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Background Rare diseases are chronic and life-threatening disorders affecting < 1 person every 2,000. For most of them, clinical symptoms and signs can be observed at birth or childhood. Approximately 80% of all rare diseases have a genetic background and most of them are monogenic conditions. In addition, while the majority of these diseases is still incurable, early diagnosis and specific treatment can improve patients’ quality of life. Transplantation is among the therapeutic options and represents the definitive treatment for end-stage organ failure, both in children and adults. The aim of this paper was to analyze, in a large cohort of Italian patients, the main rare genetic diseases that led to organ transplantation, specifically pointing the attention on the pediatric cohort. Results To the purpose of our analysis, we considered heart, lung, liver and kidney transplants included in the Transplant Registry (TR) of the Italian National Transplantation Center in the 2002–2019 timeframe. Overall, 49,404 recipients were enrolled in the cohort, 5.1% of whom in the pediatric age. For 40,909 (82.8%) transplant recipients, a disease diagnosis was available, of which 38,615 in the adult cohort, while 8,495 patients (17.2%) were undiagnosed. There were 128 disease categories, and of these, 117 were listed in the main rare disease databases. In the pediatric cohort, 2,294 (5.6%) patients had a disease diagnosis: of the 2,126 (92.7%) patients affected by a rare disease, 1,402 (61.1%) presented with a monogenic condition. As expected, the frequencies of pathologies leading to organ failure were different between the pediatric and the adult cohort. Moreover, the pediatric group was characterized, compared to the adult one, by an overall better survival of the graft at ten years after transplant, with the only exception of lung transplants. When comparing survival considering rare vs non-rare diseases or rare and monogenic vs rare non-monogenic conditions, no differences were highlighted for kidney and lung transplants, while rare diseases had a better survival in liver as opposed to heart transplants. Conclusions This work represents the first national survey analyzing the main genetic causes and frequencies of rare and/or monogenic diseases leading to organ failure and requiring transplantation both in adults and children.

Background We evaluated the role of CYP3A5, ABCB1 and SXR gene polymorphisms in the occurrence of acute kidney rejection in a cohort of pediatric renal transplant recipients. Methods Forty-nine patients were genotyped for CYP3A5, ABCB1 and SXR polymorphisms and evaluated with tacrolimus through levels in a retrospective monocenter study. Results Patients with the A allele of CYP3A5 treated with tacrolimus had a higher risk of acute rejection than those without the A allele, while patients carrying the homozygous GG variant for SXR A7635GG did not show any episode of acute rejection. Conclusion Genetic analysis of polymorphisms implicated in drug metabolism and tacrolimus trough levels may help to forecast the risk of acute rejection and individualize drug dosage in children undergoing renal transplantation.

Background Shigatoxin-associated hemolytic uremic syndrome (STEC-HUS) is a common thrombotic microangiopathy (TMA) in which central nervous system (CNS) involvement is responsible for the majority of deaths and for severe long-term sequelae. We have analyzed the role of hemoconcentration in disease severity. Methods This was a retrospective review of the records and laboratory data at presentation of all patients with STEC-HUS cases ( n = 61) over a 10-year period. The patients were grouped into three severity classes: group A, comprising patients who did not require dialysis; group B, patients who were dialyzed without CNS involvement; group C, patients with CNS involvement. Results Patients with CNS involvement (group C) had a higher mean hemoglobin level (11.2 ± 2.3 g/dL) than those of group A or B ( 9.4 ± 2.1 and 7.5 ± 1.9 g/dL, respectively; p  < 0.0001). We also observed that the higher the initial hemoglobin level, the more severe the long-term renal damage ( p  < 0.007). Conclusions In patients with STEC-HUS, hemoconcentration and hypovolemia may be responsible for more severe ischemic organ damage (both short and long term) at disease onset, and these signs should be regarded as risk factors for CNS damage and for more severe TMA. Therefore, we recommend that hydration status should be actively monitored in HUS patients and that dehydration, when diagnosed, should be promptly corrected.

Background Inborn errors of cobalamin (Cbl) absorption and metabolism form a large group of rare diseases that include Cbl-C disorder. Among the renal complications of Cbl-C disorder, atypical hemolytic uremic syndrome (HUS) is the least common and has been described only in a small number of cases. Case-diagnosis/Treatment Four patients were admitted to our clinic after 15–30 days of life with vomiting associated with poor sucking, failure to thrive, lethargy and hypotonia. Examinations showed thrombocytopenia and microangiopathic hemolytic anemia associated with renal damage. The neonates had high blood homocysteine levels, increased urinary levels of both homocystine and methylmalonic acid, increased propionylcarnitine (C3) levels and an increased C3/acetylcarnitine ratio. Homozygosity for c.271-272dupA (p.Arg91LysfsX14) of the MMACHC gene was detected in three patients, and heterozygosity for c.271-272dupA and c.666C > A(p.Tyr222X) in one patient, which confirmed the diagnosis of Cbl-C disorder. Treatment with parenteral hydroxycobalamin in combination with folic acid and betaine gradually normalized the metabolic test findings and hematological and renal parameters after about 1 week. Conclusions Atypical HUS in neonates with Cbl-C disorder may be associated with mild to moderate renal involvement also in early-onset disease, and early adequate therapy can reverse renal damage.

TrentinoSalute4.0  (TS4.0) is the recently created \"Competence Center on Digital Health\" after approval from the Trentino Provincial Council as a policy instrument to coordinate the work on digital health in the region. TS4.0 represents the meeting point between the health system, research and the territory, becoming the instrument of cohesion between the guidelines of health planning, the innovation needs expressed by the Provincial Health Service and the opportunities offered by research and new digital technologies [1]. The TS4.0 initiative responds to the need to fill the gap between planning, research and actual implementation of innovative solutions on digital healthcare to support the local Healthcare Trust while empowering Citizens for better management of their own health in Trentino Region in a sustainable way. The Center active from 2017 responds to the objectives set by policy makers and local, national and European health planning, starting from the needs expressed by health professionals and citizens, identifying new organizational models and technological solutions, studying the legal aspects and evaluating their socio-organizational and economic impact of digital health initiatives. The ultimate goal is to transform the technical-organizational solutions tested into innovative services for the healthcare sector. The Province of Trento allocated a start-up fund of 1,350,000 Euros for the three-year period 2017-2019.  Since its creation, the Center has been the container for new projects on digital health co-funded at Local, National and International level with the objective of being put into service in the Trentino territory. The Center is jointly governed, by a Steering Committee and an Executive Committee composed by the Autonomous Province of Trento, the Provincial Health Services Agency and the Bruno Kessler Foundation.The TS4.0 initiative is open to all Civil Society, Enterprises, Academy, Associations and interested actors in the domain of digital healthcare innovation and since its creation has attracted co-funding for over 1ME through European Projects such as H2020 WellCo [2] and Upright [3]. The TS4.0 initiative has attracted interest and is part of ongoing discussions in other projects such as Interreg Central Europe Digital Life project [4] and recently funded H2020 Vigour in which is presented as a good practice in Europe. Additionally, TS4.0 initiative has been presented as a commitment in the EIP-AHA network in which which Trento is a reference site [5]. References: 1 - Available from: http://trentinosalutedigitale.it/index.html 2 - Available from: http://wellco-project.eu/ 3 - Available from: http://uprightproject.eu/ 4 - Available from: https://www.interreg-central.eu/Content.Node/digitalLIFE4CE.html 5 - Available from: https://ec.europa.eu/eip/ageing/homeₑn

Hemolytic uremic syndrome (HUS) is an unrare and severe thrombotic microangiopathy (TMA) caused by several pathogenetic mechanisms among which Shiga toxin-producing Escherichia coli infections and complement dysregulation are the most common. However, very rarely and particularly in neonates and infants, disorders of cobalamin metabolism (CblC) can present with or be complicated by TMA. Herein we describe a case of atypical HUS (aHUS) related to CblC disease which first presented in a previously healthy boy at age of 13.6 years. The clinical picture was initially dominated by nephrotic range proteinuria and severe hypertension followed by renal failure. The specific treatment with high dose of hydroxycobalamin rapidly obtained the remission of TMA and the complete recovery of renal function. We conclude that plasma homocysteine and methionine determinations together with urine organic acid analysis should be included in the diagnostic work-up of any patient with TMA and/or nephrotic syndrome regardless of age.

Background: The integration of digital solutions is a cornerstone of modern integrated care, enabling enhanced coordination, communication, and personalized care across health systems. Digital health innovations are increasingly recognized as crucial for improving the efficiency and quality of care delivery, reducing fragmentation, and empowering patients to take an active role in managing their health (1). The International Foundation for Integrated Care (IFIC) emphasizes the significance of digital solutions in pillar 7 of the nine pillars of integrated care. The need for structured, effective data management frameworks is underscored by the complexity of modern health systems, where digital solutions must comply with evolving data protection laws such as the General Data Protection Regulation (GDPR) and emerging requirements like the AI Act. Without robust data governance, these systems face challenges in ensuring privacy, security, and ethical data use while striving to achieve integrated care goals. Approach: The \"Integrating Data in Integrated Care\" (IDIC) methodology, developed during the EU funded  ValueCare Project (https://projectvaluecare.eu/), responds to these challenges, offering a structured reference model for data governance that aligns with European legislation. The IDIC methodology is organized around the data life cycle of digital health projects, addressing the specific data management needs of Integrated Healthcare systems (IHC). The IDIC methodology responds to two major challenges: 1.Privacy, ethical, and legal requirements: Ensuring GDPR compliance, defining clear roles for data governance, safeguarding against bias, and implementing privacy-by-design principles. 2.Patient and technology-centered challenges: Addressing data fragmentation, enhancing data quality, and empowering patients by giving them control over their data, all of which are critical to the success of digital health solutions. IDIC organizes data management into two core categories: 1.Project Design, Dissemination, and Knowledge Data: Including co-design data from focus groups; dissemination and communication data, including databases with stakeholders’ details and knowledge produced during the project (i.e. intervention models, algorithms). 2.Patient Data in IHC Pilots: Including patient personal data (i.e demographic data gathered during recruiting phases), medical devices data (collected from monitoring devices), wellbeing data from personal devices (pedometers, apps, etc.)., interaction data (self-input data, interactions with chatbots, preferences, etc.), implementation data (record keeping, appointments, coordination meetings, etc). For each category, the methodology emphasizes: Data size and format; Storage and backup strategies; Retrospective or prospective datasets organisation; Different roles of individuals and organisations involved in data management; Compliance with the FAIR (Findable, Accessible, Interoperable, Reusable) principles; Strategies for consent, data sharing and multi-center pilot implementation; Ethical and legal issues; Long term preservation of data; Results and implications: The IDIC framework provides a replicable, GDPR-compliant approach for data management in IHC projects. IDIC ensures that patient rights are preserved while supporting the deployment of digital solutions, while promoting the IHC agenda. IDIC offers a valuable tool for the digital transformation of health systems, aligning with the broader goal of integrating care through advanced data governance practices. References: 1.Colnar S, et al. Digital transformation of integrated care: Literature review and research agenda. IFAC-PapersOnLine. 2020;53(2):16890-5.    

This study assessed the long-term renoprotective effect of intensified blood-pressure control among children receiving a fixed high dose of an angiotensin-converting–enzyme inhibitor. Intensified blood-pressure control, achieved with additional medication, to reach a targeted 24-hour blood pressure in the low range of normal appeared to confer a substantial benefit with respect to a delay in the progression of renal disease among children with chronic kidney disease. However, reappearance of proteinuria after initial successful pharmacologic control was common. Intensified blood-pressure control to reach a targeted 24-hour blood pressure in the low range of normal appeared to confer a substantial benefit with respect to a delay in the progression of renal disease among children with chronic kidney disease. However, reappearance of proteinuria was common. Among both adults and children, chronic kidney disease tends to progress to end-stage renal failure, which is a major clinical problem. Systemic hypertension and glomerular hyperfiltration lead to progressive nephron damage. 1 – 3 Effective blood-pressure control delays the progression of renal disease in adults with chronic kidney disease, and antihypertensive agents that inhibit the renin–angiotensin system provide superior renoprotection, owing to their additional antiproteinuric, antiinflammatory, and antifibrotic properties. 4 – 7 Children comprise less than 1% of the total population with chronic kidney disease and often have congenital kidney malformations, urinary tract disorders, or genetic disorders that affect nephron formation or function. Hypertension . . .

Background Atypical haemolytic uremic syndrome (aHUS) is at high risk of relapse at any time, therefore patients require lifelong monitoring. The most appropriate way to monitor patients is not yet clear. Patients could be monitored for relapse by urine dipstick testing for haemoglobinuria based on the hypothesis that thrombotic microangiopathy involving the glomerulus and associated with renal damage (like aHUS) cannot occur without haematuria. Methods The aim of this retrospective study is to analyse our experience with this approach in aHUS patients who have never previously been treated, who are currently on treatment or who have discontinued C5 inhibition. The records of all aHUS patients (children and adults) managed by or referred to our Centre from January 2009 to March 2020 were included and the analysis for the presence of haemoglobinuria was restricted to the period following primary remission. A positive test was defined as haemoglobin ≥ 1 + . Patients reporting positive urine dipstick tests underwent laboratory investigations to rule in or out the diagnosis of aHUS relapse. Results Eighty-four patients were included with 1517 determinations of haemoglobinuria during a cumulative observation period of 8904 patient-months. Haemoglobinuria for the early diagnosis of ongoing aHUS relapse shows a sensitivity of 100% and a specificity of 87.4% with a positive predictive value (PPV) of 10.5% and a negative predictive value (NPV) of 100%. The accuracy of the test was 87.6%. Conclusion Haemoglobinuria is a very sensitive and acceptably specific marker of aHUS relapse. This finding and its validation may have a positive impact on patients’ quality of life and on the outcome of this life threatening disease via early diagnosis of relapse. Graphic abstract

BackgroundAtypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy (TMA) characterized by platelet consumption, hemolysis, and organ damage. Eculizumab (ECU), a humanized antibody that blocks complement activity, has been successfully used in aHUS, but the best treatment schedule is not yet clear.MethodsHere, we report our experience with ECU maintenance treatment and the interval between subsequent doses being extended based on global classical complement pathway (CCP) activity aimed at <30% for maintaining aHUS into remission.ResultsWe report on 38 patients with aHUS, 13 children, 21 female, with a median age of 25.0 years (range 0.5–60) at disease onset treated with ECU standard schedule for a median of 2.6 months (range 0.4–24.6). Once stable TMA remission was obtained, the interval between ECU doses was extended based on complement function, with a target CCP activity of <30%. With this approach, 22 patients regularly receive ECU infusion every 28 days and 16 every 21. During a median observation period on ECU, an extended interval of 26.9 months (range 0.8–80.9), with a cumulative observation period of 1,208 months, none of the patients relapsed.ConclusionMonitoring complement activity allows a safe reduction in the frequency of ECU administration in aHUS while keeping the disease in remission.