Metabolic Fingerprint in Childhood Acute Lymphoblastic Leukemia.

INTRODUCTION: Acute lymphoblastic leukemia (ALL) is the most prevalent childhood malignancy. Despite high cure rates, several questions remain regarding predisposition, response to treatment, and prognosis of the disease. The role of intermediary metabolism in the individualized mechanistic pathways of the disease is unclear. We have hypothesized that children with any (sub)type of ALL have a distinct metabolomic fingerprint at diagnosis when compared: (i) to a control group; (ii) to children with a different (sub)type of ALL; (iii) to the end of the induction treatment. MATERIALS AND METHODS: In this prospective case-control study (NCT03035344), plasma and urinary metabolites were analyzed in 34 children with ALL before the beginning (D0) and at the end of the induction treatment (D33). Their metabolic fingerprint was defined by targeted analysis of 106 metabolites and compared to that of an equal number of matched controls. Multivariate and univariate statistical analyses were performed using SIMCAP and scripts under the R programming language. RESULTS: Metabolomic analysis showed distinct changes in patients with ALL compared to controls on both D0 and D33. The metabolomic fingerprint within the patient group differed significantly between common B-ALL and pre-B ALL and between D0 and D33, reflecting the effect of treatment. We have further identified the major components of this metabolic dysregulation, indicating shifts in fatty acid synthesis, transfer and oxidation, in amino acid and glycerophospholipid metabolism, and in the glutaminolysis/TCA cycle. CONCLUSIONS: The disease type and time point-specific metabolic alterations observed in pediatric ALL are of particular interest as they may offer potential for the discovery of new prognostic biomarkers and therapeutic targets.

Embryos from vitrified vs fresh oocytes in an oocyte donation program: A comparative morphokinetic analysis.

OBJECTIVE: To compare the morphokinetic pattern of human embryos originating from vitrified oocytes with those derived from freshly collected oocytes in oocyte donation cycles. DESIGN: A retrospective observational study SETTING: Embryolab Fertility Clinic, Embryology lab, Thessaloniki, Greece PATIENT(S): The study included embryos from 421 vitrified oocytes from 58 oocyte donation cycles and 196 fresh oocytes from 23 oocyte donation cycles. INTERVENTION(S): None MAIN OUTCOME MEASURE(S): Key time parameters, dynamic events, fertilization rate, degeneration rate, cleavage rate, blastocyst rate, pregnancy rate, clinical pregnancy rate, implantation rate and live birth rate. RESULTS: Survival rate of vitrified oocytes was 92.58% (±7.42). Fertilization rate was significantly different in the two groups (VITRI group: 71.92% ± 20.29 and CONTROL group: 80.65% ± 15.22, p=0.045) whereas degeneration, cleavage, blastocyst, pregnancy, clinical pregnancy, ongoing pregnancy, implantation and live birth rates were not significantly different between embryos derived from fresh or vitrified oocytes. Time lapse analysis showed no significant difference in any key time parameter. However, when examining dynamic parameters, CC1 [t2 - tPB2: from the second polar body extrusion(tPB2) up to 2 cells (t2)] showed significant difference (p=0.004) whereas CC1a [t2 - tPNf: from fading of the pronuclei (tPNf) up to 2 cells (t2)] was at the threshold of significance (p=0.057). CONCLUSION(S): CC1 in vitrified oocytes exhibited a comparatively slower progression in contrast to fresh oocytes. Conversely, CC1a in vitrified oocytes demonstrated faster progression compared to fresh oocytes. Noteworthily, these temporary deviations had minimal impact on the subsequent development. Despite the clinical outcomes showing a decrease in the vitrified group, none of them reached statistical significance. This lack of significance could be attributed to the limited study's size.

Management of seizures in patients with primary mitochondrial diseases: consensus statement from the InterERNs Mitochondrial Working Group.

BACKGROUND AND PURPOSE: Primary mitochondrial diseases (PMDs) are common inborn errors of energy metabolism, with an estimated prevalence of one in 4300. These disorders typically affect tissues with high energy requirements, including heart, muscle and brain. Epilepsy may be the presenting feature of PMD, can be difficult to treat and often represents a poor prognostic feature. The aim of this study was to develop guidelines and consensus recommendations on safe medication use and seizure management in mitochondrial epilepsy. METHODS: A panel of 24 experts in mitochondrial medicine, pharmacology and epilepsy management of adults and/or children and two patient representatives from seven countries was established. Experts were members of five different European Reference Networks, known as the Mito InterERN Working Group. A Delphi technique was used to allow the panellists to consider draft recommendations on safe medication use and seizure management in mitochondrial epilepsy, using two rounds with predetermined levels of agreement. RESULTS: A high level of consensus was reached regarding the safety of 14 out of all 25 drugs reviewed, resulting in endorsement of National Institute for Health and Care Excellence guidelines for seizure management, with some modifications. Exceptions including valproic acid in POLG disease, vigabatrin in patients with γ-aminobutyric acid transaminase deficiency and topiramate in patients at risk for renal tubular acidosis were highlighted. CONCLUSIONS: These consensus recommendations describe our intent to improve seizure control and reduce the risk of drug-related adverse events in individuals living with PMD-related epilepsy.

Accessibility, availability and common practices regarding genetic testing for epilepsy across Europe: A survey of the European Reference Network EpiCARE.

OBJECTIVE: The increasingly rapid pace of advancement in genetic testing may lead to inequalities in technical and human resources with a negative impact on optimal epilepsy clinical practice. In this view, the European Reference Network (ERN) for Rare and Complex Epilepsies EpiCARE conducted a survey addressing several aspects of accessibility, availability, costs, and standard practices on genetic testing across ERN EpiCARE centers. METHODS: An online Google form was sent to 70 representatives of ERN EpiCARE centers. Descriptive statistics and qualitative analysis were used for data presentation. RESULTS: We received 45 responses (1/center) representing 23 European countries with a better representation of Western Europe. Forty-five percent of the centers did not have access to all available types of genetic testing, mainly reflecting the limited availability of whole-genome sequencing (WGS). Thirty-five percent of centers report cost coverage only for some of the available tests, while costs per test varied significantly (interquartile range IQR ranging from 150 to 1173 euros per test across centers). Urgent genetic testing is available in 71.7% of countries (time-to-urgent result: 2 day to 2 months). The average time-to-result of specific tests in case of non-urgent prescription has a significant variance across centers, with the biggest range observed for whole-exome sequencing (6-128 weeks, IQR: 27 weeks). The percentage of agreement among the experts regarding the choice of genetic test at first intention in specific clinical situations was in all cases less than 50 percent (34.9% to 47% according to the proposed scenarios). SIGNIFICANCE: Costs, time to deliver the results to the clinician, and type of first-line genetic testing vary widely across Europe, even in countries where ERN EpiCARE centers are present. Increased availability of genetic tests and guidance for optimal test choices in epilepsy remains essential to avoid diagnostic delays and excess health costs. PLAIN LANGUAGE SUMMARY: The survey of the ERN EpiCARE highlights disparities in genetic testing for epilepsy across 45 ERN EpiCARE centers in 23 European countries. The findings reveal variable access to certain genetic tests, with lowest access to WGS. Costs and time-to-results vary widely. Urgent genetic testing is available in 71.7% of countries. Agreement among experts on first-line genetic tests for specific patient scenarios is below 50%. The study emphasizes the need for improved test availability and guidance to avoid diagnostic delays and unnecessary costs. EpiCARE has the mission to contribute in homogenizing best practices across Europe.

Real life retrospective study of cannabidiol therapy in alternating hemiplegia of childhood.

BACKGROUND: Many alternating hemiplegia of childhood (AHC) patients have received Cannabidiol (CBD) but, to our knowledge, there are no published data available. GOALS: Test the hypothesis that CBD has favorable effects on AHC spells. METHODS: Retrospective review of available data of AHC patients who received CBD. Primary analysis: Clinical Global Impression Scale of Improvement (CGI-I) score for response of AHC spells to CBD with calculation of 95% confidence interval (CI) for rejection of the null hypothesis. Secondary analyses, performed to achieve an understanding of the effect of CBD as compared to flunarizine, were CGI-I scores of 1) epileptic seizures to CBD, 2) AHC spells to flunarizine, 3) epileptic seizures to flunarizine. Also, Mann-Whitney test was done for comparison of CGI-I scores of CBD and flunarizine to both AHC spells and seizures. RESULTS: We studied 16 AHC patients seen at Duke University and University of Lyon. CI of CGI-I scores for AHC spells in response to CBD and to flunarizine, each separately, indicated a positive response to each of these two medications: neither overlapped with the null hypothesis score, 4, indicating significant positive responses with p < 0.05 for both. These two scores also did not differ (p = 0.84) suggesting similar efficacy of both: CBD score was 2 ± 1.1 with a 95% CI of 1.5-2.6 and flunarizine score was 2.3 ± 1.3 with a 95% CI of 1.7-3.1. In patients who had seizures, CI calculations indicated a positive effect of CBD on seizure CGI scores but not of flunarizine on seizure scores. CBD was well tolerated with no patients discontinuing it due to side effects and with some reporting positive behavioral changes. CONCLUSION: Our study indicates a real-life positive effect of CBD on AHC type spells.

Branched-chain amino acids as adjunctive-alternative treatment in patients with autism: a pilot study.

The branched-chain amino acid (BCAA) is a group of essential amino acids that are involved in maintaining the energy balance of a human being as well as the homoeostasis of GABAergic, glutamatergic, serotonergic and dopaminergic systems. Disruption of these systems has been associated with the pathophysiology of autism while low levels of these amino acids have been discovered in patients with autism. A pilot open-label, prospective, follow-up study of the use of BCAA in children with autistic behaviour was carried out. Fifty-five children between the ages of 6 and 18 participated in the study from May 2015 to May 2018. We used a carbohydrate-free BCAA-powdered mixture containing 45·5 g of leucine, 30 g of isoleucine and 24·5 g of valine in a daily dose of 0·4 g/kg of body weight which was administered every morning. Following the initiation of BCAA administration, children were submitted to a monthly psychological examination. Beyond the 4-week mark, BCAA were given to thirty-two people (58·18 %). Six of them (10·9 %) discontinued after 4-10 weeks owing to lack of improvement. The remaining twenty-six children (47·27 %) who took BCAA for longer than 10 weeks displayed improved social behaviour and interactions, as well as improvements in their speech, cooperation, stereotypy and, principally, their hyperactivity. There were no adverse reactions reported during the course of the treatment. Although these data are preliminary, there is some evidence that BCAA could be used as adjunctive treatment to conventional therapeutic methods for the management of autism.

Current management of primary mitochondrial disorders in EU countries: the European Reference Networks survey.

BACKGROUND AND PURPOSE: Primary mitochondrial diseases (PMDs) are rare diseases for which diagnosis is challenging, and management and training programs are not well defined in Europe. To capture and assess care needs, five different European Reference Networks have conducted an exploratory survey. METHODS: The survey covering multiple topics relating to PMDs was sent to all ERNs healthcare providers (HCPs) in Europe. RESULTS: We have collected answers from 220 members based in 24/27 European member states and seven non-European member states. Even though most of the responders are aware of neurogenetic diseases, difficulties arise in the ability to deliver comprehensive genetic testing. While single gene analysis is widely available in Europe, whole exome and genome sequencing are not easily accessible, with considerable variation between countries and average waiting time for results frequently above 6 months. Only 12.7% of responders were happy with the ICD-10 codes for classifying patients with PMDs discharged from the hospital, and more than 70% of them consider that PMDs deserve specific ICD codes to improve clinical management, including tailored healthcare, and for reimbursement reasons. Finally, 90% of responders declared that there is a need for further education and training in these diseases. CONCLUSIONS: This survey provides information on the current difficulties in the care of PMDs in Europe. We believe that the results of this survey are important to help rare disease stakeholders in European countries identify key care and research priorities.

Informational support and information-seeking during transition to parenthood: Baby Buddy Forward's focus groups with pregnant women and new mothers in Cyprus.

INTRODUCTION: Relevant and accurate information during the transition to parenthood is vital for active participation in decision-making. The aim of the study was to gain an in-depth understanding of informational support and information-seeking practices among women in Cyprus during the transition to parenthood with a focus on the use of the internet and informed decision making. METHODS: Qualitative descriptive exploratory design of 12 focus groups with 64 participants representing different language-cultural groups served by the Baby Buddy Cyprus app. A topic guide covering expectations, experiences and practices guided the discussions. Data were analyzed using inductive content analysis. RESULTS: Seven themes and several subthemes emerged. In an 'unsupportive system', 'void' of informational support, pregnant women strive to have a 'confident voice'. They find themselves 'self-navigating in parallel worlds' of formal and informal information, where the internet holds a prominent place. 'Supplementing and filtering', instinctively and selectively, results in a state of 'doubt and faith' towards the trustworthiness of the information but also healthcare providers. Effective communication with providers is needed to break the cycle, but seems dependent on the self-efficacy of the women themselves ('art of communication'). Women 'deconstruct and reimagine' their experiences, often assigning responsibility on themselves for not having been better prepared. CONCLUSIONS: Women want control over decisions affecting their pregnancy. While the internet is a prevalent source of information, they value communication with healthcare providers and want direction. A shift is needed from current practices of unguided information-searching. Maternity healthcare professionals need to recognize this phenomenon, offer appropriate guidance, and support active participation in informed decision-making.

Methodology of a Natural History Study of a Rare Neurodevelopmental Disorder: Alternating Hemiplegia of Childhood as a Prototype Disease.

Here, we describe the process of development of the methodology for an international multicenter natural history study of alternating hemiplegia of childhood as a prototype disease for rare neurodevelopmental disorders. We describe a systematic multistep approach in which we first identified the relevant questions about alternating hemiplegia of childhood natural history and expected challenges. Then, based on our experience with alternating hemiplegia of childhood and on pragmatic literature searches, we identified solutions to determine appropriate methods to address these questions. Specifically, these solutions included development and standardization of alternating hemiplegia of childhood-specific spell video-library, spell calendars, adoption of tailored methodologies for prospective measurement of nonparoxysmal and paroxysmal manifestations, unified data collection protocols, centralized data platform, adoption of specialized analysis methods including, among others, Cohen kappa, interclass correlation coefficient, linear mixed effects models, principal component, propensity score, and ambidirectional analyses. Similar approaches can, potentially, benefit in the study of other rare pediatric neurodevelopmental disorders.

Development and testing of methods to record and follow up spells in patients with alternating hemiplegia of childhood.

BACKGROUND: Developing methods to record Alternating Hemiplegia of Childhood (AHC) spells is essential for clinical trials and patient care. OBJECTIVES: Test the following hypotheses: 1) Video-library training improves participants' ability to correctly identify AHC spells. 2) A custom-designed event-calendar with weekly reviews results in consistent documentation of such events over time. 3) Use of an electronic diary (e-Diary) to register events is a useful tool. METHODS: 1) A video-library of AHC type spells was developed along with specific training; the effect of the training was tested in 36 caregivers. 2) An event-calendar was similarly developed and provided to 5 caregivers with weekly videoconference meetings for 8 weeks. 3) An e-Diary was developed and offered to 33 patients; time of usage and caregivers' feedback (telephone interview) were analyzed. RESULTS: 1) Video-library training: Wilcoxon test showed improvement in caregiver identification of spells (p = 0.047), Cohen's Kappa demonstrated high degree of agreement between caregivers'-experts' classifications (>0.9). 2) Event-calendar: 96.42% of entries had complete information; this did not change during follow up (p = 0.804). 3) e-Diary: whereas 52% of respondents used the e-Diary when offered (duration: 10.5 ± 8.1 months), 96.3% indicated they would use it in future studies. Those who used it for 13 months, were very likely to use it during the rest of that year. CONCLUSIONS: Video-library training improved spell identification. Calendar with weekly reviews resulted in a sustained and consistent record keeping. Caregivers' e-Diary feedback was encouraging with long-term usage in many. These approaches could be helpful for AHC and, potentially, in similar disorders.

Neurotrophin Analog ENT-A044 Activates the p75 Neurotrophin Receptor, Regulating Neuronal Survival in a Cell Context-Dependent Manner.

Neuronal cell fate is predominantly controlled based on the effects of growth factors, such as neurotrophins, and the activation of a variety of signaling pathways acting through neurotrophin receptors, namely Trk and p75 (p75NTR). Despite their beneficial effects on brain function, their therapeutic use is compromised due to their polypeptidic nature and blood-brain-barrier impermeability. To overcome these limitations, our previous studies have proven that DHEA-derived synthetic analogs can act like neurotrophins, as they lack endocrine side effects. The present study focuses on the biological characterization of a newly synthesized analog, ENT-A044, and its role in inducing cell-specific functions of p75NTR. We show that ENT-A044 can induce cell death and phosphorylation of JNK protein by activating p75NTR. Additionally, ENT-A044 can induce the phosphorylation of TrkB receptor, indicating that our molecule can activate both neurotrophin receptors, enabling the protection of neuronal populations that express both receptors. Furthermore, the present study demonstrates, for the first time, the expression of p75NTR in human-induced Pluripotent Stem Cells-derived Neural Progenitor Cells (hiPSC-derived NPCs) and receptor-dependent cell death induced via ENT-A044 treatment. In conclusion, ENT-A044 is proposed as a lead molecule for the development of novel pharmacological agents, providing new therapeutic approaches and research tools, by controlling p75NTR actions.

Vieussens' Arterial Ring: Historical Background, Medical Review and Novel Anatomical Classification.

In coronary artery disease, the presence of Vieussens' arterial ring (VAR), a ring-shaped anastomosis between the conus branch of the right coronary artery with the left anterior descending artery (LAD), will allow blood flow to return to the obstructed coronary system. We have conducted a literature review, aiming to collect all the existing information about the documented VAR cases and any related pathological conditions. A total of 54 studies entered the review, including 56 patients. The mean age of the patients was 56.12 ± 16.2 years. Angina was present in 53.6% of the patients, with 7.2% of the cases being asymptomatic. Coronary artery disease outweighed (58.9%) as the patients' most frequent diagnosis. We propose a novel VAR anatomical classification, based on the sites of origin and termination of its course, with six distinct types, for a better understanding and surgical management of VAR. Type IA, originating from the conus branch and terminating in the proximal segment of the LAD was most frequently reported (51.8%). The recognition and the subsequent evaluation of the ring's anatomy and course are crucial for a customized clinical intervention. When right and left coronary angiographies fail to reveal any collateral circulation, selective conus artery catheterization should be in order. The proposed classification offers a manageable and comprehensive context for the assessment, evaluation and planning of therapeutic strategies of VAR and sets a new terminology frame for treatment guidelines.

Selective Destabilization of Transcripts by mRNA Decapping Regulates Oocyte Maturation and Innate Immunity Gene Expression during Ageing in C. elegans.

Removal of the 5' cap structure of RNAs (termed decapping) is a pivotal event in the life of cytoplasmic mRNAs mainly catalyzed by a conserved holoenzyme, composed of the catalytic subunit DCP2 and its essential cofactor DCP1. While decapping was initially considered merely a step in the general 5'-3' mRNA decay, recent data suggest a great degree of selectivity that plays an active role in the post-transcriptional control of gene expression, and regulates multiple biological functions. Studies in Caenorhabditis elegans have shown that old age is accompanied by the accumulation of decapping factors in cytoplasmic RNA granules, and loss of decapping activity shortens the lifespan. However, the link between decapping and ageing remains elusive. Here, we present a comparative microarray study that was aimed to uncover the differences in the transcriptome of mid-aged dcap-1/DCP1 mutant and wild-type nematodes. Our data indicate that DCAP-1 mediates the silencing of spermatogenic genes during late oogenesis, and suppresses the aberrant uprise of immunity gene expression during ageing. The latter is achieved by destabilizing the mRNA that encodes the transcription factor PQM-1 and impairing its nuclear translocation. Failure to exert decapping-mediated control on PQM-1 has a negative impact on the lifespan, but mitigates the toxic effects of polyglutamine expression that are involved in human disease.

Surfing on the waves of the human γδ T cell ontogenic sea.

While γδ T cells are present virtually in all vertebrates, there is a remarkable lack of conservation of the TRG and TRD loci underlying the generation of the γδ T cell receptor (TCR), which is associated with the generation of species-specific γδ T cells. A prominent example is the human phosphoantigen-reactive Vγ9Vδ2 T cell subset that is absent in mice. Murine γδ thymocyte cells were among the first immune cells identified to follow a wave-based layered development during embryonic and early life, and since this initial observation, in-depth insight has been obtained in their thymic ontogeny. By contrast, less is known about the development of human γδ T cells, especially regarding the generation of γδ thymocyte waves. Here, after providing an overview of thymic γδ wave generation in several vertebrate classes, we review the evidence for γδ waves in the human fetal thymus, where single-cell technologies have allowed the breakdown of human γδ thymocytes into functional waves with important TCR associations. Finally, we discuss the possible mechanisms contributing to the generation of waves of γδ thymocytes and their possible significance in the periphery.

Identification of distinct functional thymic programming of fetal and pediatric human γδ thymocytes via single-cell analysis.

Developmental thymic waves of innate-like and adaptive-like γδ T cells have been described, but the current understanding of γδ T cell development is mainly limited to mouse models. Here, we combine single cell (sc) RNA gene expression and sc γδ T cell receptor (TCR) sequencing on fetal and pediatric γδ thymocytes in order to understand the ontogeny of human γδ T cells. Mature fetal γδ thymocytes (both the Vγ9Vδ2 and nonVγ9Vδ2 subsets) are committed to either a type 1, a type 3 or a type 2-like effector fate displaying a wave-like pattern depending on gestation age, and are enriched for public CDR3 features upon maturation. Strikingly, these effector modules express different CDR3 sequences and follow distinct developmental trajectories. In contrast, the pediatric thymus generates only a small effector subset that is highly biased towards Vγ9Vδ2 TCR usage and shows a mixed type 1/type 3 effector profile. Thus, our combined dataset of gene expression and detailed TCR information at the single-cell level identifies distinct functional thymic programming of γδ T cell immunity in human.

Identifying barriers to the educational role of midwives in Cyprus and defining determinants in behaviour terms using the Behaviour Change Wheel: a mixed-method formative study.

BACKGROUND: Τhe Baby Buddy Cyprus webapp was co-created with parents and health professionals within a Participatory Action Research framework. While using Baby Buddy in routine consultations can support the educational role of mother-child healthcare providers (HP), antenatal education (AE) may be currently perceived as a formal activity within the physical space of the antenatal class. We aimed to gain an understanding of influences on midwives engaging in an educational role during routine appointments and identify potential interventions using the Behaviour Change Wheel (BCW) framework. METHODS: This is a formative mixed-methods research study, with a convergent parallel design, guided by the COM-B model and related Theoretical Domains Framework (TDF). Complimentary methods were used to collect information from in-training and registered midwives: focus group (N = 11), questionnaire survey (N = 24) and Nominal Group Technique during workshops (N = 40). Deductive content analysis of qualitative data and quantitative survey analysis shaped the behaviour diagnosis along the 6 COM-B and 14 TDF domains, and informed the selection of relevant intervention functions and related Behaviour Change Techniques from the BCW taxonomy. RESULTS: AE is viewed as a core function of the professional role, yet neither supported nor prioritized by current practices. Problematic areas relate to organizational context, such as weak interprofessional collaboration and lack of policy, protocols and resources. In addition, medicalization of birth and related socio-cultural norms, pertaining to users and providers, are sustaining alienation of the midwife and conditions of power dynamics. AE was perceived as a means to enhance the autonomy of the profession but there might be issues with procedural knowledge and the need for skill development was identified. Several intervention functions were identified as promising, however cognitive re-framing through strategic communication and modelling may also be needed both in terms of providing "credible models" for the role itself as well as re-framing AE through the concept of "making every contact count". CONCLUSIONS: AE is currently perceived to be a 'bad fit' with routine practice. The study identified several barriers to the educational role of midwives, influencing Capacity, Opportunity and Motivation. While digital tools, such as Baby Buddy, can facilitate aspects of the process, a much wider behaviour and system change intervention is needed to enhance midwives' educational role and professional identity. In addition to proposing a theory-driven research-informed intervention, the process functioned as a participatory learning experience through collective reflection.

Efficacy of a Robot-Assisted Intervention in Improving Learning Performance of Elementary School Children with Specific Learning Disorders.

(1) Background: There has been significant recent interest in the potential role of social robots (SRs) in special education. Specific Learning Disorders (SpLDs) have a high prevalence in the student population, and early intervention with personalized special educational programs is crucial for optimal academic achievement. (2) Methods: We designed an intense special education intervention for children in the third and fourth years of elementary school with a diagnosis of a SpLD. Following confirmation of eligibility and informed consent, the participants were prospectively and randomly allocated to two groups: (a) the SR group, for which the intervention was delivered by the humanoid robot NAO with the assistance of a special education teacher and (b) the control group, for which the intervention was delivered by the special educator. All participants underwent pre- and post-intervention evaluation for outcome measures. (3) Results: 40 children (NAO = 19, control = 21, similar baseline characteristics) were included. Pre- and post-intervention evaluation showed comparable improvements in both groups in cognition skills (decoding, phonological awareness and reading comprehension), while between-group changes favored the NAO group only for some phonological awareness exercises. In total, no significant changes were found in any of the groups regarding the emotional/behavioral secondary outcomes. (4) Conclusion: NAO was efficient as a tutor for a human-supported intervention when compared to the gold-standard intervention for elementary school students with SpLDs.