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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.

Traditionally the amount of fluid and electrolytes needed in intravenous fluid therapy in children has been calculated by using Holliday-Segar method published in 1957. By using Holliday-Segar method, the concentration of sodium in intravenous fluids is markedly less compering to plasma. Due to concern of risk for severe hyponatremia there is an increased use of isotonic intravenous fluid therapy that contians the same amount of sodium as plasma among acutely ill children. According to our clinical experience mild hyponatremia is common among acutely ill children, whereas severe hyponatremia (serum sodium less than 125 mmol/l) is rare though hypotonic intravenous fluid therapy was used in our clinic. The increasing use of isotonic intravenous fluid therapy among acutely ill children also increased use of commercially available plasma-like fluids, though there are only limited evidence of the use of plasma-like commercially available intravenous fluids in children. To get more evidence of the use of plasma-like isotonic fluid therapy in acutely ill children, we set up a randomized clinical trial. We compared traditionally used intravenous fluid therapy (G5% with 80 mmol/l of sodium and 20 mmol/l of potassium) to commercially available plasma-like isotonic fluid therapy (Plasmalyte glucose containing 140 mmol/l of sodium and 5 mmol/l of potassium). We also set up a retrospective register-based cohort study to evaluate the occurrence and risk factor for electrolyte abnormalities. 614 children were enrolled to randomized clinical trial. According to randomized clinical trial, the use of plasma-like isotonic fluid therapy caused an increased risk for electrolyte abnormalities (20% vs 2.9 %, 95% CI 12–22%), most notably for hypokalemia (19% vs 2.9%, 95 CI 11–21%). In randomized trial, the use of plasmalike isotonic fluid therapy did not decreas the risk for hyponatremia. However, in cohort study including 10-year period, 0.1% of children receiving hypotonic intra, Tiivistelmä Perinteisesti lasten neste- ja elektrolyyttitarve on laskettu vuonna 1957 julkaistun Holliday-Segarin metodin mukaisesti, jolloin suonensisäinen nestehoito sisältää vähemmän natriumia kuin plasma. Viime aikoina lapsipotilaiden nestehoidossa on siirrytty suosimaan aiemmin käytettyä nestehoitoa enemmän natriumia sisältävää nestettä, sillä perinteisen nestehoidon on ajateltu altistavan vaikean hyponatremian kehittymiselle. Aiempi kliininen kokemuksemme on, että äkillisesti sairastuneilla lapsipotilailla on usein lievä hyponatremiaa, mutta vaikea hyponatremia (natrium alle 125 mmol/l) on harvinainen myös perinteisen nestehoidon aikana. Uusien suonensisäisten nestehoitosuositusten myötä kaupallisten plasman kaltaisten valmisnesteiden käyttö lasten suonensisäisessä nestehoidossa on lisääntynyt, vaikka näyttö niiden hyödystä lapsipotilailla on rajallinen. Jotta saisimme lisää tietoa plasmankaltaisten valmisnesteiden käytöstä äkillisesti sairailla lapsilla, suunnittelimme satunnaistetun kliinisen tutkimuksen, jossa vertasimme perinteisempää nestehoitoa (G5%, jossa natriumia 80 mmol/l ja kaliumia 20 mmol/l) kaupalliseen, plasmankaltaiseen valmisnesteeseen (Plasmalyte glukoosi, natriumia 140 mmol/l ja kaliumia 5 mmol/l). Lisäksi selvitimme elektrolyyttihäiriöiden esiintyvyyttä- ja riskitekijöitä 10 vuoden retrospektiivisellä seurantatutkimuksella. Satunnaistettuun kliiniseen tutkimukseemme rekrytoitiin yhteensä 614 lasta. Tutkimuksemme perusteella elektrolyyttisisällöltään plasmantyyppisen valmisnesteen käyttö lisäsi elektrolyyttihäiriöiden ilmaantuvuutta verrattuna perinteisesti käytettyyn nestehoitoon (20 % vs 2.9 %, 95 % CI 12–22 %). Erityisesti plasmantyyppinen valmisneste altisti hypokalemian kehittymiselle (19 % vs 2.9 %, 95 % CI 11–21 %). Seurantatutkimuksessa havaitsimme, että vaikea hyponatremia on hyvin harvinainen äkillisesti sairastuneilla lapsipotilailla (0.2 %) kun taas lievä hyponatremia on yleinen (11.5 %). Satunnaistetussa kliinisessa tutkimuksess

The mechanism by which cranberry-lingonberry juice (CLJ) prevents urinary tract infections (UTI) in children remains unknown. We hypothesized that it alters the composition of the gut or urinary microbiome. Altogether, 113 children with UTIs were randomly allocated to drink either CLJ or a placebo juice for 6 months. We collected urinary samples at 3 months and fecal samples at 3, 6 and 12 months and used next-generation sequencing of the bacterial 16S gene. The children who consumed CLJ had a lower abundance of Proteobacteria (p = 0.03) and a higher abundance of Firmicutes phylum (p = 0.04) in their urinary microbiome at 3 months than did those in the placebo group. The abundance of Escherichia coli in the urinary microbiome was 6% in the CLJ group and 13% in the placebo group (p = 0.42). In the gut microbiome the abundance of Actinobacteria at 3 and 12 months was higher in the children receiving CLJ. The diversity of the urinary and gut microbiome did not differ between the groups. The children drinking CLJ had a different urinary and gut microbiome from those receiving a placebo juice. A healthy urinary microbiome may be important in preventing UTIs in children.

Introduction: Knowledge on the human gut microbiota in health and disease continues to rapidly expand. In recent years, changes in the gut microbiota composition have been reported as a part of the pathology in numerous neurodegenerative diseases. Bacterial extracellular vesicles (EVs) have been suggested as a novel mechanism for the crosstalk between the brain and gut microbiota, physiologically connecting the observed changes in the brain to gut microbiota dysbiosis. Methods: Publications reporting findings on bacterial EVs passage through the blood–brain barrier were identified in PubMed and Scopus databases. Results: The literature search yielded 138 non-duplicate publications, from which 113 records were excluded in title and abstract screening step. From 25 publications subjected to full-text screening, 8 were excluded. The resulting 17 publications were considered for the review. Discussion: Bacterial EVs have been described with capability to cross the blood–brain barrier, but the mechanisms behind the crossing remain largely unknown. Importantly, very little data exists in this context on EVs secreted by the human gut microbiota. This systematic review summarizes the present evidence of bacterial EVs crossing the blood–brain barrier and highlights the importance of future research on gut microbiota-derived EVs in the context of gut-brain communication across the blood–brain barrier.

Both exposure to antibiotics at birth and delivery via Caesarean section influence the gut bacteriome’s development in infants. Using 16S rRNA and internal transcribed spacer sequencing on the Ion Torrent platform, we employed network analysis to investigate the bacterial and fungal interkingdom relationships in the gut microbiome from birth to age 18 months in a prospective cohort study of 140 infants. The gut microbiome at ages six and 18 months revealed distinctive microbial interactions, including both positive and negative associations between bacterial and fungal genera in the gut ecosystem. Perinatal factors, delivery mode and intrapartum antibiotic exposure affected the associations between bacterial and fungal species. In infants exposed and unexposed to perinatal antibiotics, the gut microbiome formed distinct networks for the bacteriome and mycobiome. The fungi Saccharomyces, Trichosporon, Pezoloma, Cystofilobasidium, Rigidoporus and Fomitopsis were strongly associated with exposure to antibiotics at birth. Hyaloscypha, Trichosporon, Fomitopsis and Vishniacozyma were strongly associated with the control group that was not exposed to antibiotics. Five distinct networks were formed according to delivery mode. The present study confirms that bacteria and fungi clearly interact in the infant gut ecosystem. Furthermore, perinatal factors appear to influence the relationships between bacteria and fungi in the developing gut microbiome.

The human gut microbiota is comprised of a variety of microbes, such as bacteria, fungi, viruses, and archaea. Furthermore, the gut contains bacterial extracellular vesicles (bEVs), small particles secreted by bacteria. The health effects of the gut microbiota have been explored but it is yet unclear when the gut microbiota starts developing. The womb was earlier assumed to be sterile, but recent studies imply that the fetus may already be exposed to microbes in the womb. Colonization of the gut is usually assessed from the first-pass meconium, the first stool passed after birth, which is assumed to serve as a proxy for the fetal gut microbiota. This cohort study of 513 mother-infant pairs was undertaken to elucidate the timing of gut microbiota development and factors affecting it. The first-pass meconium and later stool samples were collected from the infants and placenta and amniotic fluid from the mothers. 16S rRNA gene sequencing was performed to characterize the bacteriome and bEVs in the samples and internal transcribed spacer (ITS) gene sequencing to characterize the mycobiome. Questionnaires were used to collect information from the families on environmental and lifestyle conditions during pregnancy in order to assess the effect of prenatal factors on the microbial composition of the initial gut microbiota. A detectable meconium bacteriome and mycobiome were characterized, but no detectable placenta or amniotic fluid microbiota could be identified. The meconium microbiota was mainly affected by birth factors, including the mode of delivery and use of intrapartum antibiotics. Prenatal factors had little effect on the composition of the meconium bacteriome. The bEVs characterized in the meconium were found to be unaffected by the birth factors. Birth factors affected gut mycobiome development in the infants at least until the age of 18 months. It is concluded that the neonatal gut is probably colonized during birth, and that the birth factors influen, Tiivistelmä Ihmisen suoliston mikrobiomi koostuu monenlaisista mikrobeista, kuten bakteereista, sienistä, viruksista ja arkeista. Lisäksi suolisto sisältää bakteeriperäisiä ekstrasellulaarisia vesikkeleitä (bEV), jotka ovat pieniä partikkeleita, joita bakteerit erittävät. Suoliston mikrobiomin terveysvaikutuksia on tutkittu jo laajasti, mutta suoliston mikrobiomin alkuperää ei vielä tunneta tarkkaan. Aikaisemmin kohtua on pidetty sikiölle steriilinä kasvuympäristönä, mutta viimeaikainen tutkimus osoittaa, että sikiö saattaa altistua mikrobeille kohdussa. Suoliston kolonisointia on tutkittu lapsenpihkan eli mekoniumin, lapsen elämän ensimmäisen ulosteen avulla, jonka uskotaan kuvaavan sikiön suoliston mikrobiomia. Tutkimus koostui 513 äiti-lapsiparin kohortista, ja tutkimuksen tarkoituksena oli havainnollistaa suoliston mikrobiomin kolonisointiaikaa sekä sen kehitykseen vaikuttavia tekijöitä. Keräsimme mekonium- ja ulostenäytteitä lapsilta sekä istukka- ja lapsivesinäytteitä äideiltä, ja suoritimme 16S rRNA -geenisekvensoinnin tutkimaan bakteriomia ja bEV:itä ja ITS-geenisekvensoinnin tutkimaan mykobiomia näytteissä. Lisäksi suoritimme kyselytutkimuksen perheille heidän elinympäristöstään ja elintavoistaan raskauden aikana tutkiaksemme prenataalisia ja synnytyksenaikaisia tekijöitä, jotka ovat voineet vaikuttaa varhaisen suoliston mikrobiomin kehitykseen. Mekoniumista löytyi havaittava bakteriomi ja mykobiomi, mutta istukasta ja lapsivedestä havaittavaa mikrobiomia ei löytynyt. Mekoniumin mikrobiomiin vaikuttivat eritoten synnytyksenaikaiset tekijät, mukaan lukien synnytystapa ja synnytyksenaikaiset antibiootit. Prenataalisilla tekijöillä oli pieni vaikutus mekonium bakteriomiin. Löysimme myös mekoniumista bEV:itä, joihin synnytyksenaikaiset tekijät eivät vaikuttaneet. Lisäksi totesimme, että synnytyksenaikaiset tekijät vaikuttivat suoliston mykobiomin kehitykseen lapsilla vähintään 18 kk ikäisiksi asti. Tämä tutkimus osoitti, että varhainen suoliston mikrobiomi tode

Importance: Although topical antibiotics are often prescribed for treating acute infective conjunctivitis in children, their efficacy is uncertain. Objective: To assess the efficacy of topical antibiotic therapy for acute infective conjunctivitis. Design, Setting, and Participants: A randomized clinical trial was conducted in primary health care in Oulu, Finland, from October 15, 2014, to February 7, 2020. Children aged 6 months to 7 years with acute infective conjunctivitis were eligible for enrollment. The participants were followed up for 14 days. A subsequent meta-analysis included the present trial and 3 previous randomized clinical trials enrolling pediatric patients aged 1 month to 18 years with acute infective conjunctivitis. Interventions: Participants in the present randomized clinical trial were randomized to moxifloxacin eye drops, placebo eye drops, or no intervention. Main Outcomes and Measures: The primary outcome in the present randomized clinical trial was time to clinical cure (in days); in the meta-analysis, the primary outcome was the proportion of participants with conjunctival symptoms on days 3 to 6. Results: The randomized clinical trial included 88 participants (46 [52%] girls), of whom 30 were randomized to moxifloxacin eye drops (mean [SD] age, 2.8 [1.6] years), 27 to placebo eye drops (mean [SD], age 3.0 [1.3] years), and 31 to no intervention (mean [SD] age, 3.2 [1.8] years). The time to clinical cure was significantly shorter in the moxifloxacin eye drop group than in the no intervention group (3.8 vs 5.7 days; difference, −1.9 days; 95% CI, −3.7 to −0.1 days; P = .04), while in the survival analysis both moxifloxacin and placebo eye drops significantly shortened the time to clinical cure relative to no intervention. In the meta-analysis, a total of 584 children were randomized (300 to topical antibiotics and 284 to a placebo), and the use of topical antibiotics was associated with a significant reduction in the proportion of c

Importance: Corticosteroids administered to women at risk of imminent preterm birth is one of the most effective ways to improve the prognosis of infants born preterm. Scant data about long-term neurodevelopmental and neurosensory outcomes among the treatment-exposed children are mixed, suggesting that not all domains of neurodevelopmental and neurosensory function may be equally affected. Moreover, the long-term outcomes may vary according to whether the treatment-exposed children are being born preterm (<37 weeks and 0 days) or term (≥37 weeks and 0 days). Objectives: To study whether antenatal corticosteroid treatment is associated with psychological developmental and neurosensory disorders in children born term and preterm and whether the associations persist in a sibling-comparison design. Design, setting, and participants: This population-based retrospective register-linkage study comprised all singleton live births in Finland between January 1, 2006, and December 31, 2017, followed up until December 31, 2018, as well as a sibling comparison among term sibling pairs. Data were analyzed from March 21, 2021, to July 7, 2022. Exposures: Antenatal corticosteroid treatment. Main outcomes and measures: Cox proportional hazards regression models were used to estimate the associations between antenatal corticosteroid treatment and physician-diagnosed specific developmental disorders of speech and language, scholastic skills, and motor function; pervasive developmental disorder; other or unspecified psychological developmental disorder; disorders of vison and hearing; epilepsy; and cerebral palsy. Results: The study population comprised 670 097 singleton children (342 562 boys [51.1%]) followed up for a median of 5.8 years (IQR, 3.1–8.7 years). Of the 14 868 treatment-exposed children (2.2%; 53.9% boys), 6730 (45.3%) were born term, and 8138 (54.7%) were born preterm, and of the 655 229 nonexposed children (97.8%; 51.1% boys), 634 757 (96.9%) were born term

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.

Tiivistelmä Lasten mikrobilääkkeiden kulutus on vähentynyt kymmenen viime vuoden aikana Suomessa ja muualla Euroopassa, mutta edelleen jopa 40 % alle 15-vuotiaista saa vuosittain ainakin yhden mikrobilääkehoidon. Näyttö lasten mikrobilääkehoitojen optimaalisista pituuksista on puutteellista, ja hoitosuositusten sisältö vaihtelee kansainvälisesti. Lasten mikrobilääkehoitojen kokonaiskuormaa voitaisiin vähentää käyttämällä lyhintä suositeltua kuurin pituutta.

Aim: The aim was to evaluate the incidence, hospitalisations and deaths in acutely ill children with dysnatraemias. Methods: This was a register-based cohort study of 46 518 acutely ill children aged <16 years who visited a paediatric emergency department. Risk factors were assessed using two nested case–control studies. Results: Moderate to severe hypernatraemia occurred in 92 children (0.20%; 95% confidence interval [CI]: 0.16%–0.24%) and moderate to severe hyponatraemia in 131 children (0.28%; 95% CI: 0.24%–0.33%). Underlying medical conditions increased the risk of both moderate to severe hypernatraemia (odds ratio [OR]: 17; 95% 5.5–51) and moderate to severe hyponatraemia (OR: 3.5; 95% CI: 2.0–5.9). The use of a feeding tube (OR: 14; 95% CI: 3.2–66) and intellectual disability (OR: 7.3; 95% CI: 3.0–18) was associated with moderate to severe hypernatraemia. The risk of death was associated with moderate to severe hypernatraemia (OR: 19; 95% CI: 2.0–2564) and moderate to severe hyponatraemia (OR: 33; 95% CI: 3.7–4311). Conclusions: Severe dysnatraemias were more prevalent in acutely ill children with underlying medical conditions and were markedly associated with the risk for death.

Background: Bacterial extracellular vesicles (EVs) are more likely to cross biological barriers than whole-cell bacteria. We previously observed EV-sized particles by electron microscopy in the first-pass meconium of newborn infants. We hypothesized that EVs may be of bacterial origin and represent a novel entity in the human microbiome during fetal and perinatal periods. Methods: We extracted EVs from first-pass meconium samples of 17 newborn infants and performed bacterial 16S rRNA gene sequencing of the vesicles. We compared the EV content from the meconium samples of infants based on the delivery mode, and in vaginal delivery samples, based on the usage of intrapartum antibiotics. Results: We found bacterial EVs in all first-pass meconium samples. All EV samples had bacterial RNA. Most of the phyla present in the samples were Firmicutes (62%), Actinobacteriota (18%), Proteobacteria (10%), and Bacteroidota (7.3%). The most abundant genera were Streptococcus (21%) and Staphylococcus (17%). The differences between the delivery mode and exposure to antibiotics were not statistically significant. Conclusions: Bacterial EVs were present in the first-pass meconium of newborn infants. Bacterial EVs may represent an important novel feature of the gut microbiome during fetal and perinatal periods.

Importance: Limited data are available on the clinical impact of multiplex polymerase chain reaction (PCR) point-of-care testing for respiratory pathogens in acutely ill children. Objective: To evaluate the effect of multiplex PCR point-of-care testing for respiratory pathogens on antibiotic use in acutely ill children. Design, Setting, and Participants: This unblinded, randomized clinical trial was conducted from May 6, 2019, through March 12, 2020. The participants were followed up until hospitalization or discharge from the emergency department (ED) for primary outcome. The study was conducted at the pediatric ED of Oulu University Hospital, Finland. Eligible study participants were children aged 0 to 17 years with fever and/or any respiratory signs or symptoms. Children with underlying medical conditions were included. The statistical analyses were performed between August 11, 2020, and September 14, 2021. Interventions: The participants were randomly assigned in a 2:1 ratio either to undergo multiplex PCR point-of-care testing (18 respiratory viruses and 3 bacteria with results ready within 70 minutes) upon arrival at the ED or to receive routine care. Main Outcomes and Measures: The primary outcome was the proportion of children receiving antibiotic therapy. The secondary outcomes were the numbers of diagnostic tests and radiographic imaging procedures performed and costs. Results: A total of 1417 children were assessed for eligibility. After exclusions, 1243 children (692 boys [56%]) were randomly allocated to either the intervention (829 children) or control (414 children) group. The mean (SD) age of the participants was 3.0 (3.6) years in the intervention group (median [IQR], 1.7 [0.4–4.1] years) and 3.0 (3.5) years (median [IQR], 1.9 [0.4–4.1] years) in the control group. Multiplex PCR point-of-care testing for respiratory pathogens did not reduce the overall prescribing of antibiotics in the emergency department (226 children [27.3%] in the inter

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.

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.

Tiivistelmä Hemofagosyyttinen lymfohistiosytoosi (HLH) on henkeä uhkaava tulehdusreaktio, jonka syntymekanismina on T-imusolujen ja makrofagien keskinäinen sytokiinivälitteinen aktivaatio. Taudin tunnusmerkkejä ovat epäselvä ja pitkittynyt kuume, maksan ja pernan suurentuminen sekä verenkuvan solupuutokset. Perinnöllinen HLH (FHL) on ryhmä geneettisiä sairauksia, joissa tauti kehittyy ensimmäisten elinkuukausien aikana muutoin terveelle lapselle. FHL johtuu sytotoksisten imusolujen kyvyttömyydestä tuhota tulehdusvasteen herättäneet antigeeniä esittelevät solut, mistä seuraa sytokiinivälitteinen itseään voimistava tulehdusreaktio. FHL:n hoito perustuu T-solujen tukahduttamiseen ja allogeeniseen kantasolusiirtoon. FHL on harvinainen mutta merkittävä erotusdiagnostinen vaihtoehto, kun kuumeisen imeväisen verenkuvassa havaitaan solupuutoksia. Taudin nopea tunnistaminen on tärkeää, jotta tehokas hoito päästään aloittamaan ennen monielinvauriota.

Vertical transmission of maternal microbes is a major route for establishing the gut microbiome in newborns. The impact of perinatal antibiotics on vertical transmission of microbes and antimicrobial resistance is not well understood. Using a metagenomic approach, we analyzed the fecal samples from mothers and vaginally delivered infants from a control group (10 pairs) and a treatment group (10 pairs) receiving perinatal antibiotics. Antibiotic-usage had a significant impact on the main source of inoculum in the gut microbiome of newborns. The control group had significantly more species transmitted from mothers to infants (P = 0.03) than the antibiotic-treated group. Approximately 72% of the gut microbial population of infants at 3–7 days after birth in the control group was transmitted from their mothers, versus only 25% in the antibiotic-treated group. In conclusion, perinatal antibiotics markedly disturbed vertical transmission and changed the source of gut colonization towards horizontal transfer from the environment to the infants.

Meconium, a newborns’ first stool after birth, is the first easily available sample for gut microbiota studies. Recent studies have shown that first-pass meconium contains bacteria and that factors such as gestational age and delivery mode can impact meconium microbiota composition. The purpose of this thesis was to investigate what factors affect the bacterial composition of first-pass meconium and the impact of meconium microbiota on later health. This was a prospective cohort study of 212 consecutive newborns. The first stool after birth was collected and analyzed using next-generation sequencing of the bacterial 16S rRNA gene. Fecal samples were also collected at one year of age. Clinical follow ups were conducted until the participants reached four years of age. In total, 91% of the first-pass meconium samples contained bacterial DNA. The composition of first-pass meconium was distinct from that of the gut microbiota at one year of age. The biodiversity of the maternal living environment during pregnancy was associated with the bacterial composition of the first stool. The bacterial composition of first-pass meconium was associated with the subsequent health of the infants. The infants with infantile colic had less lactobacilli in their meconium microbiota than those without colic. The children who were overweight at three years of age had less phylum Bacteroidetes and genus Bacteroides in their first-pass meconium than children with normal weight. The composition of intestinal microbiota at 1 year of age was not associated with the risk of being overweight in early childhood. The bacterial composition of meconium microbiota was not associated with subsequent atopic eczema or wheezing. This thesis shows that earlier reported associations between intestinal microbiota, infantile colic, and overweight appear to be present immediately after birth. These findings emphasize the importance of pre- and perinatal factors on the early intestinal colonization an, Tiivistelmä Elämän ensimmäisen uloste, mekonium, tarjoaa ensimmäisen helposti saatavilla olevan näytteen suolistomikrobiston tutkimiseen. Viimeaikaiset tutkimukset ovat osoittaneet, että mekonium sisältää bakteereita. Muun muassa raskauden keston ja synnytystavan on raportoitu vaikuttavan mekoniumin bakteerikoostumukseen. Tässä väitöskirjassa tutkittiin mekoniumin mikrobiston koostumukseen vaikuttavia tekijöitä sekä mekoniumin mikrobiston yhteyttä lapsen myöhempään terveyteen. Tutkimuksen aineistona on 212 täysiaikaisen lapsen kohortti. Ensimmäinen mekonium kerättiin ja sen bakteerikoostumus analysoitiin bakteerin 16S rRNA-geenin sekvensoinnin avulla. Lisäksi lapsilta kerättiin seurantaulostenäyte yhden vuoden iässä. Tutkimukseen osallistuneita lapsia seurattiin neljän vuoden ikään asti. Tutkimus osoitti, että 91 % mekonium-näytteistä sisälsi bakteerien DNA:ta. Mekoniumin mikrobiston koostumus poikkesi selkeästi suolistomikrobiston koostumuksesta yhden vuoden iässä. Raskauden ja syntymän aikaisista tekijöistä erityisesti äidin elinympäristön monimuotoisuus oli yhteydessä mekoniumin mikrobiston koostumukseen. Tutkimuksessa havaittiin, että mekoniumin bakteerikoostumus oli yhteydessä lasten myöhempiin terveysongelmiin. Lapsilla, jotka kärsivät imeväisen koliikista, oli vähemmän laktobasilleja jo mekoniumin mikrobistossa kuin niillä lapsilla, joilla ei ollut koliikkia. Niillä lapsilla, jotka olivat ylipainoisia kolmen vuoden iässä, oli enemmän Bacteroidetes -pääjakson sekä Bacteroides -suvun bakteereita mekoniumissa kuin normaalipainoisilla lapsilla. Suolistomikrobiston koostumus yhden vuoden iässä ei ollut yhteydessä lapsen ylipainoon. Mekoniumin mikrobiston bakteerikoostumus ei ollut yhteydessä myöhempään atooppiseen ihottumaan tai hengityksen vinkumiseen. Tämä väitöskirja osoittaa, että vastasyntyneen mekoniumin mikrobiston koostumus on yhteydessä koliikkiin ja ylipainon kehittymiseen lapsuusiässä. Tämä korostaa raskauden ja synnytykseen liittyvien tekijöiden merkit

Background: Homozygous loss of DIAPH1 results in seizures, cortical blindness, and microcephaly syndrome (SCBMS). We studied 5 Finnish and 2 Omani patients with loss of DIAPH1 presenting with SCBMS, mitochondrial dysfunction, and immunodeficiency. Objective: We sought to further characterize phenotypes and disease mechanisms associated with loss of DIAPH1. Methods: Exome sequencing, genotyping and haplotype analysis, B- and T-cell phenotyping, in vitro lymphocyte stimulation assays, analyses of mitochondrial function, immunofluorescence staining for cytoskeletal proteins and mitochondria, and CRISPR-Cas9 DIAPH1 knockout in heathy donor PBMCs were used. Results: Genetic analyses found all Finnish patients homozygous for a rare DIAPH1 splice-variant (NM_005219:c.684+1G>A) enriched in the Finnish population, and Omani patients homozygous for a previously described pathogenic DIAPH1 frameshift-variant (NM_005219:c.2769delT;p.F923fs). In addition to microcephaly, epilepsy, and cortical blindness characteristic to SCBMS, the patients presented with infection susceptibility due to defective lymphocyte maturation and 3 patients developed B-cell lymphoma. Patients’ immunophenotype was characterized by poor lymphocyte activation and proliferation, defective B-cell maturation, and lack of naive T cells. CRISPR-Cas9 knockout of DIAPH1 in PBMCs from healthy donors replicated the T-cell activation defect. Patient-derived peripheral blood T cells exhibited impaired adhesion and inefficient microtubule-organizing center repositioning to the immunologic synapse. The clinical symptoms and laboratory tests also suggested mitochondrial dysfunction. Experiments with immortalized, patient-derived fibroblasts indicated that DIAPH1 affects the amount of complex IV of the mitochondrial respiratory chain. Conclusions: Our data demonstrate that individuals with SCBMS can have combined immune deficiency and implicate defective cytoskeletal organization and mitochondrial dysfunction in

We critically evaluated the fetal microbiome concept in 44 neonates with placenta, amniotic fluid, and first-pass meconium samples. Placental histology showed no signs of inflammation. Meconium samples were more often bacterial culture positive after vaginal delivery. In next-generation sequencing of the bacterial 16S gene, before and after removal of extracellular and PCR contaminant DNA, the median number of reads was low in placenta (48) and amniotic fluid (46) and high in meconium samples (14,556 C-section, 24,860 vaginal). In electron microscopy, meconium samples showed extracellular vesicles. Utilizing the analysis of composition of microbiomes (ANCOM) against water, meconium samples had a higher relative abundance of Firmicutes, Lactobacillus, Streptococcus, and Escherichia-Shigella. Our results did not support the existence of the placenta and amniotic fluid microbiota in healthy pregnancies. The first-pass meconium samples, formed in utero, appeared to harbor a microbiome that may be explained by perinatal colonization or intrauterine colonization via bacterial extracellular vesicles.

Delivery mode and perinatal antibiotics influence gut microbiome composition in children. Most microbiome studies have used the sequencing of the bacterial 16S marker gene but have not reported the metabolic function of the gut microbiome, which may mediate biological effects on the host. Here, we used the PICRUSt2 bioinformatics tool to predict the functional profiles of the gut microbiome based on 16S sequencing in two child cohorts. Both Caesarean section and perinatal antibiotics markedly influenced the functional profiles of the gut microbiome at the age of 1 year. In machine learning analysis, bacterial fatty acid, phospholipid, and biotin biosynthesis were the most important pathways that differed according to delivery mode. Proteinogenic amino acid biosynthesis, carbohydrate degradation, pyrimidine deoxyribonucleotide and biotin biosynthesis were the most important pathways differing according to antibiotic exposure. Our study shows that both Caesarean section and perinatal antibiotics markedly influence the predicted metabolic profiles of the gut microbiome at the age of 1 year.

Aim: Our aim was to survey treatment practices used for preschool children with wheezing in emergency rooms (ER) focussing on inhalation device choice and handling, face mask use, salbutamol dosing and written instructions. We sought to assess whether current protocols are in line with published evidence and guidelines. Methods: This is a cross-sectional survey done in paediatric ER units located in Finnish municipalities with more than 10 000 inhabitants. Results: Of the 100 units contacted, 50% responded. More than 50% of the units used nebulisers. Only 13% of the units administered salbutamol in single puffs. More than 30% of the units lacked criteria on face mask use. Poor co-operation had no effect on the dose of salbutamol in 62% of the units. Ensuring tight mask-to-face seal was included in the training in 20% of the units. A written action plan was provided to the caregivers in 28% of the units. Conclusion: ER treatment guidelines for preschool children with wheezing are poorly endorsed. Research is needed to identify approaches to guideline implementation that are specific for primary care. Clinical research should focus on strengthening recommendations that are currently not embraced. ER treatment protocols need to be updated and adherence to guidelines should be re-evaluated.

Periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome (PFAPA) is the most common periodic fever syndrome in children with unknown etiology, effectively treated with tonsillectomy. Earlier we have shown that tonsil microbiome is different in patients with PFAPA as compared to that in controls. Recently, fungal microbiome, mycobiome, has been linked to the pathogenesis of inflammatory diseases. We now investigated the role of mycobiome of tonsils in PFAPA. Random forest classification, a machine learning approach, was used for the analysis of mycobiome data. We examined tonsils from 30 children with PFAPA and 22 control children undergoing tonsillectomy for non-infectious reasons. We identified 103 amplicon sequence variants, mainly from two fungal phyla, Ascomycota and Basidiomycota. The mean relative abundance of Candida albicans in the tonsil mycobiome was 11% (95% CI: 19 to 27%) in cases and 3.4 % (95% CI: -0.8% to 8%) in controls, p =0.104. Mycobiome data showed no statistical difference in differentiating between PFAPA cases and controls compared to a random chance classifier (area under the curve (AUC) = 0.47, SD = 0.05, p = 0.809). In conclusion, in this controlled study, tonsillar mycobiome in children with PFAPA syndrome did not differ from that of the controls.

Altogether, 20–30% of women receive intrapartum antibiotic prophylaxis (IAP) to prevent sepsis in infants and 2–5% of newborn infants receive antibiotics due to suspected sepsis. Caesarean section has a long-term impact on the intestinal microbiome but the effects of perinatal antibiotics on gut microbiome in vaginally delivered infants are not well known. We compared the impact of IAP, postnatal antibiotics, or their combination on the gut microbiome and emergence of antimicrobial resistance in a controlled study of 149 newborn infants recruited within 24 hours after birth. We collected 659 fecal samples, including 426 daily samples from infants before discharge from the hospital and 111 follow-up samples at six months. Penicillin was mostly used for IAP and the combination of penicillin and aminoglycoside for postnatal treatment. Postnatal antibiotic groups received Lactobacillus reuteri probiotic. Newborn gut colonization differed in both IAP and postnatal antibiotics groups as compared to that in control group. The effect size of IAP was comparable to that caused by postnatal antibiotics. The observed differences were still present at six months and not prevented by lactobacilli consumption. Given the present clinical results, the impact of perinatal antibiotics on the subsequent health of newborn infants should be further evaluated.

Background: Symptomatic primary Epstein-Barr virus infection is a usually self-limiting illness in adolescents. We present a case of an adolescent who had been receiving azathioprine for inflammatory bowel disease for four years and developed a life-threatening primary Epstein-Barr virus infection successfully treated with rituximab. Case presentation: An 11-year-old girl presented with chronic, bloody diarrhea. Endoscopic biopsies confirmed a diagnosis of chronic ulcerative colitis with features of Crohn’s disease. Azathioprine was initiated after one year due to active colitis. She responded well and remission was achieved. At the age of 16 years she developed a life-threatening Epstein-Barr virus infection including severe multiple organ failure and was critically ill for 4 weeks in the intensive care unit. Natural killer cells were virtually absent in the lymphocyte subset analysis. Azathioprine was stopped on admission. She was initially treated with corticosteroids, acyclovir and intravenous immunoglobulin. Approximately 30 days after admission, she developed signs of severe hepatitis and pneumonitis and received weekly rituximab infusions for 8 weeks. Primary immunodeficiency was excluded by whole exome sequencing in two independent laboratories. Persistent viremia stopped when the natural killer cell count started to rise, approximately 90 days after the cessation of azathioprine. Conclusions: We found 17 comparable cases in the literature. None of the previous cases reported in the literature, who had been treated with azathioprine and developed either a severe or a fatal Epstein-Barr virus infection, underwent full genetic and prospective immunological workup to rule out known primary immunodeficiencies. Recently, azathioprine has been shown to cause rather specific immunosuppression, resulting in natural killer cell depletion. Our case demonstrates that slow recovery from azathioprine-induced natural killer cell depletion, 3 months after the stop

Aim: Using a high‐flow nasal cannula (HFNC) for infant bronchiolitis is increasingly common, but insufficiently studied. In this retrospective study, we examined the outcomes of HFNC and compared infants who did and did not respond to this oxygen delivery method. Methods: This 2012–2015 study of six Finnish hospitals focused on 88 infants under 12 months who received HFNC: 53 on paediatric wards and 35 in paediatric intensive care units (PICUs). We reviewed patient files for underlying factors, clinical parameters and HFNC treatment. The treatment failed if the patient was transferred to another respiratory support. Results: We found HFNC treatment was successful in 76 (86%) infants, including all 53 on the paediatric wards and 23/35 PICU patients. The responders’ heart rates were significantly lower, and their oxygen saturation was significantly higher at 60 minutes after HFNC treatment started and then stayed relatively constant. Their respiratory rate was only significantly lower after 360 minutes. In non‐responders, the respiratory rate initially decreased but was higher at 180 and 360 minutes after the start of HFNC. Conclusion: We found preliminary evidence that oxygen support needs and heart rate were useful early predictors of HFNC therapy success in infants hospitalised with bronchiolitis, but respiratory rate was not.

Around 3% of pregnant women in Finland have genital Chlamydia trachomatis infection, which can be transmitted from mother to newborn at birth. The risk of transmission has been reported to be 10–70% in vaginal deliveries resulting in conjunctivitis in 10–30% of cases and lower respiratory tract infection in 0–20% of cases. Although usually benign, Chlamydia trachomatis infections in infancy may result in long-term consequences, including conjunctival and corneal scarring, chronic cough and abnormal lung function. Based on the transmission rates published in prior studies, chlamydial conjunctivitis should occur in approximately 200 infants and chlamydial lower respiratory tract infection in 100 infants each year in our country, but in clinical practice we rarely encounter or diagnose infants with Chlamydia trachomatis infections. To investigate the reason for this discrepancy and to improve the recognition of Chlamydia trachomatis-infected infants, we set out to study the risk of vertical transmission of Chlamydia trachomatis in a population-based setting, to describe the typical features of Chlamydia trachomatis infections in infants and to evaluate the occurrence of Chlamydia trachomatis in both neonatal conjunctivitis and lower respiratory tract infections in infants. When studying the probability of vertical transmission of Chlamydia trachomatis a search through two national health registers for 1996–2011 yielded 206 children aged less than four years with a possible Chlamydia trachomatis infection. In a cohort of 933 823 births this represented an occurrence of 0.22 per 1000 live births (95% confidence interval 0.19–0.25). The risk of vertical transmission of Chlamydia trachomatis leading to a symptomatic infection in infancy was 0.8–1.8%. A review of patient charts to evaluate the typical features of Chlamydia trachomatis infections in infants (124/206) revealed that one-third of the infants with chlamydial conjunctivitis (33/124) had spontaneous blood, Tiivistelmä Noin 3 %:lla suomalaisista raskaana olevista naisista on klamydian (Chlamydia trachomatis) aiheuttama sukupuolitauti, joka voi tarttua äidistä lapseen synnytyksessä. Tartuntariskin on raportoitu olevan alatiesynnytyksessä noin 10–70 %. Noin 10–30 % tartunnan saaneista lapsista sairastuu silmätulehdukseen ja 0–20 % keuhkokuumeeseen. Vaikka imeväisten klamydiainfektiot ovat useimmiten lieviä tauteja, imeväisiällä sairastettu klamydiainfektio voi aiheuttaa silmän side- ja sarveiskalvon arpeutumista, pitkittynyttä yskää ja keuhkofunktion alenemaa. Aiempien tutkimusten perusteella arvioimme, että Suomessa sairastuu vuosittain noin 200 imeväistä klamydian aiheuttamaan silmätulehdukseen ja noin 100 imeväistä klamydiakeuhkokuumeeseen. Kliininen kokemuksemme on kuitenkin, että kohtaamme klamydiaa sairastavia imeväisiä varsin harvoin. Tämän ongelman ratkaisemiseksi ja klamydiaa sairastavien imeväisten paremmaksi tunnistamiseksi suunnittelimme tutkimuksen, jonka tarkoituksena on selvittää väestöpohjainen riski klamydian tarttumiselle äidistä vastasyntyneeseen, kuvata imeväisten klamydiainfektioiden tyypilliset piirteet sekä selvittää klamydian osuus imeväisten silmätulehduksissa ja alle kuuden kuukauden ikäisten imeväisten alahengitystieinfektioissa. Klamydian sairastaneet lapset poimittiin kahdesta suomalaisesta terveydenhuoltorekisteristä vuosina 1996–2011. Tuona aikana 206 lasta oli sairastanut mahdollisen klamydiainfektion, joten klamydian ilmaantuvuus oli 0,22/1000:tta elävänä syntynyttä kohti (95 % luottamusväli 0,19–0,25). Väestöpohjainen riski äidin sukupuoliklamydian tarttumiselle vastasyntyneeseen niin että lapselle aiheutuu oireinen infektio oli 0,8–1,8 %. Saatavilla olevien potilasasiakirjojen (124/206) perusteella kolmasosalla (33/124) imeväisistä, jotka sairastivat klamydian aiheuttamaa silmätulehdusta, oli oireena spontaani verinen kyynel- tai rähmäerite. Klamydiakeuhkokuumetta sairastavista puolella (15/32) esiintyi hengityksen vinkumista, mutta kla