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.

Association Between Chondrolabral Junction Breakdown and Conversion to Total Hip Arthroplasty After Hip Arthroscopy for Symptomatic Labral Tears: Minimum 8-Year Follow-up.

BACKGROUND: Arthroscopic treatment of femoroacetabular impingement (FAI) and symptomatic labral tears confers short- to midterm benefits, yet further long-term evidence is needed. Moreover, despite the physiological and biomechanical significance of the chondrolabral junction (CLJ), the clinical implications of damage to this transition zone remain understudied. PURPOSE: To (1) report minimum 8-year survivorship and patient-reported outcome measures after hip arthroscopy for FAI and (2) characterize associations between outcomes and patient characteristics (age, body mass index, sex), pathological parameters (Tönnis angle, alpha angle, type of FAI, CLJ breakdown), and procedures performed (labral management, FAI treatment, microfracture). STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: This retrospective cohort study included patients who underwent primary hip arthroscopy for symptomatic labral tears secondary to FAI by a single surgeon between 2002 and 2013. All patients were ≥18 years of age with minimum 8-year follow-up and available preoperative radiographs. The primary outcome was conversion to total hip arthroplasty (THA), and secondary outcomes included revision arthroscopy, patient-reported outcome measures, and patient satisfaction. CLJ breakdown was assessed using the Beck classification. Kaplan-Meier estimates and weighted Cox regression were used to estimate 10-year survivorship (no conversion to THA) and identify risk factors associated with THA conversion. RESULTS: In this study of 174 hips (50.6% female; mean age, 37.8 ± 11.2 years) with mean follow-up of 11.1 ± 2.5 years, the 10-year survivorship rate was 81.6% (95% CI, 75.9%-87.7%). Conversion to THA occurred at a mean 4.7 ± 3.8 years postoperatively. Unadjusted analyses revealed several variables significantly associated with THA conversion, including older age; higher body mass index; higher Tönnis grade; labral debridement; and advanced breakdown of the CLJ, labrum, or articular cartilage. Survivorship at 10 years was inferior in patients exhibiting severe (43.6%; 95% CI, 31.9%-59.7%) versus mild (97.9%; 95% CI, 95.1%-100%) breakdown of the CLJ (P < .001). Multivariable analysis identified worsening CLJ breakdown (weighted hazard ratio per 1-unit increase, 6.41; 95% CI, 3.11-13.24), older age (1.09; 95% CI, 1.04-1.14), and higher Tönnis grade (4.59; 95% CI, 2.13-9.90) as independent negative prognosticators (P < .001 for all). CONCLUSION: Although most patients achieved favorable minimum 8-year outcomes, several pre- and intraoperative factors were associated with THA conversion; of these, worse CLJ breakdown, higher Tönnis grade, and older age were the strongest predictors.

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.

The Exonuclease TREX1 Constitutes an Innate Immune Checkpoint Limiting cGAS/STING-Mediated Antitumor Immunity.

The DNA exonuclease three-prime repair exonuclease 1 (TREX1) is critical for preventing autoimmunity in mice and humans by degrading endogenous cytosolic DNA, which otherwise triggers activation of the innate cGAS/STING pathway leading to the production of type I IFNs. As tumor cells are prone to aberrant cytosolic DNA accumulation, we hypothesized that they are critically dependent on TREX1 activity to limit their immunogenicity. Here, we show that in tumor cells, TREX1 restricts spontaneous activation of the cGAS/STING pathway, and the subsequent induction of a type I IFN response. As a result, TREX1 deficiency compromised in vivo tumor growth in mice. This delay in tumor growth depended on a functional immune system, systemic type I IFN signaling, and tumor-intrinsic cGAS expression. Mechanistically, we show that tumor TREX1 loss drove activation of CD8+ T cells and NK cells, prevented CD8+ T-cell exhaustion, and remodeled an immunosuppressive myeloid compartment. Consequently, TREX1 deficiency combined with T-cell-directed immune checkpoint blockade. Collectively, we conclude that TREX1 is essential to limit tumor immunogenicity, and that targeting this innate immune checkpoint remodels the tumor microenvironment and enhances antitumor immunity by itself and in combination with T-cell-targeted therapies. See related article by Toufektchan et al., p. 673.

The Effect of Pelvic Incidence on Outcomes After Hip Arthroscopy for Femoroacetabular Impingement and Acetabular Labral Tears.

BACKGROUND: In the setting of femoroacetabular impingement (FAI), decompression osteoplasties reconcile deleterious loading patterns caused by cam and pincer lesions. However, native variations of spinopelvic sagittal alignment may continue to perpetuate detrimental effects on the labrum, chondrolabral junction, and articular cartilage after hip arthroscopy. PURPOSE: To evaluate the effect of pelvic incidence (PI) on postoperative outcomes after hip arthroscopy for acetabular labral tears in the setting of FAI. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A retrospective query of prospectively collected data identified patients ≥18 years of age who underwent primary hip arthroscopy for FAI and acetabular labral tears between February 2014 and January 2022, with 3-, 6-, 12-, and 24-month follow-ups. Measurements for PI, pelvic tilt (PT), sacral slope (SS), and acetabular version were obtained via advanced diagnostic imaging. Patients were stratified into low-PI (<45°), moderate-PI (45°≤ PI ≤ 60°), and high-PI (>60°) cohorts. Patient-reported outcome measures (PROMs), clinically meaningful outcomes (ie, minimal clinically important difference, Patient Acceptable Symptom State, substantial clinical benefit, and maximal outcome improvement), visual analog scale (VAS) pain scores, and patient satisfaction were compared across cohorts. RESULTS: A total of 74 patients met eligibility criteria and were stratified into low-PI (n = 28), moderate-PI (n = 31), and high-PI (n = 15) cohorts. Correspondingly, patients with high PI displayed significantly greater values for PT (P = .001), SS (P < .001), acetabular version (P < .001), and acetabular inclination (P = .049). By the 12- and 24-month follow-ups, the high-PI cohort was found to have significantly inferior PROMs, VAS pain scores, rates of clinically meaningful outcome achievement, and satisfaction relative to patients with moderate and/or low PI. No significant differences were found between cohorts regarding rates of revision arthroscopy, subsequent spine surgery, or conversion to total hip arthroplasty. CONCLUSION: After hip arthroscopy, patients with a high PI (>60°) exhibited inferior PROMs, rates of achieving clinically meaningful thresholds, and satisfaction at 12 and 24 months relative to patients with low or moderate PI. Conversely, the outcomes of patients with low PI (<45°) were found to match the trajectory of those with a neutral spinopelvic alignment (45°≤ PI ≤ 60°). These findings highlight the importance of analyzing spinopelvic parameters preoperatively to prognosticate outcomes before hip arthroscopy for acetabular labral tears and FAI.

Prevalence and Predictors of Barrett's Esophagus After Negative Initial Endoscopy: Analysis From Two National Databases.

BACKGROUND & AIMS: Guidelines suggest a single screening esophagogastroduodenoscopy (EGD) in patients with multiple risk factors for Barrett's esophagus (BE). We aimed to determine BE prevalence and predictors on repeat EGD after a negative initial EGD, using 2 large national databases (GI Quality Improvement Consortium [GIQuIC] and TriNetX). METHODS: Patients who underwent at least 2 EGDs were included and those with BE or esophageal adenocarcinoma detected at initial EGD were excluded. Patient demographics and prevalence of BE on repeat EGD were collected. Multivariate logistic regression was performed to assess for independent risk factors for BE detected on the repeat EGD. RESULTS: In 214,318 and 153,445 patients undergoing at least 2 EGDs over a median follow-up of 28-35 months, the prevalence of BE on repeat EGD was 1.7% in GIQuIC and 3.4% in TriNetX, respectively (26%-45% of baseline BE prevalence). Most (89%) patients had nondysplastic BE. The prevalence of BE remained stable over time (from 1 to >5 years from negative initial EGD) but increased with increasing number of risk factors. BE prevalence in a high-risk population (gastroesophageal reflux disease plus ≥1 risk factor for BE) was 3%-4%. CONCLUSIONS: In this study of >350,000 patients, rates of BE on repeat EGD ranged from 1.7%-3.4%, and were higher in those with multiple risk factors. Most were likely missed at initial evaluation, underscoring the importance of a high-quality initial endoscopic examination. Although routine repeat endoscopic BE screening after a negative initial examination is not recommended, repeat screening may be considered in carefully selected patients with gastroesophageal reflux disease and ≥2 risk factors for BE, potentially using nonendoscopic tools.

Risk Factors for Chronic Atrial Fibrillation Following Lung Lobectomy.

INTRODUCTION: Postoperative atrial fibrillation (POAF) is a common complication following lung lobectomy and is associated with increased risk of stroke, mortality, and prolonged hospital length of stay. The purpose of this study was to define the risk factors for POAF after lobectomy, hypothesizing that operative approach would be associated with risk of chronic POAF. METHODS: The TriNetX database was used to identify adult patients with no history of arrythmia receiving elective lung lobectomy for cancer from 7/6/2003-7/6/2023. Patients were categorized by approach: video-assisted thoracoscopic surgery (VATS) or open. The outcome of interest was the presence of POAF occurring at 1-3 months ("early") and 12-24 months postop ("chronic"). Propensity matching was performed to reduce bias between cohorts. RESULTS: We identified 22,998 patients: 8472 (36.8%) who received open and 14,526 (63.2%) VATS lobectomy. The rate of early POAF was 3.7% of VATS and 5.3% of open patients. The rate of chronic POAF was 5.5 % of VATS patients and 6.2% of open lobectomy patients. Propensity matching decreased bias between the approach groups, creating 7942 pairs for analysis. After matching, the risk of early POAF was greater in the open approach (5.5% open vs 3.4% VATS, risk ratio 1.607 (95% confidence interval 1.385-1.865), P < 0.001). Chronic POAF was (also) higher in the open approach (6.3% open vs 5.2% VATS, Risk Ratio 1.211 (95%CI 1.067-1.374), P = 0.003). CONCLUSIONS: Postoperative atrial fibrillation (POAF) occurs more commonly after open lobectomy, both acutely and chronically. Providers should counsel patients about the risk of chronic arrythmia after lung resection.

Reduced risk of de novo Barrett esophagus after bariatric surgery: a national database study.

BACKGROUND: Bariatric surgery is an effective treatment for obesity and may decrease the morbidity and mortality of obesity-associated cancers. OBJECTIVE: We investigated the risk of a new diagnosis of Barrett esophagus (BE) following bariatric surgery compared to screening colonoscopy controls. SETTING: Large national database including patients who received care in inpatient, outpatient, and specialty care services. METHODS: A national healthcare database (TriNetX, LLC) was used for this analysis. Cases included adults (aged ≥18 yr) who had undergone either sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB). Controls included adults undergoing screening colonoscopy and an esophagoduodenoscopy on the same day and had never undergone bariatric surgery. Cases and controls were propensity-matched for confounders. The risk of de novo diagnosis of BE at least 1 year after bariatric surgery was compared between cases and controls. Secondary analyses examined the effect of bariatric surgery on metabolic outcomes such as weight loss and body mass index (BMI). The risk of de novo diagnosis of BE in SG was compared with RYGB. Odds ratios (OR) and 95% CI were used to report on these associations. RESULTS: In the propensity-matched analysis, patients who had undergone a bariatric surgical procedure showed a significantly reduced risk of de novo BE when compared with screening colonoscopy controls (.67 [.48, .94]). There was substantial reduction in weight and BMI in the bariatric surgery group when compared with baseline. There was no significant difference in de novo BE diagnosis between the propensity-matched SG and RYGB groups (.77 [.5, 1.2]). CONCLUSION: Patients who underwent bariatric surgery (RYGB or SG) had a lower risk of being diagnosed with BE compared with screening colonoscopy controls who did not receive bariatric surgery. This effect appears to be largely mediated by reduction in weight and BMI.

Trends in Management of Anal Fissures.

BACKGROUND: It is unclear how patients with anal fissures are treated in real-world settings, particularly since patients may not see colorectal surgeons. This study describes trends in treatment with medical therapies (calcium-channel blockers [CCBs], nitroglycerin [NTG], and narcotics) and surgical treatments. METHODS: Cohorts were created within the TriNetX database platform using codes for anal fissures and surgical interventions. Demographics were compared between patients that received surgical intervention within 1 year of diagnosis, CCB or NTG within 1 year (or preoperatively), or narcotics within 30 days or postoperatively vs those who did not. RESULTS: 121,213 patients were included of which 4.0% had surgical intervention. Factors associated with surgical intervention were male sex (OR 1.40), White race (OR 1.17), and Hispanic ethnicity (OR 1.11). Male patients were more likely to undergo sphincterotomy (OR 1.49). Female (OR 1.27), non-Hispanic (OR 1.34), and White patients (OR 1.41) were more likely to have chemodenervation. Regarding nonoperatively managed patients, non-Hispanic (OR .91) and White patients (OR .89) were less likely to receive CCB/NTG. Male (OR 1.21), non-Hispanic (OR 1.08), and Black patients (OR 1.20) were more likely to receive narcotics. Male patients that required surgery were more likely to be prescribed CCB/NTG preoperatively (OR 1.27). Non-Hispanic surgical patients were more likely to receive narcotics (OR 1.84). DISCUSSION: Male fissure patients were more likely to undergo surgical intervention other than chemodenervation. Differences in the rates of surgery and medical therapy (especially narcotics) between races and ethnicities require exploration to enhance the care of patients with anal fissures.

DGKα/ζ inhibitors combine with PD-1 checkpoint therapy to promote T cell-mediated antitumor immunity.

Programmed cell death protein 1 (PD-1) immune checkpoint blockade therapy has revolutionized cancer treatment. Although PD-1 blockade is effective in a subset of patients with cancer, many fail to respond because of either primary or acquired resistance. Thus, next-generation strategies are needed to expand the depth and breadth of clinical responses. Toward this end, we designed a human primary T cell phenotypic high-throughput screening strategy to identify small molecules with distinct and complementary mechanisms of action to PD-1 checkpoint blockade. Through these efforts, we selected and optimized a chemical series that showed robust potentiation of T cell activation and combinatorial activity with αPD-1 blockade. Target identification was facilitated by chemical proteomic profiling with a lipid-based photoaffinity probe, which displayed enhanced binding to diacylglycerol kinase α (DGKα) in the presence of the active compound, a phenomenon that correlated with the translocation of DGKα to the plasma membrane. We further found that optimized leads within this chemical series were potent and selective inhibitors of both DGKα and DGKζ, lipid kinases that constitute an intracellular T cell checkpoint that blunts T cell signaling through diacylglycerol metabolism. We show that dual DGKα/ζ inhibition amplified suboptimal T cell receptor signaling mediated by low-affinity antigen presentation and low major histocompatibility complex class I expression on tumor cells, both hallmarks of resistance to PD-1 blockade. In addition, DGKα/ζ inhibitors combined with αPD-1 therapy to elicit robust tumor regression in syngeneic mouse tumor models. Together, these findings support targeting DGKα/ζ as a next-generation T cell immune checkpoint strategy.

Preoperative Paralabral Cysts Predict More Significant Chondral Damage but Not 2-Year Functional Outcomes Following Arthroscopic Labral Repair.

PURPOSE: To investigate whether paralabral cysts identified incidentally on preoperative magnetic resonance imaging (MRI/MRA) predict 2-year functional outcomes after arthroscopic acetabular labral repair. METHODS: Prospectively collected data for patients undergoing primary hip arthroscopy by a single surgeon from 2014 to 2020 were retrospectively reviewed. Included patients were ≥18 years and completed baseline patient-reported outcome measures (PROMs) with additional follow-up at 3, 6, 12, and 24 months. Exclusion criteria were labral debridement, hip dysplasia, advanced hip osteoarthritis (Tönnis >1), or previous ipsilateral hip surgery. Patients were stratified based on the presence of paralabral cysts identified on MRI/MRA. Primary outcomes were International Hip Outcome Tool (iHOT-33) and modified Harris Hip Score (mHHS). Secondary outcomes included other PROMs and the visual analog pain scale. Outcomes were compared between cohorts using linear mixed-effects models and Fisher's exact tests. Sensitivity analyses accounted for preoperative PROMs, nonlinear improvement trajectories, and relevant baseline characteristics. RESULTS: Of the 182 included hips (47.8% female; mean ± standard deviation age, 36.9 ± 11.4), 30 (16.4%) had paralabral cysts. During the 2-year study period, there were no significant differences between patients with and without paralabral cysts in terms of iHOT-33 scores (weighted difference = 1.60; 95% confidence interval [CI], -5.09, 8.28; P = .64), mHHS scores (weighted difference = 0.56; 95% CI, -4.16, 5.28; P = .82), or any secondary outcomes (except for HOS-Sports Subscale at 3 months [mean difference = -11.85; 95% CI, -22.85, -0.84; P = .035]). Furthermore, there were no significant differences in clinically meaningful outcomes (P > .05 for all), revision rates (P = 1.00), or conversion to total hip arthroplasty between cohorts (P = 1.00). These results held across all sensitivity analyses. CONCLUSIONS: Although preoperative paralabral cysts were associated with worse cam impingement and more severe chondral damage observed intraoperatively, they did not predict 2-year functional outcomes or clinically meaningful improvements, suggesting that incidentally discovered paralabral cysts are not a contraindication for arthroscopic labral repair. LEVEL OF EVIDENCE: Level III, retrospective cohort study.

Outcomes of Hip Arthroscopy in the Setting of Concomitant Symptomatic Lumbosacral Spine Pathology: A Matched Control Study With Minimum 24-Month Follow-up.

BACKGROUND: The overlapping biomechanical relationship between the lumbosacral spine and pelvis poses unique challenges to patients with concomitant pathologies limiting spinopelvic range of motion. PURPOSE: To assess the influence of concomitant, symptomatic lumbosacral spine pathology on patient-reported outcome measures (PROMs) after hip arthroscopy for the treatment of femoroacetabular impingement (FAI) and symptomatic labral tears. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A retrospective query of prospectively collected data identified patients aged ≥18 years with a minimum 24-month follow-up who underwent hip arthroscopy by a single surgeon for the treatment of symptomatic labral tears secondary to FAI. Patients were stratified into cohorts based on the presence (hip-spine [HS]) or absence (matched control [MC]) of symptomatic lumbosacral spine pathology. Inclusion within the HS cohort required confirmation of lower back pain/symptoms on preoperative surveys plus a diagnosis of lumbosacral spine pathology verified by radiology reports and correlating clinical documentation. Patients with previous spine surgery were excluded. PROMs were compared between groups, along with rates of achieving minimal clinically important difference (MCID) thresholds, Patient Acceptable Symptom State (PASS) thresholds, revision arthroscopy, and conversion to total hip arthroplasty (THA). RESULTS: A total of 70 patients with lumbosacral pathology were coarsened exact matched to 87 control patients without spinal pathology. The HS cohort had preoperative baseline scores that were significantly worse for nearly all PROMs. Follow-ups at 3, 6, 12, and 24 months displayed similar trends, with the HS cohort demonstrating significantly worse scores for most collected outcomes. However, at every time point, HS and MC patients exhibited similar magnitudes of improvement across all PROM and pain metrics. Furthermore, while significantly fewer HS patients achieved PASS for nearly all PROMs at 12- and 24-month follow-ups, MCID thresholds were reached at similar or greater rates across all PROMs relative to the MC cohort. Finally, there were no significant differences in rates of revision or THA between cohorts at maximum available follow-up. CONCLUSION: After hip arthroscopy to address labral tears in the setting of FAI, patients with symptomatic lumbosacral pathologies and no history of spine surgery were found to exhibit inferior pre- and postoperative PROMs but achieved statistically similar clinical benefit and rates of PROM improvement through 24-month follow-up compared with the MC cohort with isolated hip disease. These findings aid in providing a realistic recovery timeline and evidence that coexisting hip and spine disorders are not a contraindication for arthroscopic hip preservation surgery.

An allosteric pan-TEAD inhibitor blocks oncogenic YAP/TAZ signaling and overcomes KRAS G12C inhibitor resistance.

The Hippo pathway is a key growth control pathway that is conserved across species. The downstream effectors of the Hippo pathway, YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif), are frequently activated in cancers to drive proliferation and survival. Based on the premise that sustained interactions between YAP/TAZ and TEADs (transcriptional enhanced associate domain) are central to their transcriptional activities, we discovered a potent small-molecule inhibitor (SMI), GNE-7883, that allosterically blocks the interactions between YAP/TAZ and all human TEAD paralogs through binding to the TEAD lipid pocket. GNE-7883 effectively reduces chromatin accessibility specifically at TEAD motifs, suppresses cell proliferation in a variety of cell line models and achieves strong antitumor efficacy in vivo. Furthermore, we uncovered that GNE-7883 effectively overcomes both intrinsic and acquired resistance to KRAS (Kirsten rat sarcoma viral oncogene homolog) G12C inhibitors in diverse preclinical models through the inhibition of YAP/TAZ activation. Taken together, this work demonstrates the activities of TEAD SMIs in YAP/TAZ-dependent cancers and highlights their potential broad applications in precision oncology and therapy resistance.

Operative management of rotator cuff tears: identifying disparities in access on a national level.

BACKGROUND: The purpose of this study was to identify nationwide disparities in the rates of operative management of rotator cuff tears based on race, ethnicity, insurance type, and socioeconomic status. METHODS: Patients diagnosed with a full or partial rotator cuff tear from 2006 to 2014 were identified in the Healthcare Cost and Utilization Project's National Inpatient Sample database using International Classification of Diseases, Ninth Revision diagnosis codes. Bivariate analysis using chi-square tests and adjusted, multivariable logistic regression models were used to evaluate differences in the rates of operative vs. nonoperative management for rotator cuff tears. RESULTS: This study included 46,167 patients. When compared with white patients, adjusted analysis showed that minority race and ethnicity were associated with lower rates of operative management for Black (adjusted odds ratio [AOR]: 0.31, 95% confidence interval [CI]: 0.29-0.33; P < .001), Hispanic (AOR: 0.49, 95% CI: 0.45-0.52; P < .001), Asian or Pacific Islander (AOR: 0.72, 95% CI: 0.61-0.84; P < .001), and Native American patients (AOR: 0.65, 95% CI: 0.50-0.86; P = .002). In comparison to privately insured patients, our analysis also found that self-payers (AOR: 0.08, 95% CI: 0.07-0.10; P < .001), Medicare beneficiaries (AOR: 0.76, 95% CI: 0.72-0.81; P < .001), and Medicaid beneficiaries (AOR: 0.33, 95% CI: 0.30-0.36; P < .001) had lower odds of receiving surgical intervention. Additionally, relative to those in the bottom income quartile, patients in all other quartiles experienced nominally higher rates of operative repair; these differences were statistically significant for the second quartile (AOR: 1.09, 95% CI: 1.03-1.16; P = .004). CONCLUSION: There are significant nationwide disparities in the likelihood of receiving operative management for rotator cuff tear patients of differing race/ethnicity, payer status, and socioeconomic status. Further investigation is needed to fully understand and address causes of these discrepancies to optimize care pathways.

Scaffolding Protein Connector Enhancer of Kinase Suppressor of Ras 1 (CNKSR1) Regulates MAPK Inhibition Responsiveness in Pancreas Cancer via Crosstalk with AKT Signaling.

Combinatorial molecular therapy in pancreatic ductal adenocarcinoma (PDAC) has yielded largely disappointing results in clinical testing to-date as a multitude of adaptive resistance mechanisms is making selection of patients via molecular markers that capture essential, intersecting signaling routes challenging. Here, we report the scaffolding protein connector enhancer of kinase suppressor of Ras 1 (CNKSR1) as mediator of resistance to MAPK (MEK) inhibition. MEK inhibition in CNKSR1high cancer cells induces translocation of CNKSR1 to the plasma membrane where the scaffolding protein interacts with and stabilizes the phosphorylated form of AKT. CNKSR1-mediated AKT activation following MEK inhibition was associated with increased cellular p-PRAS40 levels and reduced nuclear translocation and cellular levels of FoxO1, a negative regulator of AKT signaling. In clinical PDAC specimens, high cytoplasmatic CNKSR1 levels correlated with increased cellular phospho-AKT and mTOR levels. Pharmacological co-blockade of AKT and MEK ranked top in induced synergies with MEK inhibition in CNKSR1high pancreas cancer cells among other inhibitor combinations targeting known CNKSR1 signaling. In vivo, CNKSR1high pancreatic tumors treated with AKT and MEK inhibitors showed improved outcome in the combination arm compared with single-agent treatment, an effect not observed in CNKSR1low models.Our results identify CNKSR1 as regulator of adaptive resistance to MEK inhibition by promoting crosstalk to AKT signaling via a scaffolding function for the phosphorylated form of AKT. CNSKR1 expression might be a possible molecular marker to enrich patients for future AKT-MEK inhibitor precision medicine studies. IMPLICATIONS: The CNKSR1 scaffold, identified within an RNAi screen as a novel mediator of resistance to MEK inhibition in pancreas cancer, connects the MAPK pathway and AKT signaling and may be adopted as a biomarker to select patients for combined MEK AKT blockade.

Racial disparities in arthroscopic rotator cuff repair: an analysis of utilization and perioperative outcomes.

Background: There remains a paucity of literature addressing racial disparities in utilization and perioperative metrics in arthroscopic rotator cuff repair procedures. Methods: The American College of Surgeons National Surgical Quality Improvement Program database was used to evaluate patients undergoing arthroscopic rotator cuff repair from 2010 to 2019. Baseline demographics, utilization trends, and perioperative measures, including adverse events, operative time, length of hospital stay, days from operation to discharge, and readmission, were analyzed. Results: Of 42,443 included patients, 38,090 (89.7%) were White, and 4353 (10.3%) were Black or African American. Black or African American patients had a significantly higher percentage of diabetes mellitus (23.6% vs. 15.6%), smoking (16.9% vs. 14.8%), congestive heart failure (0.3% vs. 0.1%), and hypertension (59.2% vs. 45.9%). In addition, logistic regression showed that Black or African American patients had increased odds of longer operative time (adjusted rate ratio 1.07, 95% confidence interval 1.05-1.08) and time from operation to discharge (adjusted rate ratio 1.19, 95% confidence interval 1.04-1.37). Disparities in relative utilization decreased as the proportion of Black or African American patients undergoing arthroscopic rotator cuff repair increased (7.4% in 2010 vs. 10.4% in 2019) compared with White patients (P trend < .0001). Conclusion: Racial disparities exist regarding baseline comorbidities and perioperative metrics in arthroscopic rotator cuff repair. Further investigation is needed to fully understand and address the causes of these inequalities to provide equitable care.