The Alliance AMBUSH Trial: Rationale and Design

Unlike medulloblastoma (MB) in children, robust prospective trials have not taken place for older patients due to the low incidence of MB in adults and adolescent and young adults (AYA). Current MB treatment paradigms for older patients have been extrapolated from the pediatric experience even though questions exist about the applicability of these approaches. Clinical and molecular classification of MB now provides better prognostication and is being incorporated in pediatric therapeutic trials. It has been established that genomic alterations leading to activation of the sonic hedgehog (SHH) pathway occur in approximately 60% of MB in patients over the age of 16 years. Within this cohort, protein patched homolog (PTCH) and smoothened (SMO) mutations are commonly found. Among patients whose tumors harbor the SHH molecular signature, it is estimated that over 80% of patients could respond to SHH pathway inhibitors. Given the advances in the understanding of molecular subgroups and the lack of robust clinical data for adult/AYA MB, the Alliance for Clinical Trial in Oncology group developed the AMBUSH trial: Comprehensive Management of AYA and Adult Patients with Medulloblastoma or Pineal Embryonal Tumors with a Randomized Placebo Controlled Phase II Focusing on Sonic Hedgehog Pathway Inhibition in SHH Subgroup Patients (Adult & Adolescent MedulloBlastoma Using Sonic Hedgehog Trial). This trial will enroll patients 18 years of age or older with MB (any molecular subgroup and risk stratification) or pineal embryonal tumor. Patients will be assigned to one of three cohorts: (1) average risk non-SHH-MB, (2) average risk SHH-MB, and (3) high risk MB or pineal embryonal tumors. All patients will receive protocol-directed comprehensive treatment with radiation therapy and chemotherapy. Patients with SHH-MB in cohort 1 will be randomized to a smoothened inhibitor or placebo as maintenance therapy for one year.

Breakage of intramedullary femoral nailing or femoral plating: how to prevent implant failure

Introduction Intramedullary (IM) fixation is the dominant treatment for pertrochanteric and femoral shaft fractures. In comparison to plate osteosynthesis (PO), IM fixation offers greater biomechanical stability and reduced non-union rates. Due to the minimally invasive nature, IM fixations are less prone to approach-associated complications, such as soft-tissue damage, bleeding or postoperative infection, but they are more prone to fat embolism. A rare but serious complication, however, is implant failure. Thus, the aim of this study was to identify possible risk factors for intramedullary fixation (IMF) and plate osteosynthesis (PO) failure. Materials and methods We searched our trauma surgery database for implant failure, intramedullary and plate osteosynthesis, after proximal—pertrochanteric, subtrochanteric—or femoral shaft fractures between 2011 and 2019. Implant failures in both the IMF and PO groups were included. Demographic data, fracture type, quality of reduction, duration between initial implantation and nail or plate failure, the use of cerclages, intraoperative microbiological samples, sonication, and, if available, histology were collected. Results A total of 24 femoral implant failures were identified: 11 IMFs and 13 POs. The average age of patients in the IM group was 68.2 ± 13.5 years and in the PO group was 65.6 ± 15.0 years, with men being affected in 63.6% and 39.5% of cases, respectively. A proximal femoral nail (PFN) anti-rotation was used in 7 patients, a PFN in one and a gamma nail in two patients. A total of 6 patients required cerclage wires for additional stability. A combined plate and intramedullary fixation was chosen in one patient. Initially, all intramedullary nails were statically locked. Failures were observed 34.1 weeks after the initial surgery on average. Risk factors for implant failure included the application of cerclage wires at the level of the fracture (n = 5, 21%), infection (n = 2, 8%), and the use of an additional sliding screw alongside the femoral neck screw (n = 3, 13%). In all patients, non-union was diagnosed radiographically and clinically after 6 months (n = 24, 100%). In the event of PO failure, the placement of screws within all screw holes, and interprosthetic fixation were recognised as the major causes of failure. Conclusion Intramedullary or plate osteosynthesis remain safe and reliable procedures in the treatment of proximal femoral fractures (pertrochanteric, subtrochanteric and femoral shaft fractures). Nevertheless, the surgeon needs to be aware of several implant-related limitations causing implant breakage. These may include the application of tension band wiring which can lead to a too rigid fixation, or placement of cerclage wires at the fracture site.

Causes and consequences of psychological stress in the working life and emergency services of veterinary professionals in the Federal Republic of Germany: A protocol for a nationwide cross-sectional study

Background: Veterinarians are exposed to high workloads. International studies show they have an above-average risk of suicide and burnout. Hardly any studies dealing with causes and consequences of workload and emergency services are available in Germany. Methods: The aim of the observational cross-sectional study presented here is to assess their workloads and working conditions (Slesina questionnaire), health situation and well-being (KÖPS questionnaire - physical, psychological and social symptoms; Maslach Burnout Inventory MBI-GS; WHO-5 well-being index), as well as occupational psychological aspects (irritation scales; overcommitment; questionnaire on work-related behavior and experience patterns AVEM) which will be recorded and analyzed according to general sociodemographic and occupational data (sector-, gender, assignment- and country-specific). In addition, the heart rate variability of some members of the veterinary profession will be analyzed using 24 hour electrocardiogram recordings, which together with the subjective insights into the stress situation from the questionnaires, will allow objective psychophysiological stress analyses. Conclusions: The results of the study will provide further empirical insights into the workloads and stresses faced by the veterinary profession in Germany, based on which important insights into this professional group’s mental health can be identified. In this way, it should be possible to identify (mis)stress-triggering factors in the target groups, derive target group-specific recommendations for health-promoting work design, and identify approaches to veterinary studies and career selection.

Diet- and Lifestyle‐Based Prediction Models to Estimate Cancer Recurrence and Death in Patients With Stage III Colon Cancer (CALGB 89803/Alliance)

PURPOSE Current tools in predicting survival outcomes for patients with colon cancer predominantly rely on clinical and pathologic characteristics, but increasing evidence suggests that diet and lifestyle habits are associated with patient outcomes and should be considered to enhance model accuracy. METHODS Using an adjuvant chemotherapy trial for stage III colon cancer (CALGB 89803), we developed prediction models of disease-free survival (DFS) and overall survival by additionally incorporating self-reported nine diet and lifestyle factors. Both models were assessed by multivariable Cox proportional hazards regression and externally validated using another trial for stage III colon cancer (CALGB/SWOG 80702), and visual nomograms of prediction models were constructed accordingly. We also proposed three hypothetical scenarios for patients with (1) good-risk, (2) average-risk, and (3) poor-risk clinical and pathologic features, and estimated their predictive survival by considering clinical and pathologic features with or without adding self-reported diet and lifestyle factors. RESULTS Among 1,024 patients (median age 60.0 years, 43.8% female), we observed 394 DFS events and 311 deaths after median follow-up of 7.3 years. Adding self-reported diet and lifestyle factors to clinical and pathologic characteristics meaningfully improved performance of prediction models (c-index from 0.64 [95% CI, 0.62 to 0.67] to 0.69 [95% CI, 0.67 to 0.72] for DFS, and from 0.67 [95% CI, 0.64 to 0.70] to 0.71 [95% CI, 0.69 to 0.75] for overall survival). External validation also indicated good performance of discrimination and calibration. Adding most self-reported favorable diet and lifestyle exposures to multivariate modeling improved 5-year DFS of all patients and by 6.3% for good-risk, 21.4% for average-risk, and 42.6% for poor-risk clinical and pathologic features. CONCLUSION Diet and lifestyle factors further inform current recurrence and survival prediction models for patients with stage III colon cancer.

Effects of Lockdowns And Its Impacts On Age-Specific Transmission Dynamics of SARS-Cov-2 In Georgia, USA

Social distancing measures are effective in reducing overall community transmission but much remains unknown about how they have impacted finer-scale dynamics. In particular, much is unknown about how changes of contact patterns and other behaviors including adherence to social distancing, induced by these measures, may have impacted finer-scale transmission dynamics among different age groups. In this paper, we build a stochastic age-specific transmission model to systematically characterize the degree and variation of age-specific transmission dynamics, before and after lifting the lockdown in Georgia, USA. We perform Bayesian (missing-) data-augmentation model inference, leveraging reported age-specific case, seroprevalence and mortality data. We estimate that community-level transmissibility was reduced to 41.2% with 95% CI [39%, 43.8%] of the pre-lockdown level in about a week of the announcement of the shelter-in-place order. Although it subsequently increased after the lockdown was lifted, it only bounced back to 62% [58%, 67.2%] of the pre-lockdown level after about a month. We also find that during the lockdown susceptibility to infection increases with age. Specifically, relative to the oldest age group (>65+), susceptibility for the youngest age group (0-17 years) is 0.13 [0.09, 0.18], and it increases to 0.53 [0.49, 0.59] for 18-44 and 0.75 [0.68, 0.82] for 45- 64. More importantly, our results reveal clear changes of age-specific susceptibility (defined as average risk of getting infected during an infectious contact incorporating age-dependent behavioral factors) after the lockdown was lifted, with a trend largely consistent with reported age-specific adherence levels to social distancing and preventive measures. Specifically, the older groups (>45) (with the highest levels of adherence) appear to have the most significant reductions of susceptibility (e.g., post-lockdown susceptibility reduced to 31.6% [29.3%, 34%] of the estimate before lifting the lockdown for the 65+ group). Finally, we find heterogeneity in case reporting rates among different age groups, with the lowest rate occurring among the 0-18 group (9.7% [6.4%, 19%]). Our results provide a more fundamental understanding of the impacts of stringent lockdown measures, and finer evidence that other social distancing and preventive measures may be effective in reducing SARS-CoV-2 transmission. These results may be exploited to guide more effective implementations of these measures in many current settings (with low vaccination rate globally and emerging variants) and in future potential outbreaks of novel pathogens.

A Randomized Clinical Trial of Precision Prevention Materials Incorporating MC1R Genetic Risk to Improve Skin Cancer Prevention Activities Among Hispanics

Purpose: Skin cancer incidence is increasing among Hispanics, who experience worse outcomes than non-Hispanic Whites. Precision prevention incorporating genetic testing for (melanocortin-1 receptor) MC1R, a skin cancer susceptibility marker, may improve prevention behavior. Experimental Design: Hispanic participants (n = 920) from Tampa, FL and Ponce, PR, were block-randomized within MC1R higher- and average-risk groups to precision prevention or generic prevention arms. We collected baseline information on demographics, family history of cancer, phenotypic characteristics, health literacy, health numeracy, and psychosocial measures. Participants reported weekday and weekend sun exposure (in hours), number of sunburns, frequency of five sun protection behaviors, intentional outdoor and indoor tanning, and skin examinations at baseline, 3 months, and 9 months. Participants also reported these outcomes for their eldest child ≤10 years old. Results: Among MC1R higher-risk participants, precision prevention increased sunscreen use (OR = 1.74, P = 0.03) and receipt of a clinical skin exam (OR = 6.51, P = 0.0006); and it decreased weekday sun exposure hours (β = −0.94, P = 0.005) and improved sun protection behaviors (β = 0.93, P = 0.02) in their children. There were no significant intervention effects among MC1R average-risk participants. The intervention did not elevate participant cancer worry. We also identified moderators of the intervention effect among both average- and higher-risk participants. Conclusions: Receipt of MC1R precision prevention materials improved some skin cancer prevention behaviors among higher-risk participants and their children and did not result in reduced prevention activities among average-risk participants. Despite these encouraging findings, levels of sun protection behaviors remained suboptimal among participants, warranting more awareness and prevention campaigns targeted to Hispanics Significance: Our results support a precision public health approach to reducing skin cancers among Hispanics, an underserved population in precision medicine, and may additionally improve preventive behaviors among their children.

Terrorism Risk Assessment to Children: A Study in Poso

The long history of conflict in Poso, Indonesia, causes the trauma of people living in the area, including children. This study aims to examine the risks and needs of children raised amongst terrorist organizations in Poso. 33 children whose parents were involved in terrorist groups were assessed in this study and analyzed using quantitative and qualitative methods. The findings show that the average risk is 1.35, which is at low risk. Moreover, they need to be addressed to prevent them from joining terrorist groups. The findings could help educational and counterterrorism practitioners to plan an intervention for children raised within the terrorism movement in Poso.

IMPROVING AUTOMOBILE INSURANCE CLAIMS FREQUENCY PREDICTION WITH TELEMATICS CAR DRIVING DATA

Novel navigation applications provide a driving behavior score for each finished trip to promote safe driving, which is mainly based on experts’ domain knowledge. In this paper, with automobile insurance claims data and associated telematics car driving data, we propose a supervised driving risk scoring neural network model. This one-dimensional convolutional neural network takes time series of individual car driving trips as input and returns a risk score in the unit range of (0,1). By incorporating credibility average risk score of each driver, the classical Poisson generalized linear model for automobile insurance claims frequency prediction can be improved significantly. Hence, compared with non-telematics-based insurers, telematics-based insurers can discover more heterogeneity in their portfolio and attract safer drivers with premiums discounts.