Agreement of the American Academy of Orthopaedic Surgeons Appropriate Use Criteria With Treatment Recommendations From Arthroplasty Surgeons.

Background: The American Academy of Orthopaedic Surgeons (AAOS) Appropriate Use Criteria (AUC) for Surgical Management of Osteoarthritis of the Knee (2016) and Management of Osteoarthritis of the Hip (2017) are intended to provide treatment recommendations for osteoarthritis (OA). This study examined the agreement of AUC appropriateness classifications with arthroplasty surgeon recommendations for total knee arthroplasty (TKA) and total hip arthroplasty (THA). Methods: The cohort included 558 OA patients (397 knee, 161 hip) referred to a specialty arthroplasty clinic. Surgeons completed the online AAOS AUC patient profiles to generate appropriateness ratings. Surgeons' recommendations for treatment were recorded. We performed univariate and bivariate analyses to evaluate relationships between AUC appropriateness and surgeon recommendations. Results: The knee OA AUC classified TKA as "appropriate" for 309 (77.8%) of the 397 knee OA patients. Surgeons recommended TKA for 123 (31.0%), resulting in 46.8% (n = 186) higher rate of "appropriate" classification by AUC than TKA recommendation by surgeons. Weighted Cohen's κ demonstrated slight agreement (κ = 0.06, 95% confidence interval: 0.04, 0.09) between AUC appropriateness and surgeon TKA recommendation. The hip OA AUC classified THA as "appropriate" for 98 (60.9%) of the 161 hip OA patients. Surgeons recommended THA for 76 (47.2%), resulting in 13.7% (n = 22) higher rate of "appropriate" classification by AUC than THA recommendation by surgeons. Weighted Cohen's κ demonstrated moderate agreement (κ = 0.47, 95% confidence interval: 0.37, 0.57) between the AUC appropriateness classification and the surgeon's THA recommendation. Conclusions: AAOS AUC guidelines indicated surgical appropriateness significantly more than arthroplasty surgeons. AUC agreed slightly with surgeons for TKA and moderately for THA.

Sexual dimorphism of the synovial transcriptome underpins greater PTOA disease severity in male mice following joint injury.

OBJECTIVE: Osteoarthritis (OA) is a disease with sex-dependent prevalence and severity in both human and animal models. We sought to elucidate sex differences in synovitis, mechanical sensitization, structural damage, bone remodeling, and the synovial transcriptome in the anterior cruciate ligament rupture (ACLR) mouse model of post-traumatic OA (PTOA). DESIGN: Male and female 12-week-old C57/BL6J mice were randomized to Sham or noninvasive ACLR with harvests at 7d or 28d post-ACLR (n = 9 per sex in each group - Sham, 7d ACLR, 28d ACLR). Knee hyperalgesia, mechanical allodynia, and intra-articular matrix metalloproteinase (MMP) activity (via intravital imaging) were measured longitudinally. Trabecular and subchondral bone (SCB) remodeling and osteophyte formation were assessed by µCT. Histological scoring of PTOA, synovitis, and anti-MMP13 immunostaining were performed. NaV1.8-Cre;tdTomato mice were used to document localization and sprouting of nociceptors. Bulk RNA-seq of synovium in Sham, 7d, and 28d post-ACLR, and contralateral joints (n = 6 per group per sex) assessed injury-induced and sex-dependent gene expression. RESULTS: Male mice exhibited more severe joint damage at 7d and 28d and more severe synovitis at 28d, accompanied by 19% greater MMP activity, 8% lower knee hyperalgesia threshold, and 43% lower hindpaw withdrawal threshold in injured limbs compared to female injured limbs. Females had injury-induced catabolic responses in trabecular and SCB, whereas males exhibited 133% greater normalized osteophyte volume relative to females and sclerotic remodeling of trabecular and SCB. NaV1.8+ nociceptor sprouting in SCB and medial synovium was induced by injury and comparable between sexes. RNA-seq of synovium demonstrated similar injury-induced transcriptomic programs between the sexes at 7d, but only female mice exhibited a transcriptomic signature indicative of synovial inflammatory resolution by 28d, whereas males had persistent pro-inflammatory, pro-fibrotic, pro-neurogenic, and pro-angiogenic gene expression. CONCLUSION: Male mice exhibited more severe overall joint damage and pain behavior after ACLR, which was associated with persistent activation of synovial inflammatory, fibrotic, and neuroangiogenic processes, implicating persistent synovitis in driving sex differences in murine PTOA.

Increased Variation in Esophageal Cancer Treatment and Geographic Healthcare Disparity in Michigan.

BACKGROUND: Regional variation in complex healthcare is shown to negatively impact health outcomes. We sought to characterize geographic variance in esophageal cancer operation in Michigan. STUDY DESIGN: Data for patients with locoregional esophageal cancer from the Michigan Cancer Surveillance Program from 2000 to 2013 was analyzed. We reviewed the incidence of esophageal cancer by county and region, and those with locoregional disease receiving an esophagectomy. Counties were aggregated into existing state-level "urban vs rural" designations, regions were aggregated using the Michigan Economic Recovery Council designations, and data was analyzed with ANOVA, F-test, and chi-square test. RESULTS: Of the 8,664 patients with locoregional disease, 2,370 (27.4%) were treated with operation. Men were significantly more likely to receive esophagectomy than women (p < 0.001). Likewise, White, insured, and rural patients were more likely than non-White (p < 0.001), non-insured (p = 0.004), and urban patients (p < 0.001), respectively. There were 8 regions and 83 counties, with 61 considered rural and 22 urban. Region 1 (Detroit metro area, southeast) comprises the largest urban and suburban populations; with 4 major hospital systems it was considered the baseline standard for access to care. Regions 2 (west; p = 0.011), 3 (southwest; p = 0.024), 4 (east central; p = 0.012), 6 (northern Lower Peninsula; p = 0.008), and 8 (Upper Peninsula; p < 0.001) all had statistically significant greater variance in annual rates of operation compared with region 1. Region 8 had the largest variance and was the most rural and furthest from region 1. The variance in operation rate between urban and rural differed significantly (p = 0.005). CONCLUSIONS: A significant increase in variation of care was found in rural vs urban counties, as well as in regions distant to larger hospital systems. Those of male sex, White race, rural residence, and those with health insurance were significantly more likely to receive operation.

Preoperative left shoulder elevation > 1 cm is predictive of severe postoperative shoulder imbalance in early onset idiopathic scoliosis patients treated with growth-friendly instrumentation.

PURPOSE: Prior research has demonstrated the influence of preoperative shoulder elevation (SE), proximal thoracic curve magnitude, and upper instrumented vertebra (UIV) on shoulder balance after PSF for AIS. Our purpose was to evaluate the impact of these factors on shoulder balance in early onset idiopathic scoliosis (EOIS) patients treated with growth-friendly instrumentation. METHODS: This was a multicenter retrospective review. Children with EOIS treated with dual TGR, MCGR, or VEPTR and minimum 2-year follow-up were identified. Demographics and radiographic/surgical data were collected. RESULTS: 145 patients met inclusion criteria: 74 had right SE (RSE), 49 left SE (LSE), and 22 even shoulders (EVEN) preoperatively. Mean follow-up was 5.3 years (range, 2.0-13.1 years). The LSE group had a larger pre-index mean main thoracic curve (p = 0.021) but no difference was observed between groups at the post-index or most recent timepoints. RSE patients with UIV of T2 were more likely to have balanced shoulders post-index than patients with UIV of T3 or T4 (p = 0.011). Pre-index radiographic shoulder height (RSH) was predictive of post-index shoulder imbalance ≥ 2 cm in the LSE group (p = 0.007). A ROC curve showed a cut-off of 1.0 cm for RSH. 0/16 LSE patients with pre-index RSH < 1.0 cm had post-index shoulder imbalance ≥ 2 cm compared to 8/28 (29%) patients with pre-index RSH > 1.0 cm (p = 0.006). CONCLUSION: Preoperative LSE > 1.0 cm is predictive of shoulder imbalance ≥ 2 cm after insertion of TGR, MCGR, or VEPTR in children with EOIS. In patients with preoperative RSE, UIV of T2 resulted in a higher likelihood of balanced shoulders postoperatively.

Relationship Between Socioeconomic Status and the Outcome of Lumbar Epidural Steroid Injections for Lumbar Radiculopathy.

OBJECTIVE: The aim of the study was to investigate the relationship between socioeconomic status and pain reduction from epidural steroid injections for lumbar radiculopathy. METHODS: The retrospective cohort consisted of patients undergoing epidural steroid injection for lumbar radiculopathy ( n = 544). Numeric Pain Rating Scale was measured at baseline and 2 wks after epidural steroid injection. Socioeconomic status was estimated using median family income in patients' ZIP code. Linear and mixed models examined demographic and clinical differences in pain before and after injection and whether family income moderated the effect. RESULTS: Majority of patients were White (72.4%), female (56.4%), engaged in physical activity (68.2%), and underwent unilateral, transforaminal epidural steroid injection (86.0% and 92.1%, respectively). Non-White patients and those who did not engage in physical activity had higher baseline pain ( P < 0.05). Lower socioeconomic status was associated with higher baseline pain (ß = 0.06 per $10,000, P = 0.01). Patients with lower socioeconomic status experienced larger improvement in pain after epidural steroid injection: -1.56 units for patients in the 10th percentile of family income versus -0.81 for 90th percentile. Being a current smoker was associated with higher pain (ß = 0.76, P = 0.03) and engaging in structured physical activity with less pain (ß = -0.07 P < 0.01). CONCLUSIONS: Lower socioeconomic status was independently associated with higher pain alleviation after controlling for other potentially influential demographics. Modifiable lifestyle factors may be a target of potential intervention.

For Which Children with ADHD is TBR Neurofeedback Effective? Comorbidity as a Moderator.

We examined psychiatric comorbidities moderation of a 2-site double-blind randomized clinical trial of theta/beta-ratio (TBR) neurofeedback (NF) for attention deficit hyperactivity disorder (ADHD). Seven-to-ten-year-olds with ADHD received either NF (n = 84) or Control (n = 58) for 38 treatments. Outcome was change in parent-/teacher-rated inattention from baseline to end-of-treatment (acute effect), and 13-month-follow-up. Seventy percent had at least one comorbidity: oppositional defiant disorder (ODD) (50%), specific phobias (27%), generalized anxiety (23%), separation anxiety (16%). Comorbidities were grouped into anxiety alone (20%), ODD alone (23%), neither (30%), or both (27%). Comorbidity (p = 0.043) moderated acute effect; those with anxiety-alone responded better to Control than to TBR NF (d = - 0.79, CI - 1.55- - 0.04), and the other groups showed a slightly better response to TBR NF than to Control (d = 0.22 ~ 0.31, CI - 0.3-0.98). At 13-months, ODD-alone group responded better to NF than Control (d = 0.74, CI 0.05-1.43). TBR NF is not indicated for ADHD with comorbid anxiety but may benefit ADHD with ODD.Clinical Trials Identifier: NCT02251743, date of registration: 09/17/2014.

Synovial fibroblasts assume distinct functional identities and secrete R-spondin 2 in osteoarthritis.

OBJECTIVES: Synovium is acutely affected following joint trauma and contributes to post-traumatic osteoarthritis (PTOA) progression. Little is known about discrete cell types and molecular mechanisms in PTOA synovium. We aimed to describe synovial cell populations and their dynamics in PTOA, with a focus on fibroblasts. We also sought to define mechanisms of synovial Wnt/ß-catenin signalling, given its emerging importance in arthritis. METHODS: We subjected mice to non-invasive anterior cruciate ligament rupture as a model of human joint injury. We performed single-cell RNA-sequencing to assess synovial cell populations, subjected Wnt-GFP reporter mice to joint injury to study Wnt-active cells, and performed intra-articular injections of the Wnt agonist R-spondin 2 (Rspo2) to assess whether gain of function induced pathologies characteristic of PTOA. Lastly, we used cultured fibroblasts, macrophages and chondrocytes to study how Rspo2 orchestrates crosstalk between joint cell types. RESULTS: We uncovered seven distinct functional subsets of synovial fibroblasts in healthy and injured synovium, and defined their temporal dynamics in early and established PTOA. Wnt/ß-catenin signalling was overactive in PTOA synovium, and Rspo2 was strongly induced after injury and secreted exclusively by Prg4hi lining fibroblasts. Trajectory analyses predicted that Prg4hi lining fibroblasts arise from a pool of Dpp4+ mesenchymal progenitors in synovium, with SOX5 identified as a potential regulator of this emergence. We also showed that Rspo2 orchestrated pathological crosstalk between synovial fibroblasts, macrophages and chondrocytes. CONCLUSIONS: Synovial fibroblasts assume distinct functional identities during PTOA in mice, and Prg4hi lining fibroblasts secrete Rspo2 that may drive pathological joint crosstalk after injury.

Acute Physiological Effects of Continuous Versus Intermittent Walking During Golf in Individuals With Knee Osteoarthritis: A Pilot Study.

OBJECTIVE: The aim of the study was to compare the acute effects of walking the golf course versus using a golf cart during a round of golf on biological markers of joint disease, joint pain, and cardiovascular parameters in individuals with knee osteoarthritis. METHODS: Participants with knee OA (n = 10) older than 50 yrs were recruited for this crossover designed study in which they completed two 18-hole rounds of golf: (1) walking the course and (2) using a golf cart. Five control participants (n = 5) performed the walking condition only. Step count, heart rate, rating of perceived exertion and pain using the Numeric Pain Rating Scale were measured during the round. Serum was collected at baseline, 9th hole (halfway), and 18th hole (completion) and tested for biomarkers associated with tissue turnover (cartilage oligomeric matrix protein), inflammation (tumor necrosis factor α, interleukin 1ß, interleukin 6), and degradative enzyme production (matrix metalloproteinase 3, matrix metalloproteinase 13). RESULTS: In knee OA participants, walking the course was associated with significantly higher step count and duration of moderate/vigorous physical activity (72.2% vs. 32.6% of the round) but did lead to a significant increase in knee joint pain (P < 0.05). Both conditions caused cartilage oligomeric matrix protein and matrix metalloproteinase 13 concentration increases from baseline to completion (P < 0.05), but inflammatory markers (tumor necrosis factor α, interleukin 6, and interleukin 1ß, P < 0.05) only increased when walking the course. Biomarker concentrations did not increase in control participants. CONCLUSIONS: Walking the course optimizes the duration of moderate/vigorous activity during a round of golf, but the golf cart is a beneficial option in those with exacerbated joint pain and inflammation that would otherwise limit participation.

Pregnancy in Orthopaedic Residents: Peripartum Barriers Identified.

While there are multiple barriers that may discourage women from choosing a career in orthopaedic surgery, one area of concern is pursuing pregnancy during residency training. This study's primary purpose was to determine the most prominent barriers to pursuing pregnancy during orthopaedic surgery residency. Methods: A 63-item survey designed to evaluate multiple aspects of childbearing during orthopaedic surgery residency was distributed through email and a targeted Facebook platform to female orthopaedic surgeons and orthopaedic trainees in the United States. Given the study design, statistics were largely descriptive in nature. Multivariate logistic regression was also used to determine independent factors associated with professional dissatisfaction as it related to pregnancy during orthopaedic residency. Results: A total of 328 women responded to the survey. The 3 most prominent barriers to pursuing pregnancy during orthopaedic residency were concerns about the ability to balance clinical and maternal duties (67%), fear of how the resident would be viewed by those in the program (60%), and being unable to ensure optimal prenatal and postpartum care for the mother and child given an unpredictable schedule (38%). On univariate analysis of those who reported ≥1 pregnancy during residency (n = 71), maternity leave ≤6 weeks was statistically associated with "revisiting career choice" (p = 0.02) and "lack of resources and support" (p = 0.01). Conclusion: The results raise concern that qualified female applicants may be deterred from the field of orthopaedics given perceived difficulties associated with pregnancy as a resident. If policies are created to support women who desire to have children during residency, more women may be encouraged to pursue a career in orthopaedic surgery. Level of Evidence: V.

Results-Based Financing for Health: A Case Study of Knowledge and Perceptions Among Stakeholders in a Donor-Funded Program in Zambia.

In 2015, the Zambian government and the Swedish International Development Cooperation Agency (Sida) signed an agreement in which Sida committed to funding a program for Reproductive, Maternal, Newborn, Child, Adolescent Health and Nutrition (RMNCAH). The program includes a results-based financing (RBF) model that aims to reward Zambian districts for improved district-wide results on relevant indicators with additional funding. We aimed to describe stakeholders' knowledge of the RBF model and perceptions of the incentive structure during the first 18 months of the program's implementation. This study illuminates the possible pitfalls of implementing an RBF scheme without giving attention to all necessary steps of the process. A qualitative case study was used and included a review of documents, in-depth interviews, and observations. From February-April 2017, we conducted 37 in-depth interviews, representing the views of 12 development partner agencies, government departments, and health facility staff throughout Zambia. We used a qualitative framework analysis. Findings show that the Zambian government and Sida had different perceptions on what levels of the health system RBF will incentivize and that most districts and hospital administrators interviewed were unaware of the indicators that the RBF was part of the RMNCAH program at all. The lack of knowledge about the RBF scheme among respondents suggests the possibility that the model did not ultimately have the necessary preconditions to create an effective incentive structure. These results demonstrate the need for improved communication between stakeholders and the importance of sufficiently planning an RBF model before implementation.

Vitamin D levels in children with attention deficit hyperactivity disorder: Association with seasonal and geographical variation, supplementation, inattention severity, and theta:beta ratio.

We examined seasonal and geographic effects on vitamin D [25(OH)D] levels, association with attention-deficit/hyperactivity disorder (ADHD) symptom severity, and effects of supplementation in 222 children age 7-10 with rigorously diagnosed ADHD. 25(OH)D insufficiency rates were 47.2 % in Ohio and 28.5 % 400 miles south in North Carolina. Nadir of 25(OH)D levels was reached by November in Ohio, not until January in NC. Thirty-eight children with insufficiency/deficiency took vitamin D (1000-2000 IU/day for a month); levels rose 52 %. Although inattention did not correlate with 25(OH)D at screen nor improve significantly with supplementation, inattention improvement after supplementation correlated with 25(OH)D increase (rho = 0.41, p = 0.012). A clinically significant proportion of children with ADHD have insufficient 25(OH)D even at summer's end, more so in the winter and north of the 37th parallel. The significant correlation of inattention improvement with 25(OH)D increase suggests further research on 25(OH)D as ADHD treatment.

The direct and indirect costs among U.S. privately insured employees with hypogonadism.

INTRODUCTION: While previous studies have noted that hypogonadism (HG) may pose a significant economic and quality-of-life burden, no studies have evaluated the impact of HG on healthcare utilization and costs in the United States. AIM: Compare direct (health care) and indirect (disability leave or medical absence) costs between privately insured U.S. employees with HG and controls without HG. METHODS: The study sample included 4,269 male employees, ages 35-64, with ≥ 2 HG diagnoses (International Classification of Diseases, Ninth Revision, Clinical Modification: 257.2x) or ≥ 1 HG diagnosis and ≥ 1 claim for testosterone therapy, 1/1/2005-3/31/2009, identified from a large, private insurance administrative database that includes medical, prescription drug, and disability claims data. The index date was the most recent HG diagnosis that had continuous eligibility for at least 1 year before (baseline period) and 1 year after (study period). Employees with HG were matched 1:1 on age, region, salaried vs. nonsalaried employment status, and index year to controls without HG. MAIN OUTCOME MEASURES: Descriptive analyses compared demographic characteristics, comorbidities, resource utilization, direct and indirect costs inflated to USD 2009. Multivariate analyses adjusting for baseline characteristics were used to estimate risk-adjusted costs. RESULTS: HG employees and controls had a mean age of 51 years. HG employees compared with controls had higher baseline comorbidity rates, including hyperlipidemia (50.2% vs. 25.3%), hypertension (37.7% vs. 21.1%), back/neck pain (32.0% vs. 15.7%), and human immunodeficiency virus/acquired immunodeficiency syndrome (7.1% vs. 0.3%) (all P < 0.0001). HG employees had higher mean study period direct ($10,914 vs. $3,823) and indirect costs ($3,204 vs. $1,450); HG-related direct costs were $832 (all P < 0.0001). Risk-adjusted direct ($9,291 vs. $5,248) and indirect ($2,729 vs. $1,840) costs were also higher for HG employees (all P < 0.0001). CONCLUSIONS: Employees with HG had higher comorbidity rates and costs compared with controls. Given the low HG-related costs, a primary driver of costs among HG patients appears to be their comorbidity burden.

Effect of asthma exacerbations on health care costs among asthmatic patients with moderate and severe persistent asthma.

BACKGROUND: Health care costs increase in patients with more severe asthma, but the effect of asthma exacerbations on costs among patients with more severe asthma has not been quantified. OBJECTIVE: This study compared direct health care costs between patients with moderate/severe persistent asthma with and without exacerbations. METHODS: Patients who had an asthma diagnosis (International Classification of Diseases-ninth revision-Clinical Modification code 493.x), were 12 to 64 years old, and were receiving controller therapy were identified from a large administrative claims database. Patients were categorized as having moderate/severe persistent asthma and were further evaluated for exacerbations during a 12-month exacerbation identification period. Patients with 1 or more exacerbations (asthma-related inpatient or emergency department visit or corticosteroid prescription) were matched to patients without exacerbations on demographic characteristics and asthma severity. Total and asthma-related health care costs during the 1-year study period after the exacerbation index date were calculated. RESULTS: Patients with exacerbations had significantly higher total health care costs ($9223 vs $5011, P < .0001) and asthma-related costs ($1740 vs $847, P < .0001). The cost differences remained significant after controlling for patient differences by using multivariate models. Patients with exacerbations (n = 3830) had higher rates of sinusitis, allergy-related diagnoses or medications, pneumonia, and mental disorders and higher average Charlson Comorbidity Index scores at baseline. Patients with exacerbations filled their prescriptions for controllers more often and had higher asthma-related drug costs. CONCLUSIONS: Patients with moderate/severe persistent asthma who had exacerbations had higher total and asthma-related health care costs than those without exacerbations. Moreover, controller medication use was higher in patients with exacerbations.

Impact of initiation timing of SSRI or SNRI on depressed adolescent healthcare utilization and costs.

BACKGROUND: Adolescents with newly diagnosed depression may not receive timely antidepressant therapy. Clinical and economic effects of early versus late treatment initiation are unclear. OBJECTIVE: To compare effects of early versus late initiation of second-generation (SSRI/SNRI) antidepressants on emergency room (ER) visits, hospitalizations and healthcare costs in adolescents with depression. METHODS: Patients aged 12-17 with a diagnosis of depression were identified in a claims database (1999-2007). Patients initiating antidepressants within 1 month of initial diagnosis were considered early initiators; patients initiating within 2-12 months were late initiators. Clinical resource use and healthcare costs were measured during the 6-month pre-index and 12-month post-index (study) periods and compared descriptively between groups. Logistic regression compared healthcare services utilization; a generalized linear model compared costs. All models were adjusted for baseline characteristics, including demographics, comorbidities, and healthcare services utilization. RESULTS: A total of 7344 adolescents met study criteria. 4415 (60%) initiated antidepressant treatment within 1 month of diagnosis. At baseline, early initiators had more all-cause inpatient visits (14 vs. 7%) and all-cause ER visits than late initiators (25 vs. 21%, both p<0.01). They had higher medical ($1434 vs. $1160) and total costs ($1565 vs. $1290) (both p<0.01). In the study period, late initiators had higher risk of ER visits (OR=1.13, p=0.03). They incurred higher medical costs ($5415 vs. $4061) and higher total healthcare costs ($6001 vs. $4907), but lower adjusted drug costs ($767 vs. $888) (all p<0.01). LIMITATIONS: Clinical data are scarce in the claims database, and the ability to observe disease severity and reasons for delayed treatment is limited. The definition of early and late initiation was based on empirical analysis, and no clear cutoff was identified beyond what was observed in the data. CONCLUSIONS: Adolescents who initiated SSRI/SNRI therapy earlier experienced lower risk of ER visits and had lower total costs compared to late initiators.

Chondrocyte response to growth factors is modulated by p38 mitogen-activated protein kinase inhibition.

Inhibitors of p38 mitogen-activated protein kinase (MAPK) diminish inflammatory arthritis in experimental animals. This may be effected by diminishing the production of inflammatory mediators, but this kinase is also part of the IL-1 signal pathway in articular chondrocytes. We determined the effect of p38 MAPK inhibition on proliferative and synthetic responses of lapine chondrocytes, cartilage, and synovial fibroblasts under basal and IL-1-activated conditions.Basal and growth factor-stimulated proliferation and proteoglycan synthesis were determined in primary cultures of rabbit articular chondrocytes, first-passage synovial fibroblasts, and cartilage organ cultures. Studies were performed with or without p38 MAPK inhibitors, in IL-1-activated and control cultures. Media nitric oxide and prostaglandin E2 were assayed.p38 MAPK inhibitors blunt chondrocyte and cartilage proteoglycan synthesis in response to transforming growth factor beta; responses to insulin-like growth factor 1 (IGF-1) and fetal calf serum (FCS) are unaffected. p38 MAPK inhibitors significantly reverse inhibition of cartilage organ culture proteoglycan synthesis by IL-1. p38 MAPK inhibition potentiated basal, IGF-1-stimulated and FCS-stimulated chondrocyte proliferation, and reversed IL-1 inhibition of IGF-1-stimulated and FCS-stimulated DNA synthesis. Decreases in nitric oxide but not prostaglandin E2 synthesis in IL-1-activated chondrocytes treated with p38 MAPK inhibitors are partly responsible for this restoration of response. Synovial fibroblast proliferation is minimally affected by p38 MAPK inhibition.p38 MAPK activity modulates chondrocyte proliferation under basal and IL-1-activated conditions. Inhibition of p38 MAPK enhances the ability of growth factors to overcome the inhibitory actions of IL-1 on proliferation, and thus could facilitate restoration and repair of diseased and damaged cartilage.