Long-term and real-world safety and efficacy of retroviral gene therapy for adenosine deaminase deficiency.

Adenosine deaminase (ADA) deficiency leads to severe combined immunodeficiency (SCID). Previous clinical trials showed that autologous CD34+ cell gene therapy (GT) following busulfan reduced-intensity conditioning is a promising therapeutic approach for ADA-SCID, but long-term data are warranted. Here we report an analysis on long-term safety and efficacy data of 43 patients with ADA-SCID who received retroviral ex vivo bone marrow-derived hematopoietic stem cell GT. Twenty-two individuals (median follow-up 15.4 years) were treated in the context of clinical development or named patient program. Nineteen patients were treated post-marketing authorization (median follow-up 3.2 years), and two additional patients received mobilized peripheral blood CD34+ cell GT. At data cutoff, all 43 patients were alive, with a median follow-up of 5.0 years (interquartile range 2.4-15.4) and 2 years intervention-free survival (no need for long-term enzyme replacement therapy or allogeneic hematopoietic stem cell transplantation) of 88% (95% confidence interval 78.7-98.4%). Most adverse events/reactions were related to disease background, busulfan conditioning or immune reconstitution; the safety profile of the real world experience was in line with premarketing cohort. One patient from the named patient program developed a T cell leukemia related to treatment 4.7 years after GT and is currently in remission. Long-term persistence of multilineage gene-corrected cells, metabolic detoxification, immune reconstitution and decreased infection rates were observed. Estimated mixed-effects models showed that higher dose of CD34+ cells infused and younger age at GT affected positively the plateau of CD3+ transduced cells, lymphocytes and CD4+ CD45RA+ naive T cells, whereas the cell dose positively influenced the final plateau of CD15+ transduced cells. These long-term data suggest that the risk-benefit of GT in ADA remains favorable and warrant for continuing long-term safety monitoring. Clinical trial registration: NCT00598481 , NCT03478670 .

Assessment of Epicardial Fat in Children: Its Role as a Cardiovascular Risk Factor and How It Is Influenced by Lifestyle Habits.

Epicardial adipose tissue (EAT) stands out as a distinctive repository of visceral fat, positioned in close anatomical and functional proximity to the heart. EAT has emerged as a distinctive reservoir of visceral fat, intricately interlinked with cardiovascular health, particularly within the domain of cardiovascular diseases (CVDs). The aim of our overview is to highlight the role of EAT as a marker for cardiovascular risk in children. We also explore the influence of unhealthy lifestyle habits as predisposing factors for the deposition of EAT. The literature data accentuate the consequential impact of lifestyle choices on EAT dynamics, with sedentary behavior and unwholesome dietary practices being contributory to a heightened cardiovascular risk. Lifestyle interventions with a multidisciplinary approach are therefore pivotal, involving a nutritionally balanced diet rich in polyunsaturated and monounsaturated fatty acids, regular engagement in aerobic exercise, and psychosocial support to effectively mitigate cardiovascular risks in children. Specific interventions, such as high-intensity intermittent training and circuit training, reveal favorable outcomes in diminishing the EAT volume and enhancing cardiometabolic health. Future clinical studies focusing on EAT in children are crucial for advancing our understanding and developing targeted strategies for cardiovascular risk management in this population.

The hidden scabies: a rare case of atypical Norwegian scabies, case report and literature review.

BACKGROUND: Norwegian scabies is a rare dermatological manifestation that usually affects the most fragile populations, such as elderly and immunocompromised patients, and its diagnosis is quite complex, due to its low prevalence in the general population and because of a broad spectrum manifestation. CASE PRESENTATION: Here we describe a rare case of Norwegian scabies that was previously misdiagnosed in a sixteen year old patient affected by Down syndrome and we conducted a non-systematic literature review about this topic. Lesions were atypical, pruritic and associated with periodic desquamation of the palms and soles and after a series of specialist evaluations, she finally underwent topical treatment with complete remission. CONCLUSION: It is therefore crucial to take in consideration the relation between Down syndrome and community acquired crusted scabies, to enable preventative measures, early detection, and proper treatment.

Cardiovascular Risk in Pediatrics: A Dynamic Process during the First 1000 Days of Life.

The early childhood period, encompassing prenatal and early stages, assumes a pivotal role in shaping cardiovascular risk factors. We conducted a narrative review, presenting a non-systematic summation and analysis of the available literature, focusing on cardiovascular risk from prenatal development to the first 1000 days of life. Elements such as maternal health, genetic predisposition, inadequate fetal nutrition, and rapid postnatal growth contribute to this risk. Specifically, maternal obesity and antibiotic use during pregnancy can influence transgenerational risk factors. Conditions at birth, such as fetal growth restriction and low birth weight, set the stage for potential cardiovascular challenges. To consider cardiovascular risk in early childhood as a dynamic process is useful when adopting a personalized prevention for future healthcare and providing recommendations for management throughout their journey from infancy to early adulthood. A comprehensive approach is paramount in addressing early childhood cardiovascular risks. By targeting critical periods and implementing preventive strategies, healthcare professionals and policymakers can pave the way for improved cardiovascular outcomes. Investing in children's health during their early years holds the key to alleviating the burden of cardiovascular diseases for future generations.

Thyroid function disorders and secondary cancer following haematopoietic stem cell transplantation in pediatrics: State of the art and practical recommendations for a risk-based follow-up.

Thyroid disorders (TD) represent a remarkable share of all the late morbidities experienced following pediatric haematopoietic stem cell transplantation (HSCT), with long-term reported occurrence often exceeding 70%. In addition, the data collected on wide cohorts of survivors assessed longitudinally outlined a progressive increase in the cumulative incidence of TD as far as 30 years following transplantation. Accordingly, a life-long monitoring of thyroid health is warranted among patients exposed to HSCT in childhood, in order to early detect TD and undertake a prompt dedicated treatment. Although several national and international consortia have provided recommendations for the early detection of thyroid disorders among childhood cancer survivors exposed to radiotherapy and alkylating agents, no guidelines specifically and thoroughly focused on HSCT-related TD have been published to date. As stem cell transplantation has become the standard-of-care in a growing body of non-oncological conditions, this urge has become pivotal. To highlight the challenging issues specifically involving this cohort of patients and to provide clinicians with the proposal of a practical follow-up protocol, we reviewed published literature in the light of the shared experience of a multidisciplinary team of pediatric oncologists, transplantologists, pathologists and endocrinologists involved in the long-term care of HSCT survivors. As a final result, we hereby present the proposals of a practical and customized risk-based approach to tailor thyroid health follow-up based on HSCT-related detrimental factors.