Afadin-nectin forces its way to the front.

Force transmission at cell-cell junctions critically regulates embryogenesis, tissue homeostasis, and diseases including cancer. The cadherin-catenin linkage has been considered the keystone of junctional force transmission, but new findings challenge this paradigm, arguing instead that the nectin-afadin linkage plays the more important role in mature junctions in the intestinal epithelium.

[18]F-fluoroethyl-l-tyrosine positron emission tomography for radiotherapy target delineation: Results from a Radiation Oncology credentialing program.

Background and purpose: The [18]F-fluoroethyl-l-tyrosine (FET) PET in Glioblastoma (FIG) study is an Australian prospective, multi-centre trial evaluating FET PET for newly diagnosed glioblastoma management. The Radiation Oncology credentialing program aimed to assess the feasibility in Radiation Oncologist (RO) derivation of standard-of-care target volumes (TVMR) and hybrid target volumes (TVMR+FET) incorporating pre-defined FET PET biological tumour volumes (BTVs). Materials and methods: Central review and analysis of TVMR and TVMR+FET was undertaken across three benchmarking cases. BTVs were pre-defined by a sole nuclear medicine expert. Intraclass correlation coefficient (ICC) confidence intervals (CIs) evaluated volume agreement. RO contour spatial and boundary agreement were evaluated (Dice similarity coefficient [DSC], Jaccard index [JAC], overlap volume [OV], Hausdorff distance [HD] and mean absolute surface distance [MASD]). Dose plan generation (one case per site) was assessed. Results: Data from 19 ROs across 10 trial sites (54 initial submissions, 8 resubmissions requested, 4 conditional passes) was assessed with an initial pass rate of 77.8 %; all resubmissions passed. TVMR+FET were significantly larger than TVMR (p < 0.001) for all cases. RO gross tumour volume (GTV) agreement was moderate-to-excellent for GTVMR (ICC = 0.910; 95 % CI, 0.708-0.997) and good-to-excellent for GTVMR+FET (ICC = 0.965; 95 % CI, 0.871-0.999). GTVMR+FET showed greater spatial overlap and boundary agreement compared to GTVMR. For the clinical target volume (CTV), CTVMR+FET showed lower average boundary agreement versus CTVMR (MASD: 1.73 mm vs. 1.61 mm, p = 0.042). All sites passed the planning exercise. Conclusions: The credentialing program demonstrated feasibility in successful credentialing of 19 ROs across 10 sites, increasing national expertise in TVMR+FET delineation.

Preventing extinction in an age of species migration and planetary change.

International and national conservation policies almost exclusively focus on conserving species in their historic native ranges, thus excluding species that have been introduced by people and some of those that have extended their ranges on their own accord. Given that many of such migrants are threatened in their native ranges, conservation goals that explicitly exclude these populations may overlook opportunities to prevent extinctions and respond dynamically to rapidly changing environmental and climatic conditions. Focusing on terrestrial mammals, we quantified the number of threatened mammals that have established new populations through assisted migration (i.e., introduction). We devised 4 alternative scenarios for the inclusion of assisted-migrant populations in mainstream conservation policy with the aim of preventing global species extinctions. We then used spatial prioritization algorithms to simulate how these scenarios could change global spatial conservation priorities. We found that 22% (70 species out of 265) of all identified assisted-migrant mammals were threatened in their native ranges, mirroring the 25% of all mammals that are threatened. Reassessing global threat statuses by combining native and migrant ranges reduced the threat status of 23 species (∼33% of threatened assisted migrants). Thus, including migrant populations in threat assessments provides a more accurate assessment of actual global extinction risk among species. Spatial prioritization simulations showed that reimagining the role of assisted-migrant populations in preventing species extinction could increase the importance of overlooked landscapes, particularly in central Australia, Europe, and the southwestern United States. Our results indicated that these various and nonexhaustive ways to consider assisted-migrant populations, with due consideration of potential conservation conflicts with resident taxa, may provide unprecedented opportunities to prevent species extinctions.

Prevención de la extinción en una época de migración de especies y cambios planetarios Resumen Las políticas de conservación nacionales e internacionales casi siempre se enfocan en la conservación de las especies dentro de su distribución histórica y nativa, por lo que se excluyen especies que han sido introducidas por el humano y algunas que se han extendido por cuenta propia más allá de su distribución. Ya que muchas de estas especies migrantes están amenazadas dentro de su distribución nativa, los objetivos de conservación que excluyen explícitamente a estas poblaciones pueden ignorar las oportunidades para prevenir extinciones y responder de forma dinámica a las condiciones ambientales y climáticas que cambian con rapidez. Nos enfocamos en los mamíferos terrestres para cuantificar el número de especies amenazadas que han establecido poblaciones nuevas mediante la migración asistida (introducción). Diseñamos cuatro escenarios alternativos para la inclusión de las poblaciones con migración asistida dentro de las políticas de conservación generales con el objetivo de prevenir extinciones globales de especies. Después usamos algoritmos de priorización espacial para simular cómo estos escenarios podrían cambiar las prioridades de conservación espacial en todo el mundo. Descubrimos que el 22% (70 de 765 especies) de todos los mamíferos con migración asistida están amenazados dentro de su distribución nativa, lo que es similar al 25% de especies amenazadas de todas las especies de mamíferos. La reevaluación de los estados mundiales de amenaza mediante la combinación de la distribución nativa y migrante redujo el estado de amenaza de 23 especies (∼33% de los migrantes asistidos amenazados). Por esto, incluir a las poblaciones migrantes en la evaluación de amenazas proporciona una evaluación más certera del riesgo de extinción que existe entre las especies a nivel mundial. Las simulaciones de priorización espacial mostraron que reinventar el papel que tienen las poblaciones con migración asistida en la prevención de la extinción de especies podría incrementar la importancia de los paisajes ignorados, particularmente en Australia central, Europa y el suroeste de los Estados Unidos. Nuestros resultados indican que estas maneras diversas y no exhaustivas de considerar a las poblaciones con migración asistida, con la debida consideración de los potenciales conflictos de conservación con los taxones residentes, puede proporcionar oportunidades sin precedentes para prevenir la extinción de las especies.

Does the outcome of graft materials at dental implant sites differ between patients with normal and compromised bone health?

OBJECTIVE: To assess the outcome of bone graft material at alveolar bone augmentation sites combined with dental implants in postmenopausal women with compromised bone health by evaluating cone beam computed tomography (CBCT) scans at multiple time points. MATERIALS AND METHODS: CBCT scans were analyzed on 55 postmenopausal women with compromised bone health status to determine the fate of alveolar bone augmentation. CBCT scans were taken immediately after surgery and 9 and 24 months post-operatively. The patient's medication regimens and durations were recorded, and the pixel intensity value (PIV) was measured and standardized using scoring criteria and visual assessment. Statistical analyses included two-sample t-tests for continuous variables and Fisher's exact tests for categorical variables. RESULTS: Among the normal patients, 73% received a grade 2 visual score, and 27% received a grade 1 visual score. After 24 months, 45% of patients received a grade 2 score, and 27% received a grade 3 score. In the osteoporotic group receiving medication, 77% of participants received a grade 1 visual score at the 9-month postoperative evaluation, while 23% received a grade 2 score. At the 24-month assessment, 55% of patients received a grade 1 score, 41% received a grade 2 score, and only 5% received a grade 3 score. Notably, although the graft material did not remodel into native bone, it was a scaffold for implants in controlled osteoporotic patients. CONCLUSION: The study's results show that the pixel intensity values of particulate graft materials are similar across the three different time points, suggesting that the graft material's pixel intensity value remains constant in postmenopausal women with osteoporosis. The study's limitations include a small sample size and a restricted 24-month follow-up period. This limited time frame may need to capture long-term changes or variations in graft materials adequately. FUTURE DIRECTIONS: Future research should include a larger sample size and have a longer follow-up duration to provide a more comprehensive understanding of the change in graft materials between patients with normal and compromised bone health.

Pathological claustrum activity drives aberrant cognitive network processing in human chronic pain.

Aberrant cognitive network activity and cognitive deficits are established features of chronic pain. However, the nature of cognitive network alterations associated with chronic pain and their underlying mechanisms require elucidation. Here, we report that the claustrum, a subcortical nucleus implicated in cognitive network modulation, is activated by acute painful stimulation and pain-predictive cues in healthy participants. Moreover, we discover pathological activity of the claustrum and a region near the posterior inferior frontal sulcus of the right dorsolateral prefrontal cortex (piDLPFC) in migraine patients during acute pain and cognitive task performance. Dynamic causal modeling suggests a directional influence of the claustrum on activity in this piDLPFC region, and diffusion weighted imaging verifies their structural connectivity. These findings advance understanding of claustrum function during acute pain and provide evidence of a possible circuit mechanism driving cognitive impairments in chronic pain.

Minimally invasive keyhole approach for supramaximal frontal glioma resections: technical note.

OBJECTIVE: The authors aimed to review the frontal lobe's surgical anatomy, describe their keyhole frontal lobectomy technique, and analyze the surgical results. METHODS: Patients with newly diagnosed frontal gliomas treated using a keyhole approach with supramaximal resection (SMR) from 2016 to 2022 were retrospectively reviewed. Surgeries were performed on patients asleep and awake. A human donor head was dissected to demonstrate the surgical anatomy. Kaplan-Meier curves were used for survival analysis. RESULTS: Of the 790 craniotomies performed during the study period, those in 47 patients met our inclusion criteria. The minimally invasive approach involved four steps: 1) debulking the frontal pole; 2) subpial dissection identifying the sphenoid ridge, olfactory nerve, and optic nerve; 3) medial dissection to expose the falx cerebri and interhemispheric structures; and 4) posterior dissection guided by motor mapping, avoiding crossing the inferior plane defined by the corpus callosum. A fifth step could be added for nondominant lesions by resecting the inferior frontal gyrus. Perioperative complications were recorded in 5 cases (10.6%). The average hospital length of stay was 3.3 days. High-grade gliomas had a median progression-free survival of 14.8 months and overall survival of 23.9 months. CONCLUSIONS: Keyhole approaches enabled successful SMR of frontal gliomas without added risks. Robust anatomical knowledge and meticulous surgical technique are paramount for obtaining successful resections.

5-Year Follow-Up of a Physician Performance Feedback Report Intervention to Reduce Overuse and Excess Cost: A National Cohort Study.

BACKGROUND: Mohs micrographic surgery efficiently treats skin cancer through staged resection, but surgeons' varying resection rates may lead to higher medical costs. OBJECTIVE: To evaluate the cost savings associated with a quality improvement. MATERIALS AND METHODS: The authors conducted a retrospective cohort study using 100% Medicare fee-for-service claims data to identify the change of mean stages per case for head/neck (HN) and trunk/extremity (TE) lesions before and after the quality improvement intervention from 2016 to 2021. They evaluated surgeon-level change in mean stages per case between the intervention and control groups, as well as the cost savings to Medicare over the same time period. RESULTS: A total of 2,014 surgeons performed Mohs procedures on HN lesions. Among outlier surgeons who were notified, 31 surgeons (94%) for HN and 24 surgeons (89%) for TE reduced their mean stages per case with a median reduction of 0.16 and 0.21 stages, respectively. Reductions were also observed among outlier surgeons who were not notified, reducing their mean stages per case by 0.1 and 0.15 stages, respectively. The associated total 5-year savings after the intervention was 92 million USD. CONCLUSION: The implementation of this physician-led benchmarking model was associated with broad reductions of physician utilization and significant cost savings.

Time Series Analysis of Nonlinear Head Dynamics Using Synthetic Data Generated with a Variably Saturated Model.

The performance of time series models is assessed using synthetic head series simulated with a numerical model that solves Richards' equation for variably saturated flow. Heads were simulated in a homogeneous unconfined aquifer between two parallel canals; measured daily precipitation and potential evaporation are specified at the land surface and root water uptake is simulated. The head response to a precipitation event is nonlinear and depends on the saturation degree and rainfall before and after the precipitation event while evaporation reduction occurs during summers. Synthetic series were generated for 27 years and three different soil types; the unsaturated zone thickness varies between 0 and >5 m. The synthetic head series were simulated with a linear and nonlinear time series model. Performance of a linear time series model with four parameters, using a scaled Gamma response, gave R2 values ranging from 0.67 to 0.96. The nonlinear time series model with five parameters simulates recharge using a root zone reservoir after which the head response to recharge is simulated with a scaled Gamma response function. The nonlinear time series model was able to simulate all synthetic head series very well with R2 values above 0.9 for almost all models. The head response of the nonlinear model to a single precipitation event compares well to the response of the variably saturated groundwater model. The provided scripts may be used to simulate synthetic head series for other climates or for systems with additional complexity to assess the performance of other data-driven models.

Appropriateness of Care Measures: A Novel Approach to Quality.

The clinical judgement of a physician is one of the most important aspects of medical quality, yet it is rarely captured with quality measures in use today. We propose a novel approach using individualized physician benchmarking that measures the appropriateness of care that a physician delivers by looking at their practice pattern in a specific clinical situation. A prime application of our novel approach to appropriateness measures is the surgical management of peripheral artery disease and claudication. We discuss 4 potential consensus metrics for the treatment if claudication that explore appropriateness of care of claudication management, and are meaningful, actionable, and quantifiable. Given the multitude of medical specialties involved in the care of patients with peripheral artery disease, and the consequences of both preemptive and delayed care, it is in all of our interests to promote data transparency with confidential communications to outlier physicians while advocating for evidence-based management.

Tissue-specific nonheritable influences drive endometrial immune system variation.

Although human twin studies have revealed the combined contribution of heritable and environmental factors in shaping immune system variability in blood, the contribution of these factors to immune system variability in tissues remains unexplored. The human uterus undergoes constant regeneration and is exposed to distinct environmental factors. To assess uterine immune system variation, we performed a system-level analysis of endometrial and peripheral blood immune cells in monozygotic twins. Although most immune cell phenotypes in peripheral blood showed high genetic heritability, more variation was found in endometrial immune cells, indicating a stronger influence by environmental factors. Cytomegalovirus infection was identified to influence peripheral blood immune cell variability but had limited effect on endometrial immune cells. Instead, hormonal contraception shaped the local endometrial milieu and immune cell composition with minor influence on the systemic immune system. These results highlight that the magnitude of human immune system variation and factors influencing it can be tissue specific.

Lipid clinic experience with bempedoic acid in three UK centres.

OBJECTIVE: Novel lipid-lowering therapies are being introduced. Few studies exist of the real-world effectiveness of adenosine-tri-phosphate citrate lyase inhibition with bempedoic acid. METHODS: This study audited bempedoic acid therapy in 216 consecutive patients from three hospital centres - a university hospital (n = 77) and two district general hospitals (n = 106 and 33). Cardiovascular disease (CVD) risk factors, prescription qualification criteria, efficacy and adverse effects were assessed. RESULTS: The population was aged 65.9 ± 11.0 years, 42% were male, 25% had type 2 diabetes, and 31% had familial hypercholesterolaemia. CVD was present in 19% and multibed vascular disease in 8%. Statin intolerance was reported in 92%. Bempedoic acid reduced total cholesterol by 1.58 ± 1.44 mmol/L (20%), LDL-C by 1.37 ± 1.31 mmol/L (27%), triglycerides by 0.22 mmol/L (2%) with an 0.06 mmol/L (1%) increase in HDL-C after 22 ± 9 months follow-up. An LDL-C <2.5 mmol/L was achieved in 40% and <2 mmol/L in 20%. Efficacy (r2 = .33) was predicted by baseline LDL-C (ß = .54; p <.001). No significant changes were seen in transaminases, creatinine, creatine kinase, urate or HbA1c. Treatment was discontinued by 33% of patients and occurred due to myalgia (43%), lack of efficacy (16%) and gastrointestinal adverse effects (15%). No cases of gout were observed. In a logistic regression only the number of previous drug classes not tolerated (ß = 1.60; p = .009) was a contributing factor to discontinuation. CONCLUSION: This audit suggests that bempedoic acid therapy is effective but that adverse effects and discontinuation are common. This suggests nocebo effects might be generalizable to all lipid-lowering drug therapies in susceptible individuals.

Low-cost interventions to improve ventilation in long-term care facilities.

Residents of long-term care facilities are particularly vulnerable to communicable diseases. Low-cost interventions to increase air exchange rates (AERs) may be useful in reducing the transmission of airborne communicable diseases between long-term care residents and staff. In this study, carbon dioxide gas was used as a tracer to evaluate the AER associated with the implementation of low-cost ventilation interventions. Under baseline conditions with the room's door closed, the mean AER was 0.67 ACH; while baseline conditions with the door open had a significantly higher mean AER of 3.87 ACH (p < 0.001). Subsequently opening a window with the door open increased mean AER by 1.49 ACH (p = 0.012) and adding a fan in the window further increased mean AER by 1.87 ACH (p < 0.001). Regression analyses indicated that the flow rate of air entering through the window, both passively and through the use of a fan, was significantly associated with an increase in AER (p < 0.001). These results indicate that low-cost interventions that pull outside air into resident rooms were effective in improving the air exchange rates in these facilities. While implementation of these interventions is dependent on facility rules and isolation requirements of residents with airborne communicable diseases, these interventions remain viable options for long-term care facilities to improve resident room ventilation without requiring costly ventilation system upgrades.

Changes in Photosystem II Complex and Physiological Activities in Pea and Maize Plants in Response to Salt Stress.

Salt stress significantly impacts the functions of the photosynthetic apparatus, with varying degrees of damage to its components. Photosystem II (PSII) is more sensitive to environmental stresses, including salinity, than photosystem I (PSI). This study investigated the effects of different salinity levels (0 to 200 mM NaCl) on the PSII complex in isolated thylakoid membranes from hydroponically grown pea (Pisum sativum L.) and maize (Zea mays L.) plants treated with NaCl for 5 days. The data revealed that salt stress inhibits the photochemical activity of PSII (H2O → BQ), affecting the energy transfer between the pigment-protein complexes of PSII (as indicated by the fluorescence emission ratio F695/F685), QA reoxidation, and the function of the oxygen-evolving complex (OEC). These processes were more significantly affected in pea than in maize under salinity. Analysis of the oxygen evolution curves after flashes and continuous illumination showed a stronger influence on the PSIIα than PSIIß centers. The inhibition of oxygen evolution was associated with an increase in misses (α), double hits (ß), and blocked centers (SB) and a decrease in the rate constant of turnover of PSII reaction centers (KD). Salinity had different effects on the two pathways of QA reoxidation in maize and pea. In maize, the electron flow from QA- to plastoquinone was dominant after treatment with higher NaCl concentrations (150 mM and 200 mM), while in pea, the electron recombination on QAQB- with oxidized S2 (or S3) of the OEC was more pronounced. Analysis of the 77 K fluorescence emission spectra revealed changes in the ratio of the light-harvesting complex of PSII (LHCII) monomers and trimers to LHCII aggregates after salt treatment. There was also a decrease in pigment composition and an increase in oxidative stress markers, membrane injury index, antioxidant activity (FRAP assay), and antiradical activity (DPPH assay). These effects were more pronounced in pea than in maize after treatment with higher NaCl concentrations (150 mM-200 mM). This study provides insights into how salinity influences the processes in the donor and acceptor sides of PSII in plants with different salt sensitivity.

Global spread, genetic differentiation and selection of barley spot form of net blotch isolates.

Spot form of net blotch, caused by Pyrenophora teres f. maculata, is a significant necrotrophic disease of barley that spread world-wide in the 20th century. Genetic relationships were analysed to determine the diversity, survival and dispersal of a diverse collection of 346 isolates from Australia, Southern Africa, North America, Asia Minor and Europe. The results, based on genome-wide DArTseq data, indicated isolates from Turkey were the most differentiated with regional sub-structuring, together with individuals closely related to geographically distant genotypes. Elsewhere, population subdivision related to country of origin was evident, although low levels of admixturing was found that may represent rare genotypes or migration from unsampled populations. Canadian isolates were the next most diverged and Australian and South African the most closely related. With the exception of Turkish isolates, multiple independent Cyp51A mutation events (which confer insensitivity to demethylation inhibitor fungicides) between countries and within regions was evident, with strong selection for a transposable element insertion at the 3' end of the promoter and counter-selection elsewhere. Individuals from Western Australia shared genomic regions and Cyp51A haplotypes with South African isolates, suggesting a recent common origin.

A conserved complex lipid signature marks human muscle aging and responds to short-term exercise.

Studies in preclinical models suggest that complex lipids, such as phospholipids, play a role in the regulation of longevity. However, identification of universally conserved complex lipid changes that occur during aging, and how these respond to interventions, is lacking. Here, to comprehensively map how complex lipids change during aging, we profiled ten tissues in young versus aged mice using a lipidomics platform. Strikingly, from >1,200 unique lipids, we found a tissue-wide accumulation of bis(monoacylglycero)phosphate (BMP) during mouse aging. To investigate translational value, we assessed muscle tissue of young and older people, and found a similar marked BMP accumulation in the human aging lipidome. Furthermore, we found that a healthy-aging intervention consisting of moderate-to-vigorous exercise was able to lower BMP levels in postmenopausal female research participants. Our work implicates complex lipid biology as central to aging, identifying a conserved aging lipid signature of BMP accumulation that is modifiable upon a short-term healthy-aging intervention.

Nonepisodic autobiographical memory details reflect attempts to tell a good story.

A persistent finding in the autobiographical memory (AM) literature is that older adults report more nonepisodic (or generalized/semantic) information than young adults. Since studies are usually focused on memory for episodic (or specific) autobiographical events, the reason for the age difference in nonepisodic AM remains understudied. This experiment investigated whether the higher rate of nonepisodic AM in older adults reflects (a) a difference incommunicative preferences or (b) cognitive decline, by way of either an inhibition deficit or as a means of compensating for a deficit in episodic AM. A sample of 54 young (N = 28, age range = 18-46) and older (N = 26, age range = 62-86) participants retrieved the same AM twice, under two different sets of instructions: to tell a good story for their autobiography, or to provide a detailed police witness statement. Both groups reported more general details when they were aiming to tell a good story. In addition, older adults also reported fewer specific details when the aim was to tell a good story. In a separate ranking task, young and older adults differed in their perceptions of what makes a good story; young adults ranked "detail," "grammar," and "full descriptions" more highly than older adults, whereas older ranked "linking ideas" and "explaining not just describing" more highly than young adults. The results suggest that age-related differences in nonepisodic AM might be explained by communicative preferences rather than cognitive decline. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Preliminary results of the austrian national registry with the novel iCover bridging stentgraft in fenestrated endovascular aortic repair.

OBJECTIVE: Bridging stentgrafts (BSGs) are one of the primary limiting factors regarding long-term results after fenestrated endovascular aortic repair (fEVAR). This study aims to report for the first time the outcome of a novel BSG called iCover from a national, multicentric retrospective database. METHODS: A cohort of 58 patients received 212 BSGs for the renovisceral arteries in fEVAR. Patients were followed-up clinically and with computed-tomography angiography. Study end points were mortality, occurrence of complications, technical success of the BSG implantation, defined as successful deployment with vessel patency and absence of type 1c, 3b, and 3c endoleak, and stability over the follow-up. RESULTS: Three BSG unrelated mortalities (5.1 %), four BSG unrelated major complications (6.8 %) and five minor complications (8.6 %) occurred. The technical success of iCover was 207/212 (97.6 %), target vessel patency was 100 % over a follow-up of 4.0 months, and no late BSG related endoleak was detected. In two cases, the BSG was dislodged from the balloon and could be parked in a safe position without further sequelae (0.9 %). CONCLUSION: The iCover represents a feasible BSG for fEVAR with an excellent safety profile and technical success rate in the early phase. Prudent post-dilatation and monitoring of the proximal and distal stent ends can potentially further improve outcome. Longer follow-up series are necessary.

Tackle Risk Factors for Head Injury Assessments (HIAs) in Sub-Elite Rugby League and Recommendations for Prevention: Head Contacts from Upright Tackles Increase the HIA Risk to Both Ball Carrier and Tackler.

BACKGROUND: The rugby league tackle has been identified as the game event with the greatest propensity for a clinically diagnosed concussion. This study aims to replicate the work conducted in professional rugby league and rugby union by examining Head Injury Assessment (HIA) events to determine the associated tackle characteristics that increase concussion risk in sub-elite rugby league players. This comparison between competition levels is important due to the less developed physiological and tackle proficiency characteristics of sub-elite rugby league players and the fewer resources available for an on-field diagnosis, compared to the elite level of the sport. RESULTS: Tackles resulting in Head Injury Assessments (HIAs, n = 131) and 2,088 tackles that did not result in a head injury were identified and coded from one season of the 2019 Queensland Cup. The body position of both ball carrier and tackler, tackle height, and body contact areas were evaluated. The propensity for tacklers to undergo a head injury assessment was 1.49 HIAs per 1,000 tackles, equating to a 2.5-fold higher risk than that of the ball carrier (0.59 HIAs per 1,000 tackles). The risk for an HIA was 2.75-fold greater when the tackler was upright (2.89 HIAs per 1,000 tackles) compared to a bent-at-the-waist tackler (1.05 HIAs per 1,000 tackles). The greatest risk for the tackler and ball carrier sustaining an HIA occurred when the tackle height was high, with head-to-head contact having the greatest propensity for an HIA (44.37 HIAs per 1,000 tackles). HIA risk was also greater for both players when the ball carrier did not employ an evasion strategy (3.73 HIAs per 1,000 tackles). CONCLUSIONS: The study replicates results from research in elite rugby league and rugby union. A combination of higher head contact/proximity and upright body position significantly increase an HIA risk. Tackler head position and ball carrier evasion behaviours also affect risk, suggesting that injury prevention strategies designed to reduce tackle height and improve tackle technique by focusing on head position, body position, and in a novel finding, ball carrier evasion, may reduce head injury risk in sub-elite rugby league players.

Loss of CREBBP and KMT2D cooperate to accelerate lymphomagenesis and shape the lymphoma immune microenvironment.

Despite regulating overlapping gene enhancers and pathways, CREBBP and KMT2D mutations recurrently co-occur in germinal center (GC) B cell-derived lymphomas, suggesting potential oncogenic cooperation. Herein, we report that combined haploinsufficiency of Crebbp and Kmt2d induces a more severe mouse lymphoma phenotype (vs either allele alone) and unexpectedly confers an immune evasive microenvironment manifesting as CD8+ T-cell exhaustion and reduced infiltration. This is linked to profound repression of immune synapse genes that mediate crosstalk with T-cells, resulting in aberrant GC B cell fate decisions. From the epigenetic perspective, we observe interaction and mutually dependent binding and function of CREBBP and KMT2D on chromatin. Their combined deficiency preferentially impairs activation of immune synapse-responsive super-enhancers, pointing to a particular dependency for both co-activators at these specialized regulatory elements. Together, our data provide an example where chromatin modifier mutations cooperatively shape and induce an immune-evasive microenvironment to facilitate lymphomagenesis.