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Background The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross‐sectional and prospective association analyses of blood‐derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole‐genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia). P <0.01 was used for significance. We validated most of the previously reported associations between mtDNA CN and cardiovascular disease outcomes. For example, 1‐SD unit lower level of mtDNA CN was associated with 1.08 (95% CI, 1.04–1.12; P <0.001) times the hazard for developing incident CHD, adjusting for covariates. Mendelian randomization analyses showed no causal effect from a lower level of mtDNA CN to a higher CHD risk (β=0.091; P =0.11) or in the reverse direction (β=−0.012; P =0.076). Additional bidirectional Mendelian randomization analyses revealed that low‐density lipoprotein cholesterol had a causal effect on mtDNA CN (β=−0.084; P <0.001), but the reverse direction was not significant ( P =0.059). No causal associations were observed between mtDNA CN and obesity, diabetes, and hypertension, in either direction. Multivariable Mendelian randomization analyses showed no causal effect of CHD on mtDNA CN, controlling for low‐density lipoprotein cholesterol level ( P =0.52), whereas there was a strong direct causal effect of higher low‐density lipoprotein cholesterol on lower mtDNA CN, adjusting for CHD status (β=−0.092; P <0.001). Conclusions Our findings indicate that high low‐density lipoprotein cholesterol may underlie the complex relationships between mtDNA CN and vascular atherosclerosis.

Background: Our understanding of the risk factors for and effectiveness of prophylactic measures against shoulder periprosthetic joint infections (PJIs) continues to evolve. This study’s objective was to study patient characteristics, procedural characteristics, and various infection prophylactic measures and their effects on the risk of shoulder PJI after primary arthroplasty. Methods: Nine hundred and ninety-eight patients in a longitudinally maintained, single-institution shoulder arthroplasty database who had at least 2 years of clinical follow-up were retrospectively reviewed. Patient and procedural characteristics were collected. Perioperative variables, including the use of intraoperative antibiotics, topical antibiotics, antibiotic-containing irrigation solution, and a postoperative drain, were collected. Patients who developed shoulder PJI were compared with those without shoulder PJI to identify any association with patient or procedural characteristics. Results: Of the 998 patients, 20 (2.0%) met the criteria for shoulder PJI. Cutibacterium was identified as the causative organism in 19 (95%) of 20 culture-positive reoperations. On univariate analysis, patients in the PJI group were more likely to be younger (p < 0.001), to be male (p = 0.014), to have commercial insurance (p = 0.003), to use alcohol (p = 0.048), and to have had a ream-and-run or hemiarthroplasty procedure (p = 0.005). On multivariable analysis, older age was independently associated with a lower risk of PJI (odds ratio [OR] per year = 0.95; 95% confidence interval [CI], 0.91 to 0.99; p = 0.014). Reverse total shoulder arthroplasty (OR, 10.32; 95% CI, 0.92 to 116.33; p = 0.059) and hemiarthroplasty (OR, 8.59; 95% CI, 0.86.30 to 85.50; p = 0.067) trended toward a higher risk of PJI. Conclusions: Younger patients and patients undergoing procedures other than anatomic total shoulder arthroplasty are at higher risk for shoulder PJI. The majority of culture-positive reoperations were a result of Cutibacterium species. Level of Evidence: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Background: Ream-and-run arthroplasty can improve pain and function in patients with glenohumeral arthritis while avoiding the complications and activity restrictions associated with a prosthetic glenoid component. However, stiffness is a known complication after ream-and-run arthroplasty and can lead to repeat procedures such as a manipulation under anesthesia (MUA) or open surgical revision. The objective of this study was to determine risk factors associated with repeat procedures indicated for postoperative stiffness after ream-and-run arthroplasty. Methods: We conducted a retrospective review of our shoulder arthroplasty database to identify patients who underwent ream-and-run arthroplasty and determined which patients underwent subsequent repeat procedures (MUA and/or open revision) indicated for postoperative stiffness. The minimum follow-up was 2 years. We collected baseline demographic information and preoperative and 2-year patient-reported outcome scores and analyzed preoperative radiographs. Univariate and multivariate analyses determined the factors significantly associated with repeat procedures to treat postoperative stiffness. Results: There were 340 patients who underwent ream-and-run arthroplasty. The mean Simple Shoulder Test (SST) scores for all patients improved from 5.0 ± 2.4 preoperatively to 10.2 ± 2.6 postoperatively (p < 0.001). Twenty-six patients (7.6%) underwent open revision for stiffness. An additional 35 patients (10.3%) underwent MUA. Univariate analysis found younger age (p = 0.001), female sex (p = 0.034), lower American Society of Anesthesiologists (ASA) class (p = 0.045), posterior decentering on preoperative radiographs (p = 0.010), and less passive forward elevation at the time of discharge after ream-and-run arthroplasty (p < 0.001) to be significant risk factors for repeat procedures. Multivariate analysis found younger age (p = 0.040), ASA class 1 compared with class 3 (p = 0.020), and less passive forward elevation at discharge (p < 0.001) to be independent risk factors for repeat procedures. Of the patients who underwent open revision for stiffness, 69.2% had multiple positive cultures for Cutibacterium. Conclusions: Younger age, ASA class 1 compared with class 3, and less passive forward elevation in the immediate postoperative period were independent risk factors for repeat procedures to treat postoperative stiffness after ream-and-run arthroplasty. Level of Evidence: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

Background: Periprosthetic joint infections (PJIs) following total hip arthroplasty (THA) and total knee arthroplasty (TKA) are associated with substantial morbidity. A better understanding of the costs of PJI treatment can inform prevention, treatment, and reimbursement strategies. The purpose of the present study was to describe direct inpatient medical costs associated with the treatment of hip and knee PJI. Methods: At a single tertiary care institution, 176 hips and 266 knees that underwent 2-stage revisions for the treatment of PJI from 2009 to 2015 were compared with 1,611 hips and 1,276 knees that underwent revisions for aseptic indications. In addition, 84 hips and 137 knees that underwent irrigation and debridement (I&D) with partial component exchange were compared with 39 hips and 138 knees that underwent partial component exchange for aseptic indications. Line-item details of services billed during hospitalization were retrieved, and standardized direct medical costs were calculated in 2018 inflation-adjusted dollars. Results: The mean direct medical cost of 2-stage revision THA performed for the treatment of PJI was significantly higher than that of aseptic revision THA ($58,369 compared with $22,846, p < 0.001). Similarly, the cost of 2-stage revision TKA performed for the treatment of PJI was significantly higher than that of aseptic revision TKA ($56,900 compared with $24,630, p < 0.001). Even when the total costs of aseptic revisions were doubled for a representative comparison with 2-stage procedures, the costs of PJI procedures were 15% to 28% higher than those of the doubled costs of aseptic revisions (p < 0.001). The mean direct medical cost of I&D procedures for PJI was about twofold higher than of partial component exchange for aseptic indications. Conclusions: The direct medical costs of operative treatment of PJI following THA and TKA are twofold higher than the costs of similar aseptic revisions. The high economic burden of PJI warrants efforts to reduce the incidence of PJI. Reimbursement schemes should account for the high costs of treating PJI in order to ensure sustainable patient care. Level of Evidence: Economic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Aims Options for the treatment of intra-articular ligament injuries are limited, and insufficient ligament reconstruction can cause painful joint instability, loss of function, and progressive development of degenerative arthritis. This study aimed to assess the capability of a biologically enhanced matrix material for ligament reconstruction to withstand tensile forces within the joint and enhance ligament regeneration needed to regain joint function. Materials and Methods A total of 18 New Zealand rabbits underwent bilateral anterior cruciate ligament reconstruction by autograft, FiberTape, or FiberTape-augmented autograft. Primary outcomes were biomechanical assessment (n = 17), microCT (µCT) assessment (n = 12), histological evaluation (n = 12), and quantitative polymerase chain reaction (qPCR) analysis (n = 6). Results At eight weeks, FiberTape alone or FiberTape-augmented autograft demonstrated increased biomechanical stability compared with autograft regarding ultimate load to failure (p = 0.035), elongation (p = 0.006), and energy absorption (p = 0.022). FiberTape-grafted samples also demonstrated increased bone mineral density in the bone tunnel (p = 0.039). Histological evaluation showed integration of all grafts in the bone tunnels by new bone formation, and limited signs of inflammation overall. A lack of prolonged inflammation in all samples was confirmed by quantification of inflammation biomarkers. However, no regeneration of ligament-like tissue was observed along the suture tape materials. Except for one autograft failure, no adverse events were detected. Conclusion Our results indicate that FiberTape increases the biomechanical performance of intra-articular ligament reconstructions in a verified rabbit model at eight weeks. Within this period, FiberTape did not adversely affect bone tunnel healing or invoke a prolonged elevation in inflammation. Cite this article: Bone Joint J 2019;101-B:1238–1247.

Background: Revision total hip arthroplasty (revision THA) occurs for a wide variety of indications and in the United States it is coded under Diagnosis-Related Groups (DRGs) 466, 467, and 468, which do not account for revision etiology, a potentially substantial driver of cost. This study investigates revision THA costs and 30-day complications by indication, both locally and nationally. Methods: Hospitalization costs and complication rates for 1,422 aseptic revision THAs performed at a high-volume center between 2009 and 2014 were retrospectively reviewed. Additionally, charges for 28,133 revision THAs in the National Inpatient Sample (NIS) were converted to costs using the Healthcare Cost and Utilization Project cost-to-charge ratios, and 30-day complication rates for 3,224 revision THAs were obtained with use of the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP). Costs and complications were compared between revision THAs performed for fracture, wear/loosening, and dislocation/instability with use of simultaneous and pairwise comparisons and a multivariable model accounting for American Society of Anesthesiologists (ASA) score, age, and sex. Results: Local hospitalization costs for fracture (median, $25,672) were significantly higher than those for wear/loosening ($20,228; p < 0.001) or dislocation/instability ($17,911; p < 0.001), with differences remaining significant even after adjusting for patient comorbidities (p < 0.001). NIS costs for fracture (median, $27,596) were higher than those for other aseptic indications (wear/loosening: $21,176, p < 0.001; dislocation/instability: $16,891, p< 0.001). Local 30-day orthopaedic complication rates for fracture (20.7%) were higher those than for dislocation/instability (9.0%; p = 0.007) and similar to those for wear/loosening (17.6%; p = 0.434). Nationally, combined medical and surgical complication rates for fracture (71.3% of patients with ≥1 complication) were significantly higher than those for wear/loosening (35.2%; p < 0.001) or dislocation/instability (35.1%; p < 0.001). Conclusions: Hospitalization costs for revision THA for fracture were 33% to 48% higher than for all other aseptic revision THAs, both locally and nationally. This increased cost persisted even after multivariable comorbidity adjustment, the current DRG basis for stratifying revision THA reimbursement. Additionally, 30-day complication rates suggest that increased resource utilization for fracture patients continues even after discharge. Indication-specific coding and reimbursement systems are necessary to maintain sustainable access to revision THA for all patients. Level of Evidence: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

ObjectiveTo examine the association between macrophage migration inhibitory factor (MIF) promoter polymorphisms and granulomatosis with polyangiitis (GPA) in human subjects, and to assess the role of MIF in a murine model of granulomatous vasculitis.MethodsThe human study involved 1,077 patients with GPA and healthy controls whose serum was genotyped by capillary electrophoresis for the MIF −794 CATT5−8 promoter microsatellite (rs5844572). MIF promoter, CATT‐length–dependent gene expression in response to β‐glucan was assessed by gene reporter assays. In mouse studies, granulomatous disease was induced by injection of Candida albicans β‐glucan into wild‐type (WT) or Mif‐knockout (Mif‐KO) C57BL/6 mice and C57BL/6 mice transgenically overexpressing Mif in lung epithelium (Mif lung–Tg2.1). Mice were treated with a neutralizing anti‐MIF antibody and analyzed for the density of pulmonary granulomas, expression of inflammatory chemokines, and frequency of mortality.ResultsThe percentage of human subjects carrying >5 CATT repeats in each MIF allele (high genotypic MIF expressers) was 60.2% among patients with GPA and 53.9% among healthy controls (adjusted P = 0.049). In response to granulomatous stimulation, human MIF gene expression increased proportionally with CATT length. Mif lung–Tg2.1 mice exhibited more pulmonary granulomas than WT mice, which in turn showed more granulomas than Mif‐KO mice. A significantly higher percentage of Mif lung–Tg2.1 mice, compared to Mif‐KO or WT mice, died when injected with Candida albicans β‐glucan, and treatment of these mice with an anti‐MIF monoclonal antibody protected against a lethal outcome. Levels of MIF‐dependent neutrophil/macrophage chemokines were elevated in the bronchoalveolar lavage fluid or plasma of Mif lung–Tg2.1 mice.ConclusionPatients with GPA have an increased frequency of high MIF expression CATT alleles. Higher Mif expression increases the incidence of mortality and pulmonary granulomas in Mif lung–Tg2.1 mice, while anti‐MIF treatment protects these mice against death. Blockade of MIF in high genotypic MIF expressers may therefore offer a selective pharmacologic therapy for GPA.

Abstract Background Long-term mortality after primary THA is lower than in the general population, but it is unknown whether this is also true after revision THA. Questions/Purposes We examined (1) long-term mortality according to reasons for revision after revision THA, and (2) relative mortality trends by age at surgery, years since surgery, and calendar year of surgery. Methods This retrospective study included 5417 revision THAs performed in 4532 patients at a tertiary center between 1969 and 2011. Revision THAs were grouped by surgical indication in three categories: periprosthetic joint infections (938; 17%); fractures (646; 12%); and loosening, bearing wear, or dislocation (3833; 71%). Patients were followed up until death or December 31, 2016. The observed number of deaths in the revision THA cohort was compared with the expected number of deaths using standardized mortality ratios (SMRs) and Poisson regression models. The expected number of deaths was calculated assuming that the study cohort had the same calendar year, age, and sex-specific mortality rates as the United States general population. Results The overall age- and sex-adjusted mortality was slightly higher than the general population mortality (SMR, 1.09; 95% CI, 1.05-1.13; p < 0.001). There were significant differences across the three surgical indication subgroups. Compared with the general population mortality, patients who underwent revision THA for infection (SMR, 1.35; 95% CI, 1.24-1.48; p < 0.001) and fractures (SMR, 1.23; 95% CI, 1.11-1.37; p < 0.001) had significantly increased risk of death. Patients who underwent revision THA for aseptic loosening, wear, or dislocation had a mortality risk similar to that of the general population (SMR, 1.01; 95% CI, 0.96-1.06; p = 0.647). The relative mortality risk was highest in younger patients and declined with increasing age at surgery. Although the relative mortality risk among patients with aseptic indications was lower than that of the general population during the first year of surgery, the risk increased with time and got worse than that of the general population after approximately 8 to 10 years after surgery. Relative mortality risk improved with time after revision THA for aseptic loosening, wear, or dislocation. Conclusions Shifting mortality patterns several years after surgery and the excess mortality after revision THA for periprosthetic joint infections and fractures reinforce the need for long-term followup, not only for implant survival but overall health of patients having THA. Level of Evidence Level III, therapeutic study