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BACKGROUND: Despite the frequent diagnostic delays of rare neurologic diseases (RND), it remains difficult to study RNDs and their comorbidities due to their rarity and hence the statistical underpowering. Affecting one to two in a million annually, stiff person syndrome (SPS) is an RND characterized by painful muscle spasms and rigidity. Leveraging underutilized electronic health records (EHR), this study showcased a machine-learning-based framework to identify clinical features that optimally characterize the diagnosis of SPS. METHODS: A machine-learning-based feature selection approach was employed on 319 items from the past medical histories of 48 individuals (23 with a diagnosis of SPS and 25 controls) with elevated serum autoantibodies against glutamic-acid-decarboxylase-65 (anti-GAD65) in Dartmouth Health's EHR to determine features with the highest discriminatory power. Each iteration of the algorithm implemented a Support Vector Machine (SVM) model, generating importance scores-SHapley Additive exPlanation (SHAP) values-for each feature and removing one with the least salient. Evaluation metrics were calculated through repeated stratified cross-validation. RESULTS: Depression, hypothyroidism, GERD, and joint pain were the most characteristic features of SPS. Utilizing these features, the SVM model attained precision of 0.817 (95% CI 0.795-0.840), sensitivity of 0.766 (95% CI 0.743-0.790), F-score of 0.761 (95% CI 0.744-0.778), AUC of 0.808 (95% CI 0.791-0.825), and accuracy of 0.775 (95% CI 0.759-0.790). CONCLUSIONS: This framework discerned features that, with further research, may help fully characterize the pathologic mechanism of SPS: depression, hypothyroidism, and GERD may respectively represent comorbidities through common inflammatory, genetic, and dysautonomic links. This methodology could address diagnostic challenges in neurology by uncovering latent associations and generating hypotheses for RNDs.
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Registros Eletrônicos de Saúde , Aprendizado de Máquina , Rigidez Muscular Espasmódica , Humanos , Rigidez Muscular Espasmódica/diagnóstico , Rigidez Muscular Espasmódica/imunologia , Rigidez Muscular Espasmódica/epidemiologia , Registros Eletrônicos de Saúde/estatística & dados numéricos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Máquina de Vetores de Suporte , Estudo de Prova de Conceito , Glutamato Descarboxilase/imunologia , Doenças Raras/diagnóstico , Autoanticorpos/sangueRESUMO
BACKGROUND: Parkinson disease (PD) is associated with α-synuclein (αS) aggregation within enteric neurons. ENT-01 inhibits the formation of αS aggregates and improved constipation in an open-label study in patients with PD. OBJECTIVE: To evaluate the safety and efficacy of oral ENT-01 for constipation and neurologic symptoms in patients with PD and constipation. DESIGN: Randomized, placebo-controlled phase 2b study. (ClinicalTrials.gov: NCT03781791). SETTING: Outpatient. PATIENTS: 150 patients with PD and constipation. INTERVENTION: ENT-01 or placebo daily for up to 25 days. After baseline assessment of constipation severity, daily dosing was escalated to the prokinetic dose, the maximum dose (250 mg), or the tolerability limit, followed by a washout period. MEASUREMENTS: The primary efficacy end point was the number of complete spontaneous bowel movements (CSBMs) per week. Neurologic end points included dementia (assessed using the Mini-Mental State Examination [MMSE]) and psychosis (assessed using the Scale for the Assessment of Positive Symptoms adapted for PD [SAPS-PD]). RESULTS: The weekly CSBM rate increased from 0.7 to 3.2 in the ENT-01 group versus 0.7 to 1.2 in the placebo group (P < 0.001). Improvement in secondary end points included SBMs (P = 0.002), stool consistency (P < 0.001), ease of passage (P = 0.006), and laxative use (P = 0.041). In patients with dementia, MMSE scores improved by 3.4 points 6 weeks after treatment in the ENT-01 group (n = 14) versus 2.0 points in the placebo group (n = 14). Among patients with psychosis, SAPS-PD scores improved from 6.5 to 1.7 six weeks after treatment in the ENT-01 group (n = 5) and from 6.3 to 4.4 in the placebo group (n = 6). ENT-01 was well tolerated, with no deaths or drug-related serious adverse events. Adverse events were predominantly gastrointestinal, including nausea (34.4% [ENT-01] vs. 5.3% [placebo]; P < 0.001) and diarrhea (19.4% [ENT-01] vs. 5.3% [placebo]; P = 0.016). LIMITATION: Longer treatment periods need to be investigated in future studies. CONCLUSION: ENT-01 was safe and significantly improved constipation. PRIMARY FUNDING SOURCE: Enterin, Inc.
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Demência , Doença de Parkinson , Humanos , Resultado do Tratamento , Constipação Intestinal , Defecação , Método Duplo-CegoRESUMO
Neuroinflammation is a well-characterized pathophysiology occurring in association with the progression of Parkinson's disease. Characterizing the cellular and molecular basis of neuroinflammation is critical to understanding its impact on the incidence and progression of PD and other neurologic disorders. Inflammasomes are intracellular pro-inflammatory pattern-recognition receptors capable of initiating and propagating inflammation. These cellular complexes are well characterized in the innate immune system and activity of the NLRP3 inflammasome has been reported in microglia. NLRP3 inflammasome activity has been associated with Alzheimer's disease, and recent reports, from our laboratory and others, indicate that Nlrp3 is required for neuroinflammation and nigral cell loss in animal models of PD. NLRP3 has not yet been characterized in PD patients. Here we characterize NLRP3 in PD using immunohistologic and genetic approaches. Histologic studies revealed elevated NLRP3 expression in mesencephalic neurons of PD patients. Analysis of exome sequencing data for genetic variation of NLRP3 identified multiple single-nucleotide polymorphisms (SNPs) including rs7525979 that was associated with a significantly reduced risk of developing PD. Mechanistic studies conducted in HEK293 cells indicated that the synonymous SNP, NLRP3 rs7525979, alters the efficiency of NLRP3 translation impacting NLRP3 protein stability, ubiquitination state, and solubility. These data provide evidence that dopaminergic neurons are a cell-of-origin for inflammasome activity in PD and are consistent with recent animal studies, suggesting that inflammasome activity may impact the progression of PD.
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This article was migrated. The article was marked as recommended. Introduction: Direct observation assessments that provide both formative feedback and data for summative decisions can be difficult to achieve. The mini-clinical evaluation exercise (mini-CEX) is a widely used tool of direct observation that provides opportunities for feedback. We introduced a direct observation system with frequent mini-CEXs to increase clerkship student learning opportunities and to improve competency-based summative decisions. However, students may express resistance to assessments for learning with any summative impact as they may perceive the assessments as purely a series of summative evaluations. Aims: We explored how frequent low-stakes mini-CEXs affect clerkship students' perception of learning and to understand student perceptions of these assessments supporting their end-of-rotation summative clinical performance evaluations. Methods: This qualitative study used a purposive sampling strategy of focus groups with students who completed multiple mini-CEXs during their four-week neurology clerkship at one of three sites. All eleven students chose to participate. Eight students completed eight mini-CEXs, two students completed seven, and one student completed four. Investigator triangulation was used with interpretation comparisons that included independent content analysis. The emerging themes were discussed and final theme consensus was reached. Results: Three major themes arose: perceived effects of frequent mini-CEXs for clerkship student learning by facilitating multiple opportunities for guided practice under low assessment anxiety; the importance of consistent, effective faculty feedback and engagement to maximize mini-CEXs for learning; and support for summative impact of frequent, mainly formative, low stakes mini-CEXs. Conclusions: Students perceived that frequent mini-CEXs are mainly formative assessments for learning while having summative impact. However, variable perceived faculty affinity and engagement with the mini-CEX are important considerations to maximize the assessments for learning. These findings support a shift towards workplace-based assessment programs for learning that promote frequent direct observation and feedback, while also improving the trustworthiness of summative decisions.
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INTRODUCTION: Studies in animal models of Parkinson's disease (PD) have suggested that the rate of exercise performance is important in treatment efficacy and neuroprotection. In humans with PD, lower-extremity forced-exercise (FE) produced global improvements in motor symptoms based on clinical ratings and biomechanical measures of upper extremity function. METHODS: fMRI was used to compare the underlying changes in brain activity in PD patients following the administration of anti-parkinsonian medication and following a session of FE. RESULTS: Nine individuals with PD completed fMRI scans under each condition: off anti-PD medication, on anti-PD medication, and off medication + FE. Unified Parkinson's Disease Rating Motor Scale scores improved by 50% in the FE condition compared to the off-medication condition. The pattern of fMRI activation after FE was similar to that seen with anti-PD medication. Direct comparison of the fMRI activation patterns showed high correlation between FE and anti-PD medication. CONCLUSION: These findings suggest that medication and FE likely utilize the same pathways to produce symptomatic relief in individuals with PD.
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Córtex Cerebral/diagnóstico por imagem , Terapia por Exercício , Atividade Motora/fisiologia , Doença de Parkinson/reabilitação , Adulto , Idoso , Análise de Variância , Antiparkinsonianos/uso terapêutico , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Oxigênio/sangue , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/terapia , Estatística como AssuntoAssuntos
Adenoma de Glândula Sudorípara/imunologia , Ciclosporina/efeitos adversos , Imunossupressores/efeitos adversos , Síndrome de Muir-Torre/imunologia , Recidiva Local de Neoplasia/imunologia , Adenoma de Glândula Sudorípara/epidemiologia , Comorbidade , Ciclosporina/uso terapêutico , Quimioterapia Combinada , Humanos , Imunossupressores/uso terapêutico , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/cirurgia , Transplante de Rim , Masculino , Pessoa de Meia-Idade , Síndrome de Muir-Torre/induzido quimicamente , Recidiva Local de Neoplasia/induzido quimicamente , Sirolimo/uso terapêuticoAssuntos
Fibroma/patologia , Fibroma/cirurgia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/cirurgia , Idoso de 80 Anos ou mais , Biópsia por Agulha , Feminino , Fibroma/diagnóstico , Seguimentos , Humanos , Imuno-Histoquímica , Doenças Raras , Ombro , Neoplasias Cutâneas/diagnóstico , Resultado do TratamentoRESUMO
Discrimination of pigmented and vascular lesions in skin can be difficult due to factors such as size, subungual location, and the nature of lesions containing both melanin and vascularity. Misdiagnosis may lead to precancerous or cancerous lesions not receiving proper medical care. To aid in the rapid and accurate diagnosis of such pathologies, we develop a photoacoustic system to determine the nature of skin lesions in vivo. By irradiating skin with two laser wavelengths, 422 and 530 nm, we induce photoacoustic responses, and the relative response at these two wavelengths indicates whether the lesion is pigmented or vascular. This response is due to the distinct absorption spectrum of melanin and hemoglobin. In particular, pigmented lesions have ratios of photoacoustic amplitudes of approximately 1.4 to 1 at the two wavelengths, while vascular lesions have ratios of about 4.0 to 1. Furthermore, we consider two statistical methods for conducting classification of lesions: standard multivariate analysis classification techniques and a Bayesian-model-based approach. We study 15 human subjects with eight vascular and seven pigmented lesions. Using the classical method, we achieve a perfect classification rate, while the Bayesian approach has an error rate of 20%.
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Diagnóstico por Imagem/métodos , Processamento de Imagem Assistida por Computador/métodos , Transtornos da Pigmentação/patologia , Dermatopatias Vasculares/patologia , Acústica , Teorema de Bayes , Hemoglobinas/química , Humanos , Lasers , Melaninas/química , Análise Multivariada , Nevo/patologia , Pele/patologia , Pigmentação da Pele , TransdutoresAssuntos
Síndromes Mielodisplásicas/complicações , Neutrófilos/patologia , Paniculite/complicações , Paniculite/patologia , Idoso , Anemia/tratamento farmacológico , Anemia/etiologia , Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/uso terapêutico , Forma do Núcleo Celular , Terapia por Quelação , Eritropoetina/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Masculino , Síndromes Mielodisplásicas/tratamento farmacológicoRESUMO
Disseminated histoplasmosis can have a varied presentation when it affects the skin. Presentation mimicking a cutaneous neoplasm is an uncommon manifestation. We present the case of an 86-year-old man presenting with a cutaneous lesion clinically suspicious for malignancy that was ultimately determined to be his first clinical manifestation of disseminated histoplasmosis after biopsy for histopathologic analysis. Microscopically, the lesion was a nodule with an eroded epidermis overlying a dense dermal inflammatory process. The infiltrate was characterized by numerous epithelioid histiocytes admixed with acute and chronic inflammation. On closer inspection, numerous 2-4 mum intracellular spores surrounded by a clear halo were identified. The organisms were highlighted with periodic acid schiff (PAS) stain. We present this case to highlight a unique presentation of disseminated histoplasmosis. Although this presentation is uncommon, it serves as a reminder that histopathologic confirmation of clinical diagnoses is important before undertaking more invasive procedures such as excision.
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Histoplasmose/patologia , Neoplasias Cutâneas/patologia , Idoso , Antifúngicos/uso terapêutico , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Dermatite Seborreica/complicações , Diagnóstico Diferencial , Histoplasmose/complicações , Histoplasmose/tratamento farmacológico , Humanos , Imunossupressores/uso terapêutico , Itraconazol/uso terapêutico , Ceratose Actínica/complicações , Masculino , Metotrexato/uso terapêutico , Prednisona/uso terapêuticoRESUMO
Collision (contiguous) tumors of the skin can result in misleading clinicopathological presentations, and the choice of appropriate diagnostic techniques may prevent incomplete diagnosis and management. We report 2 cases of collision tumors involving amelanotic malignant melanoma of the back. One patient is a 79-yr-old male with an 8.7 x 5.5 x 4.5 cm polypoid lesion that on shave biopsy was diagnosed as basal cell carcinoma. Subsequent excision showed that the lesion was largely composed of amelanotic melanoma underlying a relatively small and thin basal cell carcinoma, and this probably would have been demonstrated in a punch (rather than shave) biopsy. The other patient is a 71-yr-old male with a 1 cm exophytic lesion on the back, which was determined microscopically to be melanoma, and a 0.6 cm papule on the back. This lesion was composed of 2 distinct contiguous neoplastic infiltrates, the predominant component being an atypical fibroxanthoma and the smaller component an amelanotic melanoma (primary vs metastatic), with diagnostic confirmation requiring multiple immunohistochemical stains.