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Inherited white matter disorders (IWMDs) are a phenotypically and genotypically heterogeneous group of disorders affecting the central nervous system (CNS) with or without peripheral neuropathy. They are classified either as leukodystrophies (LDs), with primary glial abnormalities, or genetic leukoencephalopathies (gLEs), where other CNS cells are involved. As a group, these disorders are common, with an incidence of 1 in 7500 births. However, IWMDs often go undiagnosed or suffer delayed or misdiagnosis due to their heterogeneous presentation. Many of these disorders present with lethal secondary manifestations that can be prevented through early disease recognition, periodic surveillance, and preventative management. Emerging therapeutics, including gene therapy trials for metachromatic leukodystrophy (MLD) and adrenoleukodystrophy (ALD), suggest disease progression may be slowed or even prevented if treated early. Therapies for IWMDs that target glial cells or the peripheral immune system may provide novel insights for treating acquired disorders of white matter.
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BACKGROUND AND OBJECTIVES: Pyruvate dehydrogenase complex deficiency (PDCD) is a disorder of mitochondrial metabolism that is caused by pathogenic variants in multiple genes, including PDHA1. Typical neonatal brain imaging findings have been described, with a focus on malformative and encephaloclastic features. Fetal brain MRI in PDCD has not been comprehensively described. The aims of this study were (1) to further characterize the fetal brain MRI findings in PDCD using comprehensive fetal imaging and genetic testing and (2) to determine whether markers of diagnosis of PDCD could be identified on prenatal imaging. METHODS: Fetuses with a diagnosis of PDCD related to a genetic etiology that had undergone fetal MRI were included. Fetuses were identified retrospectively from local databases of 4 fetal diagnostic clinics within tertiary pediatric health care centers. Electronic medical records were reviewed retrospectively: demographics, maternal and pregnancy history, fetal outcomes, and neonatal outcomes (if available) were reviewed and recorded. Fetal and neonatal imaging reports were reviewed; source fetal and neonatal brain MRI scans were reviewed by a single pediatric neuroradiologist (J.W.S.) for consistency. Genetic testing strategies and results including variant type, zygosity, inheritance pattern, and pathogenicity were recorded. Deidentified data were combined and reported descriptively. RESULTS: A total of 10 fetuses with a diagnosis of PDCD were included. 8 fetuses had corpus callosum dysgenesis, 6 had an abnormal gyration pattern, 10 had reduced brain volumes, and 9 had cystic lesions. 1 fetus had intraventricular hemorrhages. 1 fetus had a midbrain malformation with aqueductal stenosis and severe hydrocephalus. 6 fetuses imaged in the second trimester had cystic lesions involving the ganglionic eminences (GEs) while GE cysts were not present in the 4 fetuses imaged in the third trimester. DISCUSSION: Fetuses with PDCD have similar brain MRI findings to neonates described in the literature, although some of these findings are subtle early in pregnancy. Additional features, such as cystic lesions of the GEs, are noted in the second trimester in fetuses with PDCD. These may represent an early diagnostic marker of PDCD, although more data are needed to validate this association. Early diagnosis of PDCD using fetal MRI may inform genetic counseling, pregnancy decision making, and neonatal care planning.
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Encéfalo , Imageamento por Ressonância Magnética , Doença da Deficiência do Complexo de Piruvato Desidrogenase , Humanos , Feminino , Doença da Deficiência do Complexo de Piruvato Desidrogenase/diagnóstico por imagem , Doença da Deficiência do Complexo de Piruvato Desidrogenase/genética , Gravidez , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encéfalo/anormalidades , Estudos Retrospectivos , Masculino , Recém-Nascido , Diagnóstico Pré-Natal , Feto/diagnóstico por imagem , Feto/anormalidades , AdultoRESUMO
OBJECTIVE: Metachromatic leukodystrophy (MLD) is a rare neurodegenerative disorder. Emerging therapies are most effective in the presymptomatic phase, and thus defining this window is critical. We hypothesize that early development delay may precede developmental plateau. With the advent of presymptomatic screening platforms and transformative therapies, it is essential to define the onset of neurologic disease. METHODS: The specific ages of gain and loss of developmental milestones were captured from the medical records of individuals affected by MLD. Milestone acquisition was characterized as: on target (obtained before the age limit of 90th percentile plus 2 standard deviations compared to a normative dataset), delayed (obtained after 90th percentile plus 2 standard deviations), or plateau (skills never gained). Regression was defined as the age at which skills were lost. LI-MLD was defined by age at onset before 2.5 years. RESULTS: Across an international cohort, 351 subjects were included (n = 194 LI-MLD subcohort). The median age at presentation of the LI-MLD cohort was 1.4 years (25th-75th %ile: 1.0-1.5). Within the LI-MLD cohort, 75/194 (39%) had developmental delay (or plateau) prior to MLD clinical presentation. Among the LI-MLD cohort with a minimum of 1.5 years of follow-up (n = 187), 73 (39.0%) subjects never attained independent ambulation. Within LI-MLD + delay subcohort, the median time between first missed milestone target to MLD decline was 0.60 years (maximum distance from delay to onset: 1.9 years). INTERPRETATION: Early developmental delay precedes regression in a subset of children affected by LI-MLD, defining the onset of neurologic dysfunction earlier than previously appreciated. The use of realworld data prior to diagnosis revealed an early deviation from typical development. Close monitoring for early developmental delay in presymptomatic individuals may help in earlier diagnosis with important consequences for treatment decisions.
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Idade de Início , Deficiências do Desenvolvimento , Leucodistrofia Metacromática , Humanos , Leucodistrofia Metacromática/diagnóstico , Leucodistrofia Metacromática/patologia , Leucodistrofia Metacromática/genética , Deficiências do Desenvolvimento/diagnóstico , Masculino , Feminino , Pré-Escolar , Lactente , Criança , Adolescente , Estudos de Coortes , Progressão da DoençaRESUMO
Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here we identify the non-coding RNA RNU4-2 as a syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 base pair region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals in whom it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to RNU4-1 and other U4 homologues. Using RNA sequencing, we show how 5' splice-site use is systematically disrupted in individuals with RNU4-2 variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 base pair region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide.
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Prenatal diagnoses of congenital malformations have increased significantly in recent years with use of high-resolution prenatal imaging. Despite more precise radiological diagnoses, discussions with expectant parents remain challenging because congenital malformations are associated with a wide spectrum of outcomes. Comprehensive prenatal genetic testing has become an essential tool that improves the accuracy of prognostication. Testing strategies include chromosomal microarray, exome sequencing, and genome sequencing. The diagnostic yield varies depending on the specific malformations, severity of the abnormalities, and multi-organ involvement. The utility of prenatal genetic diagnosis includes increased diagnostic clarity for clinicians and families, informed pregnancy decision-making, neonatal care planning, and reproductive planning. Turnaround time for results of comprehensive genetic testing remains a barrier, especially for parents that are decision-making, although this has improved over time. Uncertainty inherent to many genetic testing results is a challenge. Appropriate genetic counseling is essential for parents to understand the diagnosis and prognosis and to make informed decisions. Recent research has investigated the yield of exome or genome sequencing in structurally normal fetuses, both with non-invasive screening methods and invasive diagnostic testing; the prenatal diagnostic community must evaluate and analyze the significant ethical considerations associated with this practice prior to generalizing its use. IMPACT: Reviews available genetic testing options during the prenatal period in detail. Discusses the impact of prenatal genetic testing on care using case-based examples. Consolidates the current literature on the yield of genetic testing for prenatal diagnosis of congenital malformations.
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BACKGROUND AND OBJECTIVE: Pediatric rare diseases are often life-limiting conditions and/or require constant caregiving. Investigators assessed the initial efficacy of the FAmily CEntered (FACE) pediatric advance care planning (pACP), FACE-Rare, intervention on families' quality of life. METHODS: A pilot-phase, single-blinded, intent-to-treat, randomized controlled clinical trial enrolled families from 1 pediatric quaternary hospital between 2021 and 2023. Intervention families received 3 weekly 60-minute (FACE-Rare pACP) sessions: (1) Carer Support Needs Assessment Tool or Action Plan, (2) Carer Support Needs Assessment Tol Action Plan Review, and (3) Pediatric Next Steps: Respecting Choices pACP. Controls received treatment as usual (TAU). Outcome measures were Beck Anxiety Inventory, Family Appraisal of Caregiving, Functional Assessment of Chronic Illness Therapy (FACIT)-Spirituality, and health care utilization. Generalized mixed effect models with γ response assessed the intervention effect at 3-month follow-up. RESULTS: Children (n = 21) were aged 1 to 10 years, 48% male, 24% Black; and 100% technology dependent. Primary family caregivers (n = 21) were aged 30 to 43 years, 19% male, 19% Black; and 27% household income below the Federal poverty level. Dyads underwent 1:1 randomization: 9 to FACE-Rare and 12 to TAU. TAU caregivers reported statistically lower meaning and peace than FACE-Rare caregivers (0.9, P = .03, confidence interval [CI]: 0.75-0.99). Black caregivers reported significantly less caregiver distress (0.7, P = .04, CI: 0.47-0.98) than non-Black caregivers. Poor families reported more anxiety (3.5, P = .002, CI: 1.62-7.94), more caregiver strain (1.2, P = .006, CI: 1.07-1.42); and less family well-being (0.8, P = .02, CI: 0.64-0.95). CONCLUSIONS: FACE®-Rare was feasible, acceptable, safe, and demonstrated initial efficacy, providing greater feelings of meaning and peace to caregivers. Poverty impacted well-being. A multisite trial is needed to determine generalizability.
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Planejamento Antecipado de Cuidados , Cuidadores , Qualidade de Vida , Doenças Raras , Humanos , Masculino , Projetos Piloto , Doenças Raras/terapia , Feminino , Criança , Pré-Escolar , Método Simples-Cego , Lactente , Cuidadores/psicologia , Adulto , Avaliação das NecessidadesRESUMO
Type II D-2-Hydroxyglutaric aciduria (T2D2HGA) is caused by a gain-of-function pathogenic variant in Isocitrate Dehydrogenase 2 (IDH2). Patients with T2D2HGA commonly present with developmental delay, seizures, cardiomyopathy, and arrhythmias. The recently approved IDH2-inhibitor Enasidenib targets the p.Arg140Gln pathogenic IDH2 variant and decreases production of D2HGA. We present a 7-year-old female with T2D2HGA due to the p.Arg140Gln variant. She was diagnosed at 3-years-old after presenting with global developmental delay, leukoencephalopathy, communicating hydrocephalus, seizures, and dilated cardiomyopathy. At age 3 years 11 months, 50 mg Enasidenib daily was initiated. Primary outcomes included seizure frequency, hospital admissions, development, and cardiac structure. Laboratories were monitored biweekly for common Enasidenib side effects. Our patient tolerated Enasidenib well. Urine 2-HGA decreased significantly from 244 mg/g creatinine to undetectable within 2 weeks of treatment. Inpatient admissions decreased from 8 during the 2 years preceding treatment to 1 during treatment. She has been seizure-free since Enasidenib initiation. Echocardiography showed improvement in dilated cardiomyopathy with normal left ventricular systolic function. Developmental assessment demonstrated improvements in gross motor, fine motor, language, and socialization domains. Treatment was complicated by mild elevations in alanine transaminase (118 IU/L, range 0-28) and creatine kinase (334 U/L, range 45-198) that resolved by decreasing Enasidenib dosing frequency to three times weekly. Enasidenib is a viable treatment for Type II D2HGA with benefits including developmental gains, fewer acute medical interventions, and cardiomyopathy improvement. While drug-induced hepatitis is a novel adverse effect of Enasidenib, it can be ameliorated by decreasing dose frequency.
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Metachromatic leukodystrophy (MLD) is a fatal, progressive neurodegenerative disorder caused by biallelic pathogenic mutations in the ARSA (Arylsulfatase A) gene. With the advent of presymptomatic diagnosis and the availability of therapies with a narrow window for intervention, it is critical to define a standardized approach to diagnosis, presymptomatic monitoring, and clinical care. To meet the needs of the MLD community, a panel of MLD experts was established to develop disease-specific guidelines based on healthcare resources in the United States. This group developed a consensus opinion for best-practice recommendations, as follows: (i) Diagnosis should include both genetic and biochemical testing; (ii) Early diagnosis and treatment for MLD is associated with improved clinical outcomes; (iii) The panel supported the development of newborn screening to accelerate the time to diagnosis and treatment; (iv) Clinical management of MLD should include specialists familiar with the disease who are able to follow patients longitudinally; (v) In early onset MLD, including late infantile and early juvenile subtypes, ex vivo gene therapy should be considered for presymptomatic patients where available; (vi) In late-onset MLD, including late juvenile and adult subtypes, hematopoietic cell transplant (HCT) should be considered for patients with no or minimal disease involvement. This document summarizes current guidance on the presymptomatic monitoring of children affected by MLD as well as the clinical management of symptomatic patients. Future data-driven evidence and evolution of these recommendations will be important to stratify clinical treatment options and improve clinical care.
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Leucodistrofia Metacromática , Humanos , Recém-Nascido , Cerebrosídeo Sulfatase/genética , Consenso , Terapia Genética/métodos , Leucodistrofia Metacromática/terapia , Leucodistrofia Metacromática/diagnóstico , Leucodistrofia Metacromática/genética , Triagem Neonatal/métodos , Estados UnidosRESUMO
Pyruvate dehydrogenase complex deficiency (PDCD) is a disorder of mitochondrial metabolism that is caused by pathogenic variants in multiple genes, including PDHA1. Typical neonatal brain imaging findings in PDCD have been described, with a focus on malformative features and chronic encephaloclastic changes. However, fetal brain MRI imaging in confirmed PDCD has not been comprehensively described. We sought to demonstrate the prenatal neurological and systemic manifestations of PDCD determined by comprehensive fetal imaging and genomic sequencing. All fetuses with a diagnosis of genetic PDCD who had undergone fetal MRI were included in the study. Medical records, imaging data, and genetic testing results were reviewed and reported descriptively. Ten patients with diagnosis of PDCD were included. Most patients had corpus callosum dysgenesis, abnormal gyration pattern, reduced brain volumes, and periventricular cystic lesions. One patient had associated intraventricular hemorrhages. One patient had a midbrain malformation with aqueductal stenosis and severe hydrocephalus. Fetuses imaged in the second trimester were found to have enlargement of the ganglionic eminences with cystic cavitations, while those imaged in the third trimester had germinolytic cysts. Fetuses with PDCD have similar brain MRI findings to neonates described in the literature, although some of these findings may be subtle early in pregnancy. Additional features, such as cystic cavitations of the ganglionic eminences, are noted in the second trimester in fetuses with PDCD, and these may represent a novel early diagnostic marker for PDCD. Using fetal MRI to identify these radiological hallmarks to inform prenatal diagnosis of PDCD may guide genetic counseling, pregnancy decision-making, and neonatal care planning.
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Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Increasingly, large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here, we identify the non-coding RNA RNU4-2 as a novel syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 bp region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and Stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 119 individuals with NDD. The vast majority of individuals (77.3%) have the same highly recurrent single base-pair insertion (n.64_65insT). We estimate that variants in this region explain 0.41% of individuals with NDD. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to its contiguous counterpart RNU4-1 and other U4 homologs, supporting RNU4-2's role as the primary U4 transcript in the brain. Overall, this work underscores the importance of non-coding genes in rare disorders. It will provide a diagnosis to thousands of individuals with NDD worldwide and pave the way for the development of effective treatments for these individuals.
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Growing interest in therapeutic development for rare diseases necessitate a systematic approach to the collection and curation of natural history data that can be applied consistently across this group of heterogenous rare diseases. In this study, we discuss the challenges facing natural history studies for leukodystrophies and detail a novel standardized approach to creating a longitudinal natural history study using existing medical records. Prospective studies are uniquely challenging for rare diseases. Delays in diagnosis and overall rarity limit the timely collection of natural history data. When feasible, prospective studies are often cross-sectional rather than longitudinal and are unlikely to capture pre- or early- symptomatic disease trajectories, limiting their utility in characterizing the full natural history of the disease. Therapeutic development in leukodystrophies is subject to these same obstacles. The Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN) comprises of a network of research institutions across the United States, supported by a multi-center biorepository protocol, to map the longitudinal clinical course of disease across leukodystrophies. As part of GLIA-CTN, we developed Standard Operating Procedures (SOPs) that delineated all study processes related to staff training, source documentation, and data sharing. Additionally, the SOP detailed the standardized approach to data extraction including diagnosis, clinical presentation, and medical events, such as age at gastrostomy tube placement. The key variables for extraction were selected through face validity, and common electronic case report forms (eCRF) across leukodystrophies were created to collect analyzable data. To enhance the depth of the data, clinical notes are extracted into "original" and "imputed" encounters, with imputed encounter referring to a historic event (e.g., loss of ambulation 3 months prior). Retrospective Functional Assessments were assigned by child neurologists, using a blinded dual-rater approach and score discrepancies were adjudicated by a third rater. Upon completion of extraction, data source verification is performed. Data missingness was evaluated using statistics. The proposed methodology will enable us to leverage existing medical records to address the persistent gap in natural history data within this unique disease group, allow for assessment of clinical trajectory both pre- and post-formal diagnosis, and promote recruitment of larger cohorts.
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Doenças Raras , Humanos , Doenças Raras/diagnóstico , Doenças Raras/terapia , Doenças Raras/epidemiologia , Estudos Longitudinais , Estados Unidos , Estudos ProspectivosAssuntos
Doenças do Desenvolvimento Ósseo , Imageamento por Ressonância Magnética , Humanos , Imageamento por Ressonância Magnética/métodos , Doenças do Desenvolvimento Ósseo/diagnóstico por imagem , Feminino , Pulmão/diagnóstico por imagem , Pulmão/anormalidades , Masculino , Medidas de Volume Pulmonar/métodos , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
IMPORTANCE: The travelers' gut microbiome is potentially assaulted by acute and chronic perturbations (e.g., diarrhea, antibiotic use, and different environments). Prior studies of the impact of travel and travelers' diarrhea (TD) on the microbiome have not directly compared antibiotic regimens, and studies of different antibiotic regimens have not considered travelers' microbiomes. This gap is important to be addressed as the use of antibiotics to treat or prevent TD-even in moderate to severe cases or in regions with high infectious disease burden-is controversial based on the concerns for unintended consequences to the gut microbiome and antimicrobial resistance (AMR) emergence. Our study addresses this by evaluating the impact of defined antibiotic regimens (single-dose treatment or daily prophylaxis) on the gut microbiome and resistomes of deployed servicemembers, using samples collected during clinical trials. Our findings indicate that the antibiotic treatment regimens that were studied generally do not lead to adverse effects on the gut microbiome and resistome and identify the relative risks associated with prophylaxis. These results can be used to inform therapeutic guidelines for the prevention and treatment of TD and make progress toward using microbiome information in personalized medical care.
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Diarreia , Microbioma Gastrointestinal , Humanos , Diarreia/prevenção & controle , Viagem , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Resistência Microbiana a MedicamentosRESUMO
The optimal approach to COVID-19 surveillance in congregate populations remains unclear. Our study at the US Naval Academy in Annapolis, Maryland, USA, assessed the concordance of antibody prevalence in longitudinally collected dried blood spots and saliva in a setting of frequent PCR-based testing. Our findings highlight the utility of salivary-based surveillance.
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COVID-19 , SARS-CoV-2 , Humanos , COVID-19/diagnóstico , COVID-19/epidemiologia , Saliva , Teste para COVID-19 , Técnicas de Laboratório ClínicoRESUMO
We evaluated the diagnostic yield using genome-slice panel reanalysis in the clinical setting using an automated phenotype/gene ranking system. We analyzed whole genome sequencing (WGS) data produced from clinically ordered panels built as bioinformatic slices for 16 clinically diverse, undiagnosed cases referred to the Pediatric Mendelian Genomics Research Center, an NHGRI-funded GREGoR Consortium site. Genome-wide reanalysis was performed using Moon™, a machine-learning-based tool for variant prioritization. In five out of 16 cases, we discovered a potentially clinically significant variant. In four of these cases, the variant was found in a gene not included in the original panel due to phenotypic expansion of a disorder or incomplete initial phenotyping of the patient. In the fifth case, the gene containing the variant was included in the original panel, but being a complex structural rearrangement with intronic breakpoints outside the clinically analyzed regions, it was not initially identified. Automated genome-wide reanalysis of clinical WGS data generated during targeted panels testing yielded a 25% increase in diagnostic findings and a possibly clinically relevant finding in one additional case, underscoring the added value of analyses versus those routinely performed in the clinical setting.
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Biologia Computacional , Genômica , Humanos , Sequenciamento Completo do Genoma , Fenótipo , ÍntronsRESUMO
BACKGROUND: Fetal ventriculomegaly is a source of apprehension for expectant parents and may present prognostic uncertainty for physicians. Accurate prenatal counseling requires knowledge of its cause and associated findings as the differential diagnosis is broad. We have observed an association between ventriculomegaly and incomplete hippocampal inversion. OBJECTIVE: To determine whether ventricular size is related to incomplete hippocampal inversion. MATERIALS AND METHODS: We retrospectively evaluated pre- and postnatal brain MRIs in normal subjects (mean GA, 31 weeks; mean postnatal age, 27 days) and patients with isolated ventriculomegaly (mean GA, 31 weeks; mean postnatal age, 68 days) at a single academic medical center. Lateral ventricular diameter, multiple qualitative and quantitative markers of hippocampal inversion, and evidence of intraventricular hemorrhage were documented. RESULTS: Incomplete hippocampal inversion and ventricular size were associated in both normal subjects (n=51) and patients with ventriculomegaly (n=32) (P<0.05). Severe ventriculomegaly was significantly associated with adverse clinical outcome in postnatal (P=0.02) but not prenatal (P=0.43) groups. In all additional cases of isolated ventriculomegaly, clinical outcome was normal over the time of assessment (mean 1±1.9 years; range 0.01 to 10 years). CONCLUSION: Lateral ventricular atrial diameter and incomplete hippocampal inversion are associated. Less hippocampal inversion correlates with larger atria. For every 1-mm increase in fetal ventricular size, the odds of incomplete hippocampal inversion occurring increases by a factor of 1.6 in normal controls and 1.4 in patients with ventriculomegaly.
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Fibrilação Atrial , Hidrocefalia , Feminino , Humanos , Lactente , Gravidez , Fibrilação Atrial/complicações , Hidrocefalia/diagnóstico por imagem , Diagnóstico Pré-Natal , Estudos Retrospectivos , Rotação , Ultrassonografia Pré-NatalRESUMO
Arboviral infections, including dengue (DNV), chikungunya (CHIKV), and Zika (ZIKV), impact both travelers and native populations of endemic regions. We sought to assess the disease burden of arboviral infections in the Military Health System, the validity of arboviral diagnostic codes, and the role of pretravel counseling on insect avoidance precautions. We searched for diagnostic codes consistent with arboviral infection and grouped them into DNV, CHIKV, ZIKV, Japanese encephalitis virus (JEV), and Other. Demographic data were evaluated. A subset of charts in each category were reviewed for diagnostic validity and travel characteristics. In all, 10,547 unique subjects carried 17,135 arboviral diagnostic codes, including 1,606 subjects (15.2%) coded for DNV, 230 (2.2%) for ZIKV, 65 (0.6%) for CHIKV, and 4,317 (40.9%) for JEV. A chart review was performed on 807 outpatient charts, yielding outpatient diagnostic code positive predictive values of 60.5% (DNV), 15.3% (ZIKV), and 64.5% (CHIKV); there were no valid cases of JEV. Dengue represented the greatest burden of arboviral infections with 2.2 cases per 100,000 military healthcare enrollees over the 2012-2019 fiscal years. More than 80% of subjects with arboviral infection did not have documented pretravel counseling. Arboviral infections represent a significant disease burden in young travelers to endemic regions. After adjustment for diagnostic validity, DNV represented the greatest burden. Diagnostic codes for ZIKV and JEV overestimate the burden of these diseases. Low rates of pretravel visits represent an opportunity for increased emphasis on insect exposure precautions.
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Infecções por Arbovirus , Arbovírus , Febre de Chikungunya , Dengue , Vírus da Encefalite Japonesa (Espécie) , Serviços de Saúde Militar , Infecção por Zika virus , Zika virus , Humanos , Infecção por Zika virus/diagnóstico , Dengue/diagnóstico , Infecções por Arbovirus/epidemiologiaRESUMO
BACKGROUND: Beta-propeller protein-associated neurodegeneration (BPAN) is a rare neurodegenerative disorder characterized by iron accumulation in the brain with spectrum of neurodevelopmental and movement phenotypes. In anticipation of future clinical trials and to inform clinical care, there is an unmet need to capture the phenotypic diversity of this rare disorder and better define disease subtypes. METHODS: A total of 27 individuals with BPAN were included in our natural history study, from which traditional outcome measures were obtained in 18 subjects. Demographic and diagnostic information, along with acquisition of basic developmental skills and overall neurologic severity were extracted from the medical records. Functional outcome measures were administered at the time of the evaluation or applied retrospectively at the last clinical encounter for patients who were not able to travel for in person. Based on age and functional level, the following assessments were administered: Leiter-3, Gross Motor Function Measure (GMFM)-66 Item Sets, Vineland-3, and Peabody-2. RESULTS: Overall, cognitive function was more impaired compared to gross motor function. Onset of symptoms of BPAN within the first 6 months of life was associated with decreased gain of ambulation and gain of spoken language (ambulation: log-rank test p = 0.0015; gain of first word: p = 0.0015). There was no difference in age at seizure onset by age at initial symptom onset (p = 0.8823). Collection of prospective outcome measures was limited by attention and behavior in our patient population, reinforcing the complexity of phenotype assessment and inadequacy of available standardized tests. Overall, gross motor and adaptive behavior assessments were better able to capture the dynamic range of function across the BPAN population than the fine motor and non-verbal cognitive tests. Floor effects were noted across outcome measures in a subset of individuals for cognitive and adaptive behavior tests. CONCLUSION: Our data suggest the distinct phenotypes of BPAN: a severe, early onset form and an attenuated form with higher cognitive capabilities. Early age at onset was a key factor in predicting future neurologic impairment.
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Distúrbios do Metabolismo do Ferro , Humanos , Distúrbios do Metabolismo do Ferro/diagnóstico , Distúrbios do Metabolismo do Ferro/genética , Psicometria , Estudos Prospectivos , Estudos Retrospectivos , Proteínas de Transporte/genética , Ferro/metabolismo , Avaliação de Resultados em Cuidados de SaúdeRESUMO
BACKGROUND: The Deployment and Travel Medicine Knowledge, Attitudes, Practices, and Outcomes Study (KAPOS) evaluates health outcomes and provider practices associated with travel and deployments within the US Military Health System. We analyzed prescribing errors for chloroquine malaria chemoprophylaxis between travel medicine specialists and non-specialists over a five-year period. METHODS: A sample of 291 chloroquine prescriptions were reviewed to determine if malaria chemoprophylaxis was appropriate for destination of travel based on both transmission and chloroquine resistance risk. We included non-active-duty beneficiaries of all ages seeking care at military treatment facilities. RESULTS: 10.3% (n = 30) of patients were prescribed chloroquine inappropriately. Non-travel medicine specialists prescribed chloroquine inappropriately more frequently than travel medicine specialists with 16.5% vs 2.3% error, respectively. Physicians were less likely to erroneously prescribe chloroquine as compared to non-physicians with 6.4% vs 22.2% error, respectively. 93.3% of prescribing errors were due to chloroquine-resistance presence at the travel destination. Africa was the most common destination of erroneous prescriptions, creating significant risk for travelers. CONCLUSIONS: While chloroquine is infrequently prescribed, this analysis demonstrates travel medicine proficiency is associated with reduced errors, highlighting the need to supply travel medicine education and decision support tools to non-specialists, to safeguard patients who seek pre-travel medical care.