Incidence of juvenile idiopathic arthritis in Finland, 2000-2020.

OBJECTIVE: Previous epidemiological data of JIA in Finland are from the turn of the millennium. We aimed to determine the recent annual incidence of JIA in several consecutive years in Finland and to explore the differences in incidence between sexes, age groups, and regions. METHODS: We analyzed all children <16 years of age who met the ILAR classification criteria for JIA. Cases from 2000-2020 were identified from two national registers: the Care Register for Health Care of the Finnish Institute for Health and Welfare and the Reimbursement Register containing medication data from the Social Insurance Institution of Finland; cases from 2016-2020 were identified from the Finnish Rheumatology Quality Register. RESULTS: The incidence of JIA was 31.7 per 100 000 (95% CI 30.2, 33.1), according to the Care Register in 2000-2020 and peaked in 2010-2014. No considerable differences in incidence rates were observed among registers. In all age groups, incidence in girls was predominant compared with boys. The incidence in girls peaked at the ages of 2 years and 14-15 years. Decreasing incidence was observed among boys 0-3 years old during the entire study period, whereas increasing incidence was observed among teenage girls and boys 4-7 years old in 2000-2013. CONCLUSION: The incidence of JIA is not only very high with respect to that in other parts of the world but also higher than previously reported in Finland. The incidence varied by region and year but was not higher at the end than the beginning of the study period.

Level, types and determinants of physical activity in children with type 1 diabetes and their parents: A cross-sectional study.

AIM: The aim of the study was to describe the level, types and determinants of leisure time PA and exercise among children with type 1 diabetes and their parents. METHODS: One hundred twenty children aged 6-18 years with type 1 diabetes and 113 parents (n = 113) participated to this questionnaire-based study at Northern Ostrobothnia District Hospital in Oulu, western Finland. All participants gave informed consent before entering this study. RESULTS: Twenty-three per cent of the children exercised briskly for at least 7 h a week which corresponds to 60 min per day. The total PA occasions children had with a parent accounted for the children's total number of PA occasions in a week (ß = 0.83, 95% CI 0.20-1.47) and total weekly hours of PA (ß = 0.90, 95% CI 0.07-1.73). There was a positive association between total weekly hours of brisk PA and HbA1 c (ß = 0.65, 95% CI 0.02-0.13), while there was no such association with light PA (ß = 0.42, 95% CI -0.04-0.87). Laziness, fear of unexpected glycaemic variability and tiredness were the most frequent barriers to PA in children. CONCLUSION: Most of the children with type 1 diabetes did not reach generally recommended 60 min of brisk PA a day. Exercising with a parent was positively associated with children's weekly frequency and total hours of PA.

Risk of immune-related diseases in childhood after intrapartum antibiotic exposure.

BACKGROUND: Intrapartum antibiotic prophylaxis is effective in preventing early-onset group B streptococcal disease in newborn infants, but it influences gut microbiota development. Gut microbiota composition is, in turn, associated with immune-related diseases in childhood. OBJECTIVE: This study hypothesized that intrapartum antibiotic exposure is associated with immune-related diseases in childhood. STUDY DESIGN: We conducted a population-based cohort study of vaginally delivered children. We retrieved data on intrapartum antibiotic exposure from structured electronic medical records and obtained outcome data on childhood autoimmune, allergic, and obstructive airway diseases from comprehensive national registers. We used Cox regression analysis with adjustment for maternal and neonatal covariates and regarded death as a competing risk in the analyses. RESULTS: The study population comprised 45,575 vaginally born children of whom 9733 (21%) had been exposed to intrapartum antibiotics. Intrapartum antibiotic exposure was associated with an autoimmune disease diagnosis (adjusted hazard ratio, 1.28; 95% confidence interval, 1.02-1.62), which corresponds to 22% (95% confidence interval, 6-39) as a theoretical population-attributable fraction. Intrapartum antibiotic exposure was not associated with diagnoses of allergic (adjusted hazard ratio, 1.08; 95% confidence interval, 0.97-1.20) or obstructive airway diseases (adjusted hazard ratio, 1.04; 95% confidence interval, 0.96-1.14). CONCLUSION: Intrapartum antibiotic exposure may be associated with an increased risk for autoimmune diseases in childhood. This finding supports the efforts to develop more specific group B streptococcal disease prevention strategies in the future.

Investigating prenatal and perinatal factors on meconium microbiota: a systematic review and cohort study.

BACKGROUND: The first-pass meconium has been suggested as a proxy for the fetal gut microbiota because it is formed in utero. This systematic review and cohort study investigated how pre- and perinatal factors influence the composition of the meconium microbiota. METHODS: We performed the systematic review using Covidence by searching PubMed, Scopus, and Web of Science databases with the search terms "meconium microbiome" and "meconium microbiota". In the cohort study, we performed 16 S rRNA gene sequencing on 393 meconium samples and analyzed the sequencing data using QIIME2. RESULTS: Our systematic review identified 69 studies exploring prenatal factors, immediate perinatal factors, and microbial composition in relation to subsequent health of infants but gave only limited comparative evidence regarding factors related to the composition of the meconium microbiota. The cohort study pointed to a low-biomass microbiota consisting of the phyla Firmicutes, Proteobacteria and Actinobacteriota and the genera Staphylococcus, Escherichia-Shigella and Lactobacillus, and indicated that immediate perinatal factors affected the composition of the meconium microbiota more than did prenatal factors. CONCLUSIONS: This finding supports the idea that the meconium microbiota mostly starts developing during delivery. IMPACT: It is unclear when the first-pass meconium microbiota develops, and what are the sources of the colonization. In this systematic review, we found 69 studies exploring prenatal factors, immediate perinatal factors, and microbial composition relative to subsequent health of infants, but there was no consensus on the factors affecting the meconium microbiota development. In this cohort study, immediate perinatal factors markedly affected the meconium microbiota development while prenatal factors had little effect on it. As the meconium microbiota composition was influenced by immediate perinatal factors, the present study supports the idea that the initial gut microbiota develops mainly during delivery.

Chemotherapy-related toxicities follow a typical pattern in children treated for acute lymphoblastic leukaemia.

AIM: Acute lymphoblastic leukaemia (ALL) therapy has been associated with a significant burden of toxicities. The aim of this study was to describe the full spectrum of toxic effects associated with childhood ALL. METHODS: Toxicity-related data were collected from the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL-2008 toxicity registry, in which data on 19 clinically relevant toxicities were registered during ALL treatment, and from patient medical records. All patients treated according to the NOPHO ALL-2008 protocol in Oulu University Hospital between 2008 and 2020 were included in the study. RESULTS: The cohort consisted of 73 patients, 38 of whom were male. Mean age at diagnosis was 6.6 ± 4.2 (range 1.4-16.0) years. All but one of the patients developed at least one treatment-related toxicity and more than half had multiple toxicities. Female sex and older age were associated with a higher tendency towards toxicity. The most common toxicity was vincristine-induced peripheral neuropathy, which was observed in 70 patients. Most toxicities were moderate or severe, but even mild toxicities often affected leukaemia treatment. CONCLUSION: Moderate and severe treatment-related toxicities are common, and most toxicities occur in a typical pattern in relation to the treatment phases.

Pneumonia, wheezing and asthma were more common in children after thymectomy due to open-heart surgery.

AIM: This nationwide study evaluated the clinical impact that an early thymectomy, during congenital heart defect (CHD) surgery, had on the health of children and adolescents. METHODS: The subjects were patients aged 1-15 years who had undergone CHD surgery at the University Children's Hospital, Helsinki, where all CHD surgery in Finland is carried out, from 2006 to 2018. The parents or the cases and population-based controls, matched for sex, age and hospital district, completed electronic questionnaires. We excluded those with low birth weights or a known immunodeficiency. Adjusted odds ratios (aOR) and 95% confidence intervals (CI) were calculated for prespecified outcomes. RESULTS: We received responses relating to 260/450 (58%) cases and 1403/4500 (31%) controls and excluded 73 cases with persistent cardiac or respiratory complaints after surgery. The CHD group reported more recurrent hospitalisations due to infections (aOR 6.3, 95% CI 3.0-13) than the controls and more pneumonia episodes (aOR 3.5, 95% CI 2.1-5.6), asthma (aOR 2.5, 95% CI 1.5-4.1) and wheezing (aOR 2.1, 95% CI 1.5-2.9). CONCLUSION: Hospitalisation due to infections, pneumonia, wheezing and asthma was more common in children after a thymectomy due to open-heart surgery than population-based controls, underlining the importance of immunological follow-ups.

Early-onset group B streptococcal infections in five Nordic countries with different prevention policies, 1995 to 2019.

BackgroundNeonatal early-onset disease caused by group B Streptococcus (GBS) is a leading cause of infant morbidity. Intrapartum antibiotic prophylaxis (IAP) is effective in preventing early-onset GBS disease, but there is no agreement on the optimal strategy for identifying the pregnant women requiring this treatment, and both risk-based prophylaxis (RBP) and GBS screening-based prophylaxis (SBP) are used.AimThe aim of this study was to evaluate the effect of SBP as a public health intervention on the epidemiology of early-onset GBS infections.MethodsIn 2012, Finland started the universal SBP, while Denmark, Iceland, Norway and Sweden continued with RBP. We conducted an interrupted time series analysis taking 2012 as the intervention point to evaluate the impact of this intervention. The incidences of early- and late-onset GBS infections during Period I (1995-2011) and Period II (2012-2019) were collected from each national register, covering 6,605,564 live births.ResultsIn Finland, a reduction of 58% in the incidence of early-onset GBS disease, corresponding to an incidence rate ratio (IRR) of 0.42 (95% CI: 0.34-0.52), was observed after 2012. At the same time, the pooled IRR of other Nordic countries was 0.89 (95% CI: 0.80-1.0), specifically 0.89 (95% CI: 0.70-1.5) in Denmark, 0.34 (95% CI: 0.15-0.81) in Iceland, 0.72 (95% CI: 0.59-0.88) in Norway and 0.97 (95% CI: 0.85-1.1) in Sweden.ConclusionsIn this ecological study of five Nordic countries, early-onset GBS infections were approximately halved following introduction of the SBP approach as compared with RBP.

Parental Ability to Assess Pediatric Vital Signs.

OBJECTIVE: To evaluate parents' ability to accurately assess their child's heart and respiratory rates (RRs) in the context of potential utility for telehealth visits. STUDY DESIGN: In this controlled study of 203 child-parent pairs, parents measured their child's heart rate (HR) using 4 methods: palpation, auscultation, and 2 photoplethysmographic smartphone applications. Parents measured RR by inspecting the child and tapping the smartphone application. The gold standards were electrocardiogram for the HR and the child's breaths measured by a health care professional for 60 seconds for the RR. We plotted the measurements using a Bland-Altman plot with 95% limits of agreement. RESULTS: Parents underestimated HR by palpation with a calculated bias of -18 beats per minute (bpm) (SD, 19), with limits of agreement ranging from -56 to 19 bpm. Parents overestimated and underestimated HR by auscultation with limits of agreement ranging from -53 to 46 bpm. Smartphone applications did not improve the accuracy of measurements. The accuracy of parental RR measurements was low. For young children, bias was -0.8 breaths per minute (brpm) (SD, 9.8) with limits of agreement from -20 to 19 brpm, and for older children, bias was 0.9 brpm (SD 7.4) with limits of agreement from 6 to 15 brpm. The sensitivity of parental subjective opinion to recognize accelerated RR was 37% (95% CI, 25%-51%). CONCLUSION: Parents were not able to assess their child's RR or HR accurately. Digital remote assessment of children should not rely on parental measurements of vital signs.

Recurrent febrile seizures and serum cytokines: a controlled follow-up study.

BACKGROUND: The role of cytokines in the pathogenesis of febrile seizures (FSs) is unclear, and information regarding cytokine production outside of FS episodes is scarce. METHODS: In our controlled follow-up study of patients with FSs, we compared the levels of 12 serum cytokines after the patients' first FSs, during febrile episodes without FSs, after recurrent FSs, during healthy periods after FSs, and between patients and controls. RESULTS: Two-hundred fifty-one patients with first FS participated in the study, of whom 17 (mean age 1.6 years, SD 0.7) with recurrent FSs completed the protocol as required by the sample size calculations. The mean IL-1RA level was higher after the first FSs (2580 pg/mL, SD 1516) than during febrile episodes without FSs (1336 pg/mL, SD 1364, P = 0.006) and healthy periods after FSs (474 pg/mL, SD 901, P = 0.001). IL-1RA levels were also higher during first (2580 pg/mL) and recurrent FSs (2666 pg/mL, SD 1747) in comparison with febrile controls (746 pg/mL, SD 551) (P < 0.001 and P = 0.001, respectively), but there was no difference in the IL-1RA between febrile episodes without FSs and febrile controls. CONCLUSIONS: Patients with FSs produce stronger inflammatory reactions during febrile episodes with FSs compared with febrile episodes without FSs and febrile controls. IMPACT: In patients with FSs, IL-1RA was higher following first FS than during febrile episodes without FSs and healthy periods after FSs. IL-1RA was higher in patients with FSs following first and recurrent FSs than in febrile controls. There was no significant difference in IL-1RA between febrile episodes of patients without FSs and febrile controls. Using IL-1RA as a surrogate marker of IL-1 axis activity, our results indicate that patients with FSs produced stronger inflammatory reactions during FS episodes but not during other febrile episodes or healthy periods after FSs. Cytokines may play a role in pathogenesis of FSs.

Adverse cardiovascular events are common during dexmedetomidine administration in neonates and infants during intensive care.

AIM: This study aimed to assess the safety of a commonly used sedative, dexmedetomidine in neonates and infants during intensive care. METHODS: A retrospective cohort study was conducted in the paediatric intensive care unit at Oulu University Hospital. The study population consisted of all children from birth up to 6 months of age who received dexmedetomidine during 2010-2016. Adverse cardiovascular outcomes were defined as abnormal heart rates or blood pressure values according to the Paediatric Early Warning Score. RESULTS: Of the 172 infants, 56% had congenital malformation, and 48% had undergone surgery. Neonates and 1-3-month-olds experienced bradycardia (86% vs. 73% in 1-3-month-olds and 50% in 3-6-month-olds, p = 0.001) and severe bradycardia (17% vs. 14% in 1-3-month-olds and 0% in 3-6-month-olds, p = 0.005) more often than older patients. The median maximum rate of dexmedetomidine infusion was 0.86 µg/kg/h (IQR = 0.60-1.71 µg/kg/h). A dose-dependent increase in bradycardia and severe hypotension was found. Adverse cardiovascular events were managed with additional fluid boluses and discontinuation of the infusion. CONCLUSION: Adverse cardiovascular events were common during dexmedetomidine administration in neonates and infants. Lower dexmedetomidine doses may be required in sedating neonates.

Duration of clinical symptoms in children with acute respiratory infection.

AIM: To investigate duration of clinical symptoms associated with various respiratory viruses and with the co-detection of respiratory viral and bacterial pathogens. METHODS: This prospective cohort study included 737 acutely ill children treated in a paediatric emergency department prior to the COVID-19 pandemic. Nasal swab samples were analysed with multiplex PCR panels for 16 viral and 7 bacterial respiratory pathogens. Parents filled in a questionnaire about the symptoms at the time of the visit and 14 days afterwards. RESULTS: Persistent symptoms 2 weeks after the onset of acute illness were common: 32% of the patients with a coronavirus 229 E, NL63 or OC43 finding, 31% of those with human metapneumovirus and 25% of those with rhinovirus reported ongoing symptoms. At least one symptom lasting more than 4 weeks was observed in 3-4% of the children. Children with viral and bacterial co-detection had a longer duration of fever than those with only viral detection (3.3 days [SD 2.8] vs. 1.6 days [SD 2.4], p < 0.001). CONCLUSION: Symptoms lasting for more than 2 to 4 weeks appear to be relatively frequent in all respiratory viral infections in children. Viral and bacterial co-detection may increase the duration of illness.

Absence from day care or school and parental absence from work during children's respiratory infections.

AIM: To investigate the social burden of nasopharyngeal detection of various respiratory viruses and the co-detection of viral and bacterial pathogens. METHODS: This prospective cohort study included 737 children with a suspected respiratory tract infection or fever in a paediatric emergency department during one epidemiological year (2014-2015) in Finland. Nasopharyngeal swab samples were analysed with multiplex polymerase chain reaction for 16 viruses and 7 respiratory bacteria. Parents filled out a questionnaire regarding child's and parents' absence from day care, school, or work at the time of the visit and 14 days afterward. RESULTS: The length of the children's absence from day care or school, or parental absence from work, did not significantly differ between the detected viral pathogens. Co-detection of any respiratory virus and Streptococcus pneumoniae or Haemophilus influenzae in the nasopharynx were associated with a 2.5-day (95% CI of the difference: 0.71 to 4.3) and 3.0-day (95% CI: 0.35 to 5.7) longer parental absence from work, respectively, compared with the detection of viruses alone when adjusted for age. CONCLUSION: Nasopharyngeal detection of S. pneumoniae or H. influenzae was associated with an increase in the length of parental absence from work when compared with the detection of virus alone.

Nasopharyngeal detection of atypical bacteria by multiplex polymerase chain reaction panel in acutely ill children was associated with an increased risk of pneumonia.

AIM: We aimed to assess whether detection of respiratory bacteria by multiplex polymerase chain reaction (PCR) testing associates with clinical outcomes in acutely ill children. METHODS: This cross-sectional study enrolled children under the age of 18 with a suspected respiratory infection treated in a paediatric emergency department of Oulu University Hospital, Finland from January 2015 through December 2015. Nasopharyngeal samples were routinely analysed for 16 respiratory viruses and later, after storage, analysed with a multiplex PCR panel for seven respiratory bacteria. RESULTS: At least one bacterial pathogen was detected in 600 out of the 1195 children (50%). The mean age was 3.3 (SD 3.7) years and 54% were boys. Atypical bacteria were associated with a risk of pneumonia (adjusted odds ratio [aOR] 14.1, 95% CI 3.98-50.1). Co-detection of rhinovirus with Streptococcus pneumoniae was not associated with risk of pneumonia (aOR 2.39, 95% CI 0.78-7.30). Detection of Streptococcus pneumoniae, Haemophilus influenzae or both was not associated with the risk of hospital admission or prescription of antibiotics. CONCLUSION: Nasopharyngeal detection of atypical bacteria in acutely ill children was associated with a markedly increased risk of pneumonia. The clinical utility of wide testing for other respiratory bacteria needs further evaluation.

Girl predominance in trampoline-related forearm shaft fractures and their increasing incidence since 2000.

BACKGROUND: There are reports of increasing incidence of forearm shaft fractures in children. Their treatment has been preferably nonoperative but surgical fixation has gained popularity due to elastic stable intramedullary nailing. We aimed to study whether the incidence of pediatric both-bone forearm shaft fractures and their operative care have changed since year 2000. Trampoline injuries, in particular, and their treatment, re-displacement and short-term outcomes were the secondary outcomes of the study. METHODS: A population-based study in the geographic catchment area of Oulu University Hospital district in 20-years of time period (2000 - 2019) was performed. Altogether 481 diaphyseal both-bone forearm fractures in children (< 16 years) were included. Age- and sex-related incidence rates were determined, by using the official numbers of the population-in-risk by Statistics Finland. Trampoline jumping and other types of injury were reviewed, as well as particulars of treatment and outcomes. RESULTS: The incidence of diaphyseal both-bone forearm fractures increased from 9.4/100 000 in 2000-2001 to 41.7/100 000 in 2018-2019 (P < 0.001). Surgical treatment increased respectively (from 8.8/100 000 in 2000-2001 to 35.3/100 000 in 2018-2019, P < 0.0001). Trampoline injuries explained one in three (29%) of all fractures; they increased from 0% in 2000-2001 to 36.6% in 2018-2019 (P < 0.001). During the last four years of the study (2016-2019), most trampoline-related injuries occurred among girls (61.2%), compared to boys (38.8%) (P = 0.031). Trampoline-related injuries comprised 46.9% of all fractures in girls, compared to 26.0% among boys (Diff. 20.8%, 4.7% to 36.1%, P = 0.009). The mean age of the patients elevated from 6.4 years (2000-2001) to 8.6 years (2018-2019) (P = 0.015). Boys predominated (69.6%) in 2000-2009 but during the last ten years, there was no statistical difference in distribution between the genders (males 54.6%, P = 0.11). CONCLUSIONS: During the twenty-year's of study period, the incidence of pediatric diaphyseal forearm fractures increased fivefold. Trampolining was the most usual single reason for the fractures. More attention should be focused to increase the safety of trampoline jumping, in particular among the girls.

Microbiota of the first-pass meconium and subsequent atopic and allergic disorders in children.

BACKGROUND: Some cohort studies have suggested that gut microbiota composition is associated with allergic diseases in children. The microbiota of the first-pass meconium, which forms before birth, represents the first gut microbiota that is easily available for research and little is known about any relationship with allergic disease development. OBJECTIVE: We investigated whether the bacterial composition of the first-pass meconium is associated with the development of allergic diseases before 4 years of age. METHODS: Prospective birth cohort study. Bacterial composition of first-pass meconium was analysed using bacterial 16S rRNA gene amplicon sequencing. Atopic and allergic diseases were evaluated via online survey or telephone to age 4 years, based on the International Study of Asthma and Allergies in Childhood questionnaire. RESULTS: During a 6-week period in 2014, 312 children were born at the Central Finland Central Hospital. Meconium was collected from 212 at a mean of 8-hour age. Outcome data at 4 years were available for 177 (83%) children, and 159 of these had sufficient amplification of bacterial DNA in meconium. Meconium microbiota composition, including diversity indices and relative abundances of the main phyla and genera, was not associated with subsequent atopic eczema, wheezing or cow's milk allergy. Principal components analysis did not identify any clustering of the meconium microbiomes of children with respect to wheezing or cow's milk allergy. CONCLUSIONS: We found no evidence that gut microbiota composition of first-pass meconium is associated with atopic manifestations to age 4 years. However, larger studies are needed to fully exclude a relationship.

The natural history of emerging diabetic retinopathy and microalbuminuria from prepuberty to early adulthood in Type 1 diabetes: A 19-year prospective clinical follow-up study.

OBJECTIVE: To evaluate the impact of long-term glycaemic control and glycaemic variability on microvascular complications in adolescents and young adults with childhood-onset Type 1 diabetes. METHODS: Twenty-six participants took part in a prospective follow-up study. We used univariate generalised estimating equations (GEE) analysis with first-order autoregressive AR(1) covariance structure for repeated measurements to evaluate the relationship between emerging diabetic retinopathy (DR) and each single explanatory variable, namely age at developmental stages from late prepuberty until early adulthood, duration of diabetes and long-term HbA1c . Thereafter, the simultaneous effect of these three explanatory variables to DR was analysed in a multivariate model. RESULTS: Twenty-five participants developed DR by early adulthood after a median diabetes duration of 16.2 years (range 6.3-24.0). No participants had DR during prepuberty. Each of the three variables was independently associated with emerging DR: age (OR 1.47, 95% CI to 1.25 to 1.74, p < 0.001) stronger than diabetes duration (OR 1.42, 95% CI 1.23 to 1.63, p < 0.001) and HbA1c (OR 1.02, 95% CI 1.001 to 1.05, p = 0.041) in this population. In the multivariate analysis of these three explanatory variables, only age was associated with DR (adjusted OR 1.52, 95% CI 1.10 to 2.10, p = 0.012). CONCLUSIONS: The emergence of DR during adolescence and early adulthood is not rare and increases with age in patients with deteriorating metabolic control during puberty and thereafter. This underpins the need to prevent deterioration of glycaemic control from taking place during puberty-seen again in this follow-up study-in children with diabetes.

INnoVative trial design for testing the Efficacy, Safety and Tolerability of 6-month treatment with incretin-based therapy to prevent type 1 DIAbetes in autoantibody positive participants: A protocol for three parallel double-blind, randomised controlled trials (INVESTDIA).

AIMS: ß-cell stress and dysfunction may contribute to islet autoimmunity and progression to clinical type 1 diabetes. We present a protocol of three randomised controlled trials assessing the effects of glucagon-like peptide 1 (GLP - 1) analogue liraglutide in three early stages of type 1 diabetes. METHODS: We will test 10- to 30-year-old people with multiple islet autoantibodies for their glucose metabolism and randomise participants with stage 1 (multiple islet autoantibodies and normoglycaemia), stage 2 (multiple islet autoantibodies and dysglycaemia) and early stage 3 (clinical diagnosis) type 1 diabetes, 10-14 persons in each, to a 6-month intervention with liraglutide or placebo with 6-month follow-up in the stage 2 and stage 3 trials and 18-month follow-up in the stage 1 trial. Primary efficacy outcome in the stage 1 and stage 2 trials is a first-phase insulin response in an intravenous glucose tolerance test and C-peptide area under the curve in a 2-h mixed-meal tolerance test in the stage 3 trial. In addition, safety and tolerability of liraglutide treatment will be assessed. CONCLUSIONS: Most prevention trials of type 1 diabetes have targeted the immune system. Treatment with GLP-1 analogue liraglutide supports the pancreatic ß-cells, which should likewise attenuate islet autoimmunity. Our innovative study design allows simultaneous investigation of an intervention in three groups of people who represent various early stages of type 1 diabetes and maximises the eligibility to participate. TRIAL REGISTRATION: NCT02611232 (stage 1 trial), NCT02898506 (stage 2 trial), NCT02908087 (stage 3 trial).

Antibiotics at birth and later antibiotic courses: effects on gut microbiota.

BACKGROUND: Intrapartum antibiotic prophylaxis (IAP) is widely used, but the evidence of the long-term effects on the gut microbiota and subsequent health of children is limited. Here, we compared the impacts of perinatal antibiotic exposure and later courses of antibiotic courses on gut microbiota. METHODS: This was a prospective, controlled cohort study among 100 vaginally delivered infants with different perinatal antibiotic exposures: control (27), IAP (27), postnatal antibiotics (24), and IAP and postnatal antibiotics (22). At 1 year of age, we performed next-generation sequencing of the bacterial 16S ribosomal RNA gene of fecal samples. RESULTS: Exposure to the perinatal antibiotics had a clear impact on the gut microbiota. The abundance of the Bacteroidetes phylum was significantly higher in the control group, whereas the relative abundance of Escherichia coli was significantly lower in the control group. The impact of the perinatal antibiotics on the gut microbiota composition was greater than exposure to later courses of antibiotics (28% of participants). CONCLUSIONS: Perinatal antibiotic exposure had a marked impact on the gut microbiota at the age of 1 year. The timing of the antibiotic exposure appears to be the critical factor for the changes observed in the gut microbiota. IMPACT: Infants are commonly exposed to IAP and postnatal antibiotics, and later to courses of antibiotics during the first year of life. Perinatal antibiotics have been associated with an altered gut microbiota during the first months of life, whereas the evidence regarding the long-term impact is more limited. Perinatal antibiotic exposure had a marked impact on the infant's gut microbiota at 1 year of age. Impact of the perinatal antibiotics on the gut microbiota composition was greater than that of the later courses of antibiotics at the age of 1 year.

Severe hospital-acquired hyponatremia in acutely ill children receiving moderately hypotonic fluids.

BACKGROUND: Hypotonic fluids have been associated with hospital-acquired hyponatremia. The incidence of life-threatening severe hyponatremia associated with hypotonic fluids has not been evaluated. METHODS: This was a population-based cohort study of 46,518 acutely ill children 15 years of age or under who visited the pediatric emergency department (ED) at Oulu University Hospital, Finland, between 2007 and 2017. We retrieved all electrolyte measurements from the comprehensive electronic laboratory system and reviewed medical records for all patients with severe hyponatremia. RESULTS: The overall occurrence of severe hyponatremia (serum sodium < 125 mmol/L) was found in 27 out of 46,518 acutely ill children (0.06%, 95% confidence interval 0.04-0.08%). After admission, severe hyponatremia developed in seven of 6,984 children receiving moderately hypotonic fluid therapy (0.1%, 95% confidence interval 0.04-0.2%), usually within 8 h of admission. All children who developed severe hyponatremia during hospitalization were severely ill. CONCLUSION: In this register-based cohort study of children presenting to the ED, severe hyponatremia developed in one of 998 acutely ill children receiving moderately hypotonic fluid therapy. A higher resolution version of the Graphical abstract is available as Supplementary information.

Reduced dose folinic acid rescue after rapid high-dose methotrexate clearance is not associated with increased toxicity in a pediatric cohort.

PURPOSE: Low doses of folinic acid (FA) rescue after high-dose methotrexate (HD-MTX) have been associated with increased toxicity, whereas high doses may be related to a decreased antileukemic effect. The optimal dosage and duration of FA rescue remain controversial. This study was designed to investigate, whether a shorter duration of FA rescue in the setting of rapid HD-MTX clearance is associated with increased toxicity. METHODS: We reviewed the files of 44 children receiving a total of 350 HD-MTX courses during treatment for acute lymphoblastic leukemia according to the NOPHO ALL-2000 protocol. Following a 5 g/m2 HD-MTX infusion, pharmacokinetically guided FA rescue commenced at hour 42. As per local guidelines, the patients received only one or two 15 mg/m2 doses of FA in the case of rapid MTX clearance (serum MTX ≤ 0.2 µmol/L at hour 42 or hour 48, respectively). Data on MTX clearance, FA dosing, inpatient time, and toxicities were collected. RESULTS: Rapid MTX clearance was observed in 181 courses (51.7%). There was no difference in the steady-state MTX concentration, nephrotoxicity, hepatotoxicity, neutropenic fever, or neurotoxicity between courses followed by rapid MTX clearance and those without. One or two doses of FA after rapid MTX clearance resulted in a 7.8-h shorter inpatient time than if a minimum of three doses of FA would have been given. CONCLUSION: A pharmacokinetically guided FA rescue of one or two 15 mg/m2 doses of FA following HD-MTX courses with rapid MTX clearance results in a shorter hospitalization without an increase in toxic effects.