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BACKGROUND: Transthyretin amyloidosis, also called ATTR amyloidosis, is associated with accumulation of ATTR amyloid deposits in the heart and commonly manifests as progressive cardiomyopathy. Patisiran, an RNA interference therapeutic agent, inhibits the production of hepatic transthyretin. METHODS: In this phase 3, double-blind, randomized trial, we assigned patients with hereditary, also known as variant, or wild-type ATTR cardiac amyloidosis, in a 1:1 ratio, to receive patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks for 12 months. A hierarchical procedure was used to test the primary and three secondary end points. The primary end point was the change from baseline in the distance covered on the 6-minute walk test at 12 months. The first secondary end point was the change from baseline to month 12 in the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score (with higher scores indicating better health status). The second secondary end point was a composite of death from any cause, cardiovascular events, and change from baseline in the 6-minute walk test distance over 12 months. The third secondary end point was a composite of death from any cause, hospitalizations for any cause, and urgent heart failure visits over 12 months. RESULTS: A total of 360 patients were randomly assigned to receive patisiran (181 patients) or placebo (179 patients). At month 12, the decline in the 6-minute walk distance was lower in the patisiran group than in the placebo group (Hodges-Lehmann estimate of median difference, 14.69 m; 95% confidence interval [CI], 0.69 to 28.69; P = 0.02); the KCCQ-OS score increased in the patisiran group and declined in the placebo group (least-squares mean difference, 3.7 points; 95% CI, 0.2 to 7.2; P = 0.04). Significant benefits were not observed for the second secondary end point. Infusion-related reactions, arthralgia, and muscle spasms occurred more often among patients in the patisiran group than among those in the placebo group. CONCLUSIONS: In this trial, administration of patisiran over a period of 12 months resulted in preserved functional capacity in patients with ATTR cardiac amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO-B ClinicalTrials.gov number, NCT03997383.).
Assuntos
Amiloidose , Cardiomiopatias , Pré-Albumina , RNA Interferente Pequeno , Humanos , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/etiologia , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Pré-Albumina/genética , Pré-Albumina/metabolismo , RNA Interferente Pequeno/uso terapêutico , Amiloidose Familiar/complicações , Amiloidose Familiar/tratamento farmacológico , Amiloidose Familiar/genética , Fígado/metabolismo , Método Duplo-Cego , Amiloidose/complicações , Amiloidose/tratamento farmacológico , Amiloidose/genéticaRESUMO
BACKGROUND AND OBJECTIVES: To examine the efficacy and safety of patisiran, an RNA interference therapeutic, in patients from Taiwan with hereditary transthyretin-mediated (hATTR) amyloidosis with polyneuropathy. METHODS: The APOLLO phase 3 trial included patients from Taiwan who received patisiran 0.3 mg/kg intravenously or placebo once every 3 weeks (q3w) for 18 months (18 M), followed by patisiran 0.3 mg/kg q3w in an ongoing global open-label extension (OLE) study. The primary endpoint was change from baseline in modified Neuropathy Impairment Score +7 (mNIS+7) at 18 M. RESULTS: Eighteen Taiwanese patients were enrolled in APOLLO (patisiran, n = 8; placebo, n = 10; all A97S gene variant) and 14 continued in the global OLE. In this Taiwanese sub-population, beneficial treatment effects at 18 M were observed in mNIS+7 (least squares mean difference in change from baseline [patisiran-placebo], -26.5 points; 95% confidence interval: -45.5, -7.5). Patients who switched from placebo to patisiran demonstrated slowing of polyneuropathy progression at month 12 in the global OLE, while those who received patisiran in APOLLO maintained the beneficial treatment effects. Patisiran had an acceptable safety profile in the Taiwanese sub-population. CONCLUSIONS: This analysis suggests that patisiran is well tolerated and may provide a substantial clinical benefit for Taiwanese patients with hATTR amyloidosis with polyneuropathy. TRIAL REGISTRATION INFORMATION: The studies were registered on the ClinicalTrials.gov. The APOLLO study ClinicalTrials.gov identifier is NCT01960348 (https://clinicaltrials.gov/ct2/show/NCT01960348), with the registration date of October 10, 2013, and the first patient was enrolled on December 13, 2013. For the global OLE, the ClinicalTrials.gov identifier is NCT02510261 (https://clinicaltrials.gov/ct2/show/NCT02510261) with the registration date of July 29, 2015, and the first patient was enrolled on July 13, 2015. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that treatment with patisiran is safe and efficacious in Taiwanese patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy.
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OBJECTIVE: In current practice, treatment as usual (TAU) for suicidal adolescents includes evaluation, with little or no intervention provided in the emergency department (ED), and disposition, usually to an inpatient psychiatry unit. The family-based crisis intervention (FBCI) is an emergency psychiatry intervention designed to sufficiently stabilize suicidal adolescents within a single ED visit so that they may return home safely with their families. The objective of this article is to report efficacy outcomes related to FBCI for suicidal adolescents and their families. METHODS: A total of 142 suicidal adolescents (age, 13-18 years) and their families presenting for psychiatric evaluation to a large pediatric ED were randomized to receive FBCI or TAU. Patients and caregivers completed self-report measures of suicidality, family empowerment, and satisfaction with care provided at pretest, posttest, and 3 follow-up time points over a 1-month period. RESULTS: Patients randomized to FBCI were significantly more likely to be discharged home with outpatient follow-up care compared with their TAU counterparts (P < 0.001). Families randomized to the FBCI condition reported significantly higher levels of family empowerment and client satisfaction with care at posttest compared with their TAU counterparts. Gains were maintained over the follow-up period. No completed suicides were reported during the study period in either condition. CONCLUSIONS: Family-based crisis intervention is a model of care for suicidal adolescents that may be a viable alternative to traditional ED care that involves inpatient psychiatric hospitalization.
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Comportamento do Adolescente/psicologia , Intervenção em Crise/métodos , Família/psicologia , Suicídio/psicologia , Adolescente , Serviço Hospitalar de Emergência , Feminino , Seguimentos , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Relações Pais-Filho , Alta do Paciente/estatística & dados numéricos , Satisfação do Paciente/estatística & dados numéricos , Reincidência/estatística & dados numéricos , Prevenção do SuicídioRESUMO
OBJECTIVES: To assess psychiatric disorders and function in adolescents with repaired tetralogy of Fallot (TOF) without and with a genetic diagnosis and to evaluate associations of functioning with medical factors, IQ, and demographics. STUDY DESIGN: Adolescents with TOF (n = 91) and 87 healthy referents completed a clinician-rated structured psychiatric interview, parent-/self-report measures of psychopathology, and brain magnetic resonance imaging. Twenty-three of the adolescents with TOF had a known genetic diagnosis. RESULTS: The prevalence of anxiety disorders did not differ significantly between adolescents with TOF without genetic diagnosis (n = 68) and referents. Adolescents with TOF and a genetic diagnosis showed an increased lifetime prevalence of anxiety disorder (43%) and lower global psychosocial functioning (median, 70; IQR, 63-75) compared with adolescents with TOF without genetic diagnosis (15% and 83; IQR, 79-87, respectively; P = .04 and <.001, respectively) and referents (6% and 85; IQR, 76-90, respectively; P = .001 and <.001, respectively). Adolescents with TOF without and with a genetic diagnosis had a higher lifetime prevalence of attention deficit-hyperactivity disorder (ADHD) than referents (19% and 39%, respectively, vs 5%; P = .04 and .002, respectively) and worse outcomes on parent-/self-report ratings of anxiety and disruptive behavior compared with referents. Risk factors for anxiety, ADHD, and lower psychosocial functioning for adolescents with TOF without a genetic diagnosis included older age, male sex, and low IQ. Medical variables were not predictive of psychiatric outcomes. CONCLUSION: Adolescents with TOF, particularly those with a genetic diagnosis, show increased rates of psychiatric disorder and dysfunction. Continued mental health screening and surveillance into young adulthood is warranted for adolescents with TOF.
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Transtornos Mentais/epidemiologia , Tetralogia de Fallot/psicologia , Adolescente , Estudos Transversais , Feminino , Humanos , Testes de Inteligência , Masculino , Pais , Prevalência , Psicometria , Fatores de Risco , AutorrelatoRESUMO
Children and adolescents with critical cyanotic congenital heart disease (CHD) are at risk for deficits in aspects of executive function (EF). The primary aim of this investigation was to compare EF outcomes in three groups of children/adolescents with severe CHD and controls (ages 10-19 years). Participants included 463 children/adolescents with CHD [dextro-transposition of the great arteries (TGA), n=139; tetralogy of Fallot (TOF), n=68; and, single-ventricle anatomy requiring Fontan procedure (SVF), n=145] and 111 controls, who underwent laboratory and informant-based evaluation of EF skills. Rates of EF impairment on D-KEFS measures were nearly twice as high for CHD groups (75-81%) than controls (43%). Distinct EF profiles were documented between CHD groups on D-KEFS tasks. Deficits in flexibility/problem-solving and verbally mediated EF skills were documented in all three CHD groups; visuo-spatially mediated EF abilities were impaired in TOF and SVF groups, but preserved in TGA. Parent, teacher, and self-report ratings on the BRIEF highlighted unique patterns of metacognitive and self-regulatory concerns across informants. CHD poses a serious threat to EF development. Greater severity of CHD is associated with worse EF outcomes. With increased understanding of the cognitive and self-regulatory vulnerabilities experienced by children and adolescents with CHD, it may be possible to identify risks early and provide individualized supports to promote optimal neurodevelopment.
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Transtornos Cognitivos/etiologia , Função Executiva/fisiologia , Cardiopatias Congênitas/complicações , Adolescente , Análise de Variância , Criança , Transtornos Cognitivos/diagnóstico , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Estimulação Luminosa , Percepção Espacial , Inquéritos e Questionários , Adulto JovemRESUMO
Accurate and reproducible aortic measurements are essential in aortopathy patients. Transthoracic echocardiography (TTE) is commonly used but has several limitations. Cardiac magnetic resonance (CMR) can offset these limitations but has not been directly compared with TTE. We compared the reproducibility of CMR and TTE measurements at multiple aortic levels. Patients with a connective tissue disorder (CTD) or bicommissural aortic valve (BAV) (n = 41; 22 CTD, 19 BAV; mean age 18.8 ± 8.9 years) with TTE and CMR imaging performed within 3 months of each other were randomly selected. Two blinded observers measured the aorta at multiple anatomic levels. Intra- and interobserver variability and agreement between techniques were assessed. Aortic root diameter measurements by TTE and CMR were equally reproducible (% error 4-10 %), but TTE measurements were systematically smaller by 5-7 % (p < 0.0001). Systematic differences were larger in BAV (11-12 %, p < 0.0001) due to root asymmetry. CMR measurements of aortic root cross-sectional area were feasible and highly reproducible (% error 5-8 %). Compared with CMR, ascending aorta measurements by TTE were less reproducible, especially in BAV (% error 21-24 vs. 6-7 %, p = 0.01). Distal aortic measurements by TTE were 14-29 % smaller and had poor reproducibility compared with CMR (% error 24-42 vs. 9-10 %; p < 0.0001). CMR measurement of the largest aortic root dimension is more reliable than TTE, especially when the root is asymmetric. Measurements of the thoracic aorta distal to the root by CMR are more accurate and reproducible than by TTE. These data support a role for CMR in aortopathy patients.
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Aorta/fisiopatologia , Aortografia , Ecocardiografia , Imagem Cinética por Ressonância Magnética , Adolescente , Adulto , Aorta/diagnóstico por imagem , Valva Aórtica/anormalidades , Valva Aórtica/diagnóstico por imagem , Doença da Válvula Aórtica Bicúspide , Criança , Pré-Escolar , Doenças do Tecido Conjuntivo/diagnóstico por imagem , Feminino , Doenças das Valvas Cardíacas/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Reprodutibilidade dos Testes , Estudos Retrospectivos , Adulto JovemRESUMO
Oral iron chelators and magnetic resonance imaging (MRI) assessment of heart and liver iron burden have become widely available since the mid 2000s, allowing for improved patient compliance with chelation and noninvasive monitoring of iron levels for titration of therapy. We evaluated the impact of these changes in our center for patients with thalassemia major and transfusional iron overload. This single center, retrospective observational study covered the period from 2005 through 2012. Liver iron content (LIC) was estimated both by a T2* method and by R2 (Ferriscan® ) technique. Cardiac iron was assessed as cT2*. Forty-two patients (55% male) with transfused thalassemia and at least two MRIs were included (median age at first MRI, 17.5 y). Over a mean follow-up period of 5.2 ± 1.9 y, 190 MRIs were performed (median 4.5 per patient). Comparing baseline to last MRI, 63% of patients remained within target ranges for cT2* and LIC, and 13% improved from high values to the target range. Both the median LIC and cT2* (cR2* = 1000/cT2*) status improved over time: LIC 7.3 to 4.5 mg/g dry weight, P = 0.0004; cR2* 33.4 to 28.3 Hz, P = 0.01. Individual responses varied widely. Two patients died of heart failure during the study period. Annual MRI iron assessments and availability of oral chelators both facilitate changes in chelation dose and strategies to optimize care.
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Quelantes de Ferro/administração & dosagem , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/metabolismo , Ferro/análise , Imageamento por Ressonância Magnética/métodos , Talassemia beta/tratamento farmacológico , Talassemia beta/metabolismo , Adolescente , Adulto , Criança , Feminino , Humanos , Ferro/metabolismo , Sobrecarga de Ferro/patologia , Fígado/metabolismo , Fígado/patologia , Masculino , Adesão à Medicação , Miocárdio/metabolismo , Miocárdio/patologia , Estudos Retrospectivos , Adulto JovemRESUMO
OBJECTIVE: This study examined rates and determinants of vitamin D supplementation among Chronic Renal Insufficiency Cohort (CRIC) participants and determined the association between dose and 25-hydroxyvitamin D (25(OH)D) level. The 2010 Institute of Medicine Report noted a significant increase in vitamin D supplementation in the general population, but use in chronic kidney disease (CKD) is unknown. METHODS: CRIC is a multicenter prospective observational cohort study of 3,939 participants with a median baseline age of 60 and an estimated glomerular filtration rate (eGFR) of 42.1 mL/minute per 1.73 m2. Of the cohort, 54.9% was male, 42.1% were Black, and 48.4% were diabetic. Multivariable logistic generalized estimating equations were used to examine determinants of supplementation use assessed annually between 2003 and 2011. Cross-sectional linear regression models, based on a subset of 1,155 participants, assessed associations between supplement dose and 25(OH)D level, measured by high-performance liquid chromatography coupled with tandem mass spectrometry. RESULTS: The proportion of participants reporting supplement use increased (P < .0001), from 10% at baseline to 44% at 7-year follow-up visits. This was largely due to initiation of products containing only ergocalciferol or cholecalciferol. The odds of supplementation were greater in older, female, non-Black, married participants with greater education and lower body mass index. Among participants taking supplementation, dose was positively associated with 25(OH)D level, adjusted for race, season, diabetes, dietary intake, eGFR, and proteinuria. Only 3.8% of non-Black and 16.5% of Black participants taking a supplement were deficient (<20 ng/mL), whereas 22.7% of non-Black and 62.4% of black participants not reporting supplement use were deficient. CONCLUSIONS: Vitamin D supplementation rates rose significantly among CRIC participants over 7 years of follow-up and were associated with greater serum 25(OH)D levels. Studies of vitamin D levels on clinical outcomes in CKD and future vitamin D interventional studies should consider these changes in supplementation practices.
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Insuficiência Renal Crônica/tratamento farmacológico , Vitamina D/administração & dosagem , Fatores Etários , Idoso , Colecalciferol/administração & dosagem , Estudos de Coortes , Estudos Transversais , Suplementos Nutricionais , Ergocalciferóis/administração & dosagem , Feminino , Taxa de Filtração Glomerular , Humanos , Falência Renal Crônica/terapia , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Estudos Prospectivos , Fatores Sexuais , Vitamina D/análogos & derivados , Vitamina D/sangueRESUMO
OBJECTIVE: A study was undertaken to examine the neuropathological substrates of cognitive dysfunction and dementia in Parkinson disease (PD). METHODS: One hundred forty patients with a clinical diagnosis of PD and either normal cognition or onset of dementia 2 or more years after motor symptoms (PDD) were studied. Patients with a clinical diagnosis of dementia with Lewy bodies were excluded. Autopsy records of genetic data and semiquantitative scores for the burden of neurofibrillary tangles, senile plaques, Lewy bodies (LBs), and Lewy neurites (LNs) and other pathologies were used to develop a multivariate logistic regression model to determine the independent association of these variables with dementia. Correlates of comorbid Alzheimer disease (AD) were also examined. RESULTS: Niney-two PD patients developed dementia, and 48 remained cognitively normal. Severity of cortical LB (CLB)/LN pathology was positively associated with dementia (p < 0.001), with an odds ratio (OR) of 4.06 (95% confidence interval [CI], 1.87-8.81), as was apolipoprotein E4 (APOE4) genotype (p = 0.018; OR, 4.19; 95% CI, 1.28-13.75). A total of 28.6% of all PD cases had sufficient pathology for comorbid AD, of whom 89.5% were demented. The neuropathological diagnosis of PDD+AD correlated with an older age of PD onset (p = 0.001; OR, 1.12; 95% CI, 1.04-1.21), higher CLB/LN burden (p = 0.037; OR, 2.48; 95% CI, 1.06-5.82), and cerebral amyloid angiopathy severity (p = 0.032; OR, 4.16; 95% CI, 1.13-15.30). INTERPRETATION: CLB/LN pathology is the most significant correlate of dementia in PD. Additionally, APOE4 genotype may independently influence the risk of dementia in PD. AD pathology was abundant in a subset of patients, and may modify the clinical phenotype. Thus, therapies that target α-synuclein, tau, or amyloid ß could potentially improve cognitive performance in PD.
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Demência/patologia , Doença de Parkinson/patologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Apolipoproteína E4/metabolismo , Autopsia , Córtex Cerebral/patologia , Estudos de Coortes , Intervalos de Confiança , DNA/genética , Demência/etiologia , Demência/genética , Progressão da Doença , Feminino , Humanos , Doença por Corpos de Lewy/patologia , Modelos Logísticos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Modelos Neurológicos , Modelos Estatísticos , Transtornos dos Movimentos/patologia , Transtornos dos Movimentos/psicologia , Neuritos/patologia , Razão de Chances , Doença de Parkinson/complicações , Doença de Parkinson/genética , Curva ROCRESUMO
Biomarkers are often measured with error due to imperfect lab conditions or temporal variability within subjects. Using an internal reliability sample of the biomarker, we develop a parametric bias-correction approach for estimating a variety of diagnostic performance measures including sensitivity, specificity, the Youden index with its associated optimal cut-point, positive and negative predictive values, and positive and negative diagnostic likelihood ratios when the biomarker is subject to measurement error. We derive the asymptotic properties of the proposed likelihood-based estimators and show that they are consistent and asymptotically normally distributed. We propose confidence intervals for these estimators and confidence bands for the receiver operating characteristic curve. We demonstrate through extensive simulations that the proposed approach removes the bias due to measurement error and outperforms the naïve approach (which ignores the measurement error) in both point and interval estimation. We also derive the asymptotic bias of naïve estimates and discuss conditions in which naïve estimates of the diagnostic measures are biased toward estimates produced when the biomarker is ineffective (i.e., when sensitivity equals 1 - specificity) or are anticonservatively biased. The proposed method has broad biomedical applications and is illustrated using a biomarker study in Alzheimer's disease. We recommend collecting an internal reliability sample during the biomarker discovery phase in order to adequately evaluate the performance of biomarkers with careful adjustment for measurement error.
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Biomarcadores/análise , Interpretação Estatística de Dados , Testes Diagnósticos de Rotina/métodos , Doença de Alzheimer/líquido cefalorraquidiano , Simulação por Computador , Intervalos de Confiança , Testes Diagnósticos de Rotina/normas , Humanos , Valor Preditivo dos Testes , Curva ROC , Sensibilidade e Especificidade , Proteínas tau/líquido cefalorraquidianoRESUMO
OBJECTIVE: Assess how baseline polyneuropathy severity impacts response to patisiran regarding neurologic impairment and quality of life (QOL) in patients with hereditary transthyretin-mediated amyloidosis (ATTRv amyloidosis). METHODS: This post hoc analysis grouped patients from the Phase 3 APOLLO study (n = 225) by baseline Neuropathy Impairment Score (NIS) into quartiles: 6-<31; 31-<57; 57-<85.5; 85.5-141.6. Neurologic impairment (modified NIS+7 [mNIS+7], NIS total score), disability (Rasch-built Overall Disability Scale [R-ODS]), gait speed (10-meter walk test [10-MWT]), grip strength, and QOL (Norfolk Quality of Life-Diabetic Neuropathy [Norfolk QOL-DN] questionnaire) were assessed. RESULTS: Across all baseline NIS quartiles, patisiran improved several clinical markers of disease compared with placebo at 18 months. Patients in lower NIS quartiles, treated with patisiran earlier in the disease course, maintained better scores in mNIS+7, NIS total score, R-ODS, 10-MWT, grip strength, and Norfolk QOL-DN versus those in higher NIS quartiles, while placebo-treated patients experienced worsening of all functional measures after 18 months across all quartiles. CONCLUSIONS: Patisiran treatment improved neurologic function and QOL across a wide range of baseline polyneuropathy severities versus placebo. Timing of treatment initiation in patients with ATTRv amyloidosis remains critical for the preservation of function.(ClinicalTrials.gov number, NCT01960348).
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Neuropatias Amiloides Familiares , Polineuropatias , Humanos , Qualidade de Vida , Polineuropatias/tratamento farmacológico , Neuropatias Amiloides Familiares/tratamento farmacológico , Resultado do Tratamento , Biomarcadores , Pré-AlbuminaRESUMO
AIMS: Transthyretin-mediated (ATTR) amyloidosis is caused by deposition of transthyretin protein fibrils in the heart, nerves, and other organs. Patisiran, an RNA interference therapeutic that inhibits hepatic synthesis of transthyretin, was approved for the treatment of hereditary ATTR amyloidosis with polyneuropathy based on the phase 3 APOLLO study. We use left ventricular (LV) stroke volume (SV) to quantify LV function overtime and non-invasive pressure-volume techniques to delineate the effects of patisiran on LV mechanics in the pre-specified cardiac subpopulation of the APOLLO study. METHODS AND RESULTS: Left ventricular SV was assessed by transthoracic echocardiography at baseline, and after 9 and 18 months of therapy. To determine the mechanisms underlying changes in LV SV, non-invasive pressure-volume parameters, including the end-systolic and end-diastolic pressure-volume relationship, were derived using single beat techniques. At baseline, the mean SV was 51 ± 14 ml. At 9 months, the least-squares mean change in SV was -0.3 ± 1.2 ml for patisiran and -5.4 ± 1.9 ml for placebo (p = 0.021). At 18 months, the least-squares mean change in SV was -1.7 ± 1.3 ml for patisiran and - 8.1 ± 2.3 ml for placebo (p = 0.016). Decline in LV SV was driven by diminished LV capacitance in placebo relative to patisiran. CONCLUSIONS: Patisiran may delay progression of LV chamber dysfunction starting at 9 months of therapy. These data elucidate the mechanisms by which transthyretin-reducing therapies modulate progression of cardiac disease and need to be confirmed in ongoing phase 3 trials.
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Neuropatias Amiloides Familiares , Insuficiência Cardíaca , Humanos , Volume Sistólico , Pré-Albumina/genética , Pré-Albumina/metabolismo , Neuropatias Amiloides Familiares/complicações , Neuropatias Amiloides Familiares/tratamento farmacológicoRESUMO
Risks associated with brain biopsy limit availability of tissues and the role of brain biopsy in diagnosing neurodegeneration is unclear. We developed a simulated brain biopsy paradigm to comprehensively evaluate potential accuracy of detecting neurodegeneration in biopsies. Postmortem tissue from the frontal, temporal and parietal cortices and basal ganglia from 73 cases including Alzheimer's disease (AD), Lewy body disease (LBD), frontotemporal lobar degeneration-TDP43 (FTLD-TDP), multiple system atrophy (MSA), Pick's disease (PiD), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) were evaluated using H&E and immunostains. Brain biopsy was simulated in a blinded manner by masking each slide with opaque tape except for an area measuring 10 mm in diameter. Diagnoses obtained from frontal cortex only or all 4-brain regions were then compared with autopsy diagnoses. Diagnostic sensitivity in frontal cortex was highest in FTLD-TDP (88%), AD (80%) and LBD (79%); intermediate for MSA (71%), CBD (66%) and PiD (66%) and lowest for PSP (0%) (average 64%). Specificity was 43%. Sensitivities were enhanced with all 4-brain regions: FTLD-TDP (100%), AD (80%), LBD (100%), MSA (100%), CBD (83%), PiD (100%) and PSP (88%) (average 92%). Specificity was 71%. Simulated brain biopsy addressed limitations of standard brain biopsies such as tissue availability and lack of autopsy confirmation of diagnoses. These data could inform efforts to establish criteria for biopsy diagnosis of neurodegenerative disorders to guide care of individuals who undergo biopsy for enigmatic causes of cognitive impairment or when evidence of an underlying neurodegenerative disease may influence future therapy.
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Encéfalo/patologia , Técnicas de Diagnóstico Neurológico , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/patologia , Idoso , Idoso de 80 Anos ou mais , Autopsia , Gânglios da Base/patologia , Biópsia , Estudos de Casos e Controles , Feminino , Lobo Frontal/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sensibilidade e Especificidade , Lobo Temporal/patologiaRESUMO
BACKGROUND: Hereditary transthyretin-mediated amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We assessed the safety and efficacy of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. METHODS: This multicentre, open-label extension (OLE) trial enrolled patients at 43 hospitals or clinical centres in 19 countries as of Sept 24, 2018. Patients were eligible if they had completed the phase 3 APOLLO or phase 2 OLE parent studies and tolerated the study drug. Eligible patients from APOLLO (patisiran and placebo groups) and the phase 2 OLE (patisiran group) studies enrolled in this global OLE trial and received patisiran 0·3 mg/kg by intravenous infusion every 3 weeks with plans to continue to do so for up to 5 years. Efficacy assessments included measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress, with analysis by study groups (APOLLO-placebo, APOLLO-patisiran, phase 2 OLE patisiran) based on allocation in the parent trial. The global OLE is ongoing with no new enrolment, and current findings are based on the interim analysis of the patients who had completed 12-month efficacy assessments as of the data cutoff. Safety analyses included all patients who received one or more dose of patisiran up to the data cutoff. This study is registered with ClinicalTrials.gov, NCT02510261. FINDINGS: Between July 13, 2015, and Aug 21, 2017, of 212 eligible patients, 211 were enrolled: 137 patients from the APOLLO-patisiran group, 49 from the APOLLO-placebo group, and 25 from the phase 2 OLE patisiran group. At the data cutoff on Sept 24, 2018, 126 (92%) of 137 patients from the APOLLO-patisiran group, 38 (78%) of 49 from the APOLLO-placebo group, and 25 (100%) of 25 from the phase 2 OLE patisiran group had completed 12-month assessments. At 12 months, improvements in mNIS+7 with patisiran were sustained from parent study baseline with treatment in the global OLE (APOLLO-patisiran mean change -4·0, 95 % CI -7·7 to -0·3; phase 2 OLE patisiran -4·7, -11·9 to 2·4). Mean mNIS+7 score improved from global OLE enrolment in the APOLLO-placebo group (mean change from global OLE enrolment -1·4, 95% CI -6·2 to 3·5). Overall, 204 (97%) of 211 patients reported adverse events, 82 (39%) reported serious adverse events, and there were 23 (11%) deaths. Serious adverse events were more frequent in the APOLLO-placebo group (28 [57%] of 49) than in the APOLLO-patisiran (48 [35%] of 137) or phase 2 OLE patisiran (six [24%] of 25) groups. The most common treatment-related adverse event was mild or moderate infusion-related reactions. The frequency of deaths in the global OLE was higher in the APOLLO-placebo group (13 [27%] of 49), who had a higher disease burden than the APOLLO-patisiran (ten [7%] of 137) and phase 2 OLE patisiran (0 of 25) groups. INTERPRETATION: In this interim 12-month analysis of the ongoing global OLE study, patisiran appeared to maintain efficacy with an acceptable safety profile in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Continued long-term follow-up will be important for the overall assessment of safety and efficacy with patisiran. FUNDING: Alnylam Pharmaceuticals.
Assuntos
Neuropatias Amiloides Familiares/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Avaliação de Resultados em Cuidados de Saúde , Polineuropatias/tratamento farmacológico , Pré-Albumina/efeitos dos fármacos , RNA Interferente Pequeno/farmacologia , Adulto , Idoso , Neuropatias Amiloides Familiares/complicações , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Polineuropatias/etiologia , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/efeitos adversos , Índice de Gravidade de DoençaRESUMO
Among the most significant factors affecting quality of life in individuals with critical congenital heart disease (CCHD) are neurodevelopmental challenges, including deficits in visuospatial processing and academic achievement. Few studies have compared outcomes across CCHD subgroups, despite their significant differences in anatomy/physiology and medical/surgical courses. This study compared visuospatial processing abilities using the Developmental Scoring System for the Rey-Osterrieth Complex Figure (DSS-ROCF) across groups of adolescents with CCHD (d-transposition of the great arteries [TGA, n = 139], Tetralogy of Fallot [TOF, n = 68], single-ventricle cardiac anatomy requiring the Fontan operation [SVF, n = 145]) and a group of healthy controls (CTR, n = 111), and examined the validity of visuospatial processing in predicting concurrent academic outcomes. The CCHD subgroups were found to differ in Organization, ps < .001, Structural Accuracy, ps < .001, and Incidental Elements Accuracy scores, ps ≤ .008; the post hoc analyses show that the SVF group tended to underperform compared to the other CCHD groups. With respect to academic skills, all CCHD groups scored lower than the CTR group, ps ≤ .007; however, the CCHD groups were not different from each other, ps > .23. The regression results showed that the DSS-ROCF Style rating (reflecting integration) accounted for a small yet statistically significant portion of unique variance in "assembled" academic outcomes, over and above the variance already accounted for by DSS-ROCF Organization, p < .01. These findings support the need for comprehensive neuropsychological assessment and monitoring of children and adolescents with CCHD, as well as targeted intervention for organization and integration deficits that may increase their risk for academic underachievement.
Assuntos
Cardiopatias Congênitas/complicações , Qualidade de Vida/psicologia , Navegação Espacial/fisiologia , Sucesso Acadêmico , Adolescente , Criança , Feminino , Cardiopatias Congênitas/patologia , Humanos , MasculinoRESUMO
BACKGROUND: Young people may experience school-based violence and bullying victimization related to their gender expression, independent of sexual orientation identity. However, the associations between gender expression and bullying and violence have not been examined in racially and ethnically diverse population-based samples of high school students. METHODS: This study includes 5469 students (13-18 years) from the 2013 Youth Risk Behavior Surveys conducted in 4 urban school districts. Respondents were 51% Hispanic/Latino, 21% black/African American, 14% white. Generalized additive models were used to examine the functional form of relationships between self-reported gender expression (range: 1 = Most gender conforming, 7 = Most gender nonconforming) and 5 indicators of violence and bullying victimization. We estimated predicted probabilities across gender expression by sex, adjusting for sexual orientation identity and potential confounders. RESULTS: Statistically significant quadratic associations indicated that girls and boys at the most gender conforming and nonconforming ends of the scale had elevated probabilities of fighting and fighting-related injury, compared to those in the middle of the scale (p < .05). There was a significant linear relationship between gender expression and bullying victimization; every unit increase in gender nonconformity was associated with 15% greater odds of experiencing bullying (p < .0001). CONCLUSIONS: School-based victimization is associated with conformity and nonconformity to gender norms. School violence prevention programs should include gender diversity education.
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Bullying/estatística & dados numéricos , Vítimas de Crime/estatística & dados numéricos , Identidade de Gênero , Sexualidade/psicologia , Sexualidade/estatística & dados numéricos , Violência/estatística & dados numéricos , Adolescente , Comportamento do Adolescente , Sistema de Vigilância de Fator de Risco Comportamental , Bullying/psicologia , Vítimas de Crime/psicologia , Etnicidade , Feminino , Humanos , Modelos Logísticos , Masculino , Instituições Acadêmicas , Estudantes , Estados Unidos , População Urbana , Violência/psicologiaRESUMO
The functional significance of pulmonary arterial end-diastolic forward flow (EDFF) in patients with repaired tetralogy of Fallot (rTOF) is not fully understood, with conflicting reports regarding its associations with pulmonary regurgitation (PR), right ventricular (RV) size and function, and so-called restrictive RV physiology. To examine these associations, we retrospectively analyzed 399 patients with rTOF who had contemporaneous echocardiography (Echo) and cardiovascular magnetic resonance (CMR) studies. The median age at TOF repair was 0.7 years (0.21, 2.66), age at CMR was 19.8 years (13.0, 29.4), and interval between Echo and CMR was 48 days (0, 182). Doppler identified EDFF in 122 (31%) patients and CMR in 113 patients (28%). Compared with those without EDFF, patients with EDFF were younger, had greater PR, and higher RV end-diastolic volume, stroke volume, and ejection fraction. Markers of RV restriction such as right atrial size did not differ between groups. On multivariable regression, EDFF was associated with higher RV stroke volume and lower left ventricular end-diastolic volume. The association between Echo and CMR measurements of EDFF was modest (area under the receiver operating characteristic curve = 0.684, r = 0.374, p < 0.001). In conclusion, EDFF was common in this large cohort of patients with rTOF, but its presence and extent varied between Echo and CMR. EDFF was associated with greater PR and larger RV size, but not with markers of poor RV compliance such as right atrial enlargement. Mechanisms beyond RV noncompliance may contribute to the presence of EDFF.
Assuntos
Artéria Pulmonar/diagnóstico por imagem , Insuficiência da Valva Pulmonar/diagnóstico por imagem , Tetralogia de Fallot/cirurgia , Disfunção Ventricular Direita/diagnóstico por imagem , Adolescente , Adulto , Área Sob a Curva , Procedimentos Cirúrgicos Cardíacos , Cardiomegalia/diagnóstico por imagem , Cardiomegalia/fisiopatologia , Estudos Transversais , Diástole , Ecocardiografia , Ecocardiografia Doppler , Feminino , Átrios do Coração/diagnóstico por imagem , Átrios do Coração/fisiopatologia , Humanos , Modelos Logísticos , Imagem Cinética por Ressonância Magnética , Masculino , Análise Multivariada , Artéria Pulmonar/fisiopatologia , Circulação Pulmonar , Insuficiência da Valva Pulmonar/fisiopatologia , Curva ROC , Volume Sistólico/fisiologia , Tetralogia de Fallot/fisiopatologia , Disfunção Ventricular Direita/fisiopatologia , Adulto JovemRESUMO
PURPOSE: To determine how adolescents and young adults (AYAs) use social media to share health information and to assess attitudes toward using social media to obtain health information and communicate with medical providers. METHODS: A cross-sectional study of AYAs, 12 years or older, attending a primary care adolescent and young adult clinic. Participants completed an anonymous survey about health-related social media use, personal health, and communication with their health care team. RESULTS: Of the 244 patients approached, 204 enrolled (83.6% participation rate). Almost all (98%) had used social media within the prior month, but only 51.5% had shared health information in these networks. These participants shared about mood (76.2%), wellness (57.1%), and acute medical conditions (41.9%). Those with self-reported poor health were more likely to share health information than other groups. Privacy was the most important factor determining which platform to use. Only 25% thought that social media could provide them with useful health information. Few AYAs connected with their health care team on social media and most did not want to use this method; texting was preferred. CONCLUSIONS: AYAs maintain their privacy on social media regarding their health. Those with self-perceived poor health are more likely to share health information, potentially biasing online content and impairing the generalizability of social media research. AYAs do not view social media as a useful source of health information, which may limit the utility of public health messages through these platforms, and it may not be adequate for communication between patients and their health care team.
Assuntos
Comunicação em Saúde , Disseminação de Informação/métodos , Mídias Sociais/estatística & dados numéricos , Adolescente , Criança , Estudos Transversais , Feminino , Nível de Saúde , Humanos , Masculino , Atenção Primária à Saúde , Privacidade , Inquéritos e Questionários , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVES: Mental health outcomes for survivors of critical congenital heart disease (CHD) remain under-investigated. We sought to examine psychiatric disorders and psychosocial functioning in adolescents with single ventricle CHD and to explore whether patient-related risk factors predict dysfunction. METHODS: This cohort study recruited 156 adolescents with single ventricle CHD who underwent the Fontan procedure and 111 healthy referents. Participants underwent comprehensive psychiatric evaluation including a clinician-rated psychiatric interview and parent- and self-report ratings of anxiety, disruptive behavior, including attention-deficit/hyperactivity disorder (ADHD), and depressive symptoms. Risk factors for dysfunction included IQ, medical characteristics, and concurrent brain abnormalities. RESULTS: Adolescents with single ventricle CHD had higher rates of lifetime psychiatric diagnosis compared with referents (CHD: 65%, referent: 22%; P < .001). Specifically, they had higher rates of lifetime anxiety disorder and ADHD (P < .001 each). The CHD group scored lower on the primary psychosocial functioning measure, the Children's Global Assessment Scale, than referents (CHD median [interquartile range]: 62 [54-66], referent: 85 [73-90]; P < .001). The CHD group scored worse on measures of anxiety, disruptive behavior, and depressive symptoms. Genetic comorbidity did not impact most psychiatric outcomes. Risk factors for anxiety disorder, ADHD, and lower psychosocial functioning included lower birth weight, longer duration of deep hypothermic circulatory arrest, lower intellectual functioning, and male gender. CONCLUSIONS: Adolescents with single ventricle CHD display a high risk of psychiatric morbidity, particularly anxiety disorders and ADHD. Early identification of psychiatric symptoms is critical to the management of patients with CHD.
Assuntos
Transtornos de Ansiedade/complicações , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/complicações , Depressão/complicações , Cardiopatias Congênitas/psicologia , Disfunção Ventricular/psicologia , Adolescente , Transtornos de Ansiedade/diagnóstico , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/diagnóstico , Peso ao Nascer , Estudos de Casos e Controles , Parada Circulatória Induzida por Hipotermia Profunda , Estudos de Coortes , Depressão/diagnóstico , Feminino , Técnica de Fontan , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/cirurgia , Humanos , Deficiência Intelectual , Masculino , Fatores de Risco , Fatores Sexuais , Disfunção Ventricular/complicações , Disfunção Ventricular/cirurgiaRESUMO
Studies of cerebrospinal fluid (CSF) biomarkers in Alzheimer's disease (AD) have indicated that much of the variability observed in the biomarkers may be due to measurement error. Biomarkers are often obtained with measurement error, which may make the diagnostic biomarker appear less effective than it truly is. In the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, technical replicates of CSF biomarkers are available; the National Alzheimer's Coordinating Center database contains longitudinal replicates of CSF biomarkers. We focus on the area under the receiver operating characteristic curve (AUC) as the measure of diagnostic effectiveness for differentiating AD from normal cognition using CSF biomarkers and compare AUC estimates obtained by a more standard, naïve method (which uses a single observation per subject and ignores measurement error) to a maximum likelihood (ML) based method (which uses all replicates per subject and adjusts for measurement error). The choice of analysis method depends upon the noise to signal ratio (i.e., the magnitude of the measurement error variability relative to the true biomarker variability); moderate to high ratios may significantly bias the naïve AUC estimate, and the ML-based method would be preferred. The noise to signal ratios were low for the ADNI biomarkers but high for the tTau and pTau biomarkers in NACC. Correspondingly, the naïve and ML-based AUC estimates were nearly identical in the ADNI data but dissimilar for the tTau and pTau biomarkers in the NACC data. Therefore, using the naïve method is adequate for analysis of CSF biomarkers in the ADNI study, but the ML method is recommended for the NACC data.