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Congress mandated the creation of a postmarket Active Risk Identification and Analysis (ARIA) system containing data on 100 million individuals for monitoring risks associated with drug and biologic products using data from disparate sources to complement the US Food and Drug Administration's (FDA's) existing postmarket capabilities. We report on the first 6 years of ARIA utilization in the Sentinel System (2016–2021). The FDA has used the ARIA system to evaluate 133 safety concerns; 54 of these evaluations have closed with regulatory determinations, whereas the rest remain in progress. If the ARIA system and the FDA's Adverse Event Reporting System are deemed insufficient to address a safety concern, then the FDA may issue a postmarket requirement to a product's manufacturer. One hundred ninety‐seven ARIA insufficiency determinations have been made. The most common situation for which ARIA was found to be insufficient is the evaluation of adverse pregnancy and fetal outcomes following in utero drug exposure, followed by neoplasms and death. ARIA was most likely to be sufficient for thromboembolic events, which have high positive predictive value in claims data alone and do not require supplemental clinical data. The lessons learned from this experience illustrate the continued challenges using administrative claims data, especially to define novel clinical outcomes. This analysis can help to identify where more granular clinical data are needed to fill gaps to improve the use of real‐world data for drug safety analyses and provide insights into what is needed to efficiently generate high‐quality real‐world evidence for efficacy. [ABSTRACT FROM AUTHOR]

Purpose: Develop and test a flexible, scalable tool using interrupted time series (ITS) analysis to assess the impact of Food and Drug Administration (FDA) regulatory actions on drug use. Methods: We applied the tool in the Sentinel Distributed Database to assess the impact of FDA's 2010 drug safety communications (DSC) concerning the safety of long‐acting beta2‐agonists (LABA) in adult asthma patients. We evaluated changes in LABA use by measuring the initiation of LABA alone and concomitant use of LABA and asthma controller medications (ACM) after the DSCs. The tool generated ITS graphs and used segmented regression to estimate baseline slope, level change, slope change, and absolute and relative changes at up to two user‐specified time point (s) after the intervention. We tested the tool and compared our results against prior analyses that used similar measures. Results: Initiation of LABA alone declined among asthma patients aged 18–45 years before FDA DSCs (−0.10% per quarter; 95%CI: −0.11% to −0.09%) and the downward trend continued after. Concomitant use of LABA and ACM was stable before FDA DSCs. After FDA DSCs, there was a small trend decrease of 0.006% per quarter (95% CI, −0.008% to −0.003%). We found similar results among those aged 46–64 years and patients with poorly‐controlled asthma. Our results were consistent with previous studies, confirming the performance of the new tool. Conclusions: We developed and tested a reusable ITS tool in real‐world databases formatted to the Sentinel Common Data Model that can assess the impact of regulatory actions on drug use. [ABSTRACT FROM AUTHOR]

Process yield has been a standard metric for measuring the capability and performance of manufacturing processes. Process capability index Spk, a concise unit-less gauge with yield-sensitive functionality, communicates succinctly the genuine process yield for normally distributed processes. However, in frequentist statistics, the exact sampling distribution of Spk's natural estimator is intractable. Various frequentist approaches have attempted to address its wide-scale accuracy in statistical inference. Among them, the approach of generalized confidence interval (GCI) has been demonstrated superiority. In this paper, we incorporate Markov chain Monte Carlo (MCMC) algorithms to introduce a Bayesian-type approach. Extensive simulations in comparison of accuracy and precision performances between the Spk's frequentist and Bayesian inferences are conducted. Concerning coverage rates and average interval widths of the inferential criteria, Spk's Bayesian MCMC credibility intervals perform better than frequentist GCIs in most cases, particularly, the cases with only a few samples of information acquired from the manufacturing process. [ABSTRACT FROM AUTHOR]

The US Sentinel System and the Canadian Network for Observational Drug Effect Studies (CNODES) are two medical product safety surveillance networks. Using Sentinel's preprogrammed, parameterizable analytic tools, we reproduced two protocol‐based studies conducted by CNODES to assess the risks of acute pancreatitis and heart failure (HF) associated with the use of incretin‐based drugs, compared with use of ≥ 2 oral hypoglycemic agents. Results from the replication new‐user cohort analyses aligned with those from the CNODES nested case‐control studies. The adjusted hazard ratios were 0.95 (0.81–1.12; vs. 1.03 (0.87–1.22) in CNODES) for acute pancreatitis and 0.91 (0.84–1.00; vs. 0.82 (0.67–1.00) in CNODES) for HF among patients without HF history. The CNODES's common protocol approach allows studies tailored to specific safety questions, whereas the Sentinel's common data model plus pretested program approach enables more rapid analysis. Despite these differences, it is possible to obtain comparable results using both approaches. [ABSTRACT FROM AUTHOR]

Purpose The CHA2DS2‐VaSc and HAS‐BLED risk scores are commonly used in the studies of oral anticoagulants (OACs). The best ways to map these scores to the International Classification of Diseases, 10th Revision, Clinical Modification (ICD‐10‐CM) codes is unclear, as is how they perform in various types of OAC users. We aimed to assess the distributions of CHA2DS2‐VaSc and HAS‐BLED scores and C‐statistics for outcome prediction in the ICD‐10‐CM era using different mapping strategies. Methods: We compared the distributions of CHA2DS2‐VaSc and HAS‐BLED scores from various mapping strategies in atrial fibrillation patients before, during, and after ICD‐10‐CM transition. We estimated the C‐statistics predicting the 90‐day risk of hospitalized stroke (for CHA2DS2‐VaSc) or hospitalized bleeding (for HAS‐BLED) in patients identified at least 6 months after the ICD‐10‐CM transition, overall and by anticoagulant type. Results: Forward‐backward mapping produced higher CHA2DS2‐VaSc and HAS‐BLED scores in the ICD‐10‐CM era compared to the ICD‐9‐CM era: the mean difference was 0.074 (95% confidence interval 0.064‐0.085) for CHA2DS2‐VaSc and 0.055 (0.048‐0.062) for HAS‐BLED. Both scores had higher C‐statistics in patients taking no OACs (0.697 [0.677‐0.717] for CHA2DS2‐VaSc; 0.719 [0.702‐0.737] for HAS‐BLED) or direct OACs (0.695 [0.654‐0.735] for CHA2DS2‐VaSc; 0.700 [0.673‐0.728] for HAS‐BLED) than those taking warfarin (0.655 [0.613‐0.697] for CHA2DS2‐VaSc; 0.663 [0.6320.695] for HAS‐BLED). Conclusions: Existing mapping strategies generally preserved the distributions of CHA2DS2‐VaSc and HAS‐BLED scores after ICD‐10‐CM transition. Both scores performed better in patients on no OACs or direct OACs than patients on warfarin. [ABSTRACT FROM AUTHOR]

The effect of treating comorbid depression to achieve optimal management of chronic obstructive pulmonary disease (COPD) has not yet empirically tested. We examined the association between antidepressant treatment and use of and adherence to COPD maintenance medications among patients with new-onset COPD and comorbid depression.Methods: Using 2006-2012 Medicare data, this retrospective cohort study identified patients with newly diagnosed COPD and new-onset major depression. Two exposures-antidepressant use (versus non-use) and adherence measured by proportion of days covered (PDC) (PDC ≥0.8 versus <0.8)-were assessed quarterly. We used marginal structural models to estimate the effects of prior antidepressant use and adherence on subsequent COPD maintenance inhaler use and adherence outcomes, accounting for time-varying confounders.Results: A total of 25 458 COPD-depression patients, 82% with antidepressant treatment, were followed for a median of 2.5 years. Nearly half (48%) used at least 1 COPD maintenance inhaler in any given quarter; among users, 3 in 5 (61%) had a PDC of <0.8. Compared to patients with no antidepressant treatment, those with antidepressant use were more likely to use (relative ratio [RR] = 1.15, 95% confidence interval [CI] = 1.12- 1.17) and adhere to (RR = 1.08, 95% = 1.03-1.14) their COPD maintenance inhalers. Patients who adhered to antidepressant treatment were more likely to use and adhere to COPD maintenance inhalers.Conclusion: Regularly treated depression may increase use of and adherence to necessary maintenance medications for COPD. Antidepressant treatment may be a key determinant to improving medication-taking behaviors among COPD patients comorbid with depression. [ABSTRACT FROM AUTHOR]

Background: Epidemiological study reporting is improving but is not transparent enough for easy evaluation or replication. One barrier is insufficient details about design elements in published studies. Methods: Using a previously conducted drug safety evaluation in claims as a test case, we investigated the impact of small changes in five key design elements on risk estimation. These elements are index day of incident exposure's determination of look‐back or follow‐up periods, exposure duration algorithms, heparin exposure exclusion, propensity score model variables, and Cox proportional hazard model stratification. We covaried these elements using a fractional factorial design, resulting in 24 risk estimates for one outcome. We repeated eight of these combinations for two additional outcomes. We measured design effects on cohort sizes, follow‐up time, and risk estimates. Results: Small changes in specifications of index day and exposure algorithm affected the risk estimation process the most. They affected cohort size on average by 8 to 10%, follow‐up time by up to 31%, and magnitude of log hazard ratios by up to 0.22. Other elements affected cohort before matching or risk estimate's precision but not its magnitude. Any change in design substantially altered the matched control‐group subjects in 1:1 matching. Conclusions: Exposure‐related design elements require attention from investigators initiating, evaluating, or wishing to replicate a study or from analysts standardizing definitions. The methods we developed, using factorial design and mapping design effect on causal estimation process, are applicable to planning of sensitivity analyses in similar studies. [ABSTRACT FROM AUTHOR]

Purpose: To replicate the well-established association between angiotensinconverting enzyme inhibitors versus beta blockers and angioedema in the International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) era. Methods: We conducted a retrospective, inception cohort study in a large insurance database formatted to the Sentinel Common Data Model. We defined study periods spanning the ICD-9-CM era only, ICD-10-CM era only, and ICD-9-CM and ICD-10-CM era and conducted simple-forward mapping (SFM), simple-backward mapping (SBM), and forward-backward mapping (FBM) referencing the General Equivalence Mappings to translate the outcome (angioedema) and covariates from ICD-9-CM to ICD-10-CM. We performed propensity score (PS)-matched and PSstratified Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: In the ICD-9-CM and ICD-10-CM eras spanning April 1 to September 30 of 2015 and 2016, there were 152 017 and 145 232 angiotensin-converting enzyme inhibitor initiators and 115 073 and 116 652 beta-blocker initiators, respectively. The PS-matched HR was 4.19 (95% CI, 2.82-6.23) in the ICD-9-CM era, 4.37 (2.92-6.52) in the ICD-10-CM era using SFM, and 4.64 (3.05-7.07) in the ICD-10-CM era using SBM and FBM. The PS-matched HRs from the mixed ICD-9-CM and ICD-10-CM eras ranged from 3.91 (2.69-5.68) to 4.35 (3.33-5.70). Conclusion: The adjusted HRs across different diagnostic coding eras and the use of SFM versus SBM and FBM produced numerically different but clinically similar results. Additional investigations as ICD-10-CM data accumulate are warranted. [ABSTRACT FROM AUTHOR]

Purpose: To describe the consistency in the frequency of 5 health outcomes across the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and Tenth Revision, Clinical Modification (ICD-10-CM) eras in the US. Methods: We examined the incidence of 3 acute conditions (acute myocardial infarction [AMI], angioedema, ischemic stroke) and the prevalence of 2 chronic conditions (diabetes, hypertension) during the final 5 years of the ICD-9-CM era (January 2010-September 2015) and the first 15 months of the ICD-10-CM era (October 2015-December 2016) in 13 electronic health care databases in the Sentinel System. For each health outcome reviewed during the ICD-10-CM era, we evaluated 4 definitions, including published algorithms derived from other countries, as well as simple-forward, simple-backward, and forward-backward mapping using the General Equivalence Mappings. For acute conditions, we also compared the incidence between April to December 2014 and April to December 2016. Results: The analyses included data from approximately 172 million health plan members. While the incidence or prevalence of AMI and hypertension performed similarly across the 2 eras, the other 3 outcomes did not demonstrate consistent trends for some or all the ICD-10-CM definitions assessed. Conclusions: When using data from both the ICD-9-CM and ICD-10-CM eras, or when using results from ICD-10-CM data to compare to results from ICD-9-CM data, researchers should test multiple ICD-10-CM outcome definitions as part of sensitivity analysis. Ongoing assessment of the impact of ICD-10-CM transition on identification of health outcomes in US electronic health care databases should occur as more data accrue. [ABSTRACT FROM AUTHOR]

Objective: This study examined the latent constructs of delirium symptoms among nursing home (NH) residents in the United States. Method: Cross-sectional NH assessment data (Minimum Data Set 2.0) from the 2009 Medicare Current Beneficiary Survey were used. Data from two independent, randomly selected subsamples of residents ≥65 years were analyzed using exploratory factor analysis (EFA) and confirmatory factor analysis (CFA). Results: There were 367 and 366 individuals in the EFA and CFA, respectively. Assessment of multiple model fit statistics in CFA indicated that the two-factor structure provided better fit for the data than a one-factor solution. The two factors represented cognitive and behavioral latent constructs as suggested by the related literature. A correlation of .72 between these constructs suggested moderate discriminant validity. Conclusion: This finding emphasizes the importance of health care providers to be attentive to both cognitive and behavioral symptoms when diagnosing, treating, and managing delirium. [ABSTRACT FROM AUTHOR]

Rationale: Among individuals with chronic obstructive pulmonary disease (COPD), depression is one of the most common yet underrecognized and undertreated comorbidities. Although depression has been associated with reduced adherence to maintenance medications used in other conditions, such as diabetes, little research has assessed the role of depression in COPD medication use and adherence.Objectives: The objective of this study was to assess the impact of depression on COPD maintenance medication adherence among a nationally representative sample of Medicare beneficiaries newly diagnosed with COPD.Methods: We used a 5% random sample of Medicare administrative claims data to identify beneficiaries diagnosed with COPD between 2006 and 2010. We included beneficiaries with 2 years of continuous Medicare Parts A, B, and D coverage and at least two prescription fills for COPD maintenance medications after COPD diagnosis. We searched for prescription fills for inhaled corticosteroids, long-acting β-agonists, and long-acting anticholinergics and calculated adherence starting at the first fill. We modeled adherence to COPD maintenance medications as a function of new episodes of depression, using generalized estimated equations.Measurements and Main Results: Our primary outcome was adherence to COPD maintenance medications, measured as proportion of days covered. The exposure measure was depression. Both COPD and depression were assessed using diagnostic codes in Part A and B data. Covariates included sociodemographics, as well as clinical markers, including comorbidities, COPD severity, and depression severity. Of 31,033 beneficiaries meeting inclusion criteria, 6,227 (20%) were diagnosed with depression after COPD diagnosis. Average monthly adherence to COPD maintenance medications was low, peaking at 57% in the month after first fill and decreasing to 35% within 6 months. In our adjusted regression model, depression was associated with decreased adherence to COPD maintenance medications (odds ratio, 0.93; 95% confidence interval, 0.89-0.98).Conclusions: New episodes of depression decreased adherence to maintenance medications used to manage COPD among older adults. Clinicians who treat older adults with COPD should be aware of the development of depression, especially during the first 6 months after COPD diagnosis, and monitor patients' adherence to prescribed COPD medications to ensure best clinical outcomes. [ABSTRACT FROM AUTHOR]

Objectives: Depression is a common comorbidity of chronic obstructive pulmonary disease (COPD) and is associated with increased exacerbations, healthcare utilization, and mortality. Among Medicare beneficiaries newly diagnosed with COPD, the objectives of this study were to (1) estimate the rate of new episodes of depression and (2) identify factors associated with depression.Methods: We identified beneficiaries with a first diagnosis of COPD during 2006-2012 using a 5% random sample of Medicare administrative claims data by searching for ICD-9-CM codes 490, 491.x, 492.x, 494.x, or 496. We identified episodes of depression using ICD-9-CM codes 296.2x, 296.3x, and 311.xx. We calculated incidence rates and their 95% confidence intervals (95% CI) and used a discrete time analysis to identify factors associated with development of depression.Results: Between 2006 and 2012, 125,348 beneficiaries meeting inclusion criteria were newly diagnosed with COPD. Twenty-three percent developed depression following COPD diagnosis. The annualized incidence rate of depression per 100 beneficiaries following COPD diagnosis was 9.4 (95% CI 9.3, 9.5). Rates were highest in the first 2 months following COPD diagnosis. COPD diagnosis was associated with increased risk of depression (risk ratio 1.76; 95% CI 1.73, 1.79) as were COPD-related hospitalizations (risk ratio 4.59; 95% CI 4.09, 5.15), a measure of COPD severity.Conclusions: Diagnosis of COPD increases the risk of depression. This study will aid in the allocation of resources to monitor and provide support for individuals with COPD at high risk of developing depression. [ABSTRACT FROM AUTHOR]

Porphyromonas gingivalis is a major pathogen in the initiation and progression of periodontal disease, which is recognized as a common complication of diabetes. ICAM-1 expression by human gingival fibroblasts ( HGFs) is crucial for regulating local inflammatory responses in inflamed periodontal tissues. However, the effect of P. gingivalis in a high-glucose situation in regulating HGF function is not understood. The P. gingivalis strain CCUG25226 was used to study the mechanisms underlying the modulation of HGF ICAM-1 expression by invasion of high-glucose-treated P. gingivalis ( HGPg). A high-glucose condition upregulated fimA mRNA expression in P. gingivalis and increased its invasion ability in HGFs. HGF invasion with HGPg induced increases in the expression of ICAM-1. By using specific inhibitors and short hairpin RNA ( shRNA), we have demonstrated that the activation of p38 MAPK and Akt pathways is critical for HGPg-induced ICAM-1 expression. Luciferase reporters and chromatin immunoprecipitation assays suggest that HGPg invasion increases NF-κ B- and Sp1- DNA-binding activities in HGFs. Inhibition of NF-κ B and Sp1 activations blocked the HGPg-induced ICAM-1 promoter activity and expression. The effect of HGPg on HGF signalling and ICAM-1 expression is mediated by CXC chemokine receptor 4 ( CXCR4). Our findings identify the molecular pathways underlying HGPg-dependent ICAM-1 expression in HGFs, providing insight into the effect of P. gingivalis invasion in HGFs. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to assess data relevancy and data quality of the Innovation in Medical Evidence Development and Surveillance System Distributed Database (IMEDS-DD) for diabetes research and to evaluate comparability of its type 2 diabetes cohort to the general type 2 diabetes population., Research Design and Methods: A retrospective study was conducted using the IMEDS-DD. Eligible members were adults with a medical encounter between April 1, 2018 and March 31, 2019 (index period). Type 2 diabetes and co-existing conditions were determined using all data available from April 1, 2016 to the most recent encounter within the index period. Type 2 diabetes patient characteristics, comorbidities and hemoglobin A 1c (HbA 1c ) values were summarized and compared with those reported in national benchmarks and literature., Results: Type 2 diabetes prevalence was 12.6% in the IMEDS-DD. Of 4 14 672 patients with type 2 diabetes, 52.8% were male, and the mean age was 65.0 (SD 13.3) years. Common comorbidities included hypertension (84.5%), hyperlipidemia (82.8%), obesity (45.3%), and cardiovascular disease (44.7%). Moderate-to-severe chronic kidney disease was observed in 20.2% patients. The most commonly used antihyperglycemic agents included metformin (35.7%), sulfonylureas (14.8%), and insulin (9.9%). Less than one-half (48.9%) had an HbA 1c value recorded. These findings demonstrated the notable similarity in patient characteristics between type 2 diabetes populations identified within the IMEDS-DD and other large databases., Conclusions: Despite the limitations related to HbA 1c data, our findings indicate that the IMEDS-DD contains robust information on key data elements to conduct pharmacoepidemiological studies in diabetes, including member demographic and clinical characteristics and health services utilization., Competing Interests: Competing interests: TW and SRC are employees of Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc, Rahway, New Jersey, USA, who may own stock and/or stock options in Merck & Co, Inc, Rahway, New Jersey, USA., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: The CHA 2 DS 2 -VaSc and HAS-BLED risk scores are commonly used in the studies of oral anticoagulants (OACs). The best ways to map these scores to the International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) codes is unclear, as is how they perform in various types of OAC users. We aimed to assess the distributions of CHA 2 DS 2 -VaSc and HAS-BLED scores and C-statistics for outcome prediction in the ICD-10-CM era using different mapping strategies., Methods: We compared the distributions of CHA 2 DS 2 -VaSc and HAS-BLED scores from various mapping strategies in atrial fibrillation patients before, during, and after ICD-10-CM transition. We estimated the C-statistics predicting the 90-day risk of hospitalized stroke (for CHA 2 DS 2 -VaSc) or hospitalized bleeding (for HAS-BLED) in patients identified at least 6 months after the ICD-10-CM transition, overall and by anticoagulant type., Results: Forward-backward mapping produced higher CHA 2 DS 2 -VaSc and HAS-BLED scores in the ICD-10-CM era compared to the ICD-9-CM era: the mean difference was 0.074 (95% confidence interval 0.064-0.085) for CHA 2 DS 2 -VaSc and 0.055 (0.048-0.062) for HAS-BLED. Both scores had higher C-statistics in patients taking no OACs (0.697 [0.677-0.717] for CHA 2 DS 2 -VaSc; 0.719 [0.702-0.737] for HAS-BLED) or direct OACs (0.695 [0.654-0.735] for CHA 2 DS 2 -VaSc; 0.700 [0.673-0.728] for HAS-BLED) than those taking warfarin (0.655 [0.613-0.697] for CHA 2 DS 2 -VaSc; 0.663 [0.6320.695] for HAS-BLED)., Conclusions: Existing mapping strategies generally preserved the distributions of CHA 2 DS 2 -VaSc and HAS-BLED scores after ICD-10-CM transition. Both scores performed better in patients on no OACs or direct OACs than patients on warfarin., (© 2020 John Wiley & Sons Ltd.)

Objective: To evaluate stroke risk among users of typical antipsychotics compared to users of atypical antipsychotics in a non-elderly and non-demented US population., Methods: New users of antipsychotics aged 18-64 years without dementia were identified via electronic health care data from 13 health plans participating in the Sentinel System from January 2001 to September 2015. The risk of hospitalized stroke events, identified via ICD-9-CM diagnostic criteria, was compared between typical and atypical antipsychotic users using 1:1 matching on propensity score. Adjusted hazard ratios (HRs) and 95% CIs during the entire follow-up period and during 1- to 15-day and 16- to 90-day risk windows were estimated. The risk associated with haloperidol use was estimated separately., Results: A total of 45,495 typical antipsychotic users were matched 1:1 to atypical antipsychotic users. While unmatched HRs suggest an increased stroke risk among typical antipsychotic users compared to atypical antipsychotic users, no increased risk was observed after matching during the entire follow-up period (HR = 0.87; 95% CI, 0.54-1.41), the 1- to 15-day risk window (HR = 1.16; 95% CI, 0.41-3.32), or the 16- to 90-day risk window (HR = 0.52; 95% CI, 0.20-1.36). The adjusted HR for haloperidol was 1.31 (95% CI, 0.54-3.21)., Conclusion: These findings were not suggestive of an increased stroke risk in typical antipsychotic users compared to atypical antipsychotic users in a non-elderly and non-demented population., (© Copyright 2019 Physicians Postgraduate Press, Inc.)

Introduction: Synovial macrophages, which can release proinflammatory factors, are responsible for the upregulation of cartilage-breakdown proteases and play critical roles in cartilage degradation during the progression of osteoarthritis (OA). In addition, shear stress exerts multifunctional effects on chondrocytes by inducing the synthesis of catabolic or anabolic genes. However, the interplay of macrophages, chondrocytes, and shear stress during the regulation of cartilage function remains poorly understood. We investigated the mechanisms underlying the modulation of human chondrocyte urokinase plasminogen activator (uPA) expression by macrophages and shear stress., Methods: Human chondrocytes were stimulated by peripheral blood-macrophage- conditioned medium (PB-MCM), or exposure of chondrocytes cultured in PB-MCM to different levels of shear stress (2 to 20 dyn/cm2). Real-time polymerase chain reaction was used to analyze uPA gene expression. Inhibitors and small interfering RNA were used to investigate the mechanism for the effects of PB-MCM and shear stress in chondrocytes., Results: Stimulation of human chondrocytes with PB-MCM was found to induce uPA expression. We demonstrated that activation of the JNK and Akt pathways and NF-κB are critical for PB-MCM-induced uPA expression. Blocking assays by using IL-1ra further demonstrated that IL-1β in PB-MCM is the major mediator of uPA expression in chondrocytes. PB-MCM-treated chondrocytes subjected to a lower level of shear stress showed inhibition of MCM-induced JNK and Akt phosphorylation, NF-κB activation, and uPA expression. The PB-MCM-induced uPA expression was suppressed by AMP-activated protein kinase (AMPK) agonist. The inhibitor or siRNA for AMPK abolished the shear-mediated inhibition of uPA expression., Conclusions: These data support the hypothesis that uPA upregulation stimulated by macrophages may play an active role in the onset of OA and in the shear-stress protection against this induction.

Prior studies have investigated patients' characteristics, treatments, and outcomes for older adults with myelodysplastic syndromes, but most failed to distinguish chronic myelomonocytic leukemia. Recognizing potentially important differences between the diseases, we undertook a population-based comparison of baseline characteristics, treatments, and outcomes between older adults with chronic myelomonocytic leukemia and myelodysplastic syndromes. The patients' data were obtained from Surveillance Epidemiology and End Results registry data from 2001-2005, linked to Medicare claims. Baseline characteristics, treatment (red blood cell transfusions, hematopoietic growth factors, hypomethylating agents, chemotherapy or transplantation), progression to acute myeloid leukemia, and overall survival were compared using bivariate techniques. Multivariate logistic regression estimated differences in treatments received. Cox proportional hazard models estimated the effects of chronic myelomonocytic leukemia relative to myelodysplastic syndromes on progression-free survival. A larger proportion of patients with chronic myelomonocytic leukemia (n=792), compared to patients with myelodysplastic syndromes (n=7,385), failed to receive any treatment (25% versus 15%; P<0.0001), or only received red blood cell transfusions (19.8% versus 16.7%; P=0.037). A larger percentage of patients with chronic myelomonocytic leukemia progressed to acute myeloid leukemia (42.6% versus 15.5%, respectively; P<0.0001), with shorter time to progression. Chronic myelomonocytic leukemia patients had a shorter median survival (13.3 versus 23.3 months; P<0.0001) and lower 3-year survival rate (19% versus 36%; P<0.0001). Adjusted estimates, controlling for baseline characteristics and selected treatments, indicate that chronic myelomonocytic leukemia was associated with an increased risk of progression to acute myeloid leukemia or death (HR 2.22; P<0.0001), compared to myelodysplastic syndromes. In conclusion, chronic myelomonocytic leukemia is less frequently treated in older adults and is associated with worse outcomes, even after controlling for the patients' baseline characteristics and selected treatments. Our data suggest the need for continued evaluation of the biological differences between these diseases and clinical trials targeting chronic myelomonocytic leukemia.