Practice Pattern Variation in Adoption of New and Evolving Percutaneous Coronary Intervention Procedures.

Objective: Assess factors contributing to variation in the use of new and evolving diagnostic and interventional procedures for percutaneous coronary intervention (PCI). Background: Evidence-based practices for PCI have the potential to improve outcomes but are variably adopted. Finding possible drivers of PCI procedure-use variability is key for efforts aimed at establishing more uniform practice. Methods: Veterans Affairs Clinical Assessment, Reporting, and Tracking Program data were used to estimate a proportion of variation attributable to hospital-, operator-, and patient-level factors across (a) radial arterial access, (b) intravascular imaging/optical coherence tomography, and (c) atherectomy for PCI. We used random-effects models with hospital, operator, and patient random effects. Overlap between levels generated cumulative variability estimates greater than 100%. Results: A total of 445 operators performed 95,391 PCI procedures across 73 hospitals from 2011 to 2018. The rates of all procedures increased over this time. 24.45% of variability in the use of radial access was attributable to the hospital, 53.04% to the operator, and 57.83% to patient-level characteristics. 9.06% of the variability in intravascular imaging use was attributable to the hospital, 43.92% to the operator, and 21.20% to the patient. Lastly, 20.16% of the variability in use of atherectomy was attributed to the hospital, 34.63% to the operator, and 57.50% to the patient. Conclusions: The use of radial access, intracoronary imaging, and atherectomy is influenced by patient, operator, and hospital factors, but patient and operator-level effects predominate. Efforts to increase the use of evidence-based practices for PCI should consider interventions at these levels.

A Scoping Review of the Use of Machine Learning in Health Economics and Outcomes Research: Part 1-Data From Wearable Devices.

OBJECTIVES: With the emerging use of machine learning (ML) techniques, there has been particular interest in using wearable data for health economics and outcomes research (HEOR). We aimed to understand the emerging patterns of how ML has been applied to wearable data in HEOR. METHODS: We identified studies published in PubMed between January 2016 and March 2021. Studies that included at least 1 HEOR-related Medical Subject Headings term, applied an ML, and used wearable data were eligible for inclusion. Two reviewers abstracted information including ML application types and data on which ML was applied and analyzed them using descriptive analyses. RESULTS: A total of 148 studies were identified from PubMed, among which 32 studies met the inclusion criteria. There has been an increase over time in the number of ML studies using wearable data. ML has been more frequently used for monitoring events in real time (78%) than to predict future events (22%). There has been a wide range of outcomes examined, ranging from general physical or mental health (24%) to more disease-specific outcomes (eg, disease incidence [19%] and progression [13%]) and treatment-related outcomes (eg, treatment adherence [9%] and outcomes [9%]). Data for ML models were more often derived from wearable devices with specific medical purposes (60%) than those without (40%). CONCLUSION: There has been a wide range of applications of ML to wearable data. Both medical and nonmedical wearable devices have been used as a data source, showing the potential for providing rich data for ML studies in HEOR.

Impact of treatment experience on patient knowledge of colony-stimulating factors among patients receiving cancer chemotherapy: evidence from S1415CD-a large pragmatic trial.

PURPOSE: Primary prophylactic granulocyte colony-stimulating factors (PP-CSFs) are prescribed alongside chemotherapy regimens that carry a significant risk of febrile neutropenia (FN). As part of S1415CD, a prospective, pragmatic trial evaluating the impact of automated orders to improve PP-CSF prescribing, we evaluated patients' baseline knowledge of PP-CSF and whether that knowledge improved following the first cycle of chemotherapy. METHODS: Adult patients with breast, colorectal, or non-small-cell lung cancer initiating chemotherapy were enrolled in S1415CD between January 2016 and April 2020. Eight questions assessing knowledge of CSF indications, risks, benefits, and out-of-pocket costs were included in a baseline survey and in a follow-up survey at the end of the first cycle of chemotherapy. Responses were stratified by the trial arm and whether chemotherapy was low, intermediate, or high FN risk. RESULTS: Of the 3605 eligible patients, 3580 (99.3%) completed the baseline survey, and 3420 (95.5%) completed the follow-up survey. At baseline, 803 (22.4%) patients responded "Don't know" to all 8 questions, and all patients averaged 2.75 correct questions. At follow-up, knowledge increased by 0.34 in the high-FN-risk group (p < 0.001) but declined for the other FN-risk groups. In multivariate analysis, receiving a high-FN-risk regimen and younger age were significantly associated with knowledge improvement. CONCLUSION: Chemotherapy patients had poor knowledge of PP-CSF that improved only modestly among recipients of high-FN-risk chemotherapy. Further efforts to inform patients about the risks, benefits, and costs of PP-CSF may be warranted, particularly for those in whom prophylaxis is indicated. TRIAL REGISTRATION: NCT02728596, April 6, 2016.

Community pharmacist intervention to close statin gaps in diabetes care: The GuIDE-S study.

BACKGROUND: Statin therapy is recommended for people with type 2 diabetes (T2D) to lower cardiovascular risk; however, evidence suggests that significant gaps in statin therapy exist. OBJECTIVE: To evaluate (1) the impact of a community pharmacist-led model for initiating statin therapy in people with type 2 diabetes (T2D) on statin initiation and (2) pharmacists' self-reported perceptions of the intervention feasibility and fidelity to the intervention. METHODS: This was a type 1 hybrid effectiveness-implementation study of 9 intervention and 18 control pharmacies within a community pharmacy chain. Pharmacy staff proactively identified patients with T2D not taking a statin and prescribed a statin via a collaborative practice agreement or facilitated acquisition of a prescription from the patient's preferred prescriber. The eligible population included patients aged 18-84 years with T2D, who had filled ≥60 days' supply of one, noninsulin, diabetes medication in a rolling 6-month period, and who had not filled a statin during the same period. A Cox proportional hazards model was used to compare time to statin initiation. Pharmacists at intervention pharmacies completed a survey at 6 and 12 months after implementation (March and August 2019, respectively) to assess intervention feasibility and fidelity. RESULTS: For the statin initiation analysis, 1670 intervention patients were matched to 3358 control patients. Overall, 26.3% (n=442) of intervention patients and 25.4% (n=854) of control patients initiated a statin within 12 months of their index date. There was no difference in statin initiation likelihood between intervention and control patients (hazard ratio: 1.00; 95% CI: 0.83, 1.21). Fifteen pharmacists completed the 6-month survey (33% response rate), and 12 completed the 12-month survey (26%). The intervention's feasibility score was 4.0 at 6 months and 4.2 at 12 months, indicating an increase in perceived feasibility. Fidelity decreased from 6 to 12 months. CONCLUSION: The community pharmacist-led intervention resulted in more patients initiating statin therapy as compared to usual care; however, the differences were not statistically significant. Pharmacists perceived the intervention to be feasible; however, fidelity decreased over time.

Community pharmacist intervention to optimize statin adherence in diabetes care: The GuIDE-S study.

BACKGROUND: Statin use in people with type 2 diabetes (T2D) reduces cardiovascular events, yet adherence remains suboptimal. OBJECTIVE: This study evaluated the impact of a community pharmacist intervention on statin adherence in new users with T2D. METHODS: As part of a quasi-experimental study, community pharmacy staff proactively identified adult patients with T2D who were not prescribed a statin. When appropriate, the pharmacist prescribed a statin via a collaborative practice agreement or facilitated acquisition of a prescription from another prescriber. Patients received individualized education and follow-up and monitoring for 1 year. Adherence was defined as the proportion of days covered (PDC) by a statin over 12 months. Linear and logistic regression were used to compare the effect of the intervention on continuous and a binary adherence threshold, defined as PDC ≥ 80%, respectively. RESULTS: Overall, 185 patients started statin therapy and were matched to 370 control patients for analysis. Adjusted average PDC was 3.1% higher in the intervention group (95% CI -0.037 to 0.098). Patients in the intervention group were 21.2% more likely to have PDC ≥ 80% (95% CI 0.828-1.774). CONCLUSION: The intervention resulted in higher statin adherence than usual care; however, the differences were not statistically significant.

A Framework for Using Real-World Data and Health Outcomes Modeling to Evaluate Machine Learning-Based Risk Prediction Models.

OBJECTIVES: We propose a framework of health outcomes modeling with dynamic decision making and real-world data (RWD) to evaluate the potential utility of novel risk prediction models in clinical practice. Lung transplant (LTx) referral decisions in cystic fibrosis offer a complex case study. METHODS: We used longitudinal RWD for a cohort of adults (n = 4247) from the Cystic Fibrosis Foundation Patient Registry to compare outcomes of an LTx referral policy based on machine learning (ML) mortality risk predictions to referral based on (1) forced expiratory volume in 1 second (FEV1) alone and (2) heterogenous usual care (UC). We then developed a patient-level simulation model to project number of patients referred for LTx and 5-year survival, accounting for transplant availability, organ allocation policy, and heterogenous treatment effects. RESULTS: Only 12% of patients (95% confidence interval 11%-13%) were referred for LTx over 5 years under UC, compared with 19% (18%-20%) under FEV1 and 20% (19%-22%) under ML. Of 309 patients who died before LTx referral under UC, 31% (27%-36%) would have been referred under FEV1 and 40% (35%-45%) would have been referred under ML. Given a fixed supply of organs, differences in referral time did not lead to significant differences in transplants, pretransplant or post-transplant deaths, or overall survival in 5 years. CONCLUSIONS: Health outcomes modeling with RWD may help to identify novel ML risk prediction models with high potential real-world clinical utility and rule out further investment in models that are unlikely to offer meaningful real-world benefits.

A Scoping Review of the Use of Machine Learning in Health Economics and Outcomes Research: Part 2-Data From Nonwearables.

OBJECTIVES: Despite the increasing interest in applying machine learning (ML) methods in health economics and outcomes research (HEOR), stakeholders face uncertainties in when and how ML can be used. We reviewed the recent applications of ML in HEOR. METHODS: We searched PubMed for studies published between January 2020 and March 2021 and randomly chose 20% of the identified studies for the sake of manageability. Studies that were in HEOR and applied an ML technique were included. Studies related to wearable devices were excluded. We abstracted information on the ML applications, data types, and ML methods and analyzed it using descriptive statistics. RESULTS: We retrieved 805 articles, of which 161 (20%) were randomly chosen. Ninety-two of the random sample met the eligibility criteria. We found that ML was primarily used for predicting future events (86%) rather than current events (14%). The most common response variables were clinical events or disease incidence (42%) and treatment outcomes (22%). ML was less used to predict economic outcomes such as health resource utilization (16%) or costs (3%). Although electronic medical records (35%) were frequently used for model development, claims data were used less frequently (9%). Tree-based methods (eg, random forests and boosting) were the most commonly used ML methods (31%). CONCLUSIONS: The use of ML techniques in HEOR is growing rapidly, but there remain opportunities to apply them to predict economic outcomes, especially using claims databases, which could inform the development of cost-effectiveness models.

Successes and challenges of implementing a cancer care delivery intervention in community oncology practices: lessons learned from SWOG S1415CD.

BACKGROUND: Cancer Care Delivery (CCD) research studies often require practice-level interventions that pose challenges in the clinical trial setting. The SWOG Cancer Research Network (SWOG) conducted S1415CD, one of the first pragmatic cluster-randomized CCD trials to be implemented through the National Cancer Institute (NCI) Community Oncology Program (NCORP), to compare outcomes of primary prophylactic colony stimulating factor (PP-CSF) use for an intervention of automated PP-CSF standing orders to usual care. The introduction of new methods for study implementation created challenges and opportunities for learning that can inform the design and approach of future CCD interventions. METHODS: The order entry system intervention was administered at the site level; sites were affiliated NCORP practices that shared the same chemotherapy order system. 32 sites without existing guideline-based PP-CSF standing orders were randomized to the intervention (n = 24) or to usual care (n = 8). Sites assigned to the intervention participated in tailored training, phone calls and onboarding activities administered by research team staff and were provided with additional funding and external IT support to help them make protocol required changes to their order entry systems. RESULTS: The average length of time for intervention sites to complete reconfiguration of their order sets following randomization was 7.2 months. 14 of 24 of intervention sites met their individual patient recruitment target of 99 patients enrolled per site. CONCLUSIONS: In this paper we share seven recommendations based on lessons learned from implementation of the S1415CD intervention at NCORP community oncology practices representing diverse geographies and patient populations across the U. S. It is our hope these recommendations can be used to guide future implementation of CCD interventions in both research and community settings. TRIAL REGISTRATION: NCT02728596 , registered April 5, 2016.

Predictors of tyrosine kinase inhibitor adherence trajectories in patients with newly diagnosed chronic myeloid leukemia.

INTRODUCTION: Although consistent use of tyrosine kinase inhibitors (TKIs) confers significant improvements in long-term survival for individuals with chronic myeloid leukemia (CML), only 70% of CML patients are adherent to TKIs. Understanding the factors that contribute to non-adherence and establishing dynamic adherence patterns in this population are essential aspects of targeted drug monitoring and intervention strategies. METHODS: Newly diagnosed CML patients were identified in the MarketScan database and relevant covariate values extracted. Proportion of days covered (PDC) per 30-day interval was used to calculate adherence over a 12-month follow-up period. We conducted a latent profile analysis (LPA) on these PDC estimates to identify distinct, dynamic patterns of TKI adherence. Identified trajectories were grouped into four clinically relevant categories and predictors of membership in these categories were determined via multinomial logistic regression. RESULTS: Four broad adherence categories were identified from the LPA: never adherent, initially non-adherent becoming adherent, initially adherent becoming non-adherent, and stable adherent. Results from the subsequent multinomial logistic regression indicated that younger age, female sex, greater monthly financial burden, fewer comorbidities, fewer concomitant medications, year of diagnosis, higher starting dose, TKI type, and a longer duration from diagnosis to treatment were significantly associated with membership in at least one of the three non-stable adherent groups. CONCLUSION: Select sociodemographic and clinical characteristics were found to predict membership in clinically meaningful groups of longitudinal TKI adherence. These findings could have major implications for informing personalized monitoring and intervention strategies for individuals who are likely to be non-adherent.

Bias in Mean Survival From Fitting Cure Models With Limited Follow-Up.

OBJECTIVES: When populations contain mixtures of cured and uncured patients, the use of traditional parametric approaches to estimate overall survival (OS) can be biased. Mixture cure models may reduce bias compared with traditional parametric models, but their accuracy is subject to certain conditions. Importantly, mixture cure models assume that that there is enough follow-up to identify individuals censored at the end of the follow-up period as cured. The purpose of this article is to describe biases that can occur when mixture cure models are used to estimate mean survival from data with limited follow-up. METHODS: We analyzed 6 trials conducted by the SWOG Cancer Research Network Leukemia Committee. For each trial, we analyzed 2 data sets: the data released to the committee when the results of the trial were unblinded and a second data set with additional follow-up. We estimated mean OS using parametric survival models with and without a cure fraction. RESULTS: When using mixture cure models, in 4 trials, estimates of mean OS were higher with the first analysis (with limited follow-up) compared with estimates from data with longer follow-up. In 1 trial, the reverse pattern was observed. In 1 trial, the cure estimate changed little with additional follow-up. CONCLUSIONS: Caution should be taken when using mixture cure models in scenarios with limited follow-up. The biases resulting from fitting these models may be exacerbated when the models are being used to extrapolate OS and estimate mean OS.

Patterns of Surveillance Advanced Imaging and Serum Tumor Biomarker Testing Following Launch of the Choosing Wisely Initiative.

BACKGROUND: The purpose of this study was to assess advanced imaging (bone scan, CT, or PET/CT) and serum tumor biomarker use in asymptomatic breast cancer survivors during the surveillance period. PATIENTS AND METHODS: Cancer registry records for 2,923 women diagnosed with primary breast cancer in Washington State between January 1, 2007, and December 31, 2014, were linked with claims data from 2 regional commercial insurance plans. Clinical data including demographic and tumor characteristics were collected. Evaluation and management codes from claims data were used to determine advanced imaging and serum tumor biomarker testing during the peridiagnostic and surveillance phases of care. Multivariable logistic regression models were used to identify clinical factors and patterns of peridiagnostic imaging and biomarker testing associated with surveillance advanced imaging. RESULTS: Of 2,923 eligible women, 16.5% (n=480) underwent surveillance advanced imaging and 31.8% (n=930) received surveillance serum tumor biomarker testing. Compared with women diagnosed before the launch of the Choosing Wisely campaign in 2012, later diagnosis was associated with lower use of surveillance advanced imaging (odds ratio [OR], 0.68; 95% CI, 0.52-0.89). Factors significantly associated with use of surveillance advanced imaging included increasing disease stage (stage III: OR, 3.65; 95% CI, 2.48-5.38), peridiagnostic advanced imaging use (OR, 1.76; 95% CI, 1.33-2.31), and peridiagnostic serum tumor biomarker testing (OR, 1.35; 95% CI, 1.01-1.80). CONCLUSIONS: Although use of surveillance advanced imaging in asymptomatic breast cancer survivors has declined since the launch of the Choosing Wisely campaign, frequent use of surveillance serum tumor biomarker testing remains prevalent, representing a potential target for further efforts to reduce low-value practices.

Information Seeking and Satisfaction with Information Sources Among Spouses of Men with Newly Diagnosed Local-Stage Prostate Cancer.

Information sources about prostate cancer treatment and outcomes are typically designed for patients. Little is known about the availability and utility of information for partners. The objectives of our study were to evaluate information sources used by partners to understand prostate cancer management options, their perceived usefulness, and the relationship between sources used and satisfaction with treatment experience. A longitudinal survey of female partners of men newly diagnosed with local-stage prostate cancer was conducted in three different geographic regions. Partners and associated patients were surveyed at baseline (after patient diagnosis but prior to receiving therapy) and at 12 months following diagnosis. Information sources included provider, literature, friends or family members, Internet websites, books, traditional media, and support groups. Utility of an information source was defined as whether the partner would recommend it to caregivers of other patients with local-stage prostate cancer. Our study cohort included 179 partner-patient pairs. At diagnosis, partners consulted an average of 4.6 information sources. Non-Hispanic white partners were more likely than others to use friends and family as an information source (OR = 2.44, 95% CI (1.04, 5.56)). More educated partners were less likely to use support groups (OR = 0.31, 95% CI (0.14, 0.71)). At 12-month follow-up, partners were less likely to recommend books (OR = 0.23, 95% CI (0.11, 0.49)) compared to baseline. Partners consulted a large number of information sources in researching treatment options for local-stage prostate cancer and the types of sources accessed varied by race/ethnicity and educational attainment. Additional resources to promote selection of high-quality non-provider information sources are warranted to enable partners to better aid patients in their treatment decision-making process.

Accounting for Cured Patients in Cost-Effectiveness Analysis.

BACKGROUND: Economic evaluations often measure an intervention effect with mean overall survival (OS). Emerging types of cancer treatments offer the possibility of being "cured" in that patients can become long-term survivors whose risk of death is the same as that of a disease-free person. Describing cured and noncured patients with one shared mean value may provide a biased assessment of a therapy with a cured proportion. OBJECTIVE: The purpose of this article is to explain how to incorporate the heterogeneity from cured patients into health economic evaluation. METHODS: We analyzed clinical trial data from patients with advanced melanoma treated with ipilimumab (Ipi; n = 137) versus glycoprotein 100 (gp100; n = 136) with statistical methodology for mixture cure models. Both cured and noncured patients were subject to background mortality not related to cancer. RESULTS: When ignoring cured proportions, we found that patients treated with Ipi had an estimated mean OS that was 8 months longer than that of patients treated with gp100. Cure model analysis showed that the cured proportion drove this difference, with 21% cured on Ipi versus 6% cured on gp100. The mean OS among the noncured cohort patients was 10 and 9 months with Ipi and gp100, respectively. The mean OS among cured patients was 26 years on both arms. When ignoring cured proportions, we found that the incremental cost-effectiveness ratio (ICER) when comparing Ipi with gp100 was $324,000/quality-adjusted life-year (QALY) (95% confidence interval $254,000-$600,000). With a mixture cure model, the ICER when comparing Ipi with gp100 was $113,000/QALY (95% confidence interval $101,000-$154,000). CONCLUSIONS: This analysis supports using cure modeling in health economic evaluation in advanced melanoma. When a proportion of patients may be long-term survivors, using cure models may reduce bias in OS estimates and provide more accurate estimates of health economic measures, including QALYs and ICERs.

Is cure for chronic myeloid leukemia possible in the tyrosine kinase inhibitors era?

PURPOSE OF REVIEW: The advent of tyrosine kinase inhibitors (TKI) has remarkably changed the treatment of chronic myeloid leukemia (CML). Patients treated in chronic phase can enjoy an expected survival similar to the general population. In the last few years we have found that some patients with an excellent therapeutic response can have their TKI discontinued and still remain in molecular remission. RECENT FINDINGS: The fact that some patients can apparently have their therapy discontinued, and stay in remission for more than 2 years, is surprising, as in-vitro work suggests the CML cell is dependent on BCR-ABL signaling and mathematical models predict that extinction of the CML stem cell reservoir will take decades of therapy. However, given that unopposed BCR-ABL causes progression and CML cells can have a rather long latency (e.g., Hiroshima survivors), it may be some time until we can be completely assured that discontinuation is without risk. SUMMARY: If we can safely discontinue TKI in some patients, it will have a profound effect on both the strategy and medical economics of CML therapy. A key future finding will be factor(s) that predict which patients can be discontinued without relapse, thus targeting only the patients where discontinuation will be successful.

The Clinical and Economic Impacts of Skeletal-Related Events Among Medicare Enrollees With Prostate Cancer Metastatic to Bone.

BACKGROUND: Approximately 40% of men diagnosed with metastatic prostate cancer experience one or more skeletal-related events (SREs), defined as a pathological fracture, spinal cord compression, or surgery or radiotherapy to the bone. Accurate assessment of their effect on survival, health care resource utilization (HCRU), and cost may elucidate the value of interventions to prevent SREs. MATERIALS AND METHODS: Men older than age 65 years with prostate cancer and bone metastasis diagnosed between 2004 and 2009 were identified from linked Surveillance Epidemiology and End Results-Medicare records. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk for death associated with SREs were calculated by using Cox regression. HCRU and costs (in 2013 U.S. dollars) were evaluated in a propensity score-matched cohort by using Poisson regression and Kaplan-Meier sample average estimators, respectively. RESULTS: Among 3,297 men with prostate cancer metastatic to bone, 40% experienced ≥1 SRE (median follow-up, 19 months). Compared with men who remained SRE-free, men with ≥1 SRE had a twofold higher risk for death (HR, 2.29; 95% CI, 2.09-2.51). Pathological fracture was associated with the highest risk for death (HR, 2.77; 95% CI, 2.38-3.23). Among men with ≥1 SRE, emergency department visits were twice as frequent (95% CI, 1.77-2.28) and hospitalizations were nearly four times as frequent (95% CI, 3.20-4.40). The attributable cost of ≥1 SRE was $21,191 (≥1 SRE: $72,454 [95% CI, $67,362-$76,958]; SRE-free: $51,263 [95% CI, $45,439-$56,100]). CONCLUSION: Among men with prostate cancer metastatic to bone, experiencing ≥1 SRE is associated with poorer survival, increased HCRU, and increased costs. These negative effects emphasize the importance of SRE prevention in this population.

Group B streptococcal infection of the choriodecidua induces dysfunction of the cytokeratin network in amniotic epithelium: a pathway to membrane weakening.

Early events leading to intrauterine infection remain poorly defined, but may hold the key to preventing preterm delivery. To determine molecular pathways within fetal membranes (chorioamnion) associated with early choriodecidual infection that may progress to preterm premature rupture of membranes (PPROM), we examined the effects of a Group B Streptococcus (GBS) choriodecidual infection on chorioamnion in a nonhuman primate model. Ten chronically catheterized pregnant monkeys (Macaca nemestrina) at 118-125 days gestation (term = 172 days) received choriodecidual inoculation of either GBS (n = 5) or saline (n = 5). Cesarean section was performed in the first week after GBS or saline inoculation. RNA extracted from chorioamnion (inoculation site) was profiled by microarray. Single gene, Gene Set, and Ingenuity Pathway Analysis results were validated using qRT-PCR (chorioamnion), Luminex (amniotic fluid, AF), immunohistochemistry, and transmission electron microscopy (TEM). Despite uterine quiescence in most cases, significant elevations of AF cytokines (TNF-α, IL-8, IL-1ß, IL-6) were detected in GBS versus controls (p<0.05). Choriodecidual infection resolved by the time of cesarean section in 3 of 5 cases and GBS was undetectable by culture and PCR in the AF. A total of 331 genes were differentially expressed (>2-fold change, p<0.05). Remarkably, GBS exposure was associated with significantly downregulated expression of multiple cytokeratin (CK) and other cytoskeletal genes critical for maintenance of tissue tensile strength. Immunofluorescence revealed highly significant changes in the CK network within amniocytes with dense CK aggregates and retraction from the cell periphery (all p = 0.006). In human pregnancies affected by PPROM, there was further evidence of CK network retraction with significantly shorter amniocyte foot processes (p = 0.002). These results suggest early choriodecidual infection results in decreased cellular membrane integrity and tensile strength via dysfunction of CK networks. Downregulation of CK expression and perturbations in the amniotic epithelial cell intermediate filament network occur after GBS choriodecidual infection, which may contribute to PPROM.

Uterine overdistention induces preterm labor mediated by inflammation: observations in pregnant women and nonhuman primates.

OBJECTIVE: Uterine overdistention is thought to induce preterm labor in women with twin and multiple pregnancies, but the pathophysiology remains unclear. We investigated for the first time the pathogenesis of preterm birth associated with rapid uterine distention in a pregnant nonhuman primate model. STUDY DESIGN: A nonhuman primate model of uterine overdistention was created using preterm chronically catheterized pregnant pigtail macaques (Macaca nemestrina) by inflation of intraamniotic balloons (N = 6), which were compared to saline controls (N = 5). Cesarean delivery was performed due to preterm labor or at experimental end. Microarray, quantitative reverse transcriptase polymerase chain reaction, Luminex (Austin, TX), and enzyme-linked immunosorbent assay were used to measure messenger RNA (mRNA) and/or protein levels from monkey (amniotic fluid, myometrium, maternal plasma) and human (amniocytes, amnion, myometrium) tissues. Statistical analysis employed analysis of covariance and Wilcoxon rank sum. Biomechanical forces were calculated using the law of Laplace. RESULTS: Preterm labor occurred in 3 of 6 animals after balloon inflation and correlated with greater balloon volume and uterine wall stress. Significant elevations of inflammatory cytokines and prostaglandins occurred following uterine overdistention in an "inflammatory pulse" that correlated with preterm labor (interleukin [IL]-1ß, tumor necrosis factor [TNF]-α, IL-6, IL-8, CCL2, prostaglandin E2, prostaglandin F2α, all P < .05). A similar inflammatory response was observed in amniocytes in vitro following mechanical stretch (IL1ß, IL6, and IL8 mRNA multiple time points, P < .05), in amnion of women with polyhydramnios (IL6 and TNF mRNA, P < .05) and in amnion (TNF-α) and myometrium of women with twins in early labor (IL6, IL8, CCL2, all P < .05). Genes differentially expressed in the nonhuman primate after balloon inflation and in women with polyhydramnios and twins are involved in tissue remodeling and muscle growth. CONCLUSION: Uterine overdistention by inflation of an intraamniotic balloon is associated with an inflammatory pulse that precedes and correlates with preterm labor. Our results indicate that inflammation is an early event after a mechanical stress on the uterus and leads to preterm labor when the stress is sufficiently great. Further, we find evidence of uterine tissue remodeling and muscle growth as a common, perhaps compensatory, response to uterine distension.

Survival and lifetime costs associated with first-line bevacizumab use in older patients with metastatic colorectal cancer.

INTRODUCTION: The objective of this study was to investigate clinical effectiveness and incremental lifetime costs associated with first-line bevacizumab in older patients with metastatic colorectal cancer (mCRC). METHODS: Patients diagnosed with mCRC in 2004-2007 were identified from the Surveillance, Epidemiology, and End Results-Medicare database and stratified by first-line treatment (no chemotherapy [CTx], CTx alone, CTx plus bevacizumab). The impact of first-line bevacizumab on survival was investigated using a propensity score adjusted multivariate Cox proportional hazards model. Mean lifetime costs for each cohort were calculated using Medicare claims for all services rendered between diagnosis and end of follow-up, adjusting for death and censoring. RESULTS: A total of 4,414 patients (mean age: 77.3 years) were identified, of whom 15% received first-line bevacizumab. Among first-line-treated patients, bevacizumab receipt was associated with improved overall survival (hazard ratio: 0.85 [95% confidence interval: 0.75-0.97]; p = .013), and this benefit was limited to patients who received >1 month of bevacizumab therapy. Median and mean survival were greatest in patients treated with CTx plus bevacizumab relative to CTx alone (CTx plus bevacizumab median 19.4 months [mean 28.0 months] vs. CTx alone median 15.1 months [mean 22.9 months]; p < .001), as were mean lifetime costs (mean per patient cost $143,284 vs. $111,280). Compared with CTx alone, CTx plus bevacizumab was associated with a 5.1-month increase in mean survival and a $32,004 increase in mean lifetime treatment costs, with an incremental cost of $75,303 per life-year gained. CONCLUSION: Bevacizumab use is associated with longer survival than CTx alone in older patients treated in real-world clinical settings, at an incremental cost of $75,303 per life-year gained.

Long-term survival in patients with severe acute respiratory distress syndrome and rescue therapies for refractory hypoxemia*.

OBJECTIVES: To describe long-term survival in patients with severe acute respiratory distress syndrome and assess differences in patient characteristics and outcomes among those who receive rescue therapies (prone position ventilation, inhaled nitric oxide, or inhaled epoprostenol) versus conventional treatment. DESIGN: Cohort study of patients with severe hypoxemia. SETTING: University-affiliated level 1 trauma center. PATIENTS: Patients diagnosed with severe acute respiratory distress syndrome within 72 hours of ICU admission between January 1, 2008, and December 31, 2011. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data were abstracted from the medical record and included demographic and clinical variables, hospital and ICU length of stay, discharge disposition, and hospital costs. Patient-level data were linked to the Washington State Death Registry. Kaplan-Meier methods and Cox's proportional hazards models were used to estimate survival and hazard ratios. Four hundred twenty-eight patients meeting study inclusion criteria were identified; 62 (14%) were initiated on a rescue therapy. PaO2/FIO2 ratios were comparable at admission between patients treated with a rescue therapy and those treated conventionally but were substantially lower by 72 hours in those who received rescue therapies (54 ± 17 vs 69 ± 17 mm Hg; p < 0.01). For the entire cohort, estimated survival probability at 3 years was 55% (95% CI, 51-61%). Among 280 hospital survivors (65%), 3-year survival was 85% (95% CI, 80-89%). The relative hazard of in-hospital mortality was 68% higher among patients who received rescue therapy compared with patients treated conventionally (95% CI, 8-162%; p = 0.02). For long-term survival, the hazard ratio of death following ICU admission was 1.56 (95% CI, 1.02-2.37; p = 0.04), comparing rescue versus conventional treatment. CONCLUSIONS: Despite high hospital mortality, severe acute respiratory distress syndrome patients surviving to hospital discharge have relatively good long-term survival. Worsening hypoxemia was associated with initiation of rescue therapy. Patients on rescue therapy had higher in-hospital mortality; however, survivors to hospital discharge had long-term survival that was comparable to other acute respiratory distress syndrome survivors.

Computer Intervention: Illness Self-Management/Quality of Life of Rural Women.

The Women To Women project, a computer-based support and educational research intervention, was designed to help rural women better understand and manage their chronic illnesses. Its impact on psychosocial adaptation has been reported elsewhere. This article reports on the effect of a computer intervention on chronic illness self-management skills and quality of life. Using a parallel 2-group study design, the researchers randomized 309 middle-aged rural women with chronic conditions to either a computer-based intervention or a control group. They collected data on self-management of chronic illness and quality of life indicators at baseline and at the end of the intervention. Women in the intervention group reported significantly more self-efficacy in managing their chronic disease than those in the control group and the observed effect was of moderate size. Women in the intervention group also reported statistically significant gains in quality of life; effect sizes were small but consistent. Select chronic illness self-management skills and quality of life can be positively influenced by a well-designed computer intervention.

Le projet « Women To Women ¼, une initiative de soutien par ordinateur et de recherche en intervention éducative, a été conçu pour aider les femmes en région rurale à mieux comprendre et gérer les maladies chroniques dont elles souffrent. Son impact sur l'adaptation psychosociale a été rapporté dans une publication antérieure. L'article qui suit fait état de l'effet d'une intervention par ordinateur sur les capacités d'autogestion de maladies chroniques et de la qualité de vie. Menant une étude parallèle auprès de deux groupes, les chercheurs ont randomisé 309 femmes d'âge moyen vivant en région rurale et atteintes de maladies chroniques, les assignant à un groupe bénéficiant d'une intervention par ordinateur ou à un groupe de contrôle. Ils ont recueilli des données sur les indicateurs d'autogestion des maladies chroniques et de la qualité de vie au début et à la fin de l'intervention. Les femmes du groupe ayant eu accès aux interventions ont dit être beaucoup plus efficaces en ce qui a trait à la gestion de leurs maladies chroniques, comparativement à celles du groupe de contrôle, et l'effet observé était d'ampleur modérée. Les femmes du premier groupe ont aussi signalé des gains statistiquement significatifs quant à la qualité de vie; les valeurs des effets observés étaient faibles mais cohérentes. Une intervention par ordinateur bien conçue peut exercer une influence positive sur les habiletés d'autogestion de maladies ciblées et sur la qualité de vie.