Epidemiology of International Match Injuries in Scottish Rugby: A Prospective Cohort Study.

Fifteen-a-side rugby union ("rugby") is a full-contact sport played separately by men and women, with large injury incidences reported previously. Context specific injury surveillance fulfils governing bodies' duty of care to understand risks to player welfare, yet no contemporary match injury epidemiology studies exist for international players in Scotland. The current study therefore aimed to describe the incidence, severity, burden and nature of match injuries sustained by Scotland's men's and women's national teams. A prospective cohort study of injuries recorded in matches across the 2017/18 and 2018/19 seasons was undertaken, with injury and exposure definitions in line with the international consensus for injury surveillance in rugby. Injury incidence was 120.0 (men) and 166.7/1,000 player match hours (women), injury severity was 12.0 (median) and 31.2 days (mean) for men, and 11.0 (median) and 30.2 days (mean) for women. Injury burden was 3,745 (men) and 5,040 days absence/1,000 player match hours (women). Concussion was the most common specific injury for men (22.5/1,000 hours) and women (26.7/1,000 hours). No statistical differences were found for incidence or severity measures between sexes. Injury incidence was greater than recent Rugby World Cup studies. High incidences of concussion reinforces the need for prevention strategies targeting this injury.

Prevention strategies and modifiable risk factors for sport-related concussions and head impacts: a systematic review and meta-analysis.

OBJECTIVES: To evaluate prevention strategies, their unintended consequences and modifiable risk factors for sport-related concussion (SRC) and/or head impact risk. DESIGN: This systematic review and meta-analysis was registered on PROSPERO (CRD42019152982) and conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. DATA SOURCES: Eight databases (MEDLINE, CINAHL, APA PsycINFO, Cochrane (Systematic Review and Controlled Trails Registry), SPORTDiscus, EMBASE, ERIC0 were searched in October 2019 and updated in March 2022, and references searched from any identified systematic review. ELIGIBILITY CRITERIA: Study inclusion criteria were as follows: (1) original data human research studies, (2) investigated SRC or head impacts, (3) evaluated an SRC prevention intervention, unintended consequence or modifiable risk factor, (4) participants competing in any sport, (5) analytic study design, (6) systematic reviews and meta-analyses were included to identify original data manuscripts in reference search and (7) peer-reviewed. Exclusion criteria were as follows: (1) review articles, pre-experimental, ecological, case series or case studies and (2) not written in English. RESULTS: In total, 220 studies were eligible for inclusion and 192 studies were included in the results based on methodological criteria as assessed through the Scottish Intercollegiate Guidelines Network high ('++') or acceptable ('+') quality. Evidence was available examining protective gear (eg, helmets, headgear, mouthguards) (n=39), policy and rule changes (n=38), training strategies (n=34), SRC management strategies (n=12), unintended consequences (n=5) and modifiable risk factors (n=64). Meta-analyses demonstrated a protective effect of mouthguards in collision sports (incidence rate ratio, IRR 0.74; 95% CI 0.64 to 0.89). Policy disallowing bodychecking in child and adolescent ice hockey was associated with a 58% lower concussion rate compared with bodychecking leagues (IRR 0.42; 95% CI 0.33 to 0.53), and evidence supports no unintended injury consequences of policy disallowing bodychecking. In American football, strategies limiting contact in practices were associated with a 64% lower practice-related concussion rate (IRR 0.36; 95% CI 0.16 to 0.80). Some evidence also supports up to 60% lower concussion rates with implementation of a neuromuscular training warm-up programme in rugby. More research examining potentially modifiable risk factors (eg, neck strength, optimal tackle technique) are needed to inform concussion prevention strategies. CONCLUSIONS: Policy and rule modifications, personal protective equipment, and neuromuscular training strategies may help to prevent SRC. PROSPERO REGISTRATION NUMBER: CRD42019152982.

Injury Rates, Mechanisms, Risk Factors and Prevention Strategies in Youth Rugby Union: What's All the Ruck-Us About? A Systematic Review and Meta-analysis.

BACKGROUND: Rugby Union is a collision team sport played globally. Despite this, significant concerns have been raised regarding the sport's safety, particularly in youth players. Given this, a review of injury rates, risk factors and prevention strategies is required across different youth age groups as well as in males and females. OBJECTIVE: The objective of this systematic review (SR) and meta-analysis was to investigate injury and concussion rates, risk factors and primary prevention strategies in youth rugby. METHODS: To be included, studies were required to report either rates, risk factors or prevention strategies in youth rugby and to have a randomised controlled trial, quasi-experimental, cohort, case control, or ecological study design. Exclusion criteria included non-peer-reviewed grey literature, conference abstracts, case studies, previous systematic reviews and studies not written in English. Nine databases were searched. The full search strategy and list of sources are available and pre-registered on PROSPERO (Ref: CRD42020208343). Each study was assessed for risk of bias using the Downs and Black quality assessment tool. Meta-analyses were conducted using a DerSimonian Laird random effect model for each age group and sex. RESULTS: Sixty-nine studies were included in this SR. The match injury rates (using a 24-h time-loss definition) were 40.2/1000 match hours (95% CI 13.9-66.5) in males and 69.0/1000 match hours (95% CI 46.8-91.2) in females. Concussion rates were 6.2/1000 player-hours (95% CI 5.0-7.4) for males and 33.9/1000 player-hours (95% CI: 24.1-43.7) for females. The most common injury site was lower extremity (males) and the head/neck (females). The most common injury type was ligament sprain (males) and concussion (females). The tackle was the most common event associated with injury in matches (55% male, 71% females). Median time loss was 21 days for males and 17 days for females. Twenty-three risk factors were reported. The risk factors with the strongest evidence were higher levels of play and increasing age. Primary injury prevention strategies were the focus of only eight studies and included law changes (n = 2), equipment (n = 4), education (n = 1) and training (n = 1). The prevention strategy with the most promising evidence was neuromuscular training. The primary limitations included a broad range of injury definitions (n = 9) and rate denominators (n = 11) used, as well as a limited number of studies which could be included in the meta-analysis for females (n = 2). CONCLUSION: A focus on high-quality risk factor and primary prevention evaluation should be considered in future studies. Targeting primary prevention and stakeholder education remain key strategies in the prevention, recognition and management of injuries and concussions in youth rugby.

Wearable Sensors for Learning Enhancement in Higher Education.

Wearable sensors have traditionally been used to measure and monitor vital human signs for well-being and healthcare applications. However, there is a growing interest in using and deploying these technologies to facilitate teaching and learning, particularly in a higher education environment. The aim of this paper is therefore to systematically review the range of wearable devices that have been used for enhancing the teaching and delivery of engineering curricula in higher education. Moreover, we compare the advantages and disadvantages of these devices according to the location in which they are worn on the human body. According to our survey, wearable devices for enhanced learning have mainly been worn on the head (e.g., eyeglasses), wrist (e.g., watches) and chest (e.g., electrocardiogram patch). In fact, among those locations, head-worn devices enable better student engagement with the learning materials, improved student attention as well as higher spatial and visual awareness. We identify the research questions and discuss the research inclusion and exclusion criteria to present the challenges faced by researchers in implementing learning technologies for enhanced engineering education. Furthermore, we provide recommendations on using wearable devices to improve the teaching and learning of engineering courses in higher education.

Incorporating historical information to improve phase I clinical trials.

Incorporating historical data has a great potential to improve the efficiency of phase I clinical trials and to accelerate drug development. For model-based designs, such as the continuous reassessment method (CRM), this can be conveniently carried out by specifying a "skeleton," that is, the prior estimate of dose limiting toxicity (DLT) probability at each dose. In contrast, little work has been done to incorporate historical data into model-assisted designs, such as the Bayesian optimal interval (BOIN), Keyboard, and modified toxicity probability interval (mTPI) designs. This has led to the misconception that model-assisted designs cannot incorporate prior information. In this paper, we propose a unified framework that allows for incorporating historical data into model-assisted designs. The proposed approach uses the well-established "skeleton" approach, combined with the concept of prior effective sample size, thus it is easy to understand and use. More importantly, our approach maintains the hallmark of model-assisted designs: simplicity-the dose escalation/de-escalation rule can be tabulated prior to the trial conduct. Extensive simulation studies show that the proposed method can effectively incorporate prior information to improve the operating characteristics of model-assisted designs, similarly to model-based designs.

Machine learning for clinical trials in the era of COVID-19.

The world is in the midst of a pandemic. We still know little about the disease COVID-19 or about the virus (SARS-CoV-2) that causes it. We do not have a vaccine or a treatment (aside from managing symptoms). We do not know if recovery from COVID-19 produces immunity, and if so for how long, hence we do not know if "herd immunity" will eventually reduce the risk or if a successful vaccine can be developed - and this knowledge may be a long time coming. In the meantime, the COVID-19 pandemic is presenting enormous challenges to medical research, and to clinical trials in particular. This paper identifies some of those challenges and suggests ways in which machine learning can help in response to those challenges. We identify three areas of challenge: ongoing clinical trials for non-COVID-19 drugs; clinical trials for repurposing drugs to treat COVID-19, and clinical trials for new drugs to treat COVID-19. Within each of these areas, we identify aspects for which we believe machine learning can provide invaluable assistance.

Differentiating between benign and malignant thyroid nodules: An evidence-based approach in general practice

BACKGROUND: The widespread use of imaging techniques has led to more frequent detection of thyroid nodules, and while the majority are benign, the risk of malignancy in an adult ranges from 7% to 15%. General practitioners (GPs) must be able to evaluate thyroid nodules and refer cases when appropriate. OBJECTIVES: The aim of this article is to bring GPs up to date on the evidence-based management of thyroid nodules, with specific focus on neoplastic nodules, while highlighting significant changes in the 2015 American Thyroid Association guidelines. DISCUSSION: Thyroid nodules frequently occur in the general population. Differentiating between a benign and malignant nodule can be challenging, and community guidelines have standardised investigation, management and follow-up procedures. The key tests for risk stratification of thyroid nodules include serum thyroid-stimulating hormone testing, ultrasonography and fine-needle aspiration. GPs should be aware of the latest evidence-based recommendations for the appropriate management of a thyroid nodule.

Rendering the 3 + 3 Design to Rest: More Efficient Approaches to Oncology Dose-Finding Trials in the Era of Targeted Therapy.

Selection of the maximum tolerated dose (MTD) as the recommended dose for registration trials based on a dose-escalation trial using variations of an MTD/3 + 3 design often occurs in the development of oncology products. The MTD/3 + 3 approach is not optimal and may result in recommended doses that are unacceptably toxic for many patients and in dose reduction/interruptions that might have an impact on effectiveness. Instead of the MTD/3 + 3 approach, the authors recommend an integrated approach. In this approach, typically an adaptive/Bayesian model provides a general framework to incorporate and make decisions for dose escalation based on nonclinical data, such as animal efficacy and toxicity data; clinical data, including pharmacokinetics/pharmacodynamics data; and dose/exposure-response data for efficacy and safety. To improve dose-ranging trials, model-based estimation, rather than hypothesis testing, should be used to maximize and integrate the information gathered across trials and doses. This approach may improve identification of optimal recommended doses, which can then be confirmed in registration trials. Clin Cancer Res; 22(11); 2623-9. ©2016 AACR SEE ALL ARTICLES IN THIS CCR FOCUS SECTION, "NEW APPROACHES FOR OPTIMIZING DOSING OF ANTICANCER AGENTS".

Robust exchangeability designs for early phase clinical trials with multiple strata.

Clinical trials with multiple strata are increasingly used in drug development. They may sometimes be the only option to study a new treatment, for example in small populations and rare diseases. In early phase trials, where data are often sparse, good statistical inference and subsequent decision-making can be challenging. Inferences from simple pooling or stratification are known to be inferior to hierarchical modeling methods, which build on exchangeable strata parameters and allow borrowing information across strata. However, the standard exchangeability (EX) assumption bears the risk of too much shrinkage and excessive borrowing for extreme strata. We propose the exchangeability-nonexchangeability (EXNEX) approach as a robust mixture extension of the standard EX approach. It allows each stratum-specific parameter to be exchangeable with other similar strata parameters or nonexchangeable with any of them. While EXNEX computations can be performed easily with standard Bayesian software, model specifications and prior distributions are more demanding and require a good understanding of the context. Two case studies from phases I and II (with three and four strata) show promising results for EXNEX. Data scenarios reveal tempered degrees of borrowing for extreme strata, and frequentist operating characteristics perform well for estimation (bias, mean-squared error) and testing (less type-I error inflation).

Advancing Clinical Trials to Streamline Drug Development.

The last decade in oncology has been marked by the identification of numerous new potential cancer targets and even more agents designed to inhibit them. The matrix of new targets, new agents, and the companion diagnostics required to identify the right patient for the right drug has created a major challenge for the clinical trial process. This has been compounded by the addition of new immunomodulators targeting the host immune system rather than the tumor. Recognizing the need for new approaches, industry, investigators, and regulators have responded to this challenge. New clinical trial designs are being evaluated to incorporate the genomic sequence data being obtained almost routinely after cancer diagnosis. New dose-finding approaches are being proposed to identify the maximum effective dose rather than the maximum tolerated dose. The FDA is involved in the drug approval process from points early in development and has accepted registration quality data from expansion cohorts in support of drug approval. Despite progress on several fronts, many challenges remain, including the lack of predictability of preclinical data for clinical results and phase II data for phase III results, an infrastructure that can be an obstacle to clinical trial development and implementation, and the increasing use of contracted clinical research organizations that limit a fit-for-purpose approach to clinical trial execution. Perhaps most challenging and important of all are the difficulties with clinical trial accrual that can prevent study completion. Both the innovations and the challenges highlight the important role of process in progress in clinical oncology.

First-in-human phase I dose-escalation study of the HSP90 inhibitor AUY922 in patients with advanced solid tumors.

PURPOSE: A phase I study was conducted with the primary objective of determining the maximum tolerated dose (MTD) of AUY922 in patients with advanced solid tumors. Secondary objectives included characterization of the safety, pharmacokinetic, and pharmacodynamic profiles. PATIENTS AND METHODS: Patients with advanced solid tumors received 1-hour i.v. infusions of AUY922 once a week in a 28-day cycle. An adaptive Bayesian logistic regression model that employed observed dose-limiting toxicities (DLT) in the first treatment cycle was used to guide dose-escalation decisions, with the established MTD to be used in phase II studies. RESULTS: One hundred and one patients were enrolled and explored at doses in the range of 2 to 70 mg/m(2). DLTs occurred in 8 patients (22-70 mg/m(2)) and included diarrhea, asthenia/fatigue, anorexia, atrial flutter, and visual symptoms. At 70 mg/m(2), the AUY922 concentration achieved was consistent with active concentrations in a range of xenograft models. There was evidence of target inhibition in peripheral blood mononuclear cells (HSP70 induction) and tumor (client protein depletion and reduction of metabolic activity by (18)F-FDG PET). The recommended phase II dose (RP2D) of 70 mg/m(2) was proposed on the basis of toxicity and pharmacokinetic and pharmacodynamic profiles. CONCLUSIONS: At the RP2D of 70 mg/m(2), AUY922 exhibited acceptable tolerability, and phase II single-agent and combination studies have been initiated in patients with HER2-positive breast, gastric, and non-small cell lung cancers.

Recovery of human DNA profiles from poached deer remains part 2: improved recovery protocol without the need for LCN analysis.

Although poaching is a common wildlife crime, the high and prohibitive cost of specialised animal testing means that many cases are left un-investigated. We previously described a novel approach to wildlife crime investigation that looked at the identification of human DNA on poached animal remains (Tobe, Govan and Welch, 2011). Human DNA was successfully isolated and amplified from simulated poaching incidents, however a low template protocol was required which made this method unsuitable for use in many laboratories. We now report on an optimised recovery and amplification protocol which removes the need for low template analysis. Samples from 10 deer (40 samples total - one from each leg) analysed in the original study were re-analysed in the current study with an additional 11 deer samples. Four samples analysed using Chelex did not show any results and a new method was devised whereby the available DNA was concentrated. By combining the DNA extracts from all tapings of the same deer remains followed by concentration, the recovered quantity of human DNA was found to be 29.5pg±43.2pg, 31× greater than the previous study. The use of the Investigator Decaplex SE (QIAGEN) STR kit provided better results in the form of more complete profiles than did the AmpFℓSTR® SGM Plus® kit at 30cycles (Applied Biosystems). Re-analysis of the samples from the initial study using the new, optimised protocol resulted in an average increase of 18% of recovered alleles. Over 17 samples, 71% of the samples analysed using the optimised protocol showed sufficient amplification for comparison to a reference profile and gave match probabilities ranging from 7.7690×10(-05) to 2.2706×10(-14). The removal of low template analysis means this optimised method provides evidence of high probative value and is suitable for immediate use in forensic laboratories. All methods and techniques used are standard and are compatible with current SOPs. As no high cost non-human DNA analysis is required the overall process is no more expensive than the investigation of other volume crime samples. The technique is suitable for immediate use in poaching incidents.

A phase I study of single-agent nilotinib or in combination with imatinib in patients with imatinib-resistant gastrointestinal stromal tumors.

PURPOSE: To study the safety, tolerability, and pharmacokinetics of the selective tyrosine kinase inhibitor nilotinib as a single agent or in combination with imatinib in patients with advanced imatinib-resistant gastrointestinal stromal tumors. EXPERIMENTAL DESIGN: A phase I intercohort dose-escalation trial was done in patients who received either (a) single agent nilotinib 400 mg twice daily or (b) escalating doses of nilotinib (200 mg once daily, 400 mg qd, or 400 mg bid) plus imatinib 400 mg bid (10- and 14-hour interval daily), or (c) nilotinib 400 mg bid plus imatinib 400 mg qd. Safety, pharmacokinetics, and tumor assessments were done. RESULTS: Oral clearance (CL/F) of nilotinib was similar across the combination groups (mean CL/F, 19.1-25.6 L/h), and lower than in the single-agent cohort (mean CL/F, 35.6 L/h). A linear relationship between nilotinib daily dose and peak concentration was observed in the combination cohorts. Observed adverse events (AE) were mostly nonhematologic. Frequently reported AEs were rash (40%), fatigue (38%), abdominal pain (36%), and nausea (36%). Severe AEs (grade 3 or 4) included abdominal pain (13%) and rash (9%), the latter mainly with the combination. Thirty-eight patients had stable disease and two patients achieved partial response with a median progression-free survival of 134 days for the entire group. CONCLUSIONS: Nilotinib alone or in combination with imatinib was well tolerated overall and showed clinical activity in imatinib-resistant gastrointestinal stromal tumor patients. This phase I trial identified single-agent nilotinib 400 mg bid or combined with imatinib 400 mg qd as possible phase II doses for further evaluation.

A Bayesian case study in oncology Phase I combination dose-finding using logistic regression with covariates.

A Bayesian approach to finding the maximum tolerated dose (MTD) is presented. The approach is flexible, allowing inclusion of covariates, and enables transparent dose recommendations based on comprehensive inferential summaries on the probability of dose-limiting toxicities (DLT). A case study is presented for a Phase I combination of two oncology drugs, nilotinib and imatinib. Data obtained and decisions made during the study are described. Final determination of the MTD pair is outlined, along with discussion regarding the use and interpretability of within- and end-of-study data.