Increasing prevalence of cerebral palsy in children born very preterm in Denmark.

AIM: To analyse the rising prevalence of cerebral palsy (CP) in children born preterm in Denmark. METHOD: We included all live-born children born preterm in Denmark from 1997 to 2013. The prevalence of CP in children born preterm was categorized by gestational age and correlated with neonatal mortality and changes in clinical factors. RESULTS: Among 70 876 children, 824 (1.2%) had CP. The overall CP prevalence in children born preterm decreased substantially until 2001, from when it increased annually by 2.8% (95% confidence interval 0.6-5.0). When categorized, the prevalence only increased significantly in children born very preterm (gestational weeks 28-31). Neonatal mortality rates decreased steadily at all gestational ages during the entire study period. Clinical factors that changed during the study period were increasing numbers of high-risk pregnancies, maternal obesity, emergency caesarean sections, neonatal admissions, and usage of assisted ventilation. INTERPRETATION: The increasing prevalence of CP in children born preterm was driven by the subgroup born very preterm and matched their decrease in neonatal mortality. In similar population studies, decreased mortality was not followed by increased CP prevalence. An increase in clinical risk factors was unlikely to explain our findings, but more active neonatal life support may have played a role.

Epidemiology and outcome of infantile spasms in Denmark in 1996-2019.

PURPOSE: To investigate the treatment of infantile epileptic spasm syndrome (IESS) in Denmark. METHODS: National retrospective cohort study of all patients born 1996-2019 who had a diagnosis of IESS in the National Patient Registry. Medical records were reviewed to evaluate the diagnosis. Patients were included if semiology was compatible with IESS, or if unclear semiology if there was an abnormal EEG or EEG with hypsarrhythmia. RESULTS: Number of cases with a register based IESS diagnosis was 538. Medical records were unavailable in 48 and 164 did not fulfil the inclusion criteria. Thereby the cohort consisted of 326 children. Mean age at onset of IESS was 5.9 months and mean lead time to treatment was 26.6 days (SD= 63.5). Consistent with the Danish treatment guidelines most patients received vigabatrin as first treatment. In the cohort 44.7 % of patients solely received vigabatrin, whereas combined vigabatrin and corticosteroid was given to 28.3 % (either hydrocortisone or prednisolone). Other anti-seizure medication was given to 28.4 % within 90 days of IESS onset. Aetiology was prenatal (40.3 %), perinatal (10.5 %), postnatal (3.7 %), with unknown timing (10.2 %) or with unknown aetiology (33.5 %). The cohort was followed to a mean age of 8.2 years. At latest follow-up severe neurodevelopmental outcome was seen in 44.2 % and 76.4 % still had epilepsy. The incidence of IESS was 22 per 100.000 live births. CONCLUSION: In Denmark treatment algorithm is based on start of treatment with vigabatrin. A total of 44.7 % became seizure free by vigabatrin. Neurodevelopmental outcome was severe. A national incidence could be established.

Impact of a National Follow-Up Program on the Age at Diagnosis for Cerebral Palsy.

BACKGROUND: The Danish National Cerebral Palsy Follow-up Program (CPOP) is a nationwide program offering standardized treatment to all children with cerebral palsy (CP) since 2004. We aimed to establish if its implementation had a positive impact on the diagnostic age of CP. METHODS: Children with validated CP diagnoses were identified from the Danish Cerebral Palsy Registry and the CPOP. We then compared the age at diagnosis and the clinical features of children with CP born in 2000 to 2003 with those born in 2010 to 2013. Differences in time to diagnosis were compared using log-rank test. RESULTS: The age at diagnosis was not different in the two periods (P = 0.23), with identical overall median diagnostic ages at 13.0 months. The number of children with severe motor disability decreased markedly from 47.5% in 2000 to 2003 to 32.0% in 2010 to 2013 (P < 0.001). There was increased usage of cerebral magnetic resonance imaging; however, this was not associated with lower diagnostic age. CONCLUSIONS: The diagnostic age of CP did not change after the implementation of a nationwide follow-up program, offering standardized and early assessments. However, central clinical aspects also changed significantly between the periods compared, which possibly affected the diagnostic age.

The diagnosis of cerebral palsy in two Danish national registries: a validation study.

AIMS: To determine the quality of prospectively collected data from the highly specialized Danish Cerebral Palsy Follow-up Program (CPOP), and to establish the validity of a reported cerebral palsy (CP) diagnosis in the Danish National Patient Registry (NPR), regularly used as a proxy for neurodevelopmental disorders in epidemiological research. METHODS: We compared data from the two registries on children with registered CP, born in Denmark between 2008 and 2009, with information from medical records verified by two experienced physicians specializing in pediatric neurology. Data accuracy was estimated by completeness, correctness, and reliability. Completeness was calculated as the number of cases with correctly registered CP diagnoses divided by the total number of true CP diagnoses (similar to sensitivity). Correctness was calculated as the number of cases with correct registrations divided by the total number of cases (similar to positive predictive value). Reliability was estimated using kappa statistics. RESULTS: Registered CP diagnoses in the CPOP had high accuracy, with 94% correctness and 91% completeness. Furthermore, most key variables in the CPOP showed excellent reliability, especially variables defining the severity of the condition. In the Danish NPR, only 225 of 348 children with a noted CP diagnosis fulfilled the diagnostic criteria for CP, resulting in 65% correctness. CONCLUSIONS: Danish CPOP data are a valid source for epidemiological research. Conversely, a noted CP diagnosis in the Danish NPR was, at best, correct in only two out of three patients.

Predictors of transfer and prognosis after transfer from child and adolescent mental health services to adult mental health services-a Danish nationwide prospective register-based cohort study.

Onset of mental health disorder peaks during adolescence making continuity of care during this period of life crucial both to ensure a smooth treatment course and high quality of mental health services for adolescents. We aimed to examine which clinical and sociodemographic features predict transfer from child and adolescent mental health services to adult mental health services and if transfer is associated with prognosis. A Danish register study including all 16-17-year-olds with an outpatient contact in child and adolescent mental health services, who were discharged in the period of 1/1/06-10/05/15. Out of 27,170 Danish adolescents, 16% transferred to adult mental health services. Transfer was predicted by schizophrenia (OR 6.16; 95% CI 5.51-6.90) and personality disorders (OR 2.08; 95% CI 1.84-2.34), while hyperkinetic (OR 0.54; 95% CI 0.49-0.59) and pervasive developmental disorders (OR 0.42; 95% CI 0.31-0.58) decreased likelihood of transfer. Transfer was also substantially predicted by inpatient admission (OR 3.37; 95% CI 3.14-3.61) and psychiatric medication (OR 2.07; 95% CI 1.92-2.23). Transfer was associated with higher rates of inpatient admission to adult mental health services (IRR 5.83; 95% CI 4.37-7.77), more psychiatric emergency contacts (IRR 12.0; 95% CI 10.7-13.4), more convictions (IRR 1.40; 95% CI 1.23-1.59) and suicide attempts (IRR 5.70; 95% CI 4.72-6.90). Policy-makers and clinicians should push for improvements and open a discussion of how to ensure continuity of care for adolescents with psychiatric disorders.

Acetaminophen treatment in children and adults with spinal muscular atrophy: a lower tolerance and higher risk of hepatotoxicity.

Acute liver failure has been reported sporadically in patients with spinal muscular atrophy (SMA) and other neuromuscular disorders with low skeletal muscle mass receiving recommended dosages of acetaminophen. It is suggested that low skeletal muscle mass may add to the risk of toxicity. We aimed to describe the pharmacokinetics and safety of acetaminophen in patients with SMA. We analyzed acetaminophen metabolites and liver biomarkers in plasma from SMA patients and healthy controls (HC) every hour for six or eight hours on day 1 and day 3 of treatment with therapeutic doses of acetaminophen. Twelve patients with SMA (six adults and six children) and 11 HC participated in the study. Adult patients with SMA had significantly lower clearance of acetaminophen compared to HC (14.1 L/h vs. 21.5 L/h). Formation clearance of acetaminophen metabolites, glucuronide, sulfate, and oxidative metabolites were two-fold lower in the patients compared to HC. The liver transaminases and microRNAs increased nine-fold in one adult SMA patient after two days of treatment. The other patients and HC did not develop abnormal liver biomarkers. In this study, patients with SMA had lower clearance and slower metabolism of acetaminophen, and one patient developed liver involvement. We recommend giving 15 mg/kg/dose to SMA adults (with a maximum of 4000 mg/day) and monitoring standard liver biomarkers 48 h after first-time treatment of acetaminophen.

Current state of hemispherectomy and callosotomy for pediatric refractory epilepsy in Denmark.

OBJECTIVE: To evaluate outcomes from hemispherectomy and callosotomy related to the need for anti-seizure medication (ASM), seizure frequency, and cognition. METHODS: A review of the medical charts of all Danish pediatric patients who underwent hemispherectomy or callosotomy from January 1996 to December 2019 for preoperative and postoperative ASM use, seizure frequency, and cognitive data. RESULTS: The median age of epilepsy onset was two years (interquartile range (IQR): 0.0-5.3) for the hemispherectomy patients (n = 16) and one year (IQR: 0.6-1.7) for callosotomy patients (n = 5). Median time from onset to final surgery was 3.4 years for hemispherectomy and 10.2 years for callosotomy, while the median follow-up time was 6.9 years and 9.0 years, respectively. Preoperatively, all patients had daily seizures and were treated with ≥ 2 ASM. Hemispherectomy resulted in a reduction in seizure frequency in 87.5 % of patients, with 78.6 % achieving seizure freedom. Furthermore, 81.3 % experienced a reduction in ASM use and 56.3 % stopped all ASM. Median IQ/developmental quotient (IQ/DQ) was low preoperatively (44.0 [IQR: 40.0-55.0]) and remained unchanged postoperatively (IQ change: 0.0 [IQR: -10.0-+4.0]). Callosotomy resulted in a seizure reduction of 86-99 % in four patients, and ASM could be reduced in three patients. Median IQ/DQ was 20.0 preoperatively (IQR: 20.0-30.0) and remained unchanged postoperatively (IQ change: 0.0 [IQR: 0.0]). CONCLUSION: Hemispherectomy and callosotomy result in a substantial reduction in seizure frequency and ASM use without deterioration of IQ. Extensive epilepsy surgery should be considered early in children with drug-resistant epilepsy.

Growth in perceived clinical genetics competency among primary care providers participating in genomic population health screening.

Limited competency in genetics among primary care providers (PCPs) is a barrier to use of genetic information in healthcare. Formal genetics lessons require time and interest, and knowledge wanes. We hypothesized another path to competency: participation in our PCP-centered adult clinical genomic population health screening program. We asked participating Family Medicine PCPs about their perceptions of growth in their genetics competency. An anonymous, voluntary, cross-sectional survey was developed and distributed to PCPs offering the screening. Results were compiled after 3 weeks. PCPs rated several program resources for value and provided open-ended feedback. Seventy-five percent of respondents agreed that genetics is important to their practice. Eighty-seven percent felt that their knowledge of clinical genetics topics had grown. Eighty-seven percent perceived increased confidence in offering genetic testing and in discussing common genetic results with patients. Respondents gained appreciation for the scope of clinical utility that genetic information offers patients. Each education resource rated at least 3.75 out of 5 for contributing to genetics knowledge. The case-specific Genomic Medicine Action Plan rated highest in educational value, 4.5 out of 5. Most responding PCPs offering genomic population health screening perceived growth in their genetic competency and found hands-on, case-based resources most useful.

Effectiveness and safety of everolimus treatment in patients with tuberous sclerosis complex in real-world clinical practice.

BACKGROUND: The randomised double-blinded placebo-controlled EXIST-1-3 studies have showed everolimus effective with adverse effects reported as acceptable in treatment of symptoms in patients with tuberous sclerosis complex (TSC), although evidence of outcomes in clinical practice remains limited. This study aimed to investigate, in clinical practice, the effectiveness and safety of everolimus for epilepsy, renal angiomyolipoma (rAML), and subependymal giant cell astrocytoma (SEGA) in patients with TSC. RESULTS: The study included 64 patients with TSC (median age: 19, range 0.9-54 years) receiving everolimus treatment (Norway: n = 35; Denmark: n = 29). Among 45 patients with epilepsy, 14 (31%) were responders experiencing ≥ 50% reduction in seizure frequency in the last 3 months of treatment compared with the last 3 months before treatment. Nineteen (42%) patients changed their anti-seizure medications (ASMs). Responders were more common among patients < 18 years (46%) than among patients ≥ 18 years (14%, p = 0.03). In 29 patients with rAML, everolimus reduced (≥ 30% decrease) and stabilized (< 20% increase, ≤ 30% decrease) longest diameter of rAML in 38% and 59%, respectively, after a mean treatment duration of 37 months. SEGA volume was reduced in three patients by 71%, 43%, and 48% after 39, 34, and 82 months. Adverse effects were reported in 61 of 64 patients (95%) after a median treatment duration of 31 months (range 0-106), with oral ulceration/stomatitis (63%) and upper respiratory tract infections (38%) being the most common. The most common laboratory abnormalities were increased cholesterol (41%), anaemia (30%), and leucopoenia (25%). Grade 3-4 adverse effects were reported in 36% of cases, and life-threatening conditions were reported in two patients. Nine patients discontinued everolimus treatment. CONCLUSIONS: Seizure reduction in this study sample was consistent with results from EXIST, but might be lower than expected, given that changes in concomitant ASMs are part of clinical practice. Seizure reduction was associated with younger age. As with EXIST, everolimus reduced or stabilised rAML size in most patients. SEGA volume was reduced in all three patients. Close follow-up is needed for this group, especially for children and patients who may not be able to report adverse effects.

Cerebral Palsy - Early Diagnosis and Intervention Trial: protocol for the prospective multicentre CP-EDIT study with focus on diagnosis, prognostic factors, and intervention.

BACKGROUND: Early diagnosis of cerebral palsy (CP) is important to enable intervention at a time when neuroplasticity is at its highest. Current mean age at diagnosis is 13 months in Denmark. Recent research has documented that an early-diagnosis set-up can lower diagnostic age in high-risk infants. The aim of the current study is to lower diagnostic age of CP regardless of neonatal risk factors. Additionally, we want to investigate if an early intervention program added to standard care is superior to standard care alone. METHODS: The current multicentre study CP-EDIT (Early Diagnosis and Intervention Trial) with the GO-PLAY intervention included (Goal Oriented ParentaL supported home ActivitY program), aims at testing the feasibility of an early diagnosis set-up and the GO-PLAY early intervention. CP-EDIT is a prospective cohort study, consecutively assessing approximately 500 infants at risk of CP. We will systematically collect data at inclusion (age 3-11 months) and follow a subset of participants (n = 300) with CP or at high risk of CP until the age of two years. The GO-PLAY early intervention will be tested in 80 infants with CP or high risk of CP. Focus is on eight areas related to implementation and perspectives of the families: early cerebral magnetic resonance imaging (MRI), early genetic testing, implementation of the General Movements Assessment method, analysis of the GO-PLAY early intervention, parental perspective of early intervention and early diagnosis, early prediction of CP, and comparative analysis of the Hand Assessment for Infants, Hammersmith Infant Neurological Examination, MRI, and the General Movements method. DISCUSSION: Early screening for CP is increasingly possible and an interim diagnosis of "high risk of CP" is recommended but not currently used in clinical care in Denmark. Additionally, there is a need to accelerate identification in mild or ambiguous cases to facilitate appropriate therapy early. Most studies on early diagnosis focus on identifying CP in infants below five months corrected age. Little is known about early diagnosis in the 50% of all CP cases that are discernible later in infancy. The current study aims at improving care of patients with CP even before they have an established diagnosis. TRIAL REGISTRATION: ClinicalTrials.gov ID 22013292 (reg. date 31/MAR/2023) for the CP-EDIT cohort and ID 22041835 (reg. date 31/MAR/2023) for the GO-PLAY trial.

Ocular and systemic associations and heritability of retinal arterial wall-to-lumen ratios in a twin cohort.

PURPOSE: To investigate ocular and systemic factors associated with the retinal arterial wall-to-lumen ratio (WLR) and to determine the relative contribution of genetic and environmental variation to WLR in healthy adults. METHODS: This cross-sectional twin study included 78 monozygotic and 67 dizygotic same-sex twin pairs aged 58.4 ± 9.8 (mean ± SD) years. Lumen diameter (LD) and outer diameter (OD) of a superotemporal retinal artery were measured using adaptive optics fundus photography, and the WLR was calculated. Linear mixed model regression analysis of associations with WLR comprised the descriptive variables ocular axial length (AL), intraocular pressure (IOP), height, weight, body mass index (BMI), smoking, blood pressure, high density (HDL), low density (LDL) and very low density (VLDL) lipoproteins, total cholesterol and triglycerides. The relative influence of genes and environment on WLR was calculated through polygenetic modelling. RESULTS: Increasing age and arterial blood pressure were associated with a higher WLR, while increasing retinal artery OD and ocular AL were associated with a lower WLR. Sex, smoking status, BMI, IOP, cholesterol levels or triglycerides had no detectable impact on the WLR. Broad-sense heritability of WLR was 21% (95% CI: 1-41%), while environmental factors accounted for the remaining 79% of the interindividual variance (95% CI: 59-99%). CONCLUSION: Retinal artery wall thickness was closely linked to increasing age and higher arterial blood pressure, the latter being mediated by the environment over genes.

Low skeletal muscle mass and liver fibrosis in children with cerebral palsy.

The purpose of the study was to conduct a nutritional and metabolic assessment of children with cerebral palsy, including an investigation of liver status, body composition, and bone mineral density. In this cross-sectional study we included 22 children with cerebral palsy. By using ultrasound, transient elastography, dual x-ray absorptiometry (DXA) scan, blood samples, anthropometric measurements, and a three-day diet registration, the nutritional and metabolic status was evaluated. Liver fibrosis and steatosis were found in four patients (18.2%), all with severe motor impairments, low skeletal muscle mass, and epilepsy. All patients with liver involvement had normal liver-related blood samples. Decreased bone mineral density was found in 26.3%, and 91.0% had low skeletal muscle mass. Fat mass and muscle mass were significantly lower in the patients with severe motor impairments compared to the patients with less severe motor impairments. Within the children classified as 'underweight' or 'normal' according to body mass index, body fat determined by DXA scan was normal or high in 50% of these patients. CONCLUSIONS: This study is the first to report liver fibrosis and steatosis in children with cerebral palsy. Possible causes of liver fibrosis and/or steatosis are altered body composition with low skeletal muscle mass, decreased mobility and medical drug intake. Further investigations of liver involvement and risk factors are needed. WHAT IS KNOWN: • Children and adolescents with cerebral palsy are at risk of malnutrition and altered body composition, both of which can lead to fatty liver disease. • It is unknown whether children with cerebral palsy are at increased risk of metabolic disturbances such as fatty liver disease. WHAT IS NEW: • Altered body composition and low skeletal muscle mass, regardless of ambulation is present in 91% of the children with cerebral palsy. • Liver fibrosis and/or steatosis were found in 18.2% of the patients. Possible causes are altered body composition, decreased mobility and medical drug intake.

Severe Congenital Heart Defects and Cerebral Palsy.

OBJECTIVE: To report the prevalence of cerebral palsy (CP) in children with severe congenital heart defects (sCHD) and the outcome/severity of the CP. METHODS: Population-based, data linkage study between CP and congenital anomaly registers in Europe and Australia. The EUROCAT definition of severe CHD (sCHD) was used. Linked data from 4 regions in Europe and 2 in Australia were included. All children born in the regions from 1991 through 2009 diagnosed with CP and/or sCHD were included. Linkage was completed locally. Deidentified linked data were pooled for analyses. RESULTS: The study sample included 4989 children with CP and 3684 children with sCHD. The total number of livebirths in the population was 1 734 612. The prevalence of CP was 2.9 per 1000 births (95% CI, 2.8-3.0) and the prevalence of sCHD was 2.1 per 1000 births (95% CI, 2.1-2.2). Of children with sCHD, 1.5% (n = 57) had a diagnosis of CP, of which 35 (61%) children had prenatally or perinatally acquired CP (resulting from a brain injury at ≤28 days of life) and 22 (39%) children had a postneonatal cause (a brain injury between 28 days and 2 years). Children with CP and sCHD more often had unilateral spastic CP and more intellectual impairments than children with CP without congenital anomalies. CONCLUSIONS: In high-income countries, the proportion of children with CP is much higher in children with sCHD than in the background population. The severity of disease in children with CP and sCHD is milder compared with children with CP without congenital anomalies.

Visual Function and Inner Retinal Structure in Relation to Birth Factors in Autosomal Dominant Optic Atrophy.

Purpose: The extreme variation in expressivity of autosomal dominant optic atrophy (ADOA) is unexplained. It is present from early childhood, why there is reason to search for pre- and perinatal risk factors for poor vision in ADOA. The process of ganglion cell pruning in the fetus is of interest because mitochondria are involved in apoptosis. We hypothesized that suboptimal mitochondrial function makes the developing retina and optic nerve vulnerable to fetal stress in ADOA. We have examined visual function and inner retinal layer structure in relation to birth parameters in ADOA. Methods: The study included 142 participants with OPA1 ADOA, 62 unaffected first-degree relatives, and 90 unrelated control subjects. Outcome measures included best-corrected visual acuity, microperimetric sensitivity, nerve fiber layer (NFL) volume, and ganglion cell layer (GCL) volume. Descriptive parameters included birth weight, maternal age at birth, birth complications, and gestational age. Analysis was made using mixed modeling. Results: The analysis showed a significant positive association between microperimetric sensitivity and longer gestational age in ADOA (0.5 dB/week, P = 0.017). Interaction analysis showed a significant different association between microperimetric sensitivity and gestational age between participants with ADOA and the control groups (P = 0.007) and a significant difference in association between NFL volume and birth weight (P = 0.04) and gestational age (P = 0.02) between variant types. Conclusions: The study suggests that gestational age and birth weight may affect the expressivity of ADOA. The results support that prospectively collected pre- and perinatal data should be included in future studies of the natural history of ADOA.

Rewilding of laboratory mice enhances granulopoiesis and immunity through intestinal fungal colonization.

The paucity of blood granulocyte populations such as neutrophils in laboratory mice is a notable difference between this model organism and humans, but the cause of this species-specific difference is unclear. We previously demonstrated that laboratory mice released into a seminatural environment, referred to as rewilding, display an increase in blood granulocytes that is associated with expansion of fungi in the gut microbiota. Here, we find that tonic signals from fungal colonization induce sustained granulopoiesis through a mechanism distinct from emergency granulopoiesis, leading to a prolonged expansion of circulating neutrophils that promotes immunity. Fungal colonization after either rewilding or oral inoculation of laboratory mice with Candida albicans induced persistent expansion of myeloid progenitors in the bone marrow. This increase in granulopoiesis conferred greater long-term protection from bloodstream infection by gram-positive bacteria than by the trained immune response evoked by transient exposure to the fungal cell wall component ß-glucan. Consequently, introducing fungi into laboratory mice may restore aspects of leukocyte development and provide a better model for humans and free-living mammals that are constantly exposed to environmental fungi.

The Positive Predictive Value of Pediatric Stroke Diagnoses in Administrative Data: A Retrospective Validation Study.

Background: This retrospective cohort study aimed to examine the positive predictive value (PPV) of pediatric stroke diagnoses in the Danish National Registry of Patients (DNRP) and the impact of different stroke definitions on the PPV. Methods: We included children registered with a stroke or stroke-related diagnosis in the DNRP between January 2017 through December 2020. Two assessors reviewed medical records and validated cases according to the American Heart and American Stroke Association (AHA/ASA) stroke definition. The level of interrater agreement was examined using kappa statistics. Validation by the AHA/ASA definition was compared with validation according to the definition in the International Classification of Disease 11th version (ICD-11) and the World Health Organization's definition. Results: Stroke was confirmed in 120 of 309 included children, yielding an overall PPV of 0.39 (95% CI: 0.33-0.45). PPV varied across stroke subtypes from 0.83 (95% CI: 0.71-0.92) for ischemic stroke (AIS), 0.57 (95% CI: 0.37-0.76) for unspecified stroke, 0.42 (95% CI: 0.33-0.52) for intracerebral hemorrhage (ICH) to 0.31 (95% CI: 0.55-0.98) and 0.07 (95% CI: 0.01-0.22) for cerebral venous thrombosis and subarachnoid hemorrhage (SAH), respectively. Most non-confirmed ICH and SAH diagnoses were in children with traumatic intracranial hemorrhages (36 and 66% respectively). Among 70 confirmed AIS cases, 25 (36%) were identified in non-AIS code groups. PPV varied significantly across stroke definitions with the highest for the AHA/ASA definition (PPV = 0.39, 95% CI: 0.34-0.45) and the lowest for the WHO definition (PPV = 0.29, 95% CI: 0.24-0.34). Correspondingly, the incidence of pediatric AIS per 100.000 person-years changed from 1.5 for the AHA/ASA definition to 1.2 for ICD-11 and 1.0 for the WHO-definition. The overall interrater agreement was considered excellent (κ=0.85). Conclusion: After validation, stroke was confirmed in only half of the children registered in the DNRP with a stroke-specific diagnosis. Non-validated administrative data should be used with caution in pediatric stroke research. Pediatric stroke incidence rates may vary markedly depending on which stroke definition is used.

Acute triage of childhood stroke in Denmark.

OBJECTIVE: This 2-year observational study aimed to test the feasibility of implementing a pediatric stroke triage-setup that connected frontline providers with vascular neurologists and to examine final diagnoses in children triaged for suspected stroke. METHODS: Prospective, consecutive registration of children with suspected stroke triaged by a team of vascular neurologists from Jan 1st, 2020 and through Dec 2021, Eastern Denmark (census 530,000 children). Based on the provided clinical information, the children were triaged to either assessment at the Comprehensive Stroke Center (CSC) in Copenhagen or to a pediatric department. All included children were retrospectively followed-up for clinical presentations and final diagnosis. RESULTS: A total of 163 children with 166 suspected stroke events were triaged by the vascular neurologists. Cerebrovascular disease was present in 15 (9.0%) suspected stroke events; one child had intracerebral hemorrhage, one had subarachnoid hemorrhage, two children presented with three TIA events and nine children presented with 10 ischemic stroke events. Two children with ischemic stroke were eligible for acute revascularization treatment of which both were triaged to the CSC. The sensitivity of the triage by acute revascularization indication was 1.00 (95% confidence interval (95% CI): 0.15-1.00) and specificity 0.65 (95% CI: 0.57-0.73). Non-stroke neurological emergencies were present in 34 (20.5%) children, including seizures in 18 (10.8%) and acute demyelinating disorders in 7 (4.2%). CONCLUSION: Implementing regional triage-setup that connected frontline providers to vascular neurologists was feasible; this system was activated for the majority of children with ischemic stroke according to an expected incidence and led to identification of children eligible for revascularization treatments.

Necrocide 1 mediates necrotic cell death and immunogenic response in human cancer cells.

Many anticancer agents induce apoptosis, mitotic catastrophe or cellular senescence. Here, we report the functional characterization of an experimental inducer of tumor necrosis factor (TNF)-independent necrosis, necrocide-1 (NC1). NC1 (but not its stereoisomer) killed a panel of human cancer cells (but not normal cells) at nanomolar concentrations and with a non-apoptotic, necrotic morphotype, both in vitro and in vivo. NC1-induced killing was not inhibited by caspase blockers, anti-apoptotic BCL2 overexpression or TNFα neutralization, suggesting that NC1 elicits a bona fide necrotic pathway. However, pharmacological or genetic inhibition of necroptosis, pyroptosis and ferroptosis failed to block NC1-mediated cell death. Instead, NC1 elicited reactive oxygen species (ROS) production by mitochondria, and elimination of mitochondrial DNA, quenching of mitochondrial ROS, as well as blockade of mitochondrial permeability transition with cyclosporine A, interfered with NC1-induced cell death. NC1 induced hallmarks of immunogenic cell death incurring calreticulin (CALR) exposure, ATP secretion and high mobility group box 1 (HMGB1) release. Taken together, these data identify a previously uncharacterized signaling cascade leading to an immunogenic variant of mitochondrion-regulated necrosis, supporting the notion that eliciting regulated necrosis may constitute a valid approach for anticancer therapy.

Children in Denmark with cerebral palsy rarely complete elementary school.

AIM: To investigate how children with cerebral palsy (CP) perform in the Danish school system and which factors are associated with school performance. METHOD: This was a population-based cohort study including 463 126 children born from 1997 to 2003. Data were extracted from seven national registries. The study encompassed 818 children with CP (483 [59.0%] males, 335 [41.0%] females) and 417 731 without CP (214 535 [51.4%] males, 203 196 [48.6%] females). We evaluated two primary outcomes: not completing 10 years of elementary school, defined as attending fewer than eight final mandatory exams; and grade point averages (GPAs). Mann-Whitney U tests were used to analyse differences in GPAs and logistic regressions were used to calculate odds ratios (ORs). RESULTS: Among children with and without CP, 62.6% and 12.4% did not complete elementary school respectively (OR = 11.85 [10.28-13.66]). Additionally, children with CP who attended all final exams achieved lower overall GPAs than children without CP (6.6 vs 7.3, p = 0.001). In children with CP, comorbidities, maternal education, severity of motor impairments, and intellectual deficits were associated with increased odds of not completing elementary school. Notably, one-third of children with CP with apparent normal intelligence did not complete school, despite special educational measures. INTERPRETATION: Danish children with CP rarely complete elementary school despite initiatives for a more supportive educational system. The complexity of individual needs in children with CP may be challenging for an inclusive school environment. WHAT THIS PAPER ADDS: Children with cerebral palsy (CP) have a high risk of not completing elementary school. Children with CP achieve lower overall grades than children without CP. Motor impairment, comorbidities, and maternal education are associated with poor school performance. Intellectual impairment is the most important predictor of poor school performance.

The midbody component Prc1-like is required for microtubule reorganization during cytokinesis and dorsal determinant segregation in the early zebrafish embryo.

We show that the zebrafish maternal-effect mutation too much information (tmi) corresponds to zebrafish prc1-like (prc1l), which encodes a member of the MAP65/Ase1/PRC1 family of microtubule-associated proteins. Embryos from tmi homozygous mutant mothers display cytokinesis defects in meiotic and mitotic divisions in the early embryo, indicating that Prc1l has a role in midbody formation during cell division at the egg-to-embryo transition. Unexpectedly, maternal Prc1l function is also essential for the reorganization of vegetal pole microtubules required for the segregation of dorsal determinants. Whereas Prc1 is widely regarded to crosslink microtubules in an antiparallel conformation, our studies provide evidence for an additional function of Prc1l in the bundling of parallel microtubules in the vegetal cortex of the early embryo during cortical rotation and prior to mitotic cycling. These findings highlight common yet distinct aspects of microtubule reorganization that occur during the egg-to-embryo transition, driven by maternal product for the midbody component Prc1l and required for embryonic cell division and pattern formation.