Exertional Heat Illness: Adoption of Policies and Influencing Contextual Factors as Reported by Athletic Administrators.

BACKGROUND: Little is known about the adoption by athletic administrators (AAs) of exertional heat illness (EHI) policies, and the corresponding facilitators and barriers of such policies within high school athletics. This study describes the adoption of comprehensive EHI policies by high school AAs and explores factors influencing EHI policy adoption. HYPOTHESIS: We hypothesized that <50% of AAs would report adoption of an EHI policy, and that the most common facilitator would be access to an athletic trainer (AT), whereas the most common barrier would be financial limitations. STUDY DESIGN: Cross-sectional. LEVEL OF EVIDENCE: Level 4. METHODS: A total of 466 AAs (82.4% male; age, 48 ± 9 years) completed a validated online survey to assess EHI prevention and treatment policy adoption (11 components), as well as facilitators and barriers to policy implementation. Access to athletic training services was ascertained by matching the participants' zip codes with the Athletic Training Locations and Services Project. Policy adoption, facilitators, and barriers data are presented as summary statistics (proportions, interquartile range (IQR)). A Welch t test evaluated the association between access to athletic training services and EHI policy adoption. RESULTS: Of the AAs surveyed, 77.9% (n = 363) reported adopting a written EHI policy. The median of EHI policy components adopted was 5 (IQR = 1,7), with only 5.6% (n = 26) of AAs reporting adoption of all policy components. AAs who had access to an AT (P = 0.04) were more likely to adopt a greater number of EHI-related policies, compared with those without access to an AT. An AT employed at the school was the most frequently reported facilitator (36.9%). CONCLUSION: Most AAs reported having written EHI policy components, and access to an AT resulted in a more comprehensive policy. CLINICAL RELEVANCE: Employment of an AT within high school athletics may serve as a vital component in facilitating the adoption of comprehensive EHI policies.

Combining MRI and cognitive evaluation to classify concussion in university athletes.

Current methods of concussion assessment lack the objectivity and reliability to detect neurological injury. This multi-site study uses combinations of neuroimaging (diffusion tensor imaging and resting state functional MRI) and cognitive measures to train algorithms to detect the presence of concussion in university athletes. Athletes (29 concussed, 48 controls) completed symptom reports, brief cognitive evaluation, and MRI within 72 h of injury. Hierarchical linear regression compared groups on cognitive and neuroimaging measures while controlling for sex and data collection site. Logistic regression and support vector machine models were trained using cognitive and neuroimaging measures and evaluated for overall accuracy, sensitivity, and specificity. Concussed athletes reported greater symptoms than controls (∆R2 = 0.32, p < .001), and performed worse on tests of concentration (∆R2 = 0.07, p < .05) and delayed memory (∆R2 = 0.17, p < .001). Concussed athletes showed lower functional connectivity within the frontoparietal and primary visual networks (p < .05), but did not differ on mean diffusivity and fractional anisotropy. Of the cognitive measures, classifiers trained using delayed memory yielded the best performance with overall accuracy of 71%, though sensitivity was poor at 46%. Of the neuroimaging measures, classifiers trained using mean diffusivity yielded similar accuracy. Combining cognitive measures with mean diffusivity increased overall accuracy to 74% and sensitivity to 64%, comparable to the sensitivity of symptom report. Trained algorithms incorporating both MRI and cognitive performance variables can reliably detect common neurobiological sequelae of acute concussion. The integration of multi-modal data can serve as an objective, reliable tool in the assessment and diagnosis of concussion.

ISO 10993-23 In vitro irritation testing for medical devices: Substantiating applicability to mild irritants and non-extractables.

Irritation testing is an integral part of the biocompatibility assessment of medical devices and has historically been conducted on animals, either by direct contact or with polar and non-polar solvent extracts. In 2018 an ISO-sponsored interlaboratory validation study demonstrated that two reconstituted human epidermis (RhE) based assays, which were adapted from validated methods used for industrial chemicals, produced results essentially equivalent to those obtained with in vivo tests. This led to the publication of the ISO 10993-23:2021 standard on irritation testing, which states that RhE-based assays are now the preferred method. The 2018 validation study evaluated strong irritants, so we tested nine mild irritants (GHS Category 3), neat and spiked at different concentrations into medical device extracts, per ISO 10993-23:2021. The results substantiated the applicability of RhE-based assays for evaluating mild irritants in medical device extracts. Moreover, the 2018 validation study tested solid extractable medical device materials but did not consider non-extractable medical device materials (e.g., creams, gels, or sprays). By testing nine marketed non-extractable materials, either neat or spiked with irritants, we also confirmed that RhE-based assays are readily applicable to such medical device materials.

Using the monocyte activation test as a stand-alone release test for medical devices.

Monocyte activation tests (MAT) are widely available but rarely used in place of animal-based pyrogen tests for safety assessment of medical devices. To address this issue, the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods and the PETA International Science Consortium Ltd. convened a workshop at the National Institutes of Health on September 18-19, 2018. Participants included representatives from MAT testing laboratories, medical device manufacturers, the U.S. Food and Drug Administration's Center for Devices and Radiologic Health (CDRH), the U.S. Pharmacopeia, the International Organization for Standardization, and experts in the development of MAT protocols. Discussions covered industry experiences with the MAT, remaining challenges, and how CDRH's Medical Device Development Tools (MDDT) Program, which qualifies tools for use in evaluating medical devices to streamline device development and regulatory evaluation, could be a pathway to qualify the use of MAT in place of the rabbit pyrogen test and the limulus amebocyte lysate test for medical device testing. Workshop outcomes and follow-up activities are discussed.

Athletic Training Employment in US Secondary Schools by Geographic Setting and School Size.

CONTEXT: The Athletic Training Locations and Services (ATLAS) Annual Report suggested that athletic trainer (AT) employment status differed based on geographic locale. However, the influence of geographic locale and school size on AT employment is unknown. OBJECTIVE: To determine if differences existed in the odds of having AT services by locale for public and private schools and by student enrollment for public schools. DESIGN: Cross-sectional study. SETTING: Public and private secondary schools with athletics programs. PATIENTS OR OTHER PARTICIPANTS: Data from 20 078 US public and private secondary schools were obtained. MAIN OUTCOME MEASURES(S): Data were collected by the ATLAS Project. Athletic trainer employment status, locale (city, suburban, town, or rural) for public and private schools, and school size category (large, moderate, medium, or small) only for public schools were obtained. The employment status of ATs was examined for each category using odds ratios. Logistic regression analysis produced a prediction model. RESULTS: Of the 19 918 public and private schools with available AT employment status and locale, suburban schools had the highest access to AT services (80.1%) with increased odds compared with rural schools (odds ratio = 3.55 [95% CI = 3.28, 3.85]). Of 15 850 public schools with known AT employment status and student enrollment, large schools had the highest rate of AT services (92.1%) with nearly 18.5 times greater odds (odds ratio = 18.49 [95% CI = 16.20, 21.08]) versus small schools. The logistic model demonstrated that the odds of access to an AT increased by 2.883 times as the school size went up by 1 category. CONCLUSIONS: Nationally, suburban schools and large public schools had the greatest access to AT services compared with schools that were in more remote areas and with lower student enrollment. These findings elucidate the geographic locales and student enrollment levels with the highest prevalence of AT services.

The suitability of reconstructed human epidermis models for medical device irritation assessment: A comparison of In Vitro and In Vivo testing results.

The ISO 10993 standards on biocompatibility assessment of medical devices discourage the use of animal tests when reliable and validated in vitro methods are available. A round robin validation study of in vitro reconstructed human epidermis (RhE) assays was performed as potential replacements for rabbit skin irritation testing. The RhE assays were able to accurately identify strong irritants in dilute medical device extracts. However, there was some uncertainty about whether RhE tissues accurately predicted the results of the rabbit skin patch or intracutaneous irritation test. To address that question, this paper presents in vivo data from the round robin and subsequent follow-up studies. The follow-up studies included simultaneous in vitro RhE model and in vivo testing of round robin polymer samples and the results of dual in vitro/in vivo testing of currently marketed medical device components/materials. Our results show for the first time that for both pure chemicals and medical device extracts the intracutaneous rabbit test is more sensitive to detect irritant activity than the rabbit skin patch test. The studies showed that the RhE models produced results that were essentially equivalent to those from the intracutaneous rabbit skin irritation test. Therefore, it is concluded that RhE in vitro models are acceptable replacements for the in vivo rabbit intracutaneous irritation test for evaluating the irritant potential of medical devices.

Athletic Trainer Services in the Secondary School Setting: The Athletic Training Locations and Services Project.

CONTEXT: Previous research from a sample of US secondary schools (n = 10 553) indicated that 67% of schools had access to an athletic trainer (AT; 35% full time [FT], 30% part time [PT], and 2% per diem). However, the population-based statistic in all secondary schools with athletic programs (n = approximately 20 000) is yet to be determined. OBJECTIVE: To determine the level of AT services and employment status in US secondary schools with athletics by National Athletic Trainers' Association district. DESIGN: Cross-sectional study. SETTING: Public and private secondary schools with athletics. PATIENTS OR OTHER PARTICIPANTS: Data from all 20 272 US public and private secondary schools were obtained. MAIN OUTCOME MEASURE(S): Data were collected from September 2015 to April 2018 by phone or e-mail communication with school administrators or ATs and by online surveys of secondary school ATs. Employment categories were school district, school district with teaching, medical or university facility, and independent contractor. Data are presented as total number and percentage of ATs. Descriptive statistics were calculated for FT, PT, and no AT services data for public, private, public + private, and employment type by state and by National Athletic Trainers' Association district. RESULTS: Of the 20 272 secondary schools, 66% (n = 13 473) had access to AT services, while 34% (n = 6799) had no access. Of those schools with AT services, 53% (n = 7119) received FT services, while 47% (n = 6354) received PT services. Public schools (n = 16 076) received 37%, 32%, and 31%, whereas private schools (n = 4196) received 27%, 28%, and 45%, for FT, PT, and no AT services, respectively. Most of the Athletic Training Locations and Services Survey participants (n = 6754, 57%) were employed by a medical or university facility, followed by a school district, school district with teaching, and independent contractor. Combined, 38% of AT employment was via the school district. CONCLUSIONS: The percentages of US schools with AT access and FT and PT services were similar to those noted in previous research. One-third of secondary schools had no access to AT services. The majority of AT employment was via medical or university facilities. These data depict the largest and most updated representation of AT services in secondary schools.

Material-mediated pyrogens in medical devices: Applicability of the in vitro Monocyte Activation Test.

Pyrogenicity presents a challenge to clinicians, medical device manufacturers, and regulators. A febrile response may be caused by endotoxin contamination, microbial components other than endotoxin, or chemical agents that generate a material-mediated pyrogenic response. While test methods for the assessment of endotoxin contamination and some microbial components other than endotoxin are well-established, material-mediated pyrogens remain elusively undefined. This review presents the findings of literature searches conducted to identify material-mediated pyrogens associated with medical devices. The in vivo rabbit pyrogen test (RPT) is considered to be the "gold standard" for medical device pyrogenicity testing, despite the fact that few medical device-derived material-mediated pyrogens are known. In line with global efforts to reduce the use of research animals, an in vitro monocyte activation test (MAT) has the potential to replace the RPT. The MAT is used to detect substances that activate human monocytes to release cytokines. This review will also describe the potential opportunities and challenges associated with MAT adoption for the detection of material-mediated pyrogens in medical device testing.

Preparation of irritant polymer samples for an in vitro round robin study.

A round robin study using reconstructed human epidermis (RhE) tissues was conducted to test medical device polymer extracts for skin irritation potential. Test samples were four irritant and three non-irritant medical device polymers. Five of these polymer samples were developed and two were obtained commercially. The three non-irritant samples were comprised of 100% 80A polyurethane, one-part silicone, and polyvinyl chloride (PVC). The polyurethane samples were made using a hot-melt process, while the silicone samples were created by mixing and casting. The PVC samples were commercially produced sheets. The four irritant samples were comprised of one-part silicone and 25% heptanoic acid (HA), two-part silicone and 15% sodium dodecyl sulfate (SDS), PVC and 4% Genapol® X-100, and PVC and 5.8% Genapol® X-080. The HA, SDS, and Genapol® X-100 samples were produced using the mixing and casting method, while the Genapol® X-080 sheet samples were obtained commercially. During development, irritant polymer samples were extracted using polar and non-polar solvents that were subsequently analyzed chemically. Samples with sufficient levels of extracted irritants were tested on RhE tissues to confirm their irritation potential. Polymers that passed this screening test were used in the round robin study described elsewhere in this special edition.

Evaluation of the medical devices benchmark materials in the controlled human patch testing and in the RhE in vitro skin irritation protocol.

Several irritants were used in the in vitro irritation medical device round robin. The objective of this study was to verify their irritation potential using the human patch test (HPT), an in vitro assay, and in vivo data. The irritants were lactic acid (LA), heptanoic acid (HA), sodium dodecyl sulfate (SDS), Genapol® X-80 (GP), and Y-4 polymer. Dilute saline and sesame seed oil (SSO) solutions of each were evaluated using a 4 and 18 h HPT and the EpiDerm™ SIT-MD RhE assay; results were then compared to existing rabbit skin irritation test data. Results from the 4 h HPT were negative in most cases except for GP and SDS, while the 18 h HPT also identified some LA, HA, and GP samples as irritants. EpiDerm™ SIT-MD correctly identified all irritants except GP in SSO due to limited solubility. Data from cutaneous rabbit irritation tests were negative, while all intracutaneous results were strongly or weakly positive except for the most dilute GP solutions. These findings indicate that EpiDerm™ SIT-MD results correlate with those from the rabbit intracutaneous test and confirm that RhE assays are suitable replacements for animals in evaluating the tissue irritation potential of medical devices.

Pre-validation of an in vitro skin irritation test for medical devices using the reconstructed human tissue model EpiDerm™.

Assessment of dermal irritation is an essential component of the safety evaluation of medical devices. Reconstructed human epidermis (RhE) models have replaced rabbit skin irritation testing for neat chemicals and their mixtures (OECD Test Guideline 439). However, this guideline cannot be directly applied to the area of medical devices (MD) since their non-toxicity assessment is largely based on the testing of MD extracts that may have very low irritation potential. Therefore, the RhE-methods previously validated with neat chemicals needed to be modified to reflect the needs for detection of low levels of potential irritants. A protocol employing RhE EpiDerm was optimized in 2013 using known irritants and spiked polymers (Casas et al., 2013, TIV). In 2014 and 2015 MatTek In Vitro Life Science Laboratories (IVLSL) and RIVM assessed the transferability of the assay. After the successful transfer and standardization of the protocol, 17 laboratories were trained in the use of the protocol in the preparation for the validation. Laboratories produced data with 98% agreement of predictions for the selected references and controls. We conclude that a modified RhE skin irritation test has the potential to address the skin irritation potential of the medical devices. Standardization and focus on the technical issues is essential for accurate prediction.

From in vivo to in vitro: The medical device testing paradigm shift.

Amid growing efforts to advance the replacement, reduction, and refinement of the use of animals in research, there is a growing recognition that in vitro testing of medical devices can be more effective, both in terms of cost and time, and also more reliable than in vivo testing. Although the technological landscape has evolved rapidly in support of these concepts, regulatory acceptance of alternative testing methods has not kept pace. Despite the acceptance by regulators of some in vitro tests (cytotoxicity, gene toxicity, and some hemocompatibility assays), many toxicity tests still rely on animals (irritation, sensitization, acute toxicity, reproductive/developmental toxicity), even where other industrial sectors have already abandoned them. Bringing about change will require a paradigm shift in current approaches to testing - and a concerted effort to generate better data on risks to human health from exposure to leachable chemicals from medical devices, and to boost confidence in the use of alternative methods to test devices. To help advance these ideas, stir debate about best practices, and coalesce around a roadmap forward, the JHU-Center for Alternatives to Animal Testing (CAAT) hosted a symposium believed to be the first gathering dedicated to the topic of in vitro testing of medical devices. Industry representatives, academics, and regulators in attendance presented evidence to support the unique strengths and challenges associated with the approaches currently in use as well as new methods under development, and drew next steps to push the field forward from their presentations and discussion.

Ethanol- and/or Taurine-Induced Oxidative Stress in Chick Embryos.

Because taurine alleviates ethanol- (EtOH-) induced lipid peroxidation and liver damage in rats, we asked whether exogenous taurine could alleviate EtOH-induced oxidative stress in chick embryos. Exogenous EtOH (1.5 mmol/Kg egg or 3 mmol/Kg egg), taurine (4 µmol/Kg egg), or EtOH and taurine (1.5 mmol EtOH and 4 µmol taurine/Kg egg or 3 mmol EtOH and 4 µmol taurine/Kg egg) were injected into fertile chicken eggs during the first three days of embryonic development (E0-2). At 11 days of development (midembryogenesis), serum taurine levels and brain caspase-3 activities, homocysteine (HoCys) levels, reduced glutathione (GSH) levels, membrane fatty acid composition, and lipid hydroperoxide (LPO) levels were measured. Early embryonic EtOH exposure caused increased brain apoptosis rates (caspase-3 activities); increased brain HoCys levels; increased oxidative-stress, as measured by decreased brain GSH levels; decreased brain long-chain polyunsaturated levels; and increased brain LPO levels. Although taurine is reported to be an antioxidant, exogenous taurine was embryopathic and caused increased apoptosis rates (caspase-3 activities); increased brain HoCys levels; increased oxidative-stress (decreased brain GSH levels); decreased brain long-chain polyunsaturated levels; and increased brain LPO levels. Combined EtOH and taurine treatments also caused increased apoptosis rates and oxidative stress.

Anthropometric and leptin changes in women following different dietary approaches to weight loss.

Leptin may favorably respond to fat mass (FM) losses induced by a low-carbohydrate (LC) diet, although this is unclear. We examined serum leptin concentrations in women in midlife undergoing different dietary approaches to body weight (BW) loss. Women followed either a LC, high-protein (LCHP; n = 13) or high-carbohydrate, low-fat (HCLF; n = 12) diet for 12 weeks. Changes in anthropometric and soft-tissue mass measurements and leptin concentrations were assessed. Women in both diet groups had reductions in BW, BMI, fat-free soft-tissue mass, FM, body fat percentage, and central abdominal fat (CAF) (P < 0.001 for all variables) over the 12-week intervention. These changes were not significantly different between diet groups. Serum leptin concentrations decreased by 41.8% (P < 0.001) in the LCHP group and by 44.3% (P < 0.001) in the HCLF group from baseline to week 12, with no significant difference between groups. The association of CAF (r = 0.73) and FM (r = 0.83) change with leptin change was strong in the HCLF group. Leptin change did not relate to change in any variable in the LCHP group. Both LCHP and HCLF diets favorably lower FM, CAF, and leptin in women, suggesting that beneficial changes in leptin can be similarly achieved through different dietary approaches to BW loss.