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AbstractAllogeneic hematopoietic stem cell transplantation (AHSCT) is currently the only treatment modality that is capable of curing myelofibrosis (MF). Although outcomes of AHSCT have improved vastly in recent years owing to advancements in HLA typing, conditioning regimens, and supportive care, it remains a procedure with a considerable risk in MF patients due to conditioning regimen related toxicity, higher rates of graft failure, infections, and graft versus host disease (GVHD). Recent progress in the treatment and prevention of GVHD with post-transplant cyclophosphamide has also rendered transplantation from alternative donors feasible and safer, thus improving access to patients without HLA-identical donors. Accordingly, all patients with intermediate or high-risk MF today should be referred for potential transplant evaluation to consider the pros and cons of an early versus a delayed transplant strategy. Individual risk assessment in MF is best facilitated by contemporary prognostic models that incorporate both clinical and genetic risk factors. The current review highlights new information regarding risk stratification in MF, anchored by practical algorithms that facilitate patient selection for specific treatment actions, including AHSCT. [ABSTRACT FROM AUTHOR]

Background: Although stem cell transplantation is a promising approach for the treatment of myocardial infarction (MI), there are still some problems faced such as the low survival rate of stem cells. Here, we investigated the role of Notoginsenoside R1 (NGR1) pretreatment in improving the effects of neonatal rat bone marrow mesenchymal stem cell (MSC) transplantation for treatment of MI. Methods: Cardiac functions were detected by echocardiography and the myocardial infarct size was determined by Masson's trichrome staining in a rat model of MI. The cardioprotective effects of NGR1/LY294002 co-pretreated MSCs was evaluated to explore the underlying mechanism. The angiogenesis was determined by vWF and α-SMA immunofluorescence staining and cell apoptosis was detected by TUNEL. In vitro, the effects of NGR1 on stem cell proliferation was examined by CCK-8 and levels of P-Akt, P-CREB, P-FoxO1 were detected by western blot. Apoptosis, ROS content, and cytokine levels were examined by DAPI and TUNEL staining, a ROS assay kit, and ELISA, respectively. Results: NGR1 elevated the therapeutic effect of MSC transplantation on infarction by preserving cardiac function, increasing angiogenesis and expressions of IGF-1, VEGF, and SDF-1, and reducing cell apoptosis, whereas the addition of LY294002 prior to NGR1 treatment significantly counteracted the foregoing effects of NGR1. NGR1 pretreatment and SC79 pretreatment were similar in that both significantly increased P-Akt and P-FoxO1 levels in MSC and did not affect P-CREB levels. Besides, both NGR1 and SC79 promoted VEGF, SCF and bFGF levels in MSC cultures, and significantly reduced ROS accumulation and the attenuated cell apoptosis in MSC triggered by H2O2. Similarly, addition of LY294002 before NGR1 treatment significantly counteracted the aforementioned effects of NGR1 in vitro. Conclusions: NGR1 pretreatment enhances the effect of MSC transplantation for treatment of MI through paracrine signaling, and the mechanism underlying this effect may be associated with PI3K/Akt/FoxO1 signaling pathways. [ABSTRACT FROM AUTHOR]

• Comprehensively synthesize the functional features of OECs. • The function and mechanism of OECs in the repair of peripheral nerve injury were discussed. • Application of OECs in the treatment of pathological pain induced by peripheral nerve injury was discussed. Direct or indirect injury of peripheral nerve can lead to sensory and motor dysfunction, which can lead to pathological pain and seriously affect the quality of life and psychosomatic health of patients. While the internal repair function of the body after peripheral nerve injury is limited. Nerve regeneration is the key factor hindering the recovery of nerve function. At present, there is no effective treatment. Therefore, more and more attention have been paid to the development of foreground treatment to achieve functional recovery after peripheral nerve injury, including relief of pathological pain. Cell transplantation strategy is a therapeutic method with development potential in recent years, which can exert endogenous alternative repair by transplanting exogenous functional bioactive cells to the site of nerve injury. Olfactory ensheathing cells (OECs) are a special kind of glial cells, which have the characteristics of continuous renewal and survival. The mechanisms of promoting nerve regeneration and functional repair and relieving pathological pain by transplantation of OECs to peripheral nerve injury include secretion of a variety of neurotrophic factors, axonal regeneration and myelination, immune regulation, anti-inflammation, neuroprotection, promotion of vascular growth and improvement of inflammatory microenvironment around nerve injury. Different studies have shown that OECs combined with biomaterials have made some progress in the treatment of peripheral nerve injury and pathological pain. These biomaterials enhance the therapeutic effect of OECs. Therefore, the functional role of OECs in peripheral nerve injury and pathological pain was discussed in this paper. Although OECs are in the primary stage of exploration in the repair of peripheral nerve injury and the application of pain, but OECs transplantation may become a prospective therapeutic strategy for the treatment of peripheral nerve injury and pathological pain. [ABSTRACT FROM AUTHOR]

Objectives: High intensity exercise in individuals post solid organ transplant (SOT) remains a largely understudied phenomenon, with potential risks and benefits. Additionally, the optimal training protocols are still unclear. This narrative review aimed to explore the impact of high-intensity exercise training and strenuous sports on solid organ transplant recipients (SOTRs). Methods: We conducted a narrative review of intervention studies of any design that included high-intensity exercise training and cross-sectional studies of strenuous sports and activities. Additionally, we reviewed individual reports documenting post-SOT performance at highly competitive or physiological levels. We used MEDLINE to search for relevant articles followed by a manual search for additional articles. Data were extracted and results were summarized. Results: High-intensity and strenuous exercise appears to be safe among stable SOTRs. High-intensity protocols consistently demonstrated improvements in VO2peak and a reduction in coronary artery disease prevalence, though findings related to body composition, health-related quality of life outcomes, and cardiovascular exercise variables were inconsistent. Pre-transplant athletes showcase notable achievements and physiological adaptations post-transplantation, highlighting the capacity for athletic performance among this population. However, caution is warranted in interpreting the findings from these studies due to limitations in generalizability and other methodological limitations. Conclusion: As evidenced by current literature, high intensity exercise emerges as a promising exercise method for safely improving various physiological parameters, and reducing the prevalence of coronary heart disease in SOTRs. It can induce similar or greater effects to moderate intensity exercise, however follow-up studies indicate low retention. Further research of higher methodological rigor is warranted in this field to advance understanding, and to guide evidence-based practice. [ABSTRACT FROM AUTHOR]

ABSTRACT Pure red cell aplasia (PRCA) is a rare but significant complication following major ABO‐incompatible allogeneic hematopoietic stem cell transplantation (HSCT). The persistence of recipient B lymphocytes producing anti‐donor isohemagglutinins leads to reticulocytopenia and anemia, often resulting in transfusion dependence. Current treatment options for post‐HSCT PRCA are limited and frequently yield suboptimal responses, complicating patient management. Herein, we report three cases of post‐HSCT PRCA successfully managed with daratumumab, a monoclonal antibody targeting CD38‐expressing plasma cells. All patients demonstrated rapid reticulocyte recovery and transfusion independence after daratumumab treatment, despite prior treatment failures. These findings suggest that daratumumab may provide a more effective therapeutic approach, with a favorable safety profile compared to traditional therapies. Given its demonstrated efficacy and safety, daratumumab warrants consideration as a first‐line treatment for post‐HSCT PRCA, potentially improving patient quality of life and reducing transfusion‐related complications. Further studies should explore optimal dosing and long‐term outcomes. [ABSTRACT FROM AUTHOR]

Women suffering from absolute uterine factor infertility (AUFI), due to either lack of a uterus or one unable to sustain neonatal viability, presented as one of the last frontiers in conquering infertility. Following systematic animal research for over a decade, uterus transplantation was tested as a treatment for AUFI in 2012, which culminated in the first human live birth in 2014. The development of uterus transplantation from mouse to human has followed both the Moore criteria for introduction of a surgical innovation and the IDEAL concept for evaluation of a novel major surgical procedure. In this article we review the important preclinical animal and human studies that paved the way for the successful introduction of human uterus transplantation a decade ago. We discuss this in the context of the Moore criteria and describe the different procedures of preparation, surgeries, postoperative monitoring, and use of assisted reproduction in human uterus transplantation. We review the worldwide activities and associated results in the context of the IDEAL concept for evaluation of surgical innovation and appraise the ethical considerations relevant to uterus transplantation. We conclude that rigorous application of the Moore criteria and strict alignment with the IDEAL concept have resulted in the establishment of uterus transplantation as a novel, safe, and effective infertility therapy that is now being used worldwide for the treatment of women suffering from AUFI. [ABSTRACT FROM AUTHOR]

Objectives Demand for rapid coagulation testing for massive transfusion events led to development of an emergency hemorrhage panel (EHP; hemoglobin, platelet count, prothrombin time/international normalized ratio, and fibrinogen), with laboratory turnaround time (TAT) of less than 20 minutes. Ten years on, we asked if current laboratory practices were meeting that TAT goal and differences were evident in TAT between the 2 major institutions in our system. Methods We identified EHPs ordered at our 2 largest hospitals, February 2, 2021, to July 17, 2022, comparing order to specimen draw time, specimen draw to specimen received time, laboratory analytic time, and total TAT results from emergency department and operating room. Site 1 houses a level I trauma center; site 2 includes tertiary care, transplant, and obstetrics services. Results In total, 1137 EHPs were recorded in our study period. Laboratory TAT was significantly faster at site 1 (~14 vs ~27 minutes, P <.01). Average laboratory TAT was under 20 minutes at site 1 but only for 50% of specimens at site 2. Outlier specimens were collection delays at site 1 and specimen processing delays at site 2. Conclusions The EHP can be performed as rapidly as described. However, compromises in laboratory location, available personnel, and processing differences can degrade performance. [ABSTRACT FROM AUTHOR]

Background: Osteochondral allograft transplantation (OCAT) has become a standard-of-care treatment option for patients with large symptomatic articular defects. Recent advances in allograft science and OCAT protocols have been reported to result in consistently robust outcomes after OCAT in the knee. However, only short-term comparisons have been reported, and analyses are lacking for treatment failure risk factors that account for confounding variables. Hypothesis: Midterm functional graft survival rate would exceed 80% for all OCATs combined, with consideration of risk factors for lower survivorship including older patient age, higher body mass index (BMI), tibiofemoral bipolar OCAT, and nonadherence to prescribed postoperative rehabilitation protocols. Study Design: Case series; Level of evidence, 4. Methods: Patients with outcome data available at ≥5 years after primary OCAT using high chondrocyte–viability (HCV) osteochondral allografts were analyzed according to 2 clinically relevant definitions: (1) initial treatment failure, defined by revision or arthroplasty surgery performed for the primary OCAT at any time point during the study period; and (2) functional graft failure, defined by documented conversion to arthroplasty after primary or revision OCAT at any time point during the study period. Analyses were used to assess outcomes for each definition, separately for age group, sex, obesity status, tobacco use, type of OCAT surgery, osteotomy status, concurrent ligament surgery status, and adherence to postoperative protocols. Kaplan-Meier analyses were used to assess differences in survival rates, and Cox proportional hazards models were used to assess risk factors and multivariable relationships with survival. Patient-reported outcome measures for pain, function, mobility, and satisfaction were also analyzed. Results: Analysis included 137 primary knee OCATs performed in 134 patients with a mean follow-up of 66 months (59 female, 75 male; mean age, 37.8 years; mean BMI, 28.5). The midterm (5- to 8-year) functional graft survival rate for patients undergoing primary OCAT in the knee using HCV grafts was 82% for all cases combined, ranging from 69% for tibiofemoral bipolar HCV OCATs to 89% for patellofemoral bipolar, 94% for multisurface unipolar, and 97% for single-surface unipolar. Initial treatment failure rates (revision or arthroplasty after primary OCAT) and OCAT nonsurvival rates (arthroplasty after primary or revision OCAT) were greater for older patient age, concurrent ligament reconstruction, tibiofemoral bipolar OCAT, and nonadherence to the prescribed postoperative rehabilitation protocols. When adjusted for patients' age, BMI, and tobacco use status, different surgery types did not demonstrate an increased risk for failure, while concurrent ligament reconstruction and nonadherence did. Patients who experienced functional graft survival after primary OCAT reported significantly greater improvements in PROMIS Physical Function and Mobility (Patient-Reported Outcomes Measurement Information System), International Knee Documentation Committee questionnaire, and Single Assessment Numeric Evaluation scores such that they were significantly higher at final follow-up as compared with patients who required arthroplasty. Patient-reported improvements in pain, function, and mobility exceeded minimal clinically important differences for ≥5 years after primary OCAT. When asked if they were satisfied with primary OCAT surgery, 76.2% of patients were very satisfied or satisfied with their results, while 8.5% were neutral and 15.4% were unsatisfied or very unsatisfied. Conclusion: With use of HCV osteochondral allografts, midterm (5- to 8-year) functional graft survival rates for patients undergoing primary OCAT in the knee were notably higher than previously reported midterm rates for traditional OCATs. When adjusted for patient characteristics, risk factors for nonsurvival included concurrent ligament reconstruction for knee instability and nonadherence to the prescribed postoperative rehabilitation protocols. Patients who experienced functional graft survival for ≥5 years after primary OCAT reported statistically significant and clinically meaningful improvements in pain, function, and mobility. [ABSTRACT FROM AUTHOR]

Objectives: Transplantation is a form of treatment that requires long-term pharmacotherapy. After transplantation, patients may have difficulty adapting to medication use for various reasons, and this may result in rejection. The aim of this study is to determine participants' medication compliance and the factors affecting it. Methods: The research was conducted with a sequential explanatory mixed method. In the study, quantitative data were collected using the Turkish Immunosuppressive Medication Adherence Scale, and qualitative data were collected using the In-Depth Individual Interview Guide. Quantitative data were analyzed using statistical methods, and qualitative data were examined according to Braun and Clarke's thematic analysis framework. Results: In this study, 62.3% of the participants were male, 37.0% were 50 years old and over, 71.3% lived with their spouse, 54.0% had primary and secondary school education, and 42.0% could not work due to their current health condition. From a clinical perspective, it was determined that 78% of the transplants were kidney transplants, and 41.3% were more than 4 years after transplantation. 74.3% of the transplants were from living donors. The mean score of the immunosuppressive medication compliance scale was determined to be 40.91±4.09. In the qualitative data analysis of the study, factors affecting medication adherence were examined and the themes of "individual factors", "complexity of the regimen" and "social support resources" were obtained. The sub-themes of the individual factors theme are reluctance, hopelessness and addiction; Sub-themes of the complexity of the regimen theme are drug side effects and polypharmacy; The sub-themes of the social support resources theme are loneliness and family pressure. Conclusions: The factors influencing medication adherence among organ transplant recipients have been investigated, revealing that adherence levels vary significantly depending on various factors. These findings underscore the importance of tailored care strategies and individualized support approaches. [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]

The article discusses the importance of pediatric organ donation, highlighting the impact children and adolescents have on saving lives through organ transplantation. A retrospective study conducted in a Portuguese hospital from 2006 to 2021 found that 62 pediatric patients were eligible for organ donation, resulting in 252 solid organs being collected and benefiting 202 recipients. Kidneys were the most frequently donated organs, with a median of four organs donated per child. The study emphasizes the need for further research to better understand the contribution of pediatric organ donation to both adults and children awaiting transplants. [Extracted from the article]

A central issue in immunology is the immunological response against nonself. The prerequisite for a specific immunological response is the exposure to the immune system of a nonself antigen. Mathematical equations are presented, which define the fraction of all outcomes with a nonself allele in biallelic systems at the population level in pregnancy and transfusion/transplantation medicine. When designing assays, the mathematical descriptions can be used for estimating the number of genetic markers necessary to obtain a predetermined probability level in detecting nonself alleles of a given frequency. For instance, the equations can be helpful in the design of assays, where the nonself allele can be detected by analysis of cfDNA in plasma from pregnant women, to estimate fetal fraction or to monitor changes in cfDNA in plasma of transplantation patients. The equations give exact, quantitative descriptions of all nonself situations in pregnancy and transfusion/transplantation. [ABSTRACT FROM AUTHOR]

Vacuolation, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a multisystem disease due to a genetic mutation in the ubiquitin-activating enzyme (UBA1). Allogeneic haematopoietic stem cell transplantation (allo-HSCT) offers both therapeutic and cure but also carries significant risks. A review of VEXAS and HSCT cases was undertaken. Thirty-three patients were identified; majority males (n = 32, 97.0%), median time from symptoms to HSCT: 3 years (IQR 2.0–4.8) and median age of 59 years (IQR 52.5–65.5). UBA1 mutation Met41Thr was most common (11/32, 34.4%). The median variant allele frequency was 56.5% (IQR 43.0–73.5) with no correlation with increasing age. Prior to HSCT, 4.5 (IQR 2.8–6) treatments were trialled. Peripheral blood HSCT (30/31, 96.8%) and HLA-matched, unrelated donor (18/32, 56.3%) were most common. Conditioning regimens varied, with reduced intensity treatment with fludarabine as a co-agent most frequently administered (12/31, 38.7%). Both acute and/or chronic GVHD (18/32, 56.3%) and infections were common (12/32, 37.5%). Overall, 27 individuals (81.8%) were alive, and those undergoing HSCT prospectively had median follow up of 9 months (IQR 3.8–14.4). Of the six deceased, infection was implicated in four. In 11 cases with post-HSCT molecular data, a complete eradication of UBA1 mutation was reported. In summary, while consensus treatment strategy regarding VEXAS is lacking, this review highlights HSCT may remain not only a therapeutic option but also enable cure. However, considerations regarding comorbidities, concurrent haematological disorders as well as overall risks of GVHD and infections need to be made. Key points • Very few reported prospective cases of VEXAS and allogeneic haematopoietic stem cell transplantation (allo-HSCT) have been reported. • While risks of graft versus host disease and infection remain barriers, this treatment modality remains an option for selected patients. • Allo-HSCT is the only treatment strategy which can remove the UBA1 mutation. [ABSTRACT FROM AUTHOR]

• We transplanted embryonic spinal motor neurons (SMNs) into peripheral nerve grafts. • SMNs formed a structure similar to the spinal cord. • The diaphragm was reinnervated. • Electrical stimulation of the nerve graft caused diaphragmatic contraction. • SMN transplantation had an inhibitory effect on the atrophy of denervated muscles. Respiratory muscle paralysis due to trauma or neurodegenerative diseases can have devastating consequences. Only a few studies have investigated the reconstruction of motor function in denervated diaphragms caused by such conditions. Here, we studied the efficacy of transplanting E14 embryonic spinal motor neurons (SMNs) into peripheral nerve grafts for functionally reconstructing a denervated diaphragm in a rat model. The diaphragms of 8-week-old male Fischer 344 rats were first denervated by transecting the phrenic nerves. Subsequently, peripheral nerve grafts taken from the lower limb were used for neurotization of the denervated diaphragms. One week later, fetal E14 SMNs were transplanted into the peripheral nerve grafts. After 3 months, we observed functional contraction of the diaphragm following neuromuscular electrical stimulation (NMES) of the peripheral nerve graft. Additionally, we confirmed that SMN transplantation into the peripheral nerve graft had an inhibitory effect on diaphragm muscle atrophy. The SMNs transplanted into the peripheral nerve grafts formed a structure similar to the spinal cord, and the neuromuscular junction of the denervated diaphragm was reinnervated. These findings suggest the establishment of an ectopic motor neuron pool in the peripheral nerve graft. Free peripheral intra-nerve SMN transplantation in combination with NMES, which can be applied for diaphragmatic pacing, offers novel insights into the development of neuroregenerative therapies for treating life-threatening and intractable respiratory muscle paralysis caused by severe nerve damage and degenerative diseases. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to develop and evaluate a population PK model of mycophenolic acid (MPA) in pediatric kidney transplant patients to aid MPA dose optimization. Methods: Data were collected from pediatric kidney transplant recipients from a Dutch academic hospital (Radboudumc, the Netherlands). Pharmacokinetic model-building and model-validation analyses were performed using NONMEM. Subsequently, we externally evaluated the final model using data from another academic hospital. The final model was used to develop an optimized dosing regimen. Results: Thirty pediatric patients were included of whom 266 measured MPA plasma concentrations, including 20 full pharmacokinetic (PK) curves and 24 limited sampling curves, were available. A two-compartment model with a transition compartment for Erlang-type absorption best described the data. The final population PK parameter estimates were Ktr (1.48 h−1; 95% CI, 1.15–1.84), CL/F (16.0 L h−1; 95% CI, 10.3–20.4), Vc/F (24.9 L; 95% CI, 93.0–6.71E25), Vp/F (1590 L; 95% CI, 651–2994), and Q/F (36.2 L h−1; 95% CI, 9.63–74.7). The performance of the PK model in the external population was adequate. An optimized initial dose scheme based on bodyweight was developed. With the licensed initial dose, 35% of patients were predicted to achieve the target AUC, compared to 42% using the optimized scheme. Conclusion: We have successfully developed a pharmacokinetic model for MPA in pediatric renal transplant patients. The optimized dosing regimen is expected to result in better target attainment early in treatment. It can be used in combination with model-informed follow-up dosing to further individualize the dose when PK samples become available. [ABSTRACT FROM AUTHOR]

Background: An increasing number of centers are undertaking combined heart and liver transplantation in adult and pediatric patients with congenital heart disease. Aim: The primary aim of this study was to describe the perioperative management of a single center cohort, identifying challenges and potential solutions. Methods: We conducted a retrospective review of all patients undergoing combined heart and liver transplantation at Stanford Children's Hospital from 2006 to 2022. Preoperative information included cardiac diagnosis, hemodynamics, and severity of liver disease. Intraoperative data included length of surgery, cardiopulmonary bypass time, and blood products transfused. Postoperative data included blood products transfused in the intensive care unit, time to extubation, length of intensive care unit stay, survival outcomes and 30‐day adverse events. Results: Eighteen patients underwent en bloc combined heart and liver transplantation at Stanford Children's Hospital from 2006 to 2022, and the majority 15 (83%) were transplanted for failing Fontan circulation with Fontan Associated Liver Disease. Median surgical procedure time was 13.4 [11.5, 14.5] h with a cardiopulmonary bypass time of 4.3 [3.9, 5.8] h. Median total blood products transfused in the operating room post cardiopulmonary bypass was 89.4 [63.9, 127.0] mLs/kg. Nine patients (50%) had vasoplegia during cardiopulmonary bypass. Activated prothrombin complex concentrates were used post cardiopulmonary bypass in 15 (83%) patients with a 30‐day thromboembolism rate of 22%. Median time to extubation was 4.0 [2.8, 6.5] days, median intensive care unit length of stay 20.0 [7.8, 48.3] days and median hospital length of stay 54.0 [30.5, 68.3] days. Incidence of renal replacement therapy was 11%; however, none required renal replacement therapy by the time of hospital discharge. Neurological events within 30 days were 17% and the 30 day and 1 year survival was 89%. Conclusions: Perioperative challenges include major perioperative bleeding, unstable hemodynamics, and end organ injury including acute kidney injury and neurological events. Successful outcomes for en bloc combined heart and liver transplantation are possible with careful multidisciplinary planning, communication, patient selection, and integrated peri‐operative management. [ABSTRACT FROM AUTHOR]

Background: Pediatric patients with kidney failure often experience cognitive delays. However, academic delay (being more than one grade level below age-appropriate grade, or in special education) after pediatric kidney transplantation (KTx) has not been explored. We sought to identify patient characteristics associated with a higher risk of academic delay 1 year post-KTx. Methods: We used the United Network for Organ Sharing (UNOS) database to identify children aged 6–17 years who received a primary KTx between 2014 and 2021 and had a functioning graft 1 year after KTx. The primary outcome was the patient's academic progress at 1 year post-transplant. The secondary outcome was change in academic progress between transplant and 1-year follow-up: onset of new delay, resolution of pre-existing delay, persistence of delay, or no delay at either timepoint. Binomial and multinomial mixed effects logistic regression models were used to predict each outcome based on patient characteristics. Results: The study included 2197 patients, of whom 14% demonstrated academic delay at 1 year post-KTx, 4% demonstrated a new onset of academic delay, 5% demonstrated a resolution of academic delay, and 10% demonstrated persistent academic delay. Patients undergoing transplantation at a younger age, receiving a deceased donor kidney, experiencing longer waitlist times, and undergoing KTx for vascular or other disease indications for KTx were more likely to experience academic delays, including new-onset academic delays. Conclusions: Academic delays are frequently reported among pediatric KTx recipients. Additional academic support may help resolving or preventing academic delay for at-risk subgroups of children undergoing KTx. [ABSTRACT FROM AUTHOR]

Le front est le casque protecteur du cerveau, si l'on se réfère à l'étymologie du mot calvaria. Détruit, il convient de le reconstruire ; en priorité son infrastructure osseuse, quand bien même l'on peut vivre sans elle, dès lors que les autres tissus (peau, muscle, aponévrose, méninge) sont intègres. Chantier chirurgical complexe dont il sera fait mention quand la multiplicité des techniques décrites témoigne de leur imperfection et que jusqu'à présent la meilleure restauration d'un tissu manquant impose sa substitution par le même tissu. Invitation à inventer une véritable chirurgie régénératrice. The forehead is the protective helmet of the brain, if we refer to the etymology of the word calvaria. Destroyed, it must be rebuilt; priority is given to its bone infrastructure, even though we can live without it, as long as the other tissues (skin, muscle, aponeurosis, meninge) are intact. Complex surgical project which will be mentioned when the multiplicity of techniques described demonstrates their imperfection and until now the best restoration of a missing tissue requires its replacement by the same tissue. Invitation to invent a true regenerative surgery. [ABSTRACT FROM AUTHOR]

Background: IL-33, a pleiotropic cytokine, has been associated with a plethora of immune-related processes, both inflammatory and anti-inflammatory. T regulatory (Treg) cells, the main leukocyte population involved in immune tolerance, can be induced by the administration of IL-33, the local microbiota, and its metabolites. Here, we demonstrate that IL-33 drastically induces the production of intestinal metabolites involved on tryptophan (Trp) metabolism. Methods: naïve mice were treated with IL-33 for 4 days and leukocyte populations were analyzed by flow cytometry, and feces were processed for microbiota and intestinal metabolites studies. Using a murine skin transplantation model, the effect of Kynurenic acid (KA) on allograft survival was tested. Results: Under homeostatic conditions, animals treated with IL-33 showed an increment in Treg cell frequencies. Intestinal bacterial abundance analysis indicates that IL-33 provokes dysbiosis, demonstrated by a reduction in Enterobacteria and an increment in Lactobacillus genera. Furthermore, metabolomics analysis showed a dramatic IL-33 effect on the abundance of intestinal metabolites related to amino acid synthesis pathways, highlighting molecules linked to Trp metabolism, such as kynurenic acid (KA), 5-Hydroxyindoleacetic acid (5-HIAA), and 6-Hydroxynicotinic acid (6-HNA), which was supported by an enhanced expression of Ido and Kat mRNA in MLN cells, which are two enzymes involved on KA synthesis. Interestingly, animals receiving KA in drinking water and subjected to skin transplantation showed allograft acceptance, which is associated with an increment in Treg cell frequencies. Conclusions: Our study reveals a new property for IL-33 as a modulator of the intestinal microbiota and metabolites, especially those involved with Trp metabolism. In addition, we demonstrate that KA favors Tregs in vivo, positively affecting skin transplantation survival. [ABSTRACT FROM AUTHOR]

Regulatory T cells play a crucial role in the homeostasis of the immune response. Regulatory T cells are mainly generated in the thymus and are characterized by the expression of Foxp3, which is considered the regulatory T-cell master transcription factor. In addition, regulatory T cells can be induced from naive CD4+ T cells to express Foxp3 under specific conditions both in vivo (peripheral regulatory T cells) and in vitro (induced regulatory T cells). Both subsets of thymic regulatory T cells and peripheral regulatory T cells are necessary for the establishment of immune tolerance to self and non-self antigens. Although it has been postulated that induced regulatory T cells may be less stable compared to regulatory T cells, mainly due to epigenetic differences, accumulating evidence in animal models shows that induced regulatory T cells are stable in vivo and can be used for the treatment of inflammatory disorders, including autoimmune diseases and allogeneic transplant rejection. In this review, we describe the biological characteristics of induced regulatory T cells, as well as the key factors involved in induced regulatory T-cell transcriptional, metabolic, and epigenetic regulation, and discuss recent advances for de novo generation of stable regulatory T cells and their use as immunotherapeutic tools in different experimental models. Moreover, we discuss the challenges and considerations for the application of induced regulatory T cells in clinical trials and describe the new approaches proposed to achieve in vivo stability, including functional or metabolic reprogramming and epigenetic editing. [ABSTRACT FROM AUTHOR]

Objective: The article reviews the safety and efficacy of treatments for cytomegalovirus (CMV) in solid organ transplantation. Data Sources: A literature review was conducted in PubMed, MEDLINE, and Clinicaltrials.gov from database inception through January 2024, using terms CMV, therapy, and solid organ transplantation. Study Selection and Data Extraction: Clinical trials, meta-analyses, cohort studies, case reports, and guidelines were included. Letters to the editor, reviews, and commentaries were excluded. Data Synthesis: After abstract screening and full-text review of 728 citations for eligibility, 53 were included. Valganciclovir and intravenous ganciclovir are drugs of choice for CMV management and, until recently, the availability of alternative options has been restricted due to toxicity. For instance, foscarnet and cidofovir serve as second-line agents due to potential bone marrow and renal toxicity. In patients with refractory or resistant CMV, maribavir, a novel oral agent, has proven efficacy and a lower adverse effect profile. However, in refractory or resistant CMV, foscarnet and cidofovir are preferred in invasive disease (CMV gastritis, CMV retinitis, and CMV encephalitis), high viral loads, and inability to tolerate oral preparations. Relevance to Patient Care and Clinical Practice: Consensus guidelines have not been revised since approval of novel antivirals in solid organ transplantation. Valganciclovir and ganciclovir remain drugs of choice for initial CMV therapy. Foscarnet, cidofovir, and maribavir are treatments for refractory or resistant-CMV. Conclusions: Selection of CMV antiviral treatment should be determined by patient-specific factors, including severity of illness, resistant or refractory disease, dose-limiting adverse effects, and the preferred route of administration. [ABSTRACT FROM AUTHOR]

Introduction: Currently, no study has determined whether platelet transfusion refractoriness (PTR) post-hematopoietic stem cell transplantation (HSCT) before engraftment in patients with myelodysplastic syndrome (MDS) would impacts clinical outcomes. Methods: We performed a MDS-specific retrospective analysis to determine whether PTR in one-month post-HSCT in patients with MDS could influence outcomes. Results and discussion: Among the 315 patients enrolled, 110 (34.9 %) had PTR from stem cell infusion to one-month post-HSCT. Baseline characteristics of the PTR and non-PTR groups were similar. We found that patients with PTR had a slower and lower rate of platelet engraftment by day 28, as well as a slower recovery of neutrophils. The median days of neutrophil and platelet engraftment were 14 days (9-23) and 17 days (8-28) in the PTR groups versus 13 days (9-23) and 15 days (7-28) in the non-PTR group (P<0.001). By day 28, 84 of 110 patients (76.4%) with PTR achieved platelet engraftment compared with 181 of 205 patients (88.3%) without PTR achieving platelet engraftment (P=0.007). In addition, patients in the PTR group received significantly more red blood cell (median, 17 units vs. 10 units, P<0.001) and platelet transfusions (median, 13 units vs. 7 units, P<0.001). However, the overall survival was similar between the two groups. PTR in onemonth post-HSCT, haploidentical donor, and ferritin level>1041ng/ml (median level) were independent adverse factors of platelet engraftment. [ABSTRACT FROM AUTHOR]

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Introduction: Cytomegalovirus (CMV) is a common opportunistic infection after solid organ transplantation, with significant impact on morbidity and long-term survival. Despite advances in diagnostics and therapeutics, the management of CMV remains very challenging. Areas Covered: This article reviews emerging data on the clinical utility of laboratory assays that quantify cell-mediated immune responses to CMV. Observational studies have consistently demonstrated that a deficiency in pathogen-specific cell-mediated immunity is correlated with a heightened risk of primary, reactivation or recurrent CMV after transplantation. A limited number of interventional studies have recently investigated cell-mediated immune assays in guiding the prevention and treatment of CMV infection after solid organ transplantation. Expert Opinion: The pathogenesis and outcome of CMV after solid organ transplantion reflect the interplay between viral replication and CMV-specific immune reconstitution. Research in CMV-specific cell-mediated immunity paved way for the development of several laboratory assays that may assist clinicians in predicting the risk of CMV after transplantation, individualize the approach to CMV disease prevention, guide the need and duration of treatment of CMV infection, and predict the risk of relapse after treatment. More interventional studies are needed to further solidify the role of cell-mediated immune assays in various clinical situations after transplantation. [ABSTRACT FROM AUTHOR]

Our case demonstrated unique cytomegalovirus (CMV) encephalitis post-haploidentical donor hematopoietic stem cell transplantation (HID-HSCT), with early findings on diffusion-weighted brain magnetic resonance imaging (MRI) in the absence of any neurologic symptoms. A 54-year-old Chinese man with acute lymphoblastic leukemia (Philadelphia chromosome-negative) underwent HID-HSCT. After HSCT, the patient developed CMV viremia and severe acute graft-versus-host disease. Recurrence of CMV viremia was observed. On day 129, brain MRI was performed to determine the cause for the intermittent fever. Diffusion-weighted imaging (DWI) revealed several bright spots in the cortex of the frontal lobes and anterior angle of the left lateral ventricle. Subsequently, he developed transplant-associated thrombotic microangiopathy, posterior reversible encephalopathy syndrome, and enlargement of lesions alongside the ventricular wall on a brain MRI series. Metagenomic next-generation sequencing (NGS) of the cerebrospinal fluid (CSF) led to the final diagnosis of CMV encephalitis. Although ganciclovir combined with foscarnet was administered, the patient’s consciousness deteriorated, followed by respiratory failure. The patient died on day 198. Additionally, we performed a systematic review to comprehensively analyze this disease. Regarding treatment, immunological therapies, including virus-specific T cells from a third donor and CMV-cytotoxic T lymphocytes, may be more effective. This case report and systematic review underscores the complexities of managing CMV ventriculoencephalitis in HSCT recipients and emphasizes the importance of early diagnosis by brain MRI and CSF polymerase chain reaction or NGS and ongoing research in improving outcomes. [ABSTRACT FROM AUTHOR]

Long-term tolerance in the absence of immunosuppressive drugs is a major goal in the transplantation field, not yet attained. Recent research on the role of commensal microbiota in the control of immunity has opened new avenues for the search of novel clinical interventions. Indeed, products of intestinal metabolism generated by both host cells and the microbiota have been identified as modulators of the immune response. Among these, tryptophan (Trp) and its derivatives are being investigated to understand their impact on alloimmunity and their potential usefulness as therapeutic targets to improve allograft survival. Here, we reviewed the latest findings on the contribution of Trp metabolic pathways to transplant outcomes. [ABSTRACT FROM AUTHOR]

Introduction: The impact of deceased donor characteristics on kidney transplant outcomes is controversial. Correspondingly, the predictive performance of deceased donor scores remains moderate, and many transplant centers lack validated criteria for graft acceptance decisions. To better dissect donor-related risk from recipient and periprocedural variables, we analyzed outcomes of kidney donor pairs transplanted in different individuals. Methods: This study explored (a)symmetry of early outcomes of 328 cadaveric kidney transplant recipients from 164 donor pairs transplanted at three Eurotransplant centers. The primary discriminatory factor was (a)symmetry of partner graft function, defined as early graft loss or impaired graft function [estimated glomerular filtration rate (eGFR) <30 mL/min] 3 months after transplantation. We reasoned that a relevant impact of donor factors would result in a high concordance rate of limited graft function or failure. Results: The observed number of symmetric graft failure after transplantation was less than statistically expected (3 months: 1 versus 2, p = 0.89; and 12 months: 3 versus 5, p = 0.26). However, we found a trend toward an impaired 5-year graft survival of grafts with good function 3 months after transplantation but a failed or impaired partner graft compared to symmetrically well-functioning grafts (p = 0.09). Subsequently, we explored the impact of individual donor and recipient variables on early transplant outcomes. Generalized estimating equations after feature selection with LassoGEE bootstrap selected donor age, donor body mass index, and donor eGFR as the relevant risk factors. Discussion: Our findings indicate that donor factors impact early outcomes in kidney transplantation but may have a limited role in long-term graft survival, once a graft has been accepted for transplantation. Utilizing donor-based clinical scores has the potential to aid clinicians in acceptance decisions, giving them an estimate of individual posttransplant outcomes. However, the ultimate decision for acceptance should rest with clinicians, who must consider the complex interplay of donor factors, as well as recipient and periprocedural characteristics. [ABSTRACT FROM AUTHOR]

Tacrolimus (TAC) is a commonly used immunosuppressive drug in solid organ transplantation. Pharmacogenetics has been demonstrated before to be decisive in TAC pharmacotherapy. The CYP3A5*3 variant has been reported to be the main determinant of TAC dose requirements; however, other polymorphisms have also proven to be influential, especially in CYP3A5 non-expressor patients. The aim of this study is to evaluate the influence of genetic polymorphisms in TAC therapy in a cohort of Spanish transplant recipients. Genetic analysis including ten polymorphic variants was performed, and demographic and clinical data and pharmacotherapy of 26 patients were analyzed. No significant differences were found in weight-adjusted dose between CYP3A5 expressors and non-expressors (0.047 mg/kg vs. 0.044 mg/kg), while they were found for carriers of the CYP3A4*1B allele (0.101 mg/kg; p < 0.05). The results showed that patients with at least one CYP3A4*1B allele had a higher TAC dose and lower blood concentration. Dose-adjusted TAC blood levels were also lower in CYP3A4*1B carriers compared to non-carriers (0.72 ng/mL/mg vs. 2.88 ng/mL/mg). These results support the independence of CYP3A5*3 and CYP3A4*1B variants as determinants of dose requirements despite the linkage disequilibrium present between the two. The variability in genotype frequency between ethnicities may be responsible for the discrepancy found between studies. [ABSTRACT FROM AUTHOR]

Background: Hepatic epithelioid hemangioendothelioma (EHE) is an extremely rare tumour. The aim of this study was to investigate the long-term prognosis and its relationship with treatment modalities. Methods: From March 2014 to June 2024, a total of 234 patients with histologically confirmed hepatic EHE were treated or followed up regularly by our team. The patients' clinical data at the time of diagnosis and initial treatment modalities were retrospectively collected. Kaplan–Meier curves were constructed to determine overall survival (OS). To explore prognostic factors and treatment outcomes, univariable and multivariable Cox proportional hazard models were developed. Results: A total of 228 patients were ultimately included. The median age of the cohort was 41 years. For all patients, the OS of 1-, 3- and 5-year were 96.2%, 87.9% and 84.9%, respectively. For patients who underwent liver transplantation (LT), the OS of 1- and 3-year were 62.5% and 25%, respectively. No difference was found in the OS between patients who received surgical therapy and those who did not (1-year: 100% vs. 96.9%; 3-year: 90.1% vs. 91.5%; 5-year: 87.2% vs. 88.2%; P = 0.891). In the multivariable analysis, age ≥ 60 years [HR (95% CI): 4.207 (1.266–13.973), P = 0.019], the size of the largest lesion > 10 cm [HR (95% CI): 12.140 (1.419–103.872), P = 0.023] and LT [HR (95% CI): 5.502 (1.343–22.536), P = 0.018] were poor prognostic factors. Conclusions: Compared with nonsurgical therapy, surgical therapy has no advantage in terms of long-term survival. The role of LT in the management of hepatic EHE should be reevaluated. Age ≥ 60 years and the size of the largest lesion > 10 cm are poor prognostic factors. [ABSTRACT FROM AUTHOR]

Background: Ovarian cryopreservation is a promising technique despite being hindered by damage from freezing and thawing. Melatonin can mitigate this outcome. Objective: This study aimed to evaluate the effect of melatonin on the follicular dynamics of ovarian tissue in a cryopreserved cell culture. Methods: Three-month-old adult female Wistar rats (n = 24) weighing approximately 250 g were oophorectomized and divided into two groups (n = 12): the control group (CG) and the melatonin group (MG). In the CG, slow cryopreservation was performed according to the standard protocol with Medium M2 and dimethyl sulfoxide (DMSO). In MG, melatonin diluted in ethyl alcohol vehicle at a concentration of 0.1 μm was added to the culture medium. In both groups, the ovaries were cryopreserved by slow freezing and kept in liquid nitrogen for 24 h. Subsequently, after thawing, the ovaries were reimplanted in the retroperitoneum, one on each side of the great vessels (inferior vena cava and aorta). After 30 days, the animals were euthanized during the diestrus phase; then, the grafts were removed and processed for histomorphometric and immunohistochemical analyses, whereas the blood was subjected to biochemical analysis. Student's t test was used to assess the difference between the groups. Results: The FSH levels in MG (83.79 ± 32.37) were lower than those in CG (120.52 ± 36.59), p = 0.03. The FSH/AMH ratios were also lower in MG (3.53 ± 1.13) than in CG (6.52 ± 2.85), p = 0.001. The SOD2 immunoexpression was higher in MG than in CG regarding all parameters except for the degenerated follicles (follicular cells and internal thecal cells): CG (16.80 ± 4.80 [13.36–20.24]) and MG (14.91 ± 4.04 [12.01–17.79]) p = 0.351. Statistically, the difference in intact follicles (theca + interstitium) between CG (6.60 ± 2.59 [4.75–8.45]) and MG (9.31 ± 3.09 [7.09–11.51]) was significant (p = 0.049), with a small difference in the expression of regular antral follicles. Conclusions: Melatonin can improve the quality of cryopreserved tissues, as evidenced in this study, and the evaluation of cryopreserved ovarian grafts, as shown in the melatonin group with better hormonal parameters and greater immunohistochemical expression of the SOD2 antioxidant. Thus, damage is reduced during cryopreservation and transplantation is improved. [ABSTRACT FROM AUTHOR]

Background: During the aging process, the number and functional activity of endothelial progenitor cells (EPCs) are impaired, leading to the unsatisfactory efficacy of transplantation. Previous studies demonstrated that Yiqihuoxue decoction (Ginseng-Sanqi-Chuanxiong, GSC) exerts anti-vascular aging effects. The purpose of this study is to evaluated the effects of GSC on D-galactose (D-gal)induced senescence and the underlying mechanisms. Methods: The levels of cellular senescence-related markers P16, P21, P53, AMPK and p-AMPK were detected by Western blot analysis (WB). SA-β-gal staining was used to evaluate cell senescence. EPCs function was measured by CCK-8, Transwell cell migration and cell adhesion assay. The morphological changes of mitochondria were detected by confocal microscopy. The protein and mRNA expression of mitochondrial fusion fission Drp1, Mff, Fis1, Mfn1, Mfn2 and Opa1 in mitochondria were detect using WB and RT–qPCR. Mitochondrial membrane potential, mtROS and ATP of EPCs were measured using IF. H&E staining was used to observe the pathological changes and IMT of the aorta. The expressions of AGEs, MMP-2 and VEGF in aorta were measured using Immunohistochemical (IHC). The levels of SOD, MDA, NO and ET-1 in serum were detected by SOD, MDA and NO kits. Results: In vitro, GSC ameliorated the senescence of EPCs induced by D-gal and reduced the expression of P16, P21 and P53. The mitochondrial morphology of EPCs was restored, the expression of mitochondrial Drp1, Mff and Fis1 protein was decreased, the levels of mtROS and ATP were decreased, and mitochondrial function was improved. Meanwhile, the expression of AMPK and p-AMPK increased. The improvement effects of GSC on aging and mitochondrial morphology and function were were hindered after adding AMPK inhibitor. In vivo, GSC improved EPCs efficiency, ameliorated aortic structural disorder and decreased IMT in aging mice. The serum SOD level increased and MDA level decreased, indicating the improvement of antioxidant capacity. Increased NO content and ET-1 content suggested improvement of vascular endothelial function. The changes observed in SOD and MMP-2 suggested a reduction in vascular stiffness and the degree of vascular damage. The decreased expression of P21 and P53 indicates the delay of vascular senescence. [ABSTRACT FROM AUTHOR]

Introduction Material and Methods Results Conclusions Uterine transplantation was developed for the treatment of absolute uterine factor infertility. As it is a new modality of transplantation, there is still room for technical improvement. A factor that impacts graft survival in organ transplantation is the warm ischemia time. In uterine transplantation specifically, at least two vascular anastomoses are performed on each side of the uterus, and the graft revascularization takes place when the vascular clamps of the arteries and veins are released on both sides simultaneously. For this reason, the warm ischemia time in uterine transplant is expected to be considerably long. The purpose of this study was to compare the sequential technique of uterine graft revascularization, which aims to reduce the warm ischemia time of the procedure, with the simultaneous revascularization technique.For the procedure, the uterine auto‐transplantation technique was performed using 10 non‐pregnant adult ewes weighing about 45 kg, divided into two groups: simultaneous revascularization group (5 animals) and sequential revascularization group (5 animals). To evaluate the groups, we analyzed the procedure and warm ischemia times, graft macroscopy, hemodynamic, laboratory, and histological parameters of the uterus.The sequential revascularization technique group had similar surgical procedure times, and the warm ischemia time was significantly shorter with medians of 32 min in the sequential group versus 72 min in the simultaneous group (p < 0.008). The graft macroscopy and hemodynamic, laboratory, and histological parameters evaluated were similar between the groups.The sequential revascularization technique proved to reduce the warm ischemia time in the sheep uterine auto‐transplantation model without compromising graft viability. [ABSTRACT FROM AUTHOR]

Introduction: Tailored exercise prescription is a crucial intervention for kidney transplant recipients (KTRs). This longitudinal study investigates the impact on long-term effectiveness of exercise prescriptions over one year follow-up, implementing telehealth tools for exercise administration and adherencemonitoring. Materials and methods: KTRs were evaluated with clinical assessments including body composition, blood and urinary parameters, physical performance and quality of life at baseline (T0), after six (T6) and twelve (T12) months. The adherence to prescribed exercise training was monitored via video call interviews until T6 when the sample was divided into a group monitored via wearables (WG) and a group continuing video calls (VG) until T12. Results: Twenty-six KTRs completed the study. No changes in body composition and kidney function were reported. KTRs showed an improvement in lipid profile, systolic blood pressure, cardiorespiratory fitness and quality of life. WG showed no clinical differences compared to VG except for reported higher quality of life. Discussion: A good adherence to the exercise prescription was obtained with both monitoring methods (232 vs 253 min/week). This study reinforces the inclusion exercise training for KTRs to enhance physical fitness and reduce cardiovascular risk factors. These results emphasize the role of telehealth monitoring methods as motivators for adherence to long-term exercise prescriptions. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusion Therapeutic drug monitoring of tacrolimus based on whole blood drug concentrations is routinely performed. The concentration of tacrolimus in peripheral blood mononuclear cells (PMBCs) is likely to better reflect drug exposure at the treatment target site. We aimed to describe the relationship between tacrolimus whole blood and PBMC concentrations, and the influence of patient characteristics on this relationship by developing a population pharmacokinetic model.We prospectively enrolled 63 stable adult kidney‐transplanted patients and collected dense (12‐h, n = 18) or sparse (4‐h, n = 45) pharmacokinetic profiles of tacrolimus. PBMCs were isolated from whole blood (Ficoll density gradient centrifugation), and drug concentrations in whole blood and PBMCs were analysed using liquid chromatography‐mass spectrometry. Patient genotype (CYP3A4/5, ABCB1, NR1I2) was assessed with PCR. Population pharmacokinetic modelling and statistical evaluation was performed using NONMEM.Tacrolimus whole blood concentrations were well described using a two‐compartment pharmacokinetic model with a lag‐time and first‐order absorption and elimination. Tacrolimus PBMC concentrations were best estimated from whole blood concentrations with the use of a scaling factor, the ratio of whole blood to PBMC concentrations (RC:PBMC), which was the extent of tacrolimus distribution into PBMC. CYP3A5*1 non‐expressors and NR1I2‐25 385T allele expressors demonstrated higher RC:PBMC ratios of 42.4% and 60.7%, respectively.Tacrolimus PBMC concentration could not be accurately predicted from whole blood concentrations and covariates because of significant residual unexplained variability in the distribution of tacrolimus into PBMCs and may need to be measured directly if required for future studies. [ABSTRACT FROM AUTHOR]

Transplantation is the most efficient alternative to treat terminal functional kidney failure. To synthesize the literature on the topic, this systematic review sought to retrieve evidence that empirically analyzed the frequency of kidney transplantation in Brazil, relating it to the COVID-19 pandemic. The PUBMED, LILACS and SCIELO databases were consulted using the descriptors: "Transplantation", "Kidney", "COVID-19", and "Brazil". Thus, 146 studies were retrieved and only six were included in the review. The review showed that the COVID-19 pandemic had a negative impact on the number of kidney transplants, increased the transplant waiting list, reduced the number of donors, and there were reports of infections and deaths among patients undergoing kidney treatment and transplant recipients during the pandemic. These findings emphasize the need for more research and attention in the area of kidney transplantation and mitigate the effect of health crises similares to COVID-19. [ABSTRACT FROM AUTHOR]

The lung microbiome plays a crucial role in the development of chronic lung diseases, which may ultimately lead to the need for lung transplantation. Also, perioperative results seem to be connected with altered lung microbiomes and its dynamic changes providing a possible target for optimizing short-term outcome after transplantation. A literature review using MEDLINE, PubMed Central and Bookshelf was performed. Chronic lung allograft dysfunction (CLAD) seems to be influenced and partly triggered by changes in the pulmonary microbiome and dysbiosis, e.g. through increased bacterial load or abundance of specific species such as Pseudomonas aeruginosa. Additionally, the specific indications for transplantation, with their very heterogeneous changes and influences on the pulmonary microbiome, influence long-term outcome. Next to composition and measurable bacterial load, dynamic changes in the allografts microbiome also possess the ability to alter long-term outcomes negatively. This review discusses the "new" microbiome after transplantation and the associations with direct postoperative outcome. With the knowledge of these principles the impact of alterations in the pulmonary microbiome in hindsight to CLAD and possible therapeutic implications are described and discussed. The aim of this review is to summarize the current literature regarding pre- and postoperative lung microbiomes and how they influence different lung diseases on their progression to failure of conservative treatment. This review provides a summary of current literature for centres looking for further options in optimizing lung transplant outcomes and highlights possible areas for further research activities investigating the pulmonary microbiome in connection to transplantation. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases, particularly ischemic heart disease, area leading cause of morbidity and mortality worldwide. Myocardial infarction (MI) results in extensive cardiomyocyte loss, inflammation, extracellular matrix (ECM) degradation, fibrosis, and ultimately, adverse ventricular remodeling associated with impaired heart function. While heart transplantation is the only definitive treatment for end-stage heart failure, donor organ scarcity necessitates the development of alternative therapies. In such cases, methods to promote endogenous tissue regeneration by stimulating growth factor secretion and vascular formation alone are insufficient. Techniques for the creation and transplantation of viable tissues are therefore highly sought after. Approaches to cardiac regeneration range from stem cell injections to epicardial patches and interposition grafts. While numerous preclinical trials have demonstrated the positive effects of tissue transplantation on vasculogenesis and functional recovery, long-term graft survival in large animal models is rare. Adequate vascularization is essential for the survival of transplanted tissues, yet pre-formed microvasculature often fails to achieve sufficient engraftment. Recent studies report success in enhancing cell survival rates in vitro via tissue perfusion. However, the transition of these techniques to in vivo models remains challenging, especially in large animals. This review aims to highlight the evolution of cardiac patch and stem cell therapies for the treatment of cardiovascular disease, identify discrepancies between in vitro and in vivo studies, and discuss critical factors for establishing effective myocardial tissue regeneration in vivo. [ABSTRACT FROM AUTHOR]

The HLA profile is essential in cell and tissue transplantation, particularly in patients with autoimmune conditions and infections. Due to the extreme polymorphism in certain HLA loci, it also serves as a key tool for population genetic analysis. This study aimed to identify the allele and haplotype distributions of HLA class I (A, B, and C) and class II (DRB1) genotypes in unrelated hematopoietic stem cell donors. A retrospective analysis was conducted between 2016 and 2020 on 9832 Transylvanian volunteers, divided into Romanian and Hungarian groups based on self-reported ethnicity. Using PCR-SSO for HLA typing, significant differences were found in allele frequencies between ethnic groups. A total of 19 HLA-A, 31 HLA-B, 14 HLA-C, and 13 HLA-DRB1 distinct allele groups were identified between ethnic groups. Notably, B*18, B*51, and C*12 were more frequent in Romanians, while B*44, B*40, and C*07 were more common in Hungarians. Differences in haplotype distributions were also observed, with HLA-A*02~B*18~C*07~DRB1*11 being significantly more frequent in Romanians. Understanding these population-specific HLA profiles can improve donor matching for hematologic diseases, enhancing patient outcomes and access to life-saving hematopoietic stem cell transplantation. [ABSTRACT FROM AUTHOR]

Background: Intraoperative hypotension is associated with acute kidney injury after surgery. However, the definition (duration and magnitude) of hypotension during kidney transplantation (KT) surgery on early graft function remains unclear. Methods: We conducted a retrospective cohort study of KT recipients from December 1, 2009, to December 31, 2019. Exposure to intraoperative hypotension was characterized as the duration (minutes) of mean arterial pressure (MAP) <55, <65, <75, and <85 mmHg. Our co‐primary outcomes were DGF‐creatinine reduction ratio (DGF‐CRR, <30% creatinine reduction, postoperative days 1 and 2), and DGF‐dialysis (DGF‐D, required dialysis within the week of KT for deceased donor recipients). Logistic regression models were fitted to assess this relationship between MAP and DGF. Results: We included 1602 KT (939 deceased donors, 663 living donors) and 23 were excluded. DGF‐CRR occurred in 33% of patients. DGF‐CRR was associated with MAP < 65 (>5 min: OR 1.77, 95% confidence interval [CI]: 1.39–2.30; 6–10 min: OR 1.67, 95% CI: 0.97–2.86; 11–20 min: OR 2.18, 95% CI: 1.31–3.63) in unadjusted and <55 mmHg (5 min: OR 1.85, 95% CI: 1.47–2.32; 5–10 min: OR 2.41, 95% CI: 1.65–3.53; 11–20 min: OR 2.36, 95% CI: 1.60, 3.48) in adjusted models. There was also a signal for increased risk of DGF‐CRR at MAP < 75 (>5 min: OR 1.69, 95% CI: 1.02–2.80). DGF‐D (incidence 35%) in deceased donor KT was not associated with hypotension. Conclusions: We found an association between intraoperative hypotension and DGF‐CRR at a threshold MAP of 55 mmHg, with a consistent signal toward increased risk at both 65 and 75 mmHg, as indicated by unadjusted models. [ABSTRACT FROM AUTHOR]

Background: While coronavirus disease 2019 (COVID‐19) is no longer a public health emergency, certain patients remain at risk of severe outcomes. To better understand changing risk profiles, we studied the risk factors for patients with and without solid organ transplantation (SOT) through the various waves of the pandemic. Methods: Using the National COVID Cohort Collaborative we studied a cohort of adult patients testing positive for COVID‐19 between January 1, 2020, and May 2, 2022. We separated the data into waves of COVID‐19 as defined by the Centers for Disease Control. In our primary outcome, we used multivariable survival analysis to look at various risk factors for hospitalization in those with and without SOT. Results: A total of 3,570,032 patients were captured. We found an overall risk attenuation of adverse COVID‐19‐associated outcomes over time. In both non‐SOT and SOT populations, diabetes, chronic kidney disease, and congestive heart failure were risk factors for hospitalization. For SOT specifically, longer time periods between transplant and COVID‐19 were protective and age was a risk factor. Notably, asthma was not a risk factor for major adverse renal cardiovascular events, hospitalization, or mortality in either group. Conclusions: Our study provides a longitudinal view of the risks associated with adverse COVID‐related outcomes amongst SOT and non‐SOT patients, and how these risk factors evolved over time. Our work will help inform providers and policymakers to better target high‐risk patients. [ABSTRACT FROM AUTHOR]

Cyclosporin A (CsA), an immunosuppressive drug used in transplant recipients, inhibits graft rejection by binding to cyclophilins and competitively inhibiting calcineurin. While concerns about respiratory infections in immunosuppressed patients exist, contradictory data emerged during the COVID‐19 pandemic, prompting investigations into CsA's impact on viral infections. This study explores CsA's antiviral effects on SARS‐CoV‐2 Omicron BA.1, Delta variants, and human parainfluenza virus 3 (HPIV3) using an ex vivo model of human airway epithelium (HAE). CsA exhibited a dose‐dependent antiviral effect against the SARS‐CoV‐2 Delta variant, reducing viral load over 10 days. However, no significant impact was observed against SARS‐CoV‐2 Omicron or HPIV3, indicating a virus‐specific effect. At high concentrations, CsA was associated with an increase of IL‐8 and a decrease of IFNλ expression in infected and noninfected HAE. This study highlights the complexity of CsA's antiviral mechanisms, more likely involving intricate inflammatory pathways and interactions with specific viral proteins. The research provides novel insights into CsA's effects on respiratory viruses, emphasizing the need for understanding drug–virus interactions in optimizing therapeutic approaches for transplant recipients and advancing knowledge on immunosuppressive treatments' implications on respiratory viral infections. Limitations include the model's inability to assess T lymphocyte activation, suggesting the necessity for further comprehensive studies to decipher the intricate dynamics of immunosuppressive treatments on respiratory viral infections. [ABSTRACT FROM AUTHOR]

Simple Summary: Germ cell transplantation (GCT) has been widely used in fish breeding and genetic resource conservation. However, the technique of spermatogonial stem cell transplantation (SSCT) using female adults as recipients has not been established in Paralichthys olivaceus. There are two key points of GCT technology, one is the preparation of sterile recipients and the other is obtaining a high proportion of donor germ stem cells. We found that three-year-old fish were the most suitable recipients through the use of a combination of high temperature and busulfan. The proportion of spermatogonial stem cells (SSCs) after isolation and purification was increased by more than 60.00%, and they also successfully colonized and proliferated in the recipient ovaries. The results of this study lay a foundation for the subsequent establishment of SSCT in P. olivaceus using female adults as the recipients and provide a reference for using GCT in other fish. Since the advent of germ cell transplantation (GCT), it has been widely used in shortening the fish breeding cycle, sex-controlled breeding and the protection of rare and endangered fish. In this study, the effectiveness of female sterile recipient preparation and donor stem cell isolation and purification were comprehensively evaluated for spermatogonial stem cell transplantation (SSCT) in Paralichthys olivaceus. The best way to prepare sterile recipients was found to be giving three-year-old fish four intraovarian injections of busulfan (20 mg/kg body weight) combined with exposure to a high temperature (28 °C) after the spawning season compared with the two other ways, which induced apoptosis of most of the endogenous germ cells, resulting in shrinkage of the spawning plate and enlargement of the ovarian lumen. Further analysis showed that both the gonadosomatic index and germ-cell-specific vasa expression were significantly lower than those of the natural-temperature group before treatment (p < 0.05). A high percentage (>60.00%) of spermatogonial stem cells (SSCs) were obtained after isolation and purification and were transplanted into the prepared recipients. After three weeks of SSCT, the numbers of PKH26-labeled SSCs were increased in the ovaries of the recipients. These findings provide a basis for the establishment of an ideal SSCT technique using P. olivaceus females as the recipients, ultimately contributing to the efficient conservation of male germplasm resources and effective breeding. [ABSTRACT FROM AUTHOR]

Organoids play pivotal roles in uncovering the molecular mechanisms underlying organogenesis, intercellular communication, and high-throughput drug screening. Testicular organoids are essential for exploring the genetic and epigenetic regulation of spermatogenesis in vivo and the treatment of male infertility. However, the formation of testicular organoids with full spermatogenesis has not yet been achieved. In this study, neonatal mouse testicular cells were isolated by two-step enzymatic digestion, and they were combined with Matrigel and transplanted subcutaneously into nude mice. Histological examination (H&E) staining and immunohistochemistry revealed that cell grafts assembled to form seminiferous tubules that contained spermatogonial stem cells (SSCs) and Sertoli cells, as illustrated by the co-expression of PLZF (a hallmark for SSCs) and SOX9 (a marker for Sertoli cells) as well as the co-expression of UCHL1 (a hallmark for SSCs) and SOX9, after 8 weeks of transplantation. At 10 weeks of transplantation, SSCs could proliferate and differentiate into spermatocytes as evidenced by the expression of PCNA, Ki67, c-Kit, SYCP3, γ-HA2X, and MLH1. Notably, testicular organoids were seen, and spermatids were observed within the lumen of testicular organoids after 16 weeks of transplantation, as shown by the presence of TNP1 and ACROSIN (hallmarks for spermatids). Collectively, these results implicate that we successfully established testicular organoids with spermatogenesis in vivo. This study thus provides an excellent platform for unveiling the mechanisms underlying mammalian spermatogenesis, and it might offer valuable male gametes for treating male infertility. [ABSTRACT FROM AUTHOR]

Background: The use of mobilizing agents for hematopoietic stem cell (HSC) transplantation is insufficient for an increasing number of patients. We previously reported lipid made endocannabinoid (eCB) ligands act on the human bone marrow (hBM) HSC migration in vitro, lacking long term stability to be therapeutic candidate. In this study, we hypothesized if a novel 2-AG-loaded polycaprolactone (PCL)-based nanoparticle delivery system that actively targets BM via phosphatidylserine (Ps) can be generated and validated. Methods: PCL nanoparticles were prepared by using the emulsion evaporation method and characterized by Zetasizer and scanning electron microscopy (SEM). The encapsulation efficiency and release profile of 2-AG were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The presence of cannabinoid receptors (CBRs) in HSCs and monocytes was detected by flow cytometry. Cell morphology and viability were assessed using transmission electron microscopy (TEM), SEM, and the WST-1 viability assay. The migration efficacy of the 2-AG and 2-AG-loaded nanoparticle delivery system on HSCs and HPSCs (TF-1a and TF-1) and monocytes (THP-1) was evaluated using a transwell migration assay. Results: The 140–225 nm PCL nanoparticles exhibited an increasing polydispersity index (PDI) after the addition of Ps and 2-AG, with a surface charge ranging from − 25 to -50 mV. The nanoparticles released up to 36% of 2-AG within the first 8 h. The 2-AG-Ps-PCL did not affect cellular viability compared to control on days 5 and 10. The HSCs and monocytes expressed CB1R and CB2R and revealed increased migration to media containing 1 µM 2-AG-Ps-PCL compared to control. The migration rate of the HSCs toward monocytes incubated with 1 µM 2-AG-Ps-PCL was higher than that of the monocytes of control. The 2-AG-Ps-PCL formulation provided a real time mobilization efficacy at 1 µM dose and 8 h time window via a specific CBR agonism. Conclusion: The newly generated and validated 2-AG-loaded PCL nanoparticle delivery system can serve as a stable, long lasting, targeted mobilization agent for HSCs and as a candidate therapeutic to be included in HSC transplantation (HSCT) protocols following scale-up in vivo preclinical and subsequent clinical trials. [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) infection, which mostly causes a subclinical infection early in life, has important clinical consequences in certain patient groups. CMV is the most common congenital infection and can cause permanent disabilities such as hearing loss and motor- and cognitive deficits in affected infants. In allogeneic haematopoietic stem cell and solid organ transplant recipients, CMV still is an important infectious complication with a risk for life-threatening disease. The previous Swedish recommendations for the management of CMV infections were updated by an expert group under the guidance of The Swedish Reference Group for Antiviral Treatment (RAV) and published at the website of RAV in August 2023 (). We here provide a translation of the updated recommendations, with minor modifications regarding diagnosis of CMV pneumonia. In the present recommendations, we discuss aspects of old and new CMV antivirals, including dosing for different age groups, and cover the management of congenital infections and CMV in immunocompromised patients. The recommendations are evidence-graded in accordance with the Oxford Centre for Evidence-Based Medicine. [ABSTRACT FROM AUTHOR]

Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality worldwide. Limited evidence is available on the most effective diagnostic approaches, management strategies, and long-term outcomes for CAP in patients who have undergone solid organ transplantation. What is the acute and long-term morbidity and mortality after CAP in organ transplant recipients? We retrospectively analyzed hospitalizations for CAP in solid organ recipients at the largest German transplant center. The study included patients admitted between January 1, 2010, and May 31, 2021. The reported outcomes are in-hospital and 1-year mortality, risk of cardiovascular events during hospitalization and at 1 year, admission to the ICU, and risk of pneumonia with Pseudomonas aeruginosa. Multivariable binary logistic regression using stepwise forward selection was performed to determine predictive factors for pneumonia with P aeruginosa. We analyzed data from 403 hospitalizations of 333 solid organ recipients. In > 60% of cases, patients had multiple comorbidities, with cardiovascular and chronic kidney disease being the most prevalent. More than one-half of the patients required oxygen supplementation after admission. In-hospital mortality (13.2%) and the death rate at 1 year postevent (24.6%) were higher than data reported from immunocompetent patients. We also observed high rates of acute cardiovascular events and events occurring 1 year after admission. Early blood cultures and bronchoscopy in the first 24 h significantly increased the odds of establishing an etiology. In our low-resistance setting, the burden of antimicrobial resistance was driven by bacteria from chronically colonized patients, mostly lung transplant recipients. This comprehensive analysis highlights the high morbidity associated with CAP after transplantation. It also emphasizes the need for prospective multicenter studies to guide evidence-based practices and improve outcomes for these vulnerable patients. [ABSTRACT FROM AUTHOR]

• Patient navigation is a process that helps patients overcome barriers to transplantation. • Collaboration with nonprofit patient support organizations is key. • Telemedicine is a useful tool for patient navigation in low- and middle-income countries. Hematopoietic cell transplantation (HCT) is a promising treatment for hematological diseases, yet access barriers like cost and limited transplant centers persist. Telemedicine-based patient navigation (PN) has emerged as a solution. This study presents a cost-free PN telemedicine clinic (TC) in collaboration with the National Marrow Donor Program. Aim: to assess its feasibility and impac on HCT access determined by the cumulative incidence of transplantation. In this single-center cohort study, patients of all ages and diagnoses referred for HCT participated. Two transplant physician-navigators established patient relationships via video calls, collecting medical history, offering HCT education and recommending pretransplant tests. The analysis involved descriptive statistics and intent-to-transplant survival assessment. One hundred and three patients were included of whom n = 78 were referred for allogeneic HCT (alloHCT), with a median age of 28 years. The median time from initial contact to the first consult was 5 days. The cumulative incidence of transplantation was 50% at 6 months and 61% at 12 months, with varying outcomes based on HCT type. Notably, 49 patients were not transplanted, primarily due to refractory disease, progression or relapse (57.1%). Autologous HCT candidates and physician referrals were correlated with higher transplant success compared to alloHCT candidates and patients who were not referred by a physician. Our pretransplant TC was feasible, facilitating access to HCT. Disease relapse posed a significant barrier. Enhancing timely physician referrals should be a focus for future efforts. [ABSTRACT FROM AUTHOR]

New immunotherapy drugs, such as bispecific T-cell engager antibodies, checkpoint inhibitors and antibody–drug conjugates, are commonly used as salvage therapy for patients with non-Hodgkin lymphoma relapsing after chimeric antigen receptor (CAR) T-cell therapy. Nevertheless, their potential long-term effects on the outcome of allogeneic stem cell transplantation (Allo-SCT) are not well known. We retrospectively analyzed the outcomes of 27 relapsed/refractory non-Hodgkin lymphoma patients receiving Allo-SCT after immunotherapy in the pre-CAR T-cell therapy era and compared them with a historical cohort of 28 subjects undergoing Allo-SCT after conventional therapy. The two cohorts had similar outcomes in terms of graft-versus-host disease/relapse-free survival (4 years, 59% versus 46%), overall survival (4 years, 77% versus 44%), non-relapse mortality (4 years, 19% versus 22%) and acute (6 months, 15% versus 21%) and chronic (4 years, 18% versus 24%) graft-versus-host disease. Of note, the cumulative incidence of relapse was lower after immunotherapy (4 years, 4% versus 14%), although significance was not reached. The cumulative incidence of cytomegalovirus and fungal infection did not differ among the two cohorts. Consolidation with Allo-SCT is a safe and curative option for patients achieving disease response after new immunotherapy drugs that could represent a desirable salvage strategy for patients relapsing after CAR T-cell therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

In patients with sickle cell disease (SCD) and beta-thalassemia major (TM), allogeneic hematopoietic stem cell transplantation (HSCT) was considered the only curative treatment option with a good survival rate. However, with the recent approval of gene therapies, more information is needed to understand the benefits and risks of these interventions. We performed a retrospective analysis of the Kids Inpatient Database to describe demographic features, short-term complications, and hospital charges of patients with SCD and TM treated with HSCT during 2006–2019 in the United States. The database was filtered using the International Classification of Diseases, 9th and 10th edition codes to identify children under 20 years of age with SCD or TM who underwent HSCT. A total of 513 children with SCD or TM who received HSCT were analyzed. The prevalence of HSCT per 1000,000 U.S. population increased from 0.31 in 2006 to 1.99 in 2019 (p < 0.001). The median age of children with SCD who underwent HSCT was 10 (6–15) years, and that for TM was 6 (3–11.5) years (p < 0.001). The combined mortality rate was 4% (2.4%–6.6%) but higher in the TM group. The length-of-stay and total charges were higher in the TM population (p < 0.01). This study provides national data on HSCT among hospitalized children with SCD and TM in the United States, demonstrating an increasing use of HSCT between 2006 and 2019. Although hospital mortality of HSCT in these conditions is low, it still represents a challenge, especially in TM patients. [ABSTRACT FROM AUTHOR]

Background: In the setting of the COVID-19 pandemic, a rapid uptake of telehealth services was instituted with the aim of reducing the spread of disease to vulnerable patient populations including heart transplant recipients. Methods: Single-center, cohort study of all heart transplant patients seen by our institution's transplant program during the first 6 weeks of transition from in-person consultation to telehealth (23 March – 5 June 2020). Results: Face-to-face consultation allocation strongly favored patients in the early post-operative period (34 vs. 242 weeks post-transplant; p < 0.001). Telehealth consultation dramatically reduced patient travel and wait times (80 min per visit saved in telehealth patients). No apparent excess re-hospitalization or mortality was seen in telehealth patients. Conclusions: With appropriate triage, telehealth was feasible in heart transplant recipients, with videoconferencing being the preferred modality. Patients seen face-to-face were those triaged to be higher acuity based on time since transplant and overall clinical status. These patients have the expected higher rates of hospital re-admission, and therefore should continue to be seen in person. [ABSTRACT FROM AUTHOR]