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Pancreas transplantation improves glycemic control and mortality in patients with diabetes but requires aggressive immunosuppression to control the alloimmune and autoimmune response. Recent developments in "omics' methods have provided gene transcript-based biomarkers for organ transplant rejection. The tissue Common Response Module (tCRM) score is developed to identify the severity of rejection in kidney, heart, liver, and lung transplants. Still, it has not yet been validated in pancreas transplants (PT). We evaluated the tCRM score's relevance in PT and additional markers of acute cellular rejection (ACR) for PT. An analysis on 51 pancreas biopsies with ACR identified 37 genes and 56 genes significantly upregulated in the case of grade 3 and grade 2 ACR respectively (P

BackgroundSphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is a recently recognized inborn error of metabolism associated with steroid-resistant nephrotic syndrome as well as adrenal insufficiency and immunological, neurological, and skin manifestations. SPLIS is caused by inactivating mutations in SGPL1, encoding the pyridoxal 5'phosphate-dependent enzyme sphingosine-1-phosphate lyase, which catalyzes the final step of sphingolipid metabolism. Some SPLIS patients have undergone kidney transplantation, and others have been treated with vitamin B6 supplementation. In addition, targeted therapies including gene therapy are in preclinical development. In anticipation of clinical trials, it will be essential to characterize the full spectrum and natural history of SPLIS. We performed a retrospective analysis of 76 patients in whom the diagnosis of SPLIS was established in a proband with at least one suggestive finding and biallelic SGPL1 variants identified by molecular genetic testing. The main objective of the study was to identify factors influencing survival in SPLIS subjects.ResultsOverall survival at last report was 50%. Major influences on survival included: (1) age and organ involvement at first presentation; (2) receiving a kidney transplant, and (3) SGPL1 genotype. Among 48 SPLIS patients with nephropathy who had not received a kidney transplant, two clinical subgroups were distinguished. Of children diagnosed with SPLIS nephropathy before age one (n = 30), less than 30% were alive 2 years after diagnosis, and 17% were living at last report. Among those diagnosed at or after age one (n = 18), ~ 70% were alive 2 years after diagnosis, and 72% were living at time of last report. SPLIS patients homozygous for the SPL R222Q variant survived longer compared to patients with other genotypes. Kidney transplantation significantly extended survival outcomes.ConclusionOur results demonstrate that SPLIS is a phenotypically heterogeneous condition. We find that patients diagnosed with SPLIS nephropathy in the first year of life and patients presenting with prenatal findings represent two high-risk subgroups, whereas patients harboring the R222Q SGPL1 variant fare better than the rest. Time to progression from onset of proteinuria to end stage kidney disease varies from less than one month to five years, and kidney transplantation may be lifesaving.

The financial impact of liver transplantation has been underexplored. We aimed to identify associations between high financial burden (≥10% annual income spent on out-of-pocket medical costs) and work productivity, financial distress (coping behaviors in response to the financial burden), and financial toxicity (health-related quality of life, HRQOL) among adult recipients of liver transplant. Between June 2021 and May 2022, we surveyed 207 adult recipients of liver transplant across 5 US transplant centers. Financial burden and distress were measured by 25 items adapted from national surveys of cancer survivors. Participants also completed the Work Productivity and Activity Impairment and EQ-5D-5L HRQOL questionnaires. In total, 23% of recipients reported high financial burden which was significantly associated with higher daily activity impairment (32.9% vs. 23.3%, p =0.048). In adjusted analyses, the high financial burden was significantly and independently associated with delayed or foregone medical care (adjusted odds ratio, 3.95; 95% CI, 1.85-8.42) and being unable to afford basic necessities (adjusted odds ratio, 5.12; 95% CI: 1.61-16.37). Recipients experiencing high financial burden had significantly lower self-reported HRQOL as measured by the EQ-5D-5L compared to recipients with low financial burden (67.8 vs. 76.1, p =0.008) and an age-matched and sex-matched US general population (67.8 vs. 79.1, p

Background: Autologous tissues such as buccal mucosa (BM) are widely used for reconstruction of urethral strictures; however, limitations such as donor site morbidity and scarce tissue supply require the development of alternative biomaterials for urethral repair. The goals of this study were to determine the safety and efficacy of bi-layer silk fibroin (BLSF) matrices for urethral stricture repair and compare histological and functional outcomes to the standard approach, BM urethroplasty under good laboratory practices.Material and methods: A total of 13 rabbits exhibiting urethral stricture formation following electrocoagulation injury were treated with onlay urethroplasty with either acellular BLSF (N = 7) or autologous BM (N = 6) grafts for 3 months. Uninjured control rabbits were maintained in parallel (N = 4).Results and conclusion: Animals receiving BLSF implants were demonstrated to be functionally equivalent to BM grafts in their ability to restored strictured calibers, support micturition and promote tissue regeneration with minimal inflammation.

The acquisition or reactivation of Epstein-Barr virus (EBV) after allogeneic Hematopoietic Stem Cell Transplant (HSCT) can be associated with complications including the development of post-transplant lymphoproliferative disorder (PTLD), which is associated with significant morbidity and mortality. A number of risk factors for PTLD have been defined, including T-cell depletion, and approaches to monitoring EBV, especially in high-risk patients, with the use of preemptive therapy upon viral activation have been described. Newer therapies for the preemption or treatment of PTLD, such as EBV-specific cytotoxic T-cells, hold promise. Further studies to help define risks, diagnosis, and treatment of EBV-related complications are needed in this at-risk population.

AbstractCompared with the general population, hematopoietic cell transplantation (HCT) survivors are at elevated risk for developing solid subsequent neoplasms (SNs). The Center for International Blood and Marrow Transplant Research (CIBMTR) is a key resource for quantifying solid SN incidence following HCT, but the completeness of SN ascertainment is uncertain. Within a cohort of 18 450 CIBMTR patients linked to the California Cancer Registry (CCR), we evaluated the completeness of solid SN data reported to the CIBMTR from 1991 to 2018 to understand the implications of using CIBMTR data alone or combined with CCR data to quantify the burden of solid SNs after HCT. We estimated the cumulative incidence of developing a solid SN, accounting for the competing risk of death. Within the cohort, solid SNs were reported among 724 patients; 15.6% of these patients had an SN reported by CIBMTR only, 36.9% by CCR only, and 47.5% by both. The corresponding cumulative incidence of developing a solid SN at 10 years following a first HCT was 4.0% (95% confidence interval [CI], 3.5-4.4) according to CIBMTR data only, 5.3% (95% CI, 4.9-5.9) according to CCR data only, and 6.3% (95% CI, 5.7-6.8) according to both sources combined. The patterns were similar for allogeneic and autologous HCT recipients. Linking detailed HCT information from CIBMTR with comprehensive SN data from cancer registries provides an opportunity to optimize SN ascertainment for informing follow-up care practices and evaluating risk factors in the growing population of HCT survivors.

BackgroundPulmonary ischaemia-reperfusion injury (IRI) is a major contributor to poor lung transplant outcomes. We recently demonstrated a central role of airway-centred natural killer (NK) cells in mediating IRI; however, there are no existing effective therapies for directly targeting NK cells in humans.MethodsWe hypothesised that a depleting anti-CD94 monoclonal antibody (mAb) would provide therapeutic benefit in mouse and human models of IRI based on high levels of KLRD1 (CD94) transcripts in bronchoalveolar lavage samples from lung transplant patients.ResultsWe found that CD94 is highly expressed on mouse and human NK cells, with increased expression during IRI. Anti-mouse and anti-human mAbs against CD94 showed effective NK cell depletion in mouse and human models and blunted lung damage and airway epithelial killing, respectively. In two different allogeneic orthotopic lung transplant mouse models, anti-CD94 treatment during induction reduced early lung injury and chronic inflammation relative to control therapies. Anti-CD94 did not increase donor antigen-presenting cells that could alter long-term graft acceptance.ConclusionsLung transplant induction regimens incorporating anti-CD94 treatment may safely improve early clinical outcomes.

Dose optimization of sirolimus may further improve outcomes in allogeneic hematopoietic cell transplant (HCT) patients receiving post-transplantation cyclophosphamide (PTCy) to prevent graft-versus-host disease (GVHD). Sirolimus exposure-response association studies in HCT patients (i.e., the association of trough concentration with clinical outcomes) have been conflicting. Sirolimus has important effects on T-cells, including conventional (Tcons) and regulatory T-cells (Tregs), both of which have been implicated in the mechanisms by which PTCy prevents GVHD, but there is an absence of validated biomarkers of sirolimus effects on these cell subsets. Considering the paucity of existing biomarkers and the complexities of the immune system, we conducted a literature review to inform a quantitative systems pharmacology (QSP) model of GVHD. The published literature presented multiple challenges. The sirolimus pharmacokinetic models insufficiently describe sirolimus distribution to relevant physiological compartments. Despite multiple publications describing sirolimus effects on Tcons and Tregs in preclinical and human ex vivo models, consistent parameters relating sirolimus concentrations to circulating Tcons and Tregs could not be found. Each aspect presents a challenge in building a QSP model of sirolimus and its temporal effects on T-cell subsets and GVHD prevention. To optimize GVHD prevention regimens, phase I studies and systematic studies of immunosuppressant concentration-effect association are needed for QSP modeling.

The kidney is the most common solid organ transplant globally and rates continue to climb, driven by the increasing prevalence of end stage renal disease (ESRD). Compounded by advancements in surgical techniques and immunosuppression leading to longer graft survival, radiologists evermore commonly evaluate kidney transplant patients and candidates, underscoring their role along the transplant process. Multiphase computed tomography (CT) with multiplanar and 3D reformatting is the primary method for evaluating renal donor candidates, detailing renal size, vascular/collecting system anatomy, and identifying significant pathologies such as renal vascular diseases and nephrolithiasis. Ultrasound is the preferred initial postoperative imaging modality for graft evaluation due to its low cost, accessibility, noninvasiveness, and lack of radiation. CT and magnetic resonance imaging (MRI) may be useful adjunctive imaging techniques in diagnosing transplant pathology when ultrasound alone is not diagnostic. Kidney transplant complications are categorized by an approximate timeline framework, aiding in differential diagnosis based on onset, duration, and severity and include perinephric fluid collections, graft compression, iatrogenic injuries, vascular compromise, graft rejection, and neoplastic processes. This review discusses imaging strategies and important findings along the transplant timeline, from donor assessment to long-term recipient complications.

Background: The outcome of Low Flow-Low Gradient (LF-LG) severe aortic stenosis (AS) patients who underwent Transcatheter Aortic Valve Replacement (TAVR) procedure is not well defined. We conducted a systematic review of the literature to compare the outcomes of TAVR in LF-LG AS patients to the more traditional high gradient (HG) aortic stenosis. Methods: We comprehensively searched for controlled randomized and non-randomized studies from 4 online databases. We are presenting the data using risk ratios (95 % confidence intervals) and measuring heterogeneity using Higgins' I2 index. Results: Our analysis included 4380 patients with 3425 HG patients and 955 LF-LG patients from 6 cohort (5 retrospective and 1 prospective) studies. When compared to LFLG; TAVR was associated with significantly lower 30 days mortality in HG patients (5.1 % vs 7.4 %; relative risk [RR]: 0.55; 95 % confidence interval [CI]: 0.35 to 0.86; p < 0.01). Similar findings were also observed in 12-month cardiovascular (CV) mortality (5.5 % vs. 10.4 %; RR: 0.47; 95 % CI: 0.38 to 0.60; p < 0.01 and 12-month all-cause mortality (15.9 % vs 20.9 %; RR: 0.70; 95 % CI: 0.49 to 1.00; p < 0.05). There was no significant difference in myocardial infarction (MI) after TAVR between HG and LF-LG at 30 days (0.16 % vs. 0.95 %; p < 0.09) or 12 months (0.43 % vs. 0.95 %; p = 0.20). Similarly, there was no difference in stroke rates at 30 days (2.9 % vs. 2.86 %) or at 12 months (3.6 % vs. 3.06 %). Conclusions and relevance: Patients with LF-LG severe AS who underwent TAVR had worse 1-year all-cause mortality, 30-day all-cause, and 1-year CV mortality when compared to TAVR in HG severe AS. There was no difference in MI or stroke rates. Therefore, with heart team discussion and informed patient decision regarding the risk and benefit, TAVR would still offer better outcomes in LFLG AS compared to conservative medical management.

The introduction of posttransplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis lead to significant improvements in haploidentical stem cell transplantation (haplo-SCT) outcomes over the past decade. We retrospectively assessed long-term outcomes of patients who had their first haplo-SCT between February 2009 and March 2019. Long-term survivors were defined as patients who were alive and disease-free at 2 years after transplant. Three hundred thirty-five patients with a median age of 48 years (range, 18-72) were identified. Of these, 142 patients were disease-free and alive at 2 years after transplant. The 4-year progression-free survival (PFS) and overall survival (OS) for all study patients were 42% and 47%, respectively. With a median follow-up of 52 months for the long-term survivor group, the 4-year PFS and OS were 94% and 96%, respectively. The 4-year cumulative incidence of relapse and non-relapse mortality (NRM) were 2.9% and 3.3%, respectively. Age ≥55 years was the only predictive factor in multivariate analysis for inferior PFS (hazard ratio [HR], 3.41; 95% confidence interval [CI], 1.21-9.60; P = .020) and OS (HR, 3.31; 95% CI, 1.08-10.18; P = .037). Thirteen patients (9%) died in the long-term survivor group, only 2 of whom died of relapsed disease. Secondary primary malignancy was the most frequent cause of NRM (n = 4), followed by infection (n = 2). For haplo-SCT with PTCy-based GVHD prophylaxis, our findings suggest an excellent long-term survival for patients who were disease-free and alive at 2 years after transplant. Late relapses were rare, and age was the only predictive factor for long-term outcomes.

Juvenile myelomonocytic leukemia (JMML) is a hematologic malignancy of young children caused by mutations that increase Ras signaling output. Hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment, but patients with relapsed or refractory (advanced) disease have dismal outcomes. This phase II trial evaluated the safety and efficacy of trametinib, an oral MEK1/2 inhibitor, in patients with advanced JMML. Ten infants and children were enrolled, and the objective response rate was 50%. Four patients with refractory disease proceeded to HSCT after receiving trametinib. Three additional patients completed all 12 cycles permitted on study and continue to receive off-protocol trametinib without HSCT. The remaining three patients had progressive disease with two demonstrating molecular evolution by the end of cycle 2. Transcriptomic and proteomic analyses provided novel insights into the mechanisms of response and resistance to trametinib in JMML. ClinicalTrials.gov Identifier: NCT03190915. Significance: Trametinib was safe and effective in young children with relapsed or refractory JMML, a lethal disease with poor survival rates. Seven of 10 patients completed the maximum 12 cycles of therapy or used trametinib as a bridge to HSCT and are alive with a median follow-up of 24 months.

OBJECTIVE: Realignment osteotomy performed concomitantly with cartilage restoration typically requires early restricted weightbearing and can add significant morbidity, potentially leading to an increased risk of early perioperative complications. The purpose of this study was to compare the 30-day complication rates after isolated cartilage restoration (ICR) versus concomitant cartilage restoration and osteotomy (CRO) using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database. DESIGN: NSQIP registries between 2006 and 2019 were queried using Current Procedural Terminology codes to identify patients undergoing ICR (autologous chondrocyte implantation, osteochondral autograft transfer, or osteochondral allograft transplantation) and CRO (with concomitant high tibial osteotomy, distal femoral osteotomy, and/or tibial tubercle osteotomy). Complications rates between treatment groups were compared using multivariate logistic regression analyses adjusted for sex, age, steroid use, and respiratory status. RESULTS: A total of 773 ICR and 97 CRO surgical procedures were identified. Mean patient ages were 35.9 years for the ICR group and 31.2 years for the CRO group. Operative time was significantly longer in the CRO group (170.8 min) compared with the ICR group (97.8 min). Multivariate analysis demonstrated no significant differences in rates of PE, VTE, and all-cause readmission between the ICR and CRO groups. No events of wound disruption, SSI and reoperation were found in the CRO group, while the ICR group was characterized by low rates of wound disruption, reoperation, and SSI (

BackgroundThe optimal timing of noncardiac surgery (NCS) following transcatheter aortic valve replacement (TAVR) for aortic stenosis has not been elucidated by current national guidelines.ObjectivesThe aim of this study was to evaluate the effect of the time interval between TAVR and NCS (Δt) on the perioperative risk of major adverse events (MAEs).MethodsAll adult admissions for isolated TAVR for aortic stenosis were identified in the 2016 to 2020 Nationwide Readmissions Database. Patients who received NCS on subsequent admission were included for analysis and grouped by Δt as follows: ≤30, 31 to 60, 61 to 90, and >90 days. Multivariable regression models were constructed to examine the association of Δt with ensuing outcomes.ResultsOf 3,098 patients (median age = 79 years, 41.6% female), 19.1% underwent NCS at ≤30 days, 22.9% at 31 to 60 days, 16.7% at 61 to 90 days, and 41.3% at >90 days. After adjustment, the odds of MAEs were similar for operations performed at ≤30 days (adjusted OR [AOR]: 1.05; 95% confidence interval [CI]: 0.74-1.50), 31 to 60 days (AOR: 0.97; 95% CI: 0.71-1.31), and 61 to 90 days (AOR: 0.95; 95% CI: 0.67-1.34), with those at >90 days as reference. When examining the average marginal effect of the interval to surgery, risk-adjusted MAE rates were statistically similar across Δt groups for elective status and NCS risk category combinations.ConclusionsNCS within 30, 31 to 60, or 61 to 90 days after TAVR was not associated with increased odds of MAEs compared with operations after 90 days irrespective of NCS risk category or elective status. Our findings suggest that the interval between NCS and TAVR may not be an accurate predictor of MAE risk in this population.

Risk for transmission of SARS-CoV-2 through allogeneic human tissue transplantation is unknown. To further evaluate the risk of virus transmission, tissues were obtained from deceased donors who had tested positive for SARS-CoV-2 RNA via nasopharyngeal swab. This study evaluated an array of human tissues recovered for transplantation, including bone, tendon, skin, fascia lata, vascular tissues, and heart valves. Tissue samples and plasma or serum samples, if available, were tested for viral RNA (vRNA) using a real time PCR system for the presence of virus RNA. All samples were tested in quadruplicate for both subgenomic (sgRNA) and genomic (gRNA) RNA encoding the SARS-CoV-2 nucleocapsid gene. Amplification of a cellular housekeeping gene served as the positive control for every sample. A total of 47 tissue samples from 17 donors were tested for SARS-CoV-2 RNA. Four donors had plasma or serum available for paired testing. SARS-CoV-2 RNA was not detected from any tissue or plasma/serum sample tested. Based on these findings, risk of transmission through the transplantation of tissue types studied from SARS-CoV-2 infected donors is likely to be low.

Frailty is classically associated with advanced age but is also an important predictor of clinical outcomes in comparatively young adults with cirrhosis. We examined the association of biological aging with frailty and post-transplant outcomes in a pilot of adults with cirrhosis undergoing liver transplantation (LT). Frailty was measured via the Liver Frailty Index (LFI). The primary epigenetic clock DNA methylation (DNAm) PhenoAge was calculated from banked peripheral blood mononuclear cells; we secondarily explored two first-generation clocks (Hannum; Horvath) and two additional second-generation clocks (GrimAge; GrimAge2). Twelve adults were included: seven frail (LFI ≥ 4.4, mean age 55 years) and five robust (LFI

BackgroundAutologous tissues derived from bowel, buccal mucosa and skin are primarily used to repair or replace diseased vaginal segments as well as create neovaginas for male-to-female transgenders. These grafts are often limited by scarce tissue supply, donor site morbidity and post-operative complications. Bi-layer silk fibroin (BLSF) biomaterials represent potential alternatives for vaginoplasty given their structural strength and elasticity, low immunogenicity, and processing flexibility. The goals of the current study were to assess the potential of acellular BLSF scaffolds for vaginal tissue regeneration in respect to conventional small intestinal submucosal (SIS) matrices in a rat model of vaginoplasty.MethodsInlay vaginoplasty was performed with BLSF and SIS scaffolds (N = 21 per graft) in adult female rats for up to 2 months of implantation. Nonsurgical controls (N = 4) were investigated in parallel. Outcome analyses included histologic, immunohistochemical and histomorphometric evaluations of wound healing patterns; µ-computed tomography (CT) of vaginal continuity; and breeding assessments.ResultsAnimals in both scaffold cohorts exhibited 100% survival rates with no severe post-operative complications. At 2 months post-op, µ-CT analysis revealed normal vaginal anatomy and continuity in both graft groups similar to controls. In parallel, BLSF and SIS grafts also induced comparable constructive remodeling patterns and were histologically equivalent in their ability to support formation of vascularized vaginal neotissues with native tissue architecture, however with significantly less smooth muscle content. Vaginal tissues reconstructed with both implants were capable of supporting copulation, pregnancy and similar amounts of live births.ConclusionsBLSF biomaterials represent potential "off-the-shelf" candidates for vaginoplasty.

The developmental origin of blood-forming hematopoietic stem cells (HSCs) is a longstanding question. Here, our non-invasive genetic lineage tracing in mouse embryos pinpoints that artery endothelial cells generate HSCs. Arteries are transiently competent to generate HSCs for 2.5 days (∼E8.5-E11) but subsequently cease, delimiting a narrow time frame for HSC formation in vivo. Guided by the arterial origins of blood, we efficiently and rapidly differentiate human pluripotent stem cells (hPSCs) into posterior primitive streak, lateral mesoderm, artery endothelium, hemogenic endothelium, and >90% pure hematopoietic progenitors within 10 days. hPSC-derived hematopoietic progenitors generate T, B, NK, erythroid, and myeloid cells in vitro and, critically, express hallmark HSC transcription factors HLF and HOXA5-HOXA10, which were previously challenging to upregulate. We differentiated hPSCs into highly enriched HLF+ HOXA+ hematopoietic progenitors with near-stoichiometric efficiency by blocking formation of unwanted lineages at each differentiation step. hPSC-derived HLF+ HOXA+ hematopoietic progenitors could avail both basic research and cellular therapies.

BackgroundFecal microbiota transplantation (FMT) is increasingly used for gastrointestinal and extra-gastrointestinal diseases in veterinary medicine. However, its effects on immune responses and possible adverse events have not been systematically investigated.Hypothesis/objectivesDetermine the short-term safety profile and changes in the peripheral immune system after a single FMT administration in healthy dogs.AnimalsTen client-owned, clinically healthy dogs as FMT recipients, and 2 client-owned clinically healthy dogs as FMT donors.MethodsProspective non-randomized clinical trial. A single rectal enema of 5 g/kg was given to clinically healthy canine recipients. During the 28 days after FMT administration, owners self-reported adverse events and fecal scores. On Days 0 (baseline), 1, 4, 10, and 28 after FMT, fecal and blood samples were collected. The canine fecal dysbiosis index (DI) was calculated using qPCR.ResultsNo significant changes were found in the following variables: CBC, serum biochemistry, C-reactive protein, serum cytokines (interleukins [IL]-2, -6, -8, tumor necrosis factor [TNF]-α), peripheral leukocytes (B cells, T cells, cluster of differentiation [CD]4+ T cells, CD8+ T cells, T regulatory cells), and the canine DI. Mild vomiting (n = 3), diarrhea (n = 4), decreased activity (n = 2), and inappetence (n = 1) were reported, and resolved without intervention.Conclusions and clinical importanceFecal microbiota transplantation did not significantly alter the evaluated variables and recipients experienced minimal adverse events associated with FMT administration. Fecal microbiota transplantation was not associated with serious adverse events, changes in peripheral immunologic variables, or the canine DI in the short-term.

Because derivation of retinal organoids (ROs) and transplantation are frequently split between geographically distant locations, we developed a special shipping device and protocol capable of the organoids' delivery to any location. Human embryonic stem cell (hESC)-derived ROs were differentiated from the hESC line H1 (WA01), shipped overnight to another location, and then transplanted into the subretinal space of blind immunodeficient retinal degeneration (RD) rats. Development of transplants was monitored by spectral-domain optical coherence tomography. Visual function was accessed by optokinetic tests and superior colliculus (SC) electrophysiology. Cryostat sections through transplants were stained with hematoxylin and eosin; or processed for immunohistochemistry to label human donor cells, retinal cell types, and synaptic markers. After transplantation, ROs integrated into the host RD retina, formed functional photoreceptors, and improved vision in rats with advanced RD. The survival and vision improvement are comparable with our previous results of hESC-ROs without a long-distance delivery. Furthermore, for the first time in the stem cell transplantation field, we demonstrated that the response heatmap on the SC showed a similar shape to the location of the transplant in the host retina, which suggested the point-to-point projection of the transplant from the retina to SC. In conclusion, our results showed that using our special device and protocol, the hESC-derived ROs can be shipped over long distance and are capable of survival and visual improvement after transplantation into the RD rats. Our data provide a proof-of-concept for stem cell replacement as a therapy for RD patients.

Hematopoietic stem cell transplantation can cure various disorders but poses cardiovascular risks, especially for elderly patients and those with cardiovascular diseases. Cardiovascular evaluations are crucial in pretransplantation assessments, but guidelines are lacking. This American Heart Association scientific statement summarizes the data on transplantation-related complications and provides guidance for the cardiovascular management throughout transplantation. Hematopoietic stem cell transplantation consists of 4 phases: pretransplantation workup, conditioning therapy and infusion, immediate posttransplantation period, and long-term survivorship. Complications can occur during each phase, with long-term survivors facing increased risks for late effects such as cardiovascular disease, secondary malignancies, and endocrinopathies. In adults, arrhythmias such as atrial fibrillation and flutter are the most frequent acute cardiovascular complication. Acute heart failure has an incidence ranging from 0.4% to 2.2%. In pediatric patients, left ventricular systolic dysfunction and pericardial effusion are the most common cardiovascular complications. Factors influencing the incidence and risk of complications include pretransplantation therapies, transplantation type (autologous versus allogeneic), conditioning regimen, comorbid conditions, and patient age. The pretransplantation cardiovascular evaluation consists of 4 steps: (1) initial risk stratification, (2) exclusion of high-risk cardiovascular disease, (3) assessment of cardiac reserve, and (4) optimization of cardiovascular reserve. Clinical risk scores could be useful tools for the risk stratification of adult patients. Long-term cardiovascular management of hematopoietic stem cell transplantation survivors includes optimizing risk factors, monitoring, and maintaining a low threshold for evaluating cardiovascular causes of symptoms. Future research should prioritize refining risk stratification and creating evidence-based guidelines and strategies to optimize outcomes in this growing patient population.

BACKGROUND: Autologous stem cell transplantation (ASCT) after induction therapy improves disease-free survival for patients with multiple myeloma (MM). While the goal of ASCT is to render a minimal disease state, it is also associated with eradication of immunosuppressive cells, and we hypothesize that early introduction of immunotherapy post-ASCT may provide a window of opportunity to boost treatment efficacy. METHODS: We conducted a phase 1 clinical trial to investigate the application of autologous lymphocyte infusion and anti-SLAMF7 monoclonal antibody, elotuzumab, after ASCT in patients with newly diagnosed MM previously treated with induction therapy. In addition to CD34+ stem cells, peripheral blood mononuclear cells were harvested prior to transplant and infused on day 3 after stem cell infusion to accelerate immune reconstitution and provide autologous natural killer (NK) cells that are essential to the mechanism of elotuzumab. Elotuzumab was administered starting on day 4 and then every 28 days after until 1 year post-ASCT. Cycles 4-12 were administered with standard-of-care lenalidomide maintenance. RESULTS: All subjects were evaluated for safety, and 13 of 15 subjects completed the treatment protocol. At 1 year post-ASCT, the disease status of enrolled subjects was as follows: five stringent complete responses, one complete response, six very good partial responses, one partial response, and two progressive diseases. The treatment plan was well tolerated, with most grade 3 and 4 AEs being expected hematologic toxicities associated with ASCT. Correlative analysis of the immune microenvironment demonstrated a trend toward reduced regulatory T cells during the first 3 months post-transplant followed by an increase in NK cells and monocytes in patients achieving a complete remission. CONCLUSIONS: This phase 1 clinical trial demonstrates that early introduction of immunotherapy after ASCT is well tolerated and shows promising disease control in patients with MM, accompanied by favorable changes in the immune microenvironment. TRIAL REGISTRATION NUMBER: NCT02655458.

Allogeneic hematopoietic stem cell transplantation (aHSCT) can cure patients with otherwise fatal leukemias and lymphomas. However, the benefits of aHSCT are limited by graft-versus-host disease (GVHD). Minnelide, a water-soluble analog of triptolide, has demonstrated potent antiinflammatory and antitumor activity in several preclinical models and has proven both safe and efficacious in clinical trials for advanced gastrointestinal malignancies. Here, we tested the effectiveness of Minnelide in preventing acute GVHD as compared with posttransplant cyclophosphamide (PTCy). Strikingly, we found Minnelide improved survival, weight loss, and clinical scores in an MHC-mismatched model of aHSCT. These benefits were also apparent in minor MHC-matched aHSCT and xenogeneic HSCT models. Minnelide was comparable to PTCy in terms of survival, GVHD clinical score, and colonic length. Notably, in addition to decreased donor T cell infiltration early after aHSCT, several regulatory cell populations, including Tregs, ILC2s, and myeloid-derived stem cells in the colon were increased, which together may account for Minnelides GVHD suppression after aHSCT. Importantly, Minnelides GVHD prevention was accompanied by preservation of graft-versus-tumor activity. As Minnelide possesses anti-acute myeloid leukemia (anti-AML) activity and is being applied in clinical trials, together with the present findings, we conclude that this compound might provide a new approach for patients with AML undergoing aHSCT.

The current paradigm of medicine is mostly designed to block or prevent pathological events. Once the disease-led tissue damage occurs, the limited endogenous regeneration may lead to depletion or loss of function for cells in the tissues. Cell therapy is rapidly evolving and influencing the field of medicine, where in some instances attempts to address cell loss in the body. Due to their biological function, engineerability, and their responsiveness to stimuli, cells are ideal candidates for therapeutic applications in many cases. Such promise is yet to be fully obtained as delivery of cells that functionally integrate with the desired tissues upon transplantation is still a topic of scientific research and development. Main known impediments for cell therapy include mechanical insults, cell viability, host's immune response, and lack of required nutrients for the transplanted cells. These challenges could be divided into three different steps: 1) Prior to, 2) during the and 3) after the transplantation procedure. In this review, we attempt to briefly summarize published approaches employing biomaterials to mitigate the above technical challenges. Biomaterials are offering an engineerable platform that could be tuned for different classes of cell transplantation to potentially enhance and lengthen the pharmacodynamics of cell therapies.

Background: In the 2021 Transcatheter Valve Therapy (TVT) registry, 8.9 % of patients underwent TAVR via access sites other than the femoral artery. Transthoracic approaches may be contraindicated in some patients and may be associated with poorer outcomes. Therefore other alternative access routes are increasingly being performed. We conducted a systematic review of the literature on transcarotid transcatheter aortic valve replacement (TC-TAVR) and meta-analysis comparing outcomes of TC-TAVR and other access routes. Methods: We comprehensively searched for controlled randomized and non-randomized studies from 4 online databases. We presented data using risk ratios (95 % confidence intervals) and measured heterogeneity using Higgins' I2. Results: Sixteen observational studies on transcarotid TAVR were included in the analysis; 4 studies compared TC-TAVR vs TF-TAVR. The mean age and STS score for patients undergoing TC-TAVR were 80 years and 7.6 respectively. For TF-TAVR patients, mean age and STS score were 81.2 years and 6.5 respectively. There was no difference between patients undergoing TC-TAVR and TF-TAVR in the following 30-day outcomes: MACE [8.4 % vs 6.7 %; OR 1.32 (95 % CI 0.71–2.46 p = 0.38) I2 = 0 %], mortality [5.6 % vs 4.0 %; OR 0.42 (95 % CI 0.60–3.37, P = 0.42) I2 = 0 %] and stroke [0.7 % vs 2.3 %; OR 0.49 (95 % CI 0.09–2.56, P = 0.40) I2 = 0 %]. There was no difference in 30-day major vascular complications [0.7 % vs 3 %; OR 0.55 (95 % CI 0.06–5.29, P = 0.61) I2 = 39 %], major bleeding [0.7 % vs 3.8 %; OR 0.39 (95 % CI 0.09–1.67, P = 0.21) I2 = 0 %], and moderate or severe aortic valve regurgitation [8.6 % vs 9.9 %; OR 0.89 (95 % CI 0.48–1.65, P = 0.72) I2 = 0 %]. Conclusion: There are no significant differences in mortality, stroke MACE and major or life-threatening bleeding or vascular complications when TC-TAVR is compared to TF-TAVR approaches.

Hypoxia plays a crucial role in cell physiology. Defining the oxygen level that induces cell death within 3D tissues is vital for understanding tissue hypoxia; however, obtaining accurate measurements has been technically challenging. In this study, we introduce a non-invasive, high-throughput methodology to quantify critical survival partial oxygen pressure (pO₂) with high spatial resolution within spheroids by employing a combination of controlled hypoxic conditions, semi-automated live/dead cell imaging, and computational oxygen modeling. The oxygen-permeable, micro-pyramid patterned culture plates created a precisely controlled oxygen condition around the individual spheroid. Live/dead cell imaging provided the geometric information of the live/dead boundary within spheroids. Finally, computational oxygen modeling calculated the pO₂ at the live/dead boundary within spheroids. As proof of concept, we determined the critical survival pO₂ in two types of spheroids: isolated primary pancreatic islets and tumor-derived pseudo-islets (2.43 ± 0.08 vs. 0.84 ± 0.04 mmHg), indicating higher hypoxia tolerance in pseudo-islets due to their tumorigenic origin. We also applied this method for evaluating graft survival in cell transplantations for diabetes therapy, where hypoxia is a critical barrier to successful transplantation outcomes; thus, designing oxygenation strategies is required. Based on the elucidated critical survival pO₂, 100% viability could be maintained in a typically sized primary islet under the tissue pO₂ above 14.5 mmHg. This work presents a valuable tool that is potentially instrumental for fundamental hypoxia research. It offers insights into physiological responses to hypoxia among different cell types and may refine translational research in cell therapies.

BackgroundVascular access is a rate-limiting step for peripheral blood stem cell collection. In the absence of readily accessible superficial veins, placement of tunnelled or non-tunnelled central venous catheters (CVCs) is common. These invasive access routes create medical risks for patients and are associated with logistical challenges, thus prompting a search for alternatives. One such option is the off-label use of midline catheters.Study design and methodsWe carried out a literature search for published experience with the use of midline catheters for peripheral blood stem cell collection. Data extracted included whether collections were allogeneic or autologous, donor sex, age and weight, inlet flow rate, total blood volumes (TBV) processed, collection duration, number of collections per donor, and achievement of collection targets.ResultsThe search produced three reports (one in abstract form) comprising 19 patients and 26 collection events. Donor sex and status were provided for 18 patients; 10 were female, 8 were male, 12 were allogeneic, and 6 autologous. Median (range) for: donor age was 28 (12-59); donor body weight (kg) was 77.5 (45.4-113.4); inlet flow rate (in mL/min) was 66 (28-80); TBV processed (in mL) was 15,880 (6178-21,871); collection duration (in hours) was 5.0 (3.2-7.0); and CD34 × 106/kg collection yield was 5.9 (3.6-23.0). Target CD34 yields were achieved in 14/19 (74%) of donors with 7/19 (37%) requiring two collections days.DiscussionPeripheral blood stem cell collection does appear to be viable via midline-based catheter access, particularly for allogeneic donors and shorter collection courses. Development of institution-specific guidelines and care pathways are recommended.

ABO blood group antigens are critical determinants of immunologic self and non-self and are ubiquitously expressed on all cellular tissues. Antibodies against non-self ABO antigens are naturally present and can mediate pathologic reactions against incompatible transfused blood cells and transplanted tissues. Laboratory testing for ABO antigens and isoagglutinins is essential for safe and effective transfusion and transplantation. Testing for ABO antigens has traditionally depended on serologic testing. However, there is increasing need for evaluation of genetic analysis of ABO antigens, to enable evaluation of ABO blood group in cases where serologic testing may be ambiguous or impossible to accurately perform. The clinical need for ABO genotyping is being addressed by the development of multiple molecular diagnostic approaches. Recent data have clearly demonstrated the potential utility of ABO genotyping in solid organ transplantation, yet widespread implementation has been slow. We propose that this lag is related to practical considerations in laboratory testing, including limited regulatory guidance on the performance and reporting of these assays and the absence of widely available external proficiency testing programs for quality assurance. Here we describe approaches to ABO genotyping, current initiatives in developing ABO genotyping proficiency testing programs, and laboratory quality assurance considerations for ABO genotyping.

Astrocytes, the most abundant glial cell type in the brain, are underrepresented in traditional cortical organoid models due to the delayed onset of cortical gliogenesis. Here we introduce a new glia-enriched cortical organoid model that exhibits accelerated astrogliogenesis. We demonstrated that induction of a gliogenic switch in a subset of progenitors enabled the rapid derivation of astroglial cells, which account for 25-31% of the cell population within 8-10 weeks of differentiation. Intracerebral transplantation of these organoids reliably generated a diverse repertoire of cortical neurons and anatomical subclasses of human astrocytes. Spatial transcriptome profiling identified layer-specific expression patterns among distinct subclasses of astrocytes within organoid transplants. Using an in vivo acute neuroinflammation model, we identified a subpopulation of astrocytes that rapidly activates pro-inflammatory pathways upon cytokine stimulation. Additionally, we demonstrated that CD38 signaling has a crucial role in mediating metabolic and mitochondrial stress in reactive astrocytes. This model provides a robust platform for investigating human astrocyte function.

Allogeneic hematopoietic cell transplantation (HCT) can be complicated by life-threatening organ toxicity and infection necessitating intensive care. Epidemiologic data have been limited by single-center studies, poor database granularity, and a lack of long-term survivors. To identify contemporary trends in intensive care unit (ICU) use and long-term outcomes, we merged data from the Center for International Blood and Marrow Transplant Research and the Virtual Pediatric Systems databases. We identified 6995 pediatric patients with HCT aged ≤21 years who underwent first allogeneic HCT between 2008 and 2014 across 69 centers in the United States or Canada and followed patients until the year 2020. ICU admission was required for 1067 patients (8.3% by day +100, 12.8% by 1 year, and 15.3% by 5 years after HCT), and was linked to demographic background, pretransplant organ toxicity, allograft type and HLA-match, and the development of graft-versus-host disease or malignancy relapse. Survival to ICU discharge was 85.7%, but more than half of ICU survivors required ICU readmission, leading to 52.5% and 42.6% survival at 1- and 5-years post-ICU transfer, respectively. ICU survival was worse among patients with malignant disease, poor pretransplant organ function, and alloreactivity risk factors. Among 1-year HCT survivors, those who required ICU in the first year had 10% lower survival at 5 years and developed new dialysis-dependent renal failure at a greater rate (P

The high ecological and economic value of seagrass has been long recognized, with these foundational habitats providing myriad ecosystem services. Yet through cumulative anthropogenic impacts, seagrasses are exhibiting extensive declines globally. A litany of studies and active restoration trials have demonstrated practical methodologies to restore seagrass habitats and effectively return critical habitat functions to degraded coastal zone systems worldwide. Seagrass loss along the U.S. West Coast has precipitated decades of seagrass protection, conservation, and restoration efforts. Yet, mitigation transplanting efforts have prioritized Zostera marina (narrow-leaved eelgrass) in shallow, protected environments, while a dearth of information is available on species inhabiting offshore islands and exposed mainland coasts. In this study, we conducted a novel transplant of Zostera pacifica, a wide-leaved species found in depths of 7 – 20 m along the offshore islands and mainland coast of California. Transplants were conducted at three geographically distinct sites in Santa Monica Bay, coupled with continuous monitoring of biophysical parameters providing insight into physical drivers at transplant and donor sites. Utilizing in situ data, and environmental thresholds adapted from the literature for Z. marina, we performed exposure analyses to evaluate factors influencing Z. pacifica transplant performance. Exceedances of threshold values for environmental parameters, specifically, wave exposure and near-bed flow speeds (Hrms > 0.59 m and Urms > 0.1 m s-1), photosynthetically active radiation (< 3 and > 5 mol m-2 day-1) and dissolved oxygen (< 3 mg O2 L-1) exposure impacted transplant survivorship. These results suggest Z. pacifica persist in biophysically dynamic conditions and are sensitive to exceedances of thresholds, underlining the importance of pre-transplant site-selection processes to this species. These data represent the first holistic study of Z. pacifica transplanting on an exposed mainland coast, which provides a view into the baseline environmental envelopes within existing Z. pacifica habitat, and further, may serve as a model for investigating scalable open coast seagrass restoration for temperate regions.

Although cold preservation remains the gold standard in organ transplantation, cold stress-induced cellular injury is a significant problem in clinical orthotopic liver transplantation (OLT). Because a recent study showed that cold stress activates ferroptosis, a form of regulated cell death, we investigated whether and how ferroptosis determines OLT outcomes in mice and humans. Treatment with ferroptosis inhibitor (ferrostatin-1) during cold preservation reduced lipid peroxidation (malondialdehyde; MDA), primarily in liver sinusoidal endothelial cells (LSECs), and alleviated ischemia/reperfusion injury in mouse OLT. Similarly, ferrostatin-1 reduced cell death in cold-stressed LSEC cultures. LSECs deficient in nuclear factor erythroid 2-related factor 2 (NRF2), a critical regulator of ferroptosis, were susceptible to cold stress-induced cell death, concomitant with enhanced endoplasmic reticulum (ER) stress and expression of mitochondrial Ca2+ uptake regulator (MICU1). Indeed, supplementing MICU1 inhibitor reduced ER stress, MDA expression, and cell death in NRF2-deficient but not WT LSECs, suggesting NRF2 is a critical regulator of MICU1-mediated ferroptosis. Consistent with murine data, enhanced liver NRF2 expression reduced MDA levels, hepatocellular damage, and incidence of early allograft dysfunction in human OLT recipients. This translational study provides a clinically applicable strategy in which inhibition of ferroptosis during liver cold preservation mitigates OLT injury by protecting LSECs from peritransplant stress via an NRF2-regulatory mechanism.

While chronologic age can be precisely defined, clinical manifestations of advanced age occur in different ways and at different rates across individuals. The observed phenotype of advanced age likely reflects a superposition of several biological aging mechanisms which have gained increasing attention as the world contends with an aging population. Even within the immune system, there are multiple age-associated biological mechanisms at play, including telomere dysfunction, epigenetic dysregulation, immune senescence programs, and mitochondrial dysfunction. These biological mechanisms have associated clinical syndromes, such as telomere dysfunction leading to short telomere syndrome (STS), and optimal patient management may require recognition of biologically based aging syndromes. Within the clinical context of lung transplantation, select immune aging mechanisms are particularly pronounced. Indeed, STS is increasingly recognized as an indication for lung transplantation. At the same time, common aging phenotypes may be evoked by the stress of transplantation because lung allografts face a potent immune response, necessitating higher levels of immune suppression and associated toxicities, relative to other solid organs. Age-associated conditions exacerbated by lung transplant include bone marrow suppression, herpes viral infections, liver cirrhosis, hypogammaglobulinemia, frailty, and cancer risk. This review aims to dissect the molecular mechanisms of immune aging and describe their clinical manifestations in the context of lung transplantation. While these mechanisms are more likely to manifest in the context of lung transplantation, this mechanism-based approach to clinical syndromes of immune aging has broad relevance to geriatric medicine.

Cortical inhibitory interneurons (cINs) are born in the ventral forebrain and migrate into the cortex where they make connections with locally produced excitatory glutamatergic neurons. Cortical function critically depends on the number of cINs, which is also key to establishing the appropriate inhibitory/excitatory balance. The final number of cINs is determined during a postnatal period of programmed cell death (PCD) when ~40% of the young cINs are eliminated. Previous work shows that the loss of clustered gamma protocadherins (Pcdhgs), but not of genes in the Pcdha or Pcdhb clusters, dramatically increased BAX-dependent cIN PCD. Here, we show that PcdhγC4 is highly expressed in cINs of the mouse cortex and that this expression increases during PCD. The sole deletion of the PcdhγC4 isoform, but not of the other 21 isoforms in the Pcdhg gene cluster, increased cIN PCD. Viral expression of the PcdhγC4, in cIN lacking the function of the entire Pcdhg cluster, rescued most of these cells from cell death. We conclude that PcdhγC4 plays a critical role in regulating the survival of cINs during their normal period of PCD. This highlights how a single isoform of the Pcdhg cluster, which has been linked to human neurodevelopmental disorders, is essential to adjust cIN cell numbers during cortical development.

Treatment of hematologic malignancies with patient-derived anti-CD19 chimeric antigen receptor (CAR) T-cells has demonstrated long-term remissions for patients with otherwise treatment-refractory advanced leukemia and lymphoma. Conversely, CAR T-cell treatment of solid tumors, including advanced gastric cancer (GC), has proven more challenging due to on-target off-tumor toxicities, poor tumor T-cell infiltration, inefficient CAR T-cell expansion, immunosuppressive tumor microenvironments, and demanding preconditioning regimens. We report the exceptional results of autologous Claudin18.2-targeted CAR T cells (CT041) in a patient with metastatic GC, who had progressed on four lines of combined systemic chemotherapy and immunotherapy. After two CT041 infusions, the patient had target lesion complete response and sustained an 8-month overall partial response with only minimal ascites. Moreover, tumor-informed circulating tumor DNA (ctDNA) reductions coincided with rapid CAR T-cell expansion and radiologic response. No severe toxicities occurred, and the patient's quality of life significantly improved. This experience supports targeting Claudin18.2-positive GC with CAR T-cell therapy and helps to validate ctDNA as a biomarker in CAR T-cell therapy. Clinical Insight: Claudin18.2-targeted CAR T cells can safely provide complete objective and ctDNA response in salvage metastatic GC.

Handheld ultrasound devices can be used in revision rhinoplasty to evaluate the calcification of costal rib cartilage that is to be harvested for grafting. This article provides instructions on how to perform this technique. Laryngoscope, 134:651-653, 2024.

Effective cellular therapy using CD19 chimeric antigen receptor T-cells for the treatment of advanced B-cell malignancies raises the question of whether the administration of adoptive cellular therapy (ACT) posttransplant could reduce relapse and improve survival. Moreover, several early phase clinical studies have shown the potential beneficial effects of administration of tumor-associated antigen-specific T-cells and natural killer cells posttransplant for high-risk patients, aiming to decrease relapse and possibly improve survival. In this article, we present an in-depth review of ACT after transplantation, which has the potential to significantly improve the efficacy of this procedure and revolutionize this field.

Purpose: This review explores the current landscape of AI applications in imaging for TAVR, emphasizing the potential and limitations of these tools for (1) automating the image analysis and reporting process, (2) improving procedural planning, and (3) offering additional insight into post-TAVR outcomes. Finally, the direction of future research necessary to bridge these tools towards clinical integration is discussed. Recent Findings: Transcatheter aortic valve replacement (TAVR) has become a pivotal treatment option for select patients with severe aortic stenosis, and its indication for use continues to broaden. Noninvasive imaging techniques such as CTA and MRA have become routine for patient selection, preprocedural planning, and predicting the risk of complications. As the current methods for pre-TAVR image analysis are labor-intensive and have significant inter-operator variability, experts are looking towards artificial intelligence (AI) as a potential solution. Summary: AI has the potential to significantly enhance the planning, execution, and post-procedural follow up of TAVR. While AI tools are promising, the irreplaceable value of nuanced clinical judgment by skilled physician teams must not be overlooked. With continued research, collaboration, and careful implementation, AI can become an integral part in imaging for TAVR, ultimately improving patient care and outcomes.

IntroductionPatients with cirrhosis undergoing liver transplantation frequently exhibit systemic inflammation, coagulation derangements, and edema, indicating endothelial dysfunction. This syndrome may worsen after ischemia-reperfusion injury of the liver graft, coincident with organ dysfunction that worsens patient outcomes. Little is known about changes in endothelial permeability during liver transplantation. We hypothesized that sera from these patients would increase permeability in cultured human endothelial cells ex vivo.MethodsAdults with cirrhosis presenting for liver transplantation provided consent for blood collection during surgery. Sera were prepared at five time points spanning the entire operation. The barrier function of human pulmonary microvascular endothelial cells in culture was assessed by transendothelial resistance measured using the ECIS ZΘ system. Confluent cells from two different endothelial cell donors were stimulated with human serum from liver transplant patients. Pooled serum from healthy men and purified inflammatory agonists served as controls. The permeability response to serum was quantified as the area under the normalized resistance curve. Responses were compared between time points and analyzed for associations with clinical characteristics of liver transplant patients and their grafts.ResultsLiver transplant sera from all time points during surgery-induced permeability in both endothelial cell lines. The magnitude of permeability change was heterogeneous between patients, and there were differences in the effects of sera on the two endothelial cell lines. In one of the cell lines, the severity of liver disease was associated with greater permeability at the start of surgery. In the same cell line, serum collected 15 min after liver reperfusion induced significantly more permeability as compared to that collected at the start of surgery. Early postreperfusion sera from patients undergoing living donor transplants induced more permeability than sera from deceased donor transplants. Sera from two exemplary cases of patients on preoperative dialysis, and one patient with an unexpectedly long warm ischemia time of the liver graft, induced exaggerated and prolonged endothelial permeability.DiscussionSerum from patients with cirrhosis undergoing liver transplantation induces permeability of cultured human pulmonary microvascular endothelial cells. Increased endothelial permeability during liver transplantation may contribute to organ injury and present a target for future therapeutics.

Liver cirrhosis is a chronic condition that is associated with a variety of complications across organ systems. Patients with cirrhosis also suffer from immune dysfunction, which may predispose them to catastrophic bacterial and fungal infections. Bacterial infections in liver cirrhosis have been well-documented, however, data remains scarce regarding fungal infections. Candida and Aspergillus have been reported as the most common pathogens among patients with cirrhosis, causing both invasive and non-invasive infections. However, other pathogens such as Coccidioides, Pneumocystis, Cryptococcus, and Rhizopus have been increasing in incidence. Diagnosis of fungal infection is often difficult, particularly in regards to distinguishing colonization from invasive infection. Serum markers such as beta-D-glucan (BDG) and galactomannan are beneficial diagnostic tools in conjunction with fungal cultures and imaging modalities. Bronchoscopy with bronchoalveolar lavage (BAL) or lung biopsy can be useful adjuncts as well. Liver transplantation is another important consideration as invasive fungal infection (IFI) is a contraindication to transplant surgery. Additionally, patients are at increased risk for infection due to immunosuppression in the post-transplant period. We aim to discuss the mechanisms responsible for immune dysfunction in advanced liver disease, the epidemiology of fungal infections in this population, as well as presentations and management considerations pertaining to specific pathogens and antifungal regimens.

BackgroundThe cause of liver disease is changing, but its impact on liver transplantation (LT) for hepatocellular carcinoma (HCC) in women and men is unclear. We performed a nationwide study to assess the prevalence and posttransplant survival outcomes of the various causes of liver disease in women and men with HCC.MethodsData were obtained from the United Network for Organ Sharing database from 2000 to 2022. Data related to the listing, transplant, waitlist mortality, and posttransplant mortality for HCC were extracted. The proportion of HCC related to the various causes of liver disease among LT candidates and recipients and posttransplant survival were compared between women and men.ResultsA total of 51 721 individuals (39 465 men, 12 256 women) with HCC were included. From 2000 to 2022, nonalcoholic steatohepatitis (NASH) was the fastest-growing cause of liver disease among female LT candidates with HCC (P

BackgroundRemote ischemic conditioning (RIC) has the potential to benefit graft function following kidney transplantation by reducing ischemia-reperfusion injury; however, the current clinical evidence is inconclusive. This meta-analysis with trial sequential analysis (TSA) aimed to determine whether RIC improves graft function after kidney transplantation.MethodsA comprehensive search was conducted on PubMed, Cochrane Library, and EMBASE databases until June 20, 2023, to identify all randomized controlled trials that examined the impact of RIC on graft function after kidney transplantation. The primary outcome was the incidence of delayed graft function (DGF) post-kidney transplantation. The secondary outcomes included the incidence of acute rejection, graft loss, 3- and 12-month estimated glomerular filtration rates (eGFR), and the length of hospital stay. Subgroup analyses were conducted based on RIC procedures (preconditioning, perconditioning, or postconditioning), implementation sites (upper or lower extremity), and graft source (living or deceased donor).ResultsOur meta-analysis included eight trials involving 1038 patients. Compared with the control, RIC did not significantly reduce the incidence of DGF (8.8% vs. 15.3%; risk ratio = 0.76, 95% confidence interval [CI], 0.48-1.21, P = 0.25, I2 = 16%), and TSA results showed that the required information size was not reached. However, the RIC group had a significantly increased eGFR at 3 months after transplantation (mean difference = 2.74 ml/min/1.73 m2, 95% CI: 1.44-4.05 ml/min/1.73 m2, P

Platelets are the terminal progeny of megakaryocytes, primarily produced in the bone marrow, and play critical roles in blood homeostasis, clotting, and wound healing. Traditionally, megakaryocytes and platelets are thought to arise from multipotent hematopoietic stem cells (HSCs) via multiple discrete progenitor populations with successive, lineage-restricting differentiation steps. However, this view has recently been challenged by studies suggesting that (1) some HSC clones are biased and/or restricted to the platelet lineage, (2) not all platelet generation follows the "canonical" megakaryocytic differentiation path of hematopoiesis, and (3) platelet output is the default program of steady-state hematopoiesis. Here, we specifically investigate the evidence that in vivo lineage tracing studies provide for the route(s) of platelet generation and investigate the involvement of various intermediate progenitor cell populations. We further identify the challenges that need to be overcome that are required to determine the presence, role, and kinetics of these possible alternate pathways.

BackgroundTransthoracic approaches may be contraindicated in some patients and may be associated with poorer outcomes. Therefore other alternative access routes are increasingly being performed. We conducted a systematic review of the literature on Transcarotid transcatheter aortic valve replacement (TC-TAVR) and meta-analysis comparing outcomes of TC-TAVR and other access routes.MethodsWe comprehensively searched for controlled randomized and non-randomized studies from 4 online databases. We presented data using risk ratios (95 % confidence intervals) and measured heterogeneity using Higgins' I2.ResultsSixteen observational studies on Transcarotid TAVR were included in the analysis; 4 studies compared 180 TC-TAVR patients vs 524 TT-TAVR patients. The mean age and STS score for patients undergoing TC-TAVR were 80 years and 7.6 respectively. For TT-TAVR patients, the mean age and STS score were 79.7 years and 8.7 respectively. TC-TAVR patients had lower 30-day MACE [7.8 % vs 13.7 %; OR 0.54 (95 % CI 0.29-0.99, P = 0.05)] and major or life-threatening bleeding [4.0 % vs 14.2 %; OR 0.25 (95 % CI 0.09-0.67, P = 0.006)]. There was no significant difference in 30-day: mortality [5.0 % vs 8.6 %; OR 0.61 (95 % CI 0.29-1.30, P = 0.20)], stroke or transient ischemic attack [2.8 % vs 4.0 %; OR 0.65 (95 % CI 0.25-1.73, P = 0.39)] and moderate or severe aortic valve regurgitation [5.0 % vs 4.6 %; OR 1.14. (95 % CI 0.52-2.52, P = 0.75)]. There was a trend towards fewer major vascular complications in TC-TAVR [3.0 % vs 7.8 %; OR 0.42 (95 % CI 0.16-1.12, P = 0.08)].ConclusionCompared with transthoracic TAVR, TC-TAVR patients had lower odds of 30-day MACE and life-threatening bleeding and no differences in 30-day mortality, stroke or TIA, aortic valve regurgitation.

Rationale: Acute lung injury (ALI) carries a high risk of mortality but has no established pharmacologic therapy. We previously found that experimental ALI occurs through natural killer (NK) cell NKG2D receptor activation and that the cognate human ligand, MICB, was associated with ALI after transplantation. Objectives: To investigate the association of a common missense variant, MICBG406A, with ALI. Methods: We assessed MICBG406A genotypes within two multicenter observational study cohorts at risk for ALI: primary graft dysfunction (N = 619) and acute respiratory distress syndrome (N = 1,376). Variant protein functional effects were determined in cultured and ex vivo human samples. Measurements and Main Results: Recipients of MICBG406A-homozygous allografts had an 11.1% absolute risk reduction (95% confidence interval [CI], 3.2-19.4%) for severe primary graft dysfunction after lung transplantation and reduced risk for allograft failure (hazard ratio, 0.36; 95% CI, 0.13-0.98). In participants with sepsis, we observed 39% reduced odds of moderately or severely impaired oxygenation among MICBG406A-homozygous individuals (95% CI, 0.43-0.86). BAL NK cells were less frequent and less mature in participants with MICBG406A. Expression of missense variant protein MICBD136N in cultured cells resulted in reduced surface MICB and reduced NKG2D ligation relative to wild-type MICB. Coculture of variant MICBD136N cells with NK cells resulted in less NKG2D activation and less susceptibility to NK cell killing relative to the wild-type cells. Conclusions: These data support a role for MICB signaling through the NKG2D receptor in mediating ALI, suggesting a novel therapeutic approach.

BK virus (BKV) is a small DNA virus, a member of the polyomavirus family, that causes an opportunistic infection in immunocompromised patients, especially kidney transplant patients. This virus establishes a lifelong infection in most of the population, and once it reactivates in an immunocompromised state, leads to BKV nephropathy. This review seeks to assess the correlation between severe immunosuppression, evident by low CD4 cell counts in HIV-positive patients, and the reactivation of BKV, causing nephropathy. A literature review was conducted, extracting, and analyzing case reports of HIV-positive patients showing correlations between their degree of immunosuppression, as evidenced by their CD4 counts, and the degree of BKV infectivity, confirmed by kidney biopsy. A total of 12 cases of BKV nephropathy in HIV-infected patients were reviewed. A common finding was the presence of profound immunosuppression, with most patients having CD4 counts ≤50 cells/ mm3. A substantial number also had comorbid malignancies, with some undergoing chemotherapy, potentially increasing the risk of BKV reactivation. In addition to the HIV status and malignancies, other risk factors for BKV reactivation included older age, male gender, diabetes mellitus, Caucasian race, and ureteral stent placement. BKV nephropathy in HIV patients with native kidneys is closely correlated with severe immunosuppression. Although therapeutic strategies exist for post-transplant patients, aside from the treatment of HIV with highly active anti-retroviral therapy (HAART), which potentially helps with clearing BKV by increasing CD4 count, there is no definitive treatment for a native kidney BKV nephropathy in patients with AIDS. The complexity of the cases and severity of comorbidities indicate the need for further research to develop therapeutic strategies tailored to this population.

BackgroundIschemia-reperfusion injury (IRI) is a significant clinical concern in liver transplantation, with a key influence on short-term and long-term allograft and patient survival. Myeloid cells trigger and sustain tissue inflammation and damage associated with IRI, but the mechanisms regulating these activities are unknown. To address this, we investigated the molecular characteristics of intragraft myeloid cells present in biopsy-proven IRI- and IRI+ liver transplants.MethodsRNA-sequencing was performed on 80 pre-reperfusion and post-reperfusion biopsies from 40 human recipients of liver transplantation (23 IRI+, 17 IRI-). We used transcriptional profiling and computational approaches to identify specific gene coexpression network modules correlated with functional subsets of MPO+, lysozyme+, and CD68+ myeloid cells quantified by immunohistochemistry on sequential sections from the same patient biopsies.ResultsA global molecular map showed gene signatures related to myeloid activation in all patients regardless of IRI status; however, myeloid cell subsets differed dramatically in their spatial morphology and associated gene signatures. IRI- recipients were found to have a natural corticosteroid production and response profile from pre-reperfusion to post-reperfusion, particularly among monocytes/macrophages. The pre-reperfusion signature of IRI+ recipients included acute inflammatory responses in neutrophils and increased translation of adaptive immune-related genes in monocytes/macrophages coupled with decreased glucocorticoid responses. Subsequent lymphocyte activation at post-reperfusion identified transcriptional programs associated with the transition to adaptive immunity found only among IRI+ recipients.ConclusionsMyeloid subset-specific genes and related signaling pathways provide targets for the development of therapeutic strategies aimed at limiting IRI in the clinical setting of liver transplantation.

Despite the continued improvements in pancreas transplant outcomes in recent decades, a subset of recipients experience graft failure and can experience substantial morbidity and mortality. Here, we summarize what is known about the failed pancreas allograft and what factors are important for consideration of retransplantation. The current definition of pancreas allograft failure and its challenges for the transplant community are explored. The impacts of a failed pancreas allograft are presented, including patient survival and resultant morbidities. The signs, symptoms, and medical and surgical management of a failed pancreas allograft are described, whereas the options and consequences of immunosuppression withdrawal are reviewed. Medical and surgical factors necessary for successful retransplant candidacy are detailed with emphasis on how well-selected patients may achieve excellent retransplant outcomes. To achieve substantial medical mitigation and even pancreas retransplantation, patients with a failed pancreas allograft warrant special attention to their residual renal, cardiovascular, and pulmonary function. Future studies of the failed pancreas allograft will require improved reporting of graft failure from transplant centers and continued investigation from experienced centers.

PurposeTo evaluate the effects of mechanical disruption of the inner limiting membrane (ILM) on the ability to target interventions to the inner neurosensory retina in a rodent model. Our study used an animal model to gain insight into the normal physiology of the ILM and advances our understanding of the effects of mechanical ILM removal on the viral transduction of retinal ganglion cells and retinal ganglion cell transplantation.MethodsThe ILM in the in vivo rat eye was disrupted using mechanical forces applied to the vitreoretinal interface. Immunohistology and electron microscopy were used to verify the removal of the ILM in retina flatmounts and sections. To assess the degree to which ILM disruption enhanced transvitreal access to the retina, in vivo studies involving intravitreal injections of adeno-associated virus (AAV) to transduce retinal ganglion cells (RGCs) and ex vivo studies involving co-culture of human stem cell-derived RGCs (hRGCs) on retinal explants were performed. RGC transduction efficiency and transplanted hRGC integration with retinal explants were evaluated by immunohistology of the retinas.ResultsMechanical disruption of the ILM in the rodent eye was sufficient to remove the ILM from targeted retinal areas while preserving the underlying retinal nerve fiber layer and RGCs. Removal of the ILM enhanced the transduction efficiency of intravitreally delivered AAV threefold (1380.0 ± 290.1 vs. 442.0 ± 249.3 cells/mm2; N = 6; P = 0.034). Removal of the ILM was also sufficient to promote integration of transplanted RGCs within the inner retina.ConclusionsThe ILM is a barrier to transvitreally delivered agents including viral vectors and cells. Mechanical removal of the ILM is sufficient to enhance access to the inner retina, improve viral transduction efficiencies of RGCs, and enhance cellular integration of transplanted RGCs with the retina.