Citations

Background: Hip arthroscopy is becoming more advanced and commonly performed. However, significant controversy exists regarding whether high-grade acetabular cartilage lesions should be treated with debridement/abrasion or microfracture. In addition, patients treated with microfracture are subject to extended protected weightbearing rehabilitation to mitigate risk of subchondral plate fracture and to protect fibrocartilage tissue formation. Purpose: To determine the midterm patient-reported outcomes and failure rate of patients with grade 3 and 4 acetabular labrum articular disruption (ALAD) lesions managed with debridement/abrasion or microfracture. Study Design: Cohort study; Level of evidence, 3. Methods: Primary arthroscopic labral repair cases at 2 centers from November 2008 to April 2016 were reviewed for patients aged <55 years with unipolar ALAD grade 3 and 4 chondrolabral acetabular delamination. Patients undergoing microfracture and debridement/abrasion were compared using the visual analog pain scale (VAS), modified Harris Hip Score (mHHS), and Hip Outcome Score–Sports-Specific Subscale (HOS-SSS) to determine predictors of outcomes and failure. Results: A total of 113 hips in 110 patients (66 males, 44 females; mean age, 34.5 ± 1.1 years) undergoing debridement/abrasion (n = 82) or microfracture (n = 31) were followed for a mean of 4.9 years (range, 2.0-8.5 years). Lesion size was not statistically different between the debridement/abrasion (1.3 ± 1.0 cm 2 ) and microfracture cohorts (1.4 ± 1.0 cm 2 ) ( P = .47). Patients undergoing debridement/abrasion achieved 3.6-point mean improvements in VAS ( P < .01), 21.2-point improvements in mHHS ( P < .01), and 25.4-point improvements in HOS-SSS ( P < .01), which were not significantly different from those observed in microfracture patients ( P≥ .20). The 5-year rate of survival free of revision surgery was 84.0% in the debridement/abrasion group and 85.6% in the microfracture group ( P = .78). The cartilage treatment technique was found not to be predictive of revision risk during both univariate (hazard ratio [HR], 1.01; P = .98) and multivariate (HR, 0.93; P = .90) analysis accounting for patient age, lesion grade, and acetabular coverage. Conclusion: Patients undergoing debridement/abrasion of high-grade unipolar acetabular cartilage lesions demonstrate similar outcome scores and revision rates compared with those of patients undergoing microfracture. These outcomes support the consideration of preferential debridement/abrasion at the discretion of the treating surgeon to optimize recovery while maintaining established positive outcomes after hip arthroscopy.

Objective: The aim of this study was to determine whether a vitamin D genetic risk score (vitDGRS) is associated with 25-hydroxyvitamin D (25(OH)D) level and multiple sclerosis (MS) relapses in children. Methods: DNA samples were typed for single nucleotide polymorphisms (SNPs) from four genes previously identified to be associated with 25(OH)D levels. SNPs with strong associations with 25(OH)D after multiple comparison correction were used to create a genetic risk score (vitDGRS). Cox regression models tested associations of vitDGRS with relapse hazard. Results: Two independent SNPs within or near GC and NADSYN1/DHCR7 genes were strongly associated with 25(OH)D levels in the discovery cohort ( n = 182) after Bonferroni correction. The vitDGRS of these SNPs explained 4.5% of the variance of 25(OH)D level after adjustment for genetic ancestry. Having the highest versus lowest vitDGRS was associated with 11 ng/mL lower 25(OH)D level (95% confidence interval (CI) = −17.5, −4.5, p = 0.001) in the discovery cohort. Adjusting for ancestry, sex, disease-modifying therapy (DMT), and HLA-DRB1*15 carrier status, the highest versus lowest vitDGRS was associated with 2.6-fold (95% CI = 1.37, 5.03, p = 0.004) and 2.0-fold (95% CI = 0.75, 5.20, p = 0.16) higher relapse hazard in the discovery and replication cohorts, respectively. Conclusion: The vitDGRS identifies children at greater risk of relapse. These findings support a causal role for vitamin D in MS course.

Abstract17α-Estradiol (17α-E2) is a “non-feminizing” estrogen that extends life span in male, but not female, mice. We recently reported that 17α-E2 had robust beneficial effects on metabolic and inflammatory parameters in aged male mice. However, it remains unclear if 17α-E2 also delays other “hallmarks” of aging, particularly maintaining proteostasis. Here, we used isotope labeling methods in older mice to examine proteostatic mechanisms. We compared weight-matched mild calorie restricted (CR) and 17α-E2 treated male mice with the hypothesis that 17α-E2 would increase protein synthesis for somatic maintenance. 17α-E2 had no effect on protein synthesis or DNA synthesis in multiple tissues, including white adipose tissue. Conversely, mild short-term CR decreased DNA synthesis and increased the protein to DNA synthesis ratio in multiple tissues. Examination of individual protein synthesis and content did not differentiate treatments, although it provided insight into the regulation of protein content between tissues. Contrary to our hypothesis, we did not see the predicted differences in protein to DNA synthesis following 17α-E2 treatment. However, mild short-term CR elicited differences consistent with both lifelong CR and other treatments that curtail aging processes. These data indicated that despite similar maintenance of body mass, 17α-E2 and CR treatments elicit distinctly different proteostatic outcomes.

Purpose To elucidate the effect, if any, of acetabular chondral defect size on surgical outcomes after arthroscopic microfracture was performed with concomitant treatment for labral tears and femoroacetabular impingement (FAI) syndrome. Methods The study period was between February 2008 and November 2014. Data were collected on patients who underwent hip arthroscopy. The inclusion criteria were acetabular microfracture; concomitant treatment for labral tears and FAI syndrome; and preoperative modified Harris Hip Score, Nonarthritic Hip Score, Hip Outcome Score–Sports Specific Subscale, and visual analog scale. Exclusion criteria were Workers' Compensation, preoperative Tönnis grade >1, or previous ipsilateral hip surgeries or conditions. Patients were grouped based on smaller chondral defects (SCDs) or larger chondral defects (LCDs), then matched 1:1 by age at surgery ±10 years, sex, body mass index ±5, labral treatment, capsular treatment, acetabuloplasty, and femoroplasty. Outcomes, secondary arthroscopies, and conversions to total hip arthroplasty (THA) were documented. Results Of 131 eligible cases, 107 (81.7%) had minimum 2‐year follow‐up. Before matching, the conversion rate to THA was higher for LCDs (24.6%) than for SCDs (12.0%). Thirty‐five patients were matched for each group. Mean follow‐up time was 47.9 months (range, 24.0, 84.1) for the matched LCD group and 46.1 months (range, 24.0, 88.1) for the matched SCD group. Ligamentum teres debridement ( P = .03) was performed more frequently in the LCD group. No other differences were found regarding demographics, intraoperative findings, procedures, traction time, preoperative scores, or follow‐up scores. Both groups demonstrated significant improvements in all scores. Rates of revision or conversion to THA were similar between groups. The relative risk for conversion to THA was 2.33 for patients with defects ≥300 mm 2 compared with patients with defects ≤250 mm 2 ( P = .13). Deep vein thrombosis occurred in 3 (5.3%) patients with LCDs. Conclusions Matched patients with either SCDs or LCDs undergoing arthroscopic acetabular microfracture with concomitant treatment for labral tears and FAI syndrome demonstrated similar improvements at minimum 2‐year follow‐up. Patients with chondral defects approaching 300 mm 2 or greater may have a higher propensity toward conversion to THA. Level of Evidence Level III, retrospective comparative therapeutic trial.

Significance Statement In approximately 70%–80% of cases of primary membranous nephropathy (MN), phospholipase A2 receptor (PLA2R)/Thrombospondin Type-1 Domain–Containing 7A (THSD7A) and anti-PLA2R/THSD7A antibodies form immune complexes along the glomerular basement membrane (GBM) that characterize the condition. In other cases of primary MN and all secondary MN, the target antigen is unknown. Using proteomics and immunohistochemistry, the authors detected two proteins, exostosin 1 (EXT1) and exostosin 2 (EXT2), in the GBM of PLA2R-negative MN. EXT1 and EXT2 were absent in all cases of PLA2R-associated MN and controls. Clinical and biopsy findings showed features of autoimmune disease, including membranous lupus nephritis, in 81% of the 26 EXT1/EXT2-associated MN cases the authors identified. These findings suggest that EXT1/EXT2-associated MN represents a distinct subtype of MN, most commonly associated with autoimmune diseases (secondary MN). Background In membranous nephropathy (MN), which is characterized by deposition of immune complexes along the glomerular basement membrane (GBM), phospholipase A2 receptor (PLA2R) and thrombospondin type 1 domain–containing 7A are target antigens in approximately 70% and 1%–5% of cases of primary MN, respectively. In other cases of primary MN and in secondary MN, the target antigens are unknown. Methods We studied 224 cases of biopsy-proven PLA2R-negative MN and 102 controls (including 47 cases of PLA2R-associated MN) in pilot and discovery cohorts. We also evaluated 48 cases of PLA2R-negative presumed primary MN and lupus MN in a validation cohort. We used laser microdissection and mass spectrometry to identify new antigens, which were localized by immunohistochemistry. Results Mass spectrometry detected exostosin 1 (EXT1) and exostosin 2 (EXT2) in 21 cases of PLA2R-negative MN, but not in PLA2R-associated MN and control cases. Immunohistochemistry staining revealed bright granular GBM staining for EXT1 and EXT2. Clinical and biopsy findings showed features of autoimmune disease, including lupus, in 80.7% of the 26 EXT1/EXT2-associated MN cases we identified. In the validation cohort, we confirmed that EXT1/EXT2 staining was detected in pure class 5 lupus nephritis (eight of 18 patients) and in presumed primary MN associated with signs of autoimmunity (three of 16 patients); only one of the 14 cases of mixed class 5 and 3/4 lupus nephritis was positive for EXT1/EXT2. Tests in seven patients with EXT1/EXT2-associated MN found no circulating anti-exostosin antibodies. Conclusions A subset of MN is associated with accumulation of EXT1 and EXT2 in the GBM. Autoimmune disease is common in this group of patients.

Background Patient satisfaction with therapy is an important metric of care quality and has been associated with greater medication persistence. We evaluated the association of patient satisfaction with warfarin therapy to other metrics of anticoagulation care quality and clinical outcomes among patients with atrial fibrillation ( AF ). Methods and Results Using data from the ORBIT ‐ AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) registry, patients were identified with AF who were taking warfarin and had completed an Anti‐Clot Treatment Scale ( ACTS ) questionnaire, a validated metric of patient‐reported burden and benefit of oral anticoagulation. Multivariate regressions were used to determine association of ACTS burden and benefit scores with time in therapeutic international normalized ratio range ( TTR ; both ≥75% and ≥60%), warfarin discontinuation, and clinical outcomes (death, stroke, major bleed, and all‐cause hospitalization). Among 1514 patients with AF on warfarin therapy (75±10 years; 42% women; CHA 2 DS 2 ‐ VAS c 3.9±1.7), those most burdened with warfarin therapy were younger and more likely to be women, have paroxysmal AF , and to be treated with antiarrhythmic drugs. After adjustment for covariates, ACTS burden scores were independent of TTR ( TTR ≥75%: odds ratio, 1.01 [95% CI , 0.99–1.03]; TTR ≥60%: odds ratio, 1.01 [95% CI , 0.98–1.05]), warfarin discontinuation (odds ratio, 0.99; 95% CI , 0.97–1.01), or clinical outcomes. ACTS benefit scores were also not associated with TTR , warfarin discontinuation, or clinical outcomes. Conclusions In a large registry of patients with AF taking warfarin, ACTS scores provided independent information beyond other traditional metrics of oral anticoagulation care quality and identified patient groups at high risk for dissatisfaction with warfarin therapy.

OBJECTIVES: Expression of prostaglandin biosynthetic pathway enzymes in mucinous pancreatic cysts is unknown. Cyclooxygenase-2 (COX-2) inhibition is a potential cancer chemoprevention strategy for these lesions. We evaluated the expression of COX-2, cytosolic phospholipase A2 (cPLA2), and protein kinase B (AKT) in the epithelium of pancreatic cysts and correlated enzyme expression with aspirin (ASA) use and cyst fluid prostaglandin E 2 (PGE 2 ) concentration. METHODS: Pathology of 80 resected pancreatic cysts was reviewed. Expression of COX-2, cPLA2, and AKT was quantified by tissue immunohistochemistry immunoreactivity scores (IRSs). IRS values were compared between cyst types and (in 30 cases) with matched cyst fluid PGE 2 concentrations. RESULTS: The mean IRS was higher in the epithelium of mucinous vs nonmucinous cysts for COX-2 (6.1 ± 4.7 vs 3.2 ± 2.8, P = 0.01) and cPLA2 (6.9 ± 3.0 vs 2.9 ± 2.9, P < 0.001). Cyst epithelial COX-2 expression was higher in mucinous cysts with low-grade dysplasia vs those with high-grade dysplasia or invasive carcinoma (IRS 8.0 ± 3.9 vs 1.5 ± 2.9, P < 0.001), whereas the opposite was found for cPLA2 (6.2 ± 3.0 vs 8.6 ± 2.3, P = 0.005). Cyst fluid PGE 2 concentrations did not correlate with either the IRS or a history of low- to moderate-dose ASA use. CONCLUSIONS: COX-2 and cPLA2 are overexpressed in the epithelium of mucinous pancreatic cysts. COX-2 and/or cPLA2 inhibition might prevent the emergence or progression of mucinous pancreatic cysts, but higher doses of ASA or nonsteroidal anti-inflammatory drugs may be necessary to substantially inhibit cyst epithelial COX-2 activity.

Bevacizumab‐pemetrexed/cisplatin ( BEV ‐ PEM / CIS ) is a first‐line therapeutic for advanced nonsquamous non‐small cell lung cancer. Bevacizumab potentiates PEM / CIS cytotoxicity by inducing transient tumor vasculature normalization. BEV ‐ PEM / CIS has a narrow therapeutic window. Therefore, it is an attractive target for administration schedule optimization. The present study leverages our previous work on BEV ‐ PEM / CIS pharmacodynamic modeling in non‐small cell lung cancer–bearing mice to estimate the optimal gap in the scheduling of sequential BEV ‐ PEM / CIS . We predicted the optimal gap in BEV ‐ PEM / CIS dosing to be 2.0 days in mice and 1.2 days in humans. Our simulations suggest that the efficacy loss in scheduling BEV ‐ PEM / CIS at too great of a gap is much less than the efficacy loss in scheduling BEV ‐ PEM / CIS at too short of a gap.