O-GlcNAc modification (O-GlcNAcylation) is required for survival in mammalian cells. Genetic and biochemical experiments have found that increased modification inhibits apoptosis in tissues and cell culture and that lowering O-GlcNAcylation induces cell death. However, the molecular mechanisms by which O-GlcNAcylation might inhibit apoptosis are still being elucidated. Here, we first synthesize a new metabolic chemical reporter, 6-Alkynyl-6-deoxy-GlcNAc (6AlkGlcNAc), for the identification of O-GlcNAc-modified proteins. Subsequent characterization of 6AlkGlcNAc shows that this probe is selectively incorporated into O-GlcNAcylated proteins over cell-surface glycoproteins. Using this probe, we discover that the apoptotic caspases are O-GlcNAcylated, which we confirmed using other techniques, raising the possibility that the modification affects their biochemistry. We then demonstrate that changes in the global levels of O-GlcNAcylation result in a converse change in the kinetics of caspase-8 activation during apoptosis. Finally, we show that caspase-8 is modified at residues that can block its cleavage/activation. Our results provide the first evidence that the caspases may be directly affected by O-GlcNAcylation as a potential antiapoptotic mechanism.

Cardiac arrest (CA) afflicts~550,000 people each year in the USA. A small fraction of CA sufferers survive with a majority of these survivors emerging in a comatose state. Many CA survivors suffer devastating global brain injury with some remaining indefinitely in a comatose state. The pathogenesis of global brain injury secondary to CA is complex. Mechanisms of CAinduced brain injury include ischemia, hypoxia, cytotoxicity, inflammation, and ultimately, irreversible neuronal damage. Due to this complexity, it is critical for clinicians to have access as early as possible to quantitative metrics for diagnosing injury severity, accurately predicting outcome, and informing patient care. Current recommendations involve using multiple modalities including clinical exam, electrophysiology, brain imaging, and molecular biomarkers. This multi-faceted approach is designed to improve prognostication to avoid "self-fulfilling" prophecy and early withdrawal of life-sustaining treatments. Incorporation of emerging dynamic monitoring tools such as diffuse optical technologies may provide improved diagnosis and early prognostication to better inform treatment. Currently, targeted temperature management (TTM) is the leading treatment, with the number of patients needed to treat being~6 in order to improve outcome for one patient. Future avenues of treatment, which may potentially be combined with TTM, include pharmacotherapy, perfusion/oxygenation targets, and pre/postconditioning. In this review, we provide a bench to bedside approach to delineate the pathophysiology, prognostication methods, current targeted therapies, and future directions of research surrounding hypoxic-ischemic brain injury (HIBI) secondary to CA.

For the treatment of large chondral and osteochondral defects of the knee, osteochondral allograft transplantation (OCA) is an effective solution with relatively high rates of return to sport. In professional athletes, rehabilitation following OCA is a critical component of the process of returning the athlete to full sports activity and requires a multidisciplinary team approach with frequent communication between the surgical and rehabilitation teams (physical therapists, athletic trainers, coaching staff). In this review, we describe our five-phase approach to progressive rehabilitation of the professional athlete after OCA, which takes into account the biological processes of healing and optimization of neuromuscular function required for the demands of elite-level sport. The principles of early range of motion, proper progression through the kinetic chain, avoidance of pain and effusion, optimization of movement, regimen individuation, and integration of sports-specific activities underlie proper recovery.

Background: Comparative studies and randomized controlled trials (RCTs) often use the P (probability) value to convey the statistical significance of their findings. P values are an imperfect measure, however, and are vulnerable to a small number of outcome reversals to alter statistical significance. The inclusion of a fragility index (FI) and fragility quotient (FQ) may aid in the interpretation of a study’s statistical strength. Purpose/Hypothesis: The purpose of this study was to examine the statistical stability of studies comparing single-row to double-row rotator cuff repair. It was hypothesized that the findings of these studies would be vulnerable to a small number of outcome event reversals, often fewer than the number of patients lost to follow-up. Study Design: Systematic review; Level of evidence, 3. Methods: We analyzed comparative studies and RCTs on primary single-row versus double-row rotator cuff repair that were published between 2000 and 2021 in 10 leading orthopaedic journals. Statistical significance was defined as a P < .05. The FI for each outcome was determined by the number of event reversals necessary to alter significance. The FQ was calculated by dividing the FI by the respective sample size. Results: Of 4896 studies screened, 22 comparative studies, 10 of which were RCTs, were ultimately included for analysis. A total of 74 outcomes were examined. Overall, the median FI was 2 (interquartile range [IQR], 1-3), and the median FQ was 0.035 (IQR, 0.020-0.057). The mean FI was 2.55 ± 1.29, and the mean FQ was 0.043 ± 0.027. In 64% of outcomes, the FI was less than the number of patients lost to follow-up.) Additionally, 81% of significant outcomes needed just a single outcome reversal to lose their significance. Conclusion: Over half of the studies currently used to guide clinical practice have a number of patients lost to follow-up greater than their FI. The results of these studies should be interpreted within the context of these limitations. Future analyses may benefit from the inclusion of the FI and the FQ in their statistical analyses.

Although long term pain and mobility outcomes in total knee arthroplasties (TKA) are successful, many patients experience significant amount of debilitating pain during the immediate post-operative period that necessitates narcotic use. Percutaneous cryoneurolysis to the infrapatellar saphenous and anterior femoral cutaneous nerves may help to better restore function and rehabilitation after surgery while limiting narcotic consumption. A retrospective chart review of primary TKA patients receiving pre-operative cryoneurolysis from 2019 to 2020 was performed to assess total opioid morphine milligram equivalents (MME) consumed inpatient and at interval follow-up. Demographics and medical comorbidities were compared between cryoneurolysis and age-matched control patients to assess baseline characteristics. Functional rehabilitation outcomes, including knee range of motion (ROM), ambulation distance, and Boston AM-PAC scores, as well as patient reported outcomes using the KOOS JR and SF-12 scores were analyzed using STATA 17 Software. The analysis included 29 cryoneurolysis and 28 age-matched control TKA patients. Baseline demographics and operative technique were not significant between groups. Although not statistically significant, cryoneurolysis patients had a shorter length of stay (2.5 vs. 3.5 days) and overall less inpatient and outpatient MME requirements. Cryoneurolysis patients had statistically significant improved 6-week ROM and 1-year follow-up KOOS JR and SF-12 mental scores compared to the control. There were no differences in complication rates. Cryoneurolysis is a safe, effective treatment modality to improve active functional recovery and patient satisfaction after TKA by reducing MME requirements. Patients who underwent cryoneurolysis had on average fewer MME prescribed during the perioperative period, improved active ROM, and improved patient-reported outcomes with no associated increased risk of infections, deep vein thrombosis, or neurologic complications.