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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.
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BACKGROUND: To date, no medication has slowed the progression of Parkinson's disease (PD). Preclinical, epidemiological, and experimental data on humans all support many benefits of endurance exercise among persons with PD. The key question is whether there is a definitive additional benefit of exercising at high intensity, in terms of slowing disease progression, beyond the well-documented benefit of endurance training on a treadmill for fitness, gait, and functional mobility. This study will determine the efficacy of high-intensity endurance exercise as first-line therapy for persons diagnosed with PD within 3 years, and untreated with symptomatic therapy at baseline. METHODS: This is a multicenter, randomized, evaluator-blinded study of endurance exercise training. The exercise intervention will be delivered by treadmill at 2 doses over 18 months: moderate intensity (4 days/week for 30 min per session at 60-65% maximum heart rate) and high intensity (4 days/week for 30 min per session at 80-85% maximum heart rate). We will randomize 370 participants and follow them at multiple time points for 24 months. The primary outcome is the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor score (Part III) with the primary analysis assessing the change in MDS-UPDRS motor score (Part III) over 12 months, or until initiation of symptomatic antiparkinsonian treatment if before 12 months. Secondary outcomes are striatal dopamine transporter binding, 6-min walk distance, number of daily steps, cognitive function, physical fitness, quality of life, time to initiate dopaminergic medication, circulating levels of C-reactive protein (CRP), and brain-derived neurotrophic factor (BDNF). Tertiary outcomes are walking stride length and turning velocity. DISCUSSION: SPARX3 is a Phase 3 clinical trial designed to determine the efficacy of high-intensity, endurance treadmill exercise to slow the progression of PD as measured by the MDS-UPDRS motor score. Establishing whether high-intensity endurance treadmill exercise can slow the progression of PD would mark a significant breakthrough in treating PD. It would have a meaningful impact on the quality of life of people with PD, their caregivers and public health. TRIAL REGISTRATION: ClinicalTrials.gov NCT04284436 . Registered on February 25, 2020.
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Enfermedad de Parkinson , Antiparkinsonianos/uso terapéutico , Factor Neurotrófico Derivado del Encéfalo , Proteína C-Reactiva , Ensayos Clínicos Fase III como Asunto , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/uso terapéutico , Ejercicio Físico , Terapia por Ejercicio/métodos , Humanos , Estudios Multicéntricos como Asunto , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/tratamiento farmacológico , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
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.
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Grupos Minoritarios , Confianza , Humanos , Selección de Paciente , Proyectos Piloto , Estudios ProspectivosRESUMEN
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.
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Análisis de Intención de Tratar/métodos , Selección de Paciente , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Sesgo , Análisis por Conglomerados , Simulación por Computador , Interpretación Estadística de Datos , Humanos , Análisis de Intención de Tratar/estadística & datos numéricos , Modelos Lineales , Grupos Minoritarios , Oportunidad Relativa , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Proyectos de Investigación , Resultado del TratamientoRESUMEN
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.
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Transfusión Sanguínea/economía , Transfusión Sanguínea/métodos , Adolescente , Adulto , Recuento de Células Sanguíneas/economía , Plaquetas/citología , Transfusión Sanguínea/mortalidad , Transfusión Sanguínea/estadística & datos numéricos , Análisis Costo-Beneficio , Recuento de Eritrocitos , Transfusión de Eritrocitos/economía , Transfusión de Eritrocitos/métodos , Transfusión de Eritrocitos/mortalidad , Transfusión de Eritrocitos/estadística & datos numéricos , Eritrocitos/citología , Femenino , Hemorragia/sangre , Hemorragia/mortalidad , Hemorragia/terapia , Mortalidad Hospitalaria , Humanos , Tiempo de Internación/economía , Tiempo de Internación/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Plasma/citología , Transfusión de Plaquetas/economía , Transfusión de Plaquetas/métodos , Transfusión de Plaquetas/mortalidad , Transfusión de Plaquetas/estadística & datos numéricos , Resucitación/mortalidad , Resucitación/estadística & datos numéricos , Adulto JovenRESUMEN
BACKGROUND: Despite efforts to increase diversity in clinical trials, racial/ethnic minority groups generally remain underrepresented, limiting researchers' ability to test the efficacy and safety of new interventions across diverse populations. We describe the use of a systematic framework, intervention mapping (IM), to develop an intervention to modify recruitment behaviors of coordinators and specialist investigators with the goal of increasing diversity in trials conducted within specialty clinics. To our knowledge IM has not been used in this setting. METHODS: The IM framework was used to ensure that the intervention components were guided by health behavior theories and the evidence. The IM steps consisted of (1) conducting a needs assessment, (2) identification of determinants and objectives, (3) selection of theory-informed methods and practical applications, (4) development and creation of program components, (5) development of an adoption and implementation plan, and (6) creation of an evaluation plan. RESULTS: The intervention included five educational modules, one in-person and four web-based, plus technical assistance calls to coordinators. Modules addressed the intervention rationale, development of clinic-specific plans to obtain minority-serving physician referrals, physician-centered and patient-centered communication, and patient navigation. The evaluation, a randomized trial, was recently completed in 50 specialty clinics and is under analysis. CONCLUSIONS: Using IM we developed a recruitment intervention that focused on building relationships with minority-serving physicians to encourage minority patient referrals. IM enhanced our understanding of factors that may influence minority recruitment and helped us integrate strategies from multiple disciplines that were relevant for our audience.
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Ensayos Clínicos como Asunto/métodos , Diversidad Cultural , Etnicidad , Capacitación en Servicio , Grupos Minoritarios , Selección de Paciente , Grupos Raciales , Investigadores/educación , Sujetos de Investigación , Actitud del Personal de Salud , Disparidades en Atención de Salud/etnología , Humanos , Relaciones Interpersonales , Derivación y Consulta , Investigadores/psicología , Participación de los Interesados , ConfianzaRESUMEN
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.
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Ciencias Bioconductuales/estadística & datos numéricos , Conductas Relacionadas con la Salud , Cadenas de Markov , Algoritmos , Teorema de Bayes , Bioestadística , Simulación por Computador , Humanos , Funciones de Verosimilitud , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricosRESUMEN
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.
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Unidades Móviles de Salud , Accidente Cerebrovascular/terapia , Telemedicina/métodos , Telemedicina/tendencias , Femenino , Estudios de Seguimiento , Humanos , Masculino , Unidades Móviles de Salud/tendencias , Estadísticas no Paramétricas , Activador de Tejido Plasminógeno/uso terapéutico , Resultado del TratamientoRESUMEN
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.
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Pruebas de Estado Mental y Demencia , Enfermedad de Parkinson/diagnóstico , Índice de Severidad de la Enfermedad , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Israel , Lenguaje , Masculino , Persona de Mediana Edad , TraducciónRESUMEN
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<0.05) between QTcB and PD severity in individuals that were taking QT-interval affecting drugs. A longer QT-interval at baseline was associated with more advanced PD at 5years (P<0.05), and greater disease progression over 5years (P<0.05). There was an association between diminished HRV and an orthostatic decrease in standing blood pressure at baseline in individuals with PD (P<0.05). HRV was not associated with PD severity or progression. In conclusion, we were able to detect measurable associations between the QTcB interval and PD severity, PD severity 5years later, and the change in disease over time. However, routine ECG tracings appear inadequate for the evaluation of autonomic function in PD.
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Electrocardiografía , Frecuencia Cardíaca , Enfermedad de Parkinson/fisiopatología , Factores de Edad , Antiparkinsonianos/uso terapéutico , Sistema Nervioso Autónomo/efectos de los fármacos , Sistema Nervioso Autónomo/fisiopatología , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/tratamiento farmacológico , Índice de Severidad de la EnfermedadRESUMEN
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.
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Investigación Biomédica/métodos , Grupos Minoritarios , Selección de Paciente , Proyectos de Investigación , Disparidades en Atención de Salud/etnología , Humanos , Estudios Multicéntricos como Asunto , National Institutes of Health (U.S.) , Proyectos Piloto , Mejoramiento de la Calidad , Derivación y Consulta , Estados UnidosRESUMEN
Caffeine is neuroprotective in animal models of Parkinson's disease (PD) and caffeine intake is inversely associated with the risk of 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.
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Cafeína/uso terapéutico , Creatina/uso terapéutico , Predisposición Genética a la Enfermedad/genética , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/genética , Receptores de N-Metil-D-Aspartato/genética , Anciano , Cafeína/metabolismo , Progresión de la Enfermedad , Femenino , Interacción Gen-Ambiente , Genotipo , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
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.
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BACKGROUND: 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. METHODS: 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. RESULTS: 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) (p < 0.001). Twenty-four-hour mortality was 19% with DCL versus 4% (p < 0.001); 30-day mortality was 28% with DCL versus 19% (p < 0.001). 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 (p < 0.05). Eighty percent (135/213) of DCL patients met standard criteria. CONCLUSION: 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. LEVEL OF EVIDENCE: Therapeutic study, level III.
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Traumatismos Abdominales/cirugía , Hemorragia/terapia , Laparotomía/estadística & datos numéricos , Traumatismos Abdominales/mortalidad , Adulto , Transfusión Sanguínea/estadística & datos numéricos , Femenino , Humanos , Relación Normalizada Internacional , Laparotomía/efectos adversos , Laparotomía/mortalidad , Masculino , Persona de Mediana Edad , América del Norte , Centros Traumatológicos , Resultado del TratamientoRESUMEN
BACKGROUND: 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. METHODS: 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. RESULTS: 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 2.6âh. Approximately 85% of hemorrhagic deaths occur within 6âh. 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 6âh toâ<0.1% per hour by 9âh and thereafter. Early primary endpoints (within 6âh) 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. CONCLUSIONS: 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 6âh 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.
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Hemorragia/etiología , Hemorragia/mortalidad , Choque Hemorrágico/complicaciones , Choque Hemorrágico/mortalidad , Heridas y Lesiones/complicaciones , Heridas y Lesiones/mortalidad , Hemorragia/terapia , Humanos , Estudios Prospectivos , Resucitación , Choque Hemorrágico/terapia , Heridas y Lesiones/terapiaRESUMEN
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 (SDâ=â1.4) 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 (SEâ=â0.002, pâ=â0.001). Significant associations between duration of MAO-B inhibitor exposure and less progression were observed for ADL (pâ<â0.001), Ambulatory Capacity (pâ<â0.001), and the Rankin (pâ=â0.002). 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.
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Progresión de la Enfermedad , Inhibidores de la Monoaminooxidasa/farmacología , Evaluación de Resultado en la Atención de Salud/métodos , Enfermedad de Parkinson/tratamiento farmacológico , Índice de Severidad de la Enfermedad , Anciano , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de la Monoaminooxidasa/administración & dosificación , Factores de TiempoRESUMEN
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.
RESUMEN
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.