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Symptomatic knee osteoarthritis (SKOA) is a chronic, disabling condition, requiring long-term pain management; over 800,000 SKOA patients in the US use opioids on a prolonged basis. We aimed to characterize the societal economic burden of opioid use in this population.We used the Osteoarthritis Policy Model, a validated computer simulation of SKOA, to estimate the opioid-related lifetime and annual cost generated by the US SKOA population. We included direct medical, lost productivity, criminal justice, and diversion costs. We modeled the SKOA cohort with a mean ± SD age of 54 ± 14 years and Western Ontario and McMaster Universities Osteoarthritis Index pain score of 29 ± 17 (0-100, 100 = worst). We estimated annual costs of strong ($1,381) and weak ($671) opioid regimens using Medicare fee schedules, Red Book, the Federal Supply Schedule, and published literature. The annual lost productivity and criminal justice costs of opioid use disorder (OUD), obtained from published literature, were $11,387 and $4,264, per-person, respectively. The 2015-2016 Medicare Current Beneficiary Survey provided OUD prevalence. We conducted sensitivity analyses to examine the robustness of our estimates to uncertainty in input parameters.Assuming 5.1% prevalence of prolonged strong opioid use, the total lifetime opioid-related cost generated by the US SKOA population was estimated at $14.0 billion, of which only $7.45 billion (53%) were direct medical costs.Lost productivity, diversion, and criminal justice costs comprise approximately half of opioid-related costs generated by the US SKOA population. Reducing prolonged opioid use may lead to a meaningful reduction in societal costs that can be used for other public health causes.

OBJECTIVE: Establish the impact of pain severity on the cost-effectiveness of generic duloxetine for knee osteoarthritis (OA) in the United States. DESIGN: We used a validated computer simulation of knee OA to compare usual care (UC) – intra-articular injections, opioids, and total knee replacement (TKR) - to UC preceded by duloxetine in those no longer achieving pain relief from non-steroidal anti-inflammatory drugs (NSAIDs). Outcomes included quality-adjusted life years (QALYs), lifetime medical costs, and incremental cost-effectiveness ratios (ICERs). We considered cohorts with mean ages 57–75 years and Western Ontario and McMaster Osteoarthritis Index (WOMAC) pain 25–55 (0–100, 100-worst). We derived inputs from published data. We discounted costs and benefits 3% annually. We conducted sensitivity analyses of duloxetine efficacy, duration of pain relief, toxicity, and costs. RESULTS: Among younger subjects with severe pain (WOMAC pain=55), duloxetine led to an additional 9.6 QALYs per 1000 subjects (ICER=$88,500/QALY). The likelihood of duloxetine being cost-effective at willingness-to-pay (WTP) thresholds of $50,000/QALY and $100,000/QALY was 40% and 54%. Offering duloxetine to older patients with severe pain led to ICERs >$150,000/QALY. Offering duloxetine to subjects with moderate pain (pain=25) led to ICERs $88,500/QALY.

Objective Symptomatic knee osteoarthritis (OA) and meniscal tear are often treated with weight-bearing exercises and without ordering advanced imaging (e.g. MRI). This may lead to missed diagnoses of subchondral insufficiency fracture of the knee (SIFK). Failure to diagnose SIFK has treatment implications, as patients with SIFK are typically managed with a period of reduced weight-bearing. The primary objective of this study is to determine the prevalence of undiagnosed SIFK among persons treated non-operatively for knee pain and suspected meniscal tear(s). Methods The randomized controlled trial, TeMPO (Treatment of Meniscal Problems and Osteoarthritis), enrolls subjects whose clinicians suspect concomitant meniscal tear and knee OA. TeMPO participants undergo MRI ordered by the study to confirm meniscal tear. All study-ordered MRIs revealing a fracture were reviewed by two study radiologists who noted features of the fracture and joint. We report prevalence of SIFK and clinical and imaging features on these subjects with 95% confidence intervals. Results Ten of the 340 study-ordered MRIs had SIFK, resulting in an estimated prevalence of 2.94% (95% CI: 1.15%, 4.71%). Eight of the ten participants with SIFK had fractures located medially. The femur was involved in five of these participants, tibia in four, and both in one. Five of the ten participants did not have meniscal tears. Conclusions This is the only reported estimate of undiagnosed SIFK in adults with knee pain, to our knowledge. Approximately 3% of patients managed with weight-bearing exercise for suspected meniscal tear may have SIFK, a diagnosis typically treated with reduced weight-bearing approaches.

Summary The mammalian sex chromosomes harbor an abundance of newly acquired ampliconic genes, although their functions require elucidation [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. Here, we demonstrate that the X-linked Slx and Slxl1 ampliconic gene families represent mouse-specific neofunctionalized copies of a meiotic synaptonemal complex protein, Sycp3. In contrast to the meiotic role of Sycp3, CRISPR-loxP-mediated multi-megabase deletions of the Slx (5 Mb) and Slxl1 (2.3Mb) ampliconic regions result in post-meiotic defects, abnormal sperm, and male infertility. Males carrying Slxl1 deletions sire more male offspring, whereas males carrying Slx and Slxl1 duplications sire more female offspring, which directly correlates with Slxl1 gene dosage and gene expression levels. SLX and SLXL1 proteins interact with spindlin protein family members (SPIN1 and SSTY1/2) and males carrying Slxl1 deletions downregulate a sex chromatin modifier, Scml2, leading us to speculate that Slx and Slxl1 function in chromatin regulation. Our study demonstrates how newly acquired X-linked genes can rapidly evolve new and essential functions and how gene amplification can increase sex chromosome transmission.