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BACKGROUND AND PURPOSE: Ischemic stroke is a common cause of death in adults, however, mortality after pediatric ischemic stroke is not well explored. We investigate long-term and cause-specific mortality in children with ischemic stroke and their first-degree relatives. METHODS: Through nationwide Swedish registers, we identified 1606 individuals <18 years old with ischemic stroke between 1969 and 2016 and their first-degree relatives (n=5714). Each individual with ischemic stroke was compared with 10 reference individuals (controls) matched for age, sex, and county of residence. Our main analysis examined 1327 children with ischemic stroke still alive 1 week after the event. First-degree relatives to children with ischemic stroke were compared with first-degree relatives to the reference individuals. Using a Cox proportional hazard regression model, the risk of overall and cause-specific mortality was computed in individuals with pediatric ischemic stroke and their first-degree relatives. RESULTS: The mortality rate in the first 6 months was 40.1 (95% CI, 24.7-55.6) per 1000 person-years compared with 1.1/1000 in controls (95% CI, 0.3-1.9). The overall mortality risk was hazard ratio (HR)=10.8 (95% CI, 8.1-14.3) and remained elevated beyond 20 years (HR=3.9 [95% CI, 2.1-7.1]). Children with ischemic stroke were at increased risk of death from neurological diseases (HR=29.9 [95% CI, 12.7-70.3]), cardiovascular diseases (HR=6.2 [95% CI, 1.8-22.2]), cancers (HR=6.5 [95% CI, 2.6-15.9]) and endocrine, nutritional and metabolic diseases (HR=49.2 [95% CI, 5.7-420.8]). First-degree relatives to children with ischemic stroke had an increased mortality risk (HR=1.21 [95% CI, 1.05-1.39]), with the highest risk among siblings (HR=1.52 [95% CI, 1.09-2.11]) and relatives to individuals with ischemic stroke >28 days of age (HR=1.23 [95% CI, 1.06-1.42]) compared with the relatives of the controls. CONCLUSIONS: Long-term mortality increased after pediatric ischemic stroke, even 20 years later, with neurological diseases as the most frequent cause of death.
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AVC Isquêmico/mortalidade , Sistema de Registros , Adolescente , Fatores Etários , Doenças Cardiovasculares , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Modelos de Riscos Proporcionais , Fatores de Risco , Suécia/epidemiologiaRESUMO
BACKGROUND: Various frequencies of adverse motor outcomes (cerebral palsy and hemiplegia) after paediatric ischaemic stroke have been reported. Few reports on the risks of adverse motor outcomes in nationwide cohorts and contributing risk factors are available. OBJECTIVES: To assess risk of adverse motor outcome and potential risk factors thereof after paediatric ischaemic stroke in a nationwide cohort. METHODS: This nationwide matched cohort study identified 877 children <18 years of age diagnosed with ischaemic stroke through the Swedish national health registers from 1997 to 2016. These children, exposed to ischaemic stroke, alive 1 week after stroke, were matched for age, sex and county of residence with 10 unexposed children. Using Cox regression, we estimated the risk of adverse motor outcomes in children with stroke compared to that in unexposed children. Logistic regression was applied to compare the characteristics of children with and without adverse motor outcomes after stroke. RESULTS: Out of the 877 children with ischaemic stroke, 280 (31.9%) suffered adverse motor outcomes compared with 21 (0.2%) of the 8770 unexposed: adjusted hazard ratio (aHR) 167.78 (95% confidence interval (CI) 107.58, 261.66). There were no differences between risk estimates of adverse motor outcome according to age at stroke: perinatal stroke (aHR 124.11, 95% CI 30.45, 505.84) and childhood stroke (aHR 182.37, 95% CI 113.65, 292.64). An association between adverse motor outcome and childhood stroke aOR 1.56 (95% CI 1.05, 2.31) was found when analysing only children with ischaemic stroke. No associations were found between adverse motor outcome and sex, gestational age or parental age at birth. CONCLUSIONS: The risk of adverse motor outcome is substantial after paediatric ischaemic stroke, especially childhood stroke, confirming results of previous smaller studies. This study found no associations between sex, gestational age or parental age and adverse motor outcome after paediatric ischaemic stroke.
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Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/epidemiologia , Criança , Estudos de Coortes , Feminino , Humanos , Recém-Nascido , Gravidez , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologiaRESUMO
BACKGROUND: Intrauterine growth restriction (IUGR) may directly affect cardiovascular function in early life. Longitudinal data on left ventricular longitudinal strain (LVLS), a key measure of cardiac function independent of body size, is not available. We hypothesize impaired cardiac function among IUGR newborns and persistence of the impairment until age 3 months. METHOD: This is a prospective cohort study of consecutive pregnancies where IUGR was identified at 18-38 weeks gestational age (GA) with healthy controls randomly selected at 18-20 weeks GA. Echocardiograms were performed at birth and at age 3-4 months, and then compared. RESULTS: At birth, mean (SD) LVLS did not differ between the IUGR group [N = 19; - 15.76 (3.12) %] and controls [N = 35; - 15.53 (3.56) %]. The IUGR group demonstrated no significant change in LVLS at age 3-4 months [- 17.80 (3.82) %], while the control group [- 20.91 (3.31) %] showed a significant increase (P < 0.001). Thus, LVLS was lower in the IUGR group at age 3-4 months (P = 0.003). CONCLUSION: The lack of increase in LVLS may suggest that IUGR has a direct impact on cardiac function as early as during the first months of life. Trial registration Clinical trials.gov Identifier: NCT02583763, registration October 22, 2015. Retrospectively registered September 2014-October 2015, thereafter, registered prospectively.
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Retardo do Crescimento Fetal , Ventrículos do Coração , Criança , Ecocardiografia , Feminino , Retardo do Crescimento Fetal/diagnóstico por imagem , Idade Gestacional , Ventrículos do Coração/diagnóstico por imagem , Humanos , Lactente , Recém-Nascido , Gravidez , Estudos ProspectivosRESUMO
Background and Purpose: The risk of epilepsy after stroke has not been thoroughly explored in pediatric ischemic stroke. We examined the risk of epilepsy in children with ischemic stroke as well as in their first-degree relatives. Methods: In Swedish National Registers, we identified 1220 children <18 years with pediatric ischemic stroke diagnosed 1969 to 2016, alive 7 days after stroke and with no prior epilepsy. We used 12 155 age- and sex-matched individuals as comparators. All first-degree relatives to index individuals and comparators were also identified. The risk of epilepsy was estimated in children with ischemic stroke and in their first-degree relatives using Cox proportional hazard regression model. Results: Through this nationwide population-based study, 219 (18.0%) children with ischemic stroke and 91 (0.7%) comparators were diagnosed with epilepsy during follow-up corresponding to a 27.8-fold increased risk of future epilepsy (95% CI, 21.536.0). The risk of epilepsy was still elevated after 20 years (hazard ratio [HR], 7.9 [95% CI, 3.319.0]), although the highest HR was seen in the first 6 months (HR, 119.4 [95% CI, 48.0297.4]). The overall incidence rate of epilepsy was 27.0 per 100 000 person-years (95% CI, 21.132.8) after ischemic stroke diagnosed ≤day 28 after birth (perinatal) and 11.6 per 100 000 person-years (95% CI, 9.613.5) after ischemic stroke diagnosed ≥day 29 after birth (childhood). Siblings and parents, but not offspring, to children with ischemic stroke were at increased risk of epilepsy (siblings: HR, 1.64 [95% CI, 1.082.48] and parents: HR, 1.41 [95% CI, 1.011.98]). Conclusions: The risk of epilepsy after ischemic stroke in children is increased, especially after perinatal ischemic stroke. The risk of epilepsy was highest during the first 6 months but remained elevated even 20 years after stroke which should be taken into account in future planning for children affected by stroke.
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Epilepsia/etiologia , AVC Isquêmico/complicações , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Epilepsia/epidemiologia , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Fatores de Risco , Suécia/epidemiologiaRESUMO
AIM: The Swedish National Patient Register offers unique opportunities for epidemiological research of paediatric ischaemic stroke. We aimed to validate the diagnosis of paediatric ischaemic stroke in the National Patient Register to ensure the quality of future research. METHODS: The PedStroke cohort consists of 1606 individuals aged <18 years with a diagnosis of paediatric ischaemic stroke (ICD-10: I63, I64; ICD-8 and 9: 433, 434, 436) in Swedish national health registers between 1969 and 2016. We selected 292 cases for validation by reviewing medical charts. RESULTS: In all, 277 of the 292 medical charts were received, of which 273 had enough information to qualify for review. The diagnosis was correct in 242/273 cases, yielding a positive predictive value (PPV) of 89% (95% confidence interval (CI): 0.85-0.92) for paediatric ischaemic stroke in the National Patient Register. After validation, seven cases of 222 with childhood stroke were re-categorised to perinatal stroke, resulting in a total of 56 perinatal stroke cases. In the Medical Birth Register, 38 stroke cases were identified of which 37 had correct diagnosis, generating a PPV of 97% (95% CI: 0.92-1.0). Incorrect diagnoses decreased over time and the number of diagnoses confirmed by radiology increased correspondingly. CONCLUSION: The National Patient Register is reliable for epidemiological research of paediatric ischaemic stroke because of its high PPV for this diagnosis.
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Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/epidemiologia , Criança , Humanos , Sistema de Registros , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Suécia/epidemiologiaRESUMO
OBJECTIVE: To evaluate longitudinal serum insulin-like growth factor-I (IGF-I) in a large cohort of children and adolescents with type 1 diabetes in relation to hemoglobin A1c (HbA1c), age, diabetes duration, and body mass index (BMI), its association to height and retinopathy, and in comparison with healthy subject references. METHODS: A total of 2683 serum IGF-I values were obtained from 806 children and adolescents with T1DM, from annual blood samples for up to 6 consecutive years. RESULTS: In a multiple regression analysis IGF-I values were negatively correlated to HbA1c and diabetes duration, and positively correlated to BMI (P < .001, P < .001, and P < .001, respectively, adjusted r2 = 0.102). Children and adolescents with T1DM had lower mean IGF-I levels and reference interval limits compared to healthy subjects. In boys, mean (SD) IGF-I SD score (SDS) levels were -1.04 (±1.3) calculated from the healthy reference. IGF-I peaked at 15 years of age, similarly to healthy controls, but with markedly lower levels in late puberty. Girls were more affected at later stages of puberty but with a slightly less depressed overall mean IGF-I SDS of -0.69 (±1.2). In a subgroup of 746 subjects with fundus photography, a negative correlation was seen between individual mean IGF-I SDS and preproliferative retinopathy (P = .004, adjusted r2 = 0.021). In another subgroup of 84 adolescents, no correlation was seen between individual mean IGF-I SDS and target height SDS or distance to target height SDS. CONCLUSION: Poor metabolic control and diabetes duration impact negatively on serum IGF-I levels. A low individual mean IGF-I level was associated with progression of retinopathy independently of HbA1c, age, gender, and diabetes duration. Disease, sex and age related IGF-I SDS may become clinical helpful as a supplement to HbA1c in predicting the long-term outcome for children and adolescents with T1DM.
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Diabetes Mellitus Tipo 1/sangue , Retinopatia Diabética/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Adolescente , Desenvolvimento do Adolescente , Biomarcadores/sangue , Índice de Massa Corporal , Criança , Pré-Escolar , Estudos de Coortes , Diabetes Mellitus Tipo 1/complicações , Retinopatia Diabética/etiologia , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Estudos Longitudinais , Valores de Referência , Adulto JovemRESUMO
BACKGROUND: The use of plasma-derived immunoglobulin G (IgG) is increasing, and the number of diseases, including immunodeficiencies, neurological diseases and autoimmune conditions, treated with intravenous IgG (IVIG) is expanding. Consequently, there is a great need for high-yield production processes for plasma-derived IgG. The aim of this work was to develop a high-yield process leading to a highly purified, liquid, ready-to-use IgG for intravenous use. METHODS: Plasma from healthy, voluntary, non-remunerated donors was fractionated by ethanol precipitation. IgG was extracted from fraction II + III using a phosphate/acetate buffer, pH 4, and purified by chromatography. RESULTS: Precipitation with 6% polyethylene glycol at pH 7 removed high molecular-weight contaminating proteins, aggregates and contaminating viruses. Ion exchange chromatography at pH 5.7 on serially connected anion and cation exchange columns allowed for elution of IgG from the cation exchange column in good yield and high purity. Further safety was achieved by solvent/detergent treatment and repeated ion exchange chromatography. The product consisted of essentially only IgG monomers and dimers, and had a high purity with very low levels of IgM and IgA. CONCLUSION: A process providing highly purified IVIG in good yield was developed.
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BACKGROUND: Autism spectrum conditions (ASC) and quantitative autistic traits (QATs) are associated with sensory symptoms, which may contribute to anxiety and adversely affect social and cognitive development. Although sensory symptoms can occur across all senses, the relative roles of specific sensory modalities as contributors to the autistic phenotype and to anxiety are not well understood. The objective of this study was to examine which sensory symptoms were most predictive of high anxiety. METHODS: We recruited 257 female primary caregivers of children aged 6 to 11 years (49% girls) to a questionnaire study comprising parent-report measures for classical QATs (social, communicative, and rigid), autism-related sensorimotor symptoms (visual, auditory, tactile, olfactory, gustatory, vestibular, proprioceptive, and motor), and anxiety symptoms. First, Bayesian stochastic search variable selection (SSVS) was used to identify the most probable sensorimotor predictors of specific QATs as well as diagnosed ASC. Then, the selected predictors were used in another SSVS, using anxiety symptoms as a dependent variable, to identify which of the autism-relevant sensorimotor symptoms were most robustly predictive of anxiety. Finally, the effect sizes of anxiety-related sensory symptoms were estimated with linear regressions. RESULTS: We found that auditory symptoms and motor difficulties were most predictive of ASC diagnosis. Developmental motor difficulties were also strongly related to all individual QATs, whereas auditory symptoms were more selectively predictive of rigid traits. Tactile symptoms robustly predicted social interaction QATs, and proprioceptive symptoms predicted communicative QATs. Anxiety outcomes were most strongly predicted by difficulties with auditory and olfactory processing. CONCLUSIONS: The results support the clinical importance of being alert to complaints about sounds and hearing in neurodevelopmental populations, and that auditory processing difficulties may be evaluated as an early marker of poor mental health in children with and without diagnosed autism. Olfactory processing differences appeared to be an anxiety marker less strongly associated with ASC or QATs, while motor difficulties were highly autism-relevant but not equally strongly associated with anxiety outcomes. We suggest that future studies may focus on the mechanisms and consequences of neurodevelopmental central auditory processing dysfunction and its potential relationship to anxiety disorders.
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Ansiedade , Transtorno do Espectro Autista , Humanos , Feminino , Criança , Masculino , Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/fisiopatologia , Transtornos de Sensação/etiologia , Transtornos de Sensação/fisiopatologia , Transtorno Autístico/complicações , Transtorno Autístico/fisiopatologiaRESUMO
Two malaria transmission-blocking vaccine (TBV) candidates, R0.6C and ProC6C, have completed preclinical development including the selection of adjuvants, Alhydrogel® with or without the saponin based adjuvant Matrix-M™. Here, we report on the final drug product (formulation) design of R0.6C and ProC6C and evaluate their safety and biochemical stability in preparation for preclinical and clinical pharmacy handling. The point-of-injection stability studies demonstrated that both the R0.6C and ProC6C antigens are stable on Alhydrogel in the presence or absence of Matrix-M for up to 24 h at room temperature. As this is the first study to combine Alhydrogel and Matrix-M for clinical use, we also evaluated their potential interactions. Matrix-M adsorbs to Alhydrogel, while not displacing the > 95 % adsorbed protein. The R0.6C and ProC6C formulations were found to be safe and well tolerated in repeated dose toxicity studies in rabbits generating high levels of functional antibodies that blocked infection of mosquitoes. Further, the R0.6C and ProC6C drug products were found to be stable for minimally 24 months when stored at 2-8 °C, with studies ongoing through 36 months. Together, this data demonstrates the safety and suitability of the L. lactis expression system as well as supports the clinical testing of the R0.6C and ProC6C malaria vaccine candidates in First-In-Human clinical trials.
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Vacinas Antimaláricas , Malária Falciparum , Animais , Coelhos , Hidróxido de Alumínio , Anticorpos Antiprotozoários , Antígenos de Protozoários , Vacinas Antimaláricas/efeitos adversos , Malária Falciparum/prevenção & controle , Plasmodium falciparum , Proteínas de ProtozoáriosRESUMO
BACKGROUND: There is no vaccine against the major global pathogen Chlamydia trachomatis; its different serovars cause trachoma in the eye or chlamydia in the genital tract. We did a clinical trial administering CTH522, a recombinant version of the C trachomatis major outer membrane molecule, in different dose concentrations with and without adjuvant, to establish its safety and immunogenicity when administered intramuscularly, intradermally, and topically into the eye, in prime-boost regimens. METHODS: CHLM-02 was a phase 1, double-blind, randomised, placebo-controlled trial at the National Institute for Health Research Imperial Clinical Research Facility, London, UK. Participants were healthy men and non-pregnant women aged 18-45 years, without pre-existing C trachomatis genital infection. Participants were assigned into six groups by the electronic database in a pre-prepared randomisation list (A-F). Participants were randomly assigned (1:1:1:1:1) to each of the groups A-E (12 participants each) and 6 were randomly assigned to group F. Investigators were masked to treatment allocation. Groups A-E received investigational medicinal product and group F received placebo only. Two liposomal adjuvants were compared, CAF01 and CAF09b. The groups were intramuscular 85 µg CTH522-CAF01, or placebo on day 0 and two boosters or placebo at day 28 and 112, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (A); intramuscular 85 µg CTH522-CAF01, two boosters at day 28 and 112 with additional topical ocular administration of CTH522, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (B); intramuscular 85 µg CTH522-CAF01, two boosters at day 28 and 112 with additional intradermal administration of CTH522, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (C); intramuscular 15 µg CTH522-CAF01, two boosters at day 28 and 112, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (D); intramuscular 85 µg CTH522-CAF09b, two boosters at day 28 and 112, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (E); intramuscular placebo (F). The primary outcome was safety; the secondary outcome (humoral immunogenicity) was the percentage of trial participants achieving anti-CTH522 IgG seroconversion, defined as four-fold and ten-fold increase over baseline concentrations. Analyses were done as intention to treat and as per protocol. The trial is registered with ClinicalTrials.gov, NCT03926728, and is complete. FINDINGS: Between Feb 17, 2020 and Feb 22, 2022, of 154 participants screened, 65 were randomly assigned, and 60 completed the trial (34 [52%] of 65 women, 46 [71%] of 65 White, mean age 26·8 years). No serious adverse events occurred but one participant in group A2 discontinued dosing after having self-limiting adverse events after both placebo and investigational medicinal product doses. Study procedures were otherwise well tolerated; the majority of adverse events were mild to moderate, with only seven (1%) of 865 reported as grade 3 (severe). There was 100% four-fold seroconversion rate by day 42 in the active groups (A-E) and no seroconversion in the placebo group. Serum IgG anti-CTH522 titres were higher after 85 µg CTH522-CAF01 than 15 µg, although not significantly (intention-to-treat median IgG titre ratio groups A-C:D=5·6; p=0·062), with no difference after three injections of 85 µg CTH522-CAF01 compared with CTH522-CAF09b (group E). Intradermal CTH522 (group C) induced high titres of serum IgG anti-CTH522 neutralising antibodies against serovars B (trachoma) and D (urogenital). Topical ocular CTH522 (group B) at day 28 and 112 induced higher total ocular IgA compared with baseline (p<0·001). Participants in all active vaccine groups, particularly groups B and E, developed cell mediated immune responses against CTH522. INTERPRETATION: CTH522, adjuvanted with CAF01 or CAF09b, is safe and immunogenic, with 85 µg CTH522-CAF01 inducing robust serum IgG binding titres. Intradermal vaccination conferred systemic IgG neutralisation breadth, and topical ocular administration increased ocular IgA formation. These findings indicate CTH522 vaccine regimens against ocular trachoma and urogenital chlamydia for testing in phase 2, clinical trials. FUNDING: The EU Horizon Program TRACVAC.
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Vacinas Bacterianas , Chlamydia trachomatis , Lipossomos , Tracoma , Humanos , Adulto , Método Duplo-Cego , Feminino , Masculino , Adulto Jovem , Chlamydia trachomatis/imunologia , Tracoma/prevenção & controle , Adolescente , Vacinas Bacterianas/administração & dosagem , Vacinas Bacterianas/imunologia , Vacinas Bacterianas/efeitos adversos , Pessoa de Meia-Idade , Injeções Intramusculares , Anticorpos Antibacterianos/sangue , Adjuvantes Imunológicos/administração & dosagem , Voluntários SaudáveisRESUMO
LAY ABSTRACT: Sensory symptoms are a major source of distress for many autistic people, causing anxiety, stress, and avoidance. Sensory problems are thought to be passed on genetically together with other autistic characteristics, such as social preferences. This means that people who report cognitive rigidity and autistic-like social function are more likely to suffer from sensory issues. We do not know what role the individual senses, such as vision, hearing, smell, or touch, play in this relationship, because sensory processing is generally measured with questionnaires that target general, multisensory issues. This study aimed to investigate the individual importance of the different senses (vision, hearing, touch, smell, taste, balance, and proprioception) in the correlation with autistic traits. To ensure the results were replicable, we repeated the experiment in two large groups of adults. The first group contained 40% autistic participants, whereas the second group resembled the general population. We found that problems with auditory processing were more strongly predictive of general autistic characteristics than were problems with the other senses. Problems with touch were specifically related to differences in social interaction, such as avoiding social settings. We also found a specific relationship between proprioceptive differences and autistic-like communication preferences. The sensory questionnaire had limited reliability, so our results may underestimate the contribution of some senses. With that reservation in mind, we conclude that auditory differences are dominant over other modalities in predicting genetically based autistic traits and may therefore be of special interest for further genetic and neurobiological studies.
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Transtorno do Espectro Autista , Transtorno Autístico , Adulto , Humanos , Transtorno Autístico/psicologia , Reprodutibilidade dos Testes , Percepção Auditiva , OlfatoRESUMO
CONTEXT: The European Increlex® Growth Forum Database (Eu-IGFD) is an ongoing surveillance registry (NCT00903110) established to collect long-term safety and effectiveness data on the use of recombinant human insulin-like growth factor-1 (rhIGF-1, mecasermin, Increlex) for the treatment of children/adolescents with severe primary insulin-like growth factor-1 deficiency (SPIGFD). OBJECTIVE: This analysis of Eu-IGFD data aimed to identify the frequency and predictive factors for hypoglycemia adverse events (AEs) in children treated with rhIGF-1. METHODS: Data were collected from December 2008 to May 2021. Logistic regression was performed to identify predictive risk factors for treatment-induced hypoglycemia AEs. Odds ratios (ORs) are presented with 95% CIs for each factor. RESULTS: In total, 306 patients were enrolled in the registry; 84.6% were diagnosed with SPIGFD. Patients who experienced ≥ 1 hypoglycemia AE (n = 80) compared with those with no hypoglycemia AEs (n = 224) had a lower mean age at treatment start (8.7 years vs 9.8 years), a more frequent diagnosis of Laron syndrome (27.5% vs 10.3%), and a history of hypoglycemia (18.8% vs 4.5%). Prior history of hypoglycemia (OR 0.25; 95% CI: [0.11; 0.61]; P = .002) and Laron syndrome diagnosis (OR 0.36; 95% CI: [0.18; 0.72]; P = .004) predicted future hypoglycemia AEs. Total hypoglycemia AEs per patient per treatment year was 0.11 and total serious hypoglycemia AEs per patient per treatment year was 0.01. CONCLUSION: Hypoglycemia occurs more frequently in patients with prior history of hypoglycemia and/or Laron syndrome compared with patients without these risk factors, and these patients should be carefully monitored for this AE throughout treatment.
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Hipoglicemia , Síndrome de Laron , Criança , Adolescente , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemia/epidemiologia , Estudos Longitudinais , Fator de Crescimento Insulin-Like I , Proteínas Recombinantes/efeitos adversos , Bases de Dados Factuais , Modelos LogísticosRESUMO
BACKGROUND: Severe primary insulin-like growth factor-I (IGF-I) deficiency (SPIGFD) is a rare growth disorder characterized by short stature (standard deviation score [SDS] ≤ 3.0), low circulating concentrations of IGF-I (SDS ≤ 3.0), and normal or elevated concentrations of growth hormone (GH). Laron syndrome is the best characterized form of SPIGFD, caused by a defect in the GH receptor (GHR) gene. However, awareness of SPIGFD remains low, and individuals living with SPIGFD continue to face challenges associated with diagnosis, treatment and care. OBJECTIVE: To gather perspectives on the key challenges for individuals and families living with SPIGFD through a multi-stakeholder approach. By highlighting critical gaps in the awareness, diagnosis, and management of SPIGFD, this report aims to provide recommendations to improve care for people affected by SPIGFD globally. METHODS: An international group of clinical experts, researchers, and patient and caregiver representatives from the SPIGFD community participated in a virtual, half-day meeting to discuss key unmet needs and opportunities to improve the care of people living with SPIGFD. RESULTS: As a rare disorder, limited awareness and understanding of SPIGFD amongst healthcare professionals (HCPs) poses significant challenges in the diagnosis and treatment of those affected. Patients often face difficulties associated with receiving a formal diagnosis, delayed treatment initiation and limited access to appropriate therapy. This has a considerable impact on the physical health and quality of life for patients, highlighting a need for more education and clearer guidance for HCPs. Support from patient advocacy groups is valuable in helping patients and their families to find appropriate care. However, there remains a need to better understand the burden that SPIGFD has on individuals beyond height, including the impact on physical, emotional, and social wellbeing. CONCLUSIONS: To address the challenges faced by individuals and families affected by SPIGFD, greater awareness of SPIGFD is needed within the healthcare community, and a consensus on best practice in the care of individuals affected by this condition. Continued efforts are also needed at a global level to challenge existing perceptions around SPIGFD, and identify solutions that promote equitable access to appropriate care. Medical writing support was industry-sponsored.
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Nanismo , Síndrome de Laron , Humanos , Fator de Crescimento Insulin-Like I/uso terapêutico , Qualidade de Vida , Síndrome de Laron/diagnóstico , Síndrome de Laron/tratamento farmacológico , Síndrome de Laron/genética , Nanismo/tratamento farmacológico , Transtornos do CrescimentoRESUMO
Growth hormone (GH) is widely prescribed for children with short stature across a range of growth disorders. Recombinant human (rh) insulin-like growth factor-1 (rhIGF-1) therapy is approved for severe primary IGF-I deficiency - a state of severe GH resistance. Evidence is increasing for an unacceptably high rate of poor or unsatisfactory response to growth-promoting therapy (i.e. not leading to significant catch up growth) in terms of change in height standard deviation score (SDS) and height velocity (HV) in many approved indications. Consequently, there is a need to define poor response and to prevent or correct it by optimizing treatment regimens within accepted guidelines. Recognition of a poor response is an indication for action by the treating physician, either to modify the therapy or to review the primary diagnosis leading either to discontinuation or change of therapy. This review discusses the optimal investigation of the child who is a candidate for GH or IGF-1 therapy so that a diagnosis-based choice of therapy and dosage can be made. The relevant parameters in the evaluation of growth response are described together with the definitions of poor response. Prevention of poor response is addressed by discussion of strategy for first-year management with GH and IGF-1. Adherence to therapy is reviewed as is the recommended action following the identification of the poorly responding patient. The awareness, recognition and management of poor response to growth-promoting therapy will lead to better patient care, greater cost-effectiveness and increased opportunities for clinical benefit.
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Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento/uso terapêutico , Estatura/efeitos dos fármacos , Criança , Pré-Escolar , Transtornos do Crescimento/metabolismo , Humanos , Fator de Crescimento Insulin-Like I/uso terapêutico , Resultado do TratamentoRESUMO
Background: Autistic adults have an elevated risk of many health problems compared with the general population, making health care access extra critical. Unfortunately, autistic people often find health care settings quite aversive, and many medical providers report feeling unsure about how to interact with autistic patients. We aimed at characterizing specific challenges regarding sensory experiences and communicative barriers in health care settings. Methods: We recruited adults to complete an anonymous online questionnaire on the topic of improving health care experiences for everyone. The questions covered demographics, sensory experiences in medical settings, and communication with health care providers. We quantified the associations between autism diagnosis and experiences of sensory discomfort and communication barriers in health care settings. We also did a qualitative analysis of text responses to questions on how to improve sensory environments and communication with providers. Results: Swedish adults (62 autistic and 36 nonautistic) participated in the study. The cohort was well educated, and autistic participants received their autism diagnosis late in life (median age 36 years, range 13-57). Compared with nonautistic participants, autistic participants reported greater discomfort with background sound levels in health care settings and felt more misunderstood by health care providers. Thematic analyses showed that auditory stimuli and proximity to other people were particularly bothersome for autistic participants, causing stress or avoidance and affecting the ability to interact with providers. Providers contributed to communication barriers by failing to recognize the need for individualized information, especially when respondents' difficulties were not visible or taken seriously. Participants requested greater clarity and supplementary written information. Providers also misunderstood autistic adults' body language or eye contact patterns, as they interpreted their clients through the lens of neurotypical expectations. Conclusions: Our results extend previous research by emphasizing sensory aspects of health care settings and suggesting specific and reasonable adaptations. The results also highlight how the provider's implicit expectations of nonverbal communication caused misinterpretations of autistic people who were socially skilled but did not use typical body language. Based on the data, we suggest specific adaptations, many of which may also benefit nonautistic people.
Why was this study done?: Health care needs of autistic adults are often unmet. This may contribute to poorer health outcomes in autistic compared with nonautistic adults. Autistic differences may not be obvious in this group because of behavioral compensation strategies. Health care providers may underestimate the support needs of autistic adults, leading to decreased quality of care. By analyzing autistic adults' own experiences, we may better understand barriers to effective health care. What was the purpose of this study?: We aimed at identifying patterns of sensory and communicative experiences that autistic adults find problematic in health care settings. What did the researchers do?: In an online questionnaire, we asked autistic and nonautistic adults how they experienced various medical settings. We focused on specific sensory inputs, such as light levels and background sounds, in waiting rooms and other medical contexts. We also asked questions about communication between patients and providers. Finally, we did a qualitative analysis on free-text responses about sensory environments for both groups, and about communication for the autistic group. What were the results of the study?: Ninety-eight people (62 autistic) participated. Most of the cohort was female or gender-diverse, middle-age, and well educated. Autistic participants identified auditory inputs as one of the greatest stressors in medical settings. They discussed the impact of light levels and other people's presence on their energy levels and ability to communicate. Health care providers often misunderstood their autistic patients, leading to a failure in transferring medical information. Participants described how providers underestimated their needs, even when they were aware of the autism diagnosis. Participants wanted to get information delivered at a slower pace and with a greater amount of detail, to be better able to process medical or procedural information. What do these findings add to what was already known?: The study contributes with information on specific sensory challenges and suggests that auditory noise is particularly problematic for autistic people. On the topic of communication, the findings point to a "double empathy" problem, whereby the provider's own limitations contribute significantly to communication barriers. This was apparent in accounts of nonverbal communication, where the provider's expectations of neurotypical body language caused misunderstandings that were difficult to overcome. What are the potential weaknesses in the study?: The sample was small and comprised an ethnically narrow demographic group. Thus, the results are not generalizable to other autistic populations, such as minimally verbal adults. We also did not measure health status beyond diagnosed conditions. How will these findings help autistic adults now or in the future?: The consequences of sensory and communicative barriers may go entirely unnoticed when autistic differences are not visible. Unsuccessful interactions with the health care system may have enormous effects on the health and quality of life of autistic people. Therefore, educators and providers may use the insightful information provided by autistic participants in this study to inform decisions on staff training or design of sensory environments.
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BACKGROUND AND OBJECTIVES: Ischemic stroke increases the risk of neurodevelopmental disorders; however, the risk of autism is not thoroughly explored. Our aim was to evaluate risk of autism and risk factors for autism in children with pediatric ischemic stroke and in their first-degree relatives. METHODS: In this cohort study, individuals with ischemic stroke from 1969 to 2016, <18 years of age, alive 1 week after stroke, and without prior autism were identified in Swedish national registers. Ten matched controls per index individual and all first-degree relatives of index individuals and controls were identified. Conditional Cox regression was used to calculate the risk of autism. Unconditional logistic regression was performed to analyze sex, gestational age, age at stroke diagnoses, comorbid adverse motor outcome, comorbid epilepsy, and a sibling with autism as risk factors for autism in children with ischemic stroke. RESULTS: Of the 1,322 index individuals, 46 (3.5%) were diagnosed with autism compared to 161 (1.2%) controls (adjusted hazard ratio [aHR] 3.02, 95% CI 2.15-4.25). There was no significant difference in risk of autism according to age at stroke: perinatal (aHR 2.69, 95% CI 1.44-5.03) and childhood stroke (aHR 3.18, 95% CI 2.12-4.78). The increased risk remained after exclusion of children born preterm or small for gestational age (aHR 3.78, 95% CI 2.55-5.60) and when children with stroke diagnosed from 1997 to 2014 were analyzed (aHR 2.91, 95% CI = 1.95-4.35). Compared to controls, the risk of autism was increased in individuals with ischemic stroke and comorbid epilepsy (aHR 7.05, 95% CI 3.74-13.30), as well as adverse motor outcome (aHR 4.28, 95% CI 2.44-7.51). When individuals with adverse motor outcome and epilepsy were censored, the risk of autism was still increased (aHR 2.37, 95% CI 1.45-3.85). Sex, gestational age, and having a sibling with autism were not associated with autism in individuals with pediatric ischemic stroke. DISCUSSION: An increased risk of autism was seen after pediatric ischemic stroke, particularly in individuals with comorbid epilepsy, and could not be explained by being born preterm or small for gestational age. The risk was increased also in individuals free from epilepsy and adverse motor outcome, implying that all children with ischemic stroke should be readily screened for autism if the disorder is suspected.
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Transtorno Autístico , Epilepsia , AVC Isquêmico , Acidente Vascular Cerebral , Criança , Estudos de Coortes , Epilepsia/epidemiologia , Feminino , Humanos , Recém-Nascido , Gravidez , Fatores de Risco , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/epidemiologiaRESUMO
The broad autism phenotype (BAP) is a set of characteristics often observed in typically developing people with a genetic load for autism, such as parents of autistic children. The Broad Autism Phenotypic Questionnaire (BAPQ) is a 36-item questionnaire developed to identify the BAP in first-degree relatives of autistic people. We translated the BAPQ into Swedish and examined its psychometric properties in a Swedish sample consisting of 45 parents of children with ASC and 74 parents of non-autistic children. We found support for the original 3-factor structure (aloof, pragmatic language and rigid), good internal consistency and convergent validity with the Autism Quotient. Thus, the Swedish BAPQ exhibits acceptable psychometric properties and may be useful for assessing the BAP in non-clinical populations.
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Transtorno do Espectro Autista , Transtorno Autístico , Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/genética , Transtorno Autístico/diagnóstico , Transtorno Autístico/genética , Humanos , Idioma , Pais , Fenótipo , Inquéritos e Questionários , SuéciaRESUMO
BACKGROUND: Puberty is delayed in untreated children and adolescents with severe primary IGF-1 deficiency (SPIGFD); to date, it has not been reported whether recombinant human insulin-like growth factor-1 mecasermin (rhIGF-1) treatment affects this. Pubertal growth outcomes were extracted from the European Increlex® Growth Forum Database (Eu-IGFD) Registry (NCT00903110). METHODS: The Eu-IGFD Registry includes children and adolescents aged 2 to 18 years with growth failure associated with SPIGFD who are treated with rhIGF-1. Reported outcomes include: age at last registration of Tanner stage 1 and first registration of Tanner stage 2-5 (T2-T5; based on breast development for girls and genital development for boys, respectively); maximum height velocity during each Tanner stage; and pubertal peak height velocity (PPHV). Data cut-off was 13 May 2019. RESULTS: This analysis included 213 patients (132 boys and 81 girls). Mean (SD) age at last registration of T1 and first registration of T5 was 13.0 (2.0) and 16.3 (1.6) years, respectively, in boys and 11.6 (1.8) and 14.7 (1.5) years, respectively, in girls. Among patients reaching the end of puberty (25 boys and 11 girls), mean (SD) height SDS increased from -3.7 (1.4) at baseline in the Eu-IGFD Registry to -2.6 (1.4) at T5 in boys and from -3.1 (1.1) to -2.3 (1.5) in girls. Maximum height velocity was observed during T2 in girls and T3 in boys. Median (range) PPHV was 8.0 (0.3-13.0) cm/year in boys and 6.8 (1.3-9.6) cm/year in girls and occurred most frequently during T2. Overall, the adverse events seen in this analysis were in line with the known safety profile of rhIGF-1. CONCLUSION: Children and adolescents treated with rhIGF-1 for SPIGFD with growth failure experienced an increase in height SDS in prepubertal years compared with baseline. Despite 1.5 years delay in pubertal start and a delayed and slightly lower PPHV, height SDS gain during puberty was maintained.
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Fator de Crescimento Insulin-Like I , Adolescente , Criança , Estudos Clínicos como Assunto , Feminino , Transtornos do Crescimento , Perda Auditiva Neurossensorial , Humanos , Fator de Crescimento Insulin-Like I/deficiência , Masculino , Proteínas Recombinantes , Sistema de RegistrosRESUMO
INTRODUCTION: Anxiety disorders have a high lifetime prevalence, early-onset and long duration or chronicity. Exposure therapy is considered one of the most effective elements in cognitive behavioural therapy (CBT) for anxiety, but in vivo exposure can be challenging to access and control, and is sometimes rejected by patients because they consider it too aversive. Virtual reality allows flexible and controlled exposure to challenging situations in an immersive and protected environment. AIM: The SoREAL-trial aims to investigate the effect of group cognitive behavioural therapy (CBT-in vivo) versus group CBT with virtual reality exposure (CBT-in virtuo) for patients diagnosed with social anxiety disorder and/or agoraphobia, in mixed groups. METHODS AND ANALYSIS: The design is an investigator-initiated randomised, assessor-blinded, parallel-group and superiority-designed clinical trial. Three hundred two patients diagnosed with social anxiety disorder and/or agoraphobia will be included from the regional mental health centres of Copenhagen and North Sealand and the Northern Region of Denmark. All patients will be offered a manual-based 14-week cognitive behavioural group treatment programme, including eight sessions with exposure therapy. Therapy groups will be centrally randomised with concealed allocation sequence to either CBT-in virtuo or CBT-in vivo. Patients will be assessed at baseline, post-treatment and 1-year follow-up by treatment blinded researchers and research assistants. The primary outcome will be diagnosis-specific symptoms measured with the Liebowitz Social Anxiety Scale for patients with social anxiety disorder and the Mobility Inventory for Agoraphobia for patients with agoraphobia. Secondary outcome measures will include depression symptoms, social functioning and patient satisfaction. Exploratory outcomes will be substance and alcohol use, working alliance and quality of life. ETHICS AND DISSEMINATION: The trial has been approved by the research ethics committee in the Capital Region of Denmark. All results, positive, negative as well as inconclusive, will be published as quickly as possible and still in concordance with Danish law on the protection of confidentially and personal information. Results will be presented at national and international scientific conferences. The trial has obtained approval by the Regional Ethics Committee of Zealand (H-6-2013-015) and the Danish Data Protection Agency (RHP-2014-009-02670). The trial is registered at ClinicalTrial.gov as NCT03845101. The patients will receive information on the trial both verbally and in written form. Written informed consent will be obtained from each patient before inclusion in the trial. The consent form will be scanned and stored in the database system and the physical copy will be destroyed. It is emphasised that participation in the trial is voluntary and that the patient can withdraw his or her consent at any time without consequences for further and continued treatment. TRIAL REGISTRATION NUMBER: NCT03845101.
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Terapia Cognitivo-Comportamental , Fobia Social , Realidade Virtual , Agorafobia/terapia , Ansiedade , Terapia Cognitivo-Comportamental/métodos , Feminino , Humanos , Masculino , Fobia Social/terapia , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
OBJECTIVE: Insulin glargine offers sustained insulin delivery for 24 h. Change to glargine treatment consistently results in lower fasting glucose and fewer hypoglycemic episodes in children with type 1 diabetes compared to continuation of NPH, although glargine has not been shown to improve HbA1c in randomized trials. Studies comparing glargine and NPH in multiple injection therapy in children treated from diagnosis of type 1 diabetes are lacking. METHODS: HbA1c and insulin requirement were compared in a retrospective study of children (7-17 yr of age) with type 1 diabetes treated from diagnosis with basal insulin glargine (n = 49) or NPH (n = 49) in a multiple injection therapy (MIT) regimen with a rapid-acting insulin analogue. Patients were followed every third month for 1 yr. HbA1c, insulin dose, and weight data were retrieved. RESULTS: HbA1c (mean ± SD) was lower at 3-5 months (5.5 ± 0.89 vs. 6.2 ± 0.89%, p < 0.05) and 6-9 months (5.6 ± 1.14 vs. 6.6 ± 0.99%; p < 0.001) in glargine treated. After 12 months, HbA1c was significantly lower in glargine treated (6.3 ± 1.56 vs. 7.1 ± 1.28; p < 0.01). Reported total insulin doses were similar at nadir (0.5 U/kg BW × 24 h), but significantly lower at 12 months in glargine treated (0.64 ± 0.23 vs. 0.86 ± 0.3 U/kg BW × 24 h; p < 0.001). CONCLUSIONS: HbA1c 1 yr from diagnosis was lower in children treated with glargine from start as compared with those on NPH. This observation should be viewed in the light of a significantly lower dose of total daily insulin in the glargine group.