Search

Objetivos: Descrever o desfecho do transplante de células tronco hematopoiéticas (TCTH) em pacientes (pts) com anemia de fanconi (AF) que desenvolveram síndrome mielodisplásica (SMD) ou leucemia mieloide aguda (LMA). Material e métodos: Análise retrospectiva dos prontuários médicos dos pts com AF em fase de SMD/LMA que foram submetidos ao TCTH entre janeiro de 2012 e dezembro de 2023. Resultados: Foram analisados 35 pts, a maioria do sexo masculino (n = 20). A mediana de idade foi 17 anos (2‒44 anos), sendo 51% menores de 18 anos (n = 17). Doze pts fizeram uso de andrógeno na fase de aplasia. Quinze pts foram transplantados com citopenia refratária (n = 15), seis pts com SMD com Excesso de Blastos tipo 1 (EB1); quatro com SMD tipo 2 (EB2) e dez com LMA. A maioria dos pts transplantados em fase avançada (SMD-EB2/LMA) recebeu esquema FLAG pré TMO (n = 12). Os doadores foram haploidênticos (n = 17), não aparentados (n = 11) e aparentados compatíveis (n = 7). Todos receberam medula óssea. Os regimes de condicionamento foram feitos com CY + FLU + TBI (NAP), FLU + TBI (Haplo). Quinze pts utilizaram seroterapia (ATG n = 10/Campath n = 5). Nenhum rejeitou. Nove pts tiveram recaída da doença após TCTH, com mediana de 240 dias (80‒1691 dias). Seis pts foram retransplantados, 1 fez uso de azacitidina como manutenção pós transplante e 1 usou venetoclax, mas todos evoluíram para óbito. A mediana de follow-up foi 3,6 anos (14 dias‒11,8 anos). A sobrevida global em 5 anos foi 51,4%. Dez pts morreram numa mediana de 138 dias após o TCTH (85‒1102 dias) e 3 pts morreram durante o condicionamento. A sobrevida livre de recaída foi 67,3% e a SG em 5 anos para pts em fase avançada foi 32,4%, com taxa de recidiva em 5 anos de 25%. As causas de óbito foram infecção fúngica invasiva (n = 5), progressão da doença (n = 4), infecções (bacteriana/viral n = 3), DECHa (n = 2), neoplasia (n = 1) e toxicidade medicamentosa (n = 1). Discussão: A AF é a causa hereditária mais frequente de falência de medula óssea. A incidência de SMD é 11% a 34% e a de LMA é de 10% a 37%, com taxas de sobrevida após o TCTH de 57% e 36% respectivamente, inferiores se comparados aos pts com LMA não portadores de AF. A adolescência ou a idade adulta jovem são os períodos mais comuns de evolução clonal. O uso de andrógenos tem resposta hematológica em cerca de 80% dos pts e não tem associação com evolução clonal, conforme a literatura. Neste estudo, quase a metade dos pacientes tinham mais de 18 anos e a SG foi semelhante às publicações anteriores (SG em 5 anos: 42%). O tratamento de pts com SMD e LMA tem altas taxas de recaída, pois os pts não toleram quimioterapia intensiva além da quimio resistência intrínseca. O esquema FLAG pré TCTH usa quimioterapia de baixa intensidade e a taxa de recidiva nesta população foi inferior à descrita na literatura (taxa de recidiva em 5 anos: 40%). As infecções fúngicas invasivas são uma preocupação devido à grande mortalidade associada. Conclusão: A AF continua sendo um desafio, devido ao alto risco de neoplasias secundárias. Mas estes resultados indicam que apesar do TCTH ser a única opção com possibilidade curativa para falência de medula óssea, a morte por infecção e recaída permanecem um grande problema. Mais estudos são necessários para determinar o melhor regime de condicionamento ou terapêutica de manutenção e profilática pós TCTH.

Objetivo: A má função do enxerto (PGF) após o Transplante de Células Tronco Hematopoiéticas (TCTH) é definida por citopenias dependentes de transfusões de sangue e/ou suporte de G-CSF, apesar do quimerismo completo do doador. O objetivo deste trabalho é descrever o uso do Eltrombopag (EPAG) para PGF em pacientes (pts) pediátricos submetidos a TCTH entre 2009 e 2023. Métodos: Análise retrospectiva de prontuários médicos. Resultados: 30 pts desenvolveram PGF após o TCTH e foram tratados com EPAG. A maioria eram do sexo masculino (n = 20) e a medina de idade no TCTH foi 8,1 anos (6m‒17,4a). Os diagnósticos foram: erros inatos de imunidade (n = 12), falência medular (n = 11) e leucemias agudas (n = 7). Os doadores foram haploidênticos (n = 16), não aparentados (n = 12) ou aparentados compatíveis (n = 2). Medula óssea foi a fonte de células predominante (n = 27) e a maioria dos pts recebeu condicionamento de intensidade reduzida (n = 20). A mediana de células CD34 infundidas foi de 4,94×106/kg (1,56–12,6×106/kg). O EPAG foi iniciado em uma mediana de 116 dias após o TCTH (42d‒9,3a), devido à trombocitopenia persistente, com anemia e neutropenia concomitantes em 7 e 8 pts, respectivamente. A dose inicial foi de 25 mg/dia, e eventualmente aumentada para 150 mg/dia em caso de falta de resposta, nas crianças mais velhas. Dois pts morreram no primeiro mês após o início do EPAG e não foram avaliáveis para resposta. 28 pcts sobreviveram mais de 3 meses após o início do EPAG, com 22 exibindo uma resposta hematológica. A mediana de tempo para resposta foi de 110 dias. Entre os respondedores, o EPAG foi descontinuado sem recaídas, e todos os pacientes permaneceram vivos e bem em um acompanhamento médio de 37 meses após o EPAG. Seis pts não responderam ao EPAG. Entre eles, 3 foram submetidos a um 2º TCTH, enquanto 3 pacientes morreram (2 por complicações infecciosas e 1 por recidiva da doença), ocorrendo pelo menos 4 meses após a descontinuação do EPAG. A sobrevida global (SG) de 2 anos foi de 82% (95% IC: 0,55‒0,95). Todos os efeitos colaterais foram leves e não levaram à descontinuação do EPAG. Discussão: A má função do enxerto tem incidência variável de 5% a 26% e aumenta as taxas de morbimortalidade pós TCTH, principalmente associada à infecções. As causas da PGF são incertas e os pts apresentam hipocelularidade medular intensa relacionada a um déficit na capacidade de produção plaquetária. No presente estudo, todos os pacientes tinham plaquetopenia. O EPAG se mostrou eficaz no tratamento da citopenia tardia em pacientes submetidos ao TCTH, corroborando os dados publicados. A mediana de tempo para resposta ao EPAG é 3 meses de tratamento e os resultados dos não respondedores refletiram impacto na SG. Além disso, podemos destacar, uma maior prevalência da PGF em pts que realizaram transplante com doador alternativo (haploidêntico), o que é descrito na literatura, possivelmente associado ao uso da CFA pós. Conclusão: O EPAG demonstrou ser uma opção terapêutica viável para pts com citopenias persistentes após o TCTH. No entanto, é importante notar que o tempo médio para a resposta foi cerca de 3 meses, portanto, é crucial que os pts recebam suporte adequado durante esse período. Mais estudos são necessários para confirmar esses achados e determinar a melhor abordagem de tratamento para essa população específica.

Aplastic anaemia in infants and young children presents unique challenges due to high prevalence of inherited bone marrow failure syndromes (IBMFS) in this age group. The objective of this study is assessing clinical characteristics and outcomes of haematopoietic cell transplantation in children ≤5 years with bone marrow failure syndromes. We analysied 106 patients (66% males), median age 4.6 years, including 40 with Fanconi anaemia (FA), 32 with Acquired Severe Aplastic anaemia (aSAA), 15 with Diamond-Blackfan Anaemia, 11 with Amegakaryocytic Purpura and 8 with other IBMFS. Molecular testing was limited (39%), with 25.4% confirmed genetically. Retrospective longitudinal study across three paediatric transplantation centres (1982-2020). Overall survival (OS) was 76.4% over a median 10-year follow-up. OS rates were similar between aSAA and IBMFS (FA 77.5%, other IBMFS 76.5%). Transplant-related mortality (TRM) was lower in aSAA (9.4%) compared with IBMFS (16.2%). Recent years showed improved outcomes, with TRM declining post-2010. Choice of stem cell source impacted OS, favouring bone marrow over umbilical cord, but showing encouraging results with haploidentical. Late complications were common, including endocrine-metabolic issues and delayed neuropsychomotor development. Diagnosing and managing bone marrow failures in young children pose significant challenges. Despite advancements in transplant practices, ongoing vigilance and comprehensive care are necessary to improve long-term survival rates., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been widely linked to Parkinson's disease, where the G2019S variant has been shown to contribute uniquely to both familial and sporadic forms of the disease. LRRK2-related mutations have been extensively studied, yet the wide variety of cellular and network events related to these mutations remain poorly understood. The advancement and availability of tools for neural engineering now enable modeling of selected pathological aspects of neurodegenerative disease in human neural networks in vitro . Our study revealed distinct pathology associated dynamics in engineered human cortical neural networks carrying the LRRK2 G2019S mutation compared to healthy isogenic control neural networks. The neurons carrying the LRRK2 G2019S mutation self-organized into networks with aberrant morphology and mitochondrial dynamics, affecting emerging structure-function relationships both at the micro-and mesoscale. Taken together, the findings of our study points toward an overall heightened metabolic demand in networks carrying the LRRK2 G2019S mutation, as well as a resilience to change in response to perturbation, compared to healthy isogenic controls., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Valderhaug, Ramstad, van de Wijdeven, Heiney, Nichele, Sandvig and Sandvig.)

Background: Telomere biology diseases (TBD) result from defective telomere maintenance, leading to bone marrow failure. The only curative treatment for aplastic anemia related to TBD is a hematopoietic cell transplant (HCT). Although reduced-intensity conditioning (RIC) regimens decrease transplant-related mortality, non-hematological phenotypes represent a major challenge and are associated with poor long-term follow-up outcomes., Objective: To describe the outcome of TBD patients transplanted for marrow failure., Study Design: This is a retrospective, single-center study describing the outcomes of 32 consecutive transplants on 29 patients between 1993 and 2019., Results: The median age at transplantation was 14 years (range, 3-30 years). Most patients received a RIC regimen (n = 28) and bone marrow (BM) from an unrelated donor (n = 16). Four patients received a haploidentical transplant. Chimerism was available for 27 patients with a median time to neutrophil recovery of 20 days (13-36 days). Primary graft failure occurred in one patient, whereas second graft failure occurred in two. Acute GVHD grade II-IV and moderate to severe chronic GVHD occurred in 22% of patients at risk. Fourteen patients were alive after HCT at the last follow-up (median, 6 years; 1.4-19 years). The 5-year overall survival was better after matched sibling donor (MSD) transplantation compared to other hematopoietic stem cell sources (88.9% vs. 47.7%; p = .05; CI = 95%). Overall, 15 patients died after HCT, most of them (n = 11) after the first year of transplant, due to non-hematological disease progression or complication of chronic GVHD., Conclusions: Hematopoietic cell transplantation is a potentially curative treatment option for TBD, nonetheless the poor outcome reflects the progression of non-hematologic disease manifestations, which should be considered when transplantation is indicated., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: This study proposed to identify Fanconi anemia (FA) mutations in Brazilian patients and to investigate their impact on clinical manifestations and malignancies onset., Methods: A total of 116 patients were screened for nine mutations in FANCA, FANCC, FANCG. Those with no mutations were investigated by multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing for FANCA, FANCC, FANCE, FANCF, FANCG, FANCD1/BRCA2., Results: Genetic subtype was identified in 107/116 (78 FA-A, 8 FA-C, 13 FA-G, 8 FA-E), with only one mutation in 1/116, and no mutations in 9/116 patients. Before hematopoietic cell transplantation (HCT), malignancies were detected in 16/116 patients (14/78 FA-A, 01/08 FA-C, 01/08 FA-E), and 12 of them were hematological. Observed to expected ratio (O/E) of hematologic malignancy was 303.7 (95% CI = 148.6-458.7)., Conclusion: This study allowed the identification of biallelic mutations in 91.4% of patients. FANCG and FANCC mutations had significantly earlier bone marrow failure onset, and FANCG severe cytopenia at diagnosis. Despite the inherent limitations of the small number of malignancy events in each genetic subtype, the hematologic malignancies O/E ratio was very high. Cumulative incidence of malignancy before HCT was higher in the third and fourth decades of life, considering HCT and death as competing risks. The cumulative incidence of HCT increased during the first decade, competing with malignancy development., (© 2022 John Wiley & Sons Ltd.)

In this work, we argue that the search for Artificial General Intelligence should start from a much lower level than human-level intelligence. The circumstances of intelligent behavior in nature resulted from an organism interacting with its surrounding environment, which could change over time and exert pressure on the organism to allow for learning of new behaviors or environment models. Our hypothesis is that learning occurs through interpreting sensory feedback when an agent acts in an environment. For that to happen, a body and a reactive environment are needed. We evaluate a method to evolve a biologically-inspired artificial neural network that learns from environment reactions named Neuroevolution of Artificial General Intelligence, a framework for low-level artificial general intelligence. This method allows the evolutionary complexification of a randomly-initialized spiking neural network with adaptive synapses, which controls agents instantiated in mutable environments. Such a configuration allows us to benchmark the adaptivity and generality of the controllers. The chosen tasks in the mutable environments are food foraging, emulation of logic gates, and cart-pole balancing. The three tasks are successfully solved with rather small network topologies and therefore it opens up the possibility of experimenting with more complex tasks and scenarios where curriculum learning is beneficial., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pontes-Filho, Olsen, Yazidi, Riegler, Halvorsen and Nichele.)

Introduction: Fanconi anaemia (FA) is a rare genetic disorder marked by progressive bone marrow failure, chromosomal fragility, and increased cancer susceptibility. Laboratory diagnosis includes chromosomal instability test and mutation investigation. A total of 15%-25% of all patients may have somatic mosaicism, characterized by two distinct haematopoietic cell populations, one resistant and one sensitive to agents that induce chromosomal breakage, which complicates the diagnosis by a high incidence of reverted cells leading to inconclusive or false-negative results. The study aimed to evaluate the use of bone marrow stromal mesenchymal cells (BM-MSCs) as an alternative, non-haematopoietic tissue for diagnosis., Methods: Bone marrow mesenchymal stromal cells from 12 patients with positive diepoxybutane (DEB) tests were cultivated and analysed by cytogenetics and mutation investigation., Results: The DEB test was performed at 0.1 and 0.01 μg/ml concentrations, with an index ranging from 0.24 to 1.00. At higher concentration, the metaphases number was lower, probably due to toxicity. Regarding the molecular investigation, all the mutations previously found in peripheral blood were identified on BM-MSC., Conclusion: This study demonstrated the possibility of using BM-MSCs as an alternative tissue for cytogenetic and molecular investigation. Future tests using an intermediate DEB concentration may lead to an optimal protocol that could be non-toxic to cells but provides conclusive results., (© 2022 John Wiley & Sons Ltd.)

Cascading activity is commonly observed in complex dynamical systems, including networks of biological neurons, and how these cascades spread through the system is reliant on how the elements of the system are connected and organized. In this work, we studied networks of neurons as they matured over 50 days in vitro and evaluated both their dynamics and their functional connectivity structures by observing their electrophysiological activity using microelectrode array recordings. Correlations were obtained between features of their activity propagation and functional connectivity characteristics to elucidate the interplay between dynamics and structure. The results indicate that in vitro networks maintain a slightly subcritical state by striking a balance between integration and segregation. Our work demonstrates the complementarity of these two approaches-functional connectivity and avalanche dynamics-in studying information propagation in neurons in vitro , which can in turn inform the design and optimization of engineered computational substrates., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Heiney, Huse Ramstad, Fiskum, Sandvig, Sandvig and Nichele.)

Introduction: The consumption of yerba mate (YM), a source of antioxidants, in a fasted state increases fatty acid oxidation (FAT ox ) during low-moderate-intensity exercise and improves performance in high-intensity exercise. However, the impact of a pre-exercise carbohydrate (CHO) meal on YM effects during exercise is unknown., Objective: We investigated the effects of yerba mate drink (YMD) consumed in the fasted state (YMD-F) or after a CHO meal (YMD-CHO) on measurements of metabolism, performance, and blood oxidative stress markers in cycling exercise., Methods: In a randomized, repeated-measures, crossover design, eight trained male cyclists ingested (i) YMD-CHO, (ii) YMD-F, or (iii) control-water and CHO meal (Control-CHO). The YMD (an infusion of 5 g of ultrarefined leaves in 250 mL of water) was taken for 7 days and 40 min before exercise. CHO meal (1 g/kg body mass) was consumed 60 min before exercise. The cycling protocol included a 40-min low-intensity (~ 53% V̇O 2peak ) constant load test (CLT); a 20-min time trial (TT); and 4 × 10-s all-out sprints. Blood samples and respiratory gases were collected before, during, and/or after tests., Results: During CLT, YMD-CHO increased FAT ox  ~ 13% vs. YMD-F (P = 0.041) and ~ 27% vs. Control-CHO (P < 0.001). During TT, YMD-CHO increased FAT ox  ~ 160% vs. YMD-F (P < 0.001) and ~ 150% vs. Control-CHO (P < 0.001). Power output during TT improved ~ 3% (P = 0.022) in YMD-CHO vs. Control-CHO and was strongly correlated with changes in serum total antioxidant capacity (r = -0.87) and oxidative stress index (r = 0.76) at post-exercise in YMD-CHO. Performance in sprints was not affected by YMD., Conclusion: CHO intake did not negate the effect of YMD on FAT ox or TT performance. Instead, a synergism between the two dietary strategies may be present. Clinical Trial Registration NCT04642144. November 18, 2020. Retrospectively registered., (© 2022. The Author(s).)

The interest in a diet with a higher proportion of plant-based foods to animal-based foods is a global food pattern trend. However, there are concerns regarding adopting plants as the main dietary protein source to support muscle protein synthesis (MPS) and muscle mass. These concerns are centered on three issues: lower protein bioavailability due to antinutritional compounds in plants, lower per-serve scores of protein at similar energy intake, and amino acid scores of plants being lower than optimal. We aimed here to synthesize and discuss evidence around plant protein in human nutrition focusing on the capacity of these proteins to stimulate MPS as a key part of gaining or maintaining muscle mass. In this review, we addressed the issues of plant protein quality and provided evidence for how plant proteins can be made more effective to stimulate MPS and support muscle mass in partial or total replacement of consumption of products of animal origin. Novelty: Plant proteins are known, in general, to have lower protein quality scores than animal proteins, and this may have important implications, especially for those aiming to increase their skeletal muscle mass through exercise. A plant-based diet has been postulated to have lower protein quality limiting MPS responses and potentially compromising exercise-induced gains in muscle mass. Current evidence shows that plant proteins can stimulate MPS, as can whole foods, especially when combining food groups, increasing portion sizes, and optimizing amino acid bioavailability through processing or common preparation methods.

Fanconi anaemia is a challenging disease to manage, and haematopoietic stem-cell transplantation (HSCT) is the treatment of choice for the haematological complications related to this disease. Over these past two decades, we have observed a substantial improvement in survival outcomes after matched related and unrelated donor HSCT, even for patients living in low-income and middle-income countries. Long-term overall survival is still suboptimal because of the risk of malignancies and other disease-related complications. For patients without well matched donors, alternative donor transplantation using mismatched related donors is an option but is historically associated with a high incidence of graft failure and graft-versus-host disease (GVHD). Herein we discuss the development of a HSCT programme for Fanconi anaemia in our centre in Curitiba, Brazil. Because ex vivo, T-cell depletion is unavailable in our country, we adapted the haploidentical donor transplantation platform using post-HSCT cyclophosphamide to overcome graft failure and GVHD associated with HLA-mismatched donor transplantation. The withdrawal of pre-HSCT cyclophosphamide reduced the severity of mucositis and did not interfere with engraftment. The addition of serotherapy improved overall survival by decreasing the incidence of severe acute and chronic GVHD. Although we have improved overall survival and expanded access to HSCT for Fanconi anaemia, our patients face many challenges, especially viral reactivation and GVHD disease, that merit attention. We acknowledge that there is a learning curve to adopt the haploidentical approach for Fanconi anaemia to low-resourced settings, and this Brazilian experience might require further modifications along with national and international collaborations to be implemented in other countries., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: To describe the prevalence of acquired ocular manifestations in patients with Fanconi anemia (FA) and to describe and correlate the congenital ocular malformations with the genetic subtypes of the disease., Study Design: This is a cross-sectional observational study of 106 consecutive patients with confirmed diagnosis of FA who were followed at the Hematopoietic Stem Cell Transplantation (HSCT) Service at the Federal University of Paraná, Curitiba, Parana, Brazil. Participants underwent a complete ophthalmologic evaluation and 84 patients underwent ocular ultrasound examination. This study was conducted between November 2014 and August 2017., Results: The patients ranged in age from 6 months to 43 years of age. Microphthalmia was the most common congenital ocular abnormality (95.2%). A decrease in anthropometric measurements was observed, including palpebral fissure length (78/103 patients [76.5%]), microcornea (48/103 patients [46.6%]), and ptosis (31/103 patients [30.1%]). We identified a new ophthalmic condition in 15 patients with FA, that is, epiretinal tissue on the optic disc. The genetic subtype was identified in 78 patients (79.6%), the FA-A subtype was most prevalent (50%). The most common acquired ocular manifestation (non-graft-versus-host disease [GVHD] related) in patients who did not undergo HSCT (n = 44) was limbal neovascularization (13.6%), whereas in patients who underwent HSCT (n = 62), the GVHD-related manifestation was ocular GVHD (51.6%). The most frequent symptom of ocular GVHD was keratoconjunctivitis sicca (29%)., Conclusions: Several ocular manifestations were identified in patients with FA., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Fanconi anemia (FA) is a rare disease characterized by progressive bone marrow failure, cancer predisposition, and multiple systemic malformations, including congenital abnormalities of the kidney and urinary tract (CAKUT). Hematopoietic cell transplantation (HCT), the only potentially curative treatment for the hematological complications of FA, may precipitate acute kidney injury (AKI) and hypertension. We retrospectively investigated 107 FA patients who underwent HCT between 2009 and 2017. We investigated the incidence and risk factors of AKI within 100 days after HCT in a cohort of FA patients, and kidney function and hypertension over 2-year follow-up.The incidence of AKI (mainly stage I) was 18.7%. Patients aged ≥ 11 years at transplantation showed a higher risk of AKI (OR 3.53). The eGFR was 60-90 mL/min/1.73 m 2 in 53 (49.5%), 55 (51.4%), 50 (50.5%), 50 (51%), and 46 (59.7%) patients before HCT, at 100 days, 6 months, 1 year, and 2 years. Within the first 100 days after HCT, hypertension was observed in 72% of the patients and was associated with cyclosporine therapy. Most (62.3%) patients had stage 2 hypertension. CAKUT was observed in 33.7% of the patients and was associated with both hypertension (86%) and diminished kidney function but not with AKI.Conlusion: Although AKI, a commonly known HCT complication, was mild in this study, the prevalence of chronic kidney disease (CKD), as well as the high incidence of hypertension, specially associated with CAKUT point out the importance of kidney care in short and long-term follow up of FA patients. What is Known: • Fanconi anemia (FA) is the most frequent inherited bone marrow failure in children, and 30% of cases have congenital anomalies of kidney (CAKUT). • Acute kidney injury and hypertension after hematopoietic cell transplantation (HCT) may impact the outcomes.. What is New: • Despite the presence of CAKUT and stage 2 CKD in 33.7% and 50% of the patients, respectively, AKI was mild and transitory after HCT in FA patients. • CAKUT in FA patients was associated with lower kidney function and hypertension after HCT., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Haploidentical hematopoietic-cell transplantation using post-transplant cyclophosphamide(Haplo-PTCy) is a feasible procedure in children with haematologic malignancies. However, data of a large series of children with acute leukaemia(AL) in this setting is missing. We analysed 144 AL Haplo-PTCy paediatric recipients; median age was 10 years. Patients had acute lymphoblastic(ALL; n = 86) or myeloblastic leukaemia(AML; n = 58) and were transplanted in remission(CR1: n = 40; CR2: n = 57; CR3+: n = 27) or relapse (n = 20). Bone marrow was the graft source in 57%; donors were father (54%), mother (35%), or sibling (11%). Myeloablative conditioning was used in 87%. Median follow-up was 31 months. At day +100, cumulative incidence (CI) of neutrophil recovery and acute GVHD (II-IV) were 94% and 40%, respectively. At 2-years, CI of chronic GVHD and relapse, were 31%, 40%, and estimated 2-year overall survival (OS), leukaemia-free survival (LFS) and graft-versus-host-relapse-free survival (GRFS) were 52%, 44% and 34% respectively. For patients transplanted in remission, positive measurable residual disease (MRD) prior to transplant was associated with decreased LFS (p = 0.05) and GRFS (p = 0.003) and increased risk of relapse (p = 0.02). Mother donor was associated with increased risk of chronic GVHD (p = 0.001), decreased OS (p = 0.03) and GRFS (p = 0.004). Use of PBSC was associated with increased risk of chronic GVHD (p = 0.04). In conclusion, achieving MRD negativity pre-transplant, avoiding use of mother donors and PBSC as graft source may improve outcomes of Haplo-PTCy in children with AL., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

The paradigm of voxel-based soft robots has allowed to shift the complexity from the control algorithm to the robot morphology itself. The bodies of voxel-based soft robots are extremely versatile and more adaptable than the one of traditional robots, since they consist of many simple components that can be freely assembled. Nonetheless, it is still not clear which are the factors responsible for the adaptability of the morphology, which we define as the ability to cope with tasks requiring different skills. In this work, we propose a task-agnostic approach for automatically designing adaptable soft robotic morphologies in simulation, based on the concept of criticality. Criticality is a property belonging to dynamical systems close to a phase transition between the ordered and the chaotic regime. Our hypotheses are that 1) morphologies can be optimized for exhibiting critical dynamics and 2) robots with those morphologies are not worse, on a set of different tasks, than robots with handcrafted morphologies. We introduce a measure of criticality in the context of voxel-based soft robots which is based on the concept of avalanche analysis, often used to assess criticality in biological and artificial neural networks. We let the robot morphologies evolve toward criticality by measuring how close is their avalanche distribution to a power law distribution. We then validate the impact of this approach on the actual adaptability by measuring the resulting robots performance on three different tasks designed to require different skills. The validation results confirm that criticality is indeed a good indicator for the adaptability of a soft robotic morphology, and therefore a promising approach for guiding the design of more adaptive voxel-based soft robots., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Talamini, Medvet and Nichele.)

A patterned spread of proteinopathy represents a common characteristic of many neurodegenerative diseases. In Parkinson's disease (PD), misfolded forms of α-synuclein proteins accumulate in hallmark pathological inclusions termed Lewy bodies and Lewy neurites. Such protein aggregates seem to affect selectively vulnerable neuronal populations in the substantia nigra and to propagate within interconnected neuronal networks. Research findings suggest that these proteinopathic inclusions are present at very early time points in disease development, even before clear behavioral symptoms of dysfunction arise. In this study, we investigate the early pathophysiology developing after induced formation of such PD-related α-synuclein inclusions in a physiologically relevant in vitro setup using engineered human neural networks. We monitor the neural network activity using multielectrode arrays (MEAs) for a period of 3 wk following proteinopathy induction to identify associated changes in network function, with a special emphasis on the measure of network criticality. Self-organized criticality represents the critical point between resilience against perturbation and adaptational flexibility, which appears to be a functional trait in self-organizing neural networks, both in vitro and in vivo. We show that although developing pathology at early onset is not clearly manifest in standard measurements of network function, it may be discerned by investigating differences in network criticality states.

It has been hypothesized that the brain optimizes its capacity for computation by self-organizing to a critical point. The dynamical state of criticality is achieved by striking a balance such that activity can effectively spread through the network without overwhelming it and is commonly identified in neuronal networks by observing the behavior of cascades of network activity termed "neuronal avalanches." The dynamic activity that occurs in neuronal networks is closely intertwined with how the elements of the network are connected and how they influence each other's functional activity. In this review, we highlight how studying criticality with a broad perspective that integrates concepts from physics, experimental and theoretical neuroscience, and computer science can provide a greater understanding of the mechanisms that drive networks to criticality and how their disruption may manifest in different disorders. First, integrating graph theory into experimental studies on criticality, as is becoming more common in theoretical and modeling studies, would provide insight into the kinds of network structures that support criticality in networks of biological neurons. Furthermore, plasticity mechanisms play a crucial role in shaping these neural structures, both in terms of homeostatic maintenance and learning. Both network structures and plasticity have been studied fairly extensively in theoretical models, but much work remains to bridge the gap between theoretical and experimental findings. Finally, information theoretical approaches can tie in more concrete evidence of a network's computational capabilities. Approaching neural dynamics with all these facets in mind has the potential to provide a greater understanding of what goes wrong in neural disorders. Criticality analysis therefore holds potential to identify disruptions to healthy dynamics, granted that robust methods and approaches are considered., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Heiney, Huse Ramstad, Fiskum, Christiansen, Sandvig, Nichele and Sandvig.)

Severe aplastic anemia (SAA) is a life-threatening disease that can be cured with allogeneic cell transplantation (HCT). Haploidentical donor transplantation with post-transplantation cyclophosphamide (haplo-PTCy) is an option for patients lacking an HLA-matched donor. We analyzed 87 patients who underwent haplo-PTCy between 2010 and 2019. The median patient age was 14 years (range, 1 to 69 years), most were heavily transfused, and all received previous immunosuppression (25% without antithymocyte globulin). Almost two-thirds (63%) received standard fludarabine (Flu)/cyclophosphamide (Cy) 29/total body irradiation (TBI) 200 cGy conditioning, and the remaining patients received an augmented conditioning: Flu/Cy29/TBI 300-400 (16%), Flu/Cy50/TBI 200 (10%), or Flu/Cy50/TBI 400 (10%). All patients received PTCy-based graft-versus-host disease (GVHD) prophylaxis. Most grafts (93%) were bone marrow (BM). The median duration of follow-up was 2 years and 2 months. The median time to neutrophil recovery was 17 days. Primary graft failure occurred in 15% of the patients, and secondary or poor graft function occurred in 5%. The incidences of grade II-IV acute GVHD was 14%, and that of chronic GVHD was 9%. Two-year overall survival and event-free survival (EFS) were 79% and 70%, respectively. EFS was higher for patients who received augmented Flu/Cy/TBI (hazard ratio [HR], .28; P = .02), and those who received higher BM CD34 cell doses (>3.2 × 10E6/kg) (HR, .29; P = .004). The presence of donor-specific antibodies before HSCT was associated with lower EFS (HR, 3.92; P = .01). Graft failure (HR, 7.20; P < .0001) was associated with an elevated risk of death. Cytomegalovirus reactivation was frequent (62%). Haploidentical HCT for SAA is a feasible procedure; outcomes are improved with augmented conditioning regimens and BM grafts with higher CD34 cell doses., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

The choice of alternative donors for HCT for patients without an HLA-matched related donor depends on several factors. We compared major HCT outcomes in 212 consecutive children transplanted at 11 centers in Brazil for acute leukemia or MDS from an HLA-matched unrelated donor (MUD, n = 95), mismatched unrelated donor (MMUD, n = 47) or unrelated umbilical cord blood (UCB, n = 70). Most had ALL (61%), bone marrow (57%) as the graft source and 95% received a MAC regimen. The 3-year OS probability were 57, 55, and 37% after HCT from MUD, MMUD, and UCB, respectively (HR 1.68, 95%CI 1.07-2.63; P = .02). In comparison with MUD, OS was similar after transplantation of a ≥ 6/8 HLA-matched or a high cell dose (>5 × 10 7 TNC/kg) CB unit (HR 1.41, 95%CI 0.88-2.27; P = .15). NRM was higher for UCB (HR 3.90, 95%CI 1.43-10.7; P = .01) but not for MMUD (HR 1.03, 95%CI 0.53-2.00; P > .20). Advanced disease (HR 2.05, 95%CI 1.26-3.33; P < .001) and UCB with high probability of being < 6/8 HLA-matched (HR 5.34, 95%CI 2.0-13.9; P < .001) were associated with higher mortality. Relapse and acute GVHD were similar among groups, while PGF was higher among UCB transplants (P = .002) and chronic GVHD among MMUD group (HR 2.88, 95% CI 1.05-7.88; P = .04). Our results suggest that in Brazil HCT outcomes performed with MMUD and MUD donors were comparable, while with UCB units < 6/8 HLA-matched were associated with higher NRM for children with acute leukemia or MDS., (© 2020 Wiley Periodicals LLC.)

Although deep learning has recently increased in popularity, it suffers from various problems including high computational complexity, energy greedy computation, and lack of scalability, to mention a few. In this paper, we investigate an alternative brain-inspired method for data analysis that circumvents the deep learning drawbacks by taking the actual dynamical behavior of biological neural networks into account. For this purpose, we develop a general framework for dynamical systems that can evolve and model a variety of substrates that possess computational capacity. Therefore, dynamical systems can be exploited in the reservoir computing paradigm, i.e., an untrained recurrent nonlinear network with a trained linear readout layer. Moreover, our general framework, called EvoDynamic, is based on an optimized deep neural network library. Hence, generalization and performance can be balanced. The EvoDynamic framework contains three kinds of dynamical systems already implemented, namely cellular automata, random Boolean networks, and echo state networks. The evolution of such systems towards a dynamical behavior, called criticality, is investigated because systems with such behavior may be better suited to do useful computation. The implemented dynamical systems are stochastic and their evolution with genetic algorithm mutates their update rules or network initialization. The obtained results are promising and demonstrate that criticality is achieved. In addition to the presented results, our framework can also be utilized to evolve the dynamical systems connectivity, update and learning rules to improve the quality of the reservoir used for solving computational tasks and physical substrate modeling., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© The Author(s) 2020.)

Allogeneic hematopoietic stem cell transplantation (HCT) can cure primary immunodeficiency diseases (PID). When a HLA-matched donor is not available, a haploidentical family donor may be considered. The use of T cell-replete haploidentical HCT with post-transplantation cyclophosphamide (haplo-PTCy) in children with PID has been reported in few case series. A donor is usually readily available, and haplo-PTCy can be used in urgent cases. We studied the outcomes of 73 patients with PID who underwent haplo-PTCy, including 55 patients who did so as a first transplantation and 18 who did so as a salvage transplantation after graft failure of previous HCT. The median patient age was 1.6 years. Most of the children were male (n = 54) and had active infection at the time of transplantation (n = 50); 10 children had severe organ damage. The diagnosis was severe combined immunodeficiency (SCID) in 34 patients and non-SCID in 39 (Wiskott-Aldrich syndrome; n = 14; chronic granulomatous disease, n = 10; other PID, n = 15). The median duration of follow-up of survivors was 2 years. The cumulative incidence of neutrophil recovery was 88% in the SCID group and 84% in non-SCID group and was 81% for first transplantations and 83% after a salvage graft. At 100 days, the cumulative incidence of acute GVHD grade II-IV and III-IV was 33% and 14%, respectively. The majority of patients reached 200/μL CD4 + and 1000/μL CD3 + cell counts between 3 and 6 months. The estimated 2-year overall survival was 66%; it was 64% for SCID patients and 65% for non-SCID patients and 63% for first HCT and 77% for salvage transplantations. Twenty-five patients died, most of them due to infection early after transplantation (before 100 days). In conclusion, haplo-PTCy is a feasible procedure, can cure two-thirds of children with PID, and can be used as rescue treatment for previous graft failure. © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Patients with severe aplastic anemia (SAA) who fail immunosuppressive therapy have a dismal prognosis. Hematopoietic stem cell transplantation (HSCT) from an unrelated donor (URD) is one of the most effective treatment options. Two institutions have independently adopted a post-transplantation cyclophosphamide (PTCy) approach for patients with SAA undergoing HSCT from a URD. Thirteen patients were included, 11 of whom had been treated with immunosuppressive therapy. Eight patients had a mismatched URD. All patients were conditioned with fludarabine, cyclophosphamide, and total body irradiation, in various dosage combinations. PTCy was given at a dose of 100 mg/kg. Two patients died, and overall survival was 85% at 2 years. All patients engrafted, but 1 patient developed secondary graft failure. Of the 11 patients alive after 2 years, 9 had complete donor chimerism. All surviving patients were transfusion-independent. Ten patients (77%) had cytomegalovirus reactivation, and 2 patients had more than 1 reactivation. No Epstein-Barr virus reactivation or post-transplantation lymphoproliferative disease was observed. Four patients had mild hemorrhagic cystitis. In summary, our findings show that PTCy is a promising treatment for patients with SAA undergoing URD HSCT., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

With the number of long-term HSCT survivors steadily increasing, attention needs to be focused on the late complications and quality of life. We therefore analyzed the outcome of 101 pediatric patients (<18 years old at the time of HSCT) transplanted for acute leukemia between 1981 and 2015 at Complexo Hospital de Clínicas, Federal University of Paraná, Brazil, and who survived at least two years after HSCT. The median follow-up was 5.9 years (2.0-29.0); median age at follow-up was 17.5 years (2.98-39.0). The 5-year cumulative incidence of relapse was 27.5% (95% CI 18.6%-36.4%). Two-year cumulative incidence of chronic GVHD was 21.8% (95% CI 13.7%-29.8%). Of the 101 patients, 72 patients (71.3%) presented with late effects. Those surviving longer after HSCT experienced more complications. Patients who received TBI-based regimen developed more late effects (P = .013) and more endocrinological complications (P = .024). Endocrinological complications were the most common late sequelae found in this study. For childhood survivors, quality of life was not influenced by age (at HSCT or at last visit), time from HSCT, gender, donor, or GVHD. For survivors that no longer were children, only age at last visit impacted financial domain measures, irrespective of gender, donor, or GVHD. The current study confirms the high burden late complications after pediatric HSCT have on the survivors and underlines the importance of extended follow-up., (© 2020 Wiley Periodicals, Inc.)

The survival rates of children with high-risk acute myeloid leukemia (AML) treated with hematopoietic stem cell transplant (HSCT) range from 60% to 70% in high-income countries. The corresponding rate for Brazilian children with AML who undergo HSCT is unknown. We conducted a retrospective analysis of 114 children with AML who underwent HSCT between 2008 and 2012 at institutions participating in the Brazilian Pediatric Bone Marrow Transplant Working Group. At transplant, 38% of the children were in first complete remission (CR1), 37% were in CR2, and 25% were in CR3+ or had persistent disease. The donors included 49 matched-related, 59 matched-unrelated, and six haploidentical donors. The most frequent source of cells was bone marrow (69%), followed by the umbilical cord (19%) and peripheral blood (12%). The 4-year overall survival was 47% (95% confidence interval [CI] 30%-57%), and the 4-year progression-free survival was 40% (95% CI 30%-49%). Relapse occurred in 49 patients, at a median of 122 days after HSCT. There were 65 deaths: 40 related to AML, 19 to infection, and six to graft versus host disease. In conclusion, our study suggests that HSCT outcomes for children with AML in CR1 or CR2 are acceptable and that this should be considered in the overall treatment planning for children with AML in Brazil. Therapeutic standardization through the adoption of multicentric protocols and appropriate supportive care treatment will have a significant impact on the results of HSCT for AML in Brazil and possibly in other countries with limited resources.

The results of hematopoietic stem cell transplant (HSCT) for primary immunodeficiency diseases (PID) have been improving over time. Unfortunately, developing countries do not experience the same results. This first report of Brazilian experience of HSCT for PID describes the development and results in the field. We included data from transplants in 221 patients, performed at 11 centers which participated in the Brazilian collaborative group, from July 1990 to December 2015. The majority of transplants were concentrated in one center (n = 123). The median age at HSCT was 22 months, and the most common diseases were severe combined immunodeficiency (SCID) (n = 67) and Wiskott-Aldrich syndrome (WAS) (n = 67). Only 15 patients received unconditioned transplants. Cumulative incidence of GVHD grades II to IV was 23%, and GVHD grades III to IV was 10%. The 5-year overall survival was 71.6%. WAS patients had better survival compared to other diseases. Most deaths (n = 53) occurred in the first year after transplantation mainly due to infection (55%) and GVHD (13%). Although transplant for PID patients in Brazil has evolved since its beginning, we still face some challenges like delayed diagnosis and referral, severe infections before transplant, a limited number of transplant centers with expertise, and resources for more advanced techniques. Measures like newborn screening for SCID may hasten the diagnosis and ameliorate patients' conditions at the moment of transplant.

Wiskott-Aldrich syndrome is a severe X-linked recessive immune deficiency disorder. A scoring system of Wiskott-Aldrich syndrome severity (0.5-5) distinguishes two phenotypes: X-linked thrombocytopenia and classic Wiskott-Aldrich syndrome. Hematopoietic cell transplantation is curative for Wiskott-Aldrich syndrome; however, the use of unrelated umbilical cord blood transplantation has seldom been described. We analyzed umbilical cord blood transplantation outcomes for 90 patients. The median age at umbilical cord blood transplantation was 1.5 years. Patients were classified according to clinical scores [2 (23%), 3 (30%), 4 (23%) and 5 (19%)]. Most patients underwent HLA-mismatched umbilical cord blood transplantation and myeloablative conditioning with anti-thymocyte globulin. The cumulative incidence of neutrophil recovery at day 60 was 89% and that of grade II-IV acute graft- versus -host disease at day 100 was 38%. The use of methotrexate for graft- versus -host disease prophylaxis delayed engraftment ( P =0.02), but decreased acute graft- versus -host disease ( P =0.03). At 5 years, overall survival and event-free survival rates were 75% and 70%, respectively. The estimated 5-year event-free survival rates were 83%, 73% and 55% for patients with a clinical score of 2, 4-5 and 3, respectively. In multivariate analysis, age <2 years at the time of the umbilical cord blood transplant and a clinical phenotype of X-linked thrombocytopenia were associated with improved event-free survival. Overall survival tended to be better in patients transplanted after 2007 ( P =0.09). In conclusion, umbilical cord blood transplantation is a good alternative option for young children with Wiskott-Aldrich syndrome lacking an HLA identical stem cell donor., (Copyright© Ferrata Storti Foundation.)

We describe haploidentical bone marrow transplantation with post-transplant cyclophosphamide (PT-CY) for 30 patients with Fanconi anemia (FA). Twenty-six patients were transplanted upfront, and the preparatory regimens included fludarabine 150 mg/m 2  + total body irradiation 200 to 300 cGy ± CY 10 mg/kg without (n = 12) or with rabbit antithymocyte globulin (r-ATG) 4 to 5 mg/kg (n = 14). Four patients were rescued after primary or secondary graft failure after related or unrelated donor transplantation with the above regimen with (n = 2) or without r-ATG (n = 2). PT-CY at 25 mg/kg/day (total dose, 50 mg/kg) followed by cyclosporine and mycophenolate mofetil was given to all patients. All patients engrafted in the subgroup of patients who did not receive r-ATG (n = 14), but their transplant course was complicated by high rates of acute and chronic graft-versus-host disease (GVHD), and only 8 patients are alive. In the subgroup that received r-ATG (n = 16), 14 patients had sustained engraftment, severe GVHD rates were lower, and 13 patients are alive. Hemorrhagic cystitis occurred in 50% of patients, whereas cytomegalovirus reactivation occurred in 75%. One-year overall survival for the entire cohort was 73% (95% CI, 64% to 81%), and all surviving patients achieved full donor chimerism. In conclusion, haploidentical donor transplantation with PT-CY is a suitable option for FA patients without a matched related or unrelated donor., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Evolutionary design targets systems of continuously increasing complexity. Thus, indirect developmental mappings are often a necessity. Varying the amount of genotype information changes the cardinality of the mapping, which in turn affects the developmental process. An open question is how to find the genotype size and representation in which a developmental solution would fit. A restricted pool of genes may not be large enough to encode a solution or may need complex heuristics to find a realistic size. On the other hand, using the whole set of possible regulatory combinations may be intractable. In nature, the genomes of biological organisms are not fixed in size; they slowly evolve and acquire new genes by random gene duplications. Such incremental growth of genome information can be beneficial also in the artificial domain. For an evolutionary and developmental (evo-devo) system based on cellular automata, we investigate an incremental evolutionary growth of genomes without any a priori knowledge on the necessary genotype size. Evolution starts with simple solutions in a low-dimensional space and incrementally increases the genotype complexity by means of gene duplication, allowing the evolution of scalable genomes that are able to adapt genetic information content while compactness and efficiency are retained. The results are consistent when the target phenotypic complexity, the geometry size, and the number of cell states are scaled up.

We report on long-term survival in 157 patients with Fanconi anemia (FA) who survived 2 years or longer after their first transplantation with a median follow-up of 9 years. Marrow failure (80%) was the most common indication for transplantation. There were 20 deaths beyond 2 years after transplantation, with 12 of the deaths occurring beyond 5 years after transplantation. Donor chimerism was available for 149 patients: 112 (76%) reported > 95% chimerism, 27 (18%) reported 90% to 95% chimerism, and 8 (5%) reported 20% to 89% donor chimerism. Two patients have < 20% donor chimerism. The 10- and 15-year probabilities of survival were 90% and 79%, respectively. Results of multivariate analysis showed higher mortality risks for transplantations before 2003 (hazard ratio [HR], 7.87; P = .001), chronic graft-versus-host disease (GVHD) (HR, 3.80; P = .004) and squamous cell carcinoma after transplantation (HR, 38.17; P < .0001). The predominant cause of late mortality was squamous cell carcinoma, with an incidence of 8% and 14% at 10 and 15 years after transplantation, respectively, and was more likely to occur in those with chronic GVHD. Other causes of late mortality included chronic GVHD, infection, graft failure, other cancers, and hemorrhage. Although most patients are disease free and functional long term, our data support aggressive surveillance for long periods to identify those at risk for late mortality., (Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

The occurrence of tumor in the residual ureter after an incomplete nephroureterectomy required by a tumor of renal collecting system is an uncommon but a well described situation. The recommended treatment in this situation is the radical excision of the remaining ureter, being the open technique the most used approach. The aim of this video is to demonstrate a new approach using intravesical and transperitoneal laparoscopy to remove the residual ureter following the oncological concepts. A 67 year-old male patient underwent an incomplete open right radical nephroureterectomy for a transitional cell carcinoma of the renal collecting system. After 16 months, the cystoscopy diagnostic revealed a recurrence of it in the residual ureter. An intravesical approach followed by a transperitoneal laparoscopy has removed the remaining ureter. Operative time was 110 minutes, blood loss 100 mL, the patient was discharged on the first postoperative day and the Foley catheter was removed on the seventh one. Pathological examination revealed low grade transitional cell carcinoma and free surgical margins, no recurrence was observed after six months. To our knowledge, this is the first treatment description of a tumor in the residual ureter with these techniques. This approach can be a minimal invasive alternative in this unusual situation.