Pediatric gigantism associated with somatotropinomas is exceedingly rare. Although transsphenoidal surgery (TSS) constitutes first-line management, tumor recurrence is common. However, it remains unclear how surgical cure rates differ between transsphenoidal microsurgery (TMS) and the more contemporary endoscopic endonasal approach (EEA). Three children with somatotropinoma-induced gigantism who underwent EEA between December 2010 and October 2021 were identified via retrospective chart review. Primary outcomes collected included complications, length of stay (LOS), and rates of postoperative biochemical remission according to the 2010 Acromegaly Consensus Group criteria. A literature review compiled surgical cure rates for pediatric gigantism, stratified by TSS technique (TMS vs EEA). Three children (2F, 1 M) presented with clinical signs of gigantism at an average age of 12 years [range: 10-14y]. Two patients failed prior somatostatin analogue therapy and one underwent attempted but incomplete EEA at an outside institution. Mean tumor diameter was 0.9 ± 0.2 cm. EEA was performed without complications and a mean LOS of 4.6 days [range: 3-7d]. Biochemical remission was achieved in all patients without adjuvant therapy during follow-up [range: 1-11y]. Nineteen historical studies report surgical outcomes for 325 total pediatric patients with gigantism. Overall surgical cure rates are estimated at 24.7% (73/296). Of these, 17 studies distinguished between transsphenoidal approaches, reporting surgical cure rates of 20.5% (54/264) with TMS and 66.7% (6/9) for EEA. Rates of hypopituitarism/diabetes insipidus were notably higher in TMS compared with EEA patients (31.1% vs 6.8%). Pediatric gigantism is a rare clinical entity associated with historically low surgical cure rates. Literature review indicates that EEA is associated with higher cure rates, which is further supported by our small series in which all patients were cured. The surgical cure rate for gigantism may be higher in the contemporary endoscopic era and merits further study with larger populations of patients.
Kidney transplant is the preferred treatment for end-stage renal disease in children due to superior effects on survival, growth, and quality of life versus dialysis. However, childhood kidney transplant presents unique challenges for long-term social, academic, and professional integration as recipients transition into adulthood. We assessed the educational attainment, employment status, and marital outcomes of an adult cohort of childhood kidney transplant recipients. We retrospectively reviewed all pediatric kidney transplants at Başkent University Hospital from January 2015 through December 2024. Eligibility was defined as a renal graft before the age of 18 years with subsequent follow-up into adulthood. Data were collected via a structured, voluntary questionnaire administered during telephone interviews, which captured academic qualifications, employment status, marital status, posttransplant caregiver arrangements, and demographic information of patients' parents, including education and employment. We included 98 patients (mean age, 25.98 ±5.58 years; mean age at transplant, 14.12 ± 3.83 years), comprising 53 male (54.1%) and 45 female participants (45.9% ). Living-related donors were predominant. Regarding the recipients' parents, maternal education was predominantly low, and 82.7% of the maternal parents were homemakers. Paternal parents demonstrated higher employment rates (n = 47; 48.0% ) and more varied educational attainment. Educational attainment revealed that 48 patients (49.0% ) completed high school, 15 (15.3% ) attended university, and 9 (9.2% ) earned a bachelor-level degree. Employment status was reported by 47 recipients (47.9% ), with 48 (46.9% ) unemployed and 3 (3.1% ) employed part time. Seventeen participants (17.3% ) were married with at least 1 child. Pediatric kidney transplant recipients encounter substantial future challenges in social and professional integration as they progress through adulthood. Our cohort demonstrated moderate educational achievement and employment rates, and most were unmarried. Our findings emphasize the importance of long-term multidisciplinary support to promote successful transitions into adulthood, addressing not only medical needs but also social and occupational needs.
Diarrhea often occurs in pediatric kidney transplant recipients and can result from infectious or noninfectious causes. Identifying underlying issues can allow for proper management and prevent complications such as dehydration, graft dysfunction, and prolonged hospital stay. We retrospectively evaluated stool samples of 204 pediatric kidney transplant recipients seen at the Başkent University Hospital with complaint of diarrhea. Direct microscoping evaluation, bacterial cultures, and viral antigen testing for rotavirus and adenovirus were performed. Presence of cytomegalovirus and Clostridium difficile were evaluated in selected patients. In 18 patients, a comprehensive viral panel was performed based on clinical suspicion. One patient each showed Shigella species and enteropathogenic Escherichia coli. Candida species was isolated in 1 sample. Rotavirus was detected in 4 patients, adenovirus in 2 patients, and Clostridium difficile toxin in 0 patients. Among the 18 patients who underwent detailed panel testing, norovirus was detected in 2 patients and sapovirus in 1 patient. Forty -seven stool culture samples showed reduced or absent normal intestinal flora, suggesting possible intestinal dysbiosis. Entamoeba was detected in 7 patients. Cytomegalovirus was positive in 24 of 204 patients (11 % ). On direct microscopic examination, 19 patients showed minimal findings, and 24 patients had moderate findings. Fourteen patients had high numbers of leukocytes and erythrocytes in their stool. Because amebic colitis and Clostridium difficile infection could not be excluded, patients with moderate to severe findings were treated with metronidazole. Among pediatric kidney transplant patients with diarrhea, the rate of intestinal pathogens was slow but reduced normal flora in stool cultures was common, indicating microbiota -related etiologies. The high rate of cytomegalovirus infection among patients suggested that cytomegalovirus infection should be considered as a potential etiological factor in pediatric transplant patients presenting with diarrhea. Noninfectious causes should also be considered in differential diagnosis of diarrhea in solid -organ transplant recipients.
Adolescent depression is heterogeneous, yet many studies rely on aggregate symptom scores that may obscure meaningful differences in symptom presentation. Latent class analysis (LCA) offers a person-centered approach for identifying symptom subgroups, but few studies have examined depressive symptom classes longitudinally with attention to social determinants of health (SDoH). This study identified depressive symptom classes among youth with depression and/or suicidality, examined demographic, clinical, and socio-ecological correlates of class membership, and evaluated changes in psychological outcomes over 6 months. Participants were 1,825 youth ages 8-20 years who screened positive for depression, endorsed suicidal thoughts or behaviors, or were receiving treatment for depression. Baseline Patient Health Questionnaire for Adolescents (PHQ-A) item responses were used to identify latent classes of depressive symptoms. Associations between class membership and sociodemographic characteristics, trauma exposure, health-related social needs, treatment barriers, anxiety, suicidality and resilience were examined using chi-square tests and analyses of variance. Mixed-effect models evaluated changes in clinical symptoms and resilience across 6 months of follow-up. A five-class solution was identified: Somatic Symptoms (15.6%), No Symptoms (12.4%), Mild Symptoms (20.5%), Moderate Symptoms (27.8%), and High Symptoms (23.5%). Classes differed significantly by sex, trauma exposure, interpersonal safety concerns, treatment barriers, anxiety severity, suicidality, and resilience. In contrast, household income and basic resource insecurities did not differ significantly across classes. Longitudinally, depressive symptoms, anxiety, and suicidality showed significant time-by-class interactions; however, within- and between-class effect sizes were generally small. Resilience did not exhibit differential changes across classes. Depressive symptom classes among youth with depression or suicidality demonstrate distinct clinical and socio-ecological profiles, highlighting meaningful heterogeneity beyond symptom severity alone. Person-centered approaches may improve characterization of adolescent depression and inform more tailored assessment and intervention strategies. Future longitudinal research should examine the stability of these classes and predictors of transitions between symptom classes.
Permanent hypoparathyroidism is a lifelong condition and characterized by chronic hypocalcemia and dependence on calcium and active vitamin D therapy. Parathyroid cell transplantation has emerged as a potential restorative treatment, yet standardized tools for assessment of posttransplant recovery are lacking. This study aimed to evaluate clinical recovery following parathyroid cell transplant using a novel functional scoring system. This retrospective, single -center (in Istanbul, Türkiye ), longitudinal study included 40 consecutive parathyroid cell transplants performed between 2019 and 2024 in patients with permanent hypoparathyroidism. A 5 -level recovery scoring system (score 0 to 4 ) integrating serum calcium levels, medication requirements, and hypocalcemia -related symptoms was developed to assess outcomes. Patients were followed for up to 4 years. Clinically meaningful recovery was defined as score ≥3, corresponding to a ≥50 % reduction in calcium and/or active vitamin D supplementation. Recovery scores improved progressively over time posttransplant. Most patients demonstrated early biochemical benefit within the first 2 months, followed by stabilization and sustained improvement. By 6 months, a substantial proportion achieved clinically meaningful recovery (score ≥3 ), characterized by marked reduction in supplementation requirements and symptomatic improvement. A limited subset of patients achieved score 4, indicating complete independence from replacement therapy. Serum calcium levels showed a significant time -dependent increase, although interindividual variability in response persisted. Parathyroid cell transplant can provide sustained functional improvement in patients with permanent hypoparathyroidism. The proposed recovery scoring system offers a practical, clinically meaningful tool that integrates biochemical parameters, medication dependence, and symptoms, enabling standardized monitoring of posttransplant outcomes. This approach may facilitate long -term treatment management strategies for this challenging disease.
Organ transplant is the surgical process of removing an organ that cannot fulfill its function despite medical treatment and transplanting the corresponding organ from a donor to a recipient. Our study examined whether demographic variables such as sex, age, education status, or socioeconomic status and psychosocial variables including sensory processing sensitivity, attachment style, resilience, social support, and neuroticism predict depression, anxiety, and stress levels of living donors in the preoperative stage. Data were collected from potential organ donors aged 18 to 60 years who voluntarily applied to the Ankara Bilkent City Hospital Organ Donation and Transplantation Center Unit. A total of 69 participants (21 kidney, 48 liver ) were included in the analyses. According to the results, sex was the only demographic variable that significantly correlated with depression, anxiety, and stress, showing that female donors feel more depression, anxiety, and stress than male donors. According to regression analyses, the model including sex and other psychosocial variables was significant and explained 37 % of the variance for depression. Higher levels of resilience were linked with lower levels of depression. For anxiety, similarly, the model including sex and other psychosocial variables was significant and explained 33 % of the variance, that is, a higher level of resilience was associated with less anxiety. For stress, the model including sex and other psychosocial variables was significant and explained 40 % of the variance. In addition to resilience, which significantly predicted anxiety, neuroticism was a marginally significant predictor, that is, high resilience and low neuroticism predicted lower levels of anxiety. The findings emphasize the importance of interventions to increase the psychological resilience of potential organ donors and show that psychological support, especially for female donors and donors with high levels of neuroticism, can improve the process.
Therapeutic plasma exchange has become an increasingly important extracorporeal therapy in pediatric intensive care and transplant settings. However, evaluations in large real-world pediatric cohorts of its effectiveness and safety across multiple indications remain limited. In this 5 -year single -center study, we provided our experience with therapeutic plasma exchange in critically ill children and assessed clinical outcomes, indications, and procedure -related complications. This retrospective observational study included 88 pediatric patients who underwent 702 therapeutic plasma exchange sessions in the pediatric transplant and nephrology intensive care unit of Başkent University Hospital (Ankara, Turkey) between December 2018 and December 2023. Indications were classified according to new American Society for Apheresis categories. We analyzed demographic data, indications, replacement fluids, treatment response, and adverse events. Median age of the 88 pediatric patients who underwent 702 therapeutic plasma exchange sessions was 7.5 years (range, 0 -18 y ), and 52.3 % of patients were male. Fresh frozen plasma was used in 89.8 % of sessions and albumin in 23.9 %. The most frequent indications for therapeutic plasma exchange were posttransplant hepatic dysfunction (36.4 % ) and acute or chronic liver failure (28.4 % ), followed by antibody -mediated renal disease (13.6 % ) and multiorgan failure or sepsis (8 % ). Overall, 73 of 88 patients achieved complete or partial improvement, corresponding to a favorable response rate of 82.9 %. Renal transplant-related indications demonstrated higher response rates compared with liver -related conditions (91 % vs 78.9 % ). No life-threatening or procedure -terminating complications occurred; minor adverse events included hypotension, fever, allergic reactions, and thrombosis. Therapeutic plasma exchange is a safe and effective supportive therapy for critically ill pediatric patients across a wide range of indications. When performed in experienced centers with close monitoring, complication rates are low. Multicenter prospective studies are needed to establish standardized protocols and further clarify disease-specific outcomes.
Quantitative neuromuscular monitoring in children remains challenging, particularly in weight and age categories without equipment certification. The study compared the precision of kinemyography and electromyography in children <5 yr of age. Sixty-four children were stratified into neonates (≤44 weeks postmenstrual age), infants (44-58 weeks postmenstrual age), toddlers (>58 weeks postmenstrual age to ≤2 yr), and children (2-5 yr). Kinemyography and electromyography were applied to contralateral arms. Primary endpoints were precision of train-of-four ratios before rocuronium administration and after assumed complete recovery (i.e. after sugammadex administration). Precision was quantified using the repeatability coefficient, indicating the range within which a repeated train-of-four ratio is with 95% probability. A low repeatability coefficient indicates high precision. Median repeatability coefficients were 0.06 [IQR 0.03-0.10] for kinemyography and 0.06 [0.05-0.09] for electromyography (median difference 0.00 [95% confidence interval, CI -0.01 to 0.01]) at baseline and 0.04 [0.02-0.07] and 0.04 [0.03-0.06] after recovery (median difference 0.00 [-0.01 to 0.01]). Kinemyography precision was worse in non-certified use (<5 kg: 0.08 [0.05-0.11], ≥5 kg: 0.04 [0.02-0.06]; median difference 0.04 [0.02-0.05]), whereas electromyography performed similarly regardless of its certification (neonates 0.05 [0.03-0.11], others 0.06 [0.03-0.09]; median difference -0.01 [-0.04 to 0.05]). Train-of-four ratios <0.9 were more frequent in kinemyography than in electromyography (33% vs 16%, P<0.05). Neither kinemyography nor electromyography was inferior to the other in terms of precision. Unlike kinemyography, electromyography remained precise even when applied below recommended age or weight limits. The importance of baseline values before rocuronium is underlined by the frequently measured train-of-four ratios of <0.9. ClinicalTrials.gov; NCT06062290 (registered August 15th, 2023).
Adverse childhood experiences have been consistently linked to a range of mental health related difficulties in adulthood. One such experience is bullying, which has been shown to predict psychotic symptoms. This study aimed to explore whether bullying victimisation in early adolescence is associated with certain mental health outcomes (psychosis, depression and cannabis abuse) and whether this is mediated by the individuals' perception of social support from peers and family. This study performed secondary data analysis of a prospective cohort study, the Belfast Youth Development Study (BYDS). It used longitudinal data from 2087 participants from ages 12-21 years and performed path analysis (using Mplus V8) between bullying and the above mental health outcomes and mediators. The results showed a direct path from bullying to psychotic symptoms (estimate = 0.10; SE = 0.0; p = 0.030) as well as an indirect path mediated by peer attachment, parental attachment and depression symptoms (estimate = 0.01; bootstrapped 95% CIs 0.01, 0.02). Being bullied in childhood is directly associated with a greater risk of having psychotic symptoms as an adult. There is also an indirect path from bullying in childhood to psychosis symptoms as an adult mediated by peer attachment, parental attachment, and depression. Interventions should be aimed at addressing bullying and strengthening social support from peers and family.
The aim of this study was to investigate the extent of involvement of physical therapists in employment support for patients with cancer, types of support they provide in practice and attributes of the patients they support. This is a nationwide e-survey in Japan. A questionnaire was sent to 385 facilities of physical therapists affiliated with academic societies in Japan to investigate the status of involvement of physical therapists in employment support for patients with cancer. The attributes of the patients they support were surveyed. Responses were received from 105 of 385 facilities (27.3%). Employment support by physical therapists was implemented in 46 facilities (43.8% of responding facilities). Among the types of support provided, physical interventions were the most common (46 facilities), followed by psychoeducational interventions (7 facilities) and vocational interventions (5 facilities). Regarding the attributes of the patients, the proportion of adolescent and young adult patients with cancer receiving physical interventions in designated cancer care hospitals was significantly higher. Additionally, the barriers to physical therapist involvement in employment support for patients with cancer were staff shortages and the absence of a dedicated department. Only approximately 40% of Japanese physical therapists were involved in employment support among patients with cancer, centred on physical interventions. The further expansion of employment support provided by physical therapists in Japan is necessary.
This study aimed to investigate the relationship between body composition parameters and serum irisin and FABP4 levels in adolescent girls with polycystic ovary syndrome (PCOS). A total of 123 participants (54 with PCOS and 69 controls) were included in this cross-sectional study. Biochemical and hormonal parameters were assessed, and body composition was evaluated using bioelectrical impedance analysis (BIA). Multivariable logistic regression analysis was performed to identify factors associated with PCOS. Compared with controls, the PCOS group showed significantly higher levels of total testosterone and luteinizing hormone. Muscle mass index was also higher in the PCOS group, whereas other body composition parameters did not differ significantly between groups. In multivariable logistic regression analysis, total testosterone and Luteinizing hormone emerged as independent predictor of PCOS (OR = 1.089, 95% CI: 1.050-1.128, p < 0.001), (OR = 1.084, 95% CI: 1.003-1.172, p = 0.041) relatively. While BMI Serum irisin and FABP4 was not independently associated with PCOS. In adolescent PCOS, hyperandrogenemia, particularly total testosterone, remains the strongest independent correlate of disease status. In contrast, circulating irisin and FABP4 do not appear to provide additional independent discriminatory value. These findings should be interpreted within the limitations of a cross-sectional design, and further prospective studies are warranted. Not applicable.
From the perspective of behavioural psychology and adolescent psychopathology, non-suicidal self-harm (NSSI) among adolescents is a multidetermined behaviour shaped by biological, psychological and social factors. Digital mental health interventions are vital for adolescent self-harm support, yet their acceptance among self-harming adolescents is low with significant avoidance tendencies. Existing research focuses on technical attributes of these tools but rarely explores the psychological motivations and contextual factors driving avoidance in this group, and few studies interpret such avoidance behaviour under a unified biopsychosocial framework. A grounded theory approach was adopted, complying with the COREQ criteria. Semi-structured interviews were conducted with 21 emotionally stable adolescents aged 12-18 years who had engaged in NSSI in the past year, recruited from a tertiary hospital emergency department. Data were analysed via open, axial and selective coding with ethical approval obtained. Guided by the biopsychosocial behavioural framework, this study identified that adolescents' avoidance of digital psychological interventions is a comprehensive outcome of interactions among biological traits, psychological mechanisms and social contextual factors. Three core psychological pathways driving avoidance were extracted: emotional avoidance, trust deficit and feelings of ineffectiveness and frustration. Physiological stress responses linked to shame and anxiety (biological dimension) amplified these psychological barriers, while situational social factors moderated the entire behavioural process. Adolescents' avoidance of digital interventions is a layered, dynamic, multidetermined behavioural phenomenon embedded in the Chinese cultural context, which can be systematically interpreted via the biopsychosocial behavioural framework covering biological traits, individual psychology, interpersonal and ecological social factors. Future digital tools require trauma-informed, context-adaptive design to reduce emotional triggers, enhance user control, strengthen privacy protection and rebuild trust, thereby improving acceptability and effectiveness.
HIV/AIDS has posed continuous public health challenges for decades, impacting both physical health and socioeconomic development in sub-Saharan Africa, particularly among key populations like men who have sex with men (MSM). This study aims to determine the key factors associated with the prevalence and willingness to take HIV services among MSM in a Northern Nigeria state. The study used a cross-sectional survey of MSM in three local government areas in Kano state. HIV prevalence was measured with self-test kits, and willingness to use services was assessed via a 17-item questionnaire. Snowball sampling was used, with data collected by trained assistants and community leaders. Data were analysed using bivariate and multivariate logistic regression in IBM SPSS V.28.0. HIV prevalence was 12.3%; MSM in Fagge (adjusted OR (AOR) 4.173; 95% CI 1.193 to 14.595, p=0.025), those not abusing drugs (AOR 5.969; 95% CI 2.412 to 14.770, p<0.001) and those engaging in vaginal sex in the last 3 months (AOR 4.140; 95% CI (1.402 to 12.224), p=0.010) had higher odds to contract HIV. The major reason for taking HIV tests was to know their status (84.0%), while the major obstacle stopping them from assessing HIV services was stigmatisation by providers (25.1%). Similarly, willingness to uptake HIV services was 47.4%; MSM in Tarauni (AOR 92.453, 95% CI 30.541 to 279.876, p<0.001), those who inject drugs (AOR 3.592, 95% CI 1.207 to 10.695, p=0.030), engage in anal sex (AOR 0.075, 95% CI 0.051 to 0.302, p<0.001) and use condoms regularly (AOR 2.731, 95% CI 1.279 to 5.829, p=0.009) had higher odds of accessing HIV services. This study emphasises the critical need to address barriers and improve HIV prevention and treatment services for MSM in northern states of Nigeria.
The hypothalamus comprises histologically and functionally distinct subunits critical to major depressive disorder (MDD) pathology; however, its localized neuroanatomical alterations in affected adolescents remain poorly understood. This study aimed to investigated volumetric changes in hypothalamic subunits among drug-naïve adolescents with MDD and explored their associations with clinical symptoms and sleep quality. High-resolution 3D T1-weighted MRI data from 83 drug-naïve adolescents with MDD and 59 matched healthy controls (HCs) were preprocessed and segmented into five bilateral subunits using FreeSurfer software. We investigated volumetric alterations in hypothalamic subunits and examined whether and how these structural changes accounted for the relationships between depressive severity and sleep quality. Adolescents with MDD showed significantly smaller volumes in the left anterior-inferior subunit (a-iHyp) and larger volumes in the right inferior tubular subunit compared to HCs. The volumes of the left a-iHyp were significantly negatively correlated with both sleep quality and depressive severity in adolescents with MDD. Furthermore, exploratory analysis indicated that the volumes of the left a-iHyp partially accounted for the associations between depressive severity and sleep quality. Additionally, the volumes of the left infTub were significantly negatively correlated with cognitive impairment scores in adolescents with MDD. These findings provide new insights into distinct hypothalamic subunit alterations in adolescents with MDD, and these insights enhance our understanding of the associations between subunit-level hypothalamic alterations and clinical symptoms in this clinical population.
Traumatic experiences in early childhood trauma are increasingly recognized as a major public health concern, with infants and toddlers particularly vulnerable because of their rapidly developing brains. Repeated or prolonged exposure to trauma is shown to disrupt neurodevelopment, particularly in brain regions responsible for emotion regulation, executive functioning, stress-response processing, and memory. While it is well established that early childhood trauma negatively impacts social, emotional, and cognitive development, growing evidence demonstrates that early trauma also contributes to long term physical health challenges. In young children, trauma frequently manifests through physiological and bodily symptoms due to their limited capacity to communicate psychological distress. As a result, trauma may present as heightened arousal, somatic issues, sleep disturbances, and feeding difficulties. These concerns are commonly encountered in pediatric healthcare settings, though they may be overlooked or misattributed because of their overlap with other medical conditions. Early childhood represents a critical time for identification and intervention. Pediatric providers are uniquely positioned to identify these early physiological signs of trauma in young children because of their frequent touch points with families. A greater understanding of the manifestations of early trauma in health is needed to improve diagnostic accuracy and promote early intervention. In this paper, we review the effects of early trauma on the physical health of infants and toddlers, highlighting the critical role of pediatric providers in early identification and the integration of trauma-informed care within pediatric settings.
Clozapine was (1) first introduced in Austria and Switzerland in 1972, (2) associated with 8 Finnish deaths due to agranulocytosis in 1975 (almost leading to its withdrawal), and (3) approved in the United States (US) for treatment-resistant schizophrenia in 1989 (resulting in a worldwide resurrection). This article reviews the 1960s/1970s trials published in German that brought about the first approval of clozapine; they are not included in PubMed and received no attention in previous historical articles. Prior historical manuscripts and the references of identified articles provide us with 13 early trials published in German. The first was unsuccessful. Randomization, double-blindness, and control antipsychotic agents were used in 1 of 10 single-center trials and a multicenter trial. Most trials focused on schizophrenia. The efficacy of clozapine in (1) mania was proposed by Angst in the Swiss trials, and (2) aggression across psychiatric diagnoses by an Austrian trial. These trials did not discuss titrations; a study by Blum and Mauruschat focused on physiological changes and first identified fever in the absence of infection during clozapine titrations (called benign hyperthermia in the US). These limited early trials leading to the introduction of clozapine in the 1970s in German-speaking countries produced many unresolved issues. Our discussion reviews the most important aspects that were clarified but not completely resolved in later years, including (1) risk of agranulocytosis, (2) titration and dosing, and (3) indications. Further clarifications and advances are limited by the lack of funding, as clozapine is a generic drug.
Fragile X syndrome (FXS), the leading genetic cause of intellectual disability, arises from FMR1 gene silencing and the subsequent loss of the RNA-binding protein FMRP. N6-methyladenosine (m6A) is a prevalent mRNA modification essential for post-transcriptional regulation. FMRP binds and regulates the stability of m6A-containing transcripts. However, how FMRP deficiency impacts transcriptome-wide m6A modifications in FXS remains unknown. To address this, we generated cortical neurons from induced pluripotent stem cells (iPSCs) derived from healthy individuals and FXS patients. Electrophysiology recordings revealed synaptic and neuronal network defects in FXS iPSC-derived neurons. Transcriptome-wide analysis revealed striking m6A hypermethylation predominantly affecting synapse-associated transcripts. Mechanistically, we demonstrated that FMRP deficiency drives the aberrant translational upregulation of core m6A writers, a causal relationship definitively validated using CGG-corrected isogenic control lines. Targeted genetic knockdown of the m6A writer METTL3 successfully rescued synaptic phenotypes in FXS neurons, whereas its overexpression in control neurons phenocopied these synaptic defects, confirming the causal role of m6A dysregulation in FXS pathology. Notably, pharmacological intervention with the METTL3 inhibitor STM-2457 normalized methylation on synapse-associated transcripts and restored synaptic transmission in FXS neurons. Together, our findings uncover an FMRP-dependent epitranscriptomic mechanism contributing to FXS pathogenesis and suggest a promising avenue for m6A-targeted therapies.
De novo donor -specific antibodies are recognized mediators of alloimmune injury after kidney transplant, yet their clinical significance in pediatric recipients remains incompletely defined. We evaluated the incidence of de novo donor -specific antibodies and the associated rejection patterns and graft outcomes in a pediatric kidney transplant cohort. This retrospective single -center study included pediatric kidney transplant recipients who underwent transplants between 2009 and June 2024. Donor -specific antibody positivity was determined using Luminex -based assays (mean fluorescence intensity >1000 ). Clinical, immunologic, and functional outcomes were compared between patients positive for donor -specific antibodies and patients negative for donor -specific antibodies, including rejection phenotype, estimated glomerular filtration rate, graft loss, and duration of follow -up. Among 78 recipients, 15 recipients (19.2 % ) developed de novo donor -specific antibodies during a mean follow -up of approximately 4 years. Acute rejection occurred more frequently in patients positive for donor -specific antibodies versus patients negative for donor -specific antibodies (80 % vs 32 %, respectively; P = .053 ), predominantly antibody -mediated or mixed phenotypes. Graft loss rates were comparable between groups (13.3 % vs 14.2 %; P = 1.000 ). Although not statistically significant, recipients positive for donor -specific antibodies demonstrated numerically lower eGFR values at 1 year and at last follow -up (49.6 ± 22.2 vs 57.1 ± 29.8 mL /min /1.73 m ² at last visit, respectively; P - .445 ). In this pediatric cohort, de novo development of donor -specific antibodies was associated with a higher tendency toward antibody -mediated rejection, without a significant difference in short -term to mid -term graft survival. Continued surveillance of donor -specific antibodies and longer follow -up are warranted to clarify the long -term clinical effect of donor -specific antibodies in pediatric kidney transplants.
Primary pelvic bone sarcomas are rare and their treatment remains complex, with reconstruction after resection remaining controversial due to high complication and revision rates. Both prosthetic and non-prosthetic reconstructions carry risks including infection, implant failure, wound problems, and reoperation. The aim of this study was to review the changes in the management of these patients over the 20-year period between 2003 and 2023. This was a retrospective cohort study including 479 patients who underwent surgery for a primary pelvic sarcoma during this time, divided into a historical (2003 to 2012) and a modern (2013 to 2023) group. Postoperative complications and the rates of return to theatre (RTT) were compared, and factors associated with improved outcomes were analyzed. Early RTT within six weeks decreased significantly from 22% in the historical cohort (n = 38) to 14% in the modern cohort (n = 42; p = 0.021). Historically, the ilioinguinal incision was associated with a 44% early rate of RTT (n = 8), compared with 10% when using the question mark incision in the modern cohort (n = 10). In the modern cohort, the rate of early RTT was similar between those with prosthetic (17%; n = 13) and non-prosthetic reconstructions (13%; n = 29) (p = 0.344), although the long-term rate of RTT remained significantly higher in the prosthetic group (p = 0.007). These findings show a clear reduction in complications and rates of RTT following pelvic resection and reconstruction for patients with a primary pelvic bone sarcoma. Although no single factor can fully account for this improvement, it probably reflects a progressive refinement of surgical strategy combined with both technical and organizational advances. These were due to changes in surgical approach and an increased use of navigation and patient-specific implants, improved preoperative imaging and planning, and a more precise understanding of oncological margins and pelvic biomechanics. The centralization of care has also not only concentrated cases into high-volume centres but has encouraged further sub-specialization within these centres, allowing cumulative expertise to develop among a limited number of highly experienced surgeons. Ongoing refinement of surgical technique leading to fewer revisions due to reduced early complications and dislocations, supported by multidisciplinary decision-making, will remain key to achieving further progress.
Joubert syndrome is a rare ciliopathy in which kidney disease can quietly progress to end -stage kidney disease, often in children and young adults. For these patients and their families, kidney transplant is a turning point, yet published experience remains limited. Here, we share our center's experience with kidney transplant in 5 patients with Joubert syndrome who progressed to end -stage kidney disease, highlighting medical outcomes and practical challenges. We conducted a retrospective case series of 5 patients with Joubert syndrome and end -stage kidney disease who received kidney transplants at our center. We reviewed medical records for demographic data, neurological and extrarenal features, renal course, transplant details, immunosuppression, complications, and long -term graft and patient outcomes. The cohort included 3 male and 2 female patients who received transplants between 12 and 40 years of age. Two patients had genetically confirmed Joubert syndrome, and 3 patients had a clinical diagnosis. Nephronophthisis was the documented cause of end -stage kidney disease in 2 children, whereas 3 patients had end -stage kidney disease attributed to Joubert syndrome without further histology classification. All patients received calcineurin inhibitor -based triple immunosuppression. Delayed graft function occurred in all 5 recipients. Two patients developed biopsy -proven T -cell -mediated acute rejection, successfully treated with pulse steroids. At last follow -up, 3 patients were alive with functional grafts, 1 patient was alive on dialysis after graft loss due to chronic pyelonephritis, and 1 patient died from severe infection with a functional graft. Kidney transplant is feasible and generally effective in patients with Joubert syndrome, offering durable renal replacement in most cases. However, the universal occurrence of delayed graft function and the effect of infectious complications, which led to 1 graft loss and 1 death, emphasize the need for careful perioperative management, urological assessment, and close long -term follow -up within a multidisciplinary framework.