Experimental and Computational Investigation of Microbubble Formation in a Single Capillary Embedded T-junction Microfluidic Device.

In recent years, there has been a notable increase in the interest toward microfluidic devices for microbubble synthesis. The upsurge can be primarily attributed to the exceptional control these devices offer in terms of both the size and the size distribution of microbubbles. Among various microfluidic devices available, capillary-embedded T-junction microfluidic (CETM) devices have been extensively used for the synthesis of microbubbles. One distinguishing feature of CETM devices from conventional T-junction devices is the existence of a wall at the right-most end, which causes a backflow of the continuous phase at the mixing zone during microbubble formation. The back flow at the mixing zone can have several implications during microbubble formation. It can possibly affect the local velocity and shearing force at the mixing zone, which in turn can affect the size and production rate of the microbubbles. Therefore, in this work, we experimentally and computationally understand the process of microbubble formation in CETM devices. The process is modeled using computational fluid dynamics (CFD) with the volume-of-fluid approach, which solves the Navier-Stokes equations for both the gas and liquid phases. Three scenarios with a constant liquid velocity of 0.053 m/s with varying gas velocity and three with a constant gas velocity of 0.049 m/s at different liquid velocities were explored. Increase in the liquid and gas velocity during microbubble formation was found to enhance production rates in both experiments and simulations. Additionally, the change in microbubble size with the change in liquid velocity was found to agree closely with the findings of the simulation with a coefficient of variation of 10%. When plotted against the time required for microbubble generation, the fluctuations in the pressure showed recurrent crests and troughs throughout the microbubble formation process. The understanding of microbubble formation in CETM devices in the presence of backflow will allow improvement in size reduction of microbubbles.

The impact of enzalutamide on quality of life in men with metastatic hormone-sensitive prostate cancer based on prior therapy, risk, and symptom subgroups.

BACKGROUND: Enzalutamide plus androgen deprivation therapy (ADT) improved radiographic progression-free survival versus ADT alone in patients with metastatic hormone-sensitive prostate cancer (mHSPC) in ARCHES (NCT02677896). While health-related quality of life (HRQoL) was generally maintained in the intent-to-treat population, we further analyzed patient-reported outcomes (PROs) in defined subgroups. METHODS: ARCHES was a randomized, double-blind, placebo-controlled, phase 3 study. Patients with mHSPC received enzalutamide (160 mg/day) plus ADT (n = 574) or placebo plus ADT (n = 576). Questionnaires, including the Functional Assessment of Cancer Therapy-Prostate, Brief Pain Inventory-Short Form, and EuroQol 5-Dimension, 5-Level (EQ-5D-5L), were completed at baseline, Week 13, and every 12 weeks until disease progression. PRO endpoints were time to first confirmed clinically meaningful deterioration (TTFCD) in HRQoL or pain. Subgroups included prognostic risk, pain/HRQoL, prior docetaxel, and local therapy (radical prostatectomy [RP] and/or radiotherapy [RT]). RESULTS: There were several between-treatment differences in TTFCD for pain and functioning/HRQoL PROs. Enzalutamide plus ADT delayed TTFCD for worst pain in the prior RT group (not reached vs. 14.06 months; hazard ratio [HR]: 0.56 [95% confidence interval: 0.34-0.94]) and pain interference in low-baseline-HRQoL group (19.32 vs. 11.20 months; HR: 0.64 [0.44-0.94]) versus placebo plus ADT. In prior/no prior RP, prior RT, prior local therapy, no prior docetaxel, mild baseline pain, and low-risk subgroups, TTFCD was delayed for the EQ-5D-5L visual analog scale. CONCLUSION: Enzalutamide plus ADT provides clinical benefits in defined patient subgroups versus ADT alone, while maintaining lack of pain and high HRQoL, with delayed deterioration in several HRQoL measures.

Patient-reported outcomes from the phase II FAST trial of zolbetuximab plus EOX compared to EOX alone as first-line treatment of patients with metastatic CLDN18.2+ gastroesophageal adenocarcinoma.

BACKGROUND: Zolbetuximab plus first-line EOX (epirubicin, oxaliplatin, capecitabine; ZOL/EOX) significantly prolonged progression-free survival and overall survival in the FAST trial vs EOX alone. We report the patient-reported outcomes (PROs) of FAST in patients with advanced gastroesophageal adenocarcinoma. METHODS: Patients were randomized to ZOL/EOX or EOX alone. Patients could receive ≤ 8 EOX cycles and remained on zolbetuximab until disease progression. PROs were collected using the EORTC QLQ-C30 and QLQ-STO22 before drug administration at day 1/cycle 1, day 1/cycle 5, end of EOX treatment, and q12w thereafter until disease progression. Time to deterioration (TTD), defined as the first meaningful worsening from baseline, in the individual QLQ-C30/QLQ-STO22 scores was analyzed. Longitudinal changes in scores from baseline were analyzed using a mixed-effects model for repeated measures (MMRM). RESULTS: The per protocol population included 143 (ZOL/EOX: 69; EOX: 74) patients. Baseline QLQ-C30 and STO22 scores were comparable between arms and denoted intermediate-to-high quality of life (QoL), intermediate-to-low global health status (GHS) and low symptom burden. Descriptive analyses showed no differences between arms until end of EOX but maintenance therapy with zolbetuximab was associated with better QoL and less symptom burden thereafter. TTD for most scores favored ZOL/EOX over EOX and reached statistical significance for GHS (p = 0.008). MMRM results support TTD findings; no statistically significant differences were observed between arms in any score except for nausea and vomiting (p = 0.0181 favoring EOX). CONCLUSIONS: ZOL/EOX allowed patients to maintain good QoL and low symptom burden for longer than EOX alone.

Short-term costs associated with non-medical switching in autoimmune conditions.

OBJECTIVES: To estimate short-term costs associated with non-medical switch (NMS) from originator biologics to biosimilars among stable patients with autoimmune conditions in rheumatology, gastroenterology, and dermatology from a US provider's and third-party payer's perspective. METHODS: An economic model was constructed to estimate switching costs related to physician time and healthcare resource utilisation (HRU) at the initial NMS visit and over 3 months. The proportion of patients with relevant conditions treated with originators and expected NMS rate, physician time, HRU, and payer reimbursement were derived from a physician survey. Switching costs were estimated for a practice of 1,000 patients with relevant conditions by therapeutic area and for an insurance plan with 1 million individuals by therapeutic area and all areas combined. Switching cost drivers were assessed with one-way sensitivity analyses. RESULTS: Physicians expected extra 6 minutes for the NMS visit and 22 minutes over 3 months; NMS rates of 14.4%, 15.5%, and 17.7%; and 11.3%, 16.2%, and 33.2% of time not reimbursed for gastroenterology, rheumatology, and dermatology, respectively. The total switching costs for payer's were $771,460 (for n = 3,609 patients with an NMS rate of 16.6%), mostly due to follow-up visits and additional laboratory tests/procedures. In sensitivity analyses, the NMS rate was the main cost driver. Increasing the NMS rate to 25% and 50% increased payer's total switching costs to $1.19 and $2.39 million, respectively. CONCLUSIONS: Originator-to-biosimilar NMS in stable patients with autoimmune conditions could result in considerable switching costs for both providers and payers.

Further content validation of the 18-item NCCN/FACT Ovarian Symptom Index and its Disease Related Symptom-Physical (DRS-P) subscale for use in advanced ovarian cancer clinical trials.

BACKGROUND: This study evaluated pre-defined aspects of content validity of the 18-item NCCN FACT-Ovarian Symptom Index (NFOSI-18) and its Disease-Related Symptoms-Physical (DRS-P) subscale, as clinical trial outcome tools for patients with advanced ovarian cancer. METHODS: Twenty-one women (mean age 59.5 years) diagnosed with advanced ovarian cancer completed the NFOSI-18 and participated in a cognitive interview to explore: (1) whether 'pain' and 'cramps' are considered redundant; (2) whether 'fatigue' and 'lack of energy' are overlapping concepts; (3) whether patients consider severity when responding to the item "I am bothered by constipation;" and (4) factors considered when responding to the item "I am sleeping well." Interviews were audio-recorded, transcribed, and analyzed qualitatively. RESULTS: Pain was associated with discomfort, hurt, and life interference; 'cramps' was associated with pain, muscle tightening, and menstrual or digestive issues. Most (81%) considered the items "I have pain" and "I have cramps in my stomach area" to be more different than similar. Participants associated 'fatigue' with intense tiredness and 'lack of energy' with motivation and capability to complete daily activities. Item comparisons revealed a majority (65%) considered the items to be more different than similar. When responding to "I am bothered by constipation," patients indicated constipation severity was related to bother. Finally, patients considered disease, treatment, and other factors when responding to "I am sleeping well." CONCLUSIONS: Findings support content validity of the NFOSI-18 and its DRS-P as originally constructed. We propose an alternative scoring option that excludes the item "I am sleeping well" from the DRS-P when used as a symptom-focused index for clinical research in a regulatory context.

The risk of cardiovascular events in psoriasis patients treated with tumor necrosis factor-α inhibitors versus phototherapy: An observational cohort study.

BACKGROUND: Psoriasis is a risk factor for cardiovascular events. OBJECTIVE: To assess the risk of major cardiovascular events and the effect of cumulative treatment exposure on cardiovascular event risk in patients with psoriasis treated with tumor necrosis factor-α inhibitors (TNFis) versus phototherapy. METHODS: Adult patients with psoriasis were selected from a large US administrative claims database (from the first quarter of 2000 through the third quarter of 2014) and classified in 2 mutually exclusive cohorts based on whether they were treated with TNFis or phototherapy. Cardiovascular event risk was compared between cohorts using multivariate Cox proportional hazards models. Cumulative exposure was defined based on treatment persistence. RESULTS: A total of 11,410 TNFi and 12,433 phototherapy patients (psoralen plus ultraviolet A light phototherapy, n = 1117; ultraviolet B light phototherapy, n = 11,316) were included in this study. TNFi patients had a lower risk of cardiovascular events compared to phototherapy patients (adjusted hazard ratio 0.77, P < .05). The risk reduction associated with 6 months of cumulative exposure was 11.2% larger for patients treated with TNFis compared to phototherapy (P < .05). LIMITATIONS: Information on psoriasis severity and mortality was limited/not available. CONCLUSIONS: Patients with psoriasis who were treated with TNFis exhibited a lower cardiovascular event risk than patients treated with phototherapy. Cumulative exposure to TNFis was associated with an incremental cardiovascular risk reduction compared to phototherapy.

Increased Prevalence of Cancer in Adult Patients With Psoriasis in the United States: A Claims Based Analysis.

BACKGROUND: Psoriasis (Ps) is a chronic inflammatory immune-mediated skin disease that has been identified as a risk factor for various conditions including neoplasms. OBJECTIVE: To compare prevalence of cancer between Ps and Ps-free patients. METHODS: Adult patients continuously enrolled for ≥12 months (≥1 month in 2014) were selected from a large United States (US) claims database (Q1:2010-Q4:2014) and classified as Ps patients (≥2 Ps diagnoses; International Classification of Diseases 9th Revision, [ICD-9] code: 696.1x) and Ps-free patients (no Ps diagnosis). Patients were exactly matched (1:1) based on age, gender, state of residence, and insurance plan type. Prevalence of cancer was compared between cohorts over patients' last 12 months of continuous healthcare plan enrollment using logistic-regression models. RESULTS: A total of 179,066 pairs of Ps and Ps-free patients were selected. Median age was 54.0 years, 51.7% were females. Prevalence of cancer was higher among Ps patients for any type of neoplasms (OR [95% confidence interval (CI)]=1.86 [1.83; 1.89]), malignant neoplasms (OR [95% CI]=1.53 [1.49;1.57]), as well as malignant skin neoplasms (OR [95% CI]=1.87 [1.79; 1.95]), lymphatic and hematopoietic tissues (OR [95% CI]=1.70 [1.57;1.84]), genital (OR [95% CI]=1.33 [1.26;1.41]), breast (OR [95% CI]=1.32 [1.24;1.40]), digestive organs and peritoneum (OR [95% CI]=1.24 [1.13;1.35]), urinary organs (OR [95% CI]=1.49 [1.36;1.64]), respiratory and intrathoracic organs (OR [95% CI]=1.30 [1.17;1.44]), and metastatic cancer (OR [95% CI]=1.14 [1.06;1.24]), all P less than 0.01. LIMITATIONS: Impact of Ps severity could not be assessed. CONCLUSION: Ps patients had a higher prevalence of cancer than Ps-free patients. J Drugs Dermatol. 2018;17(2):180-186.

Prevalence of Psoriasis in Children and Adolescents in the United States: A Claims-Based Analysis.

IMPORTANCE: While psoriasis (Ps) is mainly characterized as an adult disease, it can also develop during childhood. However, prevalence estimates of pediatric psoriasis in the United States (US) are lacking. OBJECTIVE: To assess the 2015 annual prevalence of Ps and moderate-to-severe Ps in pediatric individuals in the US. DESIGN: This is a retrospective study based on a large administrative insurance claims database in the US. SETTING: Data were extracted from the Truven Health Analytics MarketScan® Commercial Claims and Encounters database, which covers over 60 million individuals with employer-provided health insurance across the US. PARTICIPANTS: Over 4.3 million of individuals continuously enrolled in their healthcare plan in 2015 and under 18 years of age were included in the study. Intervention(s) for Clinical Trials or Exposure(s) for Observational Studies: Not applicable. Main Outcome(s) and Measure(s): Ps was defined based on medical claims with a diagnosis of Ps (ICD-9-CM: 696.1); moderate-to-severe Ps was defined based on medical or pharmacy claims for a systemic treatment (biologic, conventional systemic, or phototherapy) for Ps. Overall and age- and gender-stratified prevalence was estimated for both Ps and moderate-to-severe Ps. RESULTS: The prevalence of Ps was estimated at 128 cases per 100,000 individuals (95% CI: 124-131), that of moderate-to-severe Ps at 16 cases per 100,000 individuals (95% CI: 15-17) in 2015. For both Ps and moderate-to-severe Ps, prevalence estimates were numerically higher in females than in males (146 per 100,000 vs. 110 per 100,000 and 17 per 100,000 vs. 15 per 100,000) and increased with age, ranging from 30 per 100,000 in the 0-3 year old group to 205 per 100,000 in the 12-17 year old group. CONCLUSION AND RELEVANCE: This study provides robust estimates of the prevalence of pediatric Ps that can inform decisions pertaining to the management of pediatric patients with Ps. J Drugs Dermatol. 2018;17(2):187-194.

Adverse Medical Conditions Across Treatment Options in Patients With Psoriasis: A Claims-Based Analysis

Objective: To assess the real-world risk of developing adverse medical conditions (AMCs) among patients with psoriasis treated with biologic therapies or conventional systemic/topical therapies (CST/topical). Methods: Adult patients with psoriasis were identified from the Truven MarketScan US claims database (2008 Q3­2015 Q3) and classified into cohorts based on treatment initiated on the index date (adalimumab [ADA], etanercept [ETN], ustekinumab [UST], infliximab [IFX], or CST/topical). Incident AMCs were identified while on treatment from diagnoses recorded in medical claims and included abnormal test results, infections, mental disorders, cardiovascular disease, malignancies (skin and non-skin), and respiratory disease. Cox proportional hazards models were used to compare AMC risk for (1) ADA, ETN, and UST (separately) vs CST/topical, and (2) ADA vs other biologic therapies (ETN, UST, and IFX combined). Regressions were adjusted for age, gender, region, insurance plan type, year, Charlson comorbidity index, and prior AMCs; and based on stepwise selection, comorbidities, specialist encounters, and frequently prescribed treatments. Results: A total of 42,981 patients were identified (ADA: 5,197; ETN: 3,311; UST: 1,370; IFX: 187; CST/topical: 32,916). Across cohorts, median age was 46­50 years, 46.2%­53.1% were female, and median follow-up duration was 3.3­7.9 months. For all cohorts, infection was the most frequent AMC (28.7%­41.8%). Compared with CST/topical, ADA, ETN, and UST were associated with a lower risk of infections (adjusted hazard ratio [aHR]: 0.93, 0.92, and 0.86, respectively, all P<0.05). ADA was associated with a lower risk of malignancies (aHR: 0.71, P<0.05), and ETN was associated with a lower risk of respiratory disease (aHR: 0.80, P<0.05). Compared with biologic therapies, ADA was not associated with higher risk of AMCs. Conclusions: Compared to CST/topical, biologic therapies were associated with similar or lower risk of AMCs. Comparison between ADA and other biologic therapies suggests a similar safety profile with respect to the studied AMCs.

Benefit of biologics initiation in moderate versus severe rheumatoid arthritis: evidence from a United States registry.

Objectives: To compare clinical outcomes and treatment patterns among patients with moderate vs severe RA following biologic DMARD initiation. Methods: Biologics-naive patients with moderate to severe RA [Clinical Disease Activity Index (CDAI) >10] who initiated a biologic DMARD were selected from the Corrona registry (2001-13). CDAI, functional status [modified HAQ (mHAQ)] and patterns of drug use were compared at 1 and 2 years post-initiation between patients with moderate (CDAI >10⩽22) vs severe (CDAI >22) baseline disease activity. Results: A total of 1596 patients (817 severe, 779 moderate) had ⩾1 year of follow-up and 1269 (635 severe, 634 moderate) had ⩾2 years of follow-up. Patients with severe vs moderate baseline disease activity experienced greater improvements in disease activity [mean change in CDAI -18.9 vs -6.0 at year 1; -21.0 vs -7.1 at year 2 ( P < 0.0001)] and physical function [mean change in mHAQ -0.2 vs -0.1 ( P < 0.0001) at year 1; -0.2 vs -0.1 ( P = 0.0013) at year 2]. Greater proportions of patients with moderate vs severe disease activity achieved remission (CDAI ⩽2.8) [22.7 vs 15.8% ( P = 0.0003) at year 1; 25.9 vs 20.9% ( P = 0.0396) at year 2] or low disease activity (CDAI <10) [60.1 vs 41.2% at year 1; 66.7 vs 49.4% at year 2 ( P < 0.0001)]. Most patients remained on the original biologic drug (>70% at year 1; >62% at year 2). Conclusion: With biologic therapy, RA patients with higher baseline disease activity achieved greater improvements in measures of disease activity than those with lower levels of disease, but less often achieved the common targets of remission or low disease activity.

Uncovering burden disparity: A comparative analysis of the impact of moderate-to-severe psoriasis and hidradenitis suppurativa.

BACKGROUND: Psoriasis and hidradenitis suppurativa (HS) exhibit distinct clinical features, but no studies have directly compared the health-related quality of life (HRQoL) in patients with moderate-to-severe manifestations of these conditions. OBJECTIVE: To determine which disease is associated with more severe HRQoL impairment. METHODS: Weighted averages of each of the following baseline HRQoL measures were determined and compared between HS and psoriasis populations from 5 clinical trials: Visual Analog Scale (VAS) for pain, Total Work Productivity Impairment, Dermatology Life Quality Index; EuroQOL 5D VAS, and Short Form-36 Health Survey. RESULTS: Compared with patients with psoriasis, patients with HS reported higher scores for VAS-pain (54.3 vs 36.1 [P < .0001]), Dermatology Life Quality Index (15.3 vs 11.3 [P < .0001]), EuroQOL 5D VAS (58.8 vs 50.8 [P < .0002]), and Total Work Productivity Impairment (35.4 vs 18.2). Patients with HS had lower Short Form-36 Health Survey scores than did patients with psoriasis (physical, 39.6 vs 49.0; mental, 41.5 vs 47.5 [both P < .0001]). LIMITATIONS: This analysis was performed using published summary data rather than patient-level data, and weighted pooled averages were compared. CONCLUSIONS: Patients with HS have a higher HRQoL burden than patients with psoriasis. This study clearly documents the needs of patients with HS and the potential impact of medical, scientific, and societal consensus for the development of more effective HS treatments.

Benefit-risk trade-offs for treatment decisions in moderate-to-severe rheumatoid arthritis: focus on the patient perspective.

Given the increasing number of available treatments for rheumatoid arthritis (RA) with varying efficacy and safety profiles, it is critical to understand the level of trade-offs that patients are willing to make between benefits and risks. Adult patients with moderate to severe RA were invited to participate in a discrete choice experiment that solicited their preferences for hypothetical RA treatments. Each participant was presented with 14 choice cards asking about their preference between two hypothetical RA treatments with varying levels of efficacy, adverse events, and process-related attributes. A multivariable logistic regression model assessed the association between the attributes and the patient's decision and risk-increases were calculated. 510 eligible patients with moderate to severe RA completed the study. The average age of the participants was 56.4 years, 64.7% were female, and 45.1% received biologic agents. To achieve a 50% improvement in physical function, patients were willing to accept risk-increases of 91.1, 4.7, and 18.4% for abnormal laboratory results, cancer, and serious infection, respectively. Similarly, to achieve a 50% reduction in RA-related pain, patients were willing to accept risk-increases of 70.6, 3.7, and 14.2% for each AE. Moreover, patients were willing to trade risk-increases of 42.0, 2.2, and 8.5% for each AE to obtain a 50% reduction in the number of swollen joints. Patients with moderate to severe RA are willing to accept increased treatment risks to achieve improved physical function and disease control. These attributes are helpful to clinicians to make informed treatment choices.

Effect of adalimumab on the work-related outcomes scores in patients with early rheumatoid arthritis receiving methotrexate.

OBJECTIVES: To evaluate the effects of adalimumab plus MTX (ADA + MTX) vs MTX monotherapy on work-related outcomes in early RA patients with elevated risk of employment loss. METHODS: A post hoc analysis at weeks 26 and 24 from the Optimal Protocol for Treatment Initiation with Methotrexate and Adalimumab (OPTIMA) and PRevention Of Work Disability (PROWD) trials, respectively, was conducted in MTX-naïve RA patients randomized to ADA + MTX or placebo (PBO) + MTX. Work instability was assessed using the RA-Work Instability Scale (RA-WIS) and work productivity was measured with the Work Productivity and Activity Impairment Questionnaire. Employed patients with a baseline RA-WIS score ⩾10, indicating medium to high risk for job loss, were included (OPTIMA, n = 320; PROWD, n = 124). RESULTS: Patients receiving ADA + MTX in OPTIMA had significantly greater improvements in RA-WIS compared with PBO + MTX (mean change -7.22 vs -5.23, respectively). Significantly higher percentages of patients in the ADA + MTX group experienced improvements in one or more risk category (58 vs 47%) and ⩾5 (55 vs 43%), ⩾7 (47 vs 35%) and ⩾9 (42% vs 26%) points in their RA-WIS score. These trends were seen in PROWD but were not significant. In OPTIMA, patients receiving ADA + MTX showed significant changes in percentage points from baseline vs PBO + MTX in activity impairment, presenteeism and overall work impairment (-32.0 vs -23.7, -24.6 vs -17.1, -27.3 vs -18.3, respectively). CONCLUSIONS: Among early RA patients with elevated risk of employment loss, ADA + MTX therapy was associated with a significant reduction in work instability vs PBO + MTX. Significantly greater percentages of patients receiving ADA + MTX therapy achieved clinically meaningful improvements in their RA-WIS scores.

Comprehensive disease control (CDC): what does achieving CDC mean for patients with rheumatoid arthritis?

BACKGROUND: This study assessed the impact of simultaneous achievement of clinical, functional and structural efficacy, herein referred to as comprehensive disease control (CDC), on short-term and long-term work-related outcomes, health-related quality of life (HRQoL), pain and fatigue. METHODS: Data were pooled from three randomised trials of adalimumab plus methotrexate for treatment of early-stage or late-stage rheumatoid arthritis (RA). CDC was defined as 28-joint Disease Activity Score using C reactive protein <2.6, Health Assessment Questionnaire <0.5 and change from baseline in modified Total Sharp Score ≤0.5. Changes in scores at weeks 26 and 52 for work-related outcomes, Short Form 36 (SF-36) physical (PCS) and mental component scores (MCS), a Visual Analogue Scale measuring pain (VAS-Pain) and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) were compared between patient groups defined by achievement of CDC at week 26 using linear regression with adjustment for baseline scores. RESULTS: Patients with RA who achieved CDC at week 26 (n=200) had significantly greater improvements in VAS-Pain (46.9 vs 26.9; p<0.0001), FACIT-F (13.3 vs 7.5; p<0.0001), SF-36 PCS (19.7 vs 8.9; p<0.0001) and SF-36 MCS (8.1 vs 5.0; p=0.0004) than those who did not (n=1267). Results were consistent at week 52 and among methotrexate-naive patients with early RA, methotrexate-experienced patients with late-stage RA and patients with inadequate response to methotrexate. CONCLUSIONS: Patients with RA who achieved CDC at week 26 had improved short-term and long-term HRQoL, pain, fatigue and work-related outcomes compared with patients who do not. These results demonstrate that the joint achievement of all CDC components provides meaningful benefits to patients. TRIAL REGISTRATION NUMBERS: DE019: NCT00195702, PREMIER: NCT00195702, OPTIMA: NCT00195702.

Reliability and Validity of the Work Instability Scale for Rheumatoid Arthritis.

OBJECTIVE: The objective was to evaluate the psychometric properties of the Rheumatoid Arthritis-Work Instability Scale (RA-WIS) in a clinical trial setting. METHODS: Secondary analyses were conducted using data from a 56-week, randomized controlled trial of patients with early rheumatoid arthritis (RA). Patient-reported outcome measures included the RA-WIS, the Health Assessment Questionnaire (HAQ), the Rheumatoid Arthritis Quality of Life Questionnaire, and the Global Assessment of Disease Activity and Pain, data for which were collected at baseline and at weeks 12, 16, 24, and 56. Data were analyzed for reliability, validity, and responsiveness. RESULTS: Among 148 patients whose data were analyzed, more than half were women (56.1%) with a mean age of 46.8 years. On average, patients experienced RA symptoms for 8.7 months; the mean 28-Joint Disease Activity Score (DAS28) was 5.9, and the mean HAQ - Disability Index was 1.3. The RA-WIS demonstrated excellent internal consistency and test-retest reliability (α = 0.89 and intraclass correlation coefficient = 0.91, respectively). At baseline and week 24, moderate to strong correlations were seen between RA-WIS total scores and the HAQ, the Global Assessment of Disease Activity, and the Pain Rheumatoid Arthritis Quality of Life Questionnaire, ranging from 0.47 to 0.81 (all P < 0.0001). Mean RA-WIS total scores and work disability risk levels discriminated between clinical severity scores on the DAS28, the HAQ - Disability Index, and the Physician Global Assessment of Disease Activity (all P < 0.05). Mean baseline to week 24 RA-WIS total change scores were significantly different among American College of Rheumatology responder groups (P ≤ 0.0001) and between DAS28 remission status groups (P < 0.001). CONCLUSIONS: These findings provide evidence supporting the reliability, validity, and responsiveness of the RA-WIS for evaluating work disability in patients with RA in a clinical trial setting.

A Review of Pressure Drop and Mixing Characteristics in Passive Mixers Involving Miscible Liquids.

The present review focuses on the recent studies carried out in passive micromixers for understanding the hydrodynamics and transport phenomena of miscible liquid-liquid (LL) systems in terms of pressure drop and mixing indices. First, the passive micromixers have been categorized based on the type of complexity in shape, size, and configuration. It is observed that the use of different aspect ratios of the microchannel width, presence of obstructions, flow and operating conditions, and fluid properties majorly affect the mixing characteristics and pressure drop in passive micromixers. A regime map for the micromixer selection based on optimization of mixing index (MI) and pressure drop has been identified based on the literature data for the Reynolds number (Re) range (1 ≤ Re ≤ 100). The map comprehensively summarizes the favorable, moderately favorable, or non-operable regimes of a micromixer. Further, regions for special applications of complex micromixer shapes and micromixers operating at low Re have been identified. Similarly, the operable limits for a micromixer based on pressure drop for Re range 0.1 < Re < 100,000 have been identified. A comparison of measured pressure drop with fundamentally derived analytical expressions show that Category 3 and 4 micromixers mostly have higher pressure drops, except for a few efficient ones. An MI regime map comprising diffusion, chaotic advection, and mixed advection-dominated zones has also been devised. An empirical correlation for pressure drop as a function of Reynolds number has been developed and a corresponding friction factor has been obtained. Predictions on heat and mass transfer based on analogies in micromixers have also been proposed.

Comparative analysis of survival, treatment, cost and resource use among patients newly diagnosed with brain metastasis by initial primary cancer.

Brain metastases are a frequent complication of many systemic cancers and portend a poor prognosis. This retrospective analysis of health claims data compared survival, treatment and health care utilization and costs in patients with brain metastasis by primary tumor site. Adult commercial and Medicare Advantage enrollees newly diagnosed with brain metastasis in 01 Jan 2004 through 30 Apr 2010 were identified. Inclusion required at least 2 claims that identified the same primary cancer site prior to diagnosis of brain metastasis and no evidence of primary brain tumors. Health care utilization rates and costs were calculated at the patient level for each month of follow-up. Differences among primary cancer site cohorts were assessed by ANOVA (continuous variables), Chi square test (proportions) and the Poisson distribution (utilization rates). The primary cancer cohorts comprised 1,031 lung cancer, 93 melanoma and 395 female breast cancer patients. During the 6 months prior to brain metastasis diagnosis, 59 % of lung cancer patients had no evidence of lymph node involvement or other metastatic disease compared to 55 and 42 % of melanoma and breast cancer patients (P < 0.001). Survival after brain metastasis diagnosis was less than 3 months for 52, 43 and 39 % for lung cancer, breast cancer and melanoma, respectively (P < 0.001). Melanoma patients had the highest rate of inpatient stays and outpatient visits (P ≤ 0.003). Total monthly all-cause costs were: melanoma, $23,426; breast cancer $19,708; lung cancer, $17,007 (P = 0.003). Health care utilization and costs after brain metastasis diagnosis were substantial and differed by primary tumor site.

A checklist for ascertaining study cohorts in oncology health services research using secondary data: report of the ISPOR oncology good outcomes research practices working group.

OBJECTIVES: The ISPOR Oncology Special Interest Group formed a working group at the end of 2010 to develop standards for conducting oncology health services research using secondary data. The first mission of the group was to develop a checklist focused on issues specific to selection of a sample of oncology patients using a secondary data source. METHODS: A systematic review of the published literature from 2006 to 2010 was conducted to characterize the use of secondary data sources in oncology and inform the leadership of the working group prior to the construction of the checklist. A draft checklist was subsequently presented to the ISPOR membership in 2011 with subsequent feedback from the larger Oncology Special Interest Group also incorporated into the final checklist. RESULTS: The checklist includes six elements: identification of the cancer to be studied, selection of an appropriate data source, evaluation of the applicability of published algorithms, development of custom algorithms (if needed), validation of the custom algorithm, and reporting and discussions of the ascertainment criteria. The checklist was intended to be applicable to various types of secondary data sources, including cancer registries, claims databases, electronic medical records, and others. CONCLUSIONS: This checklist makes two important contributions to oncology health services research. First, it can assist decision makers and reviewers in evaluating the quality of studies using secondary data. Second, it highlights methodological issues to be considered when researchers are constructing a study cohort from a secondary data source.

The impact of second-line agents on patients' health-related quality of life in the treatment for non-small cell lung cancer: a systematic review.

PURPOSE: In advanced non-small cell lung cancer (NSCLC), progressive disease burdens patients considerably. Second-line (2L) chemotherapy improves survival marginally but humanistic outcomes (i.e., quality of life, QOL) are underreported. The impact of 2L therapy remains an important consideration for patients and caregivers, and there have been QOL reviews for 1L, but not 2L, therapies. This review assessed QOL outcomes of approved, guideline-supported 2L chemotherapy with docetaxel, erlotinib, gefitinib, and pemetrexed in advanced NSCLC. METHODS: Clinical trial reports of approved, guideline-supported 2L or maintenance therapy for NSCLC published from 2000 to 2010 were identified from PubMed/Medline and clinical meetings. Outcomes were stratified by overall QOL impact, domain/symptom-specific effects, effect over time, and subgroup effects. RESULTS: Of 145 studies identified, 24 full-text articles were retained. Studies with docetaxel versus best supportive care (n = 1) and active comparators (n = 4) reported non-significant overall QOL improvements, as did studies of gefitinib versus placebo and active comparator (n = 7). Overall QOL improvements were seen for gefitinib versus docetaxel (n = 2) and gefitinib in a single-arm study (n = 1). At the symptom level, studies of docetaxel (n = 4/7), gefitinib (n = 7/9), and pemetrexed (n = 1) reported non-significant results. Subgroup analyses indicated improved QOL outcomes for gefitinib-treated responders versus non-responders, worse QOL for gefitinib-treated smokers versus placebo, worse QOL for gefitinib-treated Asian patients versus placebo, and longer time to symptom deterioration in erlotinib versus placebo-treated elderly patients. CONCLUSIONS: Significant improvements in overall QOL with 2L chemotherapy for advanced NSCLC were infrequent. Single-arm studies and those with less toxic regimens more commonly provided statistically significant improvements in QOL outcomes. Methodological heterogeneity impedes cross-study QOL comparisons.