Efficacy and Safety of Filgotinib for the Treatment of Perianal Fistulizing Crohn's Disease [DIVERGENCE 2]: a Phase 2, Randomized, Placebo-Controlled Trial.

BACKGROUND AND AIMS: There is an unmet need for the treatment of perianal fistulizing Crohn's disease [PFCD]. This study evaluated the efficacy and safety of the Janus kinase 1 preferential inhibitor filgotinib, for the treatment of PFCD. METHODS: This phase 2, double-blind, multicentre trial enrolled adults with PFCD and prior treatment failure. Participants were randomized [2:2:1] to receive filgotinib 200 mg, filgotinib 100 mg, or placebo once-daily orally for up to 24 weeks. The primary endpoint was combined fistula response [reduction from baseline of at least one draining external opening determined by physical assessment, and no fluid collections >1 cm on pelvic magnetic resonance imaging (MRI)] at week 24. RESULTS: Between April 2017 and July 2020, 106 individuals were screened and 57 were randomized. Discontinuations were lowest in the filgotinib 200 mg group [3/17 (17.6%) versus 13/25 (52.0%) for filgotinib 100 mg and 9/15 (60.0%) for placebo]. The proportion of participants who achieved a combined fistula response at week 24 was 47.1% [8/17; 90% confidence interval (CI) 26.0, 68.9%] in the filgotinib 200 mg group, 29.2% [7/24; 90% CI 14.6, 47.9%] in the filgotinib 100 mg group, and 25.0% [3/12; 90% CI 7.2, 52.7%] in the placebo group. Serious adverse events occurred more frequently with filgotinib 200 mg [5/17 (29.4%)] than with placebo [1/15 (6.7%)]. There were no treatment-related serious adverse events or deaths. CONCLUSIONS: Filgotinib 200 mg was associated with numerical reductions in the number of draining perianal fistulas based on combined clinical and MRI findings compared with placebo, and was generally well tolerated. [NCT03077412].

Validation of the Thai Version of the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale.

OBJECTIVE: This study aims to validate the Thai translation of the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS). METHODS: The English version was translated into Thai and then back-translated into English. The translated version underwent 2 rounds of cognitive pretesting to assess the ease of comprehension, ease of use and comfort with the scale. Then, it underwent large clinimetric testing. RESULTS: The Thai version was validated in 354 PD patients. The comparative fit index (CFI) for all four parts of the Thai version of the MDS-UPDRS was 0.93 or greater. Exploratory factor analysis identified isolated item differences in factor structure between the Thai and English versions. CONCLUSION: The overall factor structure of the Thai version was consistent with that of the English version based on the high CFIs (all CFI ≥ 0.90). Hence, it can be designated the official Thai version of the MDS-UPDRS.

Parents' parenting styles differences are associated with lifetime suicidal ideation: Evidence from Chinese medical college students.

This study aims to explore the association between parents parenting styles differences and lifetime suicidal ideation (LSI). The sample included 2598 Chinese medical students. Results showed that 10.5% of students reported LSI. Moreover, total differences in parenting styles (OR = 1.04, 95% CI = 1.02, 1.06), parental nurture rejects differences (OR = 1.11, 95% CI = 1.04, 1.18), parental emotional warmth differences (OR = 1.08, 95% CI = 1.03, 1.14), and parental overprotective differences (OR = 1.11, 95% CI = 1.06, 1.16), obtain a scholarship, physical disease and mental health were associated with LSI. The major finding reminds us of the importance of consistent parenting style for suicide prevention.

Dynamic prediction using joint models of longitudinal and recurrent event data: A Bayesian perspective.

In cardiovascular disease (CVD) studies, the events of interest may be recurrent (multiple occurrences from the same individual). During the study follow-up, longitudinal measurements are often available and these measurements are highly predictive of event recurrences. It is of great clinical interest to make personalized prediction of the next occurrence of recurrent events using the available clinical information, because it enables clinicians to make more informed and personalized decisions and recommendations. To this end, we propose a joint model of longitudinal and recurrent event data. We develop a Bayesian approach for model inference and a dynamic prediction framework for predicting target subjects' future outcome trajectories and risk of next recurrent event, based on their data up to the prediction time point. To improve computation efficiency, embarrassingly parallel MCMC (EP-MCMC) method is utilized. It partitions the data into multiple subsets, runs MCMC sampler on each subset, and applies random partition trees to combine the posterior draws from all subsets. Our method development is motivated by and applied to the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), one of the largest CVD studies to compare the effectiveness of medications to treat hypertension.

Prognostic Modeling of Parkinson's Disease Progression Using Early Longitudinal Patterns of Change.

BACKGROUND: Predicting Parkinson's disease (PD) progression may enable better adaptive and targeted treatment planning. OBJECTIVE: Develop a prognostic model using multiple, easily acquired longitudinal measures to predict temporal clinical progression from Hoehn and Yahr (H&Y) stage 1 or 2 to stage 3 in early PD. METHODS: Predictive longitudinal measures of PD progression were identified by the joint modeling method. Measures were extracted by multivariate functional principal component analysis methods and used as covariates in Cox proportional hazards models. The optimal model was developed from the Parkinson's Progression Marker Initiative (PPMI) data set and confirmed with external validation from the Longitudinal and Biomarker Study in PD (LABS-PD) study. RESULTS: The proposed prognostic model with longitudinal information of selected clinical measures showed significant advantages in predicting PD temporal progression in comparison to a model with only baseline information (iAUC = 0.812 vs. 0.743). The modeling results allowed the development of a prognostic index for categorizing PD patients into low, mid, and high risk of progression to HY 3 that is offered to facilitate physician-patient discussion on prognosis. CONCLUSION: Incorporating longitudinal information of multiple clinical measures significantly enhances predictive performance of prognostic models. Furthermore, the proposed prognostic index enables clinicians to classify patients into different risk groups, which could be adaptively updated as new longitudinal information becomes available. Modeling of this type allows clinicians to utilize observational data sets that inform on disease natural history and specifically, for precision medicine, allows the insertion of a patient's clinical data to calculate prognostic estimates at the individual case level. © 2021 International Parkinson and Movement Disorder Society.

Validation of the Polish version of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS).

BACKGROUND: In 2008, the Movement Disorders Society (MDS) published a new Unified Parkinson's Disease Rating Scale (MDS-UPDRS) as the official benchmark scale for Parkinson's Disease (PD). We have translated and validated the Polish version of the MDS-UPDRS, explored its dimensionality, and compared it to the original English one. METHODS: The MDS-UPDRS was translated into Polish by a team of Polish investigators led by JS and GO. The back-translation was completed by colleagues fluent in both languages (Polish and English) who were not involved in the original translation, and was reviewed by members of the MDS Rating Scales Programme. Then the translated version of the MDS-UPDRS underwent cognitive pretesting, and the translation was modified based on the results. The final translation was approved as the Official Working Document of the MDS-UPDRS Polish version, and was tested on 355 Polish PD patients recruited at movement disorders centres all over Poland (at Katowice, Gdansk, Lódz, Warsaw, Wroclaw, and Kraków). Confirmatory and explanatory factor analyses were applied to determine whether the factor structure of the English version could be confirmed in the Polish version. RESULTS: The Polish version of the MDS-UPDRS showed satisfactory clinimetric properties. The internal consistency of the Polish version was satisfactory. In the confirmatory factor analysis, all four parts had greater than 0.90 comparative fit index (CFI) compared to the original English MDS-UPDRS. Explanatory factor analysis suggested that the Polish version differed from the English version only within an acceptable range. CONCLUSIONS AND CLINICAL IMPLICATIONS: The Polish version of the MDS-UPDRS meets the requirements to be designated as the Official Polish Version of the MDS-UPDRS, and is available on the MDS web page. We strongly recommend using the MDS-UPDRS instead of the UPDRS for research purposes and in everyday clinical practice.

Validation of the Hebrew Version of the Unified Dyskinesia Rating Scale.

BACKGROUND: The Unified Dyskinesia Rating Scale (UDysRS) is a well-established tool for producing comprehensive assessments of severity and disability associated with dyskinesia in patients with Parkinson's disease (PD). The scale was originally developed in English, and a broad international effort has been undertaken to develop and validate versions in additional languages. Our aim was to validate the Hebrew version of the UDysRS. METHODS: We translated the UDysRS into Hebrew, back-translated it into English, and carried out cognitive pretesting. We then administered the scale to non-demented native Hebrew-speaking patients who fulfilled the Brain Bank diagnostic criteria for probable PD (n = 250). Data were compared to the Reference Standard data used for validating UDysRS translations. RESULTS: The different portions of the Hebrew UDysRS showed high internal consistency (α ≥ 0.92). A confirmatory factor analysis in which we compared the Hebrew UDysRS to the Reference Standard version produced a comparative fit index (CFI) of 0.98, exceeding the threshold criterion of CFI > 0.9 indicating factor validity. A secondary exploratory factor analysis provided further support to the consistency between the factor structures of the Hebrew and Reference Standard versions of the UDysRS. CONCLUSION: The UDysRS Hebrew version shows strong clinimetric properties and fulfills the criteria for designation as an official International Parkinson and Movement Disorder Society-approved translation for use in clinical and research settings.

Successful use of the Unified Dyskinesia Rating Scale regardless of PD- or dyskinesia-duration.

OBJECTIVE: We assessed differential item functioning (DIF) in the Unified Dyskinesia Rating Scale (UDysRS) to evaluate bias risk from the duration of Parkinson's Disease (PD) and duration of dyskinesia. BACKGROUND: Assessing DIF is a core validation step for rating scales. If DIF is present for an item, interpretation must consider influences from the tested covariates. DIF can be uniform or non-uniform, depending on the consistency of influence from the given covariate across all levels of dyskinesia. METHODS: Using a large UDysRS database (N = 2313), uniform and non-uniform DIF related to the duration of PD and/duration of dyskinesia were tested. Unidimensionality of UDysRS was first confirmed using confirmatory factor analysis. DIF analysis was conducted using two independent latent models. DIF in an item was confirmed if both methods independently identified DIF at a significance level using Bonferroni correction. McFadden pseudo R^2 measured clinical relevancy of DIF magnitude (negligible, moderate, and large) for items identified with DIF, and items with DIF were considered clinically relevant if they exceeded a negligible designation. RESULTS: Most items did not show uniform or non-uniform DIF based on PD and dyskinesia duration in isolation or in combination. For all items where DIF was identified, the magnitude statistic was in the negligible range (McFadden pseudo R^2 < 0.035) and the combined impact of multiple identified DIF items on UDysRS likewise did not exceed the negligible designation. CONCLUSION: The absence of clinically relevant DIF suggests that the UDysRS can be applied across all patients regardless of their PD- or dyskinesia-duration.

Missing Data in the Unified Dysksinesia Rating Scale (UDysRS).

OBJECTIVE: Identify the number of allowable missing values still permitting valid surrogate score calculation for the Unified Dyskinesia Rating Scale (UDysRS). BACKGROUND: Missing data frequently occur in Parkinson's disease rating scales, and they compromise data validity, risking data exclusion from final analyses. METHODS: Accessing the International Parkinson and Movement Disorder Society-sponsored UDysRS translation databases (3313 complete scores). We sequentially removed item scores, consistently or randomly from subjective and objective sections. Lin's Concordance Correlation Coefficient compared prorated scores with complete scores. We considered prorated scores valid when Coefficients exceeded 0.95. RESULTS: For consistently missing items, three from the subjective section and five from the objective section are allowable. For randomly missing items, seven from the subjective section and four from the objective section are permissible. CONCLUSIONS: We provide guidelines for constructing valid surrogate summary UDysRS scores with clear thresholds for retaining or rejecting scores based on missing values.

Predictors of weight loss in early treated Parkinson's disease from the NET-PD LS-1 cohort.

Weight loss is a common symptom of Parkinson's disease and is associated with impaired quality of life. Predictors of weight loss have not been studied in large clinical cohorts. We previously observed an association between change in body mass index and change in Unified Parkinson's Disease Rating Scale (UPDRS) motor and total scores. In this study, we performed a secondary analysis of longitudinal data (1-6 years) from 1619 participants in the NINDS Exploratory Trials in PD Long-term Study-1 (NET-PD LS1) to explore predictors of weight loss in a large prospective clinical trial cohort of early treated Parkinson's disease. The NET-PD LS1 study was a double-blind randomized placebo controlled clinical trial of creatine monohydrate 10 gm/day in early treated PD (within 5 years of diagnosis and within 2 years of starting dopaminergic medications). Linear mixed models were used to estimate the effect of baseline clinical covariates on weight change over time. On average, participants lost only 0.6 kg per year. Higher age, baseline weight, female gender, higher baseline UPDRS scores, greater postural instability, difficulty eating and drinking, lower cognitive scores and baseline levodopa use (compared to dopamine agonists) were all associated with weight loss. Surprisingly baseline difficulty swallowing, dyskinesia, depression, intestinal hypomotility (constipation) and self-reported nausea/vomiting/anorexia were not significantly associated with weight loss in this cohort of early treated Parkinson's disease patients. On average, participants with Parkinson's disease experience little weight loss during the first 1-6 years after starting dopaminergic replacement therapy, however levodopa use and postural instability were both predictors of early weight loss. Trial Registration clinicaltrials.gov identifier# NCT00449865.

Longer Duration of MAO-B Inhibitor Exposure is Associated with Less Clinical Decline in Parkinson's Disease: An Analysis of NET-PD LS1.

BACKGROUND: Monoamine oxidase type B (MAO-B) inhibitors exhibit neuroprotective effects in preclinical models of PD but clinical trials have failed to convincingly demonstrate disease modifying benefits in PD patients. OBJECTIVE: To perform a secondary analysis of NET-PD LS1 to determine if longer duration of MAO-B inhibitor exposure was associated with less clinical decline. METHODS: The primary outcome measure was the Global Outcome (GO), comprised of 5 measures: change from baseline in the Schwab and England (ADL) scale, the 39-item Parkinson's Disease Questionnaire (PDQ-39), the UPDRS Ambulatory Capacity Scale, the Symbol Digit Modalities Test, and the most recent Modified Rankin Scale. A linear mixed model was used to explore the association between the cumulative duration of MAO-B inhibitor exposure and the GO, adjusting for necessary factors and confounders. Associations between MAO-B inhibitor exposure and each of the five GO components were then studied individually. RESULTS: 1616 participants comprised the analytic sample. Mean observation was 4.1 (SD = 1.4) years, and 784 (48.5%) participants received an MAO-B inhibitor. The regression coefficient of cumulative duration of MAO-B inhibitor exposure (in years) on the GO was - 0.0064 (SE = 0.002, p = 0.001). Significant associations between duration of MAO-B inhibitor exposure and less progression were observed for ADL (p < 0.001), Ambulatory Capacity (p < 0.001), and the Rankin (p = 0.002). CONCLUSIONS: Our analysis identified a significant association between longer duration of MAO-B inhibitor exposure and less clinical decline. These findings support the possibility that MAO-B inhibitors slow clinical disease progression and suggest that a definitive prospective trial should be considered.