Systematic perturbation screens identify regulators of inflammatory macrophage states and a role for TNF mRNA m6A modification.

Macrophages exhibit remarkable functional plasticity, a requirement for their central role in tissue homeostasis. During chronic inflammation, macrophages acquire sustained inflammatory 'states' that contribute to disease, but there is limited understanding of the regulatory mechanisms that drive their generation. Here we describe a systematic functional genomics approach that combines genome-wide phenotypic screening in primary murine macrophages with transcriptional and cytokine profiling of genetic perturbations in primary human macrophages to uncover regulatory circuits of inflammatory states. This process identifies regulators of five distinct states associated with key features of macrophage function. Among these regulators, loss of the N6-methyladenosine (m6A) writer components abolishes m6A modification of TNF transcripts, thereby enhancing mRNA stability and TNF production associated with multiple inflammatory pathologies. Thus, phenotypic characterization of primary murine and human macrophages describes the regulatory circuits underlying distinct inflammatory states, revealing post-transcriptional control of TNF mRNA stability as an immunosuppressive mechanism in innate immunity.

Athletes With Partial Extensor Mechanism Tears of the Knee Achieve Variable Return-to-Sport Rates Following Operative Versus Nonoperative Management: A Systematic Review.

Purpose: (1) To systematically review treatments for partial extensor mechanism tendon tears in professional and amateur athletes and (2) to report outcomes for patients undergoing operative versus nonoperative management. Methods: PubMed, Cochrane, Scopus, Google Scholar, and Web of Science were queried in August 2023 using the following Boolean search: (quadriceps OR patella) AND (partial) AND (tear). Articles were included if they reported outcomes of operative or nonoperative management of partial extensor mechanism tears of the knee in athletes. The review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses criteria. Each study was queried for demographics, tendon injured, sport and level of athlete, prior treatments, final treatment modality, and return to sport (RTS) outcomes of that treatment. A qualitative subanalysis was performed for professional athletes. Results: Ten studies met inclusion criteria and included 191 partial patellar or quadriceps tendon tears. Of the patients, 81.6% were male and 18.4% were female, with average age ranging from 21 to 28 years; 97% of patients underwent initial nonoperative management. Ultimately, 111 patients (58.1%) were maintained on nonoperative management, and 80 (41.9%) progressed to surgery. Of surgeries, 39 (48.8%) were tendon debridements, 36 (45.0%) were repairs, and 5 (6.3%) were not specified. RTS rates ranged from 33% to 93% after surgery and 70% to 89% following conservative management. Of professional athletes, 23 (33%) underwent surgery, and 46 (67%) underwent ultimate conservative management. RTS rates ranged from 33% to 67% after surgery and were 89% for the applicable study of conservative management. Conclusions: Nearly all patients with partial extensor mechanism tears underwent initial nonoperative management. RTS rates were high but somewhat variable among both patients treated with final nonoperative versus surgical management. Even among professional athletes, most injuries were treated with initial nonoperative management and did not progress to surgery. Level of Evidence: Level V, systematic review of Level IV and V studies.

Functional RNAi screening identifies G2/M and kinetochore components as modulators of TNFα/NF-κB pro-survival signaling in head and neck squamous cell carcinoma.

Immune and radiation resistance of cancer cells to cytotoxicity mediated by Tumor Necrosis Factor-α (TNFα) is promoted by the transcription factor NF-κB in several cancers, including head and neck squamous cell carcinoma (HNSCC). Genomic alterations that converge on the TNFα/NF-κB signal axis were found in ~40% of HNSCCs by The Cancer Genome Atlas (TCGA). However, identification of therapeutic targets that contribute to aberrant TNFα/NF-κB activation and resistance has been challenging. Here, we conducted a functional RNAi screen to identify regulators of TNFα-induced NF-κB activation and cell viability, using parallel NF-κB ß-lactamase reporter and cell viability assays in a HNSCC cell line which harbors expression and genomic alterations typically found in HPV-negative HNSCC. Besides multiple components of canonical TNFα/NF-κB signaling, we identified components of the WNT, NOTCH, and TGFß pathways that we previously showed contribute to non-canonical activation of NF-κB. Unexpectedly, we also observed that multiple G2/M cell cycle kinases (AURKA, PLK1, WEE1, TTK), and structural kinetochore/microtubule components (NDC80, NUF2), modulate TNFα-induced NF-κB activation and cell viability. Several of these targets inhibit TNF-induced nuclear translocation of RELA, consistent with prior reports linking NF-B activation to G2/M kinases or microtubule assembly. Further investigation of an understudied mitotic kinase, TTK/MPS1, show that it's inhibition or depletion attenuates TNFα-induced RELA nuclear translocation, promoting cell death, DNA damage, polyploidy, and mitotic catastrophe, leading to radiosensitization. Together, our RNAi screening identifies a critical linkage between the G2/M cell cycle checkpoint/kinetochore components and NF-κB activity, and as targets that can sensitize HNSCC cells to TNFα or radiation.

Surgical Applications for Bone Marrow Aspirate Concentrate.

Bone marrow aspirate concentrate (BMAC) is an autologous orthobiologic agent that may be of benefit in specific surgical scenarios. Composed of elements isolated from bone marrow, including mesenchymal stromal cells, bone marrow-derived platelets, red and white blood cells, and hematopoietic precursors, BMAC has gained appeal for its potential to slow the progression of chondral degeneration, improve function, and provide symptomatic relief. BMAC is typically prepared during the final stages of a surgical procedure, beginning with bone marrow aspirate harvested from the iliac crest, distal femur, body of the ilium, or proximal humerus and then centrifuged to yield concentrated marrow cells. In a published technique for BMAC use in arthroscopic acetabular labral repair, 120 mL of BMA is harvested from the body of the ilium and then centrifuged to yield approximately 4 to 6 mL of BMAC. The biologic activity of BMAC is 2-fold: (1) mesenchymal stromal cells are pluripotent stem cells that stimulate a robust tissue response for cartilage repair through their potential to differentiate into chondrocytes that induce chondrogenesis, and (2) bone marrow-derived platelets produce growth factors, cytokines, and chemokines that promote collagen synthesis, wound healing, and suppression of proinflammatory cytokines. To date, BMAC has shown promise as an efficacious adjuvant therapy. When comparing patient outcomes, studies have found that patients receiving BMAC achieved lower rates of revision rotator cuff repair, higher functional outcome scores following arthroscopic acetabular labral repair, and significant reductions in pain levels in the context of knee cartilage defects. These findings, however, must be interpreted with caution, as there remains a paucity of randomized controlled trials investigating the mid- and long-term efficacy of BMAC. Overall, as treatments for patients with both progressive chondral degeneration and acute orthopaedic injuries continue to evolve, BMAC serves as promising orthobiologic therapy to improve outcomes.

Optimization of Potent, Efficacious, Selective and Blood-Brain Barrier Penetrating Inhibitors Targeting EGFR Exon20 Insertion Mutations.

Herein, we report the optimization of a series of epidermal growth factor receptor (EGFR) Exon20 insertion (Ex20Ins) inhibitors using structure-based drug design (SBDD), leading to the discovery of compound 28, a potent and wild type selective molecule, which demonstrates efficacy in multiple EGFR Ex20Ins xenograft models and blood-brain barrier penetration in preclinical species. Building on our earlier discovery of an in vivo probe, SBDD was used to design a novel bicyclic core with a lower molecular weight to facilitate blood-brain barrier penetration. Further optimization including strategic linker replacement and diversification of the ring system interacting with the c-helix enabled photolytic and metabolic stability improvements. Together with refinement of molecular properties important for achieving high brain exposure, including molecular weight, H-bonding, and polarity, 28 was identified.

Relationship Between Neighborhood-Level Socioeconomic Status and Functional Outcomes After Hip Arthroscopy.

BACKGROUND: Despite the growing volume of neighborhood-level health disparity research, there remains a paucity of prospective studies investigating the relationship between Area Deprivation Index (ADI) and functional outcomes for patients undergoing hip arthroscopy. PURPOSE: To investigate the relationship between neighborhood-level socioeconomic status and functional outcomes after hip arthroscopy. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A retrospective analysis of prospectively collected data was performed on patients aged ≥18 years with minimum 1-year follow-up who underwent hip arthroscopy for the treatment of symptomatic labral tears. The study population was divided into ADILow and ADIHigh cohorts according to ADI score: a validated measurement of neighborhood-level socioeconomic status standardized to yield a score between 1 and 100. Patient-reported outcome measures (PROMs) included the modified Harris Hip Score, Nonarthritic Hip Score, Hip Outcome Score-Activities of Daily Living, Hip Outcome Score-Sports-Specific Subscale, 33-item International Hip Outcome Tool, visual analog scale for pain, and patient satisfaction. RESULTS: A total of 228 patients met inclusion criteria and were included in the final analysis. After patients were stratified by ADI score (mean ± SD), the ADILow cohort (n = 113; 5.8 ± 3.0; range, 1-12) and ADIHigh cohort (n = 115; 28.0 ± 14.5; range, 13-97) had no differences in baseline patient demographics. The ADIHigh cohort had significantly worse preoperative baseline scores for all 5 PROMs; however, these differences were not present by 1-year follow-up. Furthermore, the 2 cohorts achieved similar rates of the minimal clinically important difference for all 5 PROMs and the Patient Acceptable Symptom State for 4 PROMs. When controlling for patient demographics, patients with higher ADI scores had greater odds of achieving the minimal clinically important difference for all PROMs except the 33-item International Hip Outcome Tool. CONCLUSION: Although hip arthroscopy patients experiencing a greater neighborhood-level socioeconomic disadvantage exhibited significantly lower preoperative baseline PROM scores, this disparity resolved at 1-year follow-up. In fact, when adjusting for patient characteristics including ADI score, more disadvantaged patients achieved greater odds of achieving the minimal clinically important difference. The present study is merely a first step toward understanding health inequities among patients seeking orthopaedic care. Further development of clinical guidelines and health policy research is necessary to advance care for patients from disadvantaged communities.

Hip Arthroscopy Versus Physical Therapy for the Treatment of Symptomatic Acetabular Labral Tears in Patients Older Than 40 Years: 24-Month Results From a Randomized Controlled Trial.

BACKGROUND: The indications for hip arthroscopy in patients aged ≥40 years remain controversial, as observational studies have suggested that advanced age portends poor functional outcomes, poor durability of improvement, and high rates of conversion to total hip arthroplasty. PURPOSE: To compare hip arthroscopy versus nonoperative management for symptomatic labral tears in patients aged ≥40 years with limited radiographic osteoarthritis. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: This single-surgeon, parallel randomized controlled trial included patients aged ≥40 years with limited osteoarthritis (Tönnis grades 0-2) who were randomized 1:1 to arthroscopic surgery with postoperative physical therapy (SPT) or physical therapy alone (PTA). Patients who received PTA and achieved unsatisfactory improvement were permitted to cross over to SPT after completing ≥14 weeks of physical therapy (CO). The primary outcomes were the International Hip Outcome Tool-33 score and modified Harris Hip Score at 24 months after surgery, and secondary outcomes included other patient-reported outcome measures and the visual analog scale for pain. The primary analysis was performed on an intention-to-treat basis using linear mixed-effects models. Sensitivity analyses included modified as-treated and treatment-failure analyses. RESULTS: A total of 97 patients were included, with 52 (53.6%) patients in the SPT group and 45 (46.4%) patients in the PTA group. Of the patients who underwent PTA, 32 (71.1%) patients crossed over to arthroscopy at a mean of 5.10 months (SD, 3.3 months) after physical therapy initiation. In both intention-to-treat and modified as-treated analyses, the SPT group displayed superior mean patient-reported outcome measure and pain scores across the study period for nearly all metrics relative to the PTA group. In the treatment-failure analysis, the SPT and CO groups showed greater improvement across all metrics compared with PTA; however, post hoc analyses revealed no significant differences in improvement between the SPT and CO groups. No significant differences were observed between groups in rates of total hip arthroplasty conversion. CONCLUSION: In patients ≥40 years of age with limited osteoarthritis, hip arthroscopy with postoperative physical therapy led to better outcomes than PTA at a 24-month follow-up. However, additional preoperative physical therapy did not compromise surgical outcomes and allowed some patients to avoid surgery. When surgery is indicated, age ≥40 years should not be considered an independent contraindication to arthroscopic acetabular labral repair. REGISTRATION: NCT03909178 (ClinicalTrials.gov identifier).

Social Determinants of Health Disparities Increase 5-Year Revision Rates but Not Postoperative Complications After Primary Hip Arthroscopy.

PURPOSE: To investigate the impact of social determinants of health (SDOH) disparities on 30-day emergency department (ED) visits, 90-day postoperative complications, and 5-year secondary surgery rates after primary hip arthroscopy using a large national database. METHODS: A national administrative claims database was used to identify patients who underwent primary hip arthroscopy with femoroplasty, acetabuloplasty, and/or labral repair between 2015 and 2022. Queries were performed to identify patients who experienced any SDOH disparities, including economic, educational, environmental, or social disparities; those experiencing SDOH disparities within 1 year prior to primary hip arthroscopy were matched 1:1 by age, sex, Elixhauser Comorbidity Index score, diabetes, obesity, and tobacco use to patients not experiencing any lifetime SDOH disparities. The odds of 90-day complications and 30-day ED visits were compared using multivariable logistic regression. Rates of 5-year revision hip arthroscopy and of any secondary surgery (revision hip arthroscopy or total hip arthroplasty) were compared by Kaplan-Meier analysis. RESULTS: A total of 3,383 primary hip arthroscopy patients who experienced SDOH disparities were matched 1:1 to a control cohort of 3,383 patients who did not experience SDOH disparities (age of 41.0 years and 79.6% female sex in both cohorts). The odds of adverse events after arthroscopy were low and did not differ between the SDOH cohort (1.51%) and no-SDOH cohort (1.57%, P = .09). Additionally, there was no difference in the odds of 30-day ED visits between the SDOH cohort (5.65%) and no-SDOH cohort (4.79%, P = .10). The rate of 5-year revision hip arthroscopy was significantly greater among patients experiencing SDOH disparities (5.4% vs 4.1%, P = .02); however, there was no difference in the rate of any secondary surgery between cohorts (11.8% vs 10.4%, P = .10). CONCLUSIONS: Patients experiencing SDOH disparities had similar odds of postoperative complications and ED visits after primary hip arthroscopy but greater rates of 5-year revision hip arthroscopy compared with a matched-control cohort of patients not experiencing SDOH disparities. LEVEL OF EVIDENCE: Level III, retrospective case-control study.

Computational Modeling of Drug Response Identifies Mutant-Specific Constraints for Dosing panRAF and MEK Inhibitors in Melanoma.

PURPOSE: This study explores the potential of pre-clinical in vitro cell line response data and computational modeling in identifying the optimal dosage requirements of pan-RAF (Belvarafenib) and MEK (Cobimetinib) inhibitors in melanoma treatment. Our research is motivated by the critical role of drug combinations in enhancing anti-cancer responses and the need to close the knowledge gap around selecting effective dosing strategies to maximize their potential. RESULTS: In a drug combination screen of 43 melanoma cell lines, we identified specific dosage landscapes of panRAF and MEK inhibitors for NRAS vs. BRAF mutant melanomas. Both experienced benefits, but with a notably more synergistic and narrow dosage range for NRAS mutant melanoma (mean Bliss score of 0.27 in NRAS vs. 0.1 in BRAF mutants). Computational modeling and follow-up molecular experiments attributed the difference to a mechanism of adaptive resistance by negative feedback. We validated the in vivo translatability of in vitro dose-response maps by predicting tumor growth in xenografts with high accuracy in capturing cytostatic and cytotoxic responses. We analyzed the pharmacokinetic and tumor growth data from Phase 1 clinical trials of Belvarafenib with Cobimetinib to show that the synergy requirement imposes stricter precision dose constraints in NRAS mutant melanoma patients. CONCLUSION: Leveraging pre-clinical data and computational modeling, our approach proposes dosage strategies that can optimize synergy in drug combinations, while also bringing forth the real-world challenges of staying within a precise dose range. Overall, this work presents a framework to aid dose selection in drug combinations.

A conserved transcription factor regulatory program promotes tendon fate.

Tendons, which transmit force from muscles to bones, are highly prone to injury. Understanding the mechanisms driving tendon fate would impact efforts to improve tendon healing, yet this knowledge is limited. To find direct regulators of tendon progenitor emergence, we performed a zebrafish high-throughput chemical screen. We established forskolin as a tenogenic inducer across vertebrates, functioning through Creb1a, which is required and sufficient for tendon fate. Putative enhancers containing cyclic AMP (cAMP) response elements (CREs) in humans, mice, and fish drove specific expression in zebrafish cranial and fin tendons. Analysis of these genomic regions identified motifs for early B cell factor (Ebf/EBF) transcription factors. Mutation of CRE or Ebf/EBF motifs significantly disrupted enhancer activity and specificity in tendons. Zebrafish ebf1a/ebf3a mutants displayed defects in tendon formation. Notably, Creb1a/CREB1 and Ebf1a/Ebf3a/EBF1 overexpression facilitated tenogenic induction in zebrafish and human pluripotent stem cells. Together, our work identifies the functional conservation of two transcription factors in promoting tendon fate.

Computational modeling of drug response identifies mutant-specific constraints for dosing panRAF and MEK inhibitors in melanoma.

Purpose: This study explores the potential of preclinical in vitro cell line response data and computational modeling in identifying optimal dosage requirements of pan-RAF (Belvarafenib) and MEK (Cobimetinib) inhibitors in melanoma treatment. Our research is motivated by the critical role of drug combinations in enhancing anti-cancer responses and the need to close the knowledge gap around selecting effective dosing strategies to maximize their potential. Results: In a drug combination screen of 43 melanoma cell lines, we identified unique dosage landscapes of panRAF and MEK inhibitors for NRAS vs BRAF mutant melanomas. Both experienced benefits, but with a notably more synergistic and narrow dosage range for NRAS mutant melanoma. Computational modeling and molecular experiments attributed the difference to a mechanism of adaptive resistance by negative feedback. We validated in vivo translatability of in vitro dose-response maps by accurately predicting tumor growth in xenografts. Then, we analyzed pharmacokinetic and tumor growth data from Phase 1 clinical trials of Belvarafenib with Cobimetinib to show that the synergy requirement imposes stricter precision dose constraints in NRAS mutant melanoma patients. Conclusion: Leveraging pre-clinical data and computational modeling, our approach proposes dosage strategies that can optimize synergy in drug combinations, while also bringing forth the real-world challenges of staying within a precise dose range.

Biceps tenotomy vs. tenodesis: an ACS-NSQIP analysis of postoperative outcomes and utilization trends.

Background: While studies have assessed comparative rates of restoration of shoulder function and alleviation of symptoms, comparative systemic postoperative complication rates between biceps tenotomy and tenodesis have yet to be assessed. The purpose of the present study was to use a national administrative database to perform a comprehensive investigation into 30-day complication rates after biceps tenotomy versus tenodesis, thus providing valuable insights for informed decision-making by clinicians and patients regarding the optimal surgical approach for pathologies of the long head of the biceps tendon. Methods: The National Surgical Quality Improvement Program database was queried to analyze postoperative complication rates and metrics associated with biceps tenotomy and tenodesis. Patient data spanning from 2012 to 2021 was extracted, with relevant variables assessed to identify and compare these two surgical approaches. Adjusted and unadjusted analyses were utilized to analyze patient demographics, comorbidities, operative times, lengths of stay, readmissions, adverse events, and yearly surgical volume, along with trends in usage, across cohorts. Results: Of 11,527 total patients, 264 (2.29%), 6826 (59.22%), and 4437 (38.49%) underwent tenotomy, tenodesis with open repair, and tenodesis with arthroscopic repair, respectively. Tenotomy operative times ([mean ± SD]: 66.25 ± 44.76 minutes) were shorter than those for open tenodesis (78.83 ± 41.82) and arthroscopic tenodesis (75.98 ± 40.16). Conversely, tenotomy patients had longer hospital days (0.88 ± 4.86 days) relative to open tenodesis (.08 ± 1.55) and arthroscopic tenodesis (.12 ± 2.70). Multivariable logistic regression controlling for demographics and comorbidities demonstrated that patients undergoing tenodesis were less likely to be readmitted (adjusted odds ratio [AOR]: 0.42, 95% confidence interval [CI]: 0.17-0.98, P = .050) or sustain serious adverse events (AOR: 0.27, 95% CI: 0.13-0.57, P < .001), but equally likely to sustain minor adverse events (AOR: 0.87, CI: 0.21-3.68, P = .850), compared with patients undergoing tenotomy. Lastly, comparing utilization rates from 2012 to 2021 revealed a significant decrease in the proportion of tenotomy (from 6.2% to 1.0%) compared to open tenodesis (from 41.0% to 57.3%) and arthroscopic tenodesis (52.8% to 41.64%; P trend = .001). Conclusion: To our knowledge, this is the first large national database study investigating postoperative complication rates between the various surgical treatments for pathologies of the long head of the biceps tendon. Our results suggest that tenodesis yields fewer serious adverse events and lower readmission rates than tenotomy. We also found a shorter operative time for tenotomy. These findings support the increased utilization of tenodesis relative to tenotomy in recent years.

Biceps tenotomy vs. tenodesis in patients undergoing transtendinous repair of partial thickness rotator cuff tears.

Background: Patients with partial thickness rotator cuff tears (PTRCTs) often present with concurrent pathology of the long head of the biceps tendon (LHBT). To address both conditions simultaneously, long head of the biceps (LHB) tenotomy or tenodesis can be performed at the time of arthroscopic rotator cuff repair (RCR). This study aims to compare postoperative shoulder active range of motion (AROM) and complications following transtendinous RCR with concurrent LHB tenodesis or tenotomy. Methods: A total of 90 patients with PTRCTs met inclusion criteria for this study. Patients who underwent tear-completion-and-repair, revision surgery, or open repair of the LHB tendon were excluded. Patients were stratified into tenotomy, arthroscopic suprapectoral tenodesis, or no biceps operation cohorts and were propensity matched 1:1:1 on age, sex, body mass index, and smoking status. Primary outcome measures included AROM in forward flexion, abduction, external rotation, and internal rotation at 6 weeks, 3 months, and 6 months postoperatively. The development of severe stiffness and rates of rotator cuff retear at final follow-up were recorded as secondary outcomes. Results: When comparing the tenotomy and tenodesis cohorts, tenotomy patients were found to have increased AROM at 3 months in forward flexion (153.2° vs. 130.1°, P = .004), abduction (138.6° vs. 114.2°, P = .019), and external rotation (60.4° vs. 43.8°, P = .014), with differences in forward flexion remaining significant at 6 months (162.4° vs. 149.4°, P = .009). There were no significant differences in interval rates of recovery in any plane between cohorts. Additionally, there were no significant differences in rates of symptomatic retears between groups (P = .458). Rates of severe postoperative stiffness approached but did not achieve statistical significance between tenotomy (4.2%) and tenodesis (29.2%) cohorts (P = .066). Smoking status was a significant predictor of severe stiffness (odds ratio, 13.69; P = .010). Conclusion: Despite significant differences in absolute AROM between cohorts, the decision to perform tenotomy or tenodesis was not found to differentially affect rates of AROM recovery for patients undergoing arthroscopic transtendinous RCR for PTRCT. Notably, however, transient stiffness complications were more commonly observed in smokers, and data trends suggested an increased risk of stiffness for patients undergoing LHB tenodesis. Overall, postoperative stiffness is likely multifactorial and attributable to both patient- and procedure-specific factors, and LHB tenotomy may be more appropriate for patients with risk factors for developing stiffness postoperatively.

Puncture Capsulotomy Technique During Hip Arthroscopy.

Background: A number of techniques have been described to enter the capsule and gain access to the hip joint during hip arthroscopy1,2. Among these, the interportal and T-capsulotomies are the most commonly utilized; however, these approaches transect the iliofemoral ligament, which normally resists anterior subluxation and stabilizes extension3. Thus, these approaches may introduce capsuloligamentous instability1,4-7 and have been associated with complications such as dislocation, postoperative pain, microinstability, seroma, and heterotopic ossification5,8-12. Although prior literature has demonstrated durable mid-term results for patients undergoing capsulotomies with capsular closure6,13, avoidance of iatrogenic injury to the hip capsule altogether is preferable. Thus, the puncture capsulotomy technique we present is minimally invasive, preserves the biomechanics of the hip joint and capsule without disrupting the iliofemoral ligament, and allows for appropriate visualization of the joint through placement of multiple small portals. Description: Following induction of anesthesia and with the patient supine on a hip traction table, the nonoperative leg is positioned at 45° abduction with support of a well-padded perineal post, and the operative hip is placed into valgus against the post14. Intra-articular fluid distention with normal saline solution is utilized to achieve approximately 9 mm of inferior migration of the femoral head and decrease risk of iatrogenic nerve injury15. Then, under fluoroscopic guidance, an anterolateral portal is created 1 cm anterior and 1 cm superior to the greater trochanter at an approximately 15° to 20° angle. Second, via arthroscopic visualization, the anterior portal is created 1 cm distal and 1 cm lateral to the intersection of a vertical line drawn at the anterior superior iliac spine and a horizontal line at the level of the anterolateral portal. Third, equidistant between the anterior and anterolateral portals, the mid-anterior portal is created distally. Finally, at one-third of the distance between the anterior superior iliac spine and the anterolateral portal, the Dienst portal is created. Thus, these 4 portals form a quadrilateral arrangement through which puncture capsulotomy can be performed5. Alternatives: Alternative approaches to the hip capsule include interportal and T-capsulotomies, with or without capsular closure1,2,4,6,7,16. Although the most frequently utilized, these approaches transect the iliofemoral ligament and thus may introduce capsuloligamentous instability1,4-7,17. Rationale: The puncture capsulotomy technique has the advantage of maintaining the integrity of the capsule through the placement of 4 small portals. The technique does not transect the iliofemoral ligament and thus does not introduce capsuloligamentous instability. Furthermore, although good mid-term outcomes have been reported with capsular closure6,13,18, the present technique avoids creating unnecessary injury to the capsule and complications of an unrepaired capsule or, conversely, of plication. Expected Outcomes: Patients who underwent the puncture capsulotomy technique showed significant improvements in multiple functional outcome scores at a mean follow-up of 30.4 months, including the International Hip Outcome Tool (iHOT-33) (39.6 preoperatively to 76.1 postoperatively), Hip Outcome Score-Activities of Daily Living subscale (HOS-ADL) (70.0 to 89.3), HOS Sport-Specific Subscale (HOS-SSS) (41.8 to 75.7), and modified Harris hip score (mHHS) (60.1 to 84.9). At 2 years postoperatively with respect to iHOT-33, 81.0% of patients achieved the minimal clinically important difference, 62.0% achieved the patient acceptable symptom state, and 58.9% achieved substantial clinical benefit. In addition, mean visual analog scale pain scores improved significantly over the follow-up period (6.3 to 2.2; p < 0.001). Finally, there were zero occurrences of infection, osteonecrosis of the femoral head, dislocation or instability, or femoral neck fracture in patients treated with puncture capsulotomy19,20. Important Tips: Anterolateral portal placement should be performed using the intra-articular fluid distention technique with fluoroscopy to avoid risk of iatrogenic labral damage and distraction-induced neurapraxia. Subsequent portals must then be placed under direct arthroscopic visualization.On establishment of the anterolateral portal, the scope should be switched to the anterior portal to ensure that the anterolateral portal has not been placed through the labrum and to adjust its placement to better access pathology. This portal, as well as all others, may be subsequently modified by adjusting the angle of the cannula, without making a new skin incision.If a cam lesion is located more anteromedially or posterolaterally, an additional accessory portal may be made distal or proximal to the anterolateral portal, respectively, in order to enhance visualization.Intermittent traction is utilized throughout the surgery. No traction is utilized during preparing and draping, suture tensioning and tie-down, and femoroplasty, with minimal traction during acetabuloplasty; these precautions serve to prevent iatrogenic superficial peroneal nerve injury.There can be a steep learning curve for this technique. In particular, greater surgical experience is required to perform adequate femoral osteoplasty for large cam lesions with this approach21.Instrument maneuverability and visualization can be somewhat constrained with this approach.It is more difficult to perform certain procedures with this technique, including segmental and circumferential labral reconstructions, particularly with remote grafts5. Acronyms and Abbreviations: iHOT-33 = International Hip Outcome Tool-33HOS-ADL = Hip Outcome Score-Activities of Daily Living subscaleHOS-SSS = Hip Outcome Score-Sport-Specific SubscaleAP = anteroposteriorMRA = magnetic resonance arthrogramMRI = magnetic resonance imagingCT = computed tomographyASIS = anterior superior iliac spinemHHS = modified Harris hip score.

Association Between Severity of Chondrolabral Junction Breakdown and Functional Outcomes After Hip Arthroscopy for Acetabular Labral Tears.

BACKGROUND: Despite focus on surgical preservation of the chondrolabral junction (CLJ), the transition zone between the acetabular cartilage and labrum, the association between severity of CLJ breakdown and functional outcomes after hip arthroscopy remains unexplored. PURPOSE: To assess the influence of CLJ breakdown on patient-reported outcome measures (PROMs) at a 24-month follow-up after hip arthroscopy for symptomatic labral tears. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A retrospective review of prospectively collected data was conducted to identify patients ≥18 years of age with a minimum 24-month follow-up who underwent hip arthroscopy by a single surgeon for the treatment of symptomatic labral tears secondary to femoroacetabular impingement. The Beck classification of transition zone cartilage was used to grade CLJ damage; patients with grades 0 to 2 were stratified into the mild CLJ damage cohort, and those with grades 3 and 4 were stratified into the severe CLJ damage cohort. PROMs were collected at baseline and at 3, 6, 12 months, and annually thereafter postoperatively. Linear mixed-effects models were used to compare PROMs. Rates of achieving clinically meaningful thresholds and subsequent surgery rates were also compared. RESULTS: In total, 198 patients met the inclusion criteria, with a mean follow-up of 3.54 ± 1.26 years. A total of 95 patients with severe CLJ damage (mean age, 34.9 ± 10.5 years) were compared with 103 patients with mild CLJ damage (mean age, 38.2 ± 11.9 years). Hip Outcome Score-Activities of Daily Living (HOS-ADL), Non-Arthritic Hip Score (NAHS), and visual analog score for pain were inferior in the severe CLJ group at enrollment and all follow-up time points (P≤ .05). However, patients with severe CLJ breakdown exhibited greater improvements in HOS-ADL and NAHS at the 24-month follow-up and achieved clinically meaningful thresholds at equivalent rates to patients with mild CLJ breakdown. Subsequent surgery rates were 6.8% and 12.6% in patients with mild versus severe CLJ damage, respectively (P = .250). CONCLUSION: Severe CLJ breakdown is associated with increased pain and decreased functional level preoperatively and up to 24 months after hip arthroscopy. Despite this, patients with severe CLJ breakdown experienced greater improvements in functional outcomes at a 24-month follow-up and achieved clinical thresholds at similar rates to patients with mild CLJ damage. Thus, while worse baseline pain and functional levels may indicate severe CLJ breakdown, these patients still benefit substantially from hip arthroscopy.

Abdominal Transplant Surgeons: The Lack of Female Surgeons and People From Underrepresented Racial and Ethnic Minority Groups in Academic and Clinical Leadership.

OBJECTIVES: The demographic disparities among surgeons in academic leadership positions is well documented. We aimed to characterize the present demographic details of abdominal transplant surgeons who have achieved academic and clinical leadership positions. MATERIALS AND METHODS: We reviewed the 2022-2023 American Society of Transplant Surgeons membership registry to identify 1007 active abdominal transplant surgeons. Demographic details (academic and clinical titles) were collected and analyzed using the chi-square test, the Fisher exact test, and t tests. Multinomial logistic regressions were conducted. RESULTS: Female surgeons (P < .001) and surgeons from racial-ethnic minorities (P = .027) were more likely to be assistants or associates rather than full professors. White male surgeons were more likely to be full professors than were White female (P < .001), Asian female (P = .008), and Asian male surgeons (P = .005). There were no Black female surgeons who were full professors. The frequency of full professorship increased with surgeon age (P < .001). Male surgeons were more likely to hold no academic titles (P < .001). Female surgeons were less likely to be chief of transplant(P = .025), chief of livertransplant (P = .001), chief of pancreas transplant (P = .037), or chair of surgery (P = .087, significance at 10%). Chief of kidney transplant was the most common clinical position held by a surgeon from a racial or ethnic minority group. Female surgeons were more likely to hold no clinical titles (P = .001). CONCLUSIONS: The underrepresentation of women and people from racial and ethnic minority groups in academic and clinical leadership positions in the field of abdominal transplant surgery remains evident. White male physicians are more likely to obtain full professorship, and they comprise most of the clinical leadership positions overall. A continued push for representative leadership is needed.

Variation in the Cost of Hip Arthroscopy for Labral Pathological Conditions: A Time-Driven Activity-Based Costing Analysis.

BACKGROUND: Despite growing interest in delivering high-value orthopaedic care, the costs associated with hip arthroscopy remain poorly understood. By employing time-driven activity-based costing (TDABC), we aimed to characterize the cost composition of hip arthroscopy for labral pathological conditions and to identify factors that drive variation in cost. METHODS: Using TDABC, we measured the costs of 890 outpatient hip arthroscopy procedures for labral pathological conditions across 5 surgeons at 4 surgery centers from 2015 to 2022. All patients were ≥18 years old and were treated by surgeons who each performed ≥20 surgeries during the study period. Costs were normalized to protect the confidentiality of internal hospital cost data. Descriptive analyses and multivariable linear regression were performed to identify factors underlying cost variation. RESULTS: The study sample consisted of 515 women (57.9%) and 375 men (42.1%), with a mean age (and standard deviation) of 37.1 ± 12.7 years. Most of the procedures were performed in patients who were White (90.6%) or not Hispanic (93.4%). The normalized total cost of hip arthroscopy per procedure ranged from 43.4 to 203.7 (mean, 100 ± 24.2). Of the 3 phases of the care cycle, the intraoperative phase was identified as the largest generator of cost (>90%). On average, supply costs accounted for 48.8% of total costs, whereas labor costs accounted for 51.2%. A 2.5-fold variation between the 10th and 90th percentiles for total cost was attributed to supplies, which was greater than the 1.8-fold variation attributed to labor. Variation in total costs was most effectively explained by the labral management method (partial R2 = 0.332), operating surgeon (partial R2 = 0.326), osteoplasty type (partial R2 = 0.087), and surgery center (partial R2 = 0.086). Male gender (p < 0.001) and younger age (p = 0.032) were also associated with significantly increased costs. Finally, data trends revealed a shift toward labral preservation techniques over debridement during the study period (with the rate of such techniques increasing from 77.8% to 93.2%; Ptrend = 0.0039) and a strong correlation between later operative year and increased supply costs, labor costs, and operative time (p < 0.001 for each). CONCLUSIONS: By applying TDABC to outpatient hip arthroscopy, we identified wide patient-to-patient cost variation that was most effectively explained by the method of labral management, the operating surgeon, the osteoplasty type, and the surgery center. Given current procedural coding trends, declining reimbursements, and rising health-care costs, these insights may enable stakeholders to design bundled payment structures that better align reimbursements with costs. LEVEL OF EVIDENCE: Economic and Decision Analysis Level IV. See Instructions for Authors for a complete description of levels of evidence.

Metabolism-driven in vitro/in vivo disconnect of an oral ERɑ VHL-PROTAC.

Targeting the estrogen receptor alpha (ERα) pathway is validated in the clinic as an effective means to treat ER+ breast cancers. Here we present the development of a VHL-targeting and orally bioavailable proteolysis-targeting chimera (PROTAC) degrader of ERα. In vitro studies with this PROTAC demonstrate excellent ERα degradation and ER antagonism in ER+ breast cancer cell lines. However, upon dosing the compound in vivo we observe an in vitro-in vivo disconnect. ERα degradation is lower in vivo than expected based on the in vitro data. Investigation into potential causes for the reduced maximal degradation reveals that metabolic instability of the PROTAC linker generates metabolites that compete for binding to ERα with the full PROTAC, limiting degradation. This observation highlights the requirement for metabolically stable PROTACs to ensure maximal efficacy and thus optimisation of the linker should be a key consideration when designing PROTACs.

The Role of Intramolecular Reactions and Chemical Degradation in the Apparent Biotransformation Pathways of a Series of SYK Inhibitors.

In vitro metabolism studies of the spleen tyrosine kinase inhibitors AZ-A and AZ-B identified four unusual metabolites. M1 (mass-to-charge ratio 411) was formed by both molecules and was common to several analogs (AZ-C to AZ-H) sharing the same core structure, appearing to derive from the complete loss of a pendent 3,4-diaminotetrahydropyran ring and pyrazole ring cleavage resulting in a nonobvious metabolite. M2-M4 were formed by AZ-A and a subset of the other compounds only and apparently resulted from a sequential loss of H2 from parent. Initial attempts to isolate M3 for identification were unsuccessful due to sample degradation, and it was subsequently found that M2 and M3 underwent sequential chemical degradation steps to M4. M4 was successfully isolated and shown by mass spectrometry and NMR spectroscopy to be a tricyclic species incorporating the pyrazole and the 3,4-diaminotetrahydropyran groups. We propose that this arises from an intramolecular reaction between the primary amine on the tetrahydropyran and a putative epoxide intermediate on the adjacent pyrazole ring, evidence for which was generated in a ß-mercaptoethanol-trapping experiment. The loss of the tetrahydropyran moiety observed in M1 was found to be enhanced in an analog that was unable to undergo the intramolecular reaction step, leading us to propose two possible reaction pathways originating from the reactive intermediate. Ultimately, we conclude that the apparently complex and unusual metabolism of this series of compounds likely resulted from a single metabolic activation step forming an epoxide intermediate, which subsequently underwent intramolecular rearrangement and/or chemical degradation to form the final observed products. SIGNIFICANCE STATEMENT: The current work provides an unusual biotransformation example showing the potential for intramolecular reactions and chemical degradation to give the appearance of complex metabolism arising from a single primary route of metabolism.

Perinatal outcomes following abdominoplasty: a retrospective study and review of current literature.

BACKGROUND: Abdominoplasty surgery is a common body contouring surgery to remove excess fat and skin and restore weakened or separated abdominal muscles caused by aging, pregnancy, or weight fluctuations. There is limited literature regarding patient and pregnancy outcomes after abdominoplasty. OBJECTIVE: This study aimed to determine whether there was a correlation between adverse pregnancy outcomes and history of abdominoplasty. STUDY DESIGN: Our study used a large federated deidentified national health research network with data sourced from 68 healthcare organizations within the United States (TriNetX; data accessed on August 19, 2022). All patients with a record of pregnancy were identified using the International Classification of Diseases, Ninth Revision and Tenth Revision, codes and were grouped into those with a history of abdominoplasty and those without. This study evaluated the perinatal outcomes of fetal growth restriction, abnormal umbilical artery Dopplers, gestational hypertension, preeclampsia, preterm delivery, preterm premature rupture of membranes, gestational diabetes mellitus, macrosomia, stillbirth, abnormal placentation, and wound disruption or infection occurring during a patient's pregnancy after abdominoplasty. Propensity matching was performed to account for potential confounders. An alpha level of <.05 was considered statistically significant. RESULTS: Of the 44,737 patients meeting our criteria, 304 had a history of abdominoplasty, whereas 44,433 did not (control). Our study found that patients with a history of abdominoplasty had significantly higher gravidity, were largely located in the Southern and Midwest region, and had higher counts of vaginal deliveries and cesarean deliveries than the control cohort (Table 1). After propensity score matching, our study found a lower risk of preeclampsia and preterm premature rupture of membranes in patients with abdominoplasty (odds ratio, 0.46; 95% confidence interval, 0.32-0.67; P<.0001) (Table 2). Furthermore, abdominoplasty was associated with an increased risk of preterm delivery (odds ratio, 2.15; 95% confidence interval, 1.48-3.13; P=.0002) (Table 2). Lastly, this study did not find significant differences in the other perinatal outcomes (Table 2). CONCLUSION: Our data suggest that abdominoplasty may be associated with a relative increase in the rates of preterm delivery and cesarean delivery and that other perinatal outcomes are not increased. This provides evidence that future desire for pregnancy need not be a relative contraindication to abdominoplasty.