67 to 6.23 mV, respectively, in the Sham group). The mean conduction velocity between the remote and MI sites was numerically higher in the VCM group compared to the Sham group (2.84 m/s vs. 1.74 m/s, respectively). Histological examination confirmed that in the VCM transplantation group, the VCM remained intact, completely covering the MI area. Conclusions: The transplantation of VCM showed a tendency to improve conduction disturbances in the porcine MI model. This suggests that the graft may synchronize with the host and function mechanically after cell transplantation.

Modification of Intestinal Flora Can Improve Host Metabolism and Alleviate the Damage Caused by Chronic Hypoxia.

Prolonged exposure to hypoxic conditions can lead to reduced appetite, stunted growth, systemic inflammation, and pulmonary hypertension. Previous studies have indicated a correlation between gut dysbiosis and the development of hypoxia-related hazards. We designed an experiment to investigate the effect of microbiota on mitigating hypoxic damage. Gut microbiota from high-altitude-adapted species (Ochotona curzoniae) were transplanted into Sprague Dawley (SD) rats, which were then housed in a simulated 6000 m altitude environment for 30 days. After the experiment, we conducted analyses on average daily weight gain (ADG), feed conversion ratio (FCR), mean pulmonary artery pressure (mPAP), gut flora, and fecal metabolism. The results demonstrated that the ADG in the transplantation group (2.98 ± 0.17 g) was significantly higher than in the control groups (2.68 ± 0.19 g and 2.26 ± 0.13 g) (p < 0.05). The FCR was reduced in the transplantation group (6.30 ± 0.33 g) compared to the control groups (8.20 ± 1.15 g and 8.83 ± 0.45 g) (p < 0.05). The mPAP was decreased in the transplantation group (38.1 ± 1.13 mmHg) compared to the control groups (43.4 ± 1.30 mmHg and 43.5 ± 1.22 mmHg) (p < 0.05). Multi-omics analysis revealed that Lachnospiraceae, Desulfovibrionaceae, and specific amino acid metabolic pathways play crucial roles in hypoxia and are associated with both inflammation and nutritional metabolism. This study proposes a novel approach to the treatment of hypoxic pulmonary hypertension and holds potential significance for improving high-altitude developmental potential.