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BackgroundUnderstanding the sensitivity and utility of clinical assessments across different HD stages is important for study/trial endpoint selection and clinical assessment development. The Integrated HD Progression Model (IHDPM) characterizes the complex symptom progression of HD and separates the disease into nine ordered disease states.ObjectiveTo generate a temporal map of discriminatory clinical measures across the IHDPM states.MethodsWe applied the IHDPM to all HD individuals in an integrated longitudinal HD dataset derived from four observational studies, obtaining disease state assignment for each study visit. Using large-scale screening, we estimated Cohen’s effect sizes to rank the discriminative power of 2,472 clinical measures for separating observations in disease state pairs. Individual trajectories through IHDPM states were examined. Discriminative analyses were limited to individuals with observations in both states of the pairs compared (N = 3,790).ResultsDiscriminative clinical measures were heterogeneous across the HD life course. UHDRS items were frequently identified as the best state pair discriminators, with UHDRS Motor items – most notably TMS – showing the highest discriminatory power between the early-disease states and early post-transition period states. UHDRS functional items emerged as strong discriminators from the transition period and on. Cognitive assessments showed good discriminative power between all state pairs examined, excepting state 1 vs. 2. Several non-UHDRS assessments were also flagged as excellent state discriminators for specific disease phases (e.g., SF-12). For certain state pairs, single assessment items other than total/summary scores were highlighted as having excellent discriminative power.ConclusionBy providing ranked quantitative scores indicating discriminatory ability of thousands of clinical measures between specific pairs of IHDPM states, our results will aid clinical trial designers select the most effective outcome measures tailored to their study cohort. Our observations may also assist in the development of end points targeting specific phases in the disease life course, through providing specific conceptual foci.

Background Risk of death from suicide in Huntington's disease is notably elevated relative to that in the general population, although the incidence within HD populations has not been precisely defined. Robust incidence estimates of suicidal behavior can serve as references for HD therapeutic research and post-marketing surveillance to help evaluate the suicidality risk of novel therapeutics. Aims To estimate the incidence rate of completed suicide and suicide attempt in the global, prospective HD cohort study Enroll-HD that records these events per protocol. Method A total of 20 912 participants were available for analysis (HD gene-expansion carriers (HDGECs) n = 15 924; non-HDGECs n = 4988) representing a collective observation period of 53 390 participant-years. Each observed event was subject to clinical review and evaluation. We generated incidence rates (events per 100 000 person-years) for suicides and suicide attempts using all available data, as well as by year of study and geographical region. Proportionate mortality statistics for suicide and respective 95% confidence intervals were also generated. Results The overall incidence rate of suicide in HDGECs was 72 per 100 000 person-years, and 8 per 100 000 person-years in non-HDGECs. Proportionate mortality attributable to suicide in HDGECs was 4.6%. For suicide attempts, the global overall incidence rate observed in HDGECs was 306–375 per 100 000 person-years, and 23–38 per 100 000 person-years in non-HDGECs. Conclusions The incidence estimates calculated here can be used as a reference to help evaluate drug safety and may also be useful in assessing progress in clinical care for HDGECs once therapeutic interventions become widely available.

Huntington's disease (HD) is an autosomal-dominant inherited neurodegenerative disorder that is caused by expansion of a CAG-repeat tract in the huntingtin gene and characterized by motor impairment, cognitive decline, and neuropsychiatric disturbances. Neuropathological studies show that disease progression follows a characteristic pattern of brain atrophy, beginning in the basal ganglia structures. The HD Regulatory Science Consortium (HD-RSC) brings together diverse stakeholders in the HD community—biopharmaceutical industry, academia, nonprofit, and patient advocacy organizations—to define and address regulatory needs to accelerate HD therapeutic development. Here, the Biomarker Working Group of the HD-RSC summarizes the cross-sectional evidence indicating that regional brain volumes, as measured by volumetric magnetic resonance imaging, are reduced in HD and are correlated with disease characteristics. We also evaluate the relationship between imaging measures and clinical change, their longitudinal change characteristics, and within-individual longitudinal associations of imaging with disease progression. This analysis will be valuable in assessing pharmacodynamics in clinical trials and supporting clinical outcome assessments to evaluate treatment effects on neurodegeneration.

Established in July 2012, Enroll-HD is both an integrated clinical research platform and a worldwide observational study designed to meet the clinical research requirements necessary to develop therapeutics for Huntington's disease (HD). The platform offers participants a low-burden entry into HD research, providing a large, well-characterized, research-engaged cohort with associated clinical data and biosamples that facilitates recruitment into interventional trials and other research studies. Additional studies that use Enroll-HD data and/or biosamples are built into the platform to further research on biomarkers and outcome measures. Enroll-HD is now operating worldwide in 21 countries at 159 clinical sites across four continents—Europe, North America, Latin America, and Australasia—and has recruited almost 25,000 participants, generating a large, rich clinical database with associated biosamples to expedite HD research; any researcher at a verifiable research organization can access the clinical datasets and biosamples from Enroll-HD and nested studies. Important operational features of Enroll-HD include a strong emphasis on standardization, data quality, and protecting participant identity, a single worldwide study protocol, a flexible EDC system capable of integrating multiple studies, a comprehensive monitoring infrastructure, an online portal to train and certify site personnel, and standardized study documents including informed consent forms and contractual agreements.

Introduction: An understanding of the clinimetric properties of clinical assessments, including their constraints, is critical to sound clinical study and trial design. Utilizing data from Enroll-HD—a global, prospective HD observational study and clinical research platform—we examined several well-established HD clinical assessments across all stages of disease for evidence of instrument constraints, specifically floor/ceiling effects, to inform selection of appropriate instruments for use in future studies/trials and identify gaps in instrument utility over the life-course of the disease.Material and Methods: Analyzing publicly available data from 6,614 HD gene-expansion carriers (HDGECs), we grouped participants into deciles based on baseline CAP score, which ranged from 26 to 229. We used descriptive statistics to characterize data distribution for 25 outcome measures (encompassing motor, function, cognition, and psychiatric/behavioral domains) in each CAP decile. A skewness statistic threshold of ±2 was defined a priori to indicate floor/ceiling effects.Results: We found evidence of floor/ceiling effects in the early premanifest stages of disease for most motor and function assessments (e.g., TMS, TFC) and select cognitive tasks (MMSE, Trail Making tests). Other cognitive assessments, and the HADS-SIS scales, performed well ubiquitously, with no evidence of floor/ceiling effects at any disease stage. Floor/ceiling effects were evident at every disease stage for certain assessments, including PBA-s measures. Ceiling effects were apparent for DCL from onset stages onwards, as expected.Discussion: Developing instruments sensitive to subtle differences in performance at the earlier stages of the disease spectrum, particularly in motor and function domains, is warranted.

In Huntington's disease (HD), accurate estimates of expected future motor impairments are key for clinical trials. Individual prognosis is only partially explained by genetics. However, studies so far have focused on predicting the time to clinical diagnosis based on fixed impairment levels, as opposed to predicting impairment in time windows comparable to the duration of a clinical trial. Here we evaluate an approach to both detect atrophy patterns associated with early degeneration and provide a prognosis of motor impairment within 3 years, using data from the TRACK-HD study on 80 premanifest HD (pre-HD) individuals and 85 age- and sex-matched healthy controls. We integrate anatomical MRI information from gray matter concentrations (estimated via voxel-based morphometry) together with baseline data from demographic, genetic and motor domains to distinguish individuals at high risk of developing pronounced future motor impairment from those at low risk. We evaluate the ability of models to distinguish between these two groups solely using baseline imaging data, as well as in combination with longitudinal imaging or non-imaging data. Our models show improved performance for motor prognosis through the incorporation of imaging features to non-imaging data, reaching 88% cross-validated accuracy when using baseline non-longitudinal information, and detect informative correlates in the caudate nucleus and the thalamus both for motor prognosis and early atrophy detection. These results show the plausibility of using baseline imaging and basic demographic/genetic measures for early detection of individuals at high risk of severe future motor impairment in relatively short timeframes. Keywords: Future motor impairment prediction, Premanifest Huntington's disease, Classification, Structural MRI, TRACK-HD

Bladder cancer (BC), the most frequent malignancy of the urinary system, is ranked the sixth most prevalent cancer worldwide. Of all newly diagnosed patients with BC, 70–75% will present disease confined to the mucosa or submucosa, the non-muscle-invasive BC (NMIBC) subtype. Of those, approximately 70% will recur after transurethral resection (TUR). Due to high rate of recurrence, patients are submitted to an intensive follow-up program maintained throughout many years, or even throughout life, resulting in an expensive follow-up, with cystoscopy being the most cost-effective procedure for NMIBC screening. Currently, the gold standard procedure for detection and follow-up of NMIBC is based on the association of cystoscopy and urine cytology. As cystoscopy is a very invasive approach, over the years, many different noninvasive assays (both based in serum and urine samples) have been developed in order to search genetic and protein alterations related to the development, progression, and recurrence of BC. TERT promoter mutations and FGFR3 hotspot mutations are the most frequent somatic alterations in BC and constitute the most reliable biomarkers for BC. Based on these, we developed an ultra-sensitive, urine-based assay called Uromonitor®, capable of detecting trace amounts of TERT promoter (c.1-124C > T and c.1-146C > T) and FGFR3 (p.R248C and p.S249C) hotspot mutations, in tumor cells exfoliated to urine samples. Cells present in urine were concentrated by the filtration of urine through filters where tumor cells are trapped and stored until analysis, presenting long-term stability. Detection of the alterations was achieved through a custom-made, robust, and highly sensitive multiplex competitive allele-specific discrimination PCR allowing clear interpretation of results. In this study, we validate a test for NMIBC recurrence detection, using for technical validation a total of 331 urine samples and 41 formalin-fixed paraffin-embedded tissues of the primary tumor and recurrence lesions from a large cluster of urology centers. In the clinical validation, we used 185 samples to assess sensitivity/specificity in the detection of NMIBC recurrence vs. cystoscopy/cytology and in a smaller cohort its potential as a primary diagnostic tool for NMIBC. Our results show this test to be highly sensitive (73.5%) and specific (93.2%) in detecting recurrence of BC in patients under surveillance of NMIBC.

The costly and burdensome nature of the current follow-up methods in non-muscle-invasive bladder cancer (NMIBC) drives the development of new methods that may alternate with regular cystoscopy and urine cytology. The Uromonitor-V2® is a new urine-based assay in the detection of hotspot mutations in three genes (TERT, FGFR3, and KRAS) for evaluation of disease recurrence. The aim of this study was to investigate the Uromonitor-V2®’s performance in detecting NMIBC recurrence and compare it with urine cytology. From February 2018 to September 2019 patients were enrolled. All subjects underwent a standard-of-care (SOC) cystoscopy, either as part of their follow-up for NMIBC or for a nonmalignant urological pathology. Urine cytology was performed in NMIBC patients. Out of the 105 patients enrolled, 97 were eligible for the study. Twenty patients presented nonmalignant lesions, 29 had a history of NMIBC with disease recurrence, and 49 had a history of NMIBC without recurrence. In NMIBC, the Uromonitor-V2® displayed a sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 93.1%, 85.4%, 79.4%, and 95.3%, respectively. Urine cytology was available for 52 patients, and the sensitivity, specificity, PPV, and NPV were 26.3%, 90.9%, 62.5%, and 68.2%, respectively. With its high NPV of 95.3%, the Uromonitor-V2® revealed promising properties for the follow-up of patients with NMIBC.

Background: Psychotic symptoms have been under-investigated in Huntington's disease (HD) and research is needed in order to elucidate the characteristics linked to the unique phenotype of HD patients presenting with psychosis.Objective: To evaluate the frequency and factors associated with psychosis in HD.Methods: Cross-sectional study including manifest individuals with HD from the Enroll-HD database. Both conventional statistical analysis (Stepwise Binary Logistic Regression) and five machine learning algorithms [Least Absolute Shrinkage and Selection Operator (LASSO); Elastic Net; Support Vector Machines (SVM); Random Forest; and class-weighted SVM] were used to describe factors associated with psychosis in manifest HD patients.Results: Approximately 11% of patients with HD presented history of psychosis. Logistic regression analysis indicated that younger age at HD clinical diagnosis, lower number of CAG repeats, history of [alcohol use disorders, depression, violent/aggressive behavior and perseverative/obsessive behavior], lower total functional capacity score, and longer time to complete trail making test-B were associated with psychosis. All machine learning algorithms were significant (chi-square p < 0.05) and capable of distinguishing individual HD patients with history of psychosis from those without a history of psychosis with prediction accuracy around 71–73%. The most relevant variables were similar to those found in the conventional analyses.Conclusions: Psychiatric and behavioral symptoms as well as poorer cognitive performance were related to psychosis in HD. In addition, psychosis was associated with lower number of CAG repeats and younger age at clinical diagnosis of HD, suggesting that these patients may represent a unique phenotype in the HD spectrum.

SDHD promoter mutations were reported in 4-10% of cutaneous melanomas. The advanced clinico-pathological and patient survival association with SDHD mutation and/or expression in cutaneous melanoma remains controversial.To evaluate the presence of SDHD promoter mutations and SDHD protein expression in a melanoma series and its possible association with prognosis and survival of the patients.We assessed SDHD promoter status in cutaneous melanomas (CM), ocular melanomas (OM) and melanoma cell lines, and the expression of SDHD protein by immunohistochemistry in CM and OM, and by western blot in melanoma cell lines. We explored the putative association between SDHD protein expression and clinico-pathological and prognostic parameters of melanoma.We detected 2% of SDHD promoter mutations in CM, but none in OM and cell lines. SDHD protein expression was present in all CM, in OM and in all CM and OM derived cell lines analysed. A significant association between lower SDHD mean protein expression and presence of ulceration and higher pT stage was found.SDHD promoter mutation seems to be a rare event in CM but SDHD lower expression might associate with worst prognostic features in CM.

Este artigo responde à seguinte questão de pesquisa: Por que - e como - o habitante não se protege do dengue, embora conheça exaustivamente os modos de procriação do mosquito e as técnicas para impedir que isso aconteça? O método consistiu na análise dos anúncios do governo feitos na televisão local, análise do conteúdo das campanhas públicas de informação de proteção contra o dengue e pesquisa qualitativa com a população local para determinar razões e motivos de abandono de medidas conhecidamente protetivas contra o dengue. Confirmou-se a hipótese inicial de que as medidas de proteção formam um conjunto complexo e variável de ações a serem freqüentemente repetidas, tão complexo e tão freqüente que não permite priorizar adequadamente as medidas contra a doença, além disso, isso ocorrendo num universo cheio de outras doenças consideradas mais graves. Embora a Saúde seja uma incumbência constitucional do Estado, faz-se a população de agente de sua própria proteção. Isso é muito ineficiente e altamente incivilizado. A população civil e pobre não serve como agente de proteção contra o dengue. Palavras-chave: Dengue. Campanha de prevenção. Aedes aeyptii. It was intended, in this study, to reflect about the ways of looking at and also of understanding the dengue case, considering it a complex phenomenon inside the logical perspective from the programs that support it. In order to reflect about this question, we tried to comprehend the popular behavior changes in the prevention campaigns and dengue control, besides analyzing the built representations about health notion, vector and disease. Through a research performed in Montes Claros,we tried to answer, specially, why the population cannot protect itself properly from the disease, getting constantly infected, even when the inhabitants seem to know well enough the prevention measures. Keywords: Dengue. Prevention campaigns. Aedes aegyptii.

Faz-se a apresentação do modelo experimental da doença de Parkinson, desenvolvido a partir do momentoem que se constatou que um derivado sintético da heroína — o MPTP — provoca nos humanos, um quadro semelhante ao da doença idiopática.Discute-se o mecanismo de acção do MPTP e as implicações que este fenómeno tem no processo da descoberta de um factor etiológico para a doença de Parkinson. Finalmente discutem-se as perspectivas terapêuticas abertas pela exploração do modelo experimental do MPTP.