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.

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.

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.

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 SYK inhibitors AZ-A and AZ-B identified four unusual metabolites. M1 (m/z 411) was formed by both molecules and was common to several analogues (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 non-obvious 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 b-mercaptoethanol trapping experiment. The loss of the THP-moiety observed in M1 was found to be enhanced in an analogue which was unable to undergo the intra-molecular 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.

The exonuclease TREX1 constitutes an innate immune checkpoint limiting cGAS/STING-mediated antitumor immunity.

The DNA exonuclease TREX1 (Three-prime repair exonuclease 1) 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. Since 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 indeed restricts the 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 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 synergized 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 anti-tumor immunity by itself and in combination with T cell-targeted therapies.

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.

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.

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.

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.

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.

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.

Allogenic Platelet-Rich Plasma for the Treatment of Adhesive Capsulitis.

Adhesive capsulitis (AC) is a common shoulder disorder leading to pain and restricted range of motion (ROM) and affects the patient's activities of daily living (ADL) and overall quality of life (QoL). Conservative therapies are prioritized, resorting to surgical intervention only when necessary. Unfortunately, these modalities have limitations and do not address the underlying pathological cause of AC. The use of autologous biologics, such as platelet-rich plasma (PRP), has evolved and shown promise for managing musculoskeletal (MSK) injuries, including AC. However, subpar functional outcomes have led clinicians to question the long-term efficacy of autologous PRP. To circumvent this, the possibility of utilizing a standardized and well-characterized allogenic PRP for AC has been explored. In this manuscript, we qualitatively present in vitro, pre-clinical, clinical, and ongoing studies investigating the varied applications of allogenic PRP for the management of AC. The results demonstrated that allogenic PRP acts in a pleiotropic manner and decreases pro-inflammatory cytokines only in the inflammatory condition. In addition, the administration of allogenic PRP is safe and potentially efficacious, in terms of reducing pain and improving range of motion, shoulder strength, and function, in non-surgical management of AC. Nonetheless, more pre-clinical studies and adequately powered, multicenter, prospective, non-randomized, and randomized controlled trials with longer follow-up are warranted to further establish the safety and efficacy of allogenic PRP and justify its routine clinical use.

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.

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.

Labral Reconstruction via Capsular Augmentation Maintains Perfusion to the Acetabular Labrum and Locally Transferred Autograft: An in Vivo Laser Doppler Flowmetry Analysis.

Background: The purpose of the present study was to examine the effects of arthroscopic labral repair with capsular augmentation on blood flow in vivo with use of laser Doppler flowmetry (LDF) to measure microvascular perfusion of the labrum and autograft tissue. Methods: The present prospective case series included patients ≥18 years old who underwent arthroscopic acetabular labral repair with capsular augmentation; all procedures were performed by a single surgeon between 2018 and 2022. The LDF probe measured microvascular blood flow flux within 1 mm3 of the surrounding labral and capsular tissue of interest. Mean baseline measurements of flux were compared with readings immediately following capsular elevation and after completing labral augmentation. Blood flux changes were expressed as the percent change from the baseline measurements. Results: The present study included 41 patients (24 men [58.5%] and 17 women [41.5%]) with a mean age (and standard deviation) of 31.3 ± 8.4 years, a mean BMI of 24.6 ± 3.4 kg/m2, a mean lateral center-edge of angle 35.3° ± 4.9°, a mean Tönnis angle of 5.8° ± 5.8°, and a mean arterial pressure of 93.7 ± 10.9 mm Hg. Following capsular elevation, the mean percent change in capsular blood flow flux was significantly different from baseline (-9.24% [95% confidence interval (CI), -18.1% to -0.04%]; p < 0.001). Following labral augmentation, the mean percent change in labral blood flow flux was significantly different from baseline both medially (-22.3% [95% CI, -32.7% to -11.9%]; p < 0.001) and laterally (-32.5% [95% CI, -41.5% to -23.6%]; p = 0.041). There was no significant difference between the changes in medial and lateral perfusion following repair (p = 0.136). Conclusions: Labral repair with capsular augmentation sustains a reduced blood flow to the native labrum and capsular tissue at the time of fixation. The biological importance of this reduction is unknown, but these findings may serve as a benchmark for other labral preservation techniques and support future correlations with clinical outcomes. Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

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.