Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and autism spectrum disorder. FXS is caused by silencing of the FMR1 gene, which encodes fragile X mental retardation protein (FMRP), an mRNA-binding protein that represses the translation of its target mRNAs. One mechanism by which FMRP represses translation is through its association with cytoplasmic FMRP-interacting protein 1 (CYFIP1), which binds to and sequesters eukaryotic initiation factor 4E (eIF4E). CYFIP1 shuttles between the FMRP–eIF4E complex and the Rac1–Wave regulatory complex, thereby connecting translation regulation to actin dynamics and dendritic spine morphology, which are dysregulated in FXS model mice that lack FMRP. Treating FXS mice with 4EGI-1, which blocks interactions between eIF4E and eukaryotic factor 4G (eIF4G), a critical interacting partner for protein synthesis, reversed defects in hippocampus-dependent memory and spine morphology. We also found that 4EGI-1 normalized the phenotypes of enhanced metabotropic glutamate receptor (mGluR)-mediated long-term depression (LTD), upregulated Rac1–p21-activated kinase (PAK)–cofilin signaling, altered actin dynamics, and dysregulated CYFIP1/eIF4E and CYFIP1/Rac1 interactions in FXS mice. Our findings are consistent with the idea that an imbalance of protein synthesis and actin dynamics contributes to pathophysiology in FXS mice, and suggest that targeting eIF4E may be a strategy for treating FXS.

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Background: The minimal clinically important difference (MCID) is a term synonymous with orthopaedic clinical research over the past decade. The term represents the smallest change in a patient-reported outcome measure that is of genuine clinical value to patients. It has been derived in a myriad of ways in existing orthopaedic literature. Purpose: To describe the various modalities for deriving the MCID. Study Design: Narrative review; Level of evidence, 4. Methods: The definitions of common MCID determinations were first identified. These were then evaluated by their clinical and statistical merits and limitations. Results: There are 3 primary ways for determining the MCID: anchor-based analysis, distribution-based analysis, and sensitivity- and specificity-based analysis. Each has unique strengths and weaknesses with respect to its ability to evaluate the patient’s clinical status change from baseline to posttreatment. Anchor-based analyses are inherently tied to clinical status yet lack standardization. Distribution-based analyses are the opposite, with strong foundations in statistics, yet they fail to adequately address the clinical status change. Sensitivity and specificity analyses offer a compromise of the other methodologies but still rely on a somewhat arbitrarily defined global transition question. Conclusion: This current concepts review demonstrates the need for (1) better standardization in the establishment of MCIDs for orthopaedic patient-reported outcome measures and (2) better study design—namely, until a universally accepted MCID derivation exists, studies attempting to derive the MCID should utilize the anchor-based within-cohort design based on Food and Drug Administration recommendations. Ideally, large studies reporting the MCID as an outcome will also derive the value for their populations. It is important to consider that there may be reasonable replacements for current derivations of the MCID. As such, future research should consider an alternative threshold score with a more universal method of derivation.

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Background: The Latarjet procedure is indicated in patients with risk factors for postoperative recurrence, including collision and competitive athletes. However, the factors that prevent athletes from being able return to play (RTP) after the open Latarjet procedure are still unclear and have not been fully elucidated in the literature. Purpose: To evaluate patient-reported outcomes and psychological and psychosocial factors associated with athletes who did not RTP after the open Latarjet procedure compared with patients who did RTP. Study Design: Cohort study; Level of evidence, 3. Methods: We conducted a retrospective review of athletes who underwent the open Latarjet procedure and subsequently did not RTP after a minimum of 12 months. These patients were pair matched in a 2:1 ratio for age, sex, sport, and level of preoperative play with a control group who returned to play. Patients were evaluated for their psychological readiness to return to sport using the Shoulder Instability–Return to Sport after Injury (SIRSI); other measures included the visual analog scale (VAS) for pain and Subjective Shoulder Value (SSV). Multivariate regression models were used to evaluate factors affecting RTP. Results: Included were 35 patients in the no-RTP group and 70 patients in the RTP group. In the no-RTP group, 7 patients (20%) passed the SIRSI benchmark of 56, with a mean overall score of 41.5 ± 21.9; in the RTP group, 57 patients (81.4%) passed the SIRSI benchmark, with a mean overall score of 74.5 ± 19.8 ( P < .0001 for both). Patients in the RTP group had better SSV (88.0 vs 75.7; P <.0001) and VAS pain (1.7 vs 2.9; P = .0046) scores. Of the athletes who did not return, 18 felt persistent pain/apprehension and 17 felt that it was a natural end to their career or that their lifestyle had changed. Multiple logistic regression revealed that thoughts of having to go through surgery and rehabilitation again was significantly associated with lower RTP ( P < .05). Conclusion: Patients who did not RTP after open Latarjet exhibited poor psychological readiness to RTP and worse pain VAS and SSV scores compared with patients who did RTP.

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Purpose The purpose of this study was to evaluate the outcomes of athletes 5-years post-operatively following arthroscopic Bankart repair, and to evaluate factors associated with satisfaction and shoulder function, as deined by subjective shoulder value. Methods A retrospective review of athletes who underwent arthroscopic Bankart repair, with a minimum of 5-year follow-up was performed. Recurrence, Visual Analogue Scale (VAS) score, Subjective Shoulder Value (SSV), satisfaction, and whether they would undergo the same surgery again, and rate, level and timing of return to play, and Shoulder Instability-Return to Sport after Injury (SIRSI) score were evaluated. Multi-linear regression models were used to evaluate factors afecting postoperative Satisfaction, and SSV level. Results Overall, 144 athletes who underwent arthroscopic Bankart repair were included, with a mean age of 26.9 years (SD: 8.1), 132 (91.7%) were males, and mean follow-up of 75.7 months. At inal follow up, 82.6% were satisied/very satisied, and the mean SSV was 85.8 (SD: 14.4). Overall, the rate of return to play was 80.5%, with 63.9% returning at the same level at a mean of 6.2 months (SD: 2.7). Overall, there was 18 (12.5%) had recurrent instability, and a further procedure was performed in 15 (10.4%) patients. Linear regression revealed that the SIRSI score (p < 0.0001), SSV (p < 0.0001), VAS (p < 0.0031), no sleep trouble (p = 0.0129) was associated with satisfaction. Logistic regression revealed whether a patient required revision surgery (p = 0.0029), or had re-dislocation (p = 0.0031) was also associated with satisfaction. Linear regression revealed that the SIRSI score (p < 0.0001), VAS score (p < 0.0001), and no sleep trouble (p < 0.0001), were associated with SSV score. Conclusion There was a high rate of satisfaction at 5-year follow-up, with excellent patient-reported outcomes and a high rate of return to play among athletes. However, there was a moderate rate of recurrent instability and further revision surgery. This study identiied that the SIRSI score, VAS score, no sleep trouble and ability to return to play at the same level were associated with both satisfaction and SSV score. Level of evidence III.