Psychological well-being of children and adolescents with inflammatory bowel disease.

OBJECTIVES: Prior studies on the psychological well-being in pediatric inflammatory bowel disease (PIBD) have reported controversial results. Our aim was to compare the psychological well-being and lifestyle factors in patients with PIBD and their controls and to assess the role of contributing disease characteristics. METHODS: This cross-sectional study included 60 PIBD patients aged 6-17 years (26 with Crohn's disease [CD], 34 with ulcerative colitis [UC] or unclassified colitis [IBD-U]) from two university hospitals in Finland, and their age- and sex-matched healthy controls. Psychological well-being was assessed with three measures: a questionnaire on overall psychological well-being (PSWB) and for adolescents also Beck Depression Inventory (BDI Ia) and Perceived Stress Scale (PSS). In addition to disease characteristics and pain, we assessed physical activity, sleep, screen time, and social well-being. RESULTS: Controls were more likely of stressing more (odds ratio [OR] = 3.67, 95% confidence interval [95% CI] 95% CI = 1.02-13.14), but other measures of psychological well-being did not differ statistically significantly between patients and controls. In CD, a clinically more active disease associated with inferior psychological well-being in adolescents (BDI [ρ = 0.63, p = 0.021], PSS [ρ = 0.70, p = 0.008], PSWB [ρ = 0.56, p = 0.049]). Longer time from diagnosis correlated with better psychological well-being on BDI (ρ = -0.39, p = 0.024) and PSS (ρ = -0.38, p = 0.034). Lifestyle was more sedentary in PIBD (less physical activity in children OR = 0.82, 95% CI = 0.68-0.99 and more screen time in adolescents OR = 1.18, 95% CI = 1.00-1.40). CONCLUSION: Although the clinical features of PIBD are potentially a burden for psychological well-being, many young patients cope well with their disease. Individual variation in well-being is remarkable, making supportive measures challenging.

Increased adiposity in juvenile idiopathic arthritis - A comparison of the bioelectrical impedance analysis and dual-energy X-ray absorptiometry for the assessment of body composition.

AIM: Higher adiposity and increased risk of cardiovascular diseases have been reported in juvenile idiopathic arthritis (JIA), but body composition measurements have produced inconsistent results. This controlled cross-sectional study assessed body composition with two methods to evaluate adiposity in children with JIA. METHODS: We measured body composition by dual- energy X-ray absorptiometry (DXA) and bioelectrical impedance analysis (BIA) from 79 JIA-patients in two Finish university hospitals in 2017-2019. Their age- and sex-matched controls (n = 79) were selected from the Physical Activity and Nutrition in Children- study and through National Registry. RESULTS: Body fat percentage measured by BIA was higher (mean, SD) in patients compared to controls (23.1 ± 9.3% vs. 20.1 ± 7.5%, p = 0.047). Also, using DXA, there was a tendency of higher body fat percentage in patients (27.1 ± 9.1% vs. 24.6 ± 8.6, p = 0.106). BIA and DXA showed strong correlation (r from 0.810 to 0.977) in all body composition variables. CONCLUSION: Increased adiposity was observed in patients with JIA. Evaluation of body composition should be included in the multidisciplinary care of JIA to reduce the possible risk of cardiovascular diseases in adulthood. BIA could be a useful tool for assessing body composition due to its clinical availability and safety.

Early disc degeneration in radiotherapy-treated childhood brain tumor survivors.

BACKGROUND: Childhood brain tumor (BT) survivors have an increased risk of treatment-related late effects, which can reduce health-related quality of life and increase morbidity. This study aimed to investigate lumbar disc degeneration in magnetic resonance imaging (MRI) in adult survivors of radiotherapy-treated childhood BT compared to age and sex-matched population controls. METHODS: In this cross-sectional comparative study, 127 survivors were identified from hospital registries. After a mean follow-up of 20.7 years (range 5-33.1), 67 survivors (mean age 28.4, range 16.2-43.5) were investigated with MRI and compared to 75 sex-matched population-based controls. Evaluated MRI phenotypes included Pfirrmann grading, , intervertebral disc protrusions, extrusions, and high-intensity-zone-lesions (HIZ). Groups were also compared for known risk factors of lumbar intervertebral disc (IVD) degeneration. RESULTS: Childhood BT survivors had higher Pfirrmann grades than controls at all lumbar levels (all p < 0.001). Lumbar disc protrusions at L4-5 (p = 0.02) and extrusions at L3-4 (p = 0.04), L4-5 (p = 0.004), and L5-S1 (p = 0.01) were significantly more common in the BT group compared to the control. The survivor cohort also had significantly more HIZ-lesons than the controls (n=13 and n=1, p=0.003). Age at diagnosis was associated with lower degree of IVD degeneration (p < 0.01). Blood pressure correlated with IVD degeneration (P < 0.05). CONCLUSIONS: Signs of early disc degeneration related to tumor treatment can be seen in the IVDs of survivors. Disc degeneration was more severe in children treated in adolescence.

Health-related quality of life in long-term survivors of childhood brain tumors: a population-based cohort study.

PURPOSE: Survivors of childhood brain tumors (BT) are at high risk for long-term physical and psychological sequelae. Still, knowledge about health-related quality of life (HRQL) and associated factors in this population is sparse. This study investigated HRQL and its predictors in long-term survivors of childhood BT. METHODS: Survivors of childhood BT (mean age = 28.1 years, SD = 6.8, n = 60) underwent clinical examination and neurocognitive examination, and completed self-rating questionnaires assessing HRQL (RAND-36) and depressive symptoms (Beck Depression Inventory-II). Socio-demographic information was gathered via a questionnaire. Tumor- and treatment-related information was collected from medical records. Control group data were collected from age-matched controls (n = 146) without a history of cancer, randomly selected from the local population registry. Multiple linear regression models were used to investigate predictors of HRQL; separate models were fitted for each domain of the RAND-36. RESULTS: Male survivors (mean age = 27.0, SD = 6.0, n = 39) reported significantly lower HRQL than male controls in the domains of physical functioning, general health, vitality, social functioning, and role limitations-emotional. Female survivors (mean age = 30.2 years, SD = 7.6, n = 21) reported comparable levels as female controls in all domains except physical functioning. A higher burden of late effects, not working/studying, being diagnosed with BT during adolescence, and reporting current depressive symptoms were significant predictors of lower HRQL. CONCLUSION: Our results highlight that male survivors of childhood BT are at particular risk of impaired HRQL. Also, results point to the close relation between symptoms of depression and impaired HRQL in survivors of childhood BT which should be acknowledged by long-term follow-up care.

Long-term outcome of biopsy-proven idiopathic tubulointersitial nephritis with or without uveitis in children-a nationwide follow-up study.

BACKGROUND: Only a few studies reporting the long-term outcome of children with idiopathic tubulointerstitial nephritis (TIN) and uveitis syndrome (TINU) are available. We studied the long-term kidney and ocular outcome in a nationwide cohort of children with TIN or TINU. METHODS: All patients followed up for a minimum of 1 year by a paediatrician and an ophthalmologist were enrolled. The data on plasma creatinine (P-Cr), estimated glomerular filtration rate (eGFR), proteinuria, hypertension and uveitis were collected retrospectively. RESULTS: Fifty-two patients were studied. Median age at time of diagnosis was 13.1 (1.8-16.9) years and median follow-up time was 5.7 (1.1-21.2) years. Forty-five (87%) patients were initially treated with glucocorticoids. The median of the maximum P-Cr was 162 µmol/l (47-1,016) and that of eGFR 47 ml/min/1.73m2 (8-124). Uveitis was diagnosed in 33 patients (63%) and 21 (40%) patients developed chronic uveitis. P-Cr normalised in a median of 2 months. Eleven (21%) patients had nephritis recurrence during or after discontinuation of glucocorticoids. At the latest follow-up, 13 (25%) patients had eGFR < 90 ml/min/1.73m2 (median 83; 61-89 ml/min/1.73m2). Six patients had tubular proteinuria; all presented with TIN without uveitis. Seven (13%) patients were hypertensive. Eleven (21%) patients had uveitis. One patient developed uraemia and was later transplanted. CONCLUSIONS: Our study questions the previously reported good long-term kidney and ocular outcome of patients with TIN/TINU. Decreased kidney function and/or ocular co-morbidities may persist for several years; thus, both kidney and ocular follow-up for at least 1 year is warranted. A higher resolution version of the Graphical abstract is available as Supplementary information.

Hemolytic uremic syndrome caused by Shiga toxin-producing Escherichia coli in children: incidence, risk factors, and clinical outcome.

BACKGROUND: Hemolytic uremic syndrome (HUS) is a multisystemic disease. In a nationwide study, we characterized the incidence, clinical course, and prognosis of HUS caused by Shiga toxin (Stx)-producing Escherichia coli (STEC) strains with emphasis on risk factors, disease severity, and long-term outcome. METHODS: The data on pediatric HUS patients from 2000 to 2016 were collected from the medical records. STEC isolates from fecal cultures of HUS and non-HUS patients were collected from the same time period and characterized by whole genome sequencing analysis. RESULTS: Fifty-eight out of 262 culture-positive cases developed verified (n = 58, 22%) STEC-HUS. Another 29 cases had probable STEC-HUS, the annual incidence of STEC-HUS being 0.5 per 100,000 children. Eleven different serogroups were detected, O157 being the most common (n = 37, 66%). Age under 3 years (OR 2.4), stx2 (OR 9.7), and stx2a (OR 16.6) were found to be risk factors for HUS. Fifty-five patients (63%) needed dialysis. Twenty-nine patients (33%) developed major neurological symptoms. Complete renal recovery was observed in 57 patients after a median 4.0 years of follow-up. Age under 3 years, leukocyte count over 20 × 109/L, and need for dialysis were predictive factors for poor renal outcome. CONCLUSIONS: Age under 3 years, stx2, and stx2a were risk factors for HUS in STEC-positive children. However, serogroup or stx types did not predict the renal outcome or major CNS symptoms.

Methylprednisolone or cyclosporine a in the treatment of Henoch-Schönlein nephritis: a nationwide study.

BACKGROUND: Optimal treatment of Henoch-Schönlein purpura nephritis (HSN) remains unclear. We evaluated outcome of pediatric HSN patients treated initially with either methylprednisolone (MP) or cyclosporine A (CyA) in Finland between 1996 and 2011. METHODS: Outcome of 62 HSN patients was evaluated by screening urine and blood samples (n = 51) or by collecting clinical parameters from medical charts until last follow-up visit (n = 11). Sixty (97%) patients had nephrotic-range proteinuria and/or ISKDC grade ≥ III before initial treatment. Patients were initially treated with either MP pulses (n = 42) followed by oral prednisone or with CyA (n = 20). Fifty-nine (95%) patients received angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers. RESULTS: Mean follow-up time was 10.8 years (range 3.2-21.2 years). One patient developed end-stage renal disease and another had decreased renal function (eGFR < 60 mL/min/1.73m2), both initially treated with MP (3%). Six patients (5 MP, 1 CyA) had eGFR between 60 and 89 mL/min/1.73m2 (10%). Eighteen patients (13 MP, 5 CyA) had proteinuria and/or hematuria (29%) and four of them had proteinuria > 0.5 g/day at end of follow-up. Sixteen (38%) MP-treated and two (10%) CyA-treated patients needed additional immunosuppressive treatment (RR 3.81, 95% CI 1.16-14.3, p = 0.035). Late initiation of treatment was associated with an increased risk for persistent proteinuria. CONCLUSIONS: Long-term outcome was relatively good in both treatment groups. However, since urinary abnormalities may persist or develop, long-term follow-up of HSN patients is mandatory. Early initiation of treatment had a favorable effect on proteinuria.

Early fecal microbiota composition in children who later develop celiac disease and associated autoimmunity.

OBJECTIVES: Several studies have reported that the intestinal microbiota composition of celiac disease (CD) patients differs from healthy individuals. The possible role of gut microbiota in the pathogenesis of the disease is, however, not known. Here, we aimed to assess the possible differences in early fecal microbiota composition between children that later developed CD and healthy controls matched for age, sex and HLA risk genotype. MATERIALS AND METHODS: We used 16S rRNA gene sequencing to examine the fecal microbiota of 27 children with high genetic risk of developing CD. Nine of these children developed the disease by the age of 4 years. Stool samples were collected at the age of 9 and 12 months, before any of the children had developed CD. The fecal microbiota composition of children who later developed the disease was compared with the microbiota of the children who did not have CD or associated autoantibodies at the age of 4 years. Delivery mode, early nutrition, and use of antibiotics were taken into account in the analyses. RESULTS: No statistically significant differences in the fecal microbiota composition were found between children who later developed CD (n = 9) and the control children without disease or associated autoantibodies (n = 18). CONCLUSIONS: Based on our results, the fecal microbiota composition at the age of 9 and 12 months is not associated with the development of CD. Our results, however, do not exclude the possibility of duodenal microbiota changes or a later microbiota-related trigger for the disease.

Bone mineral density is compromised in very long-term survivors of irradiated childhood brain tumor.

INTRODUCTION: The increase in the number of childhood brain tumor survivors warrants detailed research to increase our knowledge regarding the possible physical and psychosocial adverse outcomes of tumor and tumor therapy. The aim of this study was to evaluate the current bone health by measuring the bone mineral density (BMD) in irradiated, adult long-term survivors of childhood brain tumors. MATERIAL AND METHODS: We studied a national cohort of 74 adult survivors of childhood brain tumors treated with irradiation in Finland between 1970 and 2008. Dual X-ray absorptiometry (DXA) was performed for the femoral necks, total hips, and lumbar spine. Laboratory tests were conducted for evaluating the pituitary, thyroid, and gonadal functions. The participants were interviewed, examined clinically, and the disease and treatment related data were retrieved from the patient files. RESULTS: One fourth of the patients (23.6%) had sex- and age-normalized z-scores below the expected range for age (z-score ≤ -2.0). Mean BMD scores were decreased in all the DXA measurement sites. Male sex was associated with low BMD (p < .05), while body mass index (BMI) had a significant positive association with BMD (p < .01). Mode of irradiation (with or without spinal irradiation) or inclusion of chemotherapy in the treatment did not affect BMD significantly. However, patients with a ventriculoperitoneal shunt had lower BMD than those without a shunt (p < .05). Follicle stimulating hormone (FSH) and luteinizing hormone (LH) were negatively associated with BMD in women (p < .05). However, a higher cumulative dose of glucocorticoids during treatment was not associated with lower BMD, while low BMD was significantly associated with previous fractures in long bones. DISCUSSION: Low BMD should be taken in consideration in treatment of irradiated childhood brain tumor survivors especially in those with previous fractures in long bones.

FOXP3+ T cells are present in kidney biopsy samples in children with tubulointerstitial nephritis and uveitis syndrome.

BACKGROUND: Tubulointerstitial nephritis (TIN) is an inflammatory disease of unknown pathogenesis. To evaluate a possible role of regulatory T cells (Tregs) in the pathophysiology of TIN with (TINU) and without uveitis, we investigated the presence and quantity of FOXP3+ T regulatory lymphocytes in diagnostic kidney biopsies from pediatric patients. METHODS: A total of 33 patients (14 TIN and 19 TINU) were enrolled. The quantity of CD4+, FOXP3+ and double-positive T cells in formalin-fixed kidney biopsies was determined using double label immunohistochemistry with anti-human CD4 and FOXP3 antibodies. RESULTS: FOXP3 staining was successful in all 33 patients. In patients with chronic uveitis, the density of FOXP3+ cells was significantly lower (p = 0.046) than in TIN patients without uveitis or with uveitis lasting <3 months. CD4+ staining was successful in 23 patients. The density of all lymphocytes (CD4+, CD4+FOXP3+ and FOXP3+ cells) was significantly lower (p = 0.023) in patients with chronic uveitis than in other patients. CONCLUSIONS: FOXP3+ T cells are present in kidney biopsy samples from TIN and TINU patients. In patients with chronic uveitis, the density of FOXP3+ T cells is significantly lower than in other patients, suggesting a different pathomechanism for these clinical conditions.

Novel NPHS2 variant in patients with familial steroid-resistant nephrotic syndrome with early onset, slow progression and dominant inheritance pattern.

BACKGROUND: Steroid-resistant nephrotic syndrome (SRNS) is a common cause of end-stage renal disease in children but also occurs as an adult-onset condition. In a subset of SRNS patients, pathogenic variants are found in genes coding for podocyte foot process proteins. The aim of this study was to define the role of pathogenic variants in Finnish patients with familial and sporadic SRNS. METHODS: We analyzed SRNS-related genes NPHS1, NPHS2, NEPH1, ACTN4, TRPC6, INF2, WT1, CD2AP, LAMB2, and PLCE1 for disease-causing variants using direct sequencing of exons and intron/exon boundaries in all members of a family with dominant SRNS with early onset and slow progression to end-stage renal disease. We carried out a whole genome sequencing in two affected and two healthy family members. The function of found podocin variant was studied using co-immunoprecipitation and immunohistochemistry. Podocyte gene sequences were analyzed in a cohort of Finnish non-familial SRNS patients. RESULTS: A heterozygous de novo deletion, c.988_989delCT in NPHS2, was found in all affected family members and in none of their healthy relatives, non-familial patients or controls. No other SRNS-related gene variant, coding or non-coding co-segregated with the disease phenotype in the family. While the truncated podocin remained able to bind nephrin, the expression of nephrin was fragmented and podocin expression reduced. The gene analysis of the non-familial SRNS patients revealed few variants. CONCLUSION: The role of podocin variants in nephrotic syndrome may be more varied than previously thought.

Identification of subgroups by risk of graft failure after paediatric renal transplantation: application of survival tree models on the ESPN/ERA-EDTA Registry.

BACKGROUND: Identification of patient groups by risk of renal graft loss might be helpful for accurate patient counselling and clinical decision-making. Survival tree models are an alternative statistical approach to identify subgroups, offering cut-off points for covariates and an easy-to-interpret representation. METHODS: Within the European Society of Pediatric Nephrology/European Renal Association-European Dialysis and Transplant Association (ESPN/ERA-EDTA) Registry data we identified paediatric patient groups with specific profiles for 5-year renal graft survival. Two analyses were performed, including (i) parameters known at time of transplantation and (ii) additional clinical measurements obtained early after transplantation. The identified subgroups were added as covariates in two survival models. The prognostic performance of the models was tested and compared with conventional Cox regression analyses. RESULTS: The first analysis included 5275 paediatric renal transplants. The best 5-year graft survival (90.4%) was found among patients who received a renal graft as a pre-emptive transplantation or after short-term dialysis (<45 days), whereas graft survival was poorest (51.7%) in adolescents transplanted after long-term dialysis (>2.2 years). The Cox model including both pre-transplant factors and tree subgroups had a significantly better predictive performance than conventional Cox regression (P < 0.001). In the analysis including clinical factors, graft survival ranged from 97.3% [younger patients with estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m(2) and dialysis <20 months] to 34.7% (adolescents with eGFR <60 mL/min/1.73 m(2) and dialysis >20 months). Also in this case combining tree findings and clinical factors improved the predictive performance as compared with conventional Cox model models (P < 0.0001). CONCLUSIONS: In conclusion, we demonstrated the tree model to be an accurate and attractive tool to predict graft failure for patients with specific characteristics. This may aid the evaluation of individual graft prognosis and thereby the design of measures to improve graft survival in the poor prognosis groups.

Development of gliadin-specific immune responses in children with HLA-associated genetic risk for celiac disease.

OBJECTIVE: The development of gliadin-specific antibody and T-cell responses were longitudinally monitored in young children with genetic risk for celiac disease (CD). MATERIAL AND METHODS: 291 newborn children positive for HLA-DQB1*02 and -DQA1*05 alleles were followed until 3-4 years of age by screening for tissue transglutaminase autoantibodies (tTGA) by using a commercial ELISA-based kit and antibodies to deamidated gliadin peptide (anti-DGP) by an immunofluorometric assay. Eighty-five of the children were also followed for peripheral blood gliadin-specific CD4(+) T-cell responses by using a carboxyfluorescein diacetate succinimidyl ester-based in vitro proliferation assay. RESULTS: The cumulative incidence of tTGA seropositivity during the follow-up was 6.5%. CD was diagnosed in nine of the tTGA-positive children (3.1%) by duodenal biopsy at a median 3.5 years of age. All of the children with confirmed CD were both IgA and IgG anti-DGP positive at the time of tTGA seroconversion and in over half of the cases IgG anti-DGP positivity even preceded tTGA seroconversion. Peripheral blood T-cell responses to deamidated and native gliadin were detected in 40.5% and 22.2% of the children at the age of 9 months and these frequencies decreased during the follow-up to the levels of 22.2% and 8.9%, respectively. CONCLUSIONS: Anti-DGP antibodies may precede tTGA seroconversion and thus frequent monitoring of both tTGA and anti-DGP antibodies may allow earlier detection of CD in genetically susceptible children. Peripheral blood gliadin-specific T-cell responses are relatively common in HLA-DQ2-positive children and are not directly associated with the development of CD.

Antibodies to deamidated gliadin peptide in diagnosis of celiac disease in children.

OBJECTIVES: Determination of antibodies to synthetic deamidated gliadin peptides (anti-DGPs) may work as an alternative or complement the commonly used test for tissue transglutaminase antibodies (TGA) in the diagnosis of celiac disease (CD). We analyzed the performance of a time-resolved immunofluorometric anti-DGP assay (TR-IFMA) in the diagnosis of CD in children and also retrospectively analyzed the appearance of anti-DGP antibodies before TGA seroconversion. METHODS: The study included 92 children with biopsy-confirmed CD. Serum samples were taken at the time or just before the clinical diagnosis. The control group comprised 82 TGA-negative children who were positive for human leucocyte antigen-DQ2 or -DQ8. RESULTS: Based on receiver operating characteristic curves, the optimal cutoff value for immunoglobulin (Ig) A anti-DGP positivity was 153 arbitrary units (AUs) with a sensitivity of 92.4% and specificity of 97.6% and that for IgG anti-DGP 119 AU, with a sensitivity of 97.8% and specificity of 97.6%. All 92 children with CD were either IgA or IgG anti-DGP positive at the time of diagnosis. Sera from 48 children with CD were also analyzed retrospectively before the diagnosis. Anti-DGP antibodies preceded TGA positivity in 35 of the 48 children with CD and appeared a median of 1 year earlier. CONCLUSIONS: The TR-IFMA assay for detecting anti-DGP antibodies shows high sensitivity and specificity for the diagnosis of CD in children. In a majority of our study population, anti-DGP seropositivity preceded TGA positivity, indicating that earlier detection of CD may be possible by monitoring anti-DGP antibodies frequently in genetically susceptible children.

Radiotherapy-induced vascular cognitive impairment 20 years after childhood brain tumor.

BACKGROUND: Studies have established that radiotherapy for childhood brain tumors (BTs) increases the risk of cerebrovascular disease (CVD); however, it is unclear how this will affect cognitive function. This study aimed to investigate the associations between radiotherapy-induced CVD, white matter hyperintensities (WMHs), and neurocognitive outcomes in adult survivors of childhood BTs. METHODS: In a cross-sectional setting, we conducted a national cohort that included 68 radiotherapy-treated survivors of childhood BTs after a median follow-up of 20 years. Markers of CVD and WMHs were evaluated using brain MRI, and the sum of CVD-related findings was calculated. Additionally, the associations among CVD findings, WMHs, and neuropsychological test results were analyzed. RESULTS: Of the 68 childhood BT survivors, 54 (79%) were diagnosed with CVD and/or WMHs at a median age of 27 years. CVD and/or WMHs were associated with lower scores for verbal intelligence quotient, performance intelligence quotient (PIQ), executive function, memory, and visuospatial ability (P < .05). Additionally, survivors with microbleeds had greater impairments in the PIQ, processing speed, executive function, and visuospatial ability (P < .05). WMHs and CVD burden were associated with greater difficulties in memory function and visuospatial ability (P < .05). Small-vessel disease burden was associated with PIQ scores, processing speed, working memory, and visuospatial ability. CONCLUSIONS: The study results suggest that markers of radiotherapy-induced CVD, the additive effect of CVD markers, and risk factors of dementia are associated with cognitive impairment, which may suggest that the survivors are at a high risk of developing early-onset dementia.

Tubulointerstitial nephritis and uveitis syndrome in children: a prospective multicenter study.

PURPOSE: To evaluate the occurrence and characteristics of uveitis related to tubulointerstitial nephritis (TIN) in children. DESIGN: Prospective, observational, multicenter, partly placebo-controlled treatment trial. PARTICIPANTS: Nineteen children with a biopsy-proven TIN. METHODS: Patients were treated with prednisone or followed without treatment. In addition to the nephrologic evaluations, the prospective follow-up included structured ophthalmological examinations at the onset of TIN and at 3 and 6 months after the diagnosis. MAIN OUTCOME MEASURES: Occurrence, clinical features, and outcome of uveitis. RESULTS: Some 84% (16/19) of the patients had uveitis, 83% (5/6) in the nontreatment group and 82% (9/11) in the prednisone-treated group. The remaining 2 patients, originally in the nontreatment group, were switched to the prednisone group after 2 weeks. Both of them developed uveitis. Altogether, 3 patients developed uveitis during prednisone treatment and 2 patients showed worsening of uveitis despite the systemic corticosteroid. Some 50% (8/16) of the patients with uveitis presented with no ocular symptoms; 88% (14/16) of the patients had a chronic course of uveitis. Two patients were diagnosed with uveitis before nephritis; nephritis and uveitis were diagnosed within 1 week from each other in 7 patients, and uveitis developed 1 to 6 months after the diagnosis of TIN in 7 patients. CONCLUSIONS: There was no statistically significant difference in the occurrence of uveitis in patients with TIN in the prednisone and nontreatment groups. In this study, the occurrence of uveitis associated with TIN was considerably higher than previously reported. Uveitis related to TIN may develop late and is often asymptomatic. The ophthalmological follow-up of all patients with TIN is warranted for at least 12 months starting with 3-month intervals. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any material discussed in this article.

Prednisone in the treatment of tubulointerstitial nephritis in children.

BACKGROUND: Patients with tubulointerstitial nephritis (TIN) may develop permanent renal impairment. However, there are no prospective studies available on the treatment of TIN. METHODS: The effect of prednisone in the treatment of TIN was evaluated in a total of 17 patients who received prednisone or who were followed up without medication. The patient group was subdivided based on the initial plasma creatinine (PCr), below or above 150 µmol/l. RESULTS: All prednisone-treated patients had normal plasma creatinine (PCr) after 1 month of treatment (median 59.1 [45-85] µmol/l) whereas only 50 % of patients in the non-treatment group had normal creatinine (median 81.0 [42-123] µmol/l) at the same time point (p = 0.025). During 6 months' follow-up, PCr decreased in all patient groups; however, it decreased significantly only in prednisone-treated patients with baseline PCr >150 µmol/l (p < 0.001). At the end of follow-up, no difference in PCr, glomerular filtration rate (GFR), or low molecular weight (LMW) proteinuria could be found between the study groups. A considerable number of patients in both groups had subnormal GFR and/or persistent LMW proteinuria at the 6-month follow-up visit. Eighty-two percent of the patients had uveitis. CONCLUSIONS: Prednisone speeds up the recovery from renal symptoms of TIN, especially in patients with severe nephritis. The renal function did not differ significantly between prednisone and control patients after 6 months' follow-up.

Impaired cardiorespiratory and neuromuscular fitness in children and adolescents with juvenile idiopathic arthritis: a cross-sectional case-control study in the era of biologic drug therapies.

BACKGROUND: In recent years, biologic drug therapies have altered the course of juvenile idiopathic arthritis (JIA) possibly also improving the patients' physical fitness. However, studies measuring both cardiorespiratory and muscular fitness in children with JIA are sparse and have failed to show consistent results. Our aim was to assess both cardiorespiratory and neuromuscular fitness and contributing factors in children and adolescents with JIA in the era of biologic drug therapies. METHODS: This cross-sectional study consisted of 73 JIA patients (25 boys, 48 girls) aged 6.8- 17.5 years and 73 healthy age- and sex-matched controls, investigated in 2017-2019. Cardiorespiratory fitness was assessed by maximal ergospirometry and neuromuscular fitness by speed, agility, balance, and muscle strength tests. RESULTS: Means (± SD) of maximal workload (Wmax/kg) and peak oxygen uptake (VO2peak/kg,) were lower in JIA patients than in controls (Wmax/kg: 2.80 ± 0.54 vs. 3.14 ± 0.50 Watts, p < 0.01; VO2peak/kg: 38.7 ± 7.53 vs. 45.8 ± 6.59 ml/min/kg, p < 0.01). Shuttle-run, sit-up and standing long jump test results were lower in JIA patients than in controls (p < 0.01). Mean (± SD) daily activity was lower (89.0 ± 44.7 vs. 112.7 ± 62.1 min/day, p < 0.05), and sedentary time was higher (427 ± 213 vs. 343 ± 211 min/day, p < 0.05) in JIA patients compared to controls. Physical activity and cardiorespiratory or neuromuscular fitness were not associated with disease activity. CONCLUSIONS: JIA patients were physically less active and had lower cardiorespiratory and neuromuscular fitness than their same aged controls with no JIA. Therefore, JIA patients should be encouraged to engage in physical activities as a part of their multidisciplinary treatment protocols to prevent adverse health risks of low physical activity and fitness.

Correction: Pre- and postdiagnosis growth failure, adult short stature, and untreated growth hormone deficiency in radiotherapy-treated long-term survivors of childhood brain tumor.

[This corrects the article DOI: 10.1371/journal.pone.0274274.].

Parenteral plant sterols and intestinal failure-associated liver disease in neonates.

OBJECTIVES: We prospectively evaluated incidence of prolonged (>28 days) parenteral nutrition (PN), associated complications, and significance of parenteral plant sterols (PS) in neonatal intestinal failure-associated liver disease (IFALD) compared with children. METHODS: We recruited 28 neonates (mean age 50 days, range 28-126) and 11 children (6.9 y, 2.1-16.6) in all of Finland. Patients underwent repeated measurements of serum cholesterol, noncholesterol sterols, including PS, cholestanol and cholesterol precursors, and liver biochemistry during and 1 month after discontinuation of PN. Healthy matched neonates (n=10) and children (n=22) served as controls. RESULTS: IFALD occurred more frequently among neonates (63%) than children (27%; P<0.05). Ratios of serum PS, including stigmasterol, sitosterol, avenasterol, and campesterol, and total PS were increased among neonates compared with healthy controls and children on PN by 2- to 22- and 2- to 5-fold (P<0.005), respectively. Neonates with IFALD had significantly higher ratios of serum PS and cholestanol compared with neonates without IFALD (P<0.05). Total duration of PN associated with serum cholestanol, stigmasterol, avenasterol, alanine aminotransferase, and aspartate aminotransferase (r=0.472-0.636, P<0.05). Cholestanol and individual serum PS, excluding campesterol, reflected direct bilirubin (r=0.529-0.688, P<0.05). IFALD persisted after discontinuation of PN in 25% of neonates with 4.2- and 2.2-times higher ratios of serum stigmasterol and cholestanol compared with neonates without IFALD (P<0.05). CONCLUSIONS: Frequent occurrence of IFALD among neonates on PN displays an association to duration of PN and markedly increased serum PS, especially stigmasterol, in comparison to healthy neonates and children on PN. Striking accumulation of parenteral PS may contribute to IFALD among neonates.