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Analytical and therapeutic innovations led to a continuous but variable extension of newborn screening (NBS) programmes worldwide. Every extension requires a careful evaluation of feasibility, diagnostic (process) quality and possible health benefits to balance benefits and limitations. The aim of this study was to evaluate the suitability of 18 candidate diseases for inclusion in NBS programmes. Utilising tandem mass spectrometry as well as establishing specific diagnostic pathways with second-tier analyses, three German NBS centres designed and conducted an evaluation study for 18 candidate diseases, all of them inherited metabolic diseases. In total, 1 777 264 NBS samples were analysed. Overall, 441 positive NBS results were reported resulting in 68 confirmed diagnoses, 373 false-positive cases and an estimated cumulative prevalence of approximately 1 in 26 000 newborns. The positive predictive value ranged from 0.07 (carnitine transporter defect) to 0.67 (HMG-CoA lyase deficiency). Three individuals were missed and 14 individuals (21%) developed symptoms before the positive NBS results were reported. The majority of tested candidate diseases were found to be suitable for inclusion in NBS programmes, while multiple acyl-CoA dehydrogenase deficiency, isolated methylmalonic acidurias, propionic acidemia and malonyl-CoA decarboxylase deficiency showed some and carnitine transporter defect significant limitations. Evaluation studies are an important tool to assess the potential benefits and limitations of expanding NBS programmes to new diseases.
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Erros Inatos do Metabolismo , Acidemia Propiônica , Humanos , Recém-Nascido , Triagem Neonatal/métodos , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/epidemiologia , Espectrometria de Massas em Tandem/métodos , Carnitina/metabolismoRESUMO
BACKGROUND: Epidermolysis bullosa (EB) is a rare genetic disorder manifesting with skin and mucosal membrane blistering in different degrees of severity. OBJECTIVE: Epidemiological data from different countries have been published, but none are available from Germany. METHODS: In this population-based cross-sectional study, people living with EB in Germany were identified using the following sources: academic hospitals, diagnostic laboratories and patient organization. RESULTS: Our study indicates an overall EB incidence of 45 per million live births in Germany. With 14.23 per million live births for junctional EB, the incidence is higher than in other countries, possibly reflecting the availability of early molecular genetic diagnostics in severely affected neonates. Dystrophic EB was assessed at 15.58 cases per million live births. The relatively low incidence found for EB simplex, 14.93 per million live births, could be explained by late or missed diagnosis, but also by 33% of cases remaining not otherwise specified. Using log-linear models, we estimated a prevalence of 54 per million for all EB types, 2.44 for junctional EB, 12.16 for dystrophic EB and 28.44 per million for EB simplex. These figures are comparable to previously reported data from other countries. CONCLUSIONS: Altogether, there are at least 2000 patients with EB in the German population. These results should support national policies and pharmaceutical companies in decision-making, allow more precise planning of drug development and clinical trials, and aid patient advocacy groups in their effort to improve quality of life of people with this orphan disease.
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Epidermólise Bolhosa Distrófica , Epidermólise Bolhosa Simples , Epidermólise Bolhosa Juncional , Epidermólise Bolhosa , Recém-Nascido , Humanos , Estudos Transversais , Qualidade de Vida , Epidermólise Bolhosa/epidemiologia , Pele , Epidermólise Bolhosa Distrófica/genética , Epidermólise Bolhosa Simples/genéticaRESUMO
OBJECTIVE: To assess if metabolic control worsened during the SARS-CoV2 lockdown in spring 2020 in youth with type 1 diabetes (T1D) in Germany. METHODS: Data from 19,729 pediatric T1D patients from the diabetes prospective follow-up (DPV) registry were available. Data sets from four time-periods between January 1 and June 30, 2020, were compared with data from the whole year 2019 in the same patient; differences were adjusted for seasonality, increasing age, and longer diabetes duration. HbA1c values from laboratory measurements and estimates derived from continuous glucose monitoring (CGM) were aggregated into a combined glucose indicator (CGI), expressed in analogy to HbA1c. RESULTS: Based on regression models adjusted for differences of sex, age, diabetes duration, and migratory background between the four time-periods, CGI values in 2020 were slightly higher than in 2019, for example, by 0.044% (0.042-0.046) (median [95% CI]) in the second lockdown month, time-period 3. Insulin dose and BMI-SDS were also marginally higher. In 2020, there were fewer hospitalizations (e.g., incidence risk ratio in time-period 3 compared with 2019: 0.52 [95% CI: 0.46-0.58]). In a subgroup of patients reporting CGM data in both years, metrics in 2020 improved: time in target increased, and mean sensor glucose fell, for example, by 2.8% (2.7-2.9), and by 4.4 mg/dl (4.3-4.6) in time-period 3. CONCLUSION: Before, during, and after the lockdown in spring 2020, metabolic control in youth with T1D in Germany did not differ significantly from the preceding year. Further effects of the ongoing pandemic on pediatric T1D patients need to be evaluated.
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COVID-19 , Controle de Doenças Transmissíveis , Diabetes Mellitus Tipo 1 , Adolescente , Glicemia/metabolismo , Automonitorização da Glicemia/métodos , COVID-19/prevenção & controle , Criança , Controle de Doenças Transmissíveis/métodos , Diabetes Mellitus Tipo 1/metabolismo , Alemanha , Hemoglobinas Glicadas/análise , Humanos , Estudos ProspectivosRESUMO
The risk and potential consequences of mother-to-child transmission of severe acute respiratory syndrome-coronavirus type 2 (SARS-CoV-2) during pregnancy are still a matter of debate. We studied the impact of SARS-CoV-2 infection on 56 complete households, including 27 newborns whose mothers were pregnant when exposed to the virus. Two PCR-confirmed perinatal SARS-CoV-2 transmissions with mild symptoms in affected neonates were recorded. In addition, we observed a severe eye malformation (unilateral microphthalmia, optic nerve hypoplasia, and congenital retinopathy) associated with maternal SARS-CoV-2 infection in weeks 5 and 6 of embryonic development. This embryopathy could not be explained by other infectious agents, genetic factors, drug use, or maternal disease during pregnancy. Eight other women with a history of SARS-CoV-2 infection prior to gestational week 12, however, delivered healthy infants.Conclusion: The repeated occurrence of mother-to-child transmission in our cohort with risks that remain incompletely understood, such as long-term effects and the possibility of an embryopathy, should sensitize researchers and stimulate further studies as well as support COVID-19 vaccination recommendations for pregnant women. Trial registration number: NCT04741412. Date of registration: November 18, 2020 What is Known: â¢Materno-fetal transmission of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) during pregnancy has rarely been reported so far, but was demonstrated in isolated cases. What is New: â¢In a study of complete households with documented SARS-CoV-2 infection, including a cohort of pregnant women, we observed perinatal coronavirus transmission at a higher frequency than expected. â¢We also describe a newborn boy with an eye malformation reminiscent of rubella embryopathy but associated with early gestation SARS-CoV-2 infection of his mother. â¢A coronavirus-related embryopathy, reported here for the first time, is a finding that requires further investigation.
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COVID-19 , Complicações Infecciosas na Gravidez , Vacinas contra COVID-19 , Feminino , Humanos , Recém-Nascido , Transmissão Vertical de Doenças Infecciosas , Masculino , Gravidez , Resultado da Gravidez , SARS-CoV-2RESUMO
OBJECTIVE: To assess the role of previous episodes of diabetic ketoacidosis (DKA) and their time-lag as risk factors for recurring DKA in youth with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: In a population-based analysis, data from 29,325 children and adolescents with T1D and at least 5 years of continuous follow-up were retrieved from the "Diabetes Prospective Follow-up" (DPV) multi-center registry in March 2020. Statistical analyses included unadjusted comparisons, logistic and negative binomial regression models. RESULTS: Among 29,325 patients with T1D, 86.0% (n = 25,219) reported no DKA, 9.7% (n = 2,833) one, and 4.3% (n = 1,273) more than one episode, corresponding to a DKA rate of 4.4 [95% CI: 4.3-4.6] per 100 patient-years. Female sex, migratory background, higher HbA1c values, higher daily insulin doses, a lower glucose monitoring frequency, and less CGM usage were associated with DKA. In patients with a previous episode, the DKA rate in the most recent year was significantly higher than in patients with no DKA (17.6 [15.9-19.5] vs. 2.8 [2.7-3.1] per 100 patient-years; p < 0.001). Multiple DKAs further increased the recurrence rate. The risk for DKA in the most recent year was higher in patients with an episode in the preceding year than in patients with no previous DKA (OR: 10.0 [95% CI: 8.6-11.8]), and remained significantly elevated 4 years after an episode (OR: 2.3 [1.6-3.1]; p < 0.001). CONCLUSIONS: Each episode of DKA is an independent risk factor for recurrence, even 4 years after an event, underlining the importance of a close follow-up after each episode.
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Diabetes Mellitus Tipo 1/complicações , Cetoacidose Diabética/complicações , Cetoacidose Diabética/epidemiologia , Adolescente , Criança , Cetoacidose Diabética/diagnóstico , Feminino , Seguimentos , Humanos , Modelos Logísticos , Masculino , Estudos Prospectivos , Recidiva , Sistema de Registros , Fatores de Risco , Fatores de TempoRESUMO
BACKGROUND: Homozygous familial hypercholesterolemia (hoFH) can cause severe atherosclerotic cardiovascular disease (ASCVD) in early infancy. Diagnosis and initiation of effective lipid-lowering therapy (LLT) are recommended as early as possible to prevent ASCVD-related morbidity and mortality. METHODS: The clinical courses of a pair of siblings with an identical hoFH genotype, who exhibited major similarities of their clinical phenotype were analyzed in a case-control fashion including the family. RESULTS: The older sibling was diagnosed with hoFH at the age of 4. Untreated LDL-cholesterol (LDL-C) was 17 mmol/L (660 mg/dL). LLT including lipoprotein apheresis (LA) was initiated and has been successful for 8 years now. A reduction of estimated cholesterol burden by 74% was achieved by LA and combined drug therapy including statins and ezetimibe. The efficacy of escalation of drug therapy was limited because the underlying LDL receptor (LDLR) mutation in the family resulted in substantially reduced receptor function. Treatment with proprotein convertase subtilisin-kexin type 9 (PCSK9)-antibodies failed. His younger brother died at the age of 2 years shortly after the hoFH diagnosis of the elder sibling. Postmortem examination revealed advanced aortic root atheroma and aortic valve stenosis. In the older sibling, aortic valve stenosis and insufficiency were treated at the age of 9 years with mechanical aortic valve replacement. CONCLUSIONS: LLT including LA should be initiated as early as possible following the diagnosis of hoFH with very high LDL-C levels. With the same genotype, the phenotype of hoFH can exhibit similar patterns but outcome is substantially related to treatment.
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Valva Aórtica/fisiopatologia , Remoção de Componentes Sanguíneos/métodos , LDL-Colesterol/sangue , Homozigoto , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/terapia , Lipoproteínas/uso terapêutico , Adulto , Aorta/patologia , Biópsia , Estudos de Casos e Controles , Criança , Pré-Escolar , Ecocardiografia , Saúde da Família , Feminino , Genótipo , Humanos , Lipídeos/sangue , Masculino , Fenótipo , Pró-Proteína Convertase 9/metabolismo , Estudos Retrospectivos , Irmãos , Xantomatose/complicaçõesRESUMO
Severe generalized junctional epidermolysis bullosa (JEB), a lethal genodermatosis, is mainly caused by premature termination codons (PTCs) in one of the three genes encoding the anchoring protein laminin-332. Only symptomatic treatment has been established; overcoming PTCs by aminoglycosides may represent an interesting alternative. This retrospective study aimed at assessing for the first time the clinical effects of systemic gentamicin application in infants with severe generalized JEB. Five patients, homozygous or compound-heterozygous for PTCs in the gene LAMB3, were treated with gentamicin which was administered intravenously or by intramuscular injection at doses of 7.5 mg/kg/d for three weeks. Skin biopsies were investigated by immunofluorescence analyses. Clinical effects of the medication were recorded with a parent questionnaire and by assessing weight-for-age charts. Gentamicin application was well tolerated, long hospitalization was not required. Low levels of laminin-332 could be detected in a skin sample obtained after treatment. Gentamicin had a positive impact on skin fragility and daily life in four patients but did not influence weight gain and failed to reverse the lethal course of the disease. Gentamicin injections should be considered regularly in cases of severe generalized JEB caused by PTCs as they may attenuate JEB symptoms without impeding quality of life.
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Antibacterianos/administração & dosagem , Epidermólise Bolhosa Juncional/tratamento farmacológico , Gentamicinas/administração & dosagem , Epidermólise Bolhosa Juncional/genética , Feminino , Humanos , Lactente , Injeções Intramusculares , Injeções Intravenosas , Masculino , Estudos Retrospectivos , Resultado do TratamentoRESUMO
OBJECTIVE: In X-linked hypohidrotic ectodermal dysplasia (XLHED), dysfunction of ectodysplasin A1 (EDA1) due to EDA mutations results in malformation of hair, teeth, and sweat glands. Hypohidrosis, which can cause life-threatening hyperthermia, is amenable to intrauterine therapy with recombinant EDA1. This study aimed at evaluating tooth germ sonography as a noninvasive means to identify affected fetuses in pregnant carrier women. METHODS: Sonography, performed at 10 study sites between gestational weeks 18 and 28, led to the diagnosis of XLHED if fewer than six tooth germs were detected in mandible or maxilla. The assessment was verified postnatally by EDA sequencing and/or clinical findings. Estimated fetal weights and postnatal weight gain of boys with XLHED were assessed using appropriate growth charts. RESULTS: In 19 of 38 sonographic examinations (23 male and 13 female fetuses), XLHED was detected prenatally. The prenatal diagnosis proved to be correct in 37 cases; one affected male fetus was missed. Specificity and positive predictive value were both 100%. Tooth counts obtained by clinical examination corresponded well with findings on panoramic radiographs. We observed no weight deficits of subjects with XLHED in utero but occasionally during infancy. CONCLUSION: Tooth germ sonography is highly specific and reliable in detecting XLHED prenatally.
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Displasia Ectodérmica Anidrótica Tipo 1/diagnóstico por imagem , Germe de Dente/diagnóstico por imagem , Ultrassonografia Pré-Natal/estatística & dados numéricos , Pré-Escolar , Feminino , Humanos , Masculino , Gravidez , Estudos RetrospectivosRESUMO
Hypohidrotic ectodermal dysplasia (HED), a rare and heterogeneous hereditary disorder, is characterized by deficient development of multiple ectodermal structures including hair, sweat glands and teeth. If caused by mutations in the genes EDA, EDA1R or EDARADD, phenotypes are often very similar as the result of a common signaling pathway. Single-nucleotide polymorphisms (SNPs) affecting any gene product in this pathway may cause inter- and intrafamilial variability. In a cohort of 124 HED patients, genotyping was attempted by Sanger sequencing of EDA, EDA1R, EDARADD, TRAF6 and EDA2R and by multiplex ligation-dependent probe amplification (MLPA). Pathogenic mutations were detected in 101 subjects with HED, affecting EDA, EDA1R and EDARADD in 88%, 9% and 3% of the cases, respectively, and including 23 novel mutations. MLPA revealed exon copy-number variations in five unrelated HED families (two deletions and three duplications). In four of them, the genomic breakpoints could be localized. The EDA1R variant rs3827760 (p.Val370Ala), known to lessen HED-related symptoms, was found only in a single individual of Asian origin, but in none of the 123 European patients. Another SNP, rs1385699 (p.Arg57Lys) in EDA2R, however, appeared to have some impact on the hair phenotype of European subjects with EDA mutations.
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Pontos de Quebra do Cromossomo , Mapeamento Cromossômico , Displasia Ectodérmica Anidrótica Tipo 1/genética , Rearranjo Gênico , Mutação , Adolescente , Adulto , Idoso , Alelos , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Ectodisplasinas/genética , Feminino , Genótipo , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto JovemAssuntos
Infecções por Coronavirus , Diabetes Mellitus Tipo 1/complicações , Cetoacidose Diabética/epidemiologia , Pandemias , Pneumonia Viral , Adolescente , COVID-19 , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/diagnóstico , Cetoacidose Diabética/etiologia , Alemanha/epidemiologia , Humanos , Aceitação pelo Paciente de Cuidados de SaúdeRESUMO
OBJECTIVE: This study was conducted to evaluate the effects of early clinical diagnosis of type 1 diabetes by comparison of clinical parameters at diagnosis and during follow-up in patients with pediatric type 1 diabetes with early, intermediate, and late diagnosis. RESEARCH DESIGN AND METHODS: In a population-based analysis, data on 14,292 pediatric patients with type 1 diabetes diagnosed between 2015 and 2019 were retrieved from the Diabetes Prospective Documentation (DPV) registry in March 2023. Patients were divided into four groups: one with diabetic ketoacidosis (DKA) at diagnosis and three with early, intermediate, or late diagnosis based on age-dependent HbA1c terciles. Laboratory-measured HbA1c values and those estimated from continuous glucose monitoring were aggregated as a combined glucose indicator (CGI). Insulin-dose adjusted CGI values <9% were defined as partial remission. RESULTS: At diagnosis, patients had a median age of 9.8 years (IQR = 6.8; 13.0). Three years later, patients with early diagnosis had lower CGI than patients with late diagnosis or DKA (mean [95% CI] 7.46% [7.40; 7.53] vs. 7.81% [7.75; 7.87] or 7.74% [7.68; 7.79], respectively; each P < 0.001). More patients experienced partial remission (12.6% [11.0; 14.4] vs. 9.1% [7.7; 10.7] or 8.6% [7.3; 10.0]; each P < 0.001), and 11.7% [10.2; 13.5] of patients with intermediate diagnosis were in partial remission. CONCLUSIONS: Early clinical diagnosis of type 1 diabetes may be beneficial for metabolic control and remission after 3 years of follow-up. Patients diagnosed early may represent a distinct group with better resources or with a different disease biology and slower ß-cell destruction, which needs further evaluation.
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AIM: To assess effects of the SARS-CoV2 pandemic on metabolic control in youth with type 1 diabetes (T1D) in Germany in a population-based analysis. METHODS: Data from 33,372 pediatric T1D patients from the Diabetes Prospective Follow-up (DPV) registry, with face-to-face visits or telemedicine contacts in the years 2019-2021, were available. Datasets from eight time periods between March 15, 2020, and December 31, 2021, according to SARS-CoV2 incidence waves, were compared to those from five control time periods. Parameters of metabolic control were assessed with adjustment for sex, age, diabetes duration, and repeated measurements. Laboratory-measured HbA1c values and those estimated from CGM were aggregated into a combined glucose indicator (CGI). RESULTS: There was no clinically relevant difference in metabolic control between pandemic and control time periods with adjusted CGI values ranging from 7.61% [7.60-7.63] (mean [95% confidence interval (CI)]) in the third quarter of 2019 to 7.83% [7.82-7.85] in the time period from January 1 to March 15 2020, in the other control periods, and during the pandemic, CGI values lay between these values. BMI-SDS rose during the pandemic from 0.29 [0.28-0.30] (mean [95% CI]) in the third quarter of 2019 to 0.40 [0.39-0.41] during the fourth wave. Adjusted insulin dose rose during the pandemic. Event rates for hypoglycemic coma and diabetic ketoacidosis remained unchanged. CONCLUSIONS: We found no clinically relevant change of glycemic control or incidence of acute diabetes complications during the pandemic. The observed BMI increase may represent an important health risk for youth with T1D.
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COVID-19 , Diabetes Mellitus Tipo 1 , Adolescente , Humanos , Criança , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/metabolismo , Pandemias , Glicemia/metabolismo , Estudos Prospectivos , RNA Viral , COVID-19/epidemiologia , COVID-19/complicações , SARS-CoV-2 , GlucoseRESUMO
BACKGROUND: X-linked hypohidrotic ectodermal dysplasia (XLHED), the most common type of ectodermal dysplasia, is caused by EDA gene mutations. Reduced sweating contributes substantially to XLHED associated morbidity and mortality. To characterise the genotype-phenotype relationship, sweat gland function was assessed non-invasively in XLHED patients and healthy controls. SUBJECTS AND METHODS: In 36 genotyped XLHED patients and 29 control subjects aged 0-57 years, pilocarpine-induced sweat volume, palmar sweat pore density, and palmar skin conductance before and after stimulation were determined. RESULTS: Among 31 XLHED males, 14 had neither detectable sweat pores nor inducible sweating, 10 showed a few sweat pores but absent sweating, and 7 produced reduced sweat volumes (1-11 µl) as compared with controls (38-93 µl). Two of the low sweating XLHED subjects had normal sweat pore counts. In all 5 heterozygous females, some sweat was detected, but generally less than in female controls. Basal and stimulated skin conductance readings were reduced in 23 of 24 non-sweating, but only in 3 of 12 low-sweating XLHED subjects. There was no correlation between sweat production and number of missing teeth. CONCLUSIONS: In contrast to prior reports on non-genotyped hypohidrotic ectodermal dysplasia populations, this study confirmed a consistent, quantifiable defect of sweat gland function in male XLHED subjects as a disease biomarker. Among 26 different EDA genotypes, specific mutations were shown to be consistently associated with anhidrosis, implying that systematic mapping of EDA mutations together with the analysis of objective clinical data may help to distinguish functionally crucial mutations from those allowing residual activity of the gene product.
Assuntos
Displasia Ectodérmica Anidrótica Tipo 1/genética , Ectodisplasinas , Hipo-Hidrose/genética , Glândulas Sudoríparas/anormalidades , Sudorese/genética , Adolescente , Adulto , Sequência de Bases , Estudos de Casos e Controles , Criança , Pré-Escolar , Ectodisplasinas/genética , Éxons , Feminino , Resposta Galvânica da Pele/efeitos dos fármacos , Genes Ligados ao Cromossomo X , Estudos de Associação Genética , Genótipo , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação , Fenótipo , Pilocarpina/farmacologia , Sudorese/efeitos dos fármacosRESUMO
OBJECTIVE: To investigate whether socioeconomic deprivation and urbanization are associated with the frequency of diabetic ketoacidosis (DKA) at diagnosis of pediatric type 1 diabetes. RESEARCH DESIGN AND METHODS: Children and adolescents aged ≤18 years, living in Germany, with newly diagnosed type 1 diabetes documented between 2016 and 2019 in the Diabetes Prospective Follow-up Registry (DPV; Diabetes-Patienten-Verlaufsdokumentation), were assigned to a quintile of regional socioeconomic deprivation (German Index of Socioeconomic Deprivation) and to a degree of urbanization (Eurostat) by using their residence postal code. With multiple logistic regression models, we investigated whether the frequency of DKA at diagnosis was associated with socioeconomic deprivation or urbanization and whether associations differed by age-group, sex, or migration status. RESULTS: In 10,598 children and adolescents with newly diagnosed type 1 diabetes, the frequency of DKA was lowest in the least deprived regions (Q1: 20.6% [95% CI 19.0-22.4], and increased with growing socioeconomic deprivation to 26.9% [25.0-28.8] in the most deprived regions [Q5]; P for trend <0.001). In rural areas, the frequency of DKA at diagnosis was significantly higher than in towns and suburbs (intermediate areas) or in cities (27.6% [95% CI 26.0-29.3] vs. 22.7% [21.4-24.0], P < 0.001, or vs. 24.3% [22.9-25.7], P = 0.007, respectively). The results did not significantly differ by age-group, sex, or migration background or after additional adjustment for socioeconomic deprivation or urbanization. CONCLUSIONS: This study provides evidence that prevention of DKA at diagnosis by means of awareness campaigns and screening for presymptomatic type 1 diabetes should particularly target socioeconomically disadvantaged regions and rural areas.
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Diabetes Mellitus Tipo 1 , Cetoacidose Diabética , Adolescente , Criança , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/epidemiologia , Cetoacidose Diabética/diagnóstico , Cetoacidose Diabética/epidemiologia , Cetoacidose Diabética/etiologia , Humanos , Estudos Prospectivos , Sistema de Registros , Fatores Socioeconômicos , UrbanizaçãoRESUMO
Congenital primary hypothyroidism (CH) and congenital adrenal hyperplasia (CAH) are targeted by the German and Austrian newborn screening. For both diseases, there are registries for quality improvement, based on standardized observational data from long-term patient follow-up, under the auspices of the DGKED study group. By September 2021, the CH registry HypoDOK includes datasets from 23,348 visits of 1,840 patients, and the CAH registry contains datasets from 36,237 visits of 1,976 patients. Here, we report on the recruitment process, patient characteristics, and research contributions from the registries, and underline that the registries are an important tool to improve patient care and outcomes. Registries for rare conditions should thus be considered as an important public health measure and they should be adequately institutionalized and funded.
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A cardinal feature of systemic lupus erythematosus (SLE) is the development of autoantibodies. The first autoantibodies described in patients with SLE were those specific for nuclei and DNA, but subsequent work has shown that individuals with this disease produce a panoply of different autoantibodies. Thus, one of the constant features of SLE is a profound breakdown in tolerance in the antibody system. The appearance of self-reactive antibodies in SLE precedes clinical disease, but where in the B cell pathway tolerance is first broken has not been defined. In healthy humans, autoantibodies are removed from the B cell repertoire in two discrete early checkpoints in B cell development. We found these checkpoints to be defective in three adolescent patients with SLE. 25-50% of the mature naive B cells in SLE patients produce self-reactive antibodies even before they participate in immune responses as compared with 5-20% in controls. We conclude that SLE is associated with abnormal early B cell tolerance.
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Linfócitos B/imunologia , Tolerância Imunológica/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Adolescente , Autoanticorpos/imunologia , Linfócitos B/patologia , Linhagem Celular , Criança , Feminino , Humanos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/patologia , Masculino , Fosfatidilserinas/imunologia , Fosfatidilserinas/metabolismoRESUMO
To evaluate exertional overheating and the impact of physical exercise on individuals with hypohidrotic ectodermal dysplasia (HED) and to assess protective effects of cooling devices, 13 boys and male adolescents with X-linked HED (XLHED) and age-matched healthy male controls were studied during standardized exercise on a bicycle ergometer at ambient temperatures of 25 and 30°C, without cooling and with evaporative skin cooling devices at 30°C. Body core temperature during and after exercise, heart rate, performance, endurance, and serum lactate were investigated. XLHED subjects experienced a significantly greater rise in body temperature after cycling than healthy controls, and their body temperature remained elevated longer. Maximum heart rates and lactate values did not differ significantly between XLHED and control groups. Application of skin cooling devices led to a clinically relevant attenuation of exertional hyperthermia in XLHED patients, and a previous tendency toward lower performance disappeared. This first systematic study of the effects of physical exercise on HED patients demonstrates a rapid and lasting body temperature increase in XLHED subjects after cycling, posing them at risk of exercise-induced hyperthermia. External evaporative skin cooling attenuates exertional overheating in HED patients and may facilitate their participation in athletic activities and professional life.
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Regulação da Temperatura Corporal/fisiologia , Displasia Ectodérmica Anidrótica Tipo 1/fisiopatologia , Exercício Físico/fisiologia , Febre/fisiopatologia , Adolescente , Temperatura Corporal/fisiologia , Criança , Teste de Esforço , Frequência Cardíaca/fisiologia , Humanos , Masculino , EsportesRESUMO
BACKGROUND: Diabetic ketoacidosis (DKA) is a life-threatening emergency in children and adolescents with manifestation of type 1 diabetes mellitus (DM1) and often associated with delayed diagnosis or previous diagnostic errors. During the coronavirus disease 2019 (COVID-19) lockdown period in Germany, less patients presented at emergency departments and private practices. OBJECTIVE: The aim of this study was to investigate the DKA risk in children and adolescents with DM1 manifestation during the COVID-19 lockdown and associated risk factors. MATERIAL AND METHODS: The frequency of DKA at DM1 onset in patients <18 years between 13 March and 13 May 2020 in pediatric diabetes centers was analyzed. The centers also documented their assessment, if the presentation was delayed or the diagnosis was not made on the first medical consultation. In order to analyze the influence of the risk factors on the frequency of DKA, the data from 2020 were compared with the same periods in 2018 and 2019 using multivariable linear and logistic regression. RESULTS: The data of 532 patients from 216 diabetes centers showed that the risk for DKA increased by 84.7% and the risk for severe DKA increased by 45.3% compared to the years 2018/2019. Children <6 years had the highest risk with an 141.6% increase for DKA and 97.0% for severe DKA compared to the previous years. Migration background was a risk factor independent of COVID-19. Of the patients 31% had either a delayed presentation or a missed diagnosis. CONCLUSION: During the COVID-19 lockdown the frequency of DKA and severe DKA at DM1 onset was significantly increased for children and adolescents in Germany. Age <6 years, migration background and delayed diagnosis were the main risk factors.
RESUMO
Type 1 diabetes (T1D) is a known risk factor for fractures, but the underlying pathophysiology is still not fully understood. This study aims to define age peaks and frequent fracture sites of children and young adults with T1D. Additionally, associations of fractures with metabolic and lifestyle factors as well as with additional complications in individuals with T1D were analyzed. A total of 750 individuals with T1D aged ≤25 years with fractures were matched to 3750 patients with T1D without fractures by demographics and insulin regimen. Hemoglobin A1c (HbA1c) values were compared using linear regression, and logistic regression was used to calculate odds ratios (OR) for fractures in individuals with acute complications and diseases. Median (Q1-Q3) age was 12.7 (9.9 to 14.9) years in individuals with fractures and 16.3 (12.6 to 17.8) years in the entire control group with 65% versus 53% males. Peak age for fractures was 7 to <15 years in males and 9 to <11 years in females, which is earlier than reported for the general population. HbA1c (%) was significantly higher in individuals with fractures than in controls (difference of estimated means: 0.26%; 95% confidence interval [CI] 0.07-0.46), especially in postpubertal females (0.68; 0.10-1.26). Significantly higher odds for fractures were observed in individuals with severe hypoglycemia (OR = 1.90; 95% CI 1.47-2.47), especially in prepubertal females (OR = 2.81; 1.21-6.52]) and postpubertal males (2.44; 1.11-5.38), celiac disease (2.02; 1.67-2.45), and with a history of smoking (1.38; 1.02-1.88). The age peak of fractures seems to be earlier in T1D than in the general population. Poor glycemic control is related to fractures, even before puberty. Associations of HbA1c and severe hypoglycemia with fractures highly depend on age and sex. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Assuntos
Diabetes Mellitus Tipo 1 , Fraturas Ósseas , Adolescente , Distribuição por Idade , Criança , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/epidemiologia , Feminino , Fraturas Ósseas/epidemiologia , Hemoglobinas Glicadas , Controle Glicêmico , Humanos , Masculino , Adulto JovemRESUMO
Several newly arising human antibodies are polyreactive, but in normal individuals the majority of these potentially autodestructive antibodies are removed from the repertoire by receptor editing or B cell deletion in the bone marrow. To determine what proportion of naturally arising autoantibodies can be silenced by immunoglobulin (Ig) light chain receptor editing, we replaced the light chains in 12 such antibodies with a panel of representative Igkappa and Iglambda chains. We found that most naturally arising autoantibodies are readily silenced by light chain exchange. Thus, receptor editing may account for most autoreactive antibody silencing in humans. Light chain complementarity determining region (CDR) isoelectric points did not correlate with silencing activity, but Iglambda genes were more effective than Igkappa genes as silencers. The greater efficacy of Iglambda chains as silencer of autoreactivity provides a possible explanation for the expansion and altered configuration of the Iglambda locus in evolution.