Matched Donor Research Articles

Beyond One-Size-Fits-All: Pioneering a Zone-Based Strategy in Digital Nerve Autografting.

Digital nerve injuries significantly affect hand function and quality of life, necessitating effective reconstruction strategies. Autologous nerve grafting remains the gold standard due to its superior biocompatibility, despite recent advancements in nerve conduits and allogenic grafts. This study aims to propose a novel zone-based strategy for donor nerve selection to improve outcomes in digital nerve reconstruction. A systematic review was conducted following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, searching PubMed, Embase, Cochrane Library, and Web of Science for articles published from January 2004 to December 2023. Inclusion criteria included studies involving adult human subjects undergoing autologous nerve grafting for digital nerve reconstruction, with sensory recovery and donor site morbidity as primary outcome measures. Additionally, an anatomical study comparing donor nerves to digital nerves was included. Five studies met the inclusion criteria: 4 clinical studies and 1 anatomical study. Analysis of the 4 included clinical studies showed that the posterior interosseous nerve had the lowest donor site morbidity (6.25%), while the lateral antebrachial cutaneous nerve (LABCN) demonstrated the best sensory recovery outcomes (mean 2-point discrimination of 5.92 mm, with 100% of patients achieving good to excellent recovery). The sural nerve exhibited acceptable donor site morbidity (15%) but showed the lowest sensory recovery outcomes (mean 2-point discrimination of 10.8 mm, with only 46% of patients reporting good to very good recovery). The anatomical study indicated that the LABCN had the closest match in cross-sectional area and fascicle count to most zones of the digital nerve, supporting its suitability as a graft source. Although there are many nerve reconstruction techniques available, autologous nerve grafting remains the gold standard. Based on the analysis of five studies, this review proposes a new zone-based approach for donor nerve selection, emphasizing matching donor nerves to specific injury zones. This tailored strategy can potentially optimize both functional recovery and donor site morbidity, moving beyond the one-size-fits-all paradigm. The posterior interosseous nerve, LABCN, and SN each provide unique benefits depending on the zone of injury, suggesting that this approach may lead to improved patient outcomes. Future research is needed to validate this framework.

Multiplex-PCR technique to predict polymorphic antigens – M, N, S and s – and associations between their alleles and Mia-associated hybrid glycophorins

Serological typing of MNS polymorphic antigens – M, N, S and s – remains a fundamental technique in transfusion medicine and prenatal care, providing essential information for matching blood donors and recipients and managing haemolytic disease. Although this method is well proven and routinely used, it is not a comprehensive solution, as it has several weaknesses. Alternatively, multiplex polymerase chain reaction (PCR) is a commonly used genotyping tool due to its potency and ability to amplify several DNA targets simultaneously in a single reaction. In this work, we aimed to develop multiplex PCR and evaluate its performance for GYPA*M, GYPA*N, GYPB*S, and GYPB*s allele identification using serological and DNA sequencing methods. We also aimed to investigate the correlation between these alleles and Mia-associated hybrid glycophorins (GPs). Remarkably, multiplex PCR was well optimised, and the results aligned with serological phenotyping and DNA sequencing data with maximum accuracy and reliability; this confirmed our findings on its validity in predicting MNSs phenotypes. In addition, this work strongly demonstrates, for the first time, a moderate correlation between the GYPA*M/M and GYPB*s/s genotypes and Mia-associated hybrid GPs among Thai donors. Individuals with the GYPA*M/M and GYPB*s/s genotypes, predicted M + N − S− s + phenotypes, will thus most likely to express the Mi(a+) antigen. Nevertheless, further studies are required to validate these results and elucidate the underlying correlations.

Optimizing keratoconus treatment with AI‐driven lenticule matching using pentacam indices

Aims/Purpose: The aim of this study is to develop an advanced artificial intelligence (AI) methodology to optimize the matching of donor and recipient lenticules for the treatment of keratoconus. This approach leverages Pentacam indices related to corneal thickness and topography to minimize the preparatory modifications required for stromal lenticule implantation.Methods: We will construct a comprehensive database of donor and recipient lenticules by systematically collecting Pentacam‐derived indices, including central corneal thickness (CCT), anterior and posterior corneal elevation, and corneal curvature, at preoperative, intraoperative, and postoperative stages. Using these datasets, an AI algorithm capable of identifying the most compatible lenticule pairs will be trained and validated. The algorithm's performance will be assessed based on its accuracy in predicting optimal matches and the practical effectiveness of the process.Results: As this project is in its preliminary phase, no results are currently available. However, we hypothesize that the AI‐assisted matching system will significantly enhance the compatibility of donor and recipient lenticules. Expected outcomes include increased postoperative central corneal thickness, improved corrected distance visual acuity (CDVA), and reduced corneal irregularity.Conclusions: This study aims to validate the potential of AI‐assisted matching of donor and recipient lenticules using Pentacam indices as a transformative approach in the treatment of keratoconus. By refining the customization process, we anticipate improvements in surgical efficiency and patient outcomes.

Radial to Median Sensory Nerve Transfers to Restore Sensate Key Pinch: A Cadaveric Assessment of Size Match and Implications for Transfer.

Loss of key-pinch sensation after median nerve injury poses significant functional detriment. Nerve transfers are utilized to improve function after nerve injury and size matching of donor and recipient nerves is important to optimize success. This anthropometric study investigates the anatomy of the superficial branch of the radial nerve (SBRN) to the thumb and index finger and explores radial to median sensory nerve transfers, a necessary but not heavily discussed facet of nerve transfers for the hand. Anatomic dissection of SBRN in 15 cadaver hands was performed to assess variability in diameter and branching patterns based on nerve location. Dissection of the index radial and thumb ulnar digital nerves was performed to assess diameter based on location and calculate ideal size match for nerve transfer. All specimen thumbs had 2 SBRN branches at the level of the metacarpal shaft and proximal phalanx; 87% had 2 index SBRN branches extending to the proximal phalanx. Index radial and ulnar SBRN branches were similar in diameter at all levels (p > 0.0167). There was a significant size mismatch between the individual SBRN branches and index digital at all measured levels (p < 0.0167). The thumb radial SBRN was significantly larger than ulnar SBRN (p = 0.006). Optimal size match for transfer involved transection of radial index SBRN 1 cm distal to the MCP joint and ulnar thumb SBRN 1 cm distal to the MCP joint. Consideration should be made for transfer of both index SBRN branches at the level of the MCP joint to improve size match. Corresponding digital nerves were transected 1 cm proximal to the level of SBRN harvest.

HLA class I supertypes and HLA class I alleles influence the outcome after allogeneic hematopoietic stem cell transplant from unrelated matched donor.

This retrospective study analyses the impact HLA heterozygosity, supertypes, and alleles have on incidence of graft versus host disease (GvHD), relapse, overall survival (OS), disease-free survival (DFS) and transplant-related mortality (TRM) after HSCT. The study included patients who underwent HSCT, typed at allele resolution level for HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1 loci. The analysis performed on the entire patient cohort (N=232) showed that HLA-B07 supertype positive patients demonstrated decreased incidence of relapse, better OS and DFS in comparison to those negative for HLA-B07 supertype. Further, a higher incidence of TRM was observed among patients positive for HLA-B27 supertype. Significant association of the HLA-A*02:01 allele presence with decreased incidence of GvHD was found. The occurrence of HLA-A*11:01 allele was associated with a worse OS, DFS and a higher rate of TRM. The analysis of the subgroup of patients with AML or MDS (N=148) showed an association of HLA-A24 supertype with a worse OS. The HLA-B07 supertype positive patients demonstrated a lower incidence of relapse and a better DFS. A decline in OS and a higher TRM rate were observed among patients positive for HLA-B27 supertype. The presence of HLA-A*11:01 allele was indicative of a worse OS, DFS and a higher rate of TRM. The associations of HLA and HSCT clinical outcome parameters found in this study justify further investigation of this matter.

Preclinical ex vivo IL2RG gene therapy using autologous hematopoietic stem cells as an effective and safe treatment for X-linked severe combined immunodeficiency disease

X-linked severe combined immunodeficiency disease (X-SCID) is a rare inherited disease caused by mutations in the interleukin 2 receptor subunit gamma gene (IL2RG), which encodes the common γ chain protein, a subunit of the receptor for lymphocytes. X-SCID is characterized by profound defects in T-cell, B-cell, and natural killer cell function. Here, we report a Chinese cohort of nine X-SCID patients with six novel IL2RG mutations. Among those, the two adolescent patients carrying missense mutation with an atypical immunotype were confirmed by further analyzing IL-2-JAK-STAT5 signaling, T cell proliferation, and T cell receptor excision circles (Trecs). Interestingly, Bacillus Calmette-Guérin (BCG) disease occurred commonly in this cohort. Although allogeneic hematopoietic stem-cell transplantation is curative for the disease, it is not available to all patients due to the lack of suitable matched donors. Autologous gene therapy using a self-inactivating lentiviral vector (SIN-LV) technology, developed in recent decades has provided an alternative therapy for treating such mono-genetic diseases. Here, we performed the pre-clinical studies to assess our SIN-LV carrying IL2RG on human ED7R cells deficient in IL2RG and CD34+ stem cells derived from the bone marrow of a healthy donor and a patient with X-SCID. This work is done complied with the established “Good Manufacturing Practice” (GMP) used in the clinical trials. In addition, a safety study is performed using the transduced CD34+ cells implanted into the axilla of nude mice in vivo. Overall, our studies have demonstrated the efficiency and safety of SIN-IL2RG-LV, which paves the way for conducting X-SCID gene therapy clinical trials in China in the near future.

Multiple measures for self-identification improve matching donors with patients in unrelated hematopoietic stem cell transplant

BackgroundQuestions persist around whether and how to use race or geographic ancestry in biomedical research and medicine, but these forms of self-identification serve as a critical tool to inform matching algorithms for human leukocyte antigen (HLA) of varying levels of resolution for unrelated hematopoietic stem cell transplant in large donor registries.MethodsHere, we examined multiple self-reported measures of race and ancestry from a survey of a cohort of over 100,000 U.S. volunteer bone marrow donors alongside their high-resolution HLA genotype data.ResultsWe find that these self-report measures are often non-overlapping, and that no single self-reported measure alone provides a better fit to HLA genetic ancestry than a combination including both race and geographic ancestry. We also found that patterns of reporting for race and ancestry appear to be influenced by participation in direct-to-consumer genetic ancestry testing.ConclusionsWhile these data are not used directly in matching for transplant, our results demonstrate that there is a place for the language of both race and geographic ancestry in the critical process of facilitating accurate prediction of HLA in the donor registry context.

Right Ventricular Mass Oversizing Is Associated With Improved Post-transplant Survival in Heart Transplant Recipients With Elevated Transpulmonary Gradient

This study evaluates the effects of pre-transplant transpulmonary gradient (TPG) and donor right ventricular mass (RVM) on outcomes following heart transplantation. UNOS registry was queried to analyze adult recipients who underwent primary isolated heart transplantation from 1/1/2010 to 12/31/2018. The recipients were dichotomized into 2 groups based on their TPG at the time of transplantation, < 12 and ≥ 12 mmHg. The outcomes included 5-year survival and post-transplant complications. Propensity score-matching was performed. Subanalysis was performed to evaluate the effects of donor-recipient RVM matching, where a ratio < 0.85 was classified as undersized, 0.85-1.15 as size-matched, and > 1.15 as oversized. We analyzed 17,898 isolated heart transplant recipients, and 5129 (28.7%) recipients had TPG ≥ 12 mmHg at the time of transplantation. The recipients with TPG ≥ 12 mmHg experienced significantly lower 5-year survival rates (78.4% vs 81.2%; P < 0.001) compared to the recipients with TPG < 12 mmHg, and this finding persisted in the propensity score-matched comparison. The recipients with TPG ≥ 12 mmHg experienced a higher rate of post-transplant dialysis and a longer duration of hospitalization. Oversizing the donor RVM considerably improved the 5-year survival among the recipients with TPG ≥ 12 mmHg, comparable to those with TPG < 12 mmHg. Elevated pre-transplant TPG is associated with significantly reduced post-transplant survival. However, oversizing the donor RVM is associated with improved survival rates in recipients with elevated TPG, resulting in improved survival that is comparable to that of recipients with normal TPG. Therefore, careful risk stratification and donor matching among recipients with elevated TPG is essential to improve outcomes in this vulnerable population.

Mucosal-associated invariant T cells are functionally impaired in pediatric and young adult patients following allogeneic hematopoietic stem cell transplantation and their recovery correlates with clinical outcomes.

Mucosal-associated invariant T (MAIT) cells are innate-like T cells implicated in the response to fungal and bacterial infections. Their contribution to restoring T-cell immunity and influencing hematopoietic stem cell transplant (HSCT) outcomes remains poorly understood. We retrospectively studied MAIT-cell recovery in 145 consecutive children and young adults with hematologic malignancies undergoing allogeneic (allo)-HSCT between April 2019 and May 2022, from unrelated matched donor (MUD, N=52), with standard graft-versus-host-disease (GvHD) prophylaxis, or HLA-haploidentical (Haplo, N=93) donor after in vitro αβT/CD19-cell depletion, without post-HSCT pharmacological prophylaxis. With a median follow-up of 33 months (range, 12-49 months), overall survival (OS), disease-free survival (DFS), and non-relapse mortality (NRM) were 79.5%, 72%, and 7%, respectively; GvHD-free relapse-free survival (GRFS) was 63%, while cumulative incidence of relapse was 23%. While αβT cells were reconstituted 1-2 years post HSCT, MAIT cells showed delayed recovery and prolonged functional impairment, characterized by expression of activation (CD25, CD38), exhaustion (PD1, TIM3) and senescence (CD57) markers, and suboptimal ex vivo response. OS, DFS, and NRM were not affected by MAIT cells. Interestingly, higher MAIT cells at day +30 correlated with higher incidence of grade II-IV acute GvHD (19% vs. 7%, P=0.06). Furthermore, a greater MAIT-cell count tended to be associated with a higher incidence of chronic GvHD (cGvHD) (17% vs. 6%, P=0.07) resulting in lower GRFS (55% vs. 73%, P=0.05). Higher MAIT cells also correlated with greater cytomegalovirus (CMV) reactivation and lower late blood stream infections (BSI) (44% vs. 24%, P=0.02 and 9% vs. 18%, P=0.08, respectively). Future studies are needed to confirm the impact of early MAIT-cell recovery on cGvHD, CMV reactivation, and late BSI.

HLA Diversity in Transylvanian Ethnic Groups: Consequences for Hematopoietic Cell Transplantation

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.

Harnessing Hope in Digital Spaces for Health Equity: How Group Comparison Information and Supportive Comments Influence Bone Marrow Donor Intentions for African Americans.

Pursuing health equity necessitates recognizing health disparities that disproportionately impact disadvantaged groups and eliminating their barriers to essential health resources. Interactive digital technologies-specifically, popular social media platforms such as blogs and social networks-can be leveraged to engage underserved minority populations in collective social action aimed at addressing key determinants of health disparities and promoting equitable health outcomes. The present research focuses on the plight of African Americans-a minority group facing significant health disparities. Particularly in the domain of bone marrow donation, African Americans remain the group least likely to find a matching donor. Guided by the social comparison framing literature, we conducted an online experiment to investigate how group comparison information (GCI) emphasizing group-based disparities and supportive user comments on social media platforms influence African Americans' intentions to join a bone marrow registry. In doing so, we considered hope as a mediator and group identification as a moderator. Results based on a conditional process analysis showed that GCI led to greater bone marrow donor intentions in the presence of supportive comments through elicitation of hope, particularly among those low in group identification. The current findings demonstrate that it is important to consider the role of supportive message environments and group identification when addressing health disparities with GCI. Theoretical and practical implications are discussed.

Bloodless Medicine in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.

Allogeneic hematopoietic stem cell transplantation (alloHSCT) poses challenges for patients who decline blood products because of religious beliefs or other reasons. Despite potential curative prospects, many institutions refrain from offering alloHSCT to patients who decline blood products because of safety concerns associated with cytopenias. This review focuses on one institution's experience of conducting alloHSCT without blood components, emphasizing preparation and supportive care. The approach of conducting alloHSCT without blood components, which involves ABO-compatible donor matching, nonmyeloablative regimens, and pretransplantation optimization of red blood cell production, is discussed. The clinical team can minimize transfusion needs by using erythropoiesis-stimulating agents, thrombopoietin agonists, and peri- and post-transplantation management strategies. These recommendations can ensure patient safety and successful outcomes with bloodless medicine.

Transplant Outcomes in Myelofibrosis: Impact of Donor Type (Cord Blood Grafts Supported by CD34+ selected Cells [Haplo-Cord] Versus Matched Donors)

BackgroundDespite the established potentially curative role of allogeneic hematopoietic cell transplantation (alloHCT) in managing MF, the choice of alternative donors for patients lacking matched donors remains a challenge, and the optimal graft source in this disease entity continues to be an ongoing debate. ObjectivesWe aimed to evaluate the impact of donor type: umbilical cord blood transplant supported CD34+ haploidentical donor (haplo-cord) vs adult matched related donor (MRD) and matched unrelated donor (MUD) in 40 adult patients with primary or secondary MF, including those progressing to accelerated phase (AP) or blast phase (BP), who underwent their first allo-HCT. The primary objective of this study was to analyze the impact of stem cell source on primary endpoints of overall survival (OS), graft versus host disease (GVHD) and non-relapse mortality (NRM). ResultsMedian follow-up for all alive patients was 53 months (range 0.3-63 months). Nine patients (22.5%) underwent an MRD allo-HCT, 15 patients (37.5%) underwent a MUD allo-HCT, and 16 patients (40%) underwent a haplo-cord allo-HCT. Four patients died without neutrophil engraftment: 3 (19%) in haplo-cord group and one (4%) in MRD/MUD group. The cumulative incidence of ANC engraftment by day 60 was 80% (95%CI 45-94) in the haplo-cord group and 92% (95%CI 65-98) in the MRD/MUD group (p=0.09). The cumulative incidence of platelet engraftment by day 60 was 59% (95%CI 27-81) in haplo-cord group and 75% (95%CI 51-88) in MRD/MUD group (p=0.4). OS was 62% at 1 year (95%CI 49-79) and 34% at 3 years (95%CI 21-55). The 3-yr OS was similar between the haplo-cord group and the MRD/MUD (37% vs 32%, p=0.9). The 1-yr OS for accelerated/blast phase AP/BP patients was 50% (95%CI 27-93) in the haplo-cord group, compared to 40% (95%CI 19-86) in the MRD/MUD. The 1-yr OS for chronic phase CP patients was 83% (95%CI 58-100) in the haplo-cord group, compared to 79% (95%CI 60-100) in the MRD/MUD group. The cumulative incidence of relapse at 3 years in the haplo-cord group was 13% (95%CI 1.8-34), and in the MRD/MUD group was 28% (95%CI 10-49) (p=0.36). 1-yr non-relapse mortality (NRM) was 38% (95%CI 15-61) in the haplo-cord group and 33% (95%CI 15-52) in the MRD/MUD group. 3-yr NRM was 48% (95%CI 19-72) in the haplo-cord group and 54% (95%CI 29-73) in MRD/MUD group(p=0.95). ConclusionWe showed no significant difference in OS, relapse, and NRM outcomes after haplo-cord transplant compared to adult matched donors’ grafts (MRD or MUD) in MF patients. However, there were more graft failures in patients transplanted with a haplo-cord transplants and delayed engraftments with inadequate haplo myeloid bridges. Despite the small sample size in our study, considering our findings and the availability of other alternative donors, using haplo-cord platforms may no longer be justified for myelofibrosis unless the UCB engraftment dynamics can be optimized.

Uniform Graft-versus-Host Disease Prophylaxis using Post-Transplantation Cyclophosphamide, Methotrexate, and Cyclosporine following Peripheral Blood Hematopoietic Stem Cell Transplantation from Matched and Haploidentical Donors for Transfusion-Dependent Thalassemia: A Retrospective Report from the Bone Marrow Failure Working Group of Hunan Province, China

Although the survival of patients with transfusion-dependent thalassemia (TD-TM) is reportedly inferior after haploidentical hematopoietic stem cell transplantation (HSCT), the heterogeneity of transplantation approaches in studies suggests the need to assess the effect of conditioning regimen on matched and haploidentical transplantation outcomes. A novel post-transplantation cyclophosphamide (PTCy)-based approach for patients with TD-TM undergoing haploidentical HSCT was reported in our prior study. Here we aimed to retrospectively evaluate the real-world efficacy and safety of graft-versus-host disease (GVHD) prophylaxis in patients with TD-TM after HSCT from matched donors and haploidentical donors (HIDs). In this retrospective multicenter study, among 238 patients with TD-TM who underwent HSCT, 160 underwent peripheral blood HSCT, using uniform GVHD prophylaxis with PTCy, methotrexate, and cyclosporine, at member centers of the Bone Marrow Failure Working Group of Hunan Province between 2019 and 2023. The median age of the cohort at transplantation was 6 years (95% confidence interval [CI], 6 to 7 years). The 160 donors included 99 (61.9%) haploidentical family members, 13 matched sibling donors, and 48 matched or mismatched unrelated donors. The engraftment rate was 98.8% (95% CI, 96.1% to 97.7%). HSCT from HIDs had a lower risk of mixed chimerism (HR, .078; P = .022). Within 100 days after transplantation, 31 patients (19.6%; 95% CI, 14.0% to 26.3%) had grade II-IV acute GVHD (aGVHD), 9 of whom had grade III-IV aGVHD (5.7%; 95% CI, 2.9% to 10.1%). HIDs were significantly associated with a higher risk of grade II-IV aGVHD (HR, 3.973; P = .009). Nineteen patients (11.9%; 95% CI, 7.6% to 17.6%) developed late aGVHD after a median of 516 days (95% CI, 407 to 709 days). Twenty-six patients (16.5%; 95% CI, 11.3% to 22.8%) exhibited any 1 of the diagnostic, distinctive, or atypical features of chronic GVHD (cGVHD) according to the 2014 National Institutes of Health (NIH) criteria after a median of 690 days (95% CI, 496 to 902 days). Among these 26 patients, 7 had NIH-defined cGVHD, 14 had only 1 distinctive sign with no histologic evidence, and 5 had only atypical cGVHD signs. Of the 26 patients, 5 were classified with overlap syndrome. Of 21 patients classified with NIH-defined and potential cGVHD, 3 had moderate cGVHD and 1 had severe cGVHD. Logistic regression analyses identified that grade II-IV aGVHD independently predicted subsequent cGVHD (HR, 3.920; P = .006). The rates of cGVHD were similar in the matched donor and HID groups. Thalassemia-free survival (TFS) and event-free survival (EFS) were 97.5% (95% CI, 94.2% to 99.2%) and 90.6% (95% CI, 85.4% to 94.4%), respectively, after a median of 690 days (95% CI, 496 to 902 days). TFS rates were similar in the matched donor and HID groups (P = .549). The EFS rate was significantly higher in the matched donor group compared to the HID group (P = .033). Our study suggests that when PTCy-based uniform GVHD prophylaxis is administered, HSCT from matched donors and HIDs results in a low incidence of severe GVHD and treatment-related mortality with satisfactory survival.

The emergence and use of expanded carrier screening in gamete donation: A new form of repro-genetic selection.

With the continued expansion and commercialisation of fertility treatments, the selection and matching of donors have become more sophisticated and technologised. As part of this landscape, new form of genetic screening: 'expanded carrier screening' (ECS) is being offered as a technique to avoid the risk of donors passing on genetic conditions to future offspring. Allowing donors to be tested for hundreds of genetic conditions simultaneously, ECS marks a considerable departure from traditional 'family history' models of screening, which rely on an individual's knowledge of family health. There is growing evidence of a drive towards the use of ECS within the fertility sector, and a growing number of clinics are offering it for a fee, as part of an egg or sperm donation cycle or as an add-on to IVF treatment. In this article, we use methods of critical reflection to synthesise data from two studies to explore how ECS is being used to avoid genetic risk in IVF treatment using donor gametes. We suggest that ECS is a new form of repro-genetic selection-a selective reproductive technology-with specific and important implications for donors, recipients and clinicians and with the potential to reconfigure the scope and application of gamete donation. We examine these implications and conclude that the existing policy blind spot relating to this development in fertility treatment practice needs to be urgently addressed.

Patient-Specific Distal Femoral Guides Optimize Cartilage Topography Matching in Osteochondral Allograft Transplantations

Background: Osteochondral allograft (OCA) transplantation is an important surgical technique for full-thickness chondral defects in the knee. For patients undergoing this procedure, topography matching between the donor and recipient sites is essential to limit premature wear of the OCA. Currently, there is no standardized process of donor and recipient graft matching. Purpose: To evaluate a novel topography matching technique for distal femoral condyle OCA transplantation using 3-dimensional (3D) laser scanning to create 3D-printed patient-specific instrumentation in a human cadaveric model. Study Design: Descriptive laboratory study. Methods: Human cadaveric distal femoral condyles (n = 12) underwent 3D laser scanning. An 18-mm circular osteochondral recipient defect was virtually created on the medial femoral condyle (MFC), and the position and orientation of the best topography-matched osteochondral graft from a paired donor lateral femoral condyle (LFC) were determined using an in silico analysis algorithm minimizing articular step-off distances between the edges of the graft and recipient defect. Distances between the entire surface of the OCA graft and the underneath surface of the MFC were evaluated as surface mismatch. Donor (LFC) and recipient (MFC) 3D-printed patient-specific guides were created based on 3D reconstructions of the scanned condyles. Through use of the guides, OCAs were harvested from the LFC and transplanted to the reamed recipient defect site (MFC). The post-OCA recipient condyles were laser scanned. The 360° articular step-off and cartilage topography mismatch were measured. Results: The mean cartilage step-off and graft surface mismatch for the in silico OCA transplant were 0.073 ± 0.029 mm (range, 0.005-0.113 mm) and 0.166 ± 0.039 mm (range, 0.120-0.243 mm), respectively. Comparatively, the cadaveric specimens postimplant had significantly larger step-off differences (0.173 ± 0.085 mm; range, 0.082-0.399 mm; P = .001) but equivalent graft surface topography matching (0.181 ± 0.080 mm; range, 0.087-0.396 mm; P = .678). All 12 OCA transplants had mean circumferential step-off differences less than a clinically significant cutoff of 0.5 mm. Conclusion: These findings suggest that the use of 3D-printed patient-specific guides for OCA transplantation has the ability to reliably optimize cartilage topography matching for LFC to MFC transplantation. This study demonstrated substantially lower step-off values compared with previous orthopaedic literature when also evaluating LFC to MFC transplantation. Using this novel technique in a model performing MFC to MFC transplantation has the potential to yield further enhanced results due to improved radii of curvature matching. Clinical Relevance: Topography-matched graft implantation for focal chondral defects of the knee in patients improves surface matching and has the potential to improve long-term outcomes. Efficient selection of the allograft also allows improved availability of the limited allograft sources.

Haploidentical versus Cord Blood Transplantation in Pediatric AML. A Retrospective Outcome Analysis on Behalf of the Pediatric Subcommittee of GETH (Grupo Español de Trasplante Hematopoyético)

Haploidentical stem cell transplantation (Haplo-SCT) and cord blood transplantation (CBT) are both effective alternative treatments in patients suffering from acute myeloid leukemia (AML) and lacking a matched HLA donor. In the last years, many centers have abandoned CBT procedures mostly due to concern about poorer immune recovery compared with Haplo-SCT. We conducted a retrospective multicenter study comparing the outcomes using both alternative approaches in AML. A total of 122 transplants (86 Haplo-SCTs and 36 CBTs) from 12 Spanish centers were collected from 2007 to 2021. Median age at hematopoietic stem cell transplantation (HSCT) was 7 years (0.4-20). Thirty-nine patients (31.9%) showed positive minimal residual disease (MRD) at HSCT and a previous HSCT was performed in 37 patients (30.3%). The median infused cellularity was 14.4 × 106/kg CD34+ cells (6.0-22.07) for Haplo-SCT and 4.74 × 105/kg CD34+ cells (0.8-9.4) for CBT. Median time to neutrophil engraftment was 14 days (7-44) for Haplo-SCT and 17 days (8-29) for CBT (P = .03). The median time to platelet engraftment was 14 days (6-70) for Haplo-SCT and 43 days (10-151) for CBT (P < .001). Graft rejection was observed in 13 Haplo-SCTs (15%) and in 6 CBTs (16%). The cumulative incidence of acute graft versus host disease (GvHD) grades II-IV was 54% and 51% for Haplo-SCT and CBT, respectively (P = .50). The cumulative incidence of severe acute GvHD (grades III-IV) was 22% for Haplo-SCT and 25% for CBT (P = .90). There was a tendency to a higher risk of chronic GvHD in the Haplo-SCT group being the cumulative incidence of 30% for Haplo-SCT and 12% for CBT (P = .09). The cumulative incidence of relapse was 28% and 20% for Haplo-SCT and CBT, respectively (P = .60). We did not observe statistically significant differences in outcome measures between Haplo-SCT and CBT procedures: 5-year overall survival (OS) was 64% versus 57% (P = .50), 5-year disease-free survival (DFS) 58% versus 57% (P = .80), GvHD-free and relapse-free survival (GFRFS) 41% versus 54% (P = .30), and cumulative incidence of transplant-related mortality (TRM) 14% versus 15% (P = .80), respectively. In the multivariate analysis, MRD positivity and a disease status >CR1 at the time of HSCT were significantly associated with poorer outcomes (P < .05). In conclusion, our study supports that both haploidentical and cord blood transplantation show comparable outcomes in pediatric AML patients. We obtained comparable survival rates, although CBT showed a trend to lower rates of chronic GvHD and higher GFRFS, demonstrating that it should still be considered a valuable option, particularly for pediatric patients.

Permissible HLA mismatches in 9/10 unrelated donor pediatric stem cell transplants using HLA-EMMA: an EBMT Inborn Errors Working Party study

AbstractAllogeneic hematopoietic stem cell transplantation (HSCT) with mismatched unrelated donors (MMUD) is associated with inferior outcome compared with matched unrelated donors (MUDs). We aimed to identify permissible mismatches using HLA epitope mismatch algorithm, which determines permissibility by analyzing amino acid sequences, in a single-center cohort of 70 pediatric 9/10 MMUD HSCTs and 157 10/10 MUDs for comparison. Amino acid matching was evaluated for the whole HLA protein, the α-helices, and the β-sheets, in both host vs graft (HvG) and graft vs host (GvH) direction. Superior event-free survival (EFS) was found in 13 patients permissibly mismatched in the HvG direction (totalHvG, 92% vs 58% at 1 year; P = .009) and in 21 patients matched on the α-helices (αHvG, 90% vs 53%; P = .002). These rates were similar to EFS rates in patients with 10/10 MUDs (90% vs 80%; P = .60). EFS was not related to β-sheet amino acid matching, nor to matching in the GvH direction. Overall survival (OS) rates trended similarly to those of EFS for amino acid mismatches (totalHvG, 92% vs 74%; P = .075; αHvG, 90% vs 71%; P = .072). These findings were reproduced in an EBMT Registry inborn errors cohort of 271 pediatric 9/10 MMUD HSCTs and 929 10/10 MUD HSCTs, showing a significant effect of αHvG matching on both OS and EFS and similar OS and EFS between αHvG matched MMUDs and 10/10 MUDs. In summary, HvG amino acid matching on the α-helices identifies 9/10 MMUDs with permissible mismatches, which are correlated with favorable transplant outcomes similar to those of matched donors.

Adrenoleukodystrophy an Overview

Adrenoleukodystrophy (ALD) is a rare X-linked peroxisomal oxidation disease caused by mutations in ABCD1. It presents with various clinical manifestations, including cerebral ALD, myelopathy, and primary adrenal insufficiency. About 80% of ALD patients suffer from adrenal insufficiency, and cerebral ALD affects one-third of boys under twelve, progressing to total impairment and death without treatment. Hematopoietic stem cell transplantation (HSCT) is the only disease-modifying treatment for early-stage cerebral ALD, but it does not halt adrenal insufficiency progression and carries significant morbidity and mortality risks. A recent gene therapy clinical trial showed short-term MRI and neurological outcomes equivalent to past HSCT treatments without the adverse side effects. Additionally, over a dozen states have initiated newborn screening (NBS) for ALD, with the number expected to triple by 2020. Genetic testing of NBS-positive newborns has identified novel variations of unknown significance, raising questions about monitoring and treating preclinical or moderate adrenal insufficiency or cerebral involvement. This presents further opportunities for genetic characterization. The availability of matching donors, transplant centers, and specialists will impact prompt treatment for those diagnosed with ALD at birth. As NBS and gene therapy trials improve ALD's clinical management and prognosis, endocrine management of presymptomatic and subclinical adrenal insufficiency will become increasingly important.

NK cells with adhesion defects and reduced cytotoxic functions are associated with a poor prognosis in multiple myeloma

AbstractThe promising results obtained with immunotherapeutic approaches for multiple myeloma (MM) call for a better stratification of patients based on immune components. The most pressing being cytotoxic lymphocytes such as natural killer (NK) cells that are mandatory for MM surveillance and therapy. Here, we performed a single-cell RNA sequencing analysis of NK cells from 10 patients with MM and 10 age/sex–matched healthy donors that revealed important transcriptomic changes in the NK cell landscape affecting both the bone marrow (BM) and peripheral blood compartment. The frequency of mature cytotoxic CD56dim NK cell subsets was reduced in patients with MM at the advantage of late-stage NK cell subsets expressing NF-κB and interferon-I inflammatory signatures. These NK cell subsets accumulating in patients with MM were characterized by low CD16 and CD226 expression and poor cytotoxic functions. MM CD16/CD226Lo NK cells also had adhesion defects with reduced lymphocyte function-associated antigen 1 (LFA-1) integrin activation and actin polymerization that may account for their limited effector functions in vitro. Finally, analysis of BM-infiltrating NK cells in a retrospective cohort of 177 patients with MM from the Intergroupe Francophone du Myélome (IFM) 2009 trial demonstrated that a high frequency of NK cells and their low CD16 and CD226 expression were associated with a shorter overall survival. Thus, CD16/CD226Lo NK cells with reduced effector functions accumulate along MM development and negatively affect patients’ clinical outcomes. Given the growing interest in harnessing NK cells to treat myeloma, this improved knowledge around MM–associated NK cell dysfunction will stimulate the development of more efficient immunotherapeutic drugs against MM.