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Importance: Dysbiosis has been robustly demonstrated in Parkinson disease (PD), and fecal microbiota transplantation (FMT) has shown promising effects in preclinical PD models., Objective: To assess the safety and symptomatic efficacy of colonic single-dose anaerobically prepared FMT., Design, Setting, and Participants: This was a double-blind, placebo-controlled, randomized clinical trial conducted between November 2020 and June 2023 with a follow-up period of 12 months at 4 hospitals in Finland. Patients with PD aged 35 to 75 years in Hoehn & Yahr stage 1-3 with a mild to moderate symptom burden and dysbiosis of fecal microbiota were included. Of 229 patients screened, 48 were randomized and 47 received the intervention. One patient discontinued due to worsening of PD symptoms. Two further patients were excluded before analysis and 45 were included in the intention-to-treat analysis., Intervention: Participants were randomized in a 2:1 ratio to receive FMT or placebo via colonoscopy., Main Outcomes and Measures: The primary end point was the change of Movement Disorder Society Unified Parkinson's Disease Rating Scale parts I-III (part III off medication) at 6 months. Safety was assessed by recording adverse events (AEs)., Results: The median (IQR) age was 65 (52.5-70.0) years in the placebo group and 66 (59.25-69.75) years in the FMT group; 9 (60.0%) and 16 (53.3%) patients were male in the placebo group and the FMT group, respectively. The primary outcome did not differ between the groups (0.97 points, 95% CI, -5.10 to 7.03, P = .75). Gastrointestinal AEs were more frequent in the FMT group (16 [53%] vs 1 [7%]; P = .003). Secondary outcomes and post hoc analyses showed stronger increase of dopaminergic medication and improvement of certain motor and nonmotor outcomes in the placebo group. Microbiota changes were more pronounced after FMT but differed by donor. Nevertheless, dysbiosis status was reversed more frequently in the placebo group., Conclusions and Relevance: FMT was safe but did not offer clinically meaningful improvements. Further studies-for example, through modified FMT approaches or bowel cleansing-are warranted regarding the specific impact of donor microbiota composition and dysbiosis conversion on motor and nonmotor outcomes as well as medication needs in PD., Trial Registration: ClinicalTrials.gov Identifier: NCT04854291.

Background: Fever after cardiac arrest may impact outcome. We aimed to assess the incidence of fever in post-cardiac arrest patients, factors predicting fever and its association with functional outcome in patients treated without targeted temperature management (TTM)., Methods: The FINNRESUSCI observational cohort study in 2010-2011 included intensive care unit (ICU)-treated out-of-hospital cardiac arrest (OHCA) patients from all five Finnish university hospitals and 14 of 15 central hospitals. This post hoc analysis included those FINNRESUSCI study patients who were not treated with TH. We defined fever as at least one temperature measurement of ≥37.8°C within 72 h of ICU admission. The primary outcome was favourable functional outcome at 12 months, defined as cerebral performance category (CPC) of 1 or 2. Binary logistic regression models including witnessed arrest, bystander cardiopulmonary resuscitation (CPR), initial rhythm and delay of return of spontaneous circulation were used to compare the functional outcomes of the groups., Results: There were 67,428 temperature measurements from 192 patients, of whom 89 (46%) experienced fever. Twelve-month CPC was missing in 7 patients, and 51 (28%) patients had favourable functional outcome at 12 months. The patients with shockable initial rhythms had a lower incidence of fever within 72 h of ICU admission (28% vs. 72%, p < .01), and the patients who experienced fever had a longer median return of spontaneous circulation (ROSC) delay (20 [IQR 10-30] vs. 14 [IQR 9-22] min, p < .01). Only initial non-shockable rhythm (OR 2.99, 95% CI 1.51-5.94) was associated with increased risk of fever within the first 72 h of ICU admission. Neither time in minutes nor area (minutes  ×  degree celsius over threshold) over 37°C, 37.5°C, 38°C, 38.5°C, 39°C, 39.5°C or 40°C were significantly different in those with favourable functional outcome compared to those with unfavourable functional outcome within the first 24, 48 or 72 h from ICU admission. Fever was not associated with favourable functional outcome at 12 months (OR 0.90, 95% CI 0.44-1.84)., Conclusions: Half of OHCA patients not treated with TTM developed fever. We found no association between fever and outcome., (© 2024 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

Background: Severity of illness scoring systems are used in intensive care units to enable the calculation of adjusted outcomes for audit and benchmarking purposes. Similar tools are lacking for pre-hospital emergency medicine. Therefore, using a national helicopter emergency medical services database, we developed and internally validated a mortality prediction algorithm., Methods: We conducted a multicentre retrospective observational register-based cohort study based on the patients treated by five physician-staffed Finnish helicopter emergency medical service units between 2012 and 2019. Only patients aged 16 and over treated by physician-staffed units were included. We analysed the relationship between 30-day mortality and physiological, patient-related and circumstantial variables. The data were imputed using multiple imputations employing chained equations. We used multivariate logistic regression to estimate the variable effects and performed derivation of multiple multivariable models with different combinations of variables. The models were combined into an algorithm to allow a risk estimation tool that accounts for missing variables. Internal validation was assessed by calculating the optimism of each performance estimate using the von Hippel method with four imputed sets., Results: After exclusions, 30 186 patients were included in the analysis. 8611 (29%) patients died within the first 30 days after the incident. Eleven predictor variables (systolic blood pressure, heart rate, oxygen saturation, Glasgow Coma Scale, sex, age, emergency medical services vehicle type [helicopter vs ground unit], whether the mission was located in a medical facility or nursing home, cardiac rhythm [asystole, pulseless electrical activity, ventricular fibrillation, ventricular tachycardia vs others], time from emergency call to physician arrival and patient category) were included. Adjusted for optimism after internal validation, the algorithm had an area under the receiver operating characteristic curve of 0.921 (95% CI 0.918 to 0.924), Brier score of 0.097, calibration intercept of 0.000 (95% CI -0.040 to 0.040) and slope of 1.000 (95% CI 0.977 to 1.023)., Conclusions: Based on 11 demographic, mission-specific, and physiologic variables, we developed and internally validated a novel severity of illness algorithm for use with patients encountered by physician-staffed helicopter emergency medical services, which may help in future quality improvement., (© 2024. The Author(s).)

Background: Procedural sedation and analgesia are commonly used in the Emergency Departments. Despite this common need, there is still a lack of options for adequate and safe analgesia and sedation in children. The objective of this study was to evaluate whether intranasal dexmedetomidine could provide more effective analgesia and sedation during a procedure than intranasal esketamine., Methods: This was a double-blind equally randomized (1:1) superiority trial of 30 children aged 1-3 years presenting to the Emergency Department with a laceration or a burn and requiring procedural sedation and analgesia. Patients were randomized to receive 2.0 mcg/kg intranasal dexmedetomidine or 1.0 mg/kg intranasal esketamine. The primary outcome measure was highest pain (assessed using Face, Legs, Activity, Cry, Consolability scale (FLACC)) during the procedure. Secondary outcomes were sedation depth, parents' satisfaction, and physician's assessment. Comparisons were done using Mann-Whitney U test (continuous variables) and Fisher's test (categorical variables)., Results: Adequate analgesia and sedation were reached in 28/30 patients. The estimated sample size was not reached due to changes in treatment of minor injuries and logistical reasons. The median (IQR) of highest FLACC was 1 (0-3) with intranasal dexmedetomidine and 5 (2-6.75) with intranasal esketamine, (p-value 0.09). 85.7% of the parents with children treated with intranasal dexmedetomidine were "very satisfied" with the procedure and sedation compared to the 46.2% of those with intranasal esketamine, (p-value 0.1). No severe adverse events were reported during this trial., Conclusions: This study was underpowered and did not show any difference between intranasal dexmedetomidine and intranasal esketamine for procedural sedation and analgesia in young children. However, the results support that intranasal dexmedetomidine could provide effective analgesia and sedation during procedures in young children aged 1-3 years with minor injuries., Trial Registration: Eudra-CT 2017-00057-40, April 20, 2017. https://eudract.ema.europa.eu/., (© 2024. The Author(s).)

Ceramides and other sphingolipids are implicated in vascular dysfunction and inflammation. They have been suggested as potential biomarkers for hypertension. However, their specific association with hypertension prevalence and onset requires further investigation. This study aimed to identify specific ceramide and phosphatidylcholine species associated with hypertension prevalence and onset. The 2002 FINRISK (Finnish non-communicable risk factor survey) study investigated the association between coronary event risk scores (CERT1 and CERT2) and hypertension using prevalent and new-onset hypertension groups, both consisting of 7722 participants, over a span of 10 years. Ceramide and phosphatidylcholine levels were measured using tandem liquid chromatography-mass spectrometry. Ceramide and phosphatidylcholine ratios, including ceramide (d18:1/18:0), ceramide (d18:1/24:1), phosphatidylcholine (16:0/16:0), and the ratio of ceramide (d18:1/18:0)/(d18:1/16:0), are consistently associated with both prevalence and new-onset hypertension. Ceramide (d18:1/24:0) was also linked to both hypertension measures. Adjusting for covariates, CERT1 and CERT2 showed no-longer-significant associations with hypertension prevalence, but only CERT2 predicted new-onset hypertension. Plasma ceramides and phosphatidylcholines are crucial biomarkers for hypertension, with imbalances potentially contributing to its development. Further research is needed to understand the underlying mechanisms by which ceramides will contribute to the development of hypertension.

Scope: Specific lipid molecules circulating in plasma at low concentrations have emerged as biomarkers of atherosclerotic risk. The aim of the present study is that of evaluating, in an athero-prone mouse model, how different diets can affect plasma and aorta lipidome., Methods and Results: Thirty-six apoE knockout mice are divided in three groups and feed 12 weeks with diets differing for cholesterol and fatty acid content. Atherosclerosis is measured at the aortic sinus and aorta. Lipids are quantified in plasma and aorta with mass spectrometry. The cholesterol content of the diets is the main driver of lipid accumulation in plasma and aorta. The fatty acid composition of the diets affects plasma levels both of essential (linoleic acid) and nonessential (myristic and arachidonic acid) ones. Lipidomics show a comparable distribution, in plasma and aorta, of the main lipid components of oxidized LDL, including cholesteryl esters and lysophosphatidylcholines. Interestingly, lactosylceramide, glucosyl/galactosylceramide, and individual ceramide species are found to accumulate in diseased aortic segments., Conclusion: Both the cholesterol and fatty acid content of the diets profoundly affect plasma lipidome. Aorta lipidome is likewise affected with the accumulation of specific lipids known as markers of atherosclerosis., (© 2022 Wiley-VCH GmbH.)

Aim: To investigate paediatric emergency room (ER) visits to evaluate the immediate health effects of COVID-19 pandemic restrictions on children., Methods: We retrospectively examined paediatric ER visits in the Helsinki University Hospital (HUH) district during the first wave of the pandemic (1 March to 31 May 2020), and a 2-month period immediately before and after. These periods were compared to the corresponding time periods in 2015-2019 ('reference period')., Results: The total number of ER visits decreased by 23.4% (mean 6474 during the reference period, 4960 during the pandemic period (incidence rate ratio [IRR] 0.75, 95% confidence interval 0.72-0.77; p < 0.001). This was due to a decrease in visits related to infectious diseases; visits due to surgical reasons did not decrease. The amount or proportion of patients triaged to the most urgent class (Emergency Severity Index 1) did not increase. Paediatric ER visits returned to baseline after lifting of restrictions., Conclusions: Although paediatric ER visits substantially decreased during the pandemic restrictions, children seen at the ER were not more severely ill. Our results do not indicate immediate detrimental health effects of pandemic control measures on children., (© 2022 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Background and Importance: Emergency Severity Index is a five-level triage tool in the emergency department that predicts the need for emergency department resources and the degree of emergency. However, it is unknown whether this is valid in patients aged greater than or equal to 65 years., Objective: The aim of the study was to compare the accuracy of the Emergency Severity Index triage system between emergency department patients aged 18-64 and greater than or equal to 65 years., Design, Settings, and Participants: This was a retrospective observational cohort study of adults who presented to a Finnish emergency department between 1 February 2018 and 28 February 2018. All data were collected from electronic health records., Outcome Measures and Analysis: The primary outcome was 3-day mortality. The secondary outcomes were 30-day mortality, hospital admission, high dependency unit or ICU admission, and emergency department length of stay. The area under the receiver operating characteristic curve and cutoff performances were used to investigate significant associations between triage categories and outcomes. The results of the two age groups were compared., Main Results: There were 3141 emergency department patients aged 18-64 years and 2370 patients aged greater than or equal to 65 years. The 3-day mortality area under the curve in patients aged greater than or equal to 65 years was greater than that in patients aged 18-64 years. The Emergency Severity Index was associated with high dependency unit/ICU admissions in both groups, with moderate sensitivity [18-64 years: 61.8% (50.9-71.9%); greater than or equal to 65 years: 73.3% (63.5-81.6%)] and high specificity [18-64 years: 93.0% (92.0-93.8%); greater than or equal to 65 years: 90.9% (90.0-92.1%)]. The sensitivity was high and specificity was low for 30-day mortality and hospital admission in both age groups. The emergency department length of stay was the longest in Emergency Severity Index category 3 for both age groups. There was no significant difference in accuracy between age groups for any outcome., Conclusion: Emergency Severity Index performed well in predicting high dependency unit/ICU admission rates for both 18-64 years and greater than or equal to 65-year-old patients. It predicted the 3-day mortality for patients aged greater than or equal to 65 years with high accuracy. It was inaccurate in predicting 30-day mortality and hospital admission for both age groups., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Aim: Cholesterol-based risk prediction is often insufficient in cardiovascular disease (CVD) patients. Ceramides are a new kind of biomarkers for CVD. The Coronary Event Risk Test (CERT) is a validated cardiovascular risk predictor that uses only circulating ceramide levels, determined by coupled liquid chromatography-mass spectrometry, to allocate patients into one of four risk categories. This test has recently been modified (CERT2) by additionally including phosphatidylcholine levels., Methods and Results: In this observational cohort study, we have recruited 999 Austrian patients with CVD and followed them for up to 13 years. We found that CERT and CERT2 both predicted cardiovascular events, cardiovascular mortality, and overall mortality. CERT2 had the higher performance compared to CERT and also to the recent cardiovascular risk score of the ESC/EAS guidelines (Systematic COronary Risk Evaluation (SCORE)) for low-risk European countries. Combining CERT2 with the ESC/EAS-SCORE, predictive capacity was further increased leading to a hazard ratio of 3.58 (2.02-6.36; P < 0.001) for cardiovascular events, 11.60 (2.72-49.56; P = 0.001) for cardiovascular mortality, and 9.86 (4.23-22.99; P < 0.001) for overall mortality when patients with very high risk (category 4) were compared to those with low risk (category 1). The use of the combined score instead of the ESC/EAS-SCORE significantly improved the predictive power according to the integrated discrimination improvement index (P = 0.004)., Conclusion: We conclude that CERT and CERT2 are powerful predictors of cardiovascular events, cardiovascular mortality, and overall mortality in CVD patients. Including phosphatidylcholine to a ceramide-based score increases the predictive performance and is best in combination with classical risk factors as used in the ESC/EAS-SCORE., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Aim: Early extubation after cardiac surgery shortens paediatric intensive care unit (PICU) length of stay (LOS) and decreases complications from mechanical ventilation (MV). We explored the duration of MV in Scandinavian paediatric heart centres., Methods: We retrospectively reviewed the MV duration and PICU LOS of 696 children operated for atrial septal defect (ASD), ventricular septal defect (VSD), tetralogy of Fallot (TOF) or total cavopulmonary connection (TCPC) in four Scandinavian centres in 2015-2016. Neonates (n = 90) were included regardless of heart surgery type., Results: Patients with ASD were extubated at a median of 3.25 h (interquartile range [IQR] 2.00-4.83), followed by patients with TCPC (median 5.00 h, IQR 2.60-16.83), VSD (median 7.00 h, IQR 3.69-22.25) and TOF (median 18.08 h, IQR 6.00-41.38). Neonates were not extubated early (median 94.42 h, IQR 45.03-138.14). Although MV durations were reflected in PICU LOS, this was not as apparent among those extubated within 12 h. The Swedish centres had shortest MV durations and PICU LOS. Extubation failed in 24/696 (3.4%) of patients., Conclusion: Scandinavian paediatric heart centres differed in the duration of postoperative MV. Deferring extubation up to 12 h postoperatively did not markedly prolong PICU LOS., (© 2022 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Objectives: Recognizing stroke and other intracranial pathologies in prehospital phase facilitates prompt recanalization and other specific care. Recognizing these can be difficult in patients with decreased level of consciousness. We previously derived a scoring system combining systolic blood pressure, age and heart rate to recognize patients with intracranial pathology. In this study we aimed to validate the score in a larger, separate population., Materials and Methods: We conducted a register based retrospective study on patients ≥16 years old and Glasgow Coma Score <15 encountered by helicopter emergency medical services. Diagnoses at the end of hospitalization were used to identify if patients had intracranial lesion or not. The performance of score was evaluated by area under the receiver operating characteristics curve (AUROC)., Results: Of 9,309 patients included, 1,925 (20.7%) had an intracranial lesion including 1,211 cases of stroke. Older age, higher blood pressure and lower heart rate were predictors for an intracranial lesion (P<0.001 for all). The score distinguished patients with intracranial lesion with AUROC of 0.749 (95% CI 0.737 to 0.761). The performance slightly improved if only patients intubated in prehospital phase were included AUROC 0.780 (95% CI 0.770 to 0.806) or convulsion related diagnosis excluded AUROC of 0.788 (95% CI 0.768 to 0.792)., Conclusions: A scoring of systolic blood pressure, heart rate and age help differentiate intracranial lesions in patients with decreased level of consciousness in prehospital care. This may facilitate direct transportation to stroke center and application of neuroprotective measures in prehospital critical care., Competing Interests: Declarations of Competing Interest None., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Most emergency departments rely on acuity assessment, triage, to recognize critically ill patients that need urgent treatment, and to allocate resources according to need. The accuracy of commonly used triage instruments such as the Emergency Severity Index (ESI) is lower for older adults compared to young patients. We aim to examine, whether adjusting the triage category by age leads to improvement in sensitivity without excessive increase in patient numbers in the higher triage categories. The primary outcome measure was 3-day mortality and secondary outcomes were 30-day mortality, hospital admission, and HDU/ICU admissions., Methods: We gathered data of all adult patients who had an unscheduled visit to any of our three emergency departments within one month. The data was analysed for 3-day mortality, 30-day mortality, hospital admission, and high dependency unit or intensive care unit (HDU/ICU) admission. The analysis was run for both the standard ESI triage method and a local 3-level Helsinki University Hospital (HUH) method. A further analysis was run for both triage methods with age adjustment. Net reclassification improvement values were calculated to demonstrate the effect of age adjustment., Results: Thirteen thousand seven hundred fifty-nine patients met the study criteria, median age was 57. 3-day mortality AUCs for unadjusted HUH and ESI triage were 0.77 (0.65-0.88) and 0.72 (0.57-0.87); 30-day mortality AUCs were 0.64 (0.59-0.69) and 0.69 (0.64-0.73); hospital admission AUCs were 0.60 (0.68-0.71) and 0.66 (0.65-0.68) and HDU/ICU admission AUCs were 0.67 (0.64-0.70) and 0.82 (0.79-0.86), respectively. Age adjustment improved accuracy for 30-day mortality and hospital admission. With the threshold age of 80, AUCs for 30-day mortality were 0.73 (0.68-0.77) and 0.77 (0.73-0.81) and for hospital admission, 0.66 (0.65-0.67) and 0.72 (0.71-0.73) for the HUH and ESI triage. The effect was similar with all cut off ages., Conclusion: Moving older adults into a more urgent triage category based on age, improved the triage instruments' performance slightly in predicting 30-day mortality and hospital admission without excessive increase in patient numbers in the higher triage categories. Age adjustment did not improve HDU/ICU admission or 3-day mortality prediction., (© 2022. The Author(s).)

Background: Viral infections may trigger type 1 diabetes (T1D), and recent reports suggest an increased incidence of paediatric T1D and/or diabetic ketoacidosis (DKA) during the COVID-19 pandemic., Objective: To study whether the number of children admitted to the paediatric intensive care unit (PICU) for DKA due to new-onset T1D increased during the COVID-19 pandemic, and whether SARS-CoV-2 infection plays a role., Methods: This retrospective cohort study comprises two datasets: (1) children admitted to PICU due to new-onset T1D and (2) children diagnosed with new-onset T1D and registered to the Finnish Pediatric Diabetes Registry in the Helsinki University Hospital from 1 April to 31 October in 2016-2020. We compared the incidence, number and characteristics of children with newly diagnosed T1D between the prepandemic and pandemic periods., Results: The number of children admitted to PICU due to new-onset T1D increased from an average of 6.25 admissions in 2016-2019 to 20 admissions in 2020 (incidence rate ratio [IRR] 3.24 [95% CI 1.80 to 5.83]; p=0.0001). On average, 57.75 children were registered to the FPDR in 2016-2019, as compared with 84 in 2020 (IRR 1.45; 95% CI 1.13 to 1.86; p=0.004). 33 of the children diagnosed in 2020 were analysed for SARS-CoV-2 antibodies, and all were negative., Conclusions: More children with T1D had severe DKA at diagnosis during the pandemic. This was not a consequence of SARS-CoV-2 infection. Instead, it probably stems from delays in diagnosis following changes in parental behaviour and healthcare accessibility., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: Peripheral arterial disease (PAD) and coronary artery disease (CAD) are both caused by atherosclerosis. Serum lipids and lipoproteins are predictive of the development of atherosclerosis but it is not clear if they differ in the two manifestations, PAD and CAD. We tested whether a more detailed characterization of the lipid and lipoprotein patterns of PAD and CAD allows a clear differentiation between the two atherosclerotic phenotypes., Methods: A cohort of 274 statin-naïve patients with either newly diagnosed imaging proven PAD (n = 89) or stable CAD (n = 185) was characterized using nuclear magnetic resonance- and liquid chromatography-tandem mass spectrometry-based advanced lipid and lipoprotein analysis. An independent cohort of 1239 patients with PAD and CAD was used for validation., Results: We found a significant difference in markers of inflammation as well as ceramide and phosphatidylcholine levels between patients with PAD and CAD. In contrast, basic lipid markers including total cholesterol, LDL cholesterol, HDL cholesterol, lipoprotein(a) or detailed lipoprotein profiles did not differ significantly between patients with PAD and CAD. Applying ratios and scores derived from ceramides and phosphatidylcholines further improved the discrimination between PAD and CAD. These significant differences were independent of body composition, from the status of smoking or type 2 diabetes mellitus, and also from apolipoprotein C-III and other inflammatory parameters which were different between CAD and PAD., Conclusion: The present study clearly suggests that PAD and CAD differ in terms of their ceramide- and phosphatidylcholine-based lipid patterns but not in lipoprotein characteristics., (© 2021 The Association for the Publication of the Journal of Internal Medicine.)

Background: National Early Warning Score (NEWS) does not include age as a parameter despite age is a significant independent risk factor of death. The aim of this study was to examine whether age has an effect on predictive performance of short-term mortality of NEWS in a prehospital setting. We also evaluated whether adding age as an additional parameter to NEWS improved its short-term mortality prediction., Methods: We calculated NEWS scores from retrospective prehospital electronic patient record data for patients 18 years or older with sufficient prehospital data to calculate NEWS. We used area under receiver operating characteristic (AUROC) to analyse the predictive performance of NEWS for 1 and 7 day mortalities with increasing age in three different age groups: <65 years, 65-79 years and ≥80 years. We also explored the ORs for mortality of different NEWS parameters in these age groups. We added age to NEWS as an additional parameter and evaluated its effect on predictive performance., Results: We analysed data from 35 800 ambulance calls. Predictive performance for 7-day mortality of NEWS decreased with increasing age: AUROC (95% CI) for 1-day mortality was 0.876 (0.848 to 0.904), 0.824 (0.794 to 0.854) and 0.820 (0.788 to 0.852) for first, second and third age groups, respectively. AUROC for 7-day mortality had a similar trend. Addition of age as an additional parameter to NEWS improved its ability to predict short-term mortality when assessed with continuous Net Reclassification Improvement., Conclusions: Age should be considered as an additional parameter to NEWS, as it improved its performance in predicting short-term mortality in this prehospital cohort., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Seizures seem to represent a frequent cause for pediatric emergency medical (EM) and emergency room (ER) contacts, but few population-based data are available. Our aim was to study the incidence, prehospital and ER treatment, and outcomes of pediatric seizures necessitating out-of-hospital care., Methods: We studied the out-of-hospital evaluation procedures, ER treatment, diagnostics and 2-year prognosis of all cases of pediatric (0-16 years) seizures encountered by the emergency medical services (EMS) in Helsinki, Finland, in 2012 (population 603,968, pediatric population 92,742); 251 patients were encountered by the EMS, of which 220 seen at the ER., Results: The yearly incidence of pediatric seizures necessitating EMS activation was 2.8/1000 in the pediatric population. Febrile seizures were responsible for 97 (44.1%) of the cases transported to the ER. Only a minority of patients required advanced life support measures out-of-hospital or complex diagnostics in the ER. Still, of the 220 patients seen at ER, 68 (30.9%) were hospitalized, and 106 (48.2%) had follow-up contacts scheduled., Conclusions: Pediatric seizures were a common cause for EM and ER contacts. Advanced life support measures were seldom needed, and the prognosis was good, but seizures still required considerable resources. They often resulted in urgent EM dispatch and transport, hospitalization, follow-up visits, new medication, and complementary studies. This emphasizes the role the EMS plays in recognizing and terminating pediatric seizures and in referring these children to appropriate care., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Maternal thyroid disease, especially hypothyroidism, affects pregnancy and its outcome. In-utero exposure to autoimmune thyroid disease has been reported to associate with childhood ALL in the offspring. We evaluated the risk of childhood cancer in the offspring following exposure to maternal thyroid disease in a case-control setting using registry data. All patients with their first cancer diagnosis below the age of 20 years were identified from the Finnish Cancer Registry ( n = 2037) and matched for sex and birth year at a 1:5 ratio to population controls identified from the Medical Birth Registry ( n = 10,185). We collected national information on maternal thyroid disease from the Medical Birth Registry, Care Register for Health Care, Register for Reimbursed Drug Purchases and Register of Special Reimbursements. We used conditional logistic regression to analyze childhood cancer risk in the offspring. The adjusted OR for any childhood cancer was 1.41 (95%, CI 1.00-2.00) comparing the offspring of mothers with hypothyroidism and those with normal thyroid function. The risk of lymphomas was increased (adjusted OR for maternal hypothyroidism 3.66, 95%, CI 1.29-10.38). The results remained stable when mothers with cancer history were excluded from the analyses. Maternal hypothyroidism appears to be associated with an increased risk for childhood lymphoma in the offspring. The association exists even after excluding possible familial cancers.

Background: The COVID-19 pandemic has had profound effects on the utilization of health care services, including Emergency Medical Services (EMS). Social distancing measures taken to prevent the spread of the disease have greatly affected the functioning of societies and reduced or halted many activities with a risk of injury. The aim of this study was to report the effects of lockdown measures on trauma-related EMS calls in the Finnish capital area., Methods: We conducted a retrospective cohort study of all EMS calls in the Helsinki University Hospital (HUH) catchment area between 1 January and 31 July 2020. Calls were identified from the HUH EMS database. Calls were grouped into pre-lockdown, lockdown, and post-lockdown periods according to the restrictions set by the Finnish government and compared to the mean number of calls for the corresponding periods in 2018 and 2019. Statistical comparisons were performed using Mann-Whitney U-test for weekly numbers and percentages., Results: During the study period there was a total of 70,705 EMS calls, of which 14,998 (21.2%) were related to trauma; 67,973 patients (median age 61.6 years; IQR 35.3-78.6) were met by EMS. There was no significant change in the weekly number of total or trauma-related EMS calls during the pre-lockdown period. During the lockdown period, the number of weekly total EMS calls was reduced by 12.2% (p = 0.001) and the number of trauma-related calls was reduced by 23.3% (p = 0.004). The weekly number of injured patients met by EMS while intoxicated with alcohol was reduced by 41.8% (p = 0.002). During the post-lockdown period, the number of total and trauma-related calls and the number of injured patients intoxicated by alcohol returned to previous years' levels., Conclusions: The COVID-19 pandemic and social distancing measures reduced the number of trauma-related EMS calls. Lockdown measures had an especially significant effect on the number of injured patients intoxicated by alcohol met by the EMS., Trial Registration: Not applicable., (© 2021. The Author(s).)

Background: There is a lack of knowledge how patients with COVID-19 disease differ from patients with similar signs or symptoms (but who will have a diagnosis other than COVID-19) in the prehospital setting. The aim of this study was to compare the characteristics of these two patient groups met by the emergency medical services., Methods: All prehospital patients after the World Health Organisation (WHO) pandemic declaration 11.3.2020 until 30.6.2020 were recruited for the study. The patients were screened using modified WHO criteria for suspected COVID-19. Data from the electronic prehospital patient reporting system were linked with hospital laboratory results to check the laboratory confirmation for COVID-19. For comparison, we divided the patients into two groups: screening- and laboratory-positive patients with a hospital diagnosis of COVID-19 and screening-positive but laboratory-negative patients who eventually received a different diagnosis in hospital., Results: A total of 4157 prehospital patients fulfilled the criteria for suspected COVID-19 infection during the study period. Five-hundred-thirty-six (12.9%) of the suspected cases received a laboratory confirmation for COVID-19. The proportion of positive cases in relation to suspected ones peaked during the first 2 weeks after the declaration of the pandemic. In the comparison of laboratory-positive and laboratory-negative cases, there were clinically insignificant differences between the groups in age, tympanic temperature, systolic blood pressure, heart rate, on-scene time, urgency category of the call and mode of transportation. Foreign-language-speakers were overrepresented amongst the positive cases over native language speakers (26,6% vs. 7,4%, p < 0,001). The number of cases in which no signs or symptoms of COVID-19 disease were reported, but patients turned out to have a positive test result was 125 (0,3% of the whole EMS patient population and 11,9% of all verified COVID-19 patients encountered by the EMS)., Conclusions: In a sample of suspected COVID-19 patients, the laboratory-positive and laboratory-negative patients were clinically indistinguishable from each other during the prehospital assessment. Foreign-language-speakers had a high likelihood of having Covid-19. The modified WHO criteria still form the basis of screening of suspected COVID-19 patients in the prehospital setting., (© 2021. The Author(s).)

Aims: A risk score, CERT2, based on distinct ceramide and phosphatidylcholine lipid species, has shown robust performance in predicting cardiovascular risk in secondary prevention. Here, our aim was to investigate the predictive value of CERT2 in primary prevention compared to classical lipid biomarkers and its compatibility with clinical characteristics used in the SCORE risk chart., Methods and Results: Four ceramides [Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0), Cer(d18:1/24:1)] and three phosphatidylcholines [PC(14:0/22:6), PC(16:0/22:5), PC(16:0/16:0)] were analysed by targeted tandem liquid chromatography-mass spectrometry method in FINRISK 2002, which is a population-based risk factor survey investigating men and women aged 25-74 years. Primary prevention subjects ( N = 7324) were followed up for 10 years for the following outcomes: incident coronary heart disease (CHD), cardiovascular disease (CVD), major adverse cardiovascular event (MACE), stroke, and heart failure. Hazard ratios per standard deviation obtained from adjusted Cox proportional hazard models were significant for all these endpoints, and the highest for fatal ones, i.e. fatal CHD [1.45 (95% confidence interval 1.07-1.97)], CVD [1.39 (1.06-1.83)], and MACE [1.39 (1.07-1.80)]. The categorical net reclassification improvement was 0.051 for the 10-year risk of incident CVD. Incidence of fatal events was over 10-fold more frequent in the highest CERT2 category compared to the lowest risk category and modified SCORE risk charts, utilizing CERT2 and diabetes mellitus, increased granularity of risk assessment compared to a chart utilizing total cholesterol., Conclusion: CERT2 is a significant predictor of incident cardiovascular outcomes and risk charts utilizing this score provide an easy tool to estimate relative and absolute risk for incident CVD., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Epithelial ovarian cancer (EOC) generally responds well to oncological treatments, but the eventual development of a refractory disease is a major clinical problem. Presently, there are no prognostic blood-based biomarkers for the stratification of EOC patients at the time of diagnosis. We set out to assess and validate the prognostic utility of a novel two-lipid signature, as the lipidome is known to be markedly aberrant in EOC patients. The study consisted of 499 women with histologically confirmed EOC that were prospectively recruited at the university hospitals in Turku (Finland) and Charité (Berlin, Germany). Lipidomic screening by tandem liquid chromatography-mass spectrometry (LC-MS/MS) was performed for all baseline serum samples of these patients, and additionally for 20 patients of the Turku cohort at various timepoints. A two-lipid signature, based on the ratio of the ceramide Cer(d18:1/18:0) and phosphatidylcholine PC(O-38:4), showed consistent prognostic performance in all investigated study cohorts. In the Turku cohort, the unadjusted hazard ratios (HRs) per standard deviation (SD) (95% confidence interval) were 1.79 (1.40, 2.29) for overall and 1.40 (1.14, 1.71) for progression-free survival. In a Charité cohort incorporating only stage III completely resected patients, the corresponding HRs were 1.59 (1.08, 2.35) and 1.53 (1.02, 2.30). In linear-mixed models predicting progression of the disease, the two-lipid signature showed higher performance (beta per SD increase 1.99 (1.38, 2.97)) than cancer antigen 125 (CA-125, 1.78 (1.13, 2.87)). The two-lipid signature was able to identify EOC patients with an especially poor prognosis at the time of diagnosis, and also showed promise for the detection of disease relapse.

Background: Identifying pediatric populations at risk for traumas would enable development of emergency medical services and emergency departments for children. Elucidation of the nature of socioeconomic differences in the incidence of pediatric out-of-hospital emergencies is needed to overcome inequities in child health., Methods: We retrieved all ambulance contacts during 17.12.2014-16.12.2018 involving children (0-15 years) in Helsinki, Finland and separated traumatic and nontraumatic emergencies. We compared the incidences of these emergencies in the pediatric population with socioeconomic markers of the scene of the emergency and of the residential area of the child., Results: Of 11,742 ambulance contacts involving children 4113 (35.0%) were traumatic. Traumatic emergencies occurred more often in neighborhoods with lower median income/household (P=0.043) and were more common in children living in areas with lower median income/inhabitant (P=0.001), higher unemployment (P<0.001), and lower education (P<0.001). The associations were weaker for traumatic than nontraumatic emergencies. Higher proportion of a pediatric population in a residential area (P=0.005) had a protective effect. Exclusion of clinically unnecessary ambulance responses did not change the results., Conclusion: Traumatic emergencies in children are more common in areas with lower socioeconomic status. The possible protective effect of urban planning merits further studies., Type of Study: Prognostic., Level of Evidence: II., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Emergency care clinicians are expected to use the latest research evidence in practice. However, emergency nurses do not always consistently implement evidence-based practice (EBP). An educational intervention on EBP was implemented to promote emergency nurses' use of EBP, and the effectiveness of it was evaluated., Aims: This study aimed to evaluate the effectiveness of an EBP educational intervention on emergency nurses' EBP attitudes, knowledge, self-efficacy, skills, and behavior. The study also examined learners' satisfaction with the EBP educational intervention., Methods: A randomized controlled trial with parallel groups with evaluations before the education, immediately after it, and 6 and 12 months after the education was conducted at four emergency departments in two university hospitals. The experimental group (N = 40) received EBP education while the control group (N = 40) completed self-directed EBP education. The primary outcomes were emergency nurses' EBP attitudes, knowledge, self-efficacy, skills, and behavior, while the secondary outcome was satisfaction with the EBP education., Results: Thirty-five participants of an experimental and 29 participants of a control group completed the study. There were no statistically significant (p < .05) improvements and differences between groups in EBP attitude, self-efficacy, or behavior immediately after the EBP education. At the 6-month measurement point, the experimental group showed significantly better EBP attitudes, behavior, knowledge, and self-efficacy than the control group. At the 12-month measurement point, the improvements began to decrease. The groups also differed significantly in terms of participant satisfaction with how the teacher encouraged learners to ask clinical questions., Linking Evidence to Action: The EBP educational intervention implemented in this study had a positive effect on emergency nurses' EBP attitudes, knowledge, self-efficacy, skills, and behavior. The effects of the education appeared the best 6 months after the education. After this point, the results began to decrease and approached baseline levels. EBP educational interventions designed for emergency nurses should apply various teaching strategies to improve their EBP attitude, knowledge, self-efficacy, skills, behavior, and satisfaction with the education., (© 2021 The Authors. Worldviews on Evidence-based Nursing published by Wiley Periodicals LLC on behalf of Sigma Theta Tau International.)

Background: The challenges encountered in emergency medical services (EMS) contacts with children are likely most pronounced in infants, but little is known about their out-of-hospital care. Our primary aim was to describe the characteristics of EMS contacts with infants. The secondary aims were to examine the symptom-based dispatch system for nonverbal infants, and to observe the association of unfavorable patient outcomes with patient and EMS mission characteristics., Methods: In a population-based 5-year retrospective cohort of all 1712 EMS responses for infants (age < 1 year) in Helsinki, Finland (population 643,000, < 1-year old population 6548), we studied 1) the characteristics of EMS missions with infants; 2) mortality within 12 months; 3) pediatric intensive care unit (PICU) admissions; 4) medical state of the infant upon presentation to the emergency department (ED); 5) any medication or respiratory support given at the ED; 6) hospitalization; and 7) surgical procedures during the same hospital visit., Results: 1712 infants with a median age of 6.7 months were encountered, comprising 0.4% of all EMS missions. The most common complaints were dyspnea, low-energy falls, and choking. Two infants died on-scene. The EMS transported 683 (39.9%) infants. One (0.1%) infant died during the 12-month follow-up period. Ninety-one infants had abnormal clinical examination upon arrival at the ED. PICU admissions (n = 28) were associated with young age (P < 0.01), a history of prematurity or problems in the neonatal period (P = 0.01), and previous EMS contacts within 72 h (P = 0.04). The adult-derived dispatch codes did not associate with the final diagnoses of the infants., Conclusions: Infants form a small but distinct group in pediatric EMS care, with specific characteristics differing from the overall pediatric population. Many EMS contacts with infants were nonurgent or medically unjustified, possibly reflecting an unmet need for other family services. The use of adult-derived symptom codes for dispatching is not optimal for infants. Unfavorable patient outcomes were rare. Risk factors for such outcomes include quickly renewed contacts, young age and health problems in the neonatal period.

Background: Children are less vulnerable to serious forms of the COVID-19 disease. However, concerns have been raised about children being the second victims of the pandemic and its control measures. Therefore, we wanted to study if the pandemic, the infection control measures and their consequences to the society projected to paediatric prehospital emergency medical services (EMS) contacts., Methods: We conducted a population-based cohort study concerning all children aged 0-15 years with EMS contacts in the Helsinki University Hospital area during 1 March 2020-31 May 2020 (study period) and equivalent periods in 2017-2019 (control periods). We analysed the demographic characteristics, time of EMS contact, reason for EMS contact, priority of the dispatch, reason for transportation, priority of transportation, if any consultations were made or additional units required, any medication or oxygen or fluids given, if intubation was performed, and whether paramedics took precautions when COVID-19 infection was suspected., Results: The number of paediatric EMS contacts decreased by 30.4% from mean of 1794 contacts to 1369 (p=0.003). The EMS contacts were more often due to trauma (+23.7%, p<0.05), dispatched in the most urgent category (+139.9%, p=0.001), additional help and the mobile intensive care unit were more frequently requested (+43.3%, p=0.040 and+46.3%, p=0.049, respectively). However, EMS contacts resulted less often in ambulance transport (-21.1%, p<0.001). Alarmingly, there were four deaths during the study period compared with 0-2 during the control periods., Conclusions: The number of EMS contacts decreased during the pandemic. Nevertheless, the children encountered by the EMS were more seriously ill than during the control periods., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Intramuscular or intravenous oxytocin is used in out-of-hospital emergency care in Finland to prevent postpartum hemorrhage after unplanned out-of-hospital deliveries. However, the use of oxytocin by emergency medical services is based on in-hospital studies. The aim of this study was to determine whether the use of oxytocin is associated with diminished postpartum hemorrhage after unplanned out-of-hospital deliveries., Material and Methods: We studied patient records covering all unplanned out-of-hospital deliveries in the Helsinki University Hospital area between 1 January 2013 and 31 December 2017 inclusive. Oxytocin was available in ambulances responsible for half of the population of the study area and was not available in ambulances responsible for the other half. The study area corresponded to 25% of all deliveries in Finland. The primary outcome was the estimated total bleeding (mL). Secondary outcomes were (1) the first blood hemoglobin value measured in hospital (g/L), (2) whether blood hemoglobin was measured during the first 24 hours after delivery, (3) the need for red blood cell concentrate, (4) the need for uterotonic or prothrombotic medication in-hospital during the first 24 hours, (5) the need for any postpartum operation during the first 24 hours and (6) composite outcome combining the secondary outcomes 2-5., Results: Of all ambulance responses in the study area, .04% concerned out-of-hospital deliveries. There were 216 analyzed out-of-hospital deliveries. Altogether, 111 of these occurred in the area with oxytocin available in ambulances and 105 in the area without. Oxytocin was administered in 57 of the 111 deliveries (51%) where it was available. No differences in the primary outcome (P = .548 for oxytocin available vs not available and P = .381 for oxytocin used vs not used) or secondary outcomes were detected between those deliveries where oxytocin was available vs not available or between those where it was used vs not used., Conclusions: Out-of-hospital oxytocin was not associated with diminished postpartum hemorrhage in this study setting. Oxytocin does not seem to be an essential drug for all ambulance units. The in-hospital use of oxytocin was not evaluated and thus is not disputed by this study., (© 2020 Nordic Federation of Societies of Obstetrics and Gynecology.)

Background: Identifying stroke and other intracranial lesions in patients with a decreased level of consciousness may be challenging in prehospital settings. Our objective was to investigate whether the combination of systolic blood pressure, heart rate and age could be used to identify intracranial lesions., Methods: We conducted a retrospective case-control study including patients with a decreased level of consciousness who had their airway secured during prehospital care. Patients with intracranial lesions were identified based on the final diagnoses at the end of hospitalization. We investigated the ability of systolic blood pressure, heart rate and age to identify intracranial lesions and derived a decision instrument., Results: Of 425 patients, 127 had an intracranial lesion. Patients with a lesion were characterized by higher systolic blood pressure, lower heart rate and higher age (P < 0.0001 for all). A systolic blood pressure ≥ 140 mmHg had an odds ratio (OR) of 3.5 (95% confidence interval [CI] 1.7 to 7.0), and > 170 mmHg had an OR of 8.2 (95% CI 4.5-15.32) for an intracranial lesion (reference: < 140 mmHg). A heart rate < 100 beats/min had an OR of 3.4 (95% CI 2.0 to 6.0, reference: ≥100). Age 50-70 had an OR of 4.1 (95% CI 2.0 to 9.0), and > 70 years had an OR of 10.2 (95% CI 4.8 to 23.2), reference: < 50. Logarithms of ORs were rounded to the nearest integer to create a score with 0-2 points for age and blood pressure and 0-1 for heart rate, with an increasing risk for an intracranial lesion with higher scores. The area under the receiver operating characteristics curve for the instrument was 0.810 (95% CI 0.850-0.890)., Conclusions: An instrument combining systolic blood pressure, heart rate and age may help identify stroke and other intracranial lesions in patients with a decreased level of consciousness in prehospital settings., Trial Registration: Not applicable.

Background: To determine if prehospital blood glucose could be added to National Early Warning Score (NEWS) for improved identification of risk of short-term mortality., Methods: Retrospective observational study (2008-2015) of adult patients seen by emergency medical services in Helsinki metropolitan area for whom all variables for calculation of NEWS and a blood glucose value were available. Survival of 24 hours and 30 days were determined. The NEWS parameters and glucose were tested by multivariate logistic regression model. Based on ORs we formed NEWSgluc model with hypoglycaemia (≤3.0 mmol/L) 3, normoglycaemia 0 and hyperglycaemia (≥11.1 mmol/L) 1 points. The scores from NEWS and NEWSgluc were compared using discrimination (area under the curve), calibration (Hosmer-Lemeshow test), likelihood ratio tests and reclassification (continuous net reclassification index (cNRI))., Results: Data of 27 141 patients were included in the study. Multivariable regression model for NEWSgluc parameters revealed a strong association with glucose disturbances and 24-hour and 30-day mortality. Likelihood ratios (LRs) for mortality at 24 hours using a cut-off point of 15 were for NEWSgluc: LR+ 17.78 and LR- 0.96 and for NEWS: LR+ 13.50 and LR- 0.92. Results were similar at 30 days. Risks per score point estimation and calibration model showed glucose added benefit to NEWS at 24 hours and at 30 days. Although areas under the curve were similar, reclassification test (cNRI) showed overall improvement of classification of survivors and non-survivors at 24 days and 30 days with NEWSgluc., Conclusions: Including glucose in NEWS in the prehospital setting seems to improve identification of patients at risk of death., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Nonspecific complaint (NSC) is a common presenting complaint in the emergency setting, especially in the elderly population. Individual studies have shown that it is associated with significant morbidity and mortality. This prognostic systematic review draws a synthesis of reported outcomes for patients presenting with NSC and compares them with outcomes for patients presenting with a specific complaint., Methods: We conducted a literature search for publications, abstracts and conference presentations from Ovid, Scopus and Web of Science for the past 20 years. Studies were included which treated adult patients presenting to the Emergency Medical Services or Emergency Department with NSC. 2599 studies were screened for eligibility and quality was assessed using the SIGN assessment for bias tool. We excluded any low-quality studies, resulting in nine studies for quantitative analysis. We analysed the included studies for in-hospital mortality, triage category, emergency department length of stay, admission rate, hospital length of stay, intensive care admissions and re-visitation rate and compared outcomes to patients presenting with specific complaints (SC), where data were available. We grouped discharge diagnoses by ICD-10 category., Results: We found that patients presenting with NSC were mostly older adults. Mortality for patients with NSC was significantly increased compared to patients presenting with SC [OR 2.50 (95% CI 1.40-4.47)]. They were triaged as urgent less often than SC patients [OR 2.12 (95% CI 1.08-4.16)]. Emergency department length of stay was increased in two out of three studies. Hospital length of stay was increased by 1-3 days. Admission rates were high in most studies, 55 to 84%, and increased in comparison to patients with SC [OR 3.86 (95% CI 1.76-8.47)]. These patients seemed to require more resources than patients with SC. The number for intensive care admissions did not seem to be increased. Data were insufficient to make conclusions regarding re-visitation rates. Discharge diagnoses were spread throughout the ICD-10 main chapters, infections being the most prevalent., Conclusions: Patients with NSC have a high risk of mortality and their care in the Emergency Department requires more time and resources than for patients with SC. We suggest that NSC should be considered a major emergency presentation.

Aims: Distinct ceramide lipids have been shown to predict the risk for cardiovascular disease (CVD) events, especially cardiovascular death. As phospholipids have also been linked with CVD risk, we investigated whether the combination of ceramides with phosphatidylcholines (PCs) would be synergistic in the prediction of CVD events in patients with atherosclerotic coronary heart disease in three independent cohort studies., Methods and Results: Ceramides and PCs were analysed using liquid chromatography-mass spectrometry (LC-MS) in three studies: WECAC (The Western Norway Coronary Angiography Cohort) (N = 3789), LIPID (Long-Term Intervention with Pravastatin in Ischaemic Disease) trial (N = 5991), and KAROLA (Langzeiterfolge der KARdiOLogischen Anschlussheilbehandlung) (N = 1023). A simple risk score, based on the ceramides and PCs showing the best prognostic features, was developed in the WECAC study and validated in the two other cohorts. This score was highly significant in predicting CVD mortality [multiadjusted hazard ratios (HRs; 95% confidence interval) per standard deviation were 1.44 (1.28-1.63) in WECAC, 1.47 (1.34-1.61) in the LIPID trial, and 1.69 (1.31-2.17) in KAROLA]. In addition, a combination of the risk score with high-sensitivity troponin T increased the HRs to 1.63 (1.44-1.85) and 2.04 (1.57-2.64) in WECAC and KAROLA cohorts, respectively. The C-statistics in WECAC for the risk score combined with sex and age was 0.76 for CVD death. The ceramide-phospholipid risk score showed comparable and synergistic predictive performance with previously published CVD risk models for secondary prevention., Conclusion: A simple ceramide- and phospholipid-based risk score can efficiently predict residual CVD event risk in patients with coronary artery disease., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Not all children with an out-of-hospital emergency medical contact are transported by ambulance to the emergency department (ED). Non-transport means that after on-scene evaluation and possible treatment, ambulance personnel may advise the patient to monitor the situation at home or may refer the patient to seek medical attention by other means of transport. As selecting the right patients for ambulance transport is critical for optimising patient safety and resource use, we studied outcomes in non-transported children to identify possible risk groups that could benefit from ambulance transport., Methods: In a population-based retrospective cohort study of all children aged 0-15 years encountered but not transported by ambulance in Helsinki, Finland, between 1 January 2014 and 31 December 2016, we evaluated (1) 12-month mortality, (2) intensive care admissions, (3) unscheduled ED contacts within the following 96 hours after the non-transport decision and (4) the clinical status of the child on presentation to ED in the case of a secondary ED visit., Results: Of all children encountered by out-of-hospital emergency medical services, 3579/7765 (46%) were not transported to ED by ambulance. There was no mortality or intensive care admissions related to the non-transport. The risk factors for an unscheduled secondary ED visit after a non-transport decision were young age (p=0.001), non-transport decision during the early morning hours (p<0.001) and certain dispatch codes, including 'dyspnoea' (p<0.001), 'vomiting/diarrhoea' (p=0.030) and 'mental illness' (p=0.019). We did not detect deterioration in patients' clinical presentation at ED traceable to non-transport decisions., Conclusions: Not transporting all children by ambulance after an out-of-hospital emergency medical contact was not associated with deaths, intensive care admissions or significant deterioration in general condition in our study population and healthcare system. Special attention and a formal non-transport protocol are warranted in certain subgroups, including infants., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Viral infections are a major cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Although immune suppression plays a central role, the literature shows conflicting results on interplay between post-transplant immune reconstitution (IR) and viral infections. Methods: We prospectively studied viral infections and IR in 30 pediatric patients undergoing allogenic HSCT, with a follow-up time of 24 months. In total, 1337 blood (CMV, EBV, HHV-6, ADV and BKV) and urine (BKV and JCV) virus samples were analyzed. IR including B-cells (CD19+), T cells (CD3+, CD4+, CD8+) and NK-cells were measured. Clinical outcomes included overall survival (OS), non-relapse mortality (NRM), graft-versus-host disease (GVHD) and occurrence of blood culture positive bacterial infections. Results: We found BKV reactivation to be most frequent, 47% of the children had viremia and 77% viruria. The frequencies of CMV, HHV-6 and adeno viremia were 37%, 37% and 6%, respectively. Viremias beyond 3 months post-HSCT were uncommon. Factors such as GVHD, use of steroids, EBV and CMV infections and pre-transplant irradiation affected IR. No specific viral infection or IR related factor was associated to OS or NRM. Conclusions: Viral infections and IR interact in a bi-directional manner. Accordingly, close follow-up of both IR and viral loads is warranted.

Background: The treatment of constitutional delay of growth and puberty (CDGP) is an underinvestigated area in adolescent medicine. We tested the hypothesis that peroral aromatase inhibition with letrozole is more efficacious than intramuscular injection of low-dose testosterone in inducing puberty in boys with CDGP., Methods: We did a randomised, controlled, open-label trial at four paediatric centres in Finland. Boys aged at least 14 years with CDGP who wanted medical intervention and exhibited the first signs of puberty were randomly assigned in blocks of ten to receive either six intramuscular injections of low-dose testosterone (about 1 mg/kg bodyweight) every 4 weeks for 6 months or peroral letrozole 2·5 mg once daily for 6 months. All boys were followed up for 6 months after the end of treatment. The primary outcomes were changes in testicular volume and hormonal markers of puberty at 6 months after treatment initiation, which were assessed in all participants who received the assigned treatment. All patients were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01797718., Findings: Between Aug 1, 2013, and Jan 30, 2017, 30 boys were randomly assigned to receive testosterone (n=15) or letrozole (n=15). One boy in the testosterone group was excluded from the primary analyses because of a protocol deviation. During treatment, boys in the letrozole group had higher serum concentrations of luteinising hormone, follicle-stimulating hormone, testosterone, and inhibin B than did boys in the testosterone group. Testicular growth from baseline to 6 months was greater in the letrozole group than in the testosterone group (7·2 mL [95% CI 5·2-9·3] vs 2·2 mL [1·4-2·9]; between-group difference per month 0·9 mL [95% CI 0·6-1·2], p<0·0001). Most adverse events were mild. One boy in the testosterone group had aggressive behaviour for 1 week after each injection, and one boy in the letrozole group had increased irritability at 6 months., Interpretation: Letrozole might be a feasible alternative treatment to low-dose testosterone for boys with CDGP who opt for medical intervention. However, the risks and benefits of manipulating the reproductive axis during early puberty should be weighed carefully., Funding: Helsinki University Hospital, Academy of Finland, and Finnish Foundation for Pediatric Research., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: We wanted to study whether the socioeconomic status of a neighbourhood can predict the incidence of paediatric out-of-hospital emergencies., Methods: We conducted a population-based prospective study with all paediatric (0-15 years) out-of-hospital emergencies in Helsinki, Finland, in 2012-2013. We compared the geographical distribution of the emergencies in the paediatric population with those of mean income, unemployment level and educational level. The comparison was made both by the scene of the emergency and by the domicile of the patient. We also separately analysed the distribution of emergency medical (EM) contacts that were deemed medically unnecessary., Results: The incidence of out-of-hospital emergencies was higher in areas with lower socioeconomic status and among children living inside those areas. Higher mean income was associated with lower incidence (risk ratio (RR) 0.970, 95% CI 0.957 to 0.983), and lower unemployment level to higher incidence (RR 1.046, 95% CI 1.002 to 1.092) of out-of-hospital emergencies inside a district. Higher mean income was associated with lower incidence of emergencies in the paediatric population living inside a district (RR 0.983, 95% CI 0.974 to 0.993). The distribution of medically unnecessary EM contacts was similar in all areas., Conclusions: The socioeconomic status of a neighbourhood was associated with the need for EM services (EMS) in the area, and in children living in the area. Overusing EMS for non-urgent or non-medical problems did not explain these findings. Instead, they seem to represent true differences in the incidence of paediatric emergencies., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: Two missense mutations in KCNQ1 , an imprinted gene that encodes the alpha subunit of the voltage-gated potassium channel Kv7.1, cause autosomal dominant growth hormone deficiency and maternally inherited gingival fibromatosis. We evaluated endocrine features, birth size, and subsequent somatic growth of patients with long QT syndrome 1 (LQT1) due to loss-of-function mutations in KCNQ1 ., Design: Medical records of 104 patients with LQT1 in a single tertiary care center between 1995 and 2015 were retrospectively reviewed., Methods: Clinical and endocrine data of the LQT1 patients were included in the analyses., Results: At birth, patients with a maternally inherited mutation ( n  = 52) were shorter than those with paternal inheritance of the mutation ( n  = 29) (birth length, -0.70 ± 1.1 SDS vs. -0.2 ± 1.0 SDS, P  < 0.05). Further analyses showed, however, that only newborns ( n  = 19) of mothers who had received beta blockers during pregnancy were shorter and lighter at birth than those with paternal inheritance of the mutation ( n  = 29) (-0.89 ± 1.0 SDS vs. -0.20 ± 1.0 SDS, P  < 0.05; and 3,173 ± 469 vs. 3,515 ± 466 g, P  < 0.05). Maternal beta blocker treatment during the pregnancy was also associated with lower cord blood TSH levels ( P  = 0.011) and significant catch-up growth during the first year of life (Δ0.08 SDS/month, P  = 0.004). Later, childhood growth of the patients was unremarkable., Conclusion: Loss-of-function mutations in KCNQ1 are not associated with abnormalities in growth, whereas maternal beta blocker use during pregnancy seems to modify prenatal growth of LQT1 patients-a phenomenon followed by catch-up growth after birth.

Familial growth hormone deficiency provides an opportunity to identify new genetic causes of short stature. Here we combine linkage analysis with whole-genome resequencing in patients with growth hormone deficiency and maternally inherited gingival fibromatosis. We report that patients from three unrelated families harbor either of two missense mutations, c.347G>T p.(Arg116Leu) or c.1106C>T p.(Pro369Leu), in KCNQ1, a gene previously implicated in the long QT interval syndrome. Kcnq1 is expressed in hypothalamic GHRH neurons and pituitary somatotropes. Co-expressing KCNQ1 with the KCNE2 β-subunit shows that both KCNQ1 mutants increase current levels in patch clamp analyses and are associated with reduced pituitary hormone secretion from AtT-20 cells. In conclusion, our results reveal a role for the KCNQ1 potassium channel in the regulation of human growth, and show that growth hormone deficiency associated with maternally inherited gingival fibromatosis is an allelic disorder with cardiac arrhythmia syndromes caused by KCNQ1 mutations.