Corrigendum: Injury Incidence Across the Menstrual Cycle in International Footballers.

[This corrects the article DOI: 10.3389/fspor.2021.616999.].

Injury Incidence Across the Menstrual Cycle in International Footballers.

Objectives: This study aimed to assess how menstrual cycle phase and extended menstrual cycle length influence the incidence of injuries in international footballers. Methods: Over a 4-year period, injuries from England international footballers at training camps or matches were recorded, alongside self-reported information on menstrual cycle characteristics at the point of injury. Injuries in eumenorrheic players were categorized into early follicular, late follicular, or luteal phase. Frequencies were also compared between injuries recorded during the typical cycle and those that occurred after the cycle would be expected to have finished. Injury incidence rates (per 1,000 person days) and injury incidence rate ratios were calculated for each phase for all injuries and injuries stratified by type. Results: One hundred fifty-six injuries from 113 players were eligible for analysis. Injury incidence rates per 1,000 person-days were 31.9 in the follicular, 46.8 in the late follicular, and 35.4 in the luteal phase, resulting in injury incidence rate ratios of 1.47 (Late follicular:Follicular), 1.11 (Luteal:Follicular), and 0.76 (Luteal:Late follicular). Injury incident rate ratios showed that muscle and tendon injury rates were 88% greater in the late follicular phase compared to the follicular phase, with muscle rupture/tear/strain/cramps and tendon injuries/ruptures occurring over twice as often during the late follicular phase compared to other phases 20% of injuries were reported as occurring when athletes were "overdue" menses. Conclusion: Muscle and tendon injuries occurred almost twice as often in the late follicular phase compared to the early follicular or luteal phase. Injury risk may be elevated in typically eumenorrheic women in the days after their next menstruation was expected to start.

The Football Association Injury and Illness Surveillance Study: The Incidence, Burden and Severity of Injuries and Illness in Men's and Women's International Football.

OBJECTIVES: To determine the incidence and characteristics of injury and illness in English men's and women's senior and youth international football. METHODS: Time-loss injuries and illnesses, alongside match and training exposure, were collected across 8 seasons (2012-2020) in youth (U15, U16, U17, U18, U19) and senior (U20, U21, U23, senior) English men's and women's international teams. Analysis of incidence, burden, and severity of injury and illness was completed. Sex-specific comparisons were made between the senior and youth groups, and across the 8 seasons of data collection. RESULTS: In men's international football, 535 injuries were recorded (216 senior; 319 youth) during 73,326 h of exposure. Overall, match injury incidence (31.1 ± 10.8 injuries/1000 h) and burden (454.0 ± 195.9 d absent/1000 h) were greater than training injury incidence (4.0 ± 1.0 injuries/1000 h) and burden (51.0 ± 21.8 d absent/1000 h) (both P < 0.001). In women's international football, 503 injuries were recorded (senior: 177; youth: 326) during 80,766 h of exposure and match injury incidence (27.6 ± 11.3 injuries/1000 h) and burden (506.7 ± 350.2 days absent/1000 h) were greater than training injury incidence (5.1 ± 1.8 injuries/1000 h) and burden (87.6 ± 32.8 days absent/1000 h) (both P < 0.001). In women's international football, a group × season interaction was observed for training injury incidence (P = 0.021), with the senior group recording a greater training injury incidence during the 2015-2016 season compared to the youth group (14.4 vs 5.7 injuries/1000 h; P = 0.022). There was no difference in injury severity between match and training for men's (P = 0.965) and women's (P = 0.064) international football. CONCLUSIONS: The findings provide a comprehensive examination of injury and illness in English men's and women's senior and youth international football. Practitioners will be able to benchmark their team's injury and illness incidence and characteristics to the match-play and training information provided in the present study.

Kinase-Independent Small-Molecule Inhibition of JAK-STAT Signaling.

Phenotypic cell-based screening is a powerful approach to small-molecule discovery, but a major challenge of this strategy lies in determining the intracellular target and mechanism of action (MoA) for validated hits. Here, we show that the small-molecule BRD0476, a novel suppressor of pancreatic ß-cell apoptosis, inhibits interferon-gamma (IFN-γ)-induced Janus kinase 2 (JAK2) and signal transducer and activation of transcription 1 (STAT1) signaling to promote ß-cell survival. However, unlike common JAK-STAT pathway inhibitors, BRD0476 inhibits JAK-STAT signaling without suppressing the kinase activity of any JAK. Rather, we identified the deubiquitinase ubiquitin-specific peptidase 9X (USP9X) as an intracellular target, using a quantitative proteomic analysis in rat ß cells. RNAi-mediated and CRISPR/Cas9 knockdown mimicked the effects of BRD0476, and reverse chemical genetics using a known inhibitor of USP9X blocked JAK-STAT signaling without suppressing JAK activity. Site-directed mutagenesis of a putative ubiquitination site on JAK2 mitigated BRD0476 activity, suggesting a competition between phosphorylation and ubiquitination to explain small-molecule MoA. These results demonstrate that phenotypic screening, followed by comprehensive MoA efforts, can provide novel mechanistic insights into ostensibly well-understood cell signaling pathways. Furthermore, these results uncover USP9X as a potential target for regulating JAK2 activity in cellular inflammation.

Small-molecule inhibitors of cytokine-mediated STAT1 signal transduction in ß-cells with improved aqueous solubility.

We previously reported the discovery of BRD0476 (1), a small molecule generated by diversity-oriented synthesis that suppresses cytokine-induced ß-cell apoptosis. Herein, we report the synthesis and biological evaluation of 1 and analogues with improved aqueous solubility. By replacing naphthyl with quinoline moieties, we prepared active analogues with up to a 1400-fold increase in solubility from 1. In addition, we demonstrated that 1 and analogues inhibit STAT1 signal transduction induced by IFN-γ.

Inhibition of histone deacetylase 3 protects beta cells from cytokine-induced apoptosis.

Cytokine-induced beta-cell apoptosis is important to the etiology of type-1 diabetes. Although previous reports have shown that general inhibitors of histone deacetylase (HDAC) activity, such as suberoylanilide hydroxamic acid and trichostatin A, can partially prevent beta-cell death, they do not fully restore beta-cell function. To understand HDAC isoform selectivity in beta cells, we measured the cellular effects of 11 structurally diverse HDAC inhibitors on cytokine-induced apoptosis in the rat INS-1E cell line. All 11 compounds restored ATP levels and reduced nitrite secretion. However, caspase-3 activity was reduced only by MS-275 and CI-994, both of which target HDAC1, 2, and 3. Importantly, both MS-275 and genetic knockdown of Hdac3 alone were sufficient to restore glucose-stimulated insulin secretion in the presence of cytokines. These results suggest that HDAC3-selective inhibitors may be effective in preventing cytokine-induced beta-cell apoptosis.