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Background Up to 25% of concussed individuals experience persistent post-concussion symptoms (PPCSs) which may interfere with the return to pre-injury activities and cause significant stress. Given that multiple etiological factors are thought to contribute to PPCSs, an interdisciplinary approach is recommended. This pilot study aims to primarily investigate the feasibility of a novel interdisciplinary treatment for PPCSs. Given this intervention is novel, uncertainty exists in terms of potential recruitment and retention rates, adverse events, and treatment adherence and fidelity. These factors will be explored to inform the feasibility of a phase-2 randomised controlled trial. Preliminary efficacy of this intervention will also be explored. Methods Fifteen individuals with mild traumatic brain injury and PPCSs will receive up to 12 weeks of interdisciplinary treatments including psychology, physiotherapy, and medical interventions. Primary feasibility outcomes including data on recruitment and retention rates and treatment adherence will be explored descriptively. The cognitive therapy rating scale will be used to assess treatment fidelity. A single-case series with multiple baseline design will be used to explore preliminary efficacy. Participants will be randomly assigned to baseline phases of 2, 4, or 6 weeks. Regarding patient-centred secondary outcomes, the Rivermead Post-Concussion Symptoms Questionnaire will be assessed three times a week during baseline and treatment phases. Secondary outcomes also include measures of mood, sleep and fatigue, physical functioning, return to activity, and health-related quality of life. Patient-centred outcomes will be assessed at baseline, pretreatment, post-treatment, and one- and three-month follow-up. Thematic analysis of participant experiences will be explored through qualitative interviews. Discussion Results from this trial will inform the feasibility and preliminary efficacy of this interdisciplinary concussion intervention and whether proceeding to a future definitive phase-2 randomised controlled trial is worthwhile. Understanding the end-user perspective of the treatment will also enable modifications to the treatment protocol for future trials to best suit the needs of individuals with PPCSs after mTBI. Outcomes from this trial can be directly translated into community rehabilitation programmes. Trial registration ANZCTR, ACTRN12620001111965. Registered 27 October 2020, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=379118

Background Sensor devices have enabled estimations of head impact kinematics across contact sports. Objectives To quantitatively report the magnitude (linear and rotational acceleration) and frequency of game-related head impacts recorded in male contact sports athletes. Methods A systematic review was conducted in June 2017. Inclusion criteria were English-language in vivo studies published after 1990 with a study population of male athletes aged ≥ 16 years, in any sport, where athletes were instrumented with an accelerometer device for measuring head impacts. Study populations were not limited to players with a clinical diagnosis of concussion. Results Twenty-one studies met the inclusion criteria with 12 conducted on American Football athletes. Six of these studies were included for meta-analysis. At a threshold of 10 g , amateur rugby players sustained the most impacts per player per game (mean = 77, SD = 42), followed by amateur Australian Football (mean = 29, SD = 37) and collegiate lacrosse athletes (mean = 11.5, SD = 3.6). At thresholds of greater than 14.4 g , high school American Football athletes sustained between 19 (SD = 19.1) and 24.4 (SD = 22.4) impacts per player per game. Statistically significant heterogeneity was observed among the included studies, and meta-analysis of impact magnitude was limited. Conclusions The frequency of “head acceleration events” was quantified and demonstrated substantial variation in methodology and reporting of results. Future research with standardised reporting of head impacts and inclusion of non-helmeted sports is warranted to enable more robust comparisons across sports. Prospero ID CRD42017070065.

ObjectivesTo assess the association between soft-shell headgear (HG) use and sports-related concussion (SRC). Secondary objectives were to assess the association between HG and superficial head injury and investigate potential increase in injury risk among HG users.DesignA systematic search in Ovid MEDLINE, Cochrane Library, Scopus, PsycINFO and SPORTDiscus was conducted in April 2020. Inclusion criteria were youth <18, English language, in vivo studies published after 1980 that evaluated SRC and other injury incidence in HG users compared with non-users.Outcome measuresIncidence rates of SRC, superficial head injury or other injuries.ResultsEight studies were eligible. The majority (n=5) reported no difference in the rate of SRC among HG users versus non-users. One rugby study identified significantly lower risk of SRC for non-HG users (risk ratio (RR) 0.63; 95% CI 0.41 to 0.98) compared with HG users, whereas a cross-sectional survey of soccer players indicated higher risk of SRC for non-HG users (RR 2.65; 95% CI 1.23 to 3.12) compared with HG users. Three of the four studies investigating superficial head injury found no significant differences with HG use, though the soccer survey reported reduced risk among HG users (RR 1.86; 95% CI 0.09 to 0.11). Increased incidence of injuries to all body regions for rugby HG users was reported in two studies with adjusted RRs of 1.16 (95% CI 1.04 to 1.29) and 1.23 (95% CI 1.00 to 1.50).ConclusionsHG use was not associated with reduced rates of SRC or superficial head injury in youth soccer and rugby. The possibility of increased injury risk to all body regions for rugby HG users was raised. The need for research specific to youth and female athletes was highlighted.PROSPERO registration numberCRD42018115310.

To explore the potential utility of head acceleration event (HAE) measurements to augment identification of players for further concussion screening in non-helmeted contact sport. Prospective observational pilot study. 210 (118 female) professional Australian football players in 2017 season. Players wore the X-Patch® accelerometer for one match each with data collected across 14 matches. Players with HAEs above thresholds associated with concussion, 95 g (males) or 85.5 g (females), were compared to players identified to have suspected concussion by club personnel during the inspected matches. Video review of matches was undertaken by a physician blinded to HAEs to identify players with concussive signs. Among 26 players (50% female) with HAEs above threshold, two players were screened for concussion. Of the remaining 24 players, nine were not visible on video at the HAE time, six sustained verifiable head impacts, and nine sustained verifiable body impacts with no head impacts. Among 184 players with HAEs below threshold, five players were screened. Players were identified to have head impacts and suspected concussion in the absence of HAEs above threshold. Use of X-Patch® was not sufficiently reliable for identifying players for further concussion screening in professional Australian football. Video review of head impacts remains essential in concussion screening. •PLA values previously associated with concussion were unable to reliably identify players in need of concussion screening.•An association between accelerometer output and concussion risk is confounded by individual variability in injury tolerance.•The X-Patch® non-wearable accelerometer in its current form does not augment current best practice in concussion screening.•Video review is a useful method of verifying accelerometer output and integral to best practice in concussion screening.

ObjectiveTo assess the association between soft-shell headgear (HG) use and sports-related concussion (SRC). Secondary objectives were to assess the association between HG and superficial head injury and investigate potential increase in injury risk among HG users.DesignA systematic search in Ovid MEDLINE, Cochrane Library, Scopus, PsycINFO and SPORTDiscus was conducted in April 2020. Inclusion criteria were youth.Outcome MeasuresIncidence rates of SRC, superficial head injury or other injuries.Main ResultsEight studies were eligible. The majority (n=5) reported no difference in the rate of SRC among HG users versus non-users. One rugby study identified significantly lower risk of SRC for non-HG users (RR 0.63; 95% CI 0.41 to 0.98) compared with HG users, whereas a cross-sectional survey of soccer players indicated higher risk of SRC for non-HG users (RR 2.65; 95% CI 1.23 to 3.12) compared with HG users. Three of the four studies investigating superficial head injury found no significant differences with HG use, though the soccer survey reported reduced risk among HG users (RR 1.86; 95% CI 0.09 to 0.11). Increased incidence of injuries to all body regions for rugby HG users was reported in two studies with adjusted RRs of 1.16 (95% CI 1.04 to 1.29) and 1.23 (95% CI 1.00 to 1.50).ConclusionsHG use was not associated with reduced rates of SRC or superficial head injury in youth soccer and rugby. The possibility of increased injury risk to all body regions for rugby HG users was raised. The need for research specific to youth and female athletes was highlighted.

ObjectiveVideo surveillance and detection of players with visible signs of concussion by experienced medical staff facilitates rapid on-field screening of suspected concussion in professional sports. This method, however, has not been validated in community sports where video footage is unavailable. This study aimed to explore the utility of visible signs of concussion to identify players with decrements in performance on concussion screening measures.DesignProspective Cohort Study.SettingLive seasonal observation of 60 community male and female Australian football matches.Participants83 (54 male) included participants.Independent VariablesNon-expert personnel with basic training conducted live match observations using the Head Injury Assessment form (HIAf). Players identified to have positive signs of concussion (CoSign+) following a head impact were compared with players without signs (CoSign-).Outcome MeasuresBaseline and post-match Sport Concussion Assessment Tool (SCAT3) and Cogstate.Main ResultsCoSign+ (n = 22) and CoSign- (n = 61) groups were similar with respect to age, sex, education, baseline mood, and medical history. CoSign+ players exhibited worse orientation, concentration, and recall, and slower reaction time in attention and working memory tasks. Comparing individual change from baseline to post-match assessment revealed 100% (95% confidence interval [CI]: 84–100%) of CoSign+ players demonstrated clinically significant deficits on SCAT3 or Cogstate tasks, compared with 59% (95% CI: 46–71%) of CoSign- players. All CoSign+ players observed to have a blank/vacant look demonstrated clinically significant decline on the Standardized Assessment of Concussion (SAC).ConclusionsDetection of visible signs of concussion represents a rapid, real-time method for screening players suspected of concussion in community sports where video technology and medical personnel are rarely present. Consistent with community guidelines, it is recommended that all CoSign+ players be immediately removed from play for further concussion screening.

Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of haematological malignancies such as acute lymphoblastic leukaemia, B cell lymphoma and multiple myeloma 1 – 4 , but the efficacy of CAR T cell therapy in solid tumours has been limited 5 . This is owing to a number of factors, including the immunosuppressive tumour microenvironment that gives rise to poorly persisting and metabolically dysfunctional T cells. Analysis of anti-CD19 CAR T cells used clinically has shown that positive treatment outcomes are associated with a more ‘stem-like’ phenotype and increased mitochondrial mass 6 – 8 . We therefore sought to identify transcription factors that could enhance CAR T cell fitness and efficacy against solid tumours. Here we show that overexpression of FOXO1 promotes a stem-like phenotype in CAR T cells derived from either healthy human donors or patients, which correlates with improved mitochondrial fitness, persistence and therapeutic efficacy in vivo. This work thus reveals an engineering approach to genetically enforce a favourable metabolic phenotype that has high translational potential to improve the efficacy of CAR T cells against solid tumours. Increased effectiveness of anti-cancer chimeric antigen receptor T cell therapy is associated with a stem-like phenotype through increased expression of FOXO1.

IgE induced by type 2 immune responses in atopic dermatitis is implicated in the progression of atopic dermatitis to other allergic diseases, including food allergies, allergic rhinitis, and asthma. However, the keratinocyte-derived signals that promote IgE and ensuing allergic diseases remain unclear. Herein, in a mouse model of atopic dermatitis-like skin inflammation induced by epicutaneous Staphylococcus aureus exposure, keratinocyte release of IL‑36α along with IL-4 triggered B cell IgE class-switching, plasma cell differentiation, and increased serum IgE levels-all of which were abrogated in IL-36R-deficient mice or anti-IL‑36R-blocking antibody-treated mice. Moreover, skin allergen sensitization during S. aureus epicutaneous exposure-induced IL-36 responses was required for the development of allergen-specific lung inflammation. In translating these findings, elevated IL‑36 cytokines in human atopic dermatitis skin and in IL‑36 receptor antagonist-deficiency patients coincided with increased serum IgE levels. Collectively, keratinocyte-initiated IL‑36 responses represent a key mechanism and potential therapeutic target against allergic diseases.

We investigated type 2 diabetes (T2D) genetic susceptibility via multi-ancestry meta-analysis of 228,499 cases and 1,178,783 controls in the Million Veteran Program (MVP), DIAMANTE, Biobank Japan and other studies. We report 568 associations, including 286 autosomal, 7 X-chromosomal and 25 identified in ancestry-specific analyses that were previously unreported. Transcriptome-wide association analysis detected 3,568 T2D associations with genetically predicted gene expression in 687 novel genes; of these, 54 are known to interact with FDA-approved drugs. A polygenic risk score (PRS) was strongly associated with increased risk of T2D-related retinopathy and modestly associated with chronic kidney disease (CKD), peripheral artery disease (PAD) and neuropathy. We investigated the genetic etiology of T2D-related vascular outcomes in the MVP and observed statistical SNP–T2D interactions at 13 variants, including coronary heart disease (CHD), CKD, PAD and neuropathy. These findings may help to identify potential therapeutic targets for T2D and genomic pathways that link T2D to vascular outcomes. Genome-wide association meta-analyses among 1.4 million individuals identify 318 new risk loci for type 2 diabetes and provide insight into the contribution of these risk variants to diabetes-related vascular outcomes.