Transcriptomic analysis of intestine following administration of a transglutaminase 2 inhibitor to prevent gluten-induced intestinal damage in celiac disease.

Transglutaminase 2 (TG2) plays a pivotal role in the pathogenesis of celiac disease (CeD) by deamidating dietary gluten peptides, which facilitates antigenic presentation and a strong anti-gluten T cell response. Here, we elucidate the molecular mechanisms underlying the efficacy of the TG2 inhibitor ZED1227 by performing transcriptional analysis of duodenal biopsies from individuals with CeD on a long-term gluten-free diet before and after a 6-week gluten challenge combined with 100 mg per day ZED1227 or placebo. At the transcriptome level, orally administered ZED1227 effectively prevented gluten-induced intestinal damage and inflammation, providing molecular-level evidence that TG2 inhibition is an effective strategy for treating CeD. ZED1227 treatment preserved transcriptome signatures associated with mucosal morphology, inflammation, cell differentiation and nutrient absorption to the level of the gluten-free diet group. Nearly half of the gluten-induced gene expression changes in CeD were associated with the epithelial interferon-γ response. Moreover, data suggest that deamidated gluten-induced adaptive immunity is a sufficient step to set the stage for CeD pathogenesis. Our results, with the limited sample size, also suggest that individuals with CeD might benefit from an HLA-DQ2/HLA-DQ8 stratification based on gene doses to maximally eliminate the interferon-γ-induced mucosal damage triggered by gluten.

Measurement practices of alanine aminotransferase in children: Temporal changes and etiology for increased values.

Data on alanine aminotransferase (ALT) measurement practices and diagnoses associated with increased values are limited. We evaluated these issues by collecting ALT measurements from 1- to 16-year-old patients investigated in 1992-2018 in a tertiary center. Diagnoses were gathered in 2008-2018. Altogether 145,092 measurements from 28,118 children were taken 42% undergoing repeated testing. Testing increased from 21/1000 to 81/1000 children and the prevalence of elevated values fluctuated between 18% and 26%. An increase was seen especially in emergency care and departments of rheumatology, gastroenterology, hemato-oncology, and psychiatry. Common acute causes associated with elevated ALT were infections (45%), hemato-oncologic conditions (17%), and external reasons (13%), whereas autoimmune diseases (28%), psychiatric conditions (14%), and metabolic-dysfunction associated steatotic liver disease (10%) were common chronic causes. In conclusion, ALT testing increased 3.9-fold while the proportion of increased values remained stable, indicating that increased testing was justified. However, in some departments the testing efficiency was low.

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.

Alanine aminotransferase cutoffs for the pediatric fatty liver disease: Major impact of the reference population.

OBJECTIVES AND STUDY: The often-recommended alanine aminotransferase (ALT) cutoffs (girls 21 U/l, boys 25 U/l) are based on a NHANES cohort. A novel concept of metabolic dysfunction associated steatotic liver disease (MASLD) emphasizes the role of ALT. We tested the prevalence of increased ALT and MASLD in children with overweight or obesity applying population-based and NHANES-based cut-offs. METHODS: Six- to seventeen-year-old children underwent data collection in a prospective Physical Activity and Nutrition in Children (PANIC) study. ALT 95th percentiles were calculated from 1167 separate measurements considering various confounders. Test cohort comprised 1044 children with overweight/obesity. RESULTS: ALT values increased at puberty onset (p = 0.031) and correlated negatively with age in girls (r = -0.222, p < 0.001). Particularly overall and central obesity increased ALT, whereas underweight or metabolic abnormalities had smaller effect. After applying the tested exclusions, the age-related ALT 95th percentiles were 24-29 U/l for girls and 29-32 U/l for boys. In 6-8-year-old children with overweight/obesity, the prevalence of increased ALT and MASLD were 21.6% and 2.4% with age-specific PANIC cutoffs. In older children, when NHANES-based cutoffs were used, there was a trend for higher prevalence of increased ALT and MASLD in all age groups for both sexes, reaching significance for increased ALT in 12-16-year-old boys (NHANES 63.5%, 95% confidence interval [CI]: 56.4%-70.0% vs. PANIC 47.1%, 95% CI [40.1%-54.2%]) and 9-11-year-old girls (60.0% [49.4%-69.8%] vs. 31.8% [22.8%-42.3%]), respectively. Increased ALT/MASLD were more common in boys than in girls, and in boys these increased with age, whereas in girls these peaked at age 9-12 years. CONCLUSION: A reference population impacts on the prevalence of increased ALT and MASLD. Considering this help optimizing screening while avoiding unnecessary investigations and surveillance. The prospective part of this study is registered in clinicaltrials.gov; identifier NCT01803776.

Therapy outcome related to adalimumab trough levels in pediatric patients with inflammatory bowel disease.

OBJECTIVES: We evaluated the relationship between serum concentration and efficacy of adalimumab (ADA), an anti-tumor necrosis factor-alpha agent, in pediatric patients with inflammatory bowel disease (PIBD). MATERIALS AND METHODS: This retrospective cross-sectional study traced 75 patients with PIBD (Crohn's disease, n = 57) treated with ADA at two tertiary centers in Finland in 2012-2018. Drug levels and drug antibody titers were chart-reviewed, and the treatment continuation rate of ADA therapy was evaluated. We also assessed the impact of trough levels in the first 3 months on the continuation of ADA within one year of therapy. RESULTS: ADA was introduced at a median age of 13.4 years, and the median disease duration was 2.7 years. During the first year, 22 patients (29%) discontinued ADA due to either loss of response (20%, n = 15) or anti-drug antibody formation (5.3%, n = 4). Regarding trough levels in the first 3 months, 9/16 patients (56%) with trough levels <5 mg/L and 12/20 (60%) with trough levels <7.5 mg/L at 3 months discontinued the therapy by the end of the first year. In comparison, only 8/32 patients (25%) with trough levels >7.5 mg/L at 3 months discontinued treatment during the first year (p = .005). At the last follow-up (median 1.5 years), 52% of the 75 patients were on maintenance therapy and had a median trough level of 8.8 mg/L. CONCLUSION: Higher trough levels in the first 3 months of adalimumab treatment are associated with lower rates of discontinuation due to loss of response during the first year.

Frequency and clinical significance of histologic upper gastrointestinal tract findings in children with inflammatory bowel disease.

OBJECTIVE: Assessment of the upper gastrointestinal tract (UGI) may enable more personalized treatment strategies in pediatric inflammatory bowel disease (IBD). However, data on the frequency and significance of these findings remain limited. METHODS: Data on 132 pediatric IBD patients with systematic UGI sampling were collected and the baseline characteristics and presence of complications compared between those with and without histological UGI findings. The control group comprised 162 children who received no diagnoses. RESULTS: Seventy-six children had ulcerative colitis (UC), 47 Crohn's disease (CD) and nine IBD unclassified. UGI findings were more common in IBD patients than controls (69.7% vs. 30.9%, respectively, p < .001), particularly in the stomach (62.1% vs. 16.8%; p < .001). Among IBD patients, findings were more common in CD than in UC (80.9% vs. 63.2%; p = .038), particularly in the duodenum (21.3% vs. 2.6%, p = .001). Four patients had UGI granulomas consistent with CD. Hypoalbuminemia (OR 3.22; 95% CI 1.18-8.79) and failure to thrive (2.82; 1.17-6.78) increased the likelihood of UGI findings in IBD. In CD, perianal morbidity was less common in those with than in those without UGI findings (13.2% vs. 44.4%; p = .032) whereas in UC, UGI findings increased the risk for co-morbidities (18.8% vs. 3.6%; p = .059). The long-term outcomes did not differ between patients with or without UGI findings. CONCLUSIONS: Histologic UGI findings were more common in children with IBD than in children with no gastrointestinal diagnoses. In CD, UGI findings were more frequent than in UC, especially in the duodenum. In UC, UGI findings were associated with more complex disease.

Prevalence and Clinical Significance of Helicobacter Pylori-negative Chronic Gastritis in Children.

OBJECTIVES: The clinical significance of Helicobacter pylori-negative chronic gastritis (HPNCG) in children is unclear. We examined this issue in patients who had undergone esophagogastroduodenoscopy with systematic gastric sampling. METHODS: Data of 1178 consecutive children who underwent diagnostic esophagogastroduodenoscopy were collected. Baseline characteristics and long-term outcomes were compared between children with active and inactive HPNCG and those with normal gastric histology. Follow-up data were available for up to 13 years. RESULTS: Altogether 24 (2.0%) children had active and 235 (19.9%) inactive HPNCG, 27 (2.3%) were Hpylori-positive, 46 (3.9%) had other gastric pathology, and 846 (71.8%) normal histology. Diarrhea (31.3% vs 25.1%, P  = 0.033), poor growth (23.6% vs 14.7%, P  < 0.001), bloody stools (13.9% vs 7.2%, P < 0.001), anemia (46.5% vs 23.4%, P < 0.001), hypersedimentation (39.7% vs 21.4%, P < 0.001), hypoalbuminemia (40.4% vs 16.2%, P < 0.001), and elevated fecal calprotectin (62.4% vs 31.5%, P < 0.001) were more common and heartburn (13.9% vs 22.9%, P = 0.002) less common in the HPNCG group than in the controls. Both active (OR 3.64,95% CI 1.35-9.82) andinactive (2.98, 2.18-4.08) HPNCG predicted a diagnosis in the initial investigations. Crohn disease (41.7%) was the most common diagnosis in active HPNCG and celiac disease (37.4%) in inactive HPNCG. During follow-up, 7 (9.9%) of the 71 initially nondiagnosed HPNCG children received a diagnosis. CONCLUSIONS: HPNCG is a frequent finding in children undergoing EGD, the active form being associated especially with Crohn disease and the inactive with celiac disease. The long-term prognosis of patients with HPNCG who do not receive an initial diagnosis is good.

Impact of diagnostic delay to the clinical presentation and associated factors in pediatric inflammatory bowel disease: a retrospective study.

BACKGROUND: Undelayed diagnosis is thought to be a major determinant for good prognosis in pediatric inflammatory bowel disease (PIBD). However, factors predicting diagnostic delay and the consequences of this remain poorly defined. We investigated these issues in a well-defined cohort of PIBD patients. METHODS: Comprehensive electronic data were collected from 136 PIBD patients retrospectively. Diagnostic delay was further classified into < 6 and ≥ 6 months, and < 12 and ≥ 12 months. Logistic regression was used to calculate whether the delay was associated with clinical features and/or risk of complications and co-morbidities at diagnosis. RESULTS: The median age of patients was 12.4 years and 43.4% were females. Altogether 35.5% had Crohn´s disease (CD), 59.1% ulcerative colitis (UC) and 6.6% IBD undefined (IBD-U). The median delay before diagnosis was 5.0 months in all, 6.6 months in CD, 4.1 months in UC, and 9.8 months in IBD-U (UC vs. CD, p = 0.010). In all but IBD-U most of the delay occurred before tertiary center referral. Abdominal pain predicted a delay > 6 months in all PIBD (OR 2.07, 95% CI 1.00-4.31) and in UC patients (3.15, 1.14-8.7), while bloody stools predicted a shorter delay in all PIBD (0.28, 0.14-0.59) patients and in CD (0.10, 0.03-0.41) patients. A delay > 6 months was associated with a higher frequency of complications (2.28, 1.01-5.19). CONCLUSIONS: Delay occurred mostly before specialist consultation, was longer in children presenting with abdominal pain and in CD and was associated with risk of complications. These findings emphasize the roles of active case-finding and prompt diagnostic evaluations.

Diagnostic findings and long-term prognosis in children with anemia undergoing GI endoscopies.

BACKGROUND AND AIMS: Intestinal diseases are regarded as a common cause of anemia, but the diagnostic outcomes of children with anemia undergoing endoscopic investigations are unclear. We investigated this issue in a large cohort of children. METHODS: Indications for and findings of consecutive gastrointestinal (GI) endoscopies were collected. Clinical presentation and diagnostic outcomes were compared between anemic and nonanemic patients and between anemic patients with and without a diagnosis. Diagnoses received during follow-up were collected. RESULTS: Of 2395 consecutive endoscopies, 251 children with and 613 children without anemia had undergone either diagnostic esophagogastroduodenoscopy (EGD) (51.4% and 51.4%, respectively), colonoscopy (4.0% and 11.4%), or both (45.8% and 37.8%). Children with anemia more often received diagnoses (72.9% vs 39.3%; odds ratio [OR], 4.18; 95% confidence interval [CI], 3.03-5.77), particularly of celiac disease (26.3% vs 15.5%, P < .001) and of inflammatory bowel disease (31.1% vs 9.1%, P < .001), than did nonanemic children. The diagnosis in anemic patients was predicted by age 5 to 12 years (OR, 3.52; 95% CI, 1.27-9.75), presence of diarrhea (OR, 2.04; 95% CI, 1.07-3.90), melena/hematochezia (OR, 2.40; 95% CI, 1.17-4.92), poor growth (OR, 3.94; 95% CI, 1.70-9.15), positive celiac serology (OR, 11.81; 95% CI, 3.47-40.12), high calprotectin (OR, 12.86; 95% CI, 4.00-41.32), hypersedimentation (OR, 2.65; 95% CI, 1.29-5.44), and hypoalbuminemia (OR, 5.05; 95% CI, 1.56-16.34). Thirty children with anemia (12.0%) had no GI symptoms, and 22 of them (73.3%) were given diagnoses at the time of the endoscopies. All 22 had additional laboratory abnormalities, whereas these were present in only 2 of 8 undiagnosed children. None of them was diagnosed later in the follow-up of up to 11 years, in contrast to 4 (6.7%) of all anemic and 33 (8.9%) of all nonanemic patients. CONCLUSIONS: Anemia increased the probability of being given a diagnosis, emphasizing its importance as an alarm symptom. However, endoscopies in anemic patients without additional symptoms or laboratory abnormalities seldom improved the diagnostic yield.

Association of screen time with long-term stress and temperament in preschoolers: results from the DAGIS study.

Screen time is increasing rapidly in young children. The aim of this study was to examine associations of long-term stress and temperament with screen time in Finnish preschool children and the moderating role of socioeconomic status. Cross-sectional DAGIS data were utilized. Long-term stress was assessed using hair cortisol concentration, indicating values of the past 2 months. Temperament was reported by the parents using the Children's Behavior Questionnaire (the Very Short Form), and three broad temperament dimensions were constructed: surgency, negative affectivity, and effortful control. Screen time was reported by the parents over 7 days. The highest education level in the household was used as an indicator of socioeconomic status. In total, 779 children (mean age, 4.7 ± 0.9 years, 52% boys) were included in the study. Of the temperament dimensions, a higher effortful control was associated with less screen time (B = - 6.70, p = 0.002). There was no evidence for an association between hair cortisol concentration and screen time nor a moderating role of socioeconomic status in the associations (p > 0.05).Conclusion: Our findings indicate that preschool children with a higher score in effortful control had less screen time. Because effortful control reflects general self-regulatory abilities, promoting these skills may be effective in reducing screen time in young children. What is Known: • Screen time has increased rapidly during the last decades, and higher screen time has been linked with numerous adverse health consequences in children. • There are no previous studies investigating associations of long-term stress and temperament with screen time in young children. What is New: • Of the temperament dimensions, effortful control was associated with higher screen time in preschool children, but there was no association found between long-term stress and screen time. • Since effortful control reflects general self-regulatory abilities, promoting these skills may be effective in reducing screen time in young children.

Prevalence and clinical significance of esophageal abnormalities in children with celiac disease.

Variable endoscopic and histological findings of esophageal lining are often detected in celiac disease, with unknown significance. We investigated the frequency and significance of such abnormalities in children. Macroscopic esophageal findings as reported by endoscopist and histological results by pathologist were compared between 316 celiac disease patients and 378 disease controls who had undergone upper gastrointestinal endoscopy with systematic esophageal biopsy sampling. Association between esophageal abnormalities and other clinical and histological characteristics of the disease was evaluated in celiac disease patients. Endoscopic esophageal findings were reported least often (3.8%) of all diseases in celiac disease, whereas histopathologic abnormalities were frequent (16.8%, n = 53). Children with celiac disease and esophageal histopathology reported more reflux than those with normal esophagus (5.7 vs. 0.8%, P = 0.032), whereas the groups were comparable in the frequency and severity of other symptoms, demographic data, prevalence of celiac disease-associated and other coexisting chronic conditions, family history of celiac disease, anthropometric and laboratory parameters, and degree of villous atrophy. Only 2 (3.7%) out of the 53 children with histologic findings had esophageal symptoms at diagnosis, and altogether seven were treated with acid blockers. Four children had increased number (≥15 eosinophils per high-power field) of esophageal eosinophils, but none of them had definite eosinophilic esophagitis. The remaining 45 children had only unspecific inflammation in the esophagus and reported no esophageal problems during a median of 6.9 years follow-up. To conclude, although relatively common, histopathological esophageal findings in celiac disease are mostly unspecific and without major clinical significance even in a long-term follow-up.

Presentation of Celiac Disease in Finnish Children Is No Longer Changing: A 50-Year Perspective.

OBJECTIVES: To chart trends in the presentation of celiac disease in a large cohort of Finnish children diagnosed over a period of 48 years. STUDY DESIGN: Clinical and serologic data, severity of small-bowel mucosal damage, and presence of associated conditions were gathered from 596 children diagnosed with celiac disease in 1966-2013. The children were divided into 4 groups based on the year of diagnosis (before 1980, 1980-1999, 2000-2009, and 2010-2013), and the variables were compared between the periods. The incidence of celiac disease autoimmunity in 2001-2013 was calculated based on the number of new antibody-positive cases in each year. RESULTS: Age at diagnosis rose from median 4.3 years before 1980 to between 7.6 and 9.0 years in the later periods. The severity of clinical presentation, in general, became milder and poor growth less common during the entire study period of 50 years. Percentages of children with classical gastrointestinal presentation decreased, and those with atypical or subclinical presentation increased after the 1990s, these changes leveling off in 2000-2013. Similarly, the severity of small-bowel mucosal damage was milder after the 1990s. The incidence of celiac disease autoimmunity increased in the early 2000s but then fluctuated without a clear trend. There were no significant secular changes in sex distribution, presence of anemia, levels of celiac antibodies, or celiac disease-associated conditions. CONCLUSIONS: The clinical and histologic presentation of celiac disease in children became milder, especially in the 1980s and 1990s. However, most of these changes have reached a plateau in recent years.

Prevalence and associated factors of metabolic-associated fatty liver disease in overweight Finnish children and adolescents.

Introduction: Data on the prevalence of pediatric fatty liver disease remain limited, partly due to challenges in diagnosis. A novel concept of metabolic-associated fatty liver disease (MAFLD) makes it possible to establish the diagnosis in overweight children with sufficiently elevated alanine aminotransferase (ALT). We investigated the prevalence, risk factors, and metabolic co-morbidities of MAFLD in a large group of overweight children. Methods: Data on 703 patients aged 2-16 years examined due to overweight in different levels of healthcare in 2002-2020 were collected retrospectively from patient records. MAFLD was here defined as ALT >2x reference (>44 U/l in girls and >50 U/l in boys) in overweight children according to recently updated definition. Patients with MAFLD and without it were compared, and subgroup analyses were conducted among boys and girls. Results: Median age was 11.5 years, and 43% were girls. Altogether 11% were overweight, 42% obese and 47% severely obese. Abnormal glucose metabolism was present in 44%, dyslipidemia in 51%, hypertension in 48% and type 2 diabetes (T2D) in 2%. MAFLD prevalence varied between 14-20% in examined years without significant change (p=0.878). The pooled prevalence over the years was 15% (boys 18%, girls 11%; p=0.018), peaking in girls at early puberty and increasing in boys with age and puberty. Associated factors in boys were T2D (OR 7.55, 95% CI 1.23-46.2), postpubertal stage (5.39, 2.26-12.8), increased fasting insulin (3.20, 1.44-7.10), hypertriglyceridemia (2.97, 1.67-5.30), hyperglycemia (2.88, 1.64-5.07), decreased high-density lipoprotein (HDL) cholesterol (2.16, 1.18-3.99), older age (1.28, 1.15-1.42) and higher body-mass-index (1.01, 1.05-1.15), and in girls T2D (18.1, 3.16-103), hypertriglyceridemia (4.28, 1.99-9.21), and decreased HDL (4.06, 1.87-8.79). Conclusion: Prevalence of MAFLD was 15%, with no statistically significant increase in the 2000s. The condition was associated in general with male gender, puberty stage and disturbances in glucose and lipid metabolism, and higher age and BMI in boys.

Differential diagnosis and long-term outcomes of non-atrophic duodenal changes in children.

Objectives and study: Gastrointestinal endoscopy is often performed when investigating abdominal complaints in children. While atrophic changes of the duodenal mucosa are usually caused by celiac disease, the prevalence and clinical significance of non-atrophic duodenal changes are less clear. We studied these issues in a large pediatric endoscopic cohort. Methods: Comprehensive data on clinical features, diagnostic findings and long-term outcomes of children who had undergone upper gastrointestinal endoscopy with systematic duodenal sampling were collected. Study variables were compared between children with non-atrophic changes and normal histology, and between those with non-atrophic changes who did and did not receive a diagnosis. Results: The study comprised 1,170 consecutive children, of whom 51 (4.4%) had non-atrophic and 315 (26.9%) atrophic duodenal changes and 804 (68.7%) normal histology. The most common non-atrophic findings were non-specific inflammation (n = 19) and intraepithelial lymphocytosis (n = 14). Patients with non-atrophic changes presented more often with blood in stools (23.5 vs. 11.3%; p = 0.009), anemia (43.2 vs. 36.5%; p = 0.028) and positive celiac serology (34.3 vs. 12.9%; p < 0.001) than those with a normal duodenum. Twenty-four (44%) of those with non-atrophic changes received an initial diagnosis, the most common of which were inflammatory bowel disease (IBD) (n = 8), Helicobacter pylori infection (n = 3) and food allergy (n = 3). The prevalence of the diagnoses did not differ from those with a normal duodenum. Those who received a diagnosis had more often blood in stools (37.5 vs. 11.1%; p = 0.027), anemia (70.6 vs. 20.0%; p = 0.002) and negative celiac serology (50.0 vs. 7.7%; p = 0.013) than those without diagnosis. During a follow-up of 6.1-13.3 years, five of the 12 initially undiagnosed seropositive patients developed celiac disease, and one patient also developed ulcerative colitis. Conclusion: Non-atrophic duodenal changes are relatively common and associated with anemia, blood in stools, and positive celiac disease serology. Excluding potential celiac disease, those without an initial diagnosis have a favorable long-term prognosis.

A randomized, controlled multicenter feasibility pilot trial on imaging confirmed uncomplicated acute appendicitis: Appendectomy vs. symptomatic treatment in pediatric patients (the APPSYPP) trial study protocol.

INTRODUCTION: Imaging-confirmed uncomplicated acute appendicitis can be effectively and safely treated with antibiotics in most adults and children. Symptomatic treatment may have similar efficacy and safety. METHODS AND ANALYSIS: The APPSYPP trial is a randomized national multicenter feasibility superiority pilot study comparing appendectomy with symptomatic treatment in children with imaging-confirmed uncomplicated acute appendicitis. INCLUSION CRITERIA: 1) age ≥ 7 and < 16 years, 2) imaging-confirmed uncomplicated acute appendicitis and 3) CRP ≤ 65 mg/l. Patients are randomized to receive emergency laparoscopic appendectomy or symptomatic treatment. To ensure patient safety, symptomatically treated patients are hospitalized for at least 24 h receiving standard practice intravenous fluids and analgesics according to standard clinical practice. Primary outcome is 30-day treatment success defined by the absence of any treatment failure criteria. In appendectomy, treatment failure is defined as normal appendiceal histopathology or any postintervention complication requiring general anesthesia. In symptomatic treatment, treatment failure is defined as 1) inability for hospital discharge without appendectomy within 48 h after randomization with a finding of histopathologically inflamed appendix, 2) appendectomy during the initial hospital stay due to clinical progression of appendicitis with complicated acute appendicitis both histopathologically and surgically, 3) appendectomy with a histopathological finding of acute appendicitis after hospital discharge, or 4) any complication of appendicitis requiring general anesthesia. Detailed predefined secondary outcomes will be analyzed. ETHICS AND DISSEMINATION: Study was approved by Ethics Committee of Helsinki University Hospital (ID:HUS/1993/2021), conducted in compliance with the declaration of Helsinki with results disseminated in peer-reviewed scientific journals. TRIAL REGISTRATION: ClinicalTrials.gov (NCT05289713).

Relationship between screen time and sleep among Finnish preschool children: results from the DAGIS study.

STUDY OBJECTIVES: To examine the associations between screen time, the time spent on different screen devices, and sleep in a sample of Finnish preschool children. METHODS: The current study analyzed cross-sectional data from the DAGIS study carried out in Finland in 2015-2016 on 736 children aged 3-6 years. Parents reported in a 7-day diary the durations the child used screen devices daily, with separate details about watching TV or DVDs, using tablets or smartphones, and using computers. In addition, parents reported children's bedtimes and wake-up times, which were further used in calculating sleep duration. Parents answered questions regarding their child's sleep consistency. Statistical analyses included adjusted general linear modeling. RESULTS: An hourly increase in total screen time was associated with 11 min later bedtime (p < 0.001) and 10 min shorter sleep duration (p < 0.001). More TV/DVD watching was associated with later bedtimes (p = 0.016) and a shorter sleep duration (p = 0.001). More smartphone/tablet use was associated with later bedtimes (p = 0.005), later wake-up times (p = 0.038), and weaker sleep consistency (p = 0.024). More computer use was associated with later bedtimes (p = 0.046). Results did not differ between genders. CONCLUSIONS: Increased screen time was associated with later bedtimes and shorter sleep duration among preschool children. Adverse associations with sleep outcomes were found for each screen device. Attention should be paid to promoting balanced use of screens and regular sleep habits in young children.

Iron Transporter Protein Expressions in Children with Celiac Disease.

Anemia is a frequent finding in children with celiac disease but the detailed pathophysiological mechanisms in the intestine remain obscure. One possible explanation could be an abnormal expression of duodenal iron transport proteins. However, the results have so far been inconsistent. We investigated this issue by comparing immunohistochemical stainings of duodenal cytochrome B (DCYTB), divalent metal transporter 1 (DMT1), ferroportin, hephaestin and transferrin receptor 1 (TfR1) in duodenal biopsies between 27 children with celiac disease and duodenal atrophy, 10 celiac autoantibody-positive children with potential celiac disease and six autoantibody-negative control children. Twenty out of these 43 subjects had anemia. The expressions of the iron proteins were investigated with regard to saturation and the percentage of the stained area or stained membrane length of the enterocytes. The results showed the stained area of ferroportin to be increased and the saturation of hephaestin to be decreased in celiac disease patients compared with controls. There were no differences in the transporter protein expressions between anemic and non-anemic patients. The present results suggest an iron status-independent alteration of ferroportin and hephaestin proteins in children with histologically confirmed celiac disease.

Parental Mental Well-Being and Frequency of Adult-Child Nature Visits: The Mediating Roles of Parents' Perceived Barriers.

Regular access to green space has been shown to provide several health benefits for children. However, children today spend less time outdoors. Thus, it has become important to understand what drives and limits children's activities in nature. Based on a Finnish online survey of 1463 parents of children aged 2-7 conducted in 2019, the current study examined parents' perceived barriers to visiting nature with their children. It also examined how parental mental well-being is related to families' frequency of nature visits, and whether this association is mediated by different categories of parents' perceived barriers. Eleven out of 12 barriers were largely perceived by parents as reasons that did not prevent them from visiting nature with their children. Next, factor analysis indicated a three-factor solution to the barriers. The results of a multiple mediation analysis showed that better parental mental well-being was associated with more frequent adult-child nature visits, and this relationship was partially mediated by a "lack of competence and logistics" and a "lack of time and interest", but not by "insecurity and fear". The results indicated that parents with poor mental well-being were more likely to perceive barriers to visiting nature, which in turn appeared to be related to a higher likelihood of having children who visited nature less frequently.

First Scandinavian case of successful pregnancy during nitisinone treatment for type 1 tyrosinemia.

Background Type 1 tyrosinemia is a hereditary metabolic disease in which tyrosine metabolites damage the liver and kidneys. Nitisinone medication revolutionized the treatment, but the effects of the drug during human pregnancy are unknown. Case presentation A 17-year-old tyrosinemia patient became pregnant. Nitisinone was continued throughout pregnancy with a varying serum concentration and dose ranging from 0.8 to 1.4 mg/kg/day. Blood tyrosine remained stable until it increased in late pregnancy. α-fetoprotein increased to 284 µg/L without new changes in liver. Urine succinylacetone remained undetectable, but there were signs of possibly reoccurring kidney tubulopathy. Fetal ultrasound monitoring was normal throughout the pregnancy and the newborn healthy. After the delivery, α-fetoprotein normalized, but tyrosine continued to rise for up to 1 year. The child is developing normally. Conclusions Pregnancy during nitisinone was successful, but tailoring of the drug dose and possibly reappearing complications, as also increasing serum tyrosine concentration after delivery warranted intensified surveillance.

Clinical characteristics and long-term health in celiac disease patients diagnosed in early childhood: Large cohort study.

BACKGROUND: Early detection of celiac disease could theoretically prevent most of the disease-associated complications, but long-term effects of this approach are unclear. AIMS: To investigate features at diagnosis and adulthood health in celiac disease patients diagnosed in early childhood in 1965-2014. METHODS: Medical data on 978 pediatric patients were collected and study questionnaires sent to 559 adult patients who were diagnosed in childhood. Results were compared between patients diagnosed in early (≤3.0 years) and later (3.1-17.9 years) childhood. RESULTS: Early diagnosed patients (n=131) had more often total villous atrophy (37% vs 25%, p=0.001), gastrointestinal presentation (61% vs 47%, p<0.001), growth disturbances (70% vs 32%, p=0.001) and severe symptoms (30% vs 9%, p<0.001) and were less often screen-detected (10% vs 27%, p<0.001) at diagnosis than those diagnosed later (n=847). Among 239 adult responders, early diagnosed patients (n=36) had fewer comorbidities (33% vs 53%, p=0.034) but considered their health less often good/excellent (69% vs 84%, p=0.029). The groups were comparable in current age, dietary adherence, symptoms and health-related quality of life. CONCLUSION: Despite more severe initial presentation, the long-term health in early diagnosed patients was mostly comparable or even better to those diagnosed later in childhood. Poorer self-perceived health suggests a need for support during the transition to adulthood care.