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Increasingly long and complex informed consents have yielded studies demonstrating comparatively low participant comprehension and satisfaction with traditional face-to-face approaches. In parallel, interest in electronic consents for clinical and research genomics has steadily increased, yet limited data are available for trio-based genomic discovery studies. We describe the design, development, implementation, and validation of an electronic iConsent application for trio-based genomic research deployed to support genomic studies of cerebral palsy. iConsent development incorporated stakeholder perspectives including researchers, patient advocates, institutional review board members, and genomic data-sharing considerations. The iConsent platform integrated principles derived from prior electronic consenting research and elements of multimedia learning theory. Participant comprehension was assessed in an interactive teachback format. The iConsent application achieved nine of ten proposed desiderata for effective patient-focused electronic consenting for genomic research. Overall, participants demonstrated high comprehension and retention of key human subjects' considerations. Enrollees reported high levels of satisfaction with the iConsent, and we found that participant comprehension, iConsent clarity, privacy protections, and study goal explanations were associated with overall satisfaction. Although opportunities exist to optimize iConsent, we show that such an approach is feasible, can satisfy multiple stakeholder requirements, and can realize high participant satisfaction and comprehension while increasing study reach.
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BACKGROUND: Mutations in the NMDA receptor are known to disrupt glutamatergic signaling crucial for early neurodevelopment, often leading to severe global developmental delay/intellectual disability, epileptic encephalopathy, and cerebral palsy phenotypes. Both seizures and movement disorders can be highly treatment-refractory. RESULTS: We describe a targeted ABA n-of-1 treatment trial with intrathecal MgSO4, rationally designed based on the electrophysiologic properties of this gain of function mutation in the GRIN1 NMDA subunit. CONCLUSION: Although the invasive nature of the trial necessitated a short-term, non-randomized, unblinded intervention, quantitative longitudinal neurophysiologic monitoring indicated benefit, providing class II evidence in support of intrathecal MgSO4 for select forms of GRIN disorders.
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Deficiência Intelectual , Magnésio , Humanos , Deficiência Intelectual/genética , Magnésio/metabolismo , Mutação/genética , Proteínas do Tecido Nervoso/genética , Receptores de N-Metil-D-Aspartato/genética , Convulsões/genética , Estudos de Caso Único como AssuntoRESUMO
Spermatogenesis-associated 5 like 1 (SPATA5L1) represents an orphan gene encoding a protein of unknown function. We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families. In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy. Modeling indicated damaging effect of variants on the protein, largely via destabilizing effects on protein domains. Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals. Immunofluorescent imaging in rat hippocampal neurons revealed localization of Spata5l1 in neuronal and glial cell nuclei and more prominent expression in neurons. In the rodent inner ear, Spata5l1 is expressed in the neurosensory hair cells and inner ear supporting cells. Transcriptomic analysis performed with fibroblasts from affected individuals was able to distinguish affected from controls by principal components. Analysis of differentially expressed genes and networks suggested a role for SPATA5L1 in cell surface adhesion receptor function, intracellular focal adhesions, and DNA replication and mitosis. Collectively, our results indicate that bi-allelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype.
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Paralisia Cerebral/patologia , Epilepsia/patologia , Predisposição Genética para Doença , Variação Genética , Perda Auditiva/patologia , Deficiência Intelectual/patologia , Espasticidade Muscular/patologia , ATPases Associadas a Diversas Atividades Celulares/genética , Adolescente , Adulto , Alelos , Animais , Paralisia Cerebral/etiologia , Paralisia Cerebral/metabolismo , Pré-Escolar , Epilepsia/etiologia , Epilepsia/metabolismo , Feminino , Perda Auditiva/etiologia , Perda Auditiva/metabolismo , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/etiologia , Deficiência Intelectual/metabolismo , Masculino , Espasticidade Muscular/etiologia , Espasticidade Muscular/metabolismo , Ratos , Adulto JovemRESUMO
BACKGROUND: Cerebral palsy (CP) is the most common childhood motor disability. The emergence of genetic CP etiologies, variable inclusion of hypotonic CP in international registries, and involvement of different medical disciplines in CP diagnosis can promote diagnostic variability. This variability could adversely affect patients' understanding of their symptoms and access to care. Therefore, we sought to determine the presence and extent of practice variability in CP diagnosis. METHODS: We surveyed physicians in the United States and Canada interested in CP on the basis of membership in the American Academy of Cerebral Palsy and Developmental Medicine or the Child Neurology Society Neonatal Neurology, Movement Disorders, or Neurodevelopmental Disabilities Special Interest Groups. The survey included the 2007 consensus definition of CP and 4 hypothetical case scenarios. RESULTS: Of 695 contacted physicians, 330 (47%) completed the survey. Two scenarios yielded consensus: (1) nonprogressive spastic diplegia after premature birth with periventricular leukomalacia on brain MRI (96% would diagnose CP) and (2) progressive spastic diplegia (92% would not diagnose CP). Scenarios featuring genetic etiologies or hypotonia as the cause of nonprogressive motor disability yielded variability: only 46% to 67% of practitioners would diagnose CP in these settings. CONCLUSIONS: There is practice variability in whether a child with a nonprogressive motor disability due to a genetic etiology or generalized hypotonia will be diagnosed with CP. This variability occurred despite anchoring questions with the 2007 consensus definition of CP. On the basis of these results, we have suggested ways to reduce diagnostic variability, including clarification of the consensus definition.
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Paralisia Cerebral/diagnóstico , Paralisia Cerebral/epidemiologia , Médicos/normas , Inquéritos e Questionários/normas , Adolescente , Canadá/epidemiologia , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Masculino , Estados Unidos/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Acute necrotizing encephalopathy (ANE) is a rare condition associated with rapid progression to coma and high incidence of morbidity and mortality. METHODS: Clinical, electroencephalographic (EEG), and brain magnetic resonance imaging (MRI) characteristics and immunomodulatory therapy timing were retrospectively analyzed in children with ANE. ANE severity scores (ANE-SS) and MRI scores were also assessed. The associations of patient characteristics with 6-month modified Rankin scale (mRS) and length of hospitalization were determined using either univariate linear regression or one-way analysis of variance. RESULTS: 7 children were retrospectively evaluated. Normal EEG sleep spindles (P = .024) and early treatment (R2 = .57, P = .030) were associated with improved outcomes (ie, decreased mRS). Higher ANE-SS (R2 = .79, P = .011), higher age (R2 = .62, P = .038), and presence of brainstem lesions (P = .015) were associated with longer length of hospitalization. Other patient characteristics were not significantly associated with mRS or length of hospitalization. CONCLUSION: Early immunomodulatory therapy and normal sleep spindles are associated with better functional outcome in children with ANE.
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Imunomodulação , Leucoencefalite Hemorrágica Aguda/diagnóstico , Leucoencefalite Hemorrágica Aguda/terapia , Tempo para o Tratamento , Adolescente , Criança , Pré-Escolar , Eletroencefalografia , Feminino , Humanos , Lactente , Tempo de Internação , Imageamento por Ressonância Magnética , Masculino , Neuroimagem , Avaliação de Resultados em Cuidados de Saúde , Estudos Retrospectivos , Tálamo/patologiaRESUMO
In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. We performed whole-exome sequencing of 250 parent-offspring trios, and observed enrichment of damaging de novo mutations in cerebral palsy cases. Eight genes had multiple damaging de novo mutations; of these, two (TUBA1A and CTNNB1) met genome-wide significance. We identified two novel monogenic etiologies, FBXO31 and RHOB, and showed that the RHOB mutation enhances active-state Rho effector binding while the FBXO31 mutation diminishes cyclin D levels. Candidate cerebral palsy risk genes overlapped with neurodevelopmental disorder genes. Network analyses identified enrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Cerebral palsy risk genes in enriched pathways were shown to regulate neuromotor function in a Drosophila reverse genetics screen. We estimate that 14% of cases could be attributed to an excess of damaging de novo or recessive variants. These findings provide evidence for genetically mediated dysregulation of early neuronal connectivity in cerebral palsy.
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Paralisia Cerebral/genética , Proteínas F-Box/genética , Tubulina (Proteína)/genética , Proteínas Supressoras de Tumor/genética , beta Catenina/genética , Animais , Paralisia Cerebral/patologia , Ciclina D/genética , Citoesqueleto/genética , Drosophila/genética , Exoma/genética , Matriz Extracelular/genética , Feminino , Adesões Focais/genética , Predisposição Genética para Doença , Genoma Humano/genética , Humanos , Masculino , Mutação/genética , Neuritos/metabolismo , Neuritos/patologia , Fatores de Risco , Análise de Sequência de DNA , Transdução de Sinais/genética , Sequenciamento do Exoma , Proteína rhoB de Ligação ao GTP/genéticaRESUMO
Cohort-based whole exome and whole genome sequencing and copy number variant (CNV) studies have identified genetic etiologies for a sizable proportion of patients with cerebral palsy (CP). These findings indicate that genetic mutations collectively comprise an important cause of CP. We review findings in CP genomics and propose criteria for CP-associated genes at the level of gene discovery, research study, and clinical application. We review the published literature and report 18 genes and 5 CNVs from genomics studies with strong evidence of for the pathophysiology of CP. CP-associated genes often disrupt early brain developmental programming or predispose individuals to known environmental risk factors. We discuss the overlap of CP-associated genes with other neurodevelopmental disorders and related movement disorders. We revisit diagnostic criteria for CP and discuss how identification of genetic etiologies does not preclude CP as an appropriate diagnosis. The identification of genetic etiologies improves our understanding of the neurobiology of CP, providing opportunities to study CP pathogenesis and develop mechanism-based interventions.
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This article is a case report of the successful interdisciplinary management of a maxillary lateral incisor with a deep palatogingival groove. The tooth presented with severe periodontal destruction owing to the deep extension of the groove up to the root apex. The groove was meticulously diagnosed and treated by endodontic and subsequent periodontal surgery leading to complete resolution of the pathological process.
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Compostos de Alumínio/uso terapêutico , Substitutos Ósseos/uso terapêutico , Compostos de Cálcio/uso terapêutico , Incisivo/anormalidades , Óxidos/uso terapêutico , Equipe de Assistência ao Paciente , Silicatos/uso terapêutico , Raiz Dentária/anormalidades , Adulto , Necrose da Polpa Dentária/terapia , Combinação de Medicamentos , Seguimentos , Cimentos de Ionômeros de Vidro/uso terapêutico , Humanos , Masculino , Planejamento de Assistência ao Paciente , Periodontite Periapical/terapia , Bolsa Periodontal/terapia , Preparo de Canal Radicular/métodos , Retalhos Cirúrgicos/cirurgiaRESUMO
AIMS: This study was aimed to determine the effectiveness of Papacárie(®) for caries removal as compared to the conventional method with respect to microbial flora, time, the amount of tissue removal, child's behavior, pain perception, and preference of treatment. MATERIALS AND METHODS: Sixty primary molars of 30 children of age 4-9 years were selected randomly and divided into two groups of 30 teeth each: Group A treated by conventional method and group B with Papacárie(®) method. RESULTS: Comparatively, no statistical difference was seen in microbial growth, total bacterial count, and lactobacilli count in both the groups (P = 0.36). The mean cavity entrance size with group A was 0.98133 mm and group B was 0.26083 mm (P < 0.001). The mean preparation time for group A was 4.7 Mins (minutes) and group B was 17.96 min s (P < 0.001). Majority of kids of both group A and B scored 3 (Frankl Behavior Rating Scale) before and after the treatment showing no statistical difference in their behavioral score (P = 1). In group A 50% of children experienced no pain as compared to 86.7% in group B (P = 0.01). There was no statistical difference in the preference of treatment (P = 0.12). CONCLUSION: Thus, the Chemo mechanical caries removal method can be considered as an effective method to control pain and preserve sound tooth structure during caries excavation.
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A major emphasis of modern-day pediatric dental care is a holistic approach to children and the importance of treating them as individuals and not merely as patients with mouth diseases. We should not restrict ourselves to the oral cavity alone, but also explore the mind of an individual, for in it lays the hidden clue to successful management. In order to achieve this, we need to meet the mind of the child before meeting the mouth. Surmounting pressure on today's children builds a lot of anxiety in them, and this in turn is the foundation for various psychological problems. One such rare but important psychological disorder is "trichotillomania." The present study is an attempt to provide an insight into this intriguing disorder based on a case report. The signs and symptoms of trichotillomania are discussed, and various management options are outlined.
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Transtornos do Comportamento Infantil/diagnóstico , Tricotilomania/diagnóstico , Ansiedade/diagnóstico , Criança , Seguimentos , Humanos , Incisivo/anormalidades , Masculino , Planejamento de Assistência ao Paciente , Estresse Psicológico/diagnóstico , Dente Supranumerário/diagnósticoRESUMO
OBJECTIVE: To introduce and describe the US Border Patrol (USBP) Tucson Sector Border Patrol Search, Trauma and Rescue Unit (BORSTAR) and to analyze whether the frequency of its activities were associated with the amount of total border patrol law enforcement activities in the area. METHODS: Descriptive and nonparametric analysis was conducted on data that were obtained on total USBP apprehensions of undocumented immigrants and BORSTAR activities for a consecutive 3-year period. RESULTS: From October 2004 to September 2007 over 1 million apprehensions occurred within the Tucson Sector. During this time, a large number of search, rescue, and medical intervention events occurred. However, only a weak association was found between the frequency of apprehensions and BORSTAR activities. CONCLUSIONS: The BORSTAR unit of the Tucson Sector commonly encounters harsh conditions and provides search, rescue, and medical interventions to undocumented immigrants. The frequency of BORSTAR activities is not strongly associated with the volume of USBP law enforcement activities.
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Serviços Médicos de Emergência/estatística & dados numéricos , Emigração e Imigração , Trabalho de Resgate , Medicina Selvagem/estatística & dados numéricos , Arizona , Humanos , México , Estações do Ano , MigrantesRESUMO
BACKGROUND: ECGs from thorough QT studies must be read in a central laboratory by trained experts. Standards of expertise are not presently defined. We, therefore, studied the use of Z-scores to define reader competence. METHODS: Two hundred ECGs were read by 24 experts and the mean and standard deviation (SD) of QT measurements calculated for each ECG. Z-scores ([QT(reader)- mean QT(experts)]/ SD(experts)) for each ECG and mean of absolute Z-scores of all ECGs read by a reader were calculated. The highest mean absolute Z-score of experts was considered the cutoff to define competence. Hundred of these standardized ECGs were used to assess performance of readers from the central laboratory. RESULTS: All experts had mean absolute Z-scores < or = 1.5. Using this cutoff, one of 28 experienced readers and 7 of 15 trainees had unacceptable Z-scores. After re-training, all achieved Z-scores <1.5. Comparing histograms of actual Z-scores of the 100 ECGs of readers with unacceptable scores with that of the reader with the best Z-score showed two patterns. Readers with histograms having a peak and tails similar to that of the best reader, but with leftward or rightward shift, consistently made shorter or longer QT measurements, respectively. A histogram with a flatter peak and wider tails, suggested that measurements were long in some ECGs and short in others. CONCLUSION: Mean absolute Z-score is useful to assess competence for measuring the QT interval on ECGs. Analysis of histograms can pinpoint problems in QT measurements.
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Benchmarking/métodos , Cardiologia , Competência Clínica , Eletrocardiografia/métodos , Laboratórios , Síndrome do QT Longo/diagnóstico , Feminino , Humanos , Índia , Masculino , Variações Dependentes do Observador , Sensibilidade e Especificidade , Processamento de Sinais Assistido por Computador , Gestão da Qualidade TotalRESUMO
Idiopathic ventricular tachycardia is a defined set of tachycardias when structural or pathological cause has been ruled out for the same. This paper tries to define and classify these arrhythmias to organize a logical therapeutic approach to deal with them. 60-80% of the idiopathic tachycardias originate from the right ventricular outflow tract (RVOT) and in 10% from the left ventricular outflow tract (LVOT). Outflow tract tachycardias have either LBBB or RBBB morphology with early R wave transition in chest leads. Adenosine, beta blockers and calcium channel blockers is the common medical treatment. Radiofrequency ablation is however the treatment of choice. Verapamil sensitive left ventricular tachycardia (ILVT) and propranolol sensitive left ventricular tachycardia (IPVT) are the other two forms recognized. RF ablation seems ideal for long-term management of ILVT and implantable cardioverter defibrillator (ICD) for IPVT. Inherited channelopathies include catecholaminergic polymorphic ventricular tachycardia (CPVT), Brugada syndrome and long QT syndrome where there is an inherited disorder in the ion-exchange channels of the cell-membrane leading to tachycardia. Prognosis in these is variable; CPVT, in particular, has a malignant course when untreated. RF ablation and placement of an ICD are important in the overall management of specific arrhythmia.
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Taquicardia Ventricular , Adenosina/uso terapêutico , Antagonistas Adrenérgicos beta/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Ablação por Cateter , Desfibriladores Implantáveis , Eletrocardiografia , Humanos , Prognóstico , Taquicardia Ventricular/classificação , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/etiologia , Taquicardia Ventricular/terapiaRESUMO
Cardiomyopathy due to various ventricular and supraventricular arrhythmias, including isolated cases of atypical atrioventricular nodal reentrant tachycardia, have been described. In this case report typical slowfast atrioventricular nodal reentrant tachycardia resulting in cardiomyopathy is being documented for the first time. In the setting of depressed left ventricular function, an episode of tachycardia pushed this patient into heart failure. Radiofrequency ablation of the slow pathway was successful in eliminating her tachycardia with the return of left ventricular function to normal. A follow-up of two years post-ablation revealed the patient to be symptom-free.
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Ablação por Cateter , Eletrocardiografia , Insuficiência Cardíaca/etiologia , Taquicardia por Reentrada no Nó Atrioventricular/complicações , Taquicardia por Reentrada no Nó Atrioventricular/cirurgia , Idoso , Feminino , Seguimentos , Insuficiência Cardíaca/fisiopatologia , Humanos , Recuperação de Função Fisiológica , Medição de Risco , Índice de Gravidade de Doença , Taquicardia por Reentrada no Nó Atrioventricular/diagnóstico , Resultado do Tratamento , Função Ventricular Esquerda/fisiologiaRESUMO
Rhabdomyosarcoma (RMS) cell lines were transduced with an adenoviral vector containing the wild-type p53 (wtp53) cDNA (Ad-p53) and then exposed to four cytotoxic agents: actinomycin D, vincristine, 5-fluorouracil and bleomycin. Potentiation of cytotoxicity following wild-type p53 expression varied from 0- to 20-fold for different drugs and between cell lines. It appeared that alveolar RMS cells (n = 2) were more susceptible to p53-mediated chemosensitization than embryonal RMS cells (n = 3), although this was independent of pax3-FKHR expression. Overall, cells that were most chemosensitive prior to Ad-p53 exposure were those that were most susceptible to p53 potentiation of cytotoxicity. The different results obtained with these RMS cell lines does not appear to be related to expression of pax3-FKHR, p21, Bax or Bcl-2 but may in part be due to differential regulation of p53 target genes, such as MDM2. In conclusion, exogenous wild-type expression selectively chemosensitizes RMS cells to cytotoxic agents. However, expression of transcriptionally active wtp53 does not predict a chemosensitive phenotype.