The Dietary Supplement Chondroitin-4-Sulfate Exhibits Oncogene-Specific Pro-tumor Effects on BRAF V600E Melanoma Cells.

Dietary supplements such as vitamins and minerals are widely used in the hope of improving health but may have unidentified risks and side effects. In particular, a pathogenic link between dietary supplements and specific oncogenes remains unknown. Here we report that chondroitin-4-sulfate (CHSA), a natural glycosaminoglycan approved as a dietary supplement used for osteoarthritis, selectively promotes the tumor growth potential of BRAF V600E-expressing human melanoma cells in patient- and cell line-derived xenograft mice and confers resistance to BRAF inhibitors. Mechanistically, chondroitin sulfate glucuronyltransferase (CSGlcA-T) signals through its product CHSA to enhance casein kinase 2 (CK2)-PTEN binding and consequent phosphorylation and inhibition of PTEN, which requires CHSA chains and is essential to sustain AKT activation in BRAF V600E-expressing melanoma cells. However, this CHSA-dependent PTEN inhibition is dispensable in cancer cells expressing mutant NRAS or PI3KCA, which directly activate the PI3K-AKT pathway. These results suggest that dietary supplements may exhibit oncogene-dependent pro-tumor effects.

Editorial Commentary: Pedicled Quadriceps Tendon Autograft for Medial Patellofemoral Ligament Reconstruction Eradicates Risk of Saphenous Nerve Injury Seen With Gracilis Autograft. Allograft, When Available, Also Shows Excellent Outcomes.

Comparing a pedicled single-limbed quadriceps tendon (QT) autograft to a matched gracilis autograft (GT) group with bone tunnel anchors for patellar instability, the QT group showed similar outcome yet markedly improved complication rates involving the saphenous nerve and no anterior knee pain. These findings are reassuring for the QT usage as an option to GT autograft. Multiple systematic reviews have clearly shown that allograft medial patellofemoral ligament reconstruction has similar outcomes to autograft and is a viable option. As we have seen in anterior cruciate ligament reconstruction, there has been a march to include the QT into ligament reconstruction of the knee. The evidence is cumulating to support its use for medial patellofemoral complex reconstruction. As we await the verdict of Fulkerson's proposed double-bundle medial patellofemoral ligament and medial quadriceps tendon femoral ligament reconstruction, it appears that either QT autograft or GT allograft will be the go-to procedures of choice. Regardless the type of graft or type of patellar attachment, make sure the femoral side of the medial patellofemoral complex graft gets the most attention.

The Ultimate Goal of Medical Publishing is Practice-Changing Innovation.

New Year brings a new catchline: Practice-Changing Innovation. Publishing groundbreaking research and inventive techniques that translate to improvements in patient care is an ultimate goal.

The Second Annual Musculoskeletal Biologics Special Issue Highlights Evidence-Based Therapies.

Orthopaedic biologics continues to hold great promise. The editors of Arthroscopy; Arthroscopy Techniques; and Arthroscopy, Sports Medicine, and Rehabilitation once again Call for Papers and invite authors to submit clinical musculoskeletal biologics original scientific research and technical notes with video. Our top articles are awarded inclusion in the Annual Musculoskeletal Biologics Special Issue.

The Purpose of Journal Peer Review Is to Make Articles Better.

Authors may have the misconception that the purpose of peer review is to serve as an arbiter or referee, or in other words, to make a binary, Accept After Revision versus Reject, decision whether an article will be published in our journal. In truth, although making that difficult decision is part of the process, it is only a part. The principal goal of peer review is to make articles better.

Artificial Intelligence and Machine Learning May Resolve Health Care Information Overload.

Biomedical information doubles almost every 2 months, and this very rate is expected to double by 2025. The result is information overload for clinicians and researchers. Today, artificial intelligence (AI) and machine learning (ML) research contribute to the deluge of information. In addition, AI large language models, although capable of automating scientific writing, are flawed. They hallucinate (make things up), are trained primarily on non-peer-reviewed content, raise ethical and legal issues, and lack human empathy. Still, when it comes to AI including ML, we are optimistic. The technology is improving rapidly. In the future, AI will help us manage unwieldy information by processing data, determining diagnoses, recommending treatments, and predicting outcomes. In research, AI and ML similarly promise efficient data analysis and literature review and will create new content in response to our instructions. Human touch will be required, and we will disclose use of AI proactively, including rationale for its use, our data input, our level of confidence in the output, and the patients or populations to whom the output may be applied. In addition, we will ensure data quality is high and bias is minimized. Most of all, we will provide essential reasoning, clinical and research guidance, and diligent oversight. Humans will remain accountable.

AANA24 Delivers Knowledge and a Sense of Purpose.

The 2024 Annual Meeting of the Arthroscopy Association of North America in Boston was our largest ever. The program was innovative, and attendees departed with a sense of purpose and new knowledge. Besides intellectual exchange, the meeting fostered connections that will shape arthroscopy in years to come. We look forward to AANA25 in Washington, DC.

Disaggregation of Medical Research Data Reveals Outcome Differences in Demographic Groups and Presents Opportunity to Improve Patient Care.

Disaggregation, in the medical literature, means separation into demographic groups. This results in an opportunity to discover differences in outcomes by group, which could improve future treatments and provide outcome data, by group, that could be included in future systematic reviews. In research, the term disaggregation is most often used in reference to addressing inequities. We support the Sex and Gender Equity Research (SAGER) guidelines and encourage authors to examine how sex and gender are taken into account in their study and ensure adequate representation by sex and gender. (We respect that not all studies can or are designed to capture data by sex and gender, and that gender is "complex" and "fluid.") Disaggregation is encouraged, when possible, for other demographic variables allowing evaluation of all marginalized (as well as nonmarginalized) populations, so that we can better care for patients.

The Fragility Index is Typically Misinterpreted and of Low Value: Clinical Trials are Designed to be Fragile.

The Fragility Index (FI) is defined as the number of patients whose outcome would need to change to reverse a statistically significant finding to a nonsignificant finding. The FI is nothing more than a repackaging of statistical significance based on the P value, perpetuating the (1) ignoring of results that are "not" statistically significant, (2) treating results that are statistically significant as certain, and (3) distracting from evaluation of clinical significance. A well-designed trial includes a sample size calculation to determine the minimum number of patients required to observe a difference between study groups (if a difference exists). By including this minimum number, clinical trials are designed to be fragile, yet subsequently criticized as such, leading readers to the incorrect conclusion that the studies are flawed. It's time to move past systematic reviews focused on the FI.

Patient Acceptable Symptomatic State and Substantial Clinical Benefit Matter Most to Patients and Must Be Reported Correctly.

Despite a push for a focus on clinical rather than "statistical" significance and an emphasis on reporting of outcome thresholds such as the patient acceptable symptomatic state (PASS) and substantial clinical benefit (SCB), the PASS and SCB are rarely reported and, when reported, are often reported incorrectly. Yet, patients require satisfaction (PASS) as a result of our treatments, and patients desire to improve substantially (SCB). Determining whether patients are satisfied and/or substantially improved is simple . . . just ask them. The questions are known as anchor questions. Obviously, different patients have different PASS and SCB thresholds, and reliance on previously published literature for values of these thresholds can result in error-thus, the anchor questions. And, each patient must be assessed individually. Outcome thresholds are not group-level metrics, and they must be reported as the percentage of individuals who achieve the clinically significant outcome. Certain patients, such as athletes, have high baseline function and may demand maximum outcome improvement. In contrast, the minimal clinically important difference is a less-than-ideal measure; patients do not desire "minimal" improvement. Journals must do a better job of publishing patient-reported outcome measures that matter most to patients: satisfaction and substantial benefit.

Metabolic Rewiring by Oncogenic BRAF V600E Links Ketogenesis Pathway to BRAF-MEK1 Signaling.

Many human cancers share similar metabolic alterations, including the Warburg effect. However, it remains unclear whether oncogene-specific metabolic alterations are required for tumor development. Here we demonstrate a "synthetic lethal" interaction between oncogenic BRAF V600E and a ketogenic enzyme 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL). HMGCL expression is upregulated in BRAF V600E-expressing human primary melanoma and hairy cell leukemia cells. Suppression of HMGCL specifically attenuates proliferation and tumor growth potential of human melanoma cells expressing BRAF V600E. Mechanistically, active BRAF upregulates HMGCL through an octamer transcription factor Oct-1, leading to increased intracellular levels of HMGCL product, acetoacetate, which selectively enhances binding of BRAF V600E but not BRAF wild-type to MEK1 in V600E-positive cancer cells to promote activation of MEK-ERK signaling. These findings reveal a mutation-specific mechanism by which oncogenic BRAF V600E "rewires" metabolic and cell signaling networks and signals through the Oct-1-HMGCL-acetoacetate axis to selectively promote BRAF V600E-dependent tumor development.

Diversity in Sports Medicine and Rehabilitation Starts With Individual Kindness, Grace, and Compassion.

The definition of diversity remains ill-defined, and there is little consensus as to the solutions to increase diversity. Advancements in diversity, equity, and inclusion (DEI) might first start with kindness, grace, and compassion as an individual response; these attributes are critical ingredients as we embark to increase DEI in orthopaedic surgery, sports medicine, and rehabilitation and in the care for our patients. Given the needed focus and debate on diversity and equity issues, an Arthroscopy, Sports Medicine, and Rehabilitation Special Issue, "Diversity in Sports Medicine and Rehabilitation" can function as a starting point for discourse and a seed for future growth. The authors for the Diversity Special Issue have delivered "pearls" that can be directly incorporated into our practices and understanding of DEI.

Minimally Clinically Important Difference (MCID) Is a Low Bar.

Patients don't care about "statistical" significance. Patient-centered outcome measures focus on "clinical" significance and include minimal clinically important difference (MCID), patient acceptable symptomatic state (PASS), substantial clinical benefit (SCB), and maximal outcome improvement (MOI). "Minimal" is a low bar. MCID neither addresses whether patients are satisfied nor whether they have derived a substantial benefit. MCID is commonly reported allowing comparison between studies, and MCID can be calculated retrospectively, so reporting MCID is acceptable. However, we also need to report PASS, SCB, and, in unique patients like high-level athletes, we may also need to report MOI to adjust for high pretreatment scores and a ceiling effect. Finally, threshold scores are patient-level metrics and must be reported as percentage of patients who meet the threshold, not reported as to whether, as a group, the mean score for the cohort meets the threshold or not (which is a common error).

Return-to-Sport Outcomes After Anterior Cruciate Ligament Surgical Treatment May Be Improved by Attention to Modifiable Factors and Consideration of Nonmodifiable Factors.

Today, we who treat athletes are able to effect immediate, significant improvement in anterior cruciate ligament (ACL) patient outcomes, regardless of surgical technique, by careful determination of when an athlete is ready to return to sport. "Prehabiliation," bracing, time after surgery to various rehabilitation activities, time after surgery until return to sport, functional testing, strength testing including limb symmetry indices, psychological readiness, age, gender, and type of sport are all factors influencing successful return to sport after ACL injury and treatment. Age and gender are not modifiable, and for some athletes, type of sport may be nonnegotiable. However, each of these factors could be thoughtfully considered before returning an athlete to sport after ACL treatment. All the other factors listed above, from prehab to bracing to strength to psychological readiness, may be modifiable.

Evidence-Based Practice Should Supersede Evidence-Based Medicine Through Consideration of Clinical Experience and Patient Characteristics in Addition to the Published Literature.

On the surface, the benefits of evidence-based medicine (EBM) seem self-evident. However, reliance on the scientific literature alone has limitations. Studies may be biased, statistically fragile, and/or not reproducible. Reliance solely on EBM may ignore physician clinical experience and individual patient characteristics and input. Reliance solely on EBM may overvalue quantitative, statistical significance, resulting in a false sense of certainty. Reliance solely on EBM may fail to consider lack of generalizability of published studies to individually unique patients. The concept of evidence-based practice goes beyond EBM and incorporates (1) EBM, (2) clinical expertise, and (3) individual patient characteristics, values, and preferences. Even if branded as evidence-based, a suggested treatment may not be the best treatment. Evidence-based practice must be considered before determining what is best for our patients.

Strategies to Mitigate Against Least-Publishable Units in Medical and Scientific Research Publications.

Least-publishable units, aka minimal publishable units, smallest publishable units, fractions of scholarly effort, and "salami slicing" divide a single research publication into a number of papers with small amounts of information in each paper. This results in quantity rather than quality; is ethically inappropriate; creates extra work for readers, future authors, reviewers, and editors; and can result in redundancy, self-plagiarism, publication overlap, and duplicate reporting of patient data that can result in inaccurate conclusions in systematic reviews. Increased awareness and actionable intervention can help to reverse this growing trend.

Arthroscopy Journal: Reflections on 2023 and Auld Lang Syne.

Auld lang syne; times long past. We were unsuspecting of the coming pandemic. Things changed. COVID-19 impacted each of us, our families, our patients, our medical practices, and our daily lives. The year 2020 was one of cancellation and loss; 2021 and 2022 were years of adaptation, caution, and continued loss. Finally, 2023 began a time of recovery; while COVID-19 is still with us, the pandemic has been declared ended, and we emerge with gratitude. We slowly removed our masks and rediscovered the vitality of meeting face-to-face. And throughout, Arthroscopy has continued to develop, including new journals; special issues on rehabilitation, biologics, and diversity as they relate to musculoskeletal care; collaboration with the American Board of Orthopaedic Surgery, Maintenance of Certification, Web-Based Longitudinal Assessment Pathway; Arthroscopy Techniques; Infographics; Visual Abstracts; and Podcasts. At year end, we extend special thanks to editors whose terms have expired, our team and leaders, our reviewers, our authors and readers, and our patients who offer us their trust and an opportunity to serve.

AANA23 Confirms There is Still a Place for Face-To-Face Meetings.

AANA23, or the AANA Annual Meeting, set a high-water mark for our society and its members. Congratulations to all who planned and executed an exceptional educational meeting. Demonstrating that diversity continues to be front of mind, one of the first events of the meeting was the Diversity Session. Recognizing the topic's importance, next month in Arthroscopy, Sports Medicine, and Rehabilitation (ASMAR), Arthroscopy's companion online journal, we will publish our second annual special issue devoted to rehabilitation and return to sport, also with a focus on diversity as it relates to sports medicine. The Biologic Association held a comprehensive and clinically relevant 2-day meeting in conjunction with and following AANA23. AANA23 set the stage for a greatly anticipated AANA24 to be held in Boston from May 9 to 11, 2024.

Psychological Readiness to Return to Sport: Fear of Reinjury Is the Leading Reason for Failure to Return to Competitive Sport and Is Modifiable.

Many of our patients are athletes, and an ultimate goal is to help these athletes return to their preinjury level of activity or sport. Generally, we focus on patients' injuries and treatments, but there are modifiable factors that can improve patient outcomes independent of surgical technique. A factor frequently ignored is psychological readiness to return to sport. In patients including athletes, particularly teenagers, chronic, clinical depression is a prevalent and pathologic condition. In addition, in nondepressed patients (or in patients who are situationally depressed because of injury), the ability to deal with stressors may still govern clinical outcomes. Specific psychological traits of significance have been identified and defined, including self-efficacy; locus of control; resilience; catastrophizing; kinesiophobia; and fear of reinjury. (Fear of reinjury is the leading reason for failure to return to competitive sport, reduced activity levels after sports injury, and greater reinjury rates.) The traits may overlap and may be modifiable. Thus, like strength and functional testing, we should evaluate for signs or symptoms of depression, and we should measure psychological readiness to return to sport. With awareness, we can intervene or refer as indicated. Psychological readiness to return to sport represents an underexamined domain in which we can help our patients achieve best outcomes.

Arthroscopy and Musculoskeletal Biologics.

Orthopaedic biologics holds great promise. Absent peer-reviewed clinical musculoskeletal research, orthobiologics indications and treatment recommendations will remain opaque. In a Call for Papers, Arthroscopy; Arthroscopy Techniques; and Arthroscopy, Sports Medicine, and Rehabilitation editors invite authors to submit clinical musculoskeletal biologics original scientific research, and technical notes with video. Each year, the top articles will be awarded inclusion in an annual Biologics Special Issue. Future investigators and current readers could follow the science while being mindful of the regulatory environment.