The aim of the present Clinical Guideline of the Asociación Mexicana de Gastroenterología was to establish clear, updated, evidence-based recommendations for the diagnosis and treatment of lactose ingestion-related disorders (LIRDs), to improve diagnostic accuracy and promote effective, patient-centered clinical management. The methodology employed consisted of a Delphi process coordinated by three experts, with the participation of 15 Mexican specialists (gastroenterologists, pediatricians, and nutritionists). Three working groups (epidemiology/definitions, diagnosis, and treatment) were formed that thoroughly reviewed the medical literature published between 2010 and 2025. A total of 26 statements were formulated. The main results included the precise definition of the different LIRD phenotypes (lactase nonpersistence, hypolactasia, clinical lactose intolerance, self-perceived lactose intolerance, and lactose sensitivity); diagnostic test standardization, highlighting the lactose breath test as a highly sensitive noninvasive tool, complemented by genetic studies and biochemical tests; and the recommendation of personalized treatments ranging from the selective reduction of dietary lactose to the use of exogenous enzymes (lactase) and fermented dairy products. Likewise, the importance of avoiding unnecessary dietary restrictions that could compromise calcium and vitamin D intake was emphasized. Altogether, the present consensus provides a comprehensive framework to optimize the clinical care of patients with LIRDs in Mexico.
Fetal MRI has been proved to be a valuable complement to prenatal ultrasound in the study of congenital abnormalities, especially those of the central nervous system. However, its role in the assessment of the fetal abdomen is less known. Fetal abdominal pathology includes congenital abnormalities of the gastrointestinal tract, genitourinary tract, and abdominal wall defects. The aims of this article are to indicate an assessment protocol for the fetal abdomen, determine which patients will benefit from this technique and illustrate with examples the value of prenatal MRI and the role of the radiologist, both in diagnosis and perinatal management of these patients.
Background/Objectives: Acute lymphoblastic leukaemia (ALL) is a biologically heterogeneous disease in which transcriptional dysregulation contributes to disease onset and progression. Despite survival rates exceeding 90% in high-income countries, relapsed and high-risk cases remain a major clinical challenge, highlighting the need for improved molecular stratification, namely the classification of patients based on genetic and transcriptomic features associated with prognosis, therapeutic response, and disease biology, as well as for the identification of novel therapeutic targets. Methods: We performed an integrative cross-platform analysis to investigate the expression and potential relevance of three candidate genes: PXDN, TCF4, and TSPAN7 in ALL. Gene expression was interrogated across the MILE microarray cohort and the St. Jude Cloud PeCan paediatric RNA-sequencing dataset. Results: Differential expression analyses consistently showed significant upregulation of TCF4 and PXDN in B-cell ALL (B-ALL) across both platforms (adjusted p < 0.001), while TSPAN7 displayed higher expression in T-cell ALL (T-ALL) and variable upregulation in B-ALL. These findings were supported by preliminary validation using quantitative PCR in paediatric B-ALL samples. To explore potential functional associations, we performed gene regulatory network inference using scGraphVerse, identifying differentially expressed genes putatively linked to PXDN, TCF4, and TSPAN7. Structural modelling using AlphaFold suggested candidate protein-protein interaction interfaces for a subset of these genes, although these predictions require experimental validation. Functional enrichment analysis indicated an over-representation of developmental pathways associated with PXDN- and TCF4-related networks, whereas TSPAN7-associated genes were enriched in processes linked to neuronal lineage development. Conclusions: Collectively, our results identify, for the first time, PXDN, TCF4 and TSPAN7 as differentially expressed genes in ALL and highlight the usefulness of integrative transcriptomic analyses across independent datasets. While limited by small-scale experimental validation and reliance on computational predictions, this study provides a framework for prioritising candidate genes and generates testable hypotheses regarding their potential involvement in leukaemia-associated molecular pathways.
To describe surgical outcomes, in-hospital mortality, and variables associated with mortality in pediatric patients with congenital heart disease (CHD) at a national referral center in México over 14 years. Retrospective cross-sectional study of 4494 patients under 18 years of age with CHD undergoing cardiac surgery (2010-2024) at the Instituto Nacional de Cardiología "Ignacio Chávez," using Registro Nacional de Cirugía Cardíaca Pediátrica y Cardiopatías Congénitas (RENACCAPE) data. Comparisons used χ2, Fisher's exact, and Mann-Whitney U tests (P < .05). Analysis was univariate; RACHS-1/STAT scores were incompletely recorded and excluded from risk adjustment. Among 4494 patients (53.5% [2405/4494] male), the predominant age groups were children 1 to 12 years (56.1% [2521/4494]), infants 1 to 11 months (19.8% [888/4494]), adolescents (17.4% [784/4494]), and neonates (6.7% [301/4494]). Down syndrome (6.2% [277/4494]) and DiGeorge syndrome (1.2% [55/4494]) were the most frequent genetic comorbidities; 85.5% (3844/4494) underwent elective surgery. Leading procedures included ventricular septal defect closure (13.6%; [611/4494] mortality 1.8% [11/611]), modified Blalock-Taussig-Thomas shunt (9.8% [440/4494]; mortality 11.1% [49/440]), total anomalous pulmonary venous connection repair (7.4% [334/4494]; mortality 8.4% [28/334]), atrial septal defect closure (6.7% [303/4494]; mortality 0.0%), and tetralogy of Fallot repair (5.9% [267/4494]; mortality 7.9% [21/267]). Norwood had the highest procedure-specific mortality (71.4% [5/7]), followed by Damus-Kaye-Stansel (60.0%) and Jatene (26.0% [32/123]). Overall mortality was 9.4% (421/4494), declining from 10.5% (2010) to 7.1% (2024), with a transient rise during COVID-19. Mortality-associated variables included neonatal/infant age, low weight, cyanotic CHD, genetic syndromes, prolonged cardiopulmonary bypass (147 vs 89 min), longer aortic cross-clamp time (83 vs 54 min), and urgent surgery (all P < .001). To our knowledge this is this largest single-center Mexican pediatric CHD series, in-hospital mortality was 9.4% with a declining trend. Procedure-specific mortalities exceeded STS benchmarks, identifying targets for quality improvement. Expanding RENACCAPE and strengthening referral networks remain priorities.
Respiratory tract infections (RTIs) are among the most common causes of medical consultation in children. Although the majority of upper respiratory tract infections are viral and self-limiting, bacterial pathogens remain responsible for a relevant proportion of cases and may require targeted antimicrobial therapy. Accurate microbiological diagnosis is therefore essential to guide clinical management and support antimicrobial stewardship. This review discusses the etiology and clinical presentation of pediatric respiratory infections and examines current diagnostic approaches, including traditional culture-based methods and nucleic acid amplification tests (NAATs). The advantages of molecular diagnostics - such as rapid turnaround time, high sensitivity, and improved pathogen detection - are highlighted alongside their role in antimicrobial stewardship and public health surveillance. At the same time, important limitations are explored, including difficulties in distinguishing colonization from active infection, challenges in polymicrobial detection, absence of host-response information, and barriers related to cost and accessibility. Emerging technologies and future perspectives in pediatric molecular diagnostics are also addressed. While molecular diagnostics have transformed pathogen detection, their clinical interpretation remains complex. Future diagnostic strategies should integrate molecular data with quantitative pathogen measurements, host-response biomarkers, and clinical phenotyping to better distinguish infection from colonization. Interdisciplinary research, real-world implementation studies, and cost-effectiveness evaluations will be essential to translate technological advances into meaningful improvements in pediatric infectious disease care.
Italian Cystic Fibrosis Registry (ICFR) collects data of people with cystic fibrosis through the collaboration with Italian CF referral and support Centres (Italian law 548/93). It aims at analysing medium and long-term clinical and epidemiological trends, identifying healthcare needs at regional and national levels, contributing to healthcare programs and resource allocation (sharing the population of FC centres with the Ministry of Health). Finally, the RIFC shares some of its data with the Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA) to better define the number of people with cystic fibrosis with early access to specific treatments with innovative therapies. Moreover, ICFR data are shared with the European CF Patients' Registry (ECFSPs' Registry) to contribute to the estimation of the European incidence of the pathology and to bridge knowledge gaps on specific topics as well as to the adoption of common strategies for the standardized collection of data on people with cystic fibrosis. The objective of this report is to provide updated data from ICFR for the years 2023 and 2024. It is essential to consider that the analyses and specific studies carried out refer to a limited number of variables collected in the Registry, and that the selection of the topics covered in the chapters of this report was agreed by the scientific committee of the ICFR. The analyses and results presented in this report pertain to people with cystic fibrosis currently under care Italian National Referral Centres (CRR) and Support Centres (SS) for Cystic Fibrosis and Paediatric Hospital 'Bambino Gesù' (OPBG). Data are collected using web-based software adopted by almost all participating centres, except for the centres in Verona (which also includes the data from Treviso and Rovereto) and Messina, where data collection is carried out using a different software. The submitted data are then subject to both quantitative and qualitative quality control (QC) procedures, aimed at verifying the consistency and continuity of the information previously transmitted and shared with the European CF Registry. In the two-year period 2023-2024, 28 and 27 CF Centres, respectively, submitted their data to ICFR. However, the information from the two CF centres in Sardinia is still partial, since the data provided is limited to a small number of people with cystic fibrosis from 2023. The results section provides a comprehensive overview of various aspects of CF epidemiology and people with cystic fibrosis characteristics. 1. Demography: in 2023 and 2024, 6,127 and 6,182 people with cystic fibrosis were, respectively, included in the ICFR (median ages of 24.1 and 24.9 years). On average, 52.2% of people with cystic fibrosis are male, and most of the population (65.3%) is older than 18 years. This reflects the growth of the adult population, the number of paediatric people with cystic fibrosis remains almost unchanged compared to previous years. 2. in 2024, 66.5% of the Italian CF population received a diagnosis before reaching two years of age, 61.8% within the first year of life, while 15.5% of diagnoses were made in adulthood (>18 years). New diagnoses were 103 in 2023 and 134 in 2024, with an incidence of 1 in 5,587 live births in 2023 and 1 in 8,808 in 2024. 3. the genetic analysis of people with cystic fibrosis was performed in 99.9% of cases. The results allowed the characterization of at least one of the two alleles in 6,040 individuals (97.7%). The most frequent variant in Italy, consistent with previous years, is F508del, present in 43.6% of cases. A higher frequency, compared with other European countries, is also confirmed for the genetic variants N1303K, G542X, and 2789+5G>A. Only 1.3% of alleles carry a CFTR gene variant that has not yet been identified (unknown). 4. Lung function: lung function, measured by percent predicted FEV1%p, declined progressively before adulthood. In detail, 96.4% (in 2023) and 95.5% (in 2024) of paediatric people with cystic fibrosis aged between 6 and 17 maintain a FEV1%p>=70%. On the other hand, the percentage of paediatric people with cystic fibrosis with severely impaired respiratory function (FEV1%p<40%) is 0.2% (2023) and 0.1% (2024). In the adult population, FEV1%p values are encouraging, with an increasing proportion of people with cystic fibrosis showing preserved lung function (85.7% in 2023 and 87.1% in 2024). This report introduces a brief focus on pulmonary exacerbations, which decreased between 2023 and 2024 (from 19.8% to 15.4%; recurrent forms from 8.6% to 4.9%), with reductions across all age groups, though less marked in those over 40. The most affected remain children (1-6 years) and those over 55; the 4.9% with recurrent episodes represent the priority for therapeutic optimization. Overall, trends in respiratory function suggest a progressive improvement in health status among the adult population, likely associated with the increasing use of new targeted pharmacological therapies. 5. Nutrition: ICFR data confirm the critical nature of the first months of life, which usually precede the definitive diagnosis of CF and the subsequent initiation of specialized care. In the 12-17 years age group, the median body max index (BMI) z-score is close to zero, documenting an adequate nutritional status in half of the subjects. The proportion of malnourished males was 6.2% and 5%, while among females it was 2.3% and 2.6%, respectively, in 2023 and 2024. In the >=18 years age group, a higher percentage of underweight BMI is observed among females (9% in 2023 and 8% in 2024) compared with males (4.2% and 4.4% in 2023 and 2024, respectively). 6. in 2024, in both paediatric and adult people with cystic fibrosis, the most frequent complications were the same, but occurred at different rates, such as CF-related liver disease (24.1% and 49.4%, respectively), diabetes (3.8% and 26%), and osteoporosis (4.2% and 18.7%). A total of 50 people with cystic fibrosis with cancer were recorded in 2023 and 2024, of whom 4 were of paediatric age. 7. Transplantation: over the two-year period, 21 people with cystic fibrosis underwent double-lung transplantation, with median ages of 36.2 e 36.8 years in 2023 and 2024, respectively, with ages ranging from 15.1 to 64.7 years across the two years. 8. Microbiology: in 2024, the prevalence of adult people with cystic fibrosis with chronic Pseudomonas aeruginosa infection is 30.1%, while in paediatric people with cystic fibrosis is 5.5%. The prevalence of Staphylococcus aureus infections is 28.7% and 26.4%, respectively, in adults and paediatric people with cystic fibrosis; prevalence of infections of Burkholderia cepacia is 1.6% and 0.2%. 9. in the two-year period, ICFR data show that 36 people with cystic fibrosis died (16 males and 20 females), with median ages at death of 48.3 years in 2023 and 57.2 years in 2024 (excluding transplanted people with cystic fibrosis). The crude mortality rate ranged from 3.1‰ in 2023 to 2.8‰ in 2024; excluding transplant recipients, the crude rate was 1.6‰ and 1.0‰ in the respective years. 10. Motherhood and fatherhood: over the two-year period, 80 pregnancies were recorded, of which 62 were successfully completed (77.5%). Additionally, 22 pregnancies were still ongoing as of 31.12.2024. In 2024, 25 people with cystic fibrosis became fathers. The present report updates data published in previous years thus summarizing 2023 and 2024 results. The number of registered people with cystic fibrosis was 6,127 in 2023 and 6,182 in 2024. Population coverage estimates for 2024 to be around 98%. Over the two-year period 2023-2024, the number and percentage of people with cystic fibrosis aged over 18 years increased. In detail, the ICFR recorded 3,927 adult people with cystic fibrosis (64.1%) in 2023 and 4,034 (65.3%) in 2024. An increase in the median age of Italian people with cystic fibrosis has been observed over time, reaching 24.9 years in 2024. The absolute number of new diagnoses per year is comparable with that of the previous biennium (237 vs 234); the percentage of new diagnosis in adulthood was 39.6% in 2024. In 2024, the median age at diagnosis was 3.9 months; 61.8% of subjects are diagnosed within the first year of life; 95.1% of them were identified through neonatal screening. Analysis of different CFTR genotypes in the Italian CF population confirms the high allelic variability observed in Italy, with a substantial proportion of subjects not eligible for CFTR modulator therapy. Regarding respiratory function, findings are consistent with previous reports, showing an increasing percentage of subjects under the age of 18 with a normal respiratory function. This marked improvement observed in the adult population seems to be mainly due to the introduction of highly effective CFTR modulator therapies in Italy from 2021. In 2024, a reduction in the percentage of chronic Pseudomonas aeruginosa infection was observed in both adults (30.1% vs 38.8% in 2020) and paediatric people with cystic fibrosis (5.5% vs 7.6% in 2020). Liver disease remains the most frequent complication in both paediatric and adult populations, affecting 24.1% and 49.4% of people with cystic fibrosis, respectively. During the two-year period, 36 people with cystic fibrosis died with a median age at death between 48.3 and 57.2 years (transplant people with cystic fibrosis excluded). Only one transplanted people with cystic fibrosis under the age of 18 died in the period 2023 and 2024, confirming once again that mortality in paediatric age is a rare event. Finally, for the first time, this report introduces data related to maternity and paternity, highlighting that in more than 77% of cases pregnancies were successful; as well as estimates of tumour and pulmonary exacerbations incidence as possible complications.
Current treatment of hemophilia still represents an important burden for patients and caregivers. As a consequence, adherence can be poor, thus reducing efficiency of treatment. Then, a modified Delphi method was used to assess the burden of hemophilia treatment in Mexico. In the first round, the experts answered online a questionnaire with 32 statements structured in eight sections: overall efficacy of recombinant coagulation factors, delivery of recombinant factors, adherence to treatment with recombinant factors, emotional burden, physical load, interference with daily life, impact of adherence on efficacy, and satisfaction with treatment. Each statement was qualified from "Totally disagree" to "Totally agree". In the second round, those statements with less than 70% agreement between experts were discussed. Consensus was reached in more than half of the questions. There was a consensus on the limited efficacy of current treatments, the complexity of preparation and administration of the recombinant coagulation factors, and the negative effect of the emotional burden, among other statements. Answers to the section related to the impact of adherence on efficacy showed the concern of experts about this issue. The burden of prophylactic hemophilia treatment on patients and caregivers in Mexico is substantial. Its negative effects on adherence and efficacy of treatment require evaluation of new approaches to hemophilia treatment.
To analyze the results obtained in the different implementation phases of the INFADIMED program and to describe the role of the community nurse in its development and sustainability. A longitudinal descriptive study of the trajectory of the INFADIMED program (2011-2025), with a mixed design integrating several evaluations: a quasi-experimental pilot phase with a control group and subsequent phases with a pre-post design without a control group. Early childhood and primary schools in Catalonia linked to primary care. Pilot phase: 625 students and 880 controls. Consolidation: 2,132 students. Expansion: ∼13,000 students in 331 schools across 43 municipalities, teachers, and families. A progressive program (early childhood to 6th grade of primary school), featuring 4-5 annual sessions of 30-45minutes, delivered by nurses through gamification and audiovisual storytelling, with a methodological update in 2023 and the digital platform SalutFlix. BMI, KIDMED index, and satisfaction surveys administered to teachers and families. In the pilot phase, excess weight decreased from 22.9% to 16.6% (intervention, p<0.01) and increased from 20.8% to 29.2% (control, p<0.001). In 2017-2023, optimal adherence to the Mediterranean diet improved from 33.4% to 47.9% (p<0.001). In 2024-2025, 94% of teachers and 93.5% of families rated the program positively; 84% reported an improvement in nutritional habits. INFADIMED demonstrates sustained improvements in the Mediterranean diet and childhood weight after 15 years. The community nurse is a key figure, consolidating a reproducible school model integrated into primary care.
Urea cycle disorders (UCDs) are rare inherited metabolic diseases associated with toxic hyperammonemia, leading to severe neurological damage and early mortality. Early diagnosis of distal UCDs through newborn screening (NBS) enables presymptomatic intervention; however, comparative real-world outcome data remain limited. We conducted a retrospective, multicenter study using data from the Spanish UCD Registry to describe the clinical characteristics and compare health outcomes between patients diagnosed through NBS (n = 40) and those diagnosed after clinical presentation (n = 53). Patients identified by NBS showed a markedly more favorable clinical prognosis, with a mortality rate of 2.5% compared with 15.1% in the unscreened cohort, as well as significantly lower rates of neurological involvement, fewer hospital admissions due to metabolic decompensation, and a reduced need for liver transplantation. Screening also identified a high prevalence of argininosuccinate synthetase deficiency (ASS1D) cases with attenuated biochemical profiles, highlighting the relevance of sensitive screening cutoffs. These findings provide real-world evidence that presymptomatic diagnosis through NBS is associated with improved survival and long-term neurological outcomes in patients with distal UCDs.
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Pathogenic variants in neuroblastoma amplified sequence (NBAS) gene causes infantile liver failure type 2 (IFLS2; MIM 616483), characterised by recurrent episodes of liver failure triggered by febrile infections. The underlying pathophysiological mechanisms remain incompletely understood. With this work we try to shed light on the pathomechanism and propose a potential therapeutic option. For in vitro analyses, human skin fibroblasts were obtained from three individuals with ILFS2 and one healthy control. Cells were cultivated at 37°C or 40°C. Western blots were performed to assess NBAS protein and its interaction partners. Furthermore, immunofluorescence and electron microscopy were used to examine morphological changes associated with endoplasmic reticulum (ER) stress. Apoptosis was measured using flow cytometry. The effects of N-acetylcysteine (NAC) treatment were analysed not only in cultured fibroblasts but also in vivo retrospectively in 16 affected individuals. We demonstrate that elevated temperature induces ER stress in fibroblasts from individuals with NBAS variants, leading to increased reactive oxygen species (ROS) production and apoptosis. Treatment with the antioxidant NAC, an established therapeutic in acetaminophen-induced liver failure, effectively mitigated oxidative stress and reduced apoptosis in vitro. In a retrospective clinical analysis, there was a trend that NAC treatment was associated with reduced severity of hepatic crises, suggesting a potential therapeutic benefit. Our findings link fever-induced ER stress, ROS accumulation, and apoptosis to the pathogenesis of liver failure in NBAS deficiency. NAC attenuates these cellular stress responses and may represent a promising supportive treatment option in NBAS-associated liver failure. Genetic changes to both alleles of the NBAS gene lead to, among others, recurrent episodes of fever‐triggered liver failure. However, the reason why fever causes liver damage has not been understood. In this study, we examined skin cells from people with NBAS deficiency and compared them with cells from a healthy individual. When the cells were exposed to a higher temperature (similar to what happens during a fever), the NBAS‐deficient cells showed signs of stress within a part of the cell called the endoplasmic reticulum (ER) and there was a higher production of reactive oxygen species (ROS). Furthermore, many of the affected cells underwent programmed cell death. We then tested the effect of an antioxidant medication (called N‐acetylcysteine; NAC) used to treat certain types of liver failure. In laboratory experiments, NAC reduced the build‐up of harmful ROS and protected the NBAS‐deficient cells from dying. Furthermore, we reviewed clinical data from 16 people with NBAS deficiency. NAC treatment during fever‐related illnesses seemed to lessen the severity of liver crises. Overall, our study suggests that fever can trigger a chain reaction in NBAS deficiency—causing cellular stress, oxidative damage and cell death—which may contribute to liver failure. NAC appears to interrupt this process and might be a useful treatment during febrile illness in people with NBAS deficiency.
Hydroxyurea (HU) is the most widely prescribed disease-modifying treatment in sickle cell disease (SCD), though treatment responses vary due to metabolism and adherence. We examined HU blood levels and treatment response in patients with homozygous sickle cell disease (HbSS). We measured HU in whole blood of 955 SCD patients enrolled in GenoMed4All using mass spectrometry. HU detection was defined as Z-score > 2.5 relative to untreated healthy controls. Among HbSS patients not receiving recent transfusion therapy (n = 539), HU was detected in 39% (143/369) of HU-prescribed patients ≥ 10 years (median age 31.8 [10.0-69.9]). In only 24% (23/109) of young patients (< 10 years, median age 5.9 [1.2-9.9]), HU was detected, despite comparable HU dosing (18.8 vs. 20.3 mg/kg/day). Detectable HU was associated with increased MCV (p < 0.001), and in patients ≥ 10 years also with increased HbF, despite low HbF (< 10%) in 25%. Neutropenia occurred in 8.0% of patients with detectable HU, 4.5% with undetected HU. Only one patient had severe neutropenia (< 0.5 × 10e9/l). In young patients, neutropenia occurred in 1.4% with undetected HU, and in 8.7% with detected HU. This is the largest study to date that reports data on HU levels in HbSS patients. Most HU-prescribed patients, particularly young patients, had undetectable HU levels. Low MCV, HbF, and absent toxicity in children and limited toxicity in adults suggest that treatment for patients with undetectable HU is suboptimal. These findings warrant the need to optimize dosing and adherence to improve treatment in SCD, especially in young patients.
Robot-assisted pyeloplasty is now a gold standard in the treatment of pediatric ureteropelvic junction obstruction. We describe a standardized "3-suture" technique designed to facilitate the pyelo-ureteral anastomosis. We used this technique in 65 paediatric patients aged 3-17 years. Early major complications (Clavien-Dindo grade III) occurred in 3 patients (4.6%). The median operative time was 150 min. Surgical success was achieved in 96% of cases at a median follow-up of 9.5 months. This 3-suture approach offers a highly reproducible method for robotic pyeloplasty, facilitating accurate anatomical reconstruction with excellent surgical outcomes.
Thymidine kinase 2 deficiency (MIM 609560) is an ultra-rare, autosomal recessive mitochondrial disease, resulting in progressive myopathy, respiratory insufficiency and increased risk of early death. Doxecitine and doxribtimine represents the first approved treatment for thymidine kinase 2 deficiency in the USA and the EU; previously, management was restricted to supportive care. The overall understanding of the natural history of thymidine kinase 2 deficiency is limited. Our study describes the baseline characteristics, survival and disease progression of untreated patients with thymidine kinase 2 deficiency as part of one of the largest international datasets to date. Data from individuals with thymidine kinase 2 deficiency identified through the review of published literature and a retrospective chart review study (NCT05017818) were pooled with pretreatment data from patients later treated with pyrimidine nucleos(t)ides (NCT03701568; NCT03845712; NCT05017818; company-supported Expanded Access Programs). Subgroups were stratified by age of thymidine kinase 2 deficiency symptom onset (≤12 years and >12 years). Key outcomes measured included survival, developmental motor milestone attainment, loss, regain and use of ventilatory and feeding support. In total, 257 patients were included in the study. Most patients [n = 199 (77.4%)] had an age of symptom onset ≤12 years, while 49 (19.1%) had an age of symptom onset >12 years; age of onset was missing for 9 (3.5%). Kaplan-Meier survival analyses estimated that the median time (95% confidence interval) from symptom onset to death was 2.6 (1.3, 6.4) years with age of symptom onset ≤12 years and 24.0 (16.0, not applicable) years with age of symptom onset >12 years. Loss of previously acquired motor milestones was observed across both subgroups, though most frequently in those with age of symptom onset ≤12 years [61/75 patients (81.3%) lost ≥1 motor milestone]. Spontaneous regain of lost motor milestones was rare [3/71 patients (4.2%), all with age of symptom onset ≤12 years]. Use of ventilatory support was observed for both subgroups [81/199 patients (40.7%) with age of symptom onset ≤12 years (missing data, n = 73); 23/49 patients (46.9%) with age of symptom onset >12 years (missing data, n = 11)]. Use of feeding tube support was also reported [28/199 patients (14.1%) with age of symptom onset ≤12 years (missing data, n = 121); 4/49 patients (8.2%) with age of symptom onset >12 years (missing data, n = 21)]. This study confirms the severe disease burden and high mortality associated with thymidine kinase 2 deficiency, underscoring the devastating impact on quality of life. This comprehensive dataset provides a valuable resource for informing clinical management and future therapeutic strategies.
Medulloblastoma in infants (iMB; aged < 5 years) presents the challenge of achieving cure while minimising deleterious cranio-spinal irradiation (CSI)-associated late-effects. Non-randomised phase 2 studies have examined upfront CSI omission and chemotherapy intensification for favourable-risk desmoplastic/nodular (DN) tumours associated with the sonic hedgehog (SHH) molecular group (iMBSHH). Comparison of these therapies in large molecularly defined iMBSHH cohorts, alongside investigations of prognostic biomarkers in therapy-specific context, is urgently required to define future therapeutic strategies. In this international retrospective cohort study, a multi-national cohort of molecularly and clinically annotated iMBSHH was assembled from patient datasets in nine countries. Inclusion criteria was a principal iMBSHH group classification using DNA methylation array-based classification. Patient cohorts were assigned into upfront treatment groups based on the receipt of radiotherapy (RTx) or chemotherapy (CTx)-only. Upfront RTx treatment groups were assigned as those receiving focal-RTx or CSI. Upfront CTx only regimens used were classified into three groups to reflect disease treatment conventions: standard-dose, high-dose (intensified regimens of sufficient dosage to require stem cell support) and those including intraventricular methotrexate (IVT-MTX). We investigated molecular pathology, upfront treatments, and relationships to outcome, in this real-world setting. Outcomes of interest were progression-free survival (PFS), overall survival (OS), and post-relapse survival (PRS). Between January 20, 2018 and October 6, 2021, patient data from 267 infants with SHH medulloblastoma were collected from Canada (n = 74), Germany/USA (n = 67), and the UK (n = 54), alongside national cohorts collected from France (n = 26), Italy (n = 4), Japan (n = 20), the Netherlands (n = 11), and Spain (n = 33). 226 patients with PFS and OS data comprised the iMB survival cohort and were split into upfront treatment groups based on the receipt of RTx (n = 74, 33%) or CTx-only (n = 132, 58%). Among iMBSHH patients treated upfront with CTx-only regimens, IVT-MTX therapy (5-year PFS, 72.6%; n = 72) or high-dose therapy (73.0%; n = 29) achieved PFS outcomes comparable to upfront CSI-based regimens (n = 49; 74.0%; p = 0.51); whereas lower-intensity, standard-dose, chemotherapy-only regimens (n = 31) were inferior (48.4% PFS; p = 0.006). Rescue was common post-relapse after IVT-MTX/high-dose protocols and translated into 5-year OS of 85.6% and 88.6%, respectively. However, information on pattern of relapse and treatments received at recurrence was only available for a small proportion of our cohort (n = 43). The 5-year PFS of patients receiving focal-RTx was (58.2%; n = 25). iMBSHH encompassed SHH-1 (38%), SHH-2 (47%) and SHH-3 (14%) WHO subgroups. In CSI-naïve iMBSHH, standard-dose chemotherapy was associated with worse PFS in SHH-1 (p = 0.001), but not SHH-2. Non-DN/MBEN histology (21.2% of iMBSHH) conferred worse PFS in the upfront CSI-treated and standard-dose (p < 0.001 and p = 0.003, respectively) groups. Metastatic disease only associated with prognosis with upfront IVT-MTX-only therapies (p = 0.013), while established high-risk features of non-infant MBSHH (TP53-mutation, LCA-histology, MYCN-amplification) only associated with poor prognosis in older SHH-3 (7/7 relapsed). Finally, CSI-naïve PFS findings were validated in a re-evaluation of smaller historical trials cohorts. Our findings show that iMBSHH outcomes and prognostic biomarkers are therapy dependent. In our retrospective patient group, non-metastatic iMBSHH treated with high-dose or IVT-MTX chemotherapy-only had equivalent favourable outcomes, independent of histology and subgroup. With outcomes established, clinical trials are now encouraged to focus on quality-of-life following different intensified approaches to identify the kindest curative strategies. Cancer Research UK, Children with Cancer UK, Children's Cancer North, Star for Harris, JGW Patterson Foundation, Little Hero and Blue Skye Thinking.
Lateral condyle fractures of the humerus are the second most common elbow fracture in children. Both Kirschner wires (K-wires) and cannulated screws are widely used for fixation, but the optimal technique remains debated. This study aimed to compare these methods in terms of functional outcomes and complications. A systematic review and meta-analysis were conducted in accordance with PRISMA guidelines. Thirteen comparative studies involving 1,230 pediatric patients were included. Outcomes were analyzed using random-effects models, with risk ratios (RRs) and 95% confidence intervals (CIs). Meta-regression and prediction intervals (PIs) were applied to explore heterogeneity. Screw fixation significantly reduced the risk of postoperative infection (RR = 0.27; 95% CI: 0.12-0.60) and was associated with better functional outcomes (RR = 1.09; 95% CI: 1.01-1.18). No significant differences were observed in overall complications (RR = 0.89; 95% CI: 0.66-1.20), lateral overgrowth, range of motion limitation, or nonunion. Meta-regression did not identify age or fracture severity as effect modifiers. Cannulated screw fixation may be preferable for reducing infection and improving outcomes, but individualized clinical decisions and further high-quality research remain essential. Level of Evidence III; Systematic Review. A fratura do côndilo lateral do úmero é a segunda mais comum do cotovelo da criança. Os fios de Kirschner e os parafusos canulados são amplamente utilizados para sua fixação, mas o dispositivo ideal ainda é discutível. Este estudo teve como objetivo comparar esses métodos considerando os resultados funcionais e as complicações. Foi realizada uma revisão sistemática e uma metanálise, seguindo as diretrizes PRISMA. Treze estudos comparativos envolvendo 1.230 pacientes pediátricos foram incluídos. Os resultados foram analisados usando modelos de efeitos aleatórios, com razões de risco (RRs) e intervalos de confiança (ICs) de 95%. Meta-regressão e intervalos de predição (PIs) foram aplicados para explorar a heterogeneidade. A fixação com parafuso reduziu significativamente o risco de infecção pós-operatória (RR = 0,27; IC 95%: 0,12–0,60) e foi associada a melhores resultados funcionais (RR = 1,09; IC 95%: 1,01–1,18). Nenhuma diferença significativa foi observada considerando: complicações gerais (RR = 0,89; IC 95%: 0,66–1,20), supercrescimento lateral, limitação da amplitude de movimento ou não-união. A meta-regressão não identificou idade ou gravidade da fratura como modificadores de efeito. A fixação com parafuso canulado é preferencial para reduzir infecções e melhorar os resultados, mas decisões clínicas individualizadas e pesquisas futuras de alta qualidade continuam sendo essenciais. Nível de Evidência III; Revisão Sistemática.
Medulloblastoma is one of the most prevalent pediatric brain tumors. Currently, existing therapies for this devastating type of cancer can only prolong survival time with severe side-effects and relapse. These therapies are not curative for almost a third of treated patients, while most survivors are condemned to a poor quality of life. The addition of immune checkpoint inhibitors (ICIs) to immune therapy has given some hope to those suffering from this type of cancer. Although ICIs provide a valuable contribution to immunotherapy, the exploitation of immune checkpoint inhibition within existing therapeutic strategies to cure Medulloblastoma remains understudied. However, the identification of the main molecular subgroups of medulloblastoma is considered one of the success stories of oncology. This advancement in molecular profiling of MB paved the way to subgroup-directed clinical trials, which may lead to efficacious immune-targeted therapy. However, this relatively new development is still hampered by a substantial biological heterogeneity of the disease and the absence of a full understanding of the various mechanisms behind its resistance to existing therapeutic modalities. The inclusion of chimeric antigen receptor (CAR) T and CAR NK cell therapy within various therapeutic strategies and ongoing clinical trials has given fresh hope those suffering from this fatal disease. However, ongoing clinical trials suggest that this highly promising therapy can be impaired by a number of serious limitations, including cytokine release syndrome, Graft-versus-host disease, the scarcity of target antigens, and severe adverse events. Some of the ongoing clinical trials also suggest that CAR NK is less prone to some of these limitations. This review also highlights the contribution of mass spectrometry-based proteomics, and the increasing role of liquid biopsy rather than tissue biopsy.
Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease of prematurity; however, population-based epidemiological data from low- and middle-income countries remain scarce. Most available evidence is derived from neonatal intensive care unit cohorts, limiting generalizability and constraining health system planning. We aimed to estimate the crude and age-standardized prevalence of BPD among infants younger than 1 year in Colombia between 2015 and 2024, and to characterize temporal trends, sex-specific differences, health insurance-related disparities, and patterns of healthcare utilization. We conducted a nationwide retrospective population-based study using administrative healthcare data from the Colombian Registro Individual de Prestación de Servicios de Salud (RIPS), linked to population projections from the National Administrative Department of Statistics (DANE). BPD cases were identified using the ICD-10 code P27.1. Prevalence rates per 100,000 infants were calculated with exact 95% confidence intervals and age-standardized using the World Health Organization standard population. Temporal trends were assessed using LOESS smoothing and segmented regression. Adjusted prevalence ratios were estimated using Poisson regression models with population offsets. Between 2015 and 2024, the crude prevalence of BPD was 149.0 per 100,000 infants (95% CI: 146.1-152.0), with similar age-standardized estimates. Prevalence was consistently higher in males and among infants affiliated with the contributive insurance regime. Temporal trends exhibited a non-linear pattern, with a peak around 2019-2020. Pediatric pulmonology follow-up visits increased substantially over time, whereas the use of advanced diagnostic testing remained limited. BPD represents a substantial and evolving population-level burden in Colombia. Routinely collected administrative healthcare data offer a scalable and pragmatic approach for disease surveillance and health system planning in settings lacking national neonatal registries.
Apart from the counter-regulation of angiotensin II levels in the renin-angiotensin system, angiotensin-converting enzyme 2 (ACE2) acts as a receptor for SARS-CoV-2, which is activated by transmembrane serine protease 2 (TMPRSS2) in target cells. Sirtuin 1 (SIRT1), an aging-related protein, controls ACE2 transcription in energy stress situations. This study aimed to evaluate the protein expression of ACE2, TMPRSS2, and SIRT1 in the lungs of children, adults, and elderly individuals. We used immunohistochemistry and software-assisted analysis to evaluate ACE2, TMPRSS2, and SIRT1 protein expression in autopsied lung tissue with minimal histological abnormalities and no clinical diagnosis of pulmonary disease or infection. The study population included 25 children (newborn to 19-year-old), 7 adults (20- to 59-year-old), and 11 elderly individuals (60- to 95-year-old). Of those 43 patients, 19 were female and 24 were male. ACE2, TMPRSS2, and SIRT1 proteins were more expressed in the pulmonary parenchyma of children than in that of adults (p = 0.043, p = 0.008, and p = 0.032, respectively). SIRT1 expression was higher in the alveoli of children than in those of elderly patients (p = 0.008). No sex-based differences were observed. Spearman's correlation coefficient showed that ACE2, TMPRSS2, and SIRT1 expression decreased with aging. ACE2, TMPRSS2, and SIRT1 were more expressed in the lung parenchyma (but not in the airways) of children than in that of older individuals. This could contribute to less severe COVID-19 lung disease in children.
Occupational therapists are skilled in facilitating participation in activities of daily living and in evaluating and treating sensory integration problems that interfere with engagement in everyday activities. The Toileting Habit Profile Questionnaire (THPQ) was developed to assess sensory issues impacting toileting participation in children. The aim of this study was to examine the preliminary reliability (internal consistency) and validity (known-groups discrimination) of the THPQ-R2, an expanded version of the THPQ. We adopted a descriptive survey methodology in which parents of three- to six-year-old children with and without functional defecation disorders (FDD) completed the THPQ-R2. The hyper-reactivity subscale demonstrated acceptable internal consistency, with a Cronbach's alpha of .755. The internal consistency analysis of the hypo-reactivity/poor perception subscale yielded Cronbach's alpha of 0.616. Children without FDD had significantly higher scores (less problems) on the hyper-reactivity subscale (M = 29.22, SD = 1.22) compared to children with FDD (M = 26.36, SD = 1.70). The scores on the hypo-reactivity/poor perception subscale of children without FDD (M = 19.08, SD = 1.30) were significantly higher (less problems) than those of children with FDD (M = 17.72, SD = 1.70). Our findings provide preliminary support for both the internal consistency and construct validity of the THPQ-R2.