Head Acceleration Events During Tackle, Ball-Carry, and Ruck Events in Professional Southern Hemisphere Men's Rugby Union Matches: A Study Using Instrumented Mouthguards.

OBJECTIVES: Describe head acceleration events (HAEs) experienced by professional male rugby union players during tackle, ball-carry, and ruck events using instrumented mouthguards (iMGs). DESIGN: Prospective observational cohort. METHODS: Players competing in the 2023 Currie Cup (141 players) and Super Rugby (66 players) seasons wore iMGs. The iMG-recorded peak linear acceleration (PLA) and peak angular acceleration (PAA) were used as in vivo HAE approximations and linked to contact-event data captured using video analysis. Using the maximum PLA and PAA per contact event (HAEmax), ordinal mixed-effects regression models estimated the probabilities of HAEmax magnitude ranges occurring, while accounting for the multilevel data structure. RESULTS: As HAEmax magnitude increased the probability of occurrence decreased. The probability of a HAEmax ≥15g was 0.461 (0.435-0.488) (approximately 1 in every 2) and ≥45g was 0.031 (0.025-0.037) (1 in every 32) during ball carries. The probability of a HAEmax >15g was 0.381 (0.360-0.404) (1 in every 3) and >45g 0.019 (0.015-0.023) (1 in every 53) during tackles. The probability of higher magnitude HAEmax occurring was greatest during ball carries, followed by tackles, defensive rucks and attacking rucks, with some ruck types having similar profiles to tackles and ball carries. No clear differences between positions were observed. CONCLUSION: Higher magnitude HAEmax were relatively infrequent in professional men's rugby union players. Contact events appear different, but no differences were found between positions. The occurrence of HAEmax was associated with roles players performed within contact events, not their actual playing position. Defending rucks may warrant greater consideration in injury prevention research.

Genome-matched treatments and patient outcomes in the Maine Cancer Genomics Initiative (MCGI).

Genomic tumor testing (GTT) is an emerging technology aimed at identifying variants in tumors that can be targeted with genomically matched drugs. Due to limited resources, rural patients receiving care in community oncology settings may be less likely to benefit from GTT. We analyzed GTT results and observational clinical outcomes data from patients enrolled in the Maine Cancer Genomics Initiative (MCGI), which provided access to GTTs; clinician educational resources; and genomic tumor boards in community practices in a predominantly rural state. 1603 adult cancer patients completed enrollment; 1258 had at least one potentially actionable variant identified. 206 (16.4%) patients received a total of 240 genome matched treatments, of those treatments, 64% were FDA-approved in the tumor type, 27% FDA-approved in a different tumor type and 9% were given on a clinical trial. Using Inverse Probability of Treatment Weighting to adjust for baseline characteristics, a Cox proportional hazards model demonstrated that patients who received genome matched treatment were 31% less likely to die within 1 year compared to those who did not receive genome matched treatment (HR: 0.69; 95% CI: 0.52-0.90; p-value: 0.006). Overall, GTT through this initiative resulted in levels of genome matched treatment that were similar to other initiatives, however, clinical trials represented a smaller share of treatments than previously reported, and "off-label" treatments represented a greater share. Although this was an observational study, we found evidence for a potential 1-year survival benefit for patients who received genome matched treatments. These findings suggest that when disseminated and implemented with a supportive infrastructure, GTT may benefit cancer patients in rural community oncology settings, with further work remaining on providing genome-matched clinical trials.

Hunting for the elusive target antigen in gestational alloimmune liver disease (GALD).

The prevailing concept is that gestational alloimmune liver disease (GALD) is caused by maternal antibodies targeting a currently unknown antigen on the liver of the fetus. This leads to deposition of complement on the fetal hepatocytes and death of the fetal hepatocytes and extensive liver injury. In many cases, the newborn dies. In subsequent pregnancies early treatment of the woman with intravenous immunoglobulin can be instituted, and the prognosis for the fetus will be excellent. Without treatment the prognosis can be severe. Crucial improvements of diagnosis require identification of the target antigen. For this identification, this work was based on two hypotheses: 1. The GALD antigen is exclusively expressed in the fetal liver during normal fetal life in all pregnancies; 2. The GALD antigen is an alloantigen expressed in the fetal liver with the woman being homozygous for the minor allele and the father being, most frequently, homozygous for the major allele. We used three different experimental approaches to identify the liver target antigen of maternal antibodies from women who had given birth to a baby with the clinical GALD diagnosis: 1. Immunoprecipitation of antigens from either a human liver cell line or human fetal livers by immunoprecipitation with maternal antibodies followed by mass spectrometry analysis of captured antigens; 2. Construction of a cDNA expression library from human fetal liver mRNA and screening about 1.3 million recombinants in Escherichia coli using antibodies from mothers of babies diagnosed with GALD; 3. Exome/genome sequencing of DNA from 26 presumably unrelated women who had previously given birth to a child with GALD with husband controls and supplementary HLA typing. In conclusion, using the three experimental approaches we did not identify the GALD target antigen and the exome/genome sequencing results did not support the hypothesis that the GALD antigen is an alloantigen, but the results do not yield basis for excluding that the antigen is exclusively expressed during fetal life., which is the hypothesis we favor.

The Maine Cancer Genomics Initiative: Implementing a Community Cancer Genomics Program Across an Entire Rural State.

PURPOSE: The Maine Cancer Genomics Initiative (MCGI) aimed to overcome patient- and provider-level barriers to using genomic tumor testing (GTT) in rural practices by providing genomic tumor boards (GTBs), clinician education, and access to comprehensive large-panel next-generation sequencing to all patients with cancer in Maine. This paper describes the successful implementation of the initiative and three key services made operative between 2016 and 2020. METHODS: A community-inclusive, hub-and-spoke approach was taken to implement the three program components: (1) a centralized GTB program; (2) a modular online education program, designed using an iterative approach with broad clinical stakeholders; and (3) GTT free of charge to clinicians and patients. Implementation timelines, participation metrics, and survey data were used to describe the rollout. RESULTS: The MCGI was launched over an 18-month period at all 19 oncology practices in the State. Seventy-nine physicians (66 medical oncologists, 5 gynecologic oncologists, 1 neuro-oncologist, and 7 pediatric oncologists) enrolled on the study, representing 100% of all practicing oncologists in Maine. Between July 2017 and September 2020, 1610 patients were enrolled. A total of 515 cases were discussed by 47 (73%) clinicians in 196 GTBs. Clinicians who participated in the GTBs enrolled significantly more patients on the study, stayed in Maine, and reported less time spent in clinical patient care. CONCLUSION: The MCGI was able to engage geographically and culturally disparate cancer care practices in a precision oncology program using a hub-and-spoke model. By facilitating access to GTT, structured education, and GTBs, we narrowed the gap in the implementation of precision oncology in one of the most rural states in the country.

Sport concussion assessment in New Zealand high school rugby players: a collaborative approach to the challenges faced in primary care.

PRIMARY OBJECTIVE: To describe the collaborative development of a New Zealand Rugby Concussion Assessment (NZRCA) for primary care and to provide normative baseline data from a representative group of high school rugby players. METHODS: This study, conducted over the 2018 and 2019 community rugby season where players were baseline tested during the pre- or start of season period. RESULTS: Data were collected from 1428 players (males n = 1121, females n = 307) with a mean age of 15.9 ± 1.4 years. The mean ± SD symptom severity score was 11.3 ± 8.6, the mean number of endorsed symptoms was 8.5 ± 5.3 and the percentage feeling "normal" was 80.2 ± 15.3%. Only 5.3% of players reported no symptoms at baseline. The most common reported were: 'distracted easily' (72.5%), 'forgetful' (68.5%), and 'often tired' (62.6%). None of the participants achieved a perfect score for the SAC50. The majority of participants (89.7%) passed the tandem gait test with a time of 12.2 ± 1.7 seconds. Age, gender, and ethnicity were associated with NZRCA performance; albeit weakly. CONCLUSION: This study provides normative reference values for high-school rugby players. These data will aid healthcare providers in their identification of suspected concussion in the absence of individualized baselines.

Baseline concussion assessment performance of community-based senior rugby players: a cross-sectional study.

OBJECTIVE: To report pre-season baseline concussion assessment performance among senior rugby players and explore associations between assessment performance and player demographics. DESIGN: A cross-sectional study using the New Zealand Rugby Concussion Assessments (NZRCA), comprising symptom, cognitive and dynamic coordination assessments was conducted in the 2018-2019 season. METHODS: Players' baseline assessments were characterised using descriptive statistics; effect sizes (ES) and t-tests were used to explore associations between player demographic characteristics and NZRCA performance. RESULTS: A total of 733 players (11.4% female) aged between 16 and 52 years completed the NZRCA. The median (range) value for symptom severity, endorsed symptoms and "percentage normal" was respectively, 5 (0-40), 5 (0-21) and 90% (30-100%). A perfect standardised assessment of concussion score was achieved by one participant; seven achieved ≥27/30 for immediate recall, and 22 achieved a perfect delayed recall score. Most participants (n = 674, 92%) passed the tandem gait test. Associations between NZRCA performance and gender, concussion history, and Pasifika ethnicity were observed with effect sizes ranging from small (0.18) to large (0.70). Six hundred and twenty-three (85%) participants reported at least one symptom. CONCLUSIONS: The results from this study could help support decision-making by clinicians, improving the management of concussions in the community setting.

Predicting the severity of the grass pollen season and the effect of climate change in Northwest Europe.

Allergic rhinitis is an inflammation in the nose caused by overreaction of the immune system to allergens in the air. Managing allergic rhinitis symptoms is challenging and requires timely intervention. The following are major questions often posed by those with allergic rhinitis: How should I prepare for the forthcoming season? How will the season's severity develop over the years? No country yet provides clear guidance addressing these questions. We propose two previously unexplored approaches for forecasting the severity of the grass pollen season on the basis of statistical and mechanistic models. The results suggest annual severity is largely governed by preseasonal meteorological conditions. The mechanistic model suggests climate change will increase the season severity by up to 60%, in line with experimental chamber studies. These models can be used as forecasting tools for advising individuals with hay fever and health care professionals how to prepare for the grass pollen season.

Comparison of Cultured Human Cardiomyocyte Clusters Obtained from Embryos/Fetuses or Derived from Human Embryonic Stem Cells.

Cardiomyocytes (CMs) derived from human embryonic stem cells (hESCs) or induced pluripotent stem cells (iPSCs) are used to study cardiogenesis and mechanisms of heart disease, and are being used in methods for toxiological screening of drugs. The phenotype of stem-cell-derived CMs should ideally resemble native CMs. Here, we compare embryonic/fetal CMs with hESC-derived CMs according to function and morphology. CM clusters were obtained from human embryonic/fetal hearts from elective terminated pregnancies before gestational week 12, and separated into atrial and ventricular tissues. Specific markers for embryonic CMs and primary cilia were visualized using immunofluorescence microscopy analysis. Contracting human embryonic cardiomyocyte (hECM) clusters morphologically and phenotypically resemble CMs in the embryonic/fetal heart. In addition, the contracting hECM clusters expressed primary cilia similar to that of cells in the embryonic/fetal heart. The electrophysiological characteristics of atrial and ventricular CMs were established by recording action potentials (APs) using sharp electrodes. In contrast to ventricular APs, atrial APs displayed a marked early repolarization followed by a plateau phase. hESC-CMs displayed a continuum of AP shapes. In all embryonic/fetal clusters, both atrial and ventricular, AP duration was prolonged by exposure to the KV11.1 channel inhibitor dofetilide (50 nM); however, the prolongation was not significant, possibly due to the relatively small number of experiments. This study provides novel information on APs and functional characteristics of atrial and ventricular CMs in first trimester hearts, and demonstrates that Kv11.1 channels play a functional role already at these early stages. These results provide information needed to validate methods being developed on the basis of in vitro-derived CMs from either hESC or iPSC, and although there was a good correlation between the morphology of the two types of CMs, differences in electrophysiological characteristics exist.

Oak pollen seasonality and severity across Europe and modelling the season start using a generalized phenological model.

Oak pollen seasons are relatively unexplored in large parts of Europe despite producing allergens and being a common tree in both continental and northern parts. Many studies are concentrated only on the Iberian Peninsula. In this study, the seasonal pattern of oak pollen in Europe was analysed using 10 observation sites, ranging from Spain to Sweden. The magnitude of peaks and annual pollen integral together with season-length were studied and substantially higher pollen levels and longer seasons were found in Spain. Two northern sites in Denmark and Sweden showed high oak pollen peaks together with two sites in Spain and United Kingdom. The study also tested four common definitions of season start and applied a generalized phenological model for computing the start of the pollen season. The most accurate definition for a European-wide description of the observed oak pollen start was when the cumulative daily average pollen count reached 50 grains per cubic meter. For the modelling of the start a thermal time method based on Growing Degree Day (GDD) was implemented, utilizing daily temperatures and a generalized approach to identify model parameters applicable to all included sites. GDD values varied between sites and generally followed a decreasing gradient from south to north, with some exceptions. Modelled onsets with base temperatures below 7 °C matched well with observed onsets and 76% of the predictions differed ≤4 days compared to observed onsets when using a base temperature of 2 °C. Base temperatures above 7 °C frequently predicted onsets differing >1 week from the observed. This general approach can be extended to a larger area where pollen observations are non-existent. The presented work will increase the understanding of oak pollen variation in Europe and provide knowledge of its phenology, which is a critical aspect both for modelling purposes on large-scale and assessing the human exposure to oak allergens.

Association of patient navigation with care coordination in an Lynch syndrome screening program.

Lynch syndrome (LS) identification leads to improved health outcomes. Universal tumor screening (UTS) facilitates LS identification among colorectal cancer (CRC) and uterine cancer (UC) cases; institutional management affects screening program implementation and outcomes. There has been limited study of institutional UTS program care coordination needs, including patient navigation of genetic counseling referrals. We examined the influence of patient navigators on access to cancer genetic services among LS UTS screen-positive cases within a single institution. Electronic health record review of screen-positive CRC and UC cases for a 12-month period assessed the relationship between patient navigation and follow-through to genetic services. Among 451 newly diagnosed CRC (n = 175) and UC (n = 276) cases, 96 (21%; 28 CRC/68 UC cases) had abnormal UTS results. Among these, 66 (69%) showed MLH1 promoter hypermethylation (i.e., screen-negative). Of 30 screen-positive cases, 16 (53%) received navigation services. Among these, 14/16 (88%) and 13/14 (81%) underwent genetic counseling and testing, respectively; 7/13 (54%) had pathogenic or likely pathogenic variants detected. Among non-navigated screen-positive patients, 2/14 (14%) were excluded due to incomplete UTS results. Five of the remaining 12 cases (42%) sought genetic counseling, 4/12 (33%) underwent genetic testing; 1/4 (25%) tested positive for a pathogenic variant. The difference in navigated (88%) versus non-navigated cases (42%) undergoing genetic counseling was statistically significant (p = .02). Patient navigation was associated with follow-through to genetic counseling and testing services among LS screen-positive cases. This model deserves additional prospective investigation to confirm these findings and to assess their generalizability.

Climate-change-induced range shifts of three allergenic ragweeds (Ambrosia L.) in Europe and their potential impact on human health.

Invasive allergenic plant species may have severe health-related impacts. In this study we aim to predict the effects of climate change on the distribution of three allergenic ragweed species (Ambrosia spp.) in Europe and discuss the potential associated health impact. We built species distribution models based on presence-only data for three ragweed species, using MAXENT software. Future climatic habitat suitability was modeled under two IPCC climate change scenarios (RCP 6.0 and RCP 8.5). We quantify the extent of the increase in 'high allergy risk' (HAR) areas, i.e., parts of Europe with climatic conditions corresponding to the highest quartile (25%) of present day habitat suitability for each of the three species. We estimate that by year 2100, the distribution range of all three ragweed species increases towards Northern and Eastern Europe under all climate scenarios. HAR areas will expand in Europe by 27-100%, depending on species and climate scenario. Novel HAR areas will occur mostly in Denmark, France, Germany, Russia and the Baltic countries, and overlap with densely populated cities such as Paris and St. Petersburg. We conclude that areas in Europe affected by severe ragweed associated allergy problems are likely to increase substantially by year 2100, affecting millions of people. To avoid this, management strategies must be developed that restrict ragweed dispersal and establishment of new populations. Precautionary efforts should limit the spread of ragweed seeds and reduce existing populations. Only by applying cross-countries management plans can managers mitigate future health risks and economical consequences of a ragweed expansion in Europe.

Development and validation of the JAX Cancer Treatment Profile™ for detection of clinically actionable mutations in solid tumors.

BACKGROUND: The continued development of targeted therapeutics for cancer treatment has required the concomitant development of more expansive methods for the molecular profiling of the patient's tumor. We describe the validation of the JAX Cancer Treatment Profile™ (JAX-CTP™), a next generation sequencing (NGS)-based molecular diagnostic assay that detects actionable mutations in solid tumors to inform the selection of targeted therapeutics for cancer treatment. METHODS: NGS libraries are generated from DNA extracted from formalin fixed paraffin embedded tumors. Using hybrid capture, the genes of interest are enriched and sequenced on the Illumina HiSeq 2500 or MiSeq sequencers followed by variant detection and functional and clinical annotation for the generation of a clinical report. RESULTS: The JAX-CTP™ detects actionable variants, in the form of single nucleotide variations and small insertions and deletions (≤50 bp) in 190 genes in specimens with a neoplastic cell content of ≥10%. The JAX-CTP™ is also validated for the detection of clinically actionable gene amplifications. CONCLUSIONS: There is a lack of consensus in the molecular diagnostics field on the best method for the validation of NGS-based assays in oncology, thus the importance of communicating methods, as contained in this report. The growing number of targeted therapeutics and the complexity of the tumor genome necessitate continued development and refinement of advanced assays for tumor profiling to enable precision cancer treatment.

Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors.

BACKGROUND: Although numerous mouse models of breast carcinomas have been developed, we do not know the extent to which any faithfully represent clinically significant human phenotypes. To address this need, we characterized mammary tumor gene expression profiles from 13 different murine models using DNA microarrays and compared the resulting data to those from human breast tumors. RESULTS: Unsupervised hierarchical clustering analysis showed that six models (TgWAP-Myc, TgMMTV-Neu, TgMMTV-PyMT, TgWAP-Int3, TgWAP-Tag, and TgC3(1)-Tag) yielded tumors with distinctive and homogeneous expression patterns within each strain. However, in each of four other models (TgWAP-T121, TgMMTV-Wnt1, Brca1Co/Co;TgMMTV-Cre;p53+/- and DMBA-induced), tumors with a variety of histologies and expression profiles developed. In many models, similarities to human breast tumors were recognized, including proliferation and human breast tumor subtype signatures. Significantly, tumors of several models displayed characteristics of human basal-like breast tumors, including two models with induced Brca1 deficiencies. Tumors of other murine models shared features and trended towards significance of gene enrichment with human luminal tumors; however, these murine tumors lacked expression of estrogen receptor (ER) and ER-regulated genes. TgMMTV-Neu tumors did not have a significant gene overlap with the human HER2+/ER- subtype and were more similar to human luminal tumors. CONCLUSION: Many of the defining characteristics of human subtypes were conserved among the mouse models. Although no single mouse model recapitulated all the expression features of a given human subtype, these shared expression features provide a common framework for an improved integration of murine mammary tumor models with human breast tumors.

Classification and risk stratification of invasive breast carcinomas using a real-time quantitative RT-PCR assay.

INTRODUCTION: Predicting the clinical course of breast cancer is often difficult because it is a diverse disease comprised of many biological subtypes. Gene expression profiling by microarray analysis has identified breast cancer signatures that are important for prognosis and treatment. In the current article, we use microarray analysis and a real-time quantitative reverse-transcription (qRT)-PCR assay to risk-stratify breast cancers based on biological 'intrinsic' subtypes and proliferation. METHODS: Gene sets were selected from microarray data to assess proliferation and to classify breast cancers into four different molecular subtypes, designated Luminal, Normal-like, HER2+/ER-, and Basal-like. One-hundred and twenty-three breast samples (117 invasive carcinomas, one fibroadenoma and five normal tissues) and three breast cancer cell lines were prospectively analyzed using a microarray (Agilent) and a qRT-PCR assay comprised of 53 genes. Biological subtypes were assigned from the microarray and qRT-PCR data by hierarchical clustering. A proliferation signature was used as a single meta-gene (log2 average of 14 genes) to predict outcome within the context of estrogen receptor status and biological 'intrinsic' subtype. RESULTS: We found that the qRT-PCR assay could determine the intrinsic subtype (93% concordance with microarray-based assignments) and that the intrinsic subtypes were predictive of outcome. The proliferation meta-gene provided additional prognostic information for patients with the Luminal subtype (P = 0.0012), and for patients with estrogen receptor-positive tumors (P = 3.4 x 10-6). High proliferation in the Luminal subtype conferred a 19-fold relative risk of relapse (confidence interval = 95%) compared with Luminal tumors with low proliferation. CONCLUSION: A real-time qRT-PCR assay can recapitulate microarray classifications of breast cancer and can risk-stratify patients using the intrinsic subtype and proliferation. The proliferation meta-gene offers an objective and quantitative measurement for grade and adds significant prognostic information to the biological subtypes.