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When no single outcome is sufficient to capture the multidimensional impairments of a disease, investigators often rely on multiple outcomes for comprehensive assessment of global disease status. Methods for assessing covariate effects on global disease status include the composite outcome and global test procedures. One global test procedure is the O'Brien's rank-sum test, which combines information from multiple outcomes using a global rank-sum score. However, existing methods for the global rank-sum do not lend themselves to regression modeling. We consider sensible regression strategies for the global percentile outcome (GPO), under the transformed linear model and the monotonic index model. Posing minimal assumptions, we develop estimation and inference procedures that account for the special features of the GPO. Asymptotics are established using U-statistic and U-process techniques. We illustrate the practical utilities of the proposed methods via extensive simulations and application to a Parkinson's disease study.

Study objective The transfusion of older packed RBCs may be harmful in critically ill patients. We seek to determine the association between packed RBC age and mortality among trauma patients requiring massive packed RBC transfusion. Methods We analyzed data from the Pragmatic, Randomized Optimal Platelet and Plasma Ratios trial. Subjects in the parent trial included critically injured adult patients admitted to 1 of 12 North American Level I trauma centers who received at least 1 unit of packed RBCs and were predicted to require massive blood transfusion. The primary exposure was volume of packed RBC units transfused during the first 24 hours of hospitalization, stratified by packed RBC age category: 0 to 7 days, 8 to 14 days, 15 to 21 days, and greater than or equal to 22 days. The primary outcome was 24-hour mortality. We evaluated the association between transfused volume of each packed RBC age category and 24-hour survival, using random-effects logistic regression, adjusting for total packed RBC volume, patient age, sex, race, mechanism of injury, Injury Severity Score, Revised Trauma Score, clinical site, and trial treatment group. Results The 678 patients included in the analysis received a total of 8,830 packed RBC units. One hundred patients (14.8%) died within the first 24 hours. On multivariable analysis, the number of packed RBCs greater than or equal to 22 days old was independently associated with increased 24-hour mortality (adjusted odds ratio [OR] 1.05 per packed RBC unit; 95% confidence interval [CI] 1.01 to 1.08): OR 0.97 for 0 to 7 days old (95% CI 0.88 to 1.08), OR 1.04 for 8 to 14 days old (95% CI 0.99 to 1.09), and OR 1.02 for 15 to 21 days old (95% CI 0.98 to 1.06). Results of sensitivity analyses were similar only among patients who received greater than or equal to 10 packed RBC units. Conclusion Increasing quantities of older packed RBCs are associated with increased likelihood of 24-hour mortality in trauma patients receiving massive packed RBC transfusion (≥10 units), but not in those who receive fewer than 10 units.

Background Cluster randomized trials are designed to evaluate interventions at the cluster or group level. When clusters are randomized but some clusters report no or non-analyzable data, intent-to-treat analysis, the gold standard for the analysis of randomized controlled trials, can be compromised. This article presents a very flexible statistical methodology for cluster randomized trials whose outcome is a cluster-level proportion (e.g. proportion from a cluster reporting an event) in the setting where clusters report non-analyzable data (which in general could be due to nonadherence, dropout, missingness, etc.). The approach is motivated by a previously published stratified randomized controlled trial called, “The Randomized Recruitment Intervention Trial (RECRUIT),” designed to examine the effectiveness of a trust-based continuous quality improvement intervention on increasing minority recruitment into clinical trials (ClinicalTrials.gov Identifier: NCT01911208). Methods The novel approach exploits the use of generalized estimating equations for cluster-level reports, such that all clusters randomized at baseline are able to be analyzed, and intervention effects are presented as risk ratios. Simulation studies under different outcome missingness scenarios and a variety of intra-cluster correlations are conducted. A comparative analysis of the method with imputation and per protocol approaches for RECRUIT is presented. Results Simulation results show the novel approach produces unbiased and efficient estimates of the intervention effect that maintain the nominal type I error rate. Application to RECRUIT shows similar effect sizes when compared to the imputation and per protocol approach. Conclusion The article demonstrates that an innovative bivariate generalized estimating equations framework allows one to implement an intent-to-treat analysis to obtain risk ratios or odds ratios, for a variety of cluster randomized designs.

While extensive literature exists on barriers and strategies to increase minority participation in clinical trials, progress is limited. Few strategies were evaluated in randomized trials. We studied the impact of RECRUIT, a trust-based, cluster randomized minority recruitment trial layered on top of four traditional NIH-funded parent trials (BMT CTN, CABANA, PACES, STEADY-PD III; fifty specialty sites). RECRUIT was conducted from July 2013 through April 2017. Intervention sites implemented trust-based approaches customized to individual sites, promoting relationships between physician-investigators and minority-serving physicians and their minority patients. Control sites implemented only parent trials' recruitment procedures. Adjusting for within-site clustering, we detected no overall intervention effect, odds ratio 1.3 (95% confidence limits 0.7,2.4). Heterogeneity among parent trials may have obscured the effect. Of the four parent trials, three enrolled more minorities in intervention versus control sites. CABANA odds ratio = 4.2 (adjusted 95%CL 1.5,11.3). PACES intervention sites enrolled 63% (10/16) minorities; control sites enrolled one participant in total, a minority, yielding an incalculable odds ratio. STEADY-PD III odds ratio = 2.2 (adjusted 95%CL 0.6,8.5). BMT CTN odds ratio 1, 0.8 (adjusted 95%CL 0.4,1.8). In conclusion, RECRUIT findings suggest the unique trust-based intervention increased minority recruitment to intervention trials in ¾ of studied trials. Physician-investigators' participation was critical to recruitment success. Lack of commitment to minority recruitment remained a barrier for some physician-investigators, especially in control sites. We recommend prospective physician investigators commit to minority recruitment activities prior to selection as site investigators and trial funding include some compensation for minority recruitment efforts. TRIAL REGISTRATION ClinicalTrials.govNCT01911208.

Parkinson disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms and signs. Many reports suggest that diminished heart rate variability occurs early, even prior to the cardinal signs of PD. In a longitudinal study of PD, we evaluated whether heart rate variability (HRV) obtained using a 10 second ECG tracing, and the electrocardiographic QT-interval would be associated with PD severity and progression. Subjects were derived from a longitudinal study of 1741 individuals with early, stable PD. The severity of PD was measured using the global statistical test (GST). In a subset, the heart rate corrected QT-interval (QTcB) was calculated for each electrocardiogram (ECG). The HRV was measured for each ECG and then transformed to fit a normal distribution. The baseline analysis included 653 subjects, with 256 completing the 5-year follow up study. There was an association (P

Rationale Mobile stroke units speed treatment for acute ischemic stroke, thereby possibly improving outcomes. Aim To compare mobile stroke unit and standard management clinical outcomes, healthcare utilization, and cost-effectiveness in tissue plasminogen activator-eligible acute ischemic stroke patients calling 911. Sample size 693. Eighty percent power with 0.05 type I error rate to detect a difference of 0.09 in mean utility-weighted modified Rankin scale between groups. Design Phase III, multicenter, prospective cluster-randomized (mobile stroke unit versus standard management weeks) comparative effectiveness study in tissue plasminogen activator-eligible patients. Outcomes Primary: Ninety-day mean utility-weighted modified Rankin scale. Coprimary: cost-effectiveness based on EQ5D quality of life and one year poststroke costs. Analysis Two-sample t-test and linear regression adjusting for covariates; incremental cost-effectiveness ratio and net benefit regression. Results As of March 2017, 288 tissue plasminogen activator-eligible patients have been enrolled (173 in the mobile stroke unit arm and 115 in the standard management arm). Two new centers start in early 2017 with target end of recruitment September 2019. Conclusion This is the first randomized study to test for disability, healthcare utilization, and cost-effectiveness of a mobile stroke unit. The progress of the study suggests that it is feasible. Management of tissue plasminogen activator eligible acute ischemic stroke patients by a mobile stroke unit could potentially result in less disability and healthcare utilization, and be cost effective. Mobile stroke units are very costly. This trial may determine if the fixed cost can be justified by a reduction in disability and healthcare utilization. Clinical Trial Registration NCT02190500.

Choosing the appropriate endpoint for a trauma hemorrhage control trial can determine the likelihood of its success. Recent Phase 3 trials and observational studies have used 24-h and/or 30-day all-cause mortality as the primary endpoint and some have not used exception from informed consent (EFIC), resulting in multiple failed trials. Five recent high-quality prospective studies among 4,064 hemorrhaging trauma patients provide new evidence to support earlier primary endpoints.The goal of this project was to determine the optimal endpoint for hemorrhage control trials using existing literature and new analyses of previously published data.Recent studies among bleeding trauma patients show that hemorrhagic deaths occur rapidly, at a high rate, and in a consistent pattern. Early preventable deaths among trauma patients are largely due to hemorrhage and the median time to hemorrhagic death from admission is 2.0 to 2.6 h. Approximately 85% of hemorrhagic deaths occur within 6 h. The hourly mortality rate due to traumatic injury decreases rapidly after enrollment from 4.6% per hour at 1 hour postenrollment to 1% per hour at 6 h to 0.1% per hour by 9 h and thereafter. Early primary endpoints (within 6 h) have critically important benefits for hemorrhage control trials, including being congruent with the median time to hemorrhagic death, biologic plausibility, and enabling the use of all-cause mortality, which is definitive and objective.Primary endpoints should be congruent with the timing of the disease process. Therefore, if a resuscitation/hemorrhage control intervention is under study, a primary endpoint of all-cause mortality evaluated within the first 6 h is appropriate. Before choosing the timing of the primary endpoint for a large multicenter trial, we recommend performing a Phase 2 trial under EFIC to better understand the effects of the hemorrhage control intervention and distribution of time to death. When early primary endpoints are used, patients should be monitored for multiple subsequent secondary safety endpoints, including 24 h and 30-day all-cause mortality as well as the customary safety endpoints.

Caffeine is neuroprotective in animal models of PD and caffeine intake is inversely associated with the risk of Parkinson’s disease (PD). This association may be influenced by the genotype of GRIN2A, which encodes an NMDA-glutamate-receptor subunit. In two placebo-controlled studies, we detected no association of caffeine intake with the rate of clinical progression of PD, except among subjects taking creatine, for whom higher caffeine intake was associated with more rapid progression. We now have analyzed data from 420 subjects for whom DNA samples and caffeine intake data were available from a placebo-controlled study of creatine in PD. The GRIN2A genotype was not associated with the rate of clinical progression of PD in the placebo group. However, there was a 4-way interaction between GRIN2A genotype, caffeine, creatine and the time since baseline. Among subjects in the creatine group with high levels of caffeine intake, but not among those with low caffeine intake, the GRIN2A T allele was associated with more rapid progression (p = 0.03). These data indicate that the deleterious interaction between caffeine and creatine with respect to rate of progression of PD is influenced by GRIN2A genotype. This example of a genetic factor interacting with environmental factors illustrates the complexity of gene-environment interactions in the progression of PD.

Background: Racial/ethnic minority groups remain underrepresented in clinical trials. Many strategies to increase minority recruitment focus on minority communities and emphasize common diseases such as hypertension. Scant literature focuses on minority recruitment to trials of less common conditions, often conducted in specialty clinics and dependent on physician referrals. We identified trust/mistrust of specialist physician investigators and institutions conducting medical research and consequent participant reluctance to participate in clinical trials as key-shared barriers across racial/ethnic groups. We developed a trust-based continuous quality improvement intervention to build trust between specialist physician investigators and community minority-serving physicians and ultimately potential trial participants. To avoid the inherent biases of non-randomized studies, we evaluated the intervention in the national Randomized Recruitment Intervention Trial (RECRUIT). This report presents the design of RECRUIT. Specialty clinic follow-up continues through April 2017. Methods: We hypothesized that specialist physician investigators and coordinators trained in the trust-based continuous quality improvement intervention would enroll a greater proportion of minority participants in their specialty clinics than specialist physician investigators in control specialty clinics. Specialty clinic was the unit of randomization. Using continuous quality improvement, the specialist physician investigators and coordinators tailored recruitment approaches to their specialty clinic characteristics and populations. Primary analyses were adjusted for clustering by specialty clinic within parent trial and matching covariates. Results: RECRUIT was implemented in four multi-site clinical trials (parent trials) supported by three National Institutes of Health institutes and included 50 associated specialty clinics from these parent trials. Using current data, we have 88% power or greater to detect a 0.15 or greater difference from the currently observed control proportion adjusting for clustering. We detected no differences in baseline matching criteria between intervention and control specialty clinics (all p values > 0.17). Conclusion: RECRUIT was the first multi-site randomized control trial to examine the effectiveness of a trust-based continuous quality improvement intervention to increase minority recruitment into clinical trials. RECRUIT’s innovations included its focus on building trust between specialist investigators and minority-serving physicians, the use of continuous quality improvement to tailor the intervention to each specialty clinic’s specific racial/ethnic populations and barriers to minority recruitment, and the use of specialty clinics from more than one parent multi-site trial to increase generalizability. The effectiveness of the RECRUIT intervention will be determined after the completion of trial data collection and planned analyses.

Damage control laparotomy (DCL) is intended to limit deleterious effects from trauma-induced coagulopathy. DCL has been associated with mortality reduction, but may increase complications including sepsis, abscess, respiratory failure, hernia, and gastrointestinal fistula. We hypothesized that (1) DCL incidence would vary between institutions; (2) mortality rates would vary with DCL rates; (3) standard DCL criteria of pH, international normalized ratio, temperature and major intra-abdominal vascular injury would not adequately capture all patients.Trauma patients at 12 Level 1 North American trauma centers were randomized based on transfusion ratios as described in the Pragmatic, Randomized Optimal Platelet and Plasma Ratios trial. We analyzed outcomes after emergent laparotomy using a mixed-effects logistic model comparing DCL versus definitive surgical management with random effect for study site. Primary outcomes were 24-hour and 30-day mortality.Three hundred twenty-nine patients underwent emergent laparotomy: 213 (65%) DCL and 116 (35%) definitive surgical management. DCL rates varied between institutions (33-83%), (p = 0.002). Median Injury Severity Score (ISS) was higher in the DCL group, 29 (interquartile range, 13-34) versus 21 (interquartile range, 22-41) (p0.001). Twenty-four-hour mortality was 19% with DCL versus 4% (p0.001); 30-day mortality was 28% with DCL versus 19% (p0.001). In a mixed-effects model, ISS and major intra-abdominal vascular injury were correlates of DCL (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.02-1.07 and OR, 2.7; 95% CI, 1.4-5.2). DCL was not associated with 30-day mortality (OR, 2.33; 95% CI, 0.97-5.60). Correlates included ISS (OR, 1.06; 95% CI, 1.02-1.09), PRBCs in 24 hours (OR, 1.10; 95% CI, 1.03-1.18), and age (OR, 1.04; 95% CI, 1.01-1.06). No significant mortality difference was detected between institutions (p = 0.63). Sepsis and VAP occurred more frequently with DCL (p0.05). Eighty percent (135/213) of DCL patients met standard criteria.Although DCL utilization varied significantly between institutions, there was no significant mortality difference between centers. This finding suggests tempering DCL use may not decrease mortality, but could decrease related complications.Therapeutic study, level III.

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

Background and objectives Inadequate minority participation in clinical research can threaten the applicability and strength of scientific findings. Previous research suggests that trial participation rates are lowest among Asian Americans, compared to other groups. This study explored barriers to clinical research participation among elder Chinese living in Houston, Texas. Additionally we administered the Trust in Medical Researchers Scale (TIMRS), used previously in researching trust in medical researchers as related to research participation. Design In this mixed methods study, a semi-structured interview, including the TIMRS were administered to 30 adults of Chinese ancestry aged 50 years or older recruited from a Chinese community center. Interviews were conducted in English, Mandarin and Cantonese and independently coded and analyzed using thematic content analysis. TIMRS scores were calculated for participants. Results Participants were 70% female, 70% were 60 or elder, all were foreign born and on average lived in the US for 21.8 years. Participants perceived risks to research participation and preferred language concordant research staff. Interviewees were more willing to participate if they perceived personal and community health-related benefits. The overall TIMRS score was 23.9 (±5.0), lower than the overall TIMRS for Whites in a previous study (P Conclusions The barriers and facilitators to research participation confirmed previous research among Asians. Our participant TIMRS scores were consistent with decreased levels of trust observed in the original TIMRS study for African Americans as compared and lower than Whites. Employing strategies that utilize language concordant staff who build trust with participants may aid in recruiting elder Chinese, especially if the research is personally relevant to those being recruited.

Background There have been no prior investigations of the cost effectiveness of transfusion strategies for trauma resuscitation. The Pragmatic, Randomized, Optimal Platelet and Plasma Ratios (PROPPR) study was a Phase III multisite, randomized trial in 680 subjects comparing the efficacy of 1:1:1 transfusion ratios of plasma and platelets to red blood cells with the 1:1:2 ratio. We hypothesized that 1:1:1 transfusion results in an acceptable incremental cost-effectiveness ratio, when estimated using patients' age-specific life expectancy and cost of care during the 30-day PROPPR trial period. Study design and methods International Classification of Diseases, Ninth Revision codes were prospectively collected, and subjects were matched 1:2 to subjects in the Healthcare Utilization Program State Inpatient Data to estimate cost weights. We used a decision tree analysis, combined with standard costs and estimated years of expected survival to determine the cost effectiveness of the two treatments. Results The 1:1:1 group had higher overall costs for the blood products but were more likely to achieve hemostasis and decreased hemorrhagic death by 24 hours (p = 0.006). For every 100 patients treated in the 1:1:1 group, eight more achieved hemostasis than in the 1:1:2 group. At 30 days, the total hospital cost per 100 patients was $5.6 million in the 1:1:1 group compared with $5.0 million in the 1:1:2 group. For each 100 patients, the 1:1:1 group had 218.5 more years of life expectancy. This was at a cost of $2994 per year gained. Conclusion The 1:1:1 transfusion ratio in severely injured hemorrhaging trauma patients is a very cost-effective strategy for increasing hemostasis and decreasing trauma deaths.

Objective Assess MDS-UPDRS items for gender-, age-, and race/ethnicity-based differential item functioning. Background Assessing differential item functioning is a core rating scale validation step. For the MDS-UPDRS, differential item functioning occurs if item-score probability among people with similar levels of parkinsonism differ according to selected covariates (gender, age, race/ethnicity). If the magnitude of differential item functioning is clinically relevant, item-score interpretation must consider influences by these covariates. Differential item functioning can be nonuniform (covariate variably influences an item-score across different levels of parkinsonism) or uniform (covariate influences an item-score consistently over all levels of parkinsonism). Methods Using the MDS-UPDRS translation database of more than 5,000 PD patients from 14 languages, we tested gender-, age-, and race/ethnicity-based differential item functioning. To designate an item as having clinically relevant differential item functioning, we required statistical confirmation by 2 independent methods, along with a McFadden pseudo-R2 magnitude statistic greater than “negligible.” Results Most items showed no gender-, age- or race/ethnicity-based differential item functioning. When differential item functioning was identified, the magnitude statistic was always in the “negligible” range, and the scale-level impact was minimal. Conclusions The absence of clinically relevant differential item functioning across all items and all parts of the MDS-UPDRS is strong evidence that the scale can be used confidently. As studies of Parkinson's disease increasingly involve multinational efforts and the MDS-UPDRS has several validated non-English translations, the findings support the scale's broad applicability in populations with varying gender, age, and race/ethnicity distributions. © 2016 International Parkinson and Movement Disorder Society.

BackgroundMedication dispensing errors are common in clinical trials, and have a significant impact on the quality and validity of a trial. Therefore, the definition, calculation and evaluation of such errors are important for supporting a trial’s conclusions. A variety of medication dispensing errors can occur. In this paper, we focus on errors in trials where the intervention includes multiple therapies that must be given in a pre-specified order that varies across treatment arms and varies in duration.MethodsThe Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial was a Phase III multi-site, randomized trial to compare the effectiveness and safety of 1:1:1 transfusion ratios of plasma and platelets to red blood cells with a 1:1:2 ratio. In this trial, these three types of blood products were to be transfused in a pre-defined order that differed by treatment arm. In this paper, we present approaches from the PROPPR trial that we used to define and calculate the occurrence of out of order blood transfusion errors. We applied the proposed method to calculate protocol adherence to the specified order of transfusion in each treatment arm.ResultsUsing our proposed method, protocol adherence was greater in the 1:1:1 group than in the 1:1:2 group (96% vs 93%) (p

Background: Communicating with trial participants is an important aspect of study conduct, relevant for informed consent and respect for participants. Group teleconferences are one means to convey information to trial participants. We used group teleconferences during an ongoing large-scale clinical trial to communicate important trial updates. Methods: The National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinson’s Disease Longitudinal Study-1 trial studied creatine for treatment of early-stage Parkinson’s disease. A total of 1741 participants enrolled at 45 sites in the United States and Canada to take part in a double-blind randomized trial of 5 years of treatment with creatine versus placebo. The study leadership held two teleconferences with study participants and their caregivers after each of two pre-specified interim analyses, for a total of four teleconferences. Each agenda included a presentation by study leadership followed by an open question and answer period. Teleconference recordings were made available to all site personnel and trial participants. Recordings were reviewed and abstracted for themes and topics of the presentations, participant questions, and discussion. Number of participants, connection time for each participant, number of questions, and caller connection time were summarized using descriptive statistics. After the first teleconferences, participants who remained on the call until the end were invited to complete a voluntary, four-question survey about the teleconference process. During the second teleconferences, participants were notified of premature study closure. Results: There were 258 callers for the first pair of teleconferences and 604 callers for the second pair of teleconferences. Study leaders answered more than 110 questions from study participants and caregivers across all calls. The most frequently asked question themes related to study drug, Parkinson’s disease, side effects, future research, and data analysis. The initial teleconferences were well received by participants. Based on responses to the post-call survey, 98% (118/121) of participants found the call useful, 91% (115/127) were interested in future similar calls, 88% stated the call made them more likely to continue in the study (112/128), and 85% (90/106) were satisfied overall with study communications. Conclusion: Teleconferences provide a convenient way to communicate with trial participants and can be used during the conduct of clinical trials to convey study progress and other information. For multi-site trials, teleconferences enable participants to engage directly with study leadership and to ask questions. Survey respondents were highly satisfied with the group teleconference experience. Future research is needed to determine whether teleconferences improve participants’ satisfaction with clinical trial participation and improve retention.

Objective:To investigate ICU utilization and hospital outcomes of oncological patients admitted to a comprehensive cancer center.Design:Observational cohort study.Setting:The University of Texas MD Anderson Cancer Center.Patients:Consecutive adults with cancer discharged over a 20-year period.Interv

Continuous time Markov chain models are frequently employed in medical research to study the disease progression but are rarely applied to the transtheoretical model, a psychosocial model widely used in the studies of health-related outcomes. The transtheoretical model often includes more than three states and conceptually allows for all possible instantaneous transitions (referred to as general continuous time Markov chain). This complicates the likelihood function because it involves calculating a matrix exponential that may not be simplified for general continuous time Markov chain models. We undertook a Bayesian approach wherein we numerically evaluated the likelihood using ordinary differential equation solvers available from the gnu scientific library. We compared our Bayesian approach with the maximum likelihood method implemented with the R package MSM. Our simulation study showed that the Bayesian approach provided more accurate point and interval estimates than the maximum likelihood method, especially in complex continuous time Markov chain models with five states. When applied to data from a four-state transtheoretical model collected from a nutrition intervention study in the next step trial, we observed results consistent with the results of the simulation study. Specifically, the two approaches provided comparable point estimates and standard errors for most parameters, but the maximum likelihood offered substantially smaller standard errors for some parameters. Comparable estimates of the standard errors are obtainable from package MSM, which works only when the model estimation algorithm converges.

Background The Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial has demonstrated that damage-control resuscitation, a massive transfusion strategy targeting a balanced delivery of plasma-platelet-red blood cell in a ratio of 1:1:1, results in improved survival at 3 hours and a reduction in deaths caused by exsanguination in the first 24 hours compared with a 1:1:2 ratio. In light of these findings, we hypothesized that patients receiving 1:1:1 ratio would have improved survival after emergency laparotomy. Methods Severely injured patients predicted to receive a massive transfusion admitted to 12 Level I North American trauma centers were randomized to 1:1:1 versus 1:1:2 as described in the PROPPR trial. From these patients, the subset that underwent an emergency laparotomy, defined previously in the literature as laparotomy within 90 minutes of arrival, were identified. We compared rates and timing of emergency laparotomy as well as postsurgical survival at 24 hours and 30 days. Results Of the 680 enrolled patients, 613 underwent a surgical procedure, 397 underwent a laparotomy, and 346 underwent an emergency laparotomy. The percentages of patients undergoing emergency laparotomy were 51.5% (174 of 338) and 50.3% (172 of 342) for 1:1:1 and 1:1:2, respectively (p = 0.20). Median time to laparotomy was 28 minutes in both treatment groups. Among patients undergoing an emergency laparotomy, the proportions of patients surviving to 24 hours and 30 days were similar between treatment arms; 24-hour survival was 86.8% (151 of 174) for 1:1:1 and 83.1% (143 of 172) for 1:1:2 (p = 0.29), and 30-day survival was 79.3% (138 of 174) for 1:1:1 and 75.0% (129 of 172) for 1:1:2 (p = 0.30). Conclusion We found no evidence that resuscitation strategy affects whether a patient requires an emergency laparotomy, time to laparotomy, or subsequent survival. Level of evidence Therapeutic study, level IV.

Endotheliopathy of trauma is characterized by breakdown of the endothelial glycocalyx. Elevated biomarkers of endotheliopathy, such as serum syndecan-1 (Synd-1) ≥ 40 ng/mL, have been associated with increased need for transfusions, complications, and mortality. We hypothesized that severely injured trauma patients who exhibit elevated Synd-1 levels shortly after admission have an increased likelihood of developing sepsis.We analyzed a subset of patients from the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial who survived at least 72 hours after hospital admission, and we determined elevated Synd-1 levels (≥ 40 ng/mL) 4 hours after hospital arrival. Sepsis was defined a priori as meeting systemic inflammatory response criteria and having a known or suspected infection. Univariate analysis was performed to identify variables associated with elevated Synd-1 levels and sepsis. Significant variables at a value of p0.2 in the univariate analysis were chosen by purposeful selection and analyzed in a mixed effects multivariate logistic regression model to account for the 12 different study sites.We included 512 patients. Of these, 402 (79%) had elevated Synd-1 levels, and 180 (35%) developed sepsis. Median Synd-1 levels at 4 hours after admission were 70 ng/dL (interquartile range [IQR] 36 to 157 ng/dL) in patients who did not develop sepsis, and 165 ng/dL [IQR 67 to 336 ng/dL] in those who did (p0.001). Adjusting for treatment arm and site, multivariable analyses revealed that elevated Synd-1 status, Injury Severity Score (ISS), and total blood transfused were significantly associated with an increased likelihood of developing sepsis.Elevated Synd-1 levels 4 hours after admission in severely injured adult trauma patients who survived the initial 72 hours after hospital admission are associated with subsequent sepsis.

BACKGROUND The effect of red blood cell (RBC) storage on oxygenation in critically ill patients is still unknown. The objective of this study was to determine the association of RBC storage with oxygenation, long-term neurologic recovery, and death after traumatic brain injury. METHODS We used data from a 2 × 2 factorial randomized controlled trial of administration of erythropoietin or placebo and of assignment to transfusion threshold of less than 7g/dL or less than 10 g/dL in neurosurgical intensive care units in two US Level 1 trauma centers. Patients had severe traumatic brain injury with closed head injury, were unable to follow commands, and were enrolled within 6 hours of injury. Blood oxygenation 1 hour after the transfusion as measured by jugular venous oxygen saturation (n = 59) was the primary outcome. Secondary outcomes were brain tissue oxygenation (n = 77), 6-month Glasgow Outcome Scale (GOS) score (n = 122) collected using a structured interview and dichotomized into favorable (good recovery or moderate disability) or unfavorable outcome (severe disability, vegetative state, or dead), and mortality (n = 125). RBC age was defined as the maximum age of RBCs over all units in one transfusion per patient. For long-term outcomes, RBC age was defined as the mean age over all units given. RESULTS We failed to detect an association of RBC age with jugular venous oxygen saturation (linear regression β = 1.59; 95% confidence interval [CI], -2.99 to 6.18; p = 0.49), brain tissue oxygenation (linear regression β = 0.20; 95% CI, -0.23 to 0.63; p = 0.36), GOS score (odds ratio, 1.37; 95% CI, 0.53-3.57; p = 0.52), and mortality (hazard ratio, 1.35; 95% CI, 0.61-2.98; p = 0.46). CONCLUSION Limitations of this study include the fact that the RBC ages were not randomized, although this was a prospective study. We conclude that older blood does not seem to have adverse effects in severe traumatic brain injury. LEVEL OF EVIDENCE Prognostic study, level III.

Objective Increased caffeine intake is associated with a lower risk of Parkinson disease (PD) and is neuroprotective in mouse models of PD. However, in a previous study, an exploratory analysis suggested that, in patients taking creatine, caffeine intake was associated with a faster rate of progression. In the current study, we investigated the association of caffeine with the rate of progression of PD and the interaction of this association with creatine intake. Methods Data were analyzed from a large phase 3 placebo-controlled clinical study of creatine as a potentially disease-modifying agent in PD. Subjects were recruited for this study from 45 movement disorders centers across the United States and Canada. A total of 1741 subjects with PD participated in the primary clinical study, and caffeine intake data were available for 1549 of these subjects. The association of caffeine intake with rate of progression of PD as measured by the change in the total Unified Parkinson Disease Rating Scale score and the interaction of this association with creatine intake were assessed. Results Caffeine intake was not associated with the rate of progression of PD in the main analysis, but higher caffeine intake was associated with significantly faster progression among subjects taking creatine. Conclusions This is the largest and longest study conducted to date that addresses the association of caffeine with the rate of progression of PD. These data indicate a potentially deleterious interaction between caffeine and creatine with respect to the rate of progression of PD.

Summary Background A systematic assessment of potential disease-modifying compounds for Parkinson's disease concluded that pioglitazone could hold promise for the treatment of patients with this disease. We assessed the effect of pioglitazone on the progression of Parkinson's disease in a multicentre, double-blind, placebo-controlled, futility clinical trial. Methods Participants with the diagnosis of early Parkinson's disease on a stable regimen of 1 mg/day rasagiline or 10 mg/day selegiline were randomly assigned (1:1:1) to 15 mg/day pioglitazone, 45 mg/day pioglitazone, or placebo. Investigators were masked to the treatment assignment. Only the statistical centre and the central pharmacy knew the treatment name associated with the randomisation number. The primary outcome was the change in the total Unified Parkinson's Disease Rating Scale (UPDRS) score between the baseline and 44 weeks, analysed by intention to treat. The primary null hypothesis for each dose group was that the mean change in UPDRS was 3 points less than the mean change in the placebo group. The alternative hypothesis (of futility) was that pioglitazone is not meaningfully different from placebo. We rejected the null if there was significant evidence of futility at the one-sided alpha level of 0·10. The study is registered at ClinicalTrials.gov , number NCT01280123 . Findings 210 patients from 35 sites in the USA were enrolled between May 10, 2011, and July 31, 2013. The primary analysis included 72 patients in the 15 mg group, 67 in the 45 mg group, and 71 in the placebo group. The mean total UPDRS change at 44 weeks was 4·42 (95% CI 2·55–6·28) for 15 mg pioglitazone, 5·13 (95% CI 3·17–7·08) for 45 mg pioglitazone, and 6·25 (95% CI 4·35–8·15) for placebo (higher change scores are worse). The mean difference between the 15 mg and placebo groups was −1·83 (80% CI −3·56 to −0·10) and the null hypothesis could not be rejected (p=0·19). The mean difference between the 45 mg and placebo groups was −1·12 (80% CI −2·93 to 0·69) and the null hypothesis was rejected in favour of futility (p=0·09). Planned sensitivity analyses of the primary outcome, using last value carried forward (LVCF) to handle missing data and using the completers' only sample, suggested that the 15 mg dose is also futile (p=0·09 for LVCF, p=0·09 for completers) but failed to reject the null hypothesis for the 45 mg dose (p=0·12 for LVCF, p=0·19 for completers). Six serious adverse events occurred in the 15 mg group, nine in the 45 mg group, and three in the placebo group; none were thought to be definitely or probably related to the study interventions. Interpretation These findings suggest that pioglitazone at the doses studied here is unlikely to modify progression in early Parkinson's disease. Further study of pioglitazone in a larger trial in patients with Parkinson's disease is not recommended. Funding National Institute of Neurological Disorders and Stroke.

BACKGROUND The Pragmatic, Randomized Optimal Platelets and Plasma Ratios (PROPPR) trial was a randomized clinical trial comparing survival after transfusion of two different blood component ratios for emergency resuscitation of traumatic massive hemorrhage. Transfusion services supporting the study were expected to provide thawed plasma, platelets, and red blood cells within 10 minutes of request. STUDY DESIGN AND METHODS At the 12 Level 1 trauma centers participating in PROPPR, blood components transfused and delivery times were tabulated, with a focus on universal donor (UD) plasma management. The adequacy of site plans was assessed by comparing the bedside blood availability times to study goals and the new American College of Surgeons guidelines. RESULTS Eleven of 12 sites were able to consistently deliver 6 units of thawed UD plasma to their trauma-receiving unit within 10 minutes and 12 units in 20 minutes. Three sites used blood group A plasma instead of AB for massive transfusion without complications. Approximately 4700 units of plasma were given to the 680 patients enrolled in the trial. No site experienced shortages of AB plasma that limited enrollment. Two of 12 sites reported wastage of thawed AB plasma approaching 25% of AB plasma prepared. CONCLUSION Delivering UD plasma to massively hemorrhaging patients was accomplished consistently and rapidly and without excessive wastage in high-volume trauma centers. The American College of Surgeons Trauma Quality Improvement Program guidelines for massive transfusion protocol UD plasma availability are practicable in large academic trauma centers. Use of group A plasma in trauma resuscitation needs further study.

Background: There are very limited prospective data on the significance of persistent antiphospholipid antibodies (aPL) and recurrent thrombo-occlusive events (TOEs). We investigated the prognostic value of (1) 2 newer aPL assays, (2) an aPL portfolio and (3) persistent aPL positivity following stroke. Methods: A total of 1,770 subjects from the APASS-WARSS study underwent further aPL testing for antibodies to phosphatidylserine (aPS) and anti-β2-glycoprotein-I (anti-β2GPI) from stored sera. Follow-up aPL status was also tested in a subset of subjects. Primary analysis was based on time to any TOE (ischemic stroke, myocardial infarction, transient ischemic attack, deep vein thrombosis, pulmonary embolism or systemic arterial occlusion)/death at 2 years. Cox proportional hazard analyses assessed whether aPL independently related to outcome. Results: Persistent anti-β2GPI decreased the time to TOE/death after adjustment for potential confounders (hazards ratio (HR) 2.86, 95% CI 1.21-6.76, p = 0.017). When persistent anti-β2GPI was combined with another persistently positive aPL, time to TOE/death was also reduced (HR 3.79, 95% CI 1.18-12.14, p = 0.025). Neither persistent anticardiolipin antibodies nor persistent aPS alone nor a single positive anti-β2GPI nor aPS was associated with decreased time to TOE/death. No single positive aPL, portfolio of baseline aPL or any persistent aPL increased the rate of TOE/death. Conclusions: Rates of TOE/death were not influenced by aPL results at baseline or follow-up. Persistent anti-β2GPI alone, and with persistent second aPL, was independently associated with decreased time to TOE/death. Persistent aPL, an aPL portfolio and newer aPL in ischemic stroke patients are not helpful in predicting an increased rate of recurrent TOEs.

Background The Movement Disorders Society (MDS) published the English new Unified Parkinson's Disease Rating Scale (MDS-UPDRS) as the official benchmark scale for Parkinson's disease (PD) in 2008. We aimed to validate the Hebrew version of the MDS-UPDRS, explore its dimensionality and compare it to the original English one. Methods The MDS-UPDRS questionnaire was translated to Hebrew and was tested on 389 patients with PD, treated at the Movement Disorders Unit at Tel-Aviv Medical Center. The MDS-UPDRS is made up of four sections. The higher the score, the worst the clinical situation of the patient is. Confirmatory and explanatory factor analysis were applied to determine if the factor structure of the English version could be confirmed in the Hebrew version. Results The Hebrew version of the MDS-UPDRS showed satisfactory clinimetric properties. The internal consistency of the Hebrew-version was satisfactory, with Cronbach's alpha values 0.79, 0.90, 0.93, 0.80, for parts 1 to 4 respectively. In the confirmatory factor analysis, all four parts had high (greater than 0.90) comparative fit index (CFI) in comparison to the original English MDS-UPDRS with high factor structure (0.96, 0.99, 0.94, 1.00, respectively), thus confirming the pre-specified English factor structure. Explanatory factor analysis yielded that the Hebrew responses differed from the English one within an acceptable range: in isolated item differences in factor structure and in the findings of few items having cross loading on multiple factors. Conclusions The Hebrew version of the MDS-UPDRS meets the requirements to be designated as the Official Hebrew Version of the MDS-UPDRS.

Background Given the importance of ethnic differences in the evaluation of various aspects of symptoms in patients with Parkinson's disease (PD), we present the formal procedure for completing the traditional Chinese translation of the International and Parkinson and Movement Disorder Society/UPDRS (MDS-UPDRS) and highlight the discrepancy in nonmotor symptoms (NMS) between patients in Eastern and Western countries. Methods A total of 350 native Chinese-speaking PD patients were recruited from multiple hospitals in Eastern countries; they completed the MDS-UPDRS. The translation process was executed and factor analysis was performed to determine the structure of the scale. Chi-squared and t tests were used to compare frequency and severity of PD symptoms between the Chinese-speaking and English-speaking groups (n = 876). Results NMS and motor symptoms were more severe in the Western population (Part I: t(1205) = 5.36, P < 0.0001; and Part III: t(1205) = 7.64, P < 0.0001); however, the prevalence of cognitive dysfunction and impairments in activities of daily living were more frequent in the Eastern patients. The comparative fit index was 0.93 or greater, and the exploratory factor analysis revealed compatible results between the translated scale and the original version. Conclusion The traditional Chinese version of the MDS-UPDRS can be designated as an official translation of the original scale, and it is now available for use. Moreover, NMS in PD constitute a major issue worldwide, and the pattern of NMS among the Chinese population is more marked in terms of cognition-based symptoms and activities of daily living.

BACKGROUND: The Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) is a newly developed tool to assess Parkinson's disease (PD). Changes in scores on the scale over the course of PD, including increasing disease duration and Hoehn and Yahr (HY) stages, have not been described. The objectives of this study were to analyze MDS‐UPDRS scores on Parts I through IV and their differences based on HY stage and disease duration in a large cohort of patients with PD. METHODS: For this cross‐sectional study, demographic data and MDS‐UPDRS scores were collected, including HY stage. Subscores on MDS‐UPDRS Parts I through IV were analyzed using 1‐way analyses of variance for each HY stage and in 5‐year increments of disease duration. Part III (motor assessment) scores were analyzed separately for on and off states. RESULTS: The mean age of the 3206 patients was 65.8 ± 10.6 years, 53.3% were men, the mean disease duration was 11.5 ± 4.6 years, and the median HY stage was 2 (range, 0–5); 2156 patients were examined in an on state and 987 were examined in an off state. Scores for all MDS‐UPDRS parts increased significantly through HY stages 1 through 5, with an average increase of 3.8, 7.7, 14.6, and 2.0 points consecutively for parts I through IV, respectively. For the 5‐year increments of disease duration, MDS‐UPDRS subscores increased by an average of 1.6, 3.3, 4.2, and 1.4 points consecutively for parts I through IV, respectively. This increase was significant only during the first 15 years of disease for all 4 parts, including part III scores evaluated in both on and off states. CONCLUSIONS: MDS‐UPDRS scores for all 4 parts increase significantly with every HY stage and also with 5‐year increments of disease duration in the first 15 years of the disease.

Non-motor complications of Parkinson's disease (PD), specifically cognitive impairment, sleep disturbances, and fatigue, are recognized as important contributors to poor patient outcomes and quality of life. How sleep problems and fatigue interrelate and impact cognitive function, however, has not systematically been investigated across the stages of PD. The aim of our study was to investigate the relationships among cognitive impairment, night-time sleep problems, daytime sleepiness, and fatigue across all severities of PD.We examined these non-motor problems using the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) in a study of 1319 PD patients drawn from three large cohort studies: the Parkinson's Progressive Markers Initiative, the Rush University PD Cognitive-Behavioral-Imaging study, and the Movement Disorder Society-Unified Parkinson's Disease Rating Scale Clinimetric testing program study, which spanned the gamut of disease, from early to advanced PD. Generalized linear mixed models with logit linking functions and covariates including study cohort, age, PD duration, and presence/absence of PD medications were used to examine relationships between these three non-motor symptoms and cognitive impairment.Of these three frequent, and often inter-twined, non-motor complications, greater daytime sleepiness and fatigue were associated with worse cognitive impairment across the full spectrum of PD (F[16,1158] = 2.40 and F[16,1158] = 3.45 respectively, p's 0.0005), but an association with night-time sleep was not detected (p = 0.83).Given this association of daytime sleepiness and fatigue with cognitive impairment, clinical monitoring for these problems should be considered across all points in the PD spectrum, from early to more advanced disease.

The International Parkinson and Movement Disorder Society (MDS)-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) has been developed and is now available in English. Part of the overall program includes the establishment of official non-English translations of the MDS-UPDRS. We present the process for completing the official Japanese translation of the MDS-UPDRS with clinimetric testing results. In this trial, the MDS-UPDRS was translated into Japanese, underwent cognitive pretesting, and the translation was modified after taking the results into account. The final translation was approved as the Official Working Draft of the MDS-UPDRS Japanese version and tested in 365 native-Japanese–speaking patients with PD. Confirmatory analyses were used to determine whether the factor structure for the English-language MDS-UPDRS could be confirmed in data collected using the Official Working Draft of the Japanese translation. As a secondary analysis, we used exploratory factor analyses to examine the underlying factor structure without the constraint of a prespecified factor organization. Confirmatory factor analysis revealed that Comparative Fit Index for all parts of the MDS-UPDRS exceeded the minimal standard of 0.90, relative to the English version, and therefore the Japanese translation met the prespecified criterion to be designated, called an official MDS translation. Secondary analyses revealed some differences between the English-language MDS-UPDRS and the Japanese translation; however, these differences were considered to be within an acceptable range. The Japanese version of the MDS-UPDRS met the criterion as an Official MDS Translation and is now available for use (www.movementdisorders.org).

We present the methodology and results of the clinimetric testing program for non-English translations of International Parkinson and Movement Disorder Society (MDS)–sponsored scales. The programs focus on the MDS revision of the UPDRS (MDS-UPDRS) and the Unified Dyskinesia Rating Scale (UDysRS). The original development teams of both the MDS-UPDRS and UDysRS envisioned official non-English translations and instituted a rigorous translation methodology. The formal process includes five core steps: (1) registration and start-up; (2) translation and independent back-translation; (3) cognitive pretesting to establish that the translation is clear and that it is comfortably administered to and completed by native-speaker raters and patients; (4) field testing in the native language using a large sample of Parkinson’s disease patients; and (5) full clinimetric testing. To date, the MDS-UPDRS has 21 active language programs. Nine official translations are available, having completed all phases successfully, and the others are in different stages of development. For the UDysRS, 19 programs are active, with three official translations now available and the rest in development at different stages. Very few scales in neurology and none in movement disorders have fully validated translations, and this model may be adopted or modified by other scale programs to allow careful validation of translations. Having validated translations allows for maximal homogeneity of tools utilized in multicenter research or clinical trial programs.

Exciting new medical therapies for a number of diseases that disproportionately affect African Americans and Latinos are currently being developed and tested in clinical trials (Robinson & Trochim, 2007). Despite bearing an unequal burden of disease, African Americans and Latinos continue to be underrepresented in clinical trials research, even though the National Institutes of Health Revitalization Act of 1993 (P.L. 103-43) stipulating the participation of women and minority groups in research was created in 1993 and updated in 2001 (Pinsky et al., 2008). Insufficient representation of racially and ethnically diverse groups and women in clinical trials results in inequitable distribution of the risks and benefits of research participation and reduces the generalizability of trial results (Pinsky et al., 2008). Health disparities in the United States could be reduced if targeted therapies were discovered that work equally well in all populations or work especially well in members of affected racial and ethnic groups. The purpose of this study was to use qualitative data obtained via focus groups with African American and Latino adults ages 50 years and older to elicit potential solutions to the problem of low rates of participation of such populations in clinical trials research. The conceptual framework of the study was based on the Institute of Medicine (IOM) report Unequal Treatment: Confronting Racial and Ethnic Disparities in Healthcare (Smedley & Nelson, 2003), which identified three factors as major sources of racial and ethnic disparities in health outcomes: (1) characteristics of health care systems, (2) perceptions of and actual interactions with health care providers, and (3) preferences and attitudes of patients. We applied IOM's conceptual framework to the arena of disparities in recruitment of diverse populations to clinical trials research by revising the wording of the IOM framework to refer to clinical trials research instead of to health care disparities. For example, in the framework, we replaced “health care systems” with “health care systems and study processes,” “health care providers” with “researchers,” and “patients” with “potential trial participants.” The revised framework is depicted in Figure ​Figure11 and is described in the following sections. The conceptual framework is related to the systems approach in the field of social work, in which clients and their needs are related to a multilevel model of resources, systems, and institutions (Darnell, 2007; NASW, 2008). Figure 1: Model Framework of Multilevel Factors Affecting Decision to Participate in a Clinical Trial

The Unified Dyskinesia Rating Scale (UDysRS) assesses the severity and disability caused by dyskinesias in Parkinson's disease (PD). As part of the UDysRS development plan, the International Parkinson and Movement Disorder Society (MDS) established guidelines for official non-English translations. We present here the formal process for completing this program and the data on the first officially approved non-English version of the UDysRS (Spanish). The UDysRS translation program involves four steps: translation and back-translation; cognitive pretesting to ensure that raters and patients understand the scale and are comfortable with its content; field testing of the finalized version; and analysis of the factor structure of the tested version against the original English-language version. To be designated an official MDS translation, the confirmatory factor analysis comparative fit index (CFI) had to be ≥0.90. The Spanish UDysRS was tested in 253 native-Spanish-speaking patients with PD. For all four parts of the UDysRS, the CFI, was ≥0.94. Exploratory factor analyses of the Spanish version revealed a very clear factor structure, with three factors related to ON dyskinesia, OFF dystonia, and patient perceptions of the functional effect of dyskinesias. The Spanish version of the UDysRS successfully followed the MDS Translation Program protocol, reached the criterion to be designated as an official translation, and is now available on the MDS website for use.

Assess MDS-UPDRS items for gender-, age-, and race/ethnicity-based differential item functioning.Assessing differential item functioning is a core rating scale validation step. For the MDS-UPDRS, differential item functioning occurs if item-score probability among people with similar levels of parkinsonism differ according to selected covariates (gender, age, race/ethnicity). If the magnitude of differential item functioning is clinically relevant, item-score interpretation must consider influences by these covariates. Differential item functioning can be nonuniform (covariate variably influences an item-score across different levels of parkinsonism) or uniform (covariate influences an item-score consistently over all levels of parkinsonism).Using the MDS-UPDRS translation database of more than 5,000 PD patients from 14 languages, we tested gender-, age-, and race/ethnicity-based differential item functioning. To designate an item as having clinically relevant differential item functioning, we required statistical confirmation by 2 independent methods, along with a McFadden pseudo-RMost items showed no gender-, age- or race/ethnicity-based differential item functioning. When differential item functioning was identified, the magnitude statistic was always in the "negligible" range, and the scale-level impact was minimal.The absence of clinically relevant differential item functioning across all items and all parts of the MDS-UPDRS is strong evidence that the scale can be used confidently. As studies of Parkinson's disease increasingly involve multinational efforts and the MDS-UPDRS has several validated non-English translations, the findings support the scale's broad applicability in populations with varying gender, age, and race/ethnicity distributions. © 2016 International Parkinson and Movement Disorder Society.

The incidence of adult respiratory distress syndrome (ARDS) in severe traumatic brain injury (TBI) is poorly reported. Recently, a new definition for ARDS was proposed, the Berlin definition. The percentage of patients represented by TBI in the Berlin criteria study is limited. This study describes the incidence and associated mortality of ARDS in TBI patients.The study was an analysis of the safety of erythropoietin administration and transfusion threshold on the incidence of ARDS in severe TBI patients. Three reviewers independently assessed all patients enrolled in the study for acute lung injury/ARDS using the Berlin and the American-European Consensus Conference (AECC) definitions. A Cox proportional hazards model was used to assess the relationship between ARDS and mortality and 6-month Glasgow Outcome Scale (GOS) score.Two hundred patients were enrolled in the study. Of the patients, 21% (41 of 200) and 26% (52 of 200) developed ARDS using the AECC and Berlin definitions, respectively, with a median time of 3 days (interquartile range, 3) after injury. ARDS by either definition was associated with increased mortality (p = 0.04) but not with differences in functional outcome as measured by the GOS score at 6 months. Adjusted analysis using the Berlin criteria showed an increased mortality associated with ADS (p = 0.01).Severe TBI is associated with an incidence of ARDS ranging from 20% to 25%. The incidence is comparable between the Berlin and AECC definitions. ARDS is associated with increased mortality in severe TBI patients, but further studies are needed to validate these findings.Epidemiologic study, level II.

Introduction To examine in a randomize controlled feasibility clinical trial the efficacy of a cognitive-behavioral intervention designed to manage pain, enhance disease adjustment and adaptation and improve quality of life among female adolescents with systemic lupus erythematosus. Methods Female adolescents (n = 53) ranging in age from 12 to 18 years were randomly assigned to 1 of 3 groups including a cognitive-behavioral intervention, an education-only arm and a no-contact control group. Participants were assessed at baseline, postintervention and at 3- and 6-month intervals after completion of the intervention. Results No significant differences were revealed among the 3 treatment arms for any of the dependent measures at any of the assessment points. For the mediator variables, a posthoc secondary analysis did reveal increases in coping skills from baseline to postintervention among the participants in the cognitive-behavioral intervention group compared with both the no-contact control group and the education-only group. Conclusion Although no differences were detected in the primary outcome, a possible effect on coping of female adolescents with systemic lupus erythematosus was detected in this feasibility study. Whether the impact of training in the area of coping was of sufficient magnitude to generalize to other areas of functioning, such as adjustment and adaptation, is unclear. Future phase III randomized trials will be needed to assess additional coping models and to evaluate the dose of training and its influence on pain management, adjustment and health-related quality of life.

The aim of this study was to develop formulas to convert the UPDRS to Movement Disorder Society (MDS)-UPDRS scores. The MDS-UPDRS is a revision of the UPDRS with sound clinimetric properties. Reliable formulas to recalculate UPDRS scores into MDS-UPDRS equivalents are pivotal to the practical transition and definitive adoption of the MDS-UPDRS. UPDRS and MDS-UPDRS scores were collected on 875 PD patients. A developmental sample was used to regress UPDRS scores on corresponding MDS-UPDRS scores based on three H & Y groupings (I/II, III, and IV/V). Regression weighting factors and intercept terms provided formulas for UPDRS conversions to be tested in a validation sample. Concordance between the true MDS-UPDRS Part scores and those derived from the formulas was compared using Bland-Altman's plots and Lin's concordance coefficient (LCC). Significant concordance between UPDRS-estimated MDS-UPDRS scores was achieved for Parts II (Motor Experiences of Daily Living) (LCC = 0.93) and III (Motor Examination) (LCC = 0.97). The formulas resulted in mean differences between the true MDS-UPDRS and estimated MDS-UPDRS scores of less than 1 point for both Parts II and III. Concordance was not achieved for Parts I and IV (Non-motor Experiences of Daily Living and Complications of Therapy). Formulas allow archival UPDRS Parts II and III individual patient data to be accurately transferred to MDS-UPDRS scores. Because Part I collects data on much more extensive information than the UPDRS, and because Part IV is structured differently in the two versions, old ratings for these parts cannot be converted. © 2012 Movement Disorder Society.

Comparative effectiveness research (CER) is the study of existing treatments or ways to deliver health care to determine what intervention works best under specific circumstances. CER evaluates evidence from existing studies or generates new evidence, in different populations and under specific conditions in which the treatments are actually used. CER does not embrace one research design over another but compares treatments and variations in practice using methods that are most likely to yield widely generalizable results that are directly relevant to clinical practice. Treatments used in transfusion medicine (TM) are among the most widely used in clinical practice, but are among the least well studied. High-quality evidence is lacking for most transfusion practices, with research efforts hampered by regulatory restrictions and ethical barriers. To begin addressing these issues, the National Heart, Lung, and Blood Institute convened a workshop in June 2011 to address the potential role of CER in the generation of high-quality evidence for TM decision making. Workshop goals were to: 1) evaluate the current landscape of clinical research, 2) review the potential application of CER methods to clinical research, 3) assess potential barriers to the use of CER methodology, 4) determine whether pilot or vanguard studies can be used to facilitate planning of future CER research, and 5) consider the need for and delivery of training in CER methods for researchers.

Objective To evaluate the subject-investigator agreement on the Unified Parkinson’s Disease Rating Scale (UPDRS) subsections I and II. Methods Subject-investigator agreement was estimated at baseline and endpoint by Kappa statistics for individual items and concordance correlations for subscale totals using data from two NIH Exploratory Trials in Parkinson’s Disease studies. Results All but two questions had moderate subject-investigator agreement at baseline and endpoint. Participants consistently rated their disease activity worse that investigators. Conclusion UPDRS self-administration produces similar results to investigator-administration. Although slightly elevated, UPDRS self-administration can be accommodated in a clinical trial setting.

This study demonstrated reliability and factor structure of the Medical Outcomes Study Short-Form Health Survey (SF-36) among older Americans with Traumatic brain injury (TBI), and evaluated effects of injury severity and race on SF-36's items and latent domains. A representative sample of 654 older, racially diverse patients with TBI was selected from the South Carolina Traumatic Brain Injury Follow-up Registry. Reliability and factor structure of SF-36 were evaluated using Cronbach’s alpha and confirmatory factor analysis (CFA). Multiple-indicator multiple-causes (MIMIC) models were used to study effects of injury severity and race on items (differential item functioning, DIF) and latent domains (population heterogeneity) of SF-36. SF-36 was reliable and its current eightfactor structure was confirmed. While TBI severity did not impact latent domain scores of SF-36, race did. Blacks had higher vitality and lower role-emotional scores than whites. The measurement model was invariant to injury severity and race (free of DIF), and DIF did not contribute to the differences of vitality and role-emotional between black and white older TBI patients. SF-36 was valid to measure quality of life (OoL) after TBI in racially diverse elderly population. Blacks tend to assert to strong coping behaviors in the presence of physical stress while admitting low performance due to emotional stress. In QoL research where the primary outcomes are usually composite scores from instruments, MIMIC models have advantages over conventional multivariable regression models in testing the validity of the instruments and assessing covariate effects on latent traits of instruments while controlling for DIF effects.

Sick preterm and term newborns are highly vulnerable to neural injury, and thus there has been a major search for new, safe and efficacious neuroprotective interventions in recent decades. Preclinical studies are essential to select candidate drugs for clinical trials in humans. This article focuses on ‘negative’ preclinical studies, i.e. studies where significant differences cannot be detected. Such findings are critical to inform both clinical and preclinical investigators, but historically they have been difficult to publish. A significant amount of time and resources is lost when negative results or nonpromising therapeutics are replicated in separate laboratories because these negative results were not shared with the research community in an open and accessible format. In this article, we discuss approaches to strengthen conclusions from negative preclinical studies and, conversely, to reduce false-negative preclinical evaluations of potential therapeutic compounds. Without being exhaustive, we address three major issues in conducting and interpreting preclinical experiments, including: (a) the choice of animal models, (b) the experimental design, and (c) issues concerning statistical analyses of the experiments. This general introduction is followed by synopses of negative data obtained from studies of three potential therapeutics for perinatal brain injury: (1) the somatostatin analog octreotide, (2) an AMPA/kainate receptor antagonist, topiramate, and (3) a pyruvate derivative, ethyl pyruvate.

Background and Purpose: Ischemic stroke lesion volumes have proven difficult to analyze due to the extremely skewed shape of their underlying distribution. We introduce an extension of generalized linear models, beta regression, as a possible method of modeling extremely skewed distributions as evidenced in ischemic stroke lesion volumes. Methods: The NINDS rt-PA clinical trials measured ischemic stroke lesion volume as a secondary trial outcome. Three-month lesion volumes from these trials were analyzed using beta regression. A multi-variable regression model associating explanatory variables with ischemic stroke lesion volumes was constructed using accepted model building strategies and compared with the previously published volumetric analysis. Results: Beta regression produced a similar model when compared to the previous analysis published by the study group. All previously identified variables of importance were detected in the model building process. The age by treatment interaction described in previous studies was also found in this analysis, confirming the strong effect age has on stroke outcomes. Further, a treatment effect was elicited in terms of odds ratios, yielding a previously unknown quantification of the effect of rt-PA on lesion volumes. Conclusions: Beta regression proved adept in modeling ischemic stroke lesions and offered the interpretation of covariates in terms of odds ratios. Beta regression is seen as a legitimate alternative to analyze ischemic stroke volumes.

There is a broad spectrum of sleep disturbances observed in Parkinson's disease (PD). A variety of scales have been applied to the evaluation of PD sleep and wakefulness, but only a small number have been assessed specifically for clinimetric properties in the PD population. The movement disorder society has commissioned this task force to examine these scales and to assess their use in PD. A systematic literature review was conducted to explore the use of sleep scales in PD and to determine which scales qualified for a detailed critique. The task force members, all of whom have extensive experience in assessing sleep in PD reviewed each of the scales using a structured proforma. Scales were categorized into recommended, suggested and listed according to predefined criteria. A total of 48 potential scales were identified from the search and reviewed. Twenty-nine were excluded because they did not meet review criteria or were variations of scales already included, leaving 19 scales that were critiqued and rated by the task force based on the rating criteria. Only six were found to meet criteria for recommendation or suggestion by the task force: the PD sleep scale (PDSS) and the Pittsburgh sleep quality index (PSQI) are recommended for rating overall sleep problems to screen and to measure severity, the SCOPA-sleep (SCOPA) is recommended for rating overall sleep problems both to screen and to measure severity, and for rating daytime sleepiness; the Epworth sleepiness scale (ESS) is recommended for rating daytime sleepiness to screen and to measure severity; the inappropriate sleep composite score (ISCS) is suggested for rating severe daytime sleepiness or sleep attacks to screen and to measure severity; and the Stanford sleepiness scale (SSS) is suggested for rating sleepiness and to measure severity at a specific moment. The task force does not recommend the development of new scales, but emphasizes the need for educational efforts to train physicians in sleep interview techniques and polysomnography.

We explored the hypotheses that an investigator's belief in a putative neuroprotective agent might influence the timing of symptomatic intervention and the assessment of signs and symptoms of patients with Parkinson's disease with the Unified Parkinson's Disease Rating Scale (UPDRS). These hypotheses were tested with Cox and general linear modeling, using data from a previously published double-blind placebo-controlled futility trial of coenzyme Q(10) and GPI-1485. We found the investigators' level of confidence in these agents had no effect on the time to symptomatic therapy or on the change in UPDRS during 12 months of treatment.