Second-line tislelizumab versus chemotherapy in Japanese patients with advanced or metastatic esophageal squamous cell carcinoma: subgroup analysis from RATIONALE-302.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) has a poor prognosis, with limited second-line systemic therapy options, and represents an increasing disease burden in Japan. In the phase 3 RATIONALE-302 study, the anti-programmed cell death protein 1 antibody, tislelizumab, significantly improved overall survival (OS) versus chemotherapy as second-line treatment for advanced/metastatic ESCC. Here, we report the Japanese patient subgroup results. METHODS: Patients with advanced/metastatic ESCC, with disease progression during/after first-line systemic therapy were randomized 1:1 to open-label tislelizumab 200 mg every 3 weeks or investigator's choice of chemotherapy (paclitaxel/docetaxel). Efficacy and safety were assessed in all randomized Japanese patients. RESULTS: The Japanese subgroup comprised 50 patients (n = 25 per arm). Tislelizumab improved OS versus chemotherapy (median: 9.8 vs. 7.6 months; HR 0.59; 95% CI 0.31, 1.12). Among patients with programmed death-ligand 1 score ≥ 10%, median OS was 12.5 months with tislelizumab (n = 10) versus 2.9 months with chemotherapy (n = 6) (HR 0.31; 95% CI 0.09, 1.03). Tislelizumab improved progression-free survival versus chemotherapy (median: 3.6 vs. 1.7 months, respectively; HR 0.50; 95% CI 0.27, 0.95). Objective response rate was greater with tislelizumab (32.0%) versus chemotherapy (20.0%), and responses were more durable (median duration of response: 8.8 vs. 2.6 months, respectively). Fewer patients experienced ≥ grade 3 treatment-related adverse events with tislelizumab (24.0%) versus chemotherapy (47.8%). Tislelizumab demonstrated an improvement in health-related quality of life versus chemotherapy. CONCLUSIONS: As second-line therapy for advanced/metastatic ESCC, tislelizumab improved OS versus chemotherapy, with a favorable safety profile, in the Japanese patient subgroup, consistent with the overall population. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov: NCT03430843.

Proportional likelihood ratio mixed model for discrete longitudinal data.

Rathouz and Gao [2] and Luo and Tsai [3] proposed valuable extensions to the generalized linear model for modeling a nonlinear monotonic relationship between the mean response and a set of covariates. In their extensions for discrete data the baseline response distribution is unspecified and is estimated from the data. We propose to extend this model for the analysis of longitudinal data by incorporating random effects into the linear predictor, and using maximum likelihood for estimation and inference. Motivated in particular by longitudinal studies of clinical scale outcomes, we developed an estimation procedure for a finite-support response using a generalized expectation-maximization algorithm where Gauss-Hermite quadrature is employed to approximate the integrals in the E step of the algorithm. Upon convergence, the observed information matrix is estimated through second-order numerical differentiation of the log-likelihood function. Asymptotic properties of the maximum likelihood estimates follow under the usual regularity conditions. Simulation studies are conducted to assess its finite-sample properties and compare the proposed model to the generalized linear mixed model. The proposed method is illustrated in an analysis of data from a longitudinal study of Huntington's disease.

Longitudinal beta-binomial modeling using GEE for overdispersed binomial data.

Longitudinal binomial data are frequently generated from multiple questionnaires and assessments in various scientific settings for which the binomial data are often overdispersed. The standard generalized linear mixed effects model may result in severe underestimation of standard errors of estimated regression parameters in such cases and hence potentially bias the statistical inference. In this paper, we propose a longitudinal beta-binomial model for overdispersed binomial data and estimate the regression parameters under a probit model using the generalized estimating equation method. A hybrid algorithm of the Fisher scoring and the method of moments is implemented for computing the method. Extensive simulation studies are conducted to justify the validity of the proposed method. Finally, the proposed method is applied to analyze functional impairment in subjects who are at risk of Huntington disease from a multisite observational study of prodromal Huntington disease. Copyright © 2016 John Wiley & Sons, Ltd.

Lighting and marking policies are associated with reduced farm equipment-related crash rates: a policy analysis of nine Midwestern US states.

OBJECTIVE: To evaluate the effectiveness of roadway policies for lighting and marking of farm equipment in reducing crashes in Illinois, Iowa, Kansas, Minnesota, Missouri, Nebraska, North Dakota, South Dakota and Wisconsin. METHODS: In this ecological study, state policies on lighting and marking of farm equipment were scored for compliance with standards of the American Society of Agricultural and Biological Engineers (ASABE). Using generalized estimating equations negative binomial models, we estimated the relationships between lighting and marking scores, and farm equipment crash rates, per 100 000 farm operations. RESULTS: A total of 7083 crashes involving farm equipment was reported from 2005 to 2010 in the Upper Midwest and Great Plains. As the state lighting and marking score increased by 5 units, crash rates reduced by 17% (rate ratio=0.83; 95% CI 0.78 to 0.88). Lighting-only (rate ratio=0.48; 95% CI 0.45 to 0.51) and marking-only policies (rate ratio=0.89; 95% CI 0.83 to 0.96) were each associated with reduced crash rates. CONCLUSIONS: Aligning lighting and marking policies with ASABE standards may effectively reduce crash rates involving farm equipment.

The effect of field condition and shoe type on lower extremity injuries in American Football.

BACKGROUND/AIM: Considerable improvement has been made in football field surfaces and types of shoe, yet relatively few epidemiological studies have investigated their roles in the risk of football injuries. This study examined the effects of field surface, surface condition and shoe type on the likelihood of lower extremity football injuries. METHODS: Deidentified data from 188 players from one division I university football team during the 2007-2010 seasons were analysed. Lower extremity injury rate and rate ratio, along with 95% confidence limits, were calculated by football activity, playing surface condition and shoe type. RESULTS: A total of 130 lower extremity injuries were sustained, with an overall lower extremity injury rate of 33.5/10 000 athlete-sessions. The lower extremity injury rate was 2.61 times higher when the surface condition was abnormal compared with when the surface condition was normal. During games, the risk for lower extremity injury was 3.34 times higher (95% CI 1.70 to 6.56) on artificial turf compared with natural grass. However, this trend was not statistically significant in practice sessions. Furthermore, neither the number of shoe cleats nor the height of the shoe top was statistically associated with risk of lower extremity injuries. CONCLUSIONS: Football players who played on artificial turf or when the surface condition was abnormal were susceptible to lower extremity injuries. Evidence from this study suggests that further research into playing surfaces and shoe types may provide fruitful opportunities to reduce injuries to collegiate football players.

PD-1 Blockade in Anaplastic Thyroid Carcinoma.

PURPOSE: Anaplastic thyroid carcinoma is an aggressive malignancy that is almost always fatal and lacks effective systemic treatment options for patients with BRAF-wild type disease. As part of a phase I/II study in patients with advanced/metastatic solid tumors, patients with anaplastic thyroid carcinoma were treated with spartalizumab, a humanized monoclonal antibody against the programmed death-1 (PD-1) receptor. METHODS: We enrolled patients with locally advanced and/or metastatic anaplastic thyroid carcinoma in a phase II cohort of the study. Patients received 400 mg spartalizumab intravenously, once every 4 weeks. The overall response rate was determined according to RECIST v1.1. RESULTS: Forty-two patients were enrolled. Adverse events were consistent with those previously observed with PD-1 blockade. Most common treatment-related adverse events were diarrhea (12%), pruritus (12%), fatigue (7%), and pyrexia (7%). The overall response rate was 19%, including three patients with a complete response and five with a partial response. Most patients had baseline tumor biopsies positive for PD-L1 expression (n = 28/40 evaluable), and response rates were higher in PD-L1-positive (8/28; 29%) versus PD-L1-negative (0/12; 0%) patients. The highest rate of response was observed in the subset of patients with PD-L1 ≥ 50% (6/17; 35%). Responses were seen in both BRAF-nonmutant and BRAF-mutant patients and were durable, with a 1-year survival of 52.1% in the PD-L1-positive population. CONCLUSION: To our knowledge, this is the first clinical trial to show responsiveness of anaplastic thyroid carcinoma to PD-1 blockade.

A first-in-human phase 1 dose escalation study of spartalizumab (PDR001), an anti-PD-1 antibody, in patients with advanced solid tumors.

BACKGROUND: Spartalizumab is a humanized IgG4κ monoclonal antibody that binds programmed death-1 (PD-1) and blocks its interaction with PD-L1 and PD-L2. This phase 1/2 study was designed to assess the safety, pharmacokinetics, and preliminary efficacy of spartalizumab in patients with advanced or metastatic solid tumors. METHODS: In the phase 1 part of the study, 58 patients received spartalizumab, intravenously, at doses of 1, 3, or 10 mg/kg, administered every 2 weeks (Q2W), or 3 or 5 mg/kg every 4 weeks (Q4W). RESULTS: Patients had a wide range of tumor types, most commonly sarcoma (28%) and metastatic renal cell carcinoma (10%); other tumor types were reported in ≤3 patients each. Most patients (93%) had received prior antineoplastic therapy (median three prior lines) and two-thirds of the population had tumor biopsies negative for PD-L1 expression at baseline. The maximum tolerated dose was not reached. The recommended phase 2 doses were selected as 400 mg Q4W or 300 mg Q3W. No dose-limiting toxicities were observed, and adverse events included those typical of other PD-1 antibodies. The most common treatment-related adverse events of any grade were fatigue (22%), diarrhea (17%), pruritus (14%), hypothyroidism (10%), and nausea (10%). Partial responses occurred in two patients (response rate 3.4%); one with atypical carcinoid tumor of the lung and one with anal cancer. Paired tumor biopsies from patients taken at baseline and on treatment suggested an on-treatment increase in CD8+ lymphocyte infiltration in patients with clinical benefit. CONCLUSIONS: Spartalizumab was well tolerated at all doses tested in patients with previously treated advanced solid tumors. On-treatment immune activation was seen in tumor biopsies; however, limited clinical activity was reported in this heavily pretreated, heterogeneous population. The phase 2 part of this study is ongoing in select tumor types. TRIAL REGISTRATION NUMBER: NCT02404441.

Public health application of predictive modeling: an example from farm vehicle crashes.

BACKGROUND: The goal of predictive modelling is to identify the likelihood of future events, such as the predictive modelling used in climate science to forecast weather patterns and significant weather occurrences. In public health, increasingly sophisticated predictive models are used to predict health events in patients and to screen high risk individuals, such as for cardiovascular disease and breast cancer. Although causal modelling is frequently used in epidemiology to identify risk factors, predictive modelling provides highly useful information for individual risk prediction and for informing courses of treatment. Such predictive knowledge is often of great utility to physicians, counsellors, health education specialists, policymakers or other professionals, who may then advice course correction or interventions to prevent adverse health outcomes from occurring. In this manuscript, we use an example dataset that documents farm vehicle crashes and conventional statistical methods to forecast the risk of an injury or death in a farm vehicle crash for a specific individual or a scenario. RESULTS: Using data from 7094 farm crashes that occurred between 2005 and 2010 in nine mid-western states, we demonstrate and discuss predictive model fitting approaches, model validation techniques using external datasets, and the calculation and interpretation of predicted probabilities. We then developed two automated risk prediction tools using readily available software packages. We discuss best practices and common limitations associated with predictive models built from observational datasets. CONCLUSIONS: Predictive analysis offers tools that could aid the decision making of policymakers, physicians, and environmental health practitioners to improve public health.

Prevalence of alcohol impairment and odds of a driver injury or fatality in on-road farm equipment crashes.

OBJECTIVE: The objective of this article was to estimate the prevalence of alcohol impairment in crashes involving farm equipment on public roadways and the effect of alcohol impairment on the odds of crash injury or fatality. METHODS: On-road farm equipment crashes were collected from 4 Great Plains state departments of transportation during 2005-2010. Alcohol impairment was defined as an involved driver having blood alcohol content of ≥0.08 g/100 ml or a finding of alcohol impairment as a driver contributing circumstance recorded on the police crash report. Injury or fatality was categorized as (a) no injury (no and possible injury combined), (b) injury (nonincapacitating or incapacitating injury), and (c) fatality. Hierarchical multivariable logistic regression modeling, clustered on crash, was used to estimate the odds of an injury/fatality in crashes involving an alcohol-impaired driver. RESULTS: During the 5 years under study, 3.1% (61 of 1971) of on-road farm equipment crashes involved an alcohol-impaired driver. One in 20 (5.6%) injury crashes and 1 in 6 (17.8%) fatality crashes involved an alcohol-impaired driver. The non-farm equipment driver was significantly more likely to be alcohol impaired than the farm equipment driver (2.4% versus 1.1% respectively, P = .0012). After controlling for covariates, crashes involving an alcohol-impaired driver had 4.10 (95% confidence interval [CI], 2.30-7.28) times the odds of an injury or fatality. In addition, the non-farm vehicle driver was at 2.28 (95% CI, 1.92-2.71) times higher odds of an injury or fatality than the farm vehicle driver. No differences in rurality of the crash site were found in the multivariable model. CONCLUSION: On-road farm equipment crashes involving alcohol result in greater odds of an injury or fatality. The risk of injury or fatality is higher among the non-farm equipment vehicle drivers who are also more likely to be alcohol impaired. Further studies are needed to measure the impact of alcohol impairment in on-road farm equipment crashes.

A comparative analysis of child passenger restraint use in China and the United States.

BACKGROUND: Few published studies have examined child passenger safety practices across countries. This study compared the prevalence and associated factors of child passenger restraint use among children, aged 0 to 17 in the state of Iowa in the United States, and the city of Shantou in China. METHODS: Child restraint use observations were conducted in Iowa and in Shantou in 2012, respectively, among child passengers. Observations in Iowa were conducted at randomly selected gas stations, while in Shantou observations were completed at randomly selected schools or medical clinics. Research observers approached the driver, observed restraint use, and collected brief survey data. RESULTS: A total of 3049 children from Iowa and 3333 children aged 0 to 17 years from Shantou were observed. For children aged 0 to 3 years, only 0.1% were compliantly restrained in Shantou as compared to 95.9% in Iowa. The proportion of children who were compliantly restrained in Shantou increased with age, but generally decreased with age in Iowa. In Shantou, 36.0% of children aged 0 to 3 were sitting in the front seat as compared to only 1.7% of children of the same age in Iowa. Driver seat belt use was significantly associated with child restraint in both Iowa and Shantou; the association was stronger in Iowa than Shantou for all age groups. CONCLUSIONS: A significantly higher prevalence of children who were not appropriately restrained was observed in Shantou than in Iowa. Our findings support the need of mandatory child safety restraint use legislation in China.

Disaster Preparedness in Rural Families of Children With Special Health Care Needs.

OBJECTIVE: The purpose of this study was to describe disaster preparedness strategies and behaviors among rural families who have children with special health care needs and to examine the effect of self-efficacy and response-efficacy on disaster preparedness. METHODS: Data for this study were drawn from the baseline surveys of 287 rural families with children with special health care needs who were part of a randomized controlled trial examining the impact of an intervention on disaster preparedness. Distributions of child, parent, and family characteristics were examined by preparedness. Linear regression models were built to examine the impact of self-efficacy and response-efficacy on level of disaster preparedness. RESULTS: Disaster preparedness (overall, emergency plan, discussion/practice, and supplies) was low (40.9-69.7%) among study families. Disaster preparedness was found to increase with each unit increase in the level of self-efficacy and family resilience sources across all 4 categories of preparedness. CONCLUSIONS: Disaster preparedness among rural families with children with special health care needs is low, which is concerning because these children may have increased vulnerability to adverse outcomes compared to the general population. Results suggest that increasing the levels of self-efficacy and family resilience sources may increase disaster preparedness.

Video-Enhanced Telemedicine Improves the Care of Acutely Injured Burn Patients in a Rural State.

The acute care of burn patients is critical and can be a daunting experience for emergency personnel because of the scarcity of burn injuries. Telemedicine that incorporates a visual component can provide immediate expertise in the treatment and management of these injuries. The authors sought to evaluate the addition of video telemedicine to our current telephone burn transfer program. During a 2-year period, 282 patients, 59.4% of all burn patients transferred from outside hospitals, were enrolled in the study. In addition to the scripted call with the charge nurse (ChargeRN) and the accepting physician, nine hospitals also transmitted video images of the wounds before transfer as part of a store and forward telemedicine transfer program (77, 27.6%). The accuracy of burn size estimations (BSA burned) and management changes (fluid requirements, transfer mode, and final disposition) were analyzed between the telephones-only sites (T only) and the video-enhanced sites. Referringstaff participating in video-enhanced telemedicine were sent a Google survey assessing their experience the following day. The referring staff (Referringstaff) was correct in their burn assessment 20% of the time. Video assessment improved the ChargeRN BSA burned and resulted in more accurate fluid resuscitation (P = .030), changes in both transportation mode (P = .042), and disposition decisions (P = .20). The majority of the Referringstaff found that video-enhanced telemedicine helped them communicate with the burn staff more effectively (3.4 ± 0.37, scale 1-4). This study reports the successful implementation of video-enhanced telemedicine pilot project in a rural state. Video-enhanced telemedicine using a store and forward process improved burn size estimation and facilitated management changes. Although not quantitatively assessed, the low cost of the system coupled with the changes in transportation and disposition strongly suggests a decrease in healthcare costs associated with the addition of video to a telephone-only transfer program.