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BACKGROUND: Cord blood units (CBUs) that are ineligible for licensure due to incomplete compliance with FDA recommendations may be used for hematopoietic stem cell transplantation under urgent medical need and an Investigational Drug Application. The largest reason for CBU donor ineligibility is Zika virus (ZIKV) risk. The study's objective was to analyze the impact of current FDA recommendations for ZIKA risk on a large public cord blood bank and propose updated recommendations. METHODS: We performed a retrospective analysis of Carolinas Cord Blood Bank (CCBB), an FDA licensed public CBB, using data from January 1, 2016 to November 21, 2023 and compared FDA recommendations for transfusion transmitted infections (TTI) for blood products and relevant communicable disease agents or diseases for human cell, tissue, or cellular or tissue-based products (HCT/Ps). RESULTS: CCBB: 9057 (84.3% licensed) CBUs were banked. 984/1682 (58.5%) of unlicensed CBUs had ZIKV risk. 22.0% of CBUs with ZIKV risk were from Hispanic parents, compared to 16.1% of all units. 31 of IND CBUs (11 due to ZIKV risk without reported ZIKV transmission) were safely infused. FDA Guidance: HCT/P ZIKV, HIV, and vCJD recommendations have not been updated since 2018 in contrast to FDA removal of ZIKV as a relevant TTI in 2021 and updating HIV and vCJD guidance related to TTI in 2023 and 2022, respectively. DISCUSSION: The FDA should consider new data to revise the HCT/P donor eligibility recommendations, which will increase the number of eligible HCT/P donors, and potentially improve access to therapies for a more diverse patient population.
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Bancos de Sangue , Sangue Fetal , United States Food and Drug Administration , Infecção por Zika virus , Humanos , Estados Unidos , Infecção por Zika virus/transmissão , Sangue Fetal/virologia , Bancos de Sangue/normas , Zika virus , Estudos Retrospectivos , Feminino , MasculinoRESUMO
Krabbe disease (KD) is part of newborn screening (NBS) in 11 states with at least one additional state preparing to screen. In July 2021, KD was re-nominated for addition to the federal Recommended Uniform Screening Panel (RUSP) in the USA with a two-tiered strategy based on psychosine (PSY) as the determinant if an NBS result is positive or negative after a first-tier test revealed decreased galactocerebrosidase activity. Nine states currently screening for KD include PSY analysis in their screening strategy. However, the nomination was rejected in February 2023 because of perceived concerns about a high false positive rate, potential harm to newborns with an uncertain prognosis, and inadequate data on presymptomatic treatment benefit or harm. To address the concern about false positive NBS results, a survey was conducted of the eight NBS programs that use PSY and have been screening for KD for at least 1 year. Seven of eight states responded. We found that: (1) the use of PSY is variable; (2) when modeling the data based on the recommended screening strategy for KD, and applying different cutoffs for PSY, each state could virtually eliminate false positive results without major impact on sensitivity; (3) the reason for the diverse strategies appears to be primarily the difficulty of state programs to adjust screening algorithms due to the concern of possibly missing even an adult-onset case following a change that focuses on infantile and early infantile KD. Contracts with outside vendors and the effort/cost of making changes to a program's information systems can be additional obstacles. We recommend that programs review their historical NBS outcomes for KD with their advisory committees and make transparent decisions on whether to accept false positive results for such a devastating condition or to adjust their procedures to ensure an efficient, effective, and manageable NBS program for KD.
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The central nervous system (CNS) tightly regulates access of circulating immune cells. Immunosurveillance is therefore managed in the meninges at the borders of the CNS. Here, we demonstrated that mural cells, which include pericytes and smooth muscle cells, decreased coverage around blood vessels in the dura, the outermost layer of the meninges, and upregulated gene pathways involved in leukocyte migration in presymptomatic experimental autoimmune encephalomyelitis (EAE). Partially depleting mural cells promoted the trafficking of CNS antigen-specific T cells to the dura in a process that depended on resident antigen-presenting cells, thereby increasing susceptibility to passive EAE. Mechanistically, mural cells physically contacted macrophages in the dura and transferred cytoplasmic components, including processing bodies (RNA granules shown to reprogram transcriptomes), which were critical to suppress antigen-dependent T helper (TH) cell activation and TH17 differentiation. Our study revealed a mechanism by which mural cell-macrophage interactions regulate the trafficking of CNS antigen-specific T cells to the dura.
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Dura-Máter , Encefalomielite Autoimune Experimental , Animais , Sistema Nervoso Central , Meninges , Macrófagos , PericitosRESUMO
Stroke remains a leading cause of death and disability in the US, and time-limited reperfusion strategies remain the only approved treatment options. To address this unmet clinical need, we conducted a phase II randomized clinical trial to determine whether intravenous infusion of banked, non-HLA matched unrelated donor umbilical cord blood (UCB) improved functional outcome after stroke. Participants were randomized 2:1 to UCB or placebo within strata of National Institutes of Health Stroke Scale Score (NIHSS) and study center. Study product was infused 3-10 days following index stroke. The primary endpoint was change in modified Rankin Scale (mRS) from baseline to day 90. Key secondary outcomes included functional independence, NIHSS, the Barthel Index, and assessment of adverse events. The trial was terminated early due to slow accrual and logistical concerns associated with the COVID-19 pandemic, and a total of 73 of a planned 100 participants were included in primary analyses. The median (range) of the change in mRS was 1 point (-2, 3) in UCB and 1 point (-1,4) in Placebo (Pâ =â 0.72). A shift analysis comparing the mRS at day 90 utilizing proportional odds modeling showed a common odds ratio of 0.9 (95% CI: 0.4, 2.3) after adjustment for baseline NIHSS and randomization strata. The distribution of adverse events was similar between arms. Although this study did not suggest any safety concerns related to UCB in ischemic stroke, we did not show a clinical benefit in the reduced sample size evaluated.
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Isquemia Encefálica , Transplante de Células-Tronco Hematopoéticas , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Sangue Fetal , Pandemias , Doadores não Relacionados , Método Duplo-Cego , Acidente Vascular Cerebral/terapia , Resultado do Tratamento , Isquemia Encefálica/terapia , Isquemia Encefálica/complicaçõesRESUMO
BACKGROUND AIMS: White matter diseases are commonly associated with microglial activation and neuroinflammation. Mesenchymal stromal cells (MSCs) have immunomodulatory properties and thus have the potential to be developed as cell therapy for white matter disease. MSCs interact with resident macrophages to alter the trajectory of inflammation; however, the impact MSCs have on central nervous system macrophages and the effect this has on the progression of white matter disease are unclear. METHODS: In this study, we utilized numerous assays of varying complexity to model different aspects of white matter disease. These assays ranged from an in vivo spinal cord acute demyelination model to a simple microglial cell line activation assay. Our goal was to investigate the influence of human umbilical cord tissue MSCs on the activation of microglia. RESULTS: MSCs reduced the production of tumor necrosis factor (TNF) by microglia and decreased demyelinated lesions in the spinal cord after acute focal injury. To determine if MSCs could directly suppress the activation of microglia and to develop an efficient potency assay, we utilized isolated primary microglia from mouse brains and the Immortalized MicroGlial Cell Line (IMG). MSCs suppressed the activation of microglia and the release of TNF after stimulation with lipopolysaccharide, a toll-like receptor agonist. CONCLUSIONS: In this study, we demonstrated that MSCs altered the immune response after acute injury in the spinal cord. In numerous assays, MSCs suppressed activation of microglia and release of the pro-inflammatory cytokine TNF. Of these assays, IMG could be standardized and used as an effective potency assay to determine the efficacy of MSCs for treating white matter disease or other neuroinflammatory conditions associated with microglial activation.
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Leucoencefalopatias , Células-Tronco Mesenquimais , Camundongos , Animais , Humanos , Microglia/metabolismo , Macrófagos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Leucoencefalopatias/metabolismoRESUMO
Various types of cellular injection have become a popular and costly treatment option for patients with knee osteoarthritis despite a paucity of literature establishing relative efficacy to each other or corticosteroid injections. Here we aimed to identify the safety and efficacy of cell injections from autologous bone marrow aspirate concentrate, autologous adipose stromal vascular fraction and allogeneic human umbilical cord tissue-derived mesenchymal stromal cells, in comparison to corticosteroid injection (CSI). The study was a phase 2/3, four-arm parallel, multicenter, single-blind, randomized, controlled clinical trial with 480 patients with a diagnosis of knee osteoarthritis (Kellgren-Lawrence II-IV). Participants were randomized to the three different arms with a 3:1 distribution. Arm 1: autologous bone marrow aspirate concentrate (n = 120), CSI (n = 40); arm 2: umbilical cord tissue-derived mesenchymal stromal cells (n = 120), CSI (n = 40); arm 3: stromal vascular fraction (n = 120), CSI (n = 40). The co-primary endpoints were the visual analog scale pain score and Knee injury and Osteoarthritis Outcome Score pain score at 12 months versus baseline. Analyses of our primary endpoints, with 440 patients, revealed that at 1 year post injection, none of the three orthobiologic injections was superior to another, or to the CSI control. In addition, none of the four groups showed a significant change in magnetic resonance imaging osteoarthritis score compared to baseline. No procedure-related serious adverse events were reported during the study period. In summary, this study shows that at 1 year post injection, there was no superior orthobiologic as compared to CSI for knee osteoarthritis. ClinicalTrials.gov Identifier: NCT03818737.
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Osteoartrite do Joelho , Humanos , Osteoartrite do Joelho/complicações , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/tratamento farmacológico , Dor/tratamento farmacológico , Dor/etiologia , Método Simples-Cego , Resultado do TratamentoRESUMO
Objectives: Thymus implantation is a recently FDA-approved therapy for congenital athymia. Patients receiving thymus implantation develop a functional but incomplete T cell compartment. Our objective was to develop a mouse model to study clinical thymus implantation in congenital athymia and to optimise implantation procedures to maximise T cell education and expansion of naïve T cells. Methods: Using Foxn1 nu athymic mice as recipients, we tested MHC-matched and -mismatched donor thymi that were implanted as fresh tissue or cultured to remove donor T cells. We first implanted thymus under the kidney capsule and then optimised intramuscular implantation. Using competitive adoptive transfer assays, we investigated whether the failure of newly developed T cells to expand into a complete T cell compartment was because of intrinsic deficits or whether there were deficits in engaging MHC molecules in the periphery. Finally, we tested whether recombinant IL-7 would promote the expansion of host naïve T cells educated by the implanted thymus. Results: We determined that thymus implants in Foxn1 nu athymic mice mimic many aspects of clinical thymus implants in patients with congenital athymia. When we implanted cultured, MHC-mismatched donor thymus into Foxn1 nu athymic mice, mice developed a limited T cell compartment with notably underdeveloped naïve populations and overrepresented memory-like T cells. Newly generated T cells were predominantly educated by MHC molecules expressed by the donor thymus, thus potentially undergoing another round of selection once in the peripheral circulation. Using competitive adoptive transfer assays, we compared expansion rates of T cells educated on donor thymus versus T cells educated during typical thymopoiesis in MHC-matched and -mismatched environments. Once in the circulation, regardless of the MHC haplotypes, T cells educated on a donor thymus underwent abnormal expansion with initially more robust proliferation coupled with greater cell death, resembling IL-7 independent spontaneous expansion. Treating implanted mice with recombinant interleukin (IL-7) promoted homeostatic expansion that improved T cell development, expanded the T cell receptor repertoire, and normalised the naïve T cell compartment. Conclusion: We conclude that implanting cultured thymus into the muscle of Foxn1 nu athymic mice is an appropriate system to study thymus implantation for congenital athymia and immunodeficiencies. T cells are educated by the donor thymus, yet naïve T cells have deficits in expansion. IL-7 greatly improves T cell development after thymus implantation and may offer a novel strategy to improve outcomes of clinical thymus implantation.
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Human cytomegalovirus (HCMV) profoundly modulates host T and natural killer (NK) cells across the lifespan, expanding unique effector cells bridging innate and adaptive immunity. Though HCMV is the most common congenital infection worldwide, how this ubiquitous herpesvirus impacts developing fetal T and NK cells remains unclear. Using computational flow cytometry and transcriptome profiling of cord blood from neonates with and without congenital HCMV (cCMV) infection, we identify major shifts in fetal cellular immunity marked by an expansion of Fcγ receptor III (FcγRIII)-expressing CD8+ T cells (FcRT) following HCMV exposure in utero. FcRT cells from cCMV-infected neonates express a cytotoxic NK cell-like transcriptome and mediate antigen-specific antibody-dependent functions including degranulation and IFNγ production, the hallmarks of NK cell antibody-dependent cellular cytotoxicity (ADCC). FcRT cells may represent a previously unappreciated effector population with innate-like functions that could be harnessed for maternal-infant vaccination strategies and antibody-based therapeutics in early life.
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Hypoxic ischemic encephalopathy (HIE) in neonates causes increased mortality and long-term morbidity in surviving babies. Hypothermia (HT) has improved outcomes, however, mortality remains high with ~half of surviving babies developing neurological impairment in their first years. We previously explored the use of autologous cord blood (CB) to determine if CB cells could lessen long-term damage to the brain. However, the feasibility of CB collection from sick neonates limited the utility of this approach. Allogeneic cord tissue mesenchymal stromal cells (hCT-MSC), cryopreserved and readily available, have been shown to ameliorate brain injury in animal models of HIE. We, therefore, conducted a pilot, phase I, clinical trial to test the safety and describe the preliminary efficacy of hCT-MSC in neonates with HIE. The study treated infants with moderate to severe HIE, treated with HT, with 1 or 2 doses of 2 million cells/kg/dose of hCT-MSC given intravenously. The babies were randomized to receive 1 or 2 doses with the first dose during HT and the second dose 2 months later. Babies were followed for survival and development with scoring of Bayley's at 12 postnatal months. Six neonates with moderate (4) or severe (2) HIE were enrolled. All received 1 dose of hCT-MSC during HT and 2 received a 2nd dose, 2 months later. hCT-MSC infusions were well tolerated although 5/6 babies developed low titer anti-HLA antibodies by 1 year of age. All babies survived, with average to low-average developmental assessment standard scores for ages between 12 and 17 postnatal months. Further study is warranted.
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Transplante de Células-Tronco Hematopoéticas , Hipotermia Induzida , Hipóxia-Isquemia Encefálica , Células-Tronco Mesenquimais , Hipóxia-Isquemia Encefálica/terapia , Cordão Umbilical , Humanos , Recém-NascidoRESUMO
OBJECTIVE: To model the long-term clinical and economic outcomes of potential cord blood therapy in autism spectrum disorder (ASD). STUDY DESIGN: Markov microsimulation of ASD over the lifespan was used to compare two strategies: 1) standard of care (SOC), including behavioral and educational interventions, and 2) novel cord blood (CB) intervention in addition to SOC. Input data reflecting behavioral outcomes included baseline Vineland Adaptive Behavior Scale (VABS-3), monthly VABS-3 changes, and CB intervention efficacy on adaptive behavior based on a randomized, placebo-controlled trial (DukeACT). Quality-adjusted life-years (QALYs) were correlated to VABS-3. Costs for children with ASD ($15,791, ages 2-17 years) and adults with ASD ($56,559, ages 18+ years), and the CB intervention (range $15,000-45,000) were incorporated. Alternative CB efficacy and costs were explored. RESULTS: We compared model-projected results to published data on life-expectancy, mean VABS-3 changes, and lifetime costs. Undiscounted lifetime QALYs in the SOC and CB strategies were 40.75 and 40.91. Discounted lifetime costs in the SOC strategy were $1,014,000, and for CB ranged from $1,021,000-$1,058,000 with CB intervention cost ($8,000-$45,000). At $15,000 cost, CB was borderline cost-effective (ICER = $105,000/QALY). In one-way sensitivity analysis, CB cost and efficacy were the most influential parameters on CB ICER. CB intervention was cost-effective at costs<$15,000 and efficacies ≥2.0. Five-year healthcare payer projected budgetary outlays at a $15,000 CB cost were $3.847B. CONCLUSIONS: A modestly effective intervention designed to improve adaptive behavior in autism can be cost-effective under certain circumstances. Intervention cost and efficacy most affected the cost-effectiveness results and should be targeted to increase economic efficiency.
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Transtorno do Espectro Autista , Adulto , Humanos , Criança , Pré-Escolar , Adolescente , Análise Custo-Benefício , Transtorno do Espectro Autista/terapia , Sangue Fetal , Expectativa de Vida , Anos de Vida Ajustados por Qualidade de VidaRESUMO
BACKGROUND: Treatment options for patients with COVID-19-related acute respiratory distress syndrome (ARDS) are desperately needed. Allogeneic human umbilical cord derived mesenchymal stromal cells (hCT-MSCs) have potential therapeutic benefits in these critically ill patients, but feasibility and safety data are lacking. MATERIALS AND METHODS: In this phase I multisite study, 10 patients with COVID-19-related ARDS were treated with 3 daily intravenous infusions of hCT-MSCs (1 million cells/kg, maximum dose 100 million cells). The primary endpoint assessed safety. RESULTS: Ten patients (7 females, 3 males; median age 62 years (range 39-79)) were enrolled at 2 sites and received a total of 30 doses of study product. The average cell dose was 0.93 cells/kg (range 0.56-1.45 cells/kg and total dose range 55-117 million cells) with 5/30 (17%) of doses lower than intended dose. Average cell viability was 85% (range 63%-99%) with all but one meeting the >70% release criteria. There were no infusion-related reactions or study-related adverse events, 28 non-serious adverse events in 3 unique patients, and 2 serious adverse events in 2 unique patients, which were expected and unrelated to the study product. Five patients died: 3 by day 28 and 5 by day 90 of the study (median 27 days, range 7-76 days). All deaths were determined to be unrelated to the hCT-MSCs. CONCLUSION: We were able to collect relevant safety outcomes for the use of hCT-MSCs in patients with COVID-19-related ARDS. Future studies to explore their safety and efficacy are warranted.
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COVID-19 , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Síndrome do Desconforto Respiratório , Masculino , Feminino , Humanos , Adulto , Pessoa de Meia-Idade , Idoso , COVID-19/terapia , COVID-19/etiologia , Estudos de Viabilidade , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/terapiaRESUMO
Omidubicel is an umbilical cord blood (UCB)-derived ex vivo-expanded cellular therapy product that has demonstrated faster engraftment and fewer infections compared with unmanipulated UCB in allogeneic hematopoietic cell transplantation. Although the early benefits of omidubicel have been established, long-term outcomes remain unknown. We report on a planned pooled analysis of 5 multicenter clinical trials including 105 patients with hematologic malignancies or sickle cell hemoglobinopathy who underwent omidubicel transplantation at 26 academic transplantation centers worldwide. With a median follow-up of 22 months (range, .3 to 122 months), the 3-year estimated overall survival and disease-free survival were 62.5% and 54.0%, respectively. With up to 10 years of follow-up, omidubicel showed durable trilineage hematopoiesis. Serial quantitative assessments of CD3+, CD4+, CD8+, CD19+, CD116+CD56+, and CD123+ immune subsets revealed median counts remaining within normal ranges through up to 8 years of follow-up. Secondary graft failure occurred in 5 patients (5%) in the first year, with no late cases reported. One case of donor-derived myeloid neoplasm was reported at 40 months post-transplantation. This was also observed in a control arm patient who received only unmanipulated UCB. Overall, omidubicel demonstrated stable trilineage hematopoiesis, immune competence, and graft durability in extended follow-up.
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Transplante de Células-Tronco Hematopoéticas , Humanos , Seguimentos , Estudos Prospectivos , Intervalo Livre de Doença , Estudos Multicêntricos como AssuntoRESUMO
Four decades ago, Broxmeyer et al. demonstrated that umbilical cord blood (CB) contained hematopoietic stem cells (HSC) and hypothesized that CB could be used as a source of donor HSC for rescue of myeloablated bone marrow. In 1988, Gluckman et al. reported the first successful matched sibling cord blood transplant (CBT) in a child with Fanconi Anemia. In 1991, Rubinstein et al. established an unrelated donor CB bank, and in 1993, the first unrelated CBT used a unit from this bank. Since that time, >40 000 CBTs have been performed worldwide. Early outcomes of CBT were mixed and demonstrated the importance of cell dose from the CB donor. We hypothesized that improvements in CB banking and transplantation favorably impacted outcomes of CBT today and performed a retrospective study combining data from Eurocord and Duke University in 4834 children transplanted with a single unrelated CB unit (CBU) from 1993 to 2019. Changes in standard transplant outcomes (overall survival [OS], disease free survival [DFS], acute and chronic graft-versus-host disease [GvHD], treatment related mortality [TRM], and relapse) over 3 time periods (1: <2005; 2: 2005 to <2010; and 3: >2010 to 2019) were studied. Increased cell dose and degree of HLA matching were observed over time. OS, times to engraftment, and DFS improved over time. The incidence of TRM and GvHD decreased while the incidence of relapse remained unchanged. Relative contributions of cell dose and HLA matching to transplant outcomes were also assessed and showed that HLA matching was more important than cell dose in this pediatric cohort.
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Transplante de Células-Tronco de Sangue do Cordão Umbilical , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Criança , Doadores não Relacionados , Estudos Retrospectivos , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença Enxerto-Hospedeiro/etiologia , Recidiva , Sangue FetalRESUMO
The non-POU domain-containing octamer-binding (NONO) protein is involved in multiple steps of gene regulation such as RNA metabolism and DNA repair. Hemizygous pathogenic variants in the NONO gene were confirmed to cause a rare X-linked syndromic disorder. Through our in-house diagnostics and subsequent matchmaking, we identified six unrelated male individuals with pathogenic or likely pathogenic NONO variants. For a detailed comparison, we reviewed all published characterizations of the NONO-associated disorder. The combined cohort consists of 16 live-born males showing developmental delay, corpus callosum anomalies, non-compaction cardiomyopathy and relative macrocephaly as leading symptoms. Seven prenatal literature cases were characterized by cardiac malformations. In this study, we extend the phenotypic spectrum through two more cases with epilepsy as well as two more cases with hematologic anomalies. By RNA expression analysis and structural modeling of a new in-frame splice deletion, we reinforce loss-of-function as the pathomechanism for the NONO-associated syndromic disorder.
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Cardiomiopatias , Cardiopatias Congênitas , Humanos , Masculino , Proteínas de Ligação a DNA/genética , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/genética , Cardiomiopatias/genética , Genes Ligados ao Cromossomo X , RNA , Proteínas de Ligação a RNA/genéticaRESUMO
Diffusion tensor imaging (DTI) has been used as an outcome measure in clinical trials for several psychiatric disorders but has rarely been explored in autism clinical trials. This is despite a large body of research suggesting altered white matter structure in autistic individuals. The current study is a secondary analysis of changes in white matter connectivity from a double-blind placebo-control trial of a single intravenous cord blood infusion in 2-7-year-old autistic children (1). Both clinical assessments and DTI were collected at baseline and 6 months after infusion. This study used two measures of white matter connectivity: change in node-to-node connectivity as measured through DTI streamlines and a novel measure of feedback network connectivity, Ollivier-Ricci curvature (ORC). ORC is a network measure which considers both local and global connectivity to assess the robustness of any given pathway. Using both the streamline and ORC analyses, we found reorganization of white matter pathways in predominantly frontal and temporal brain networks in autistic children who received umbilical cord blood treatment versus those who received a placebo. By looking at changes in network robustness, this study examined not only the direct, physical changes in connectivity, but changes with respect to the whole brain network. Together, these results suggest the use of DTI and ORC should be further explored as a potential biomarker in future autism clinical trials. These results, however, should not be interpreted as evidence for the efficacy of cord blood for improving clinical outcomes in autism. This paper presents a secondary analysis using data from a clinical trial that was prospectively registered with ClinicalTrials.gov(NCT02847182).
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AIM: To evaluate safety and motor function after treatment with allogeneic umbilical cord blood (AlloCB) or umbilical cord tissue-derived mesenchymal stromal cells (hCT-MSC) in children with cerebral palsy (CP). METHOD: Ninety-one children (52 males, 39 females; median age 3 years 7 months [range 2-5 years]) with CP due to hypoxic-ischemic encephalopathy, stroke, or periventricular leukomalacia were randomized to three arms: (1) the AlloCB group received 10 × 107 AlloCB total nucleated cells (TNC) per kilogram at baseline (n = 31); (2) the hCT-MSC group received 2 × 106 hCT-MSC at baseline, 3 months, and 6 months (n = 28); (3) the natural history control group received 10 × 107 AlloCB TNC per kilogram at 12 months (n = 31). Motor function was assessed with the Gross Motor Function Measure-66 (GMFM-66) and Peabody Developmental Motor Scale, Second Edition. RESULTS: Infusions (n = 143) were well tolerated, with eight infusion reactions (three in the AlloCB group, five in hCT-MSC) and no other safety concerns. At 12 months, the mean differences (95% confidence intervals [CI]) between actual and expected changes in GMFM-66 score were AlloCB 5.8 points (3.4-8.2), hCT-MSC 4.3 (2.2-6.4), and natural history 3.1 (1.4-5.0). In exploratory, post hoc analysis, the mean GMFM-66 score (95% CI) of the hCT-MSC group was 1.4 points higher than natural history (-1.1 to 4.0; p = 0.27), and the AlloCB group was 3.3 points higher than natural history (0.59-5.93; p = 0.02) after adjustment for baseline Gross Motor Function Classification System level, GMFM-66 score, and etiology. INTERPRETATION: High-dose AlloCB is a potential cell therapy for CP and should be further tested in a randomized, blinded, placebo-controlled trial. WHAT THIS PAPER ADDS: Unrelated donor allogeneic umbilical cord blood (AlloCB) and human umbilical cord tissue-derived mesenchymal stromal cell infusion is safe in young children with cerebral palsy. Significant changes in motor function were not observed 6 months after treatment. One year later, treatment with AlloCB was associated with greater increases in Gross Motor Function Measure-66 scores.
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Paralisia Cerebral , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Mesenquimais , Criança , Masculino , Feminino , Humanos , Pré-Escolar , Lactente , Paralisia Cerebral/terapia , Sangue Fetal , Terapia Baseada em Transplante de Células e TecidosRESUMO
Human cytomegalovirus (HCMV) is the most common congenital infection and a leading cause of stillbirth, neurodevelopmental impairment, and pediatric hearing loss worldwide. Development of a maternal vaccine or therapeutic to prevent congenital HCMV has been hindered by limited knowledge of the immune responses that protect against HCMV transmission in utero. To identify protective antibody responses, we measured HCMV-specific IgG binding and antiviral functions in paired maternal and cord blood sera from HCMV-seropositive transmitting (n = 41) and non-transmitting (n = 40) mother-infant dyads identified via a large, US-based, public cord blood bank. We found that high-avidity IgG binding to HCMV and antibody-dependent cellular phagocytosis (ADCP) were associated with reduced risk of congenital HCMV infection. We also determined that HCMV-specific IgG activation of FcγRI and FcγRII was enhanced in non-transmitting dyads and that increased ADCP responses were mediated through both FcγRI and FcγRIIA expressed on human monocytes. These findings suggest that engagement of FcγRI/FcγRIIA and Fc effector functions including ADCP may protect against congenital HCMV infection. Taken together, these data can guide future prospective studies on immune correlates against congenital HCMV transmission and inform HCMV vaccine and immunotherapeutic development.