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Objective: The objective of this analysis was to evaluate the cost-effectiveness of duloxetine when considered as an additional treatment option for UK-based patients suffering from diabetic peripheral neuropathic pain.Research Design and Methods: A decision-analytic model was used to represent the sequential management of patients with diabetic peripheral neuropathic pain. The standard UK treatment strategy was defined as first-line tricyclic antidepressants (amitriptyline), second-line anticonvulsants (gabapentin) and lastly an opioid-related treatment. The cost-effectiveness of duloxetine was evaluated as an additional first, second, third or fourth-line therapy over a 6-month treatment period for a cohort of 1000 patients. Treatment response was modelled based on changes from baseline pain severity using a standard 11-point pain scale (0-10); full response (>or= 50% change), partial response (30-49%) and no response (< 30%). The model was populated with efficacy and discontinuation data using indirect comparisons of treatment efficacy based on relative effects to a common placebo comparator.Results: The second-line use of duloxetine resulted in cost savings of pound 77,071 for every 1000 treated patients, with an additional 29 patients achieving a full pain response when compared to standard UK treatment. Additional quality-adjusted life years (QALYs) were achieved at 1.88 QALYs per 1000 patients.Conclusions: This UK-based economic model suggests that second-line use of duloxetine is a beneficial and cost-effective treatment strategy for diabetic peripheral neuropathic pain. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To estimate the point prevalence of diabetic peripheral neuropathy (DPN) and pain associated with DPN (pDPN) in French adults with diabetes and compare severity of symptoms across demographic subpopulations. DESIGN: The participant-administered portion of the Michigan Neuropathy Screening Instrument (MNSI) and selected items of the Brief Pain Inventory (BPI) formed part of a computer-aided telephone survey posed to a representative, random sample of French households from March 1, 2005 to April 30, 2005. Questions from the MNSI and the BPI were used to assess the point prevalence of DPN and pDPN in French adults with self-reported diabetes. RESULTS: The mean age of the study sample was 68 years (SD = 15), the mean duration of diabetes was 15 years (SD = 12) and 56% of participants were female. The prevalence rates of DPN and pDPN in French adults with diabetes were 11 and 8%, respectively. The average age and diabetes duration of participants with DPN and pDPN were not different from participants in the total sample. Among those participants with pDPN, 35% classified their pain as severe, 49% as moderate, and 17% as mild. The prevalence of DPN was higher in participants with type 1 diabetes (14%) than those with type 2 (9%). Among participants with DPN, 88% with severe pain received pain treatment compared to 71% with moderate pain and 58% with mild pain. The most significant limitation of this study is the lack of validation for administering only a portion of the MNSI, but other limitations include the imprecision associated with self-reported questionnaires, a survey sample that does not include participants with undiagnosed diabetes, and a bias toward elderly participants. CONCLUSION: This study concluded that 8% of participants with diabetes in France had pDPN. [ABSTRACT FROM AUTHOR]

Asha Hareendran,1 Nancy K Leidy,2 Brigitta U Monz,3 Randall Winnette,1 Karin Becker,3 Donald A Mahler41United BioSource Corporation, London, UK; 2United BioSource Corporation, Bethesda, MD, USA; 3Boehringer Ingelheim, Ingelheim, Germany; 4Dartmouth Medical School, Hanover, NH, USABackground: Measuring dyspnea intensity associated with exercise provides insights into dyspnea-limited exercise capacity, and has been used to evaluate treatment outcomes for chronic obstructive pulmonary disease (COPD). Three patient-reported outcome scales commonly cited for rating dyspnea during exercise are the modified Borg scale (MBS), numerical rating scale for dyspnea (NRS-D), and visual analogue scale for dyspnea (VAS-D). Various versions of each scale were found. Our objective was to evaluate the content validity of scales commonly used in COPD studies, to explore their ability to capture patients' experiences of dyspnea during exercise, and to evaluate a standardized version of the MBS.Methods: A two-stage procedure was used, with each stage involving one-on-one interviews with COPD patients who had recently completed a clinic-based exercise event on a treadmill or cycle ergometer. An open-ended elicitation interview technique was used to understand patients' experiences of exercise-induced dyspnea, followed by patients completing the three scales. The cognitive interviewing component of the study involved specific questions to evaluate the patients' perspectives of the content and format of the scales. Results from Stage 1 were used to develop a standardized version of the MBS, which was then subjected to further content validity assessment during Stage 2.Results: Thirteen patients participated in the two-stage process (n = 6; n = 7). Mean forced expiratory volume in 1 second (FEV1) percent predicted was 40%, mean age 57 years, and 54% were male. Participants used a variety of terms to describe the intensity and variability of exercise-induced dyspnea. Subjects understood the instructions and format of the standardized MBS, and were able to easily select a response to report the level of dyspnea associated with their recent standardized exercise.Conclusion: This study provides initial evidence in support of using a standardized version of the MBS version for quantifying dyspnea intensity associated with exercise in patients with COPD.Keywords: Borg scale, dyspnea assessment, COPD, exercise testing

Lucas MA Goossens1, Christine L Baker2, Brigitta U Monz3, Kelly H Zou2, Maureen PMH Rutten-van Mölken11Institute for Medical Technology Assessment, Erasmus University, Rotterdam, The Netherlands; 2Pfizer Inc, New York City, NY, USA; 3Boehringer Ingelheim International GmbH, Ingelheim am Rhein, GermanyPurpose: When comparing chronic obstructive lung disease (COPD) interventions in database research, it is important to adjust for severity. Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines grade severity according to lung function. Most databases lack data on lung function. Previous database research has approximated COPD severity using demographics and healthcare utilization. This study aims to derive an algorithm for COPD severity using baseline data from a large respiratory trial (UPLIFT).Methods: Partial proportional odds logit models were developed for probabilities of being in GOLD stages II, III and IV. Concordance between predicted and observed stage was assessed using kappa-statistics. Models were estimated in a random selection of 2/3 of patients and validated in the remainder. The analysis was repeated in a subsample with a balanced distribution across severity stages. Univariate associations of COPD severity with the covariates were tested as well.Results: More severe COPD was associated with being male and younger, having quit smoking, lower BMI, osteoporosis, hospitalizations, using certain medications, and oxygen. After adjusting for these variables, co-morbidities, previous healthcare resource use (eg, emergency room, hospitalizations) and inhaled corticosteroids, xanthines, or mucolytics were no longer independently associated with COPD severity, although they were in univariate tests. The concordance was poor (kappa = 0.151) and only slightly better in the balanced sample (kappa = 0.215).Conclusion: COPD severity cannot be reliably predicted from demographics and healthcare use. This limitation should be considered when interpreting findings from database studies, and additional research should explore other methods to account for COPD severity.Keywords: GOLD, healthcare resource use, partial proportional odds logit

Abstract Background Few direct head-to-head comparisons have been conducted between drugs for the treatment of diabetic peripheral neuropathic pain (DPNP). Approved or recommended drugs in this indication include duloxetine (DLX), pregabalin (PGB), gabapentin (GBP) and amitriptyline (AMT). We conducted an indirect meta-analysis to compare the efficacy and tolerability of DLX with PGB and GBP in DPNP, using placebo as a common comparator. Methods We searched PubMed, EMBASE, CENTRAL databases and regulatory websites for randomized, double-blind, placebo-controlled, parallel group or crossover clinical trials (RCTs) assessing DLX, PGB, GBP and AMT in DPNP. Study arms using approved dosages with assessments after 5–13 weeks were eligible. Efficacy criteria were: reduction in 24-hour pain severity (24 h PS) for all three drugs, and response rate (≥ 50% pain reduction) and Patient Global Impression of Improvement/Change (PGI-I/C) for DLX and PGB only. Tolerability criteria included: discontinuation, diarrhoea, dizziness, headache, nausea and somnolence. Direct comparisons versus placebo were conducted with pooled fixed – and random-effects analyses on endpoints reported in at least two studies of each drug. Indirect comparisons were performed between DLX and each of PGB and GBP using Bayesian simulation. Results Three studies of DLX, six of PGB, two of GBP and none of AMT met the inclusion criteria. In random-effects and fixed-effects analyses of DLX, PGB and GBP, all were superior to placebo for all efficacy parameters, with some tolerability trade-offs. Indirect comparison of DLX with PGB found no differences in 24 h PS, but significant differences in PGI-I/C, favouring PGB, and in dizziness, favouring DLX were apparent. Comparing DLX and GBP, there were no statistically significant differences. Conclusion From the few available studies suitable for indirect comparison, DLX shows comparable efficacy and tolerability to GBP and PGB in DPNP. Duloxetine provides an important treatment option for this disabling condition.

Real-world data (RWD) and the derivations of these data into real-world evidence (RWE) are rapidly expanding from informing healthcare decisions at the patient and health system level to influencing major health policy decisions, including regulatory approvals and coverage. Recent examples include the approval of palbociclib in combination with endocrine therapy for male breast cancer and the inclusion of RWE in the label of paliperidone palmitate for schizophrenia. This interest has created an urgency to develop processes that promote trust in the evidence-generation process. Key stakeholders and decision-makers include patients and their healthcare providers; learning health systems; health technology assessment bodies and payers; pharmacoepidemiologists and other clinical reseachers, and policy makers interested in bioethical and regulatory issues. A key to optimal uptake of RWE is transparency of the research process to enable decision-makers to evaluate the quality of the methods used and the applicability of the evidence that results from the RWE studies. Registration of RWE studies-particularly for hypothesis evaluating treatment effectiveness (HETE) studies-has been proposed to improve transparency, trust, and research replicability. Although registration would not guarantee better RWE studies would be conducted, it would encourage the prospective disclosure of study plans, timing, and rationale for modifications. A joint task force of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and the International Society for Pharmacoepidemiology (ISPE) recommended that investigators preregister their RWE studies and post their study protocols in a publicly available forum before starting studies to reduce publication bias and improve the transparency of research methods. Recognizing that published recommendations alone are insufficient, especially without accessible registration options and with no incentives, a group of experts gathered on February 25 and 26, 2019, in National Harbor, Maryland, to explore the structural and practical challenges to the successful implementation of the recommendations of the ISPOR/ISPE task force for preregistration. This positioning article describes a plan for making registration of HETE RWE studies routine. The plan includes specifying the rationale for registering HETE RWE studies, the studies that should be registered, where and when these studies should be registered, how and when analytic deviations from protocols should be reported, how and when to publish results, and incentives to encourage registration. Table 1 summarizes the rationale, goals, and potential solutions that increase transparency, in addition to unique concerns about secondary data studies. Definitions of terms used throughout this report are provided in Table 2., (© 2020 ISPOR-The Professional Society for Health Economics and Outcomes Research and John Wiley & Sons Limited. [Published by Elsevier Inc on behalf of ISPOR-The Professional Society for Health Economics and Outcomes Research and by John Wiley & Sons Limited (“Wiley”)]. All rights reserved.)

The Autism impact measure (AIM) is a caregiver-reported questionnaire assessing autism symptom frequency and impact in children, previously shown to have good test-retest reliability, convergent validity and structural validity. This study extended previous work by exploring the AIM's ability to discriminate between 'known-groups' of children, and estimating thresholds for clinically important responses. Data were collected online and electronically on computer and mobile devices; hence, it was also possible to confirm other psychometric properties of the AIM in this format. This study provides confirmatory and additional psychometric validation of the AIM. The AIM offers a valid, quick and inexpensive method for caregivers to report core symptoms of autism spectrum disorder (ASD) including communication deficits, difficulties with social interactions and repetitive behaviors.

Background: Regulatory agencies often request prospective, product-specific post-authorization pregnancy exposure registries to monitor safety during pregnancy, even though studies using existing health databases could also be employed., Objectives: Using multiple sclerosis (MS) as a case study, we evaluated various study designs and data sources previously used to study medication exposure in pregnancy., Methods: We examined (1) strengths and limitations of study designs used for pregnancy safety studies in women exposed to MS-specific medications during pregnancy and (2) existing data sources used to conduct such studies in other disease areas. For the data sources identified, we contacted data custodians to determine the feasibility of assessing the risk of adverse outcomes in women with MS exposed to disease-modifying therapies (DMTs) during pregnancy., Results: Of 43 MS-specific studies identified, most of which were prospective registries, very few, regardless of design and study population, produced timely and robust results for spontaneous abortions and major congenital malformations, considering study duration, achievement of target enrollment numbers, inclusion of internal comparators, and publication of results. Building on the successful use of existing healthcare databases to investigate drug safety during pregnancy in other disease areas, we identified 13 data sources that could be used to study intravenous DMT exposures in women with MS., Conclusions: Prospective, treatment-specific registries have generally failed to deliver robust information. For this reason, other study approaches, in particular cohort studies using existing healthcare databases, should be considered for evaluating the safety of drug exposure in pregnancy, including in MS.

Objective: The objective of this study was to quantify the direct medical and nonmedical costs of stroke among patients with nonvalvular atrial fibrillation in India., Methods: An observational, multicenter cost-of-illness study was conducted within large tertiary care hospitals across three metropolitan cities in India. Medical chart records of eligible patients who were hospitalized during the study period were reviewed. A standardized data collection form was designed and used to capture resources expended in the treatment and management of stroke during the inpatient stay. In addition, direct medical and nonmedical outpatient care resources and informal care burden were captured using a detailed questionnaire, following the patients' discharge. Factors associated with acute care costs were investigated using multivariate linear regression analysis., Results: Data were collected on a total of 400 patients with incident strokes. Their mean age was 61.4 ± 9.4 years. About 84% of the patients were diagnosed with ischemic stroke. On average, patients spent 16 ± 10 days in the hospital. Total mean direct health care costs per patient amounted to `504,973 (US $8,020) during the first year, with about 47% (mean `235,471; US $3,750) of the total costs due to the index hospitalization. The modified Rankin scale score was strongly associated with costs, whereby severely disabled patients had 32% higher costs (P = 0.001) compared with moderately disabled patients during the first 3 months postdischarge., Conclusions: Overall, the financial burden associated with medical care for patients with stroke with atrial fibrillation along with rehabilitation and long-term care costs places a significant demand on health services in India., (Copyright © 2014 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Background: Anticoagulation is recommended in patients with atrial fibrillation (AF) to prevent strokes. Vitamin K antagonists, such as warfarin, are associated with numerous practical limitations--frequent anticoagulation monitoring, lifestyle and dietary restrictions--that complicate patient management and may impact health-related quality of life (HRQoL). This study derived HRQoL estimates for AF patients receiving warfarin or dabigatran etexilate (dabigatran), a new oral anticoagulant not requiring anticoagulation monitoring, during one year of stable treatment, i.e. in the absence of outcome events, such as strokes or major bleedings., Methods: Changes in HRQoL over time and between treatments were assessed using the EQ-5D (utility and Visual Analogue Scale (VAS) scores) at baseline, 3 and 12 months in a sub-group of 1435 patients participating in the RE-LY trial. RE-LY was a phase III study that compared the safety and efficacy of warfarin, dabigatran 150 mg bid and dabigatran 110 mg bid for stroke prevention in patients with AF., Results: Utilities ranged from 0.805 (dabigatran 150 mg bid) to 0.811 (dabigatran 110 mg bid) at baseline, and did not change over the one year observation period. No differences between the dabigatran groups and warfarin were statistically significant except for the dabigatran 150 mg bid group at 3 months. Similarly, none of the within-group or between-group differences in VAS scores were statistically significant., Conclusions: Over the course of one year, all anticoagulated patients without outcome events (e.g. strokes or major bleedings) had stable HRQoL. Scores between dabigatran and warfarin were comparable, which was unexpected given the known complexities of warfarin treatment., (Copyright © 2013. Published by Elsevier Ireland Ltd.)

Although cough and sputum production may impact patients' well being and functioning in COPD and chronic bronchitis, there is no validated instrument for cough and sputum symptoms and their impact on patients' daily activities. To fill that gap, we developed and validated a specific, multilingual Cough and Sputum Assessment Questionnaire (CASA-Q) that evaluates clinical symptoms and their impact on patients with COPD or chronic bronchitis. In a three-country validation study (n=671), there was adequate internal consistency (Cronbach's alphas, 0.80-0.91) and test-retest reliability (correlation coefficients>0.70) for the CASA-Q. The cough impact and sputum impact domains correlated with the SGRQ impact domain and SGRQ total score, as did the cough impact domain with the SF-36 social functioning domain. The cough symptom and sputum symptom domains correlated with sputum wet weight (p<0.05; r=-0.56), but not with cough recordings. The mean CASA-Q cough symptom and sputum symptom domain scores indicated responsiveness towards both worse and improved symptoms, whereas the impact domains scored already in the upper third of the scale range, indicating the need for further improvement of its properties. Differences in the CASA-Q domain scores by smoking status (current vs. former smokers) were highest for cough symptoms and lowest for sputum impact. These data indicate that the CASA-Q may be a useful measure of cough and sputum production, and their impact in patients with COPD and/or chronic bronchitis. Further validation will need to assess the responsiveness of the CASA-Q to changes in symptoms.

Objectives: In the last two decades, there has been considerable evolution of methods for cost-effectiveness modelling. Some of the first models were developed in the area of venous thromboembolism (VTE) prophylaxis. Hence, this area can serve as an important example to illustrate evolving standards. Our objectives are to document evolving methodology by describing VTE models, assess their critical strengths and weaknesses, and inform future advances for models in this therapeutic area., Research Design and Methods: A systematic review of economic models of primary VTE prevention following hip and knee replacement surgery was undertaken. Electronic searches of PubMed, EMBASE, the Cochrane library, and grey literature were conducted (1985-2006). Reference lists of included articles and reviews were examined for relevant studies., Results: Twenty-nine cost-effectiveness models were identified. Nineteen other cost-effectiveness analyses were excluded because they were not model-based; 16 were simple cost calculations and three were analyses of resource use data collected alongside clinical trials. The majority of models (24) were constructed as decision trees, frequently utilising previously published model structures, with some adaptation for new comparators, and/or addition of relevant events omitted by earlier models (e.g., bleeding due to prophylactic treatment). Later models have included Markov processes to model potential long-term consequences of VTE (recurrent VTE and post-thrombotic syndrome) over longer time horizons. Systematic identification of clinical evidence and more sophisticated analysis methods (e.g., Bayesian mixed-treatment comparisons and probabilistic sensitivity analyses) have recently been introduced., Conclusions: Model structures have evolved substantially in this highly studied therapeutic area, with improvements made to the model structure, the comprehensiveness of clinical evidence included, and the underlying calculation methodology.

Current health care policies advocate patient participation in treatment decision making. Little evidence on possible differences between European women's preferences for involvement in this process exists. In this study we explore preferences for involvement in treatment decision making in 15 European countries in a sample of 9434 women seeking treatment for urinary incontinence in an outpatient setting. Their generally preferred role in treatment decisions was assessed using the Control Preferences Scale. Results show variations within and between countries in preferences for involvement in treatment decision making. The 'collaborative role' was the most preferred role in Austria, Belgium, Denmark, France, Germany, Ireland, Sweden, Switzerland, the Netherlands and the UK. In Greece, Portugal and Spain the 'passive role' was most preferred. Over a third of women in Denmark, Finland and Norway preferred an 'active role'. Multinominal regression analyses found that, after adjusting for case mix and factors previously associated with role preferences, country membership was strongly associated with role preferences, with women living in Southern European countries preferring a more passive role. Such clear differences are of interest in the current health care environment where active patient participation is being encouraged. Greater efforts need to be made to establish whether patient preferences are genuine or merely a learned response influenced by cultural attitudes and traditions so that a balance can be struck between assisting women to play a more active role in the treatment decision-making process without disregarding some women's genuine preferences to play a more passive role.

Objective: To investigate the association between patient characteristics and disease-specific and generic quality of life (QOL) as well as the degree of bother in women seeking treatment for urinary incontinence (UI)., Methods: The Prospective Urinary Incontinence Research (PURE) was a 6-mo observational study with 1055 physicians from 15 European countries enrolling 9487 women. QOL was assessed at the enrolment visit using the urinary Incontinence Quality of Life questionnaire (I-QOL) and the generic EQ-5D. A single-item instrument was used to measure the degree of bother. UI severity was assessed using the Sandvik Index. UI was categorised into stress (SUI), mixed (MUI), and urge (UUI) urinary incontinence by a patient-administered instrument (Stress and Urge Incontinence Questionnaire [S/UIQ]). Multivariate linear (I-QOL, EQ-5D Visual Analogue Scale) and logistic (bother, EQ-5D health state index) regressions were performed., Results: Mean total I-QOL scores were significantly and independently associated with UI severity, nocturia, age, UI subtype, number of selected concomitant medical conditions, length of suffering from UI before contacting a doctor, smoking status, ongoing use of UI medication, and country. After adjusting for all the covariates, the total I-QOL scores for SUI, MUI, and UUI were 62.7, 53.8 and 60.1, respectively. As with I-QOL, UI severity was also the most important predictor for bother. The number of concomitant medical conditions, together with UI severity, was the variable most strongly associated with EQ-5D., Conclusion: In addition to the UI subtypes, severity of UI should be given more importance in treatment algorithms and in treatment decision-making by both the patient and the physician.

Objective: To describe the medical resource use and direct costs of treatment for women with urinary incontinence (UI) in European countries., Design: PURE is a non-interventional, observational study of patients seeking treatment for UI in an outpatient setting., Setting: Investigators being either general practitioners (GPs) and/or specialists, i.e. urologists and gynaecologists, in 14 European countries participated in PURE. The results for medical resource use and cost of treatment in Germany, Spain and the UK/Ireland recorded retrospectively at the enrolment visit for the preceding 12 months are presented here., Subjects: Treatment-seeking women aged over 18 years who were under treatment or seeking treatment for UI, and who presented within the normal course of care for UI were enrolled in the 6 months study., Measurements: Information on the incontinence resource use was gathered on standard data collection forms. The direct medical costs were calculated by attaching the unit costs from the perspective of the relevant health insurance in each country to the country-specific resource use. Furthermore, the contribution of patients to the costs of pads, or any treatment for UI was assessed., Results: Variation in medical resource use and cost of treatment between the three countries was observed, reflective of the differences in the healthcare systems and whether specialists and/or GPs provided the care. We found that women in Spain and Germany are more likely to have consulted a specialist for their UI symptoms, which had implications for utilisation of diagnostic procedures. Conservative treatment, particularly pelvis floor muscle exercises, was more common in patients in the UK/Ireland treated in primary care by GPs. In all three countries most of the women had used protective pads, which more than half the patients paying for them out-of-pocket, despite potential healthcare reimbursement schemes. Mean total UI-related costs per year ranged from 359 in the UK/Ireland for patients predominantly treated in the GP setting to 515 in Germany and 655 in Spain for patients treated by specialists and GPs., Conclusions: Our study provides an estimation of resource use and costs associated with UI in treatment-seeking European women, exemplified here in three countries.

Background: Female urinary incontinence is a prevalent condition, but only about one-third of women seek treatment., Objectives: To describe the health care provision for women with urinary incontinence from a European perspective, selecting France, Germany, Spain, Sweden, and the United Kingdom as examples, and to investigate whether specific barriers for treatment exist., Methods: Available health care system information, a literature review and clinical expert information identified patterns of treatment provision., Results: In Spain, Sweden, and the UK, access to medical care in general is primarily through the general practitioners. However, in Spain and Sweden, women with urinary incontinence can directly visit specialists. In France and Germany, women have equal access to either general practitioners or specialists. Aside from general practitioners, gynaecologists play a major role in urinary incontinence care in all countries except the UK. In Germany, urologists are also involved in initial female urinary incontinence care; however, only in about 16% of women. There are no waiting lists in France and Germany for appointments with physicians or procedures, contrary to Spain, which has long waiting lists. Access to general practitioners in the UK is unrestricted whereas advanced diagnosis and treatment in secondary care requires long waits. A specific Swedish policy mandates that no woman is required to wait longer than 3 months for incontinence visits and related surgery. In Sweden and the UK, specialist nurses and other health care workers provide incontinence services. Almost all treatment options for urinary incontinence are at least in part reimbursed. However, various co-payments and fees in France, Germany, Spain and Sweden exist and constitute out-of-pocket expenses for women if no complementary additional private health insurance is available. In some countries, financial incentives for physicians to provide incontinence services are low, raising concerns about their interest to engage in continued patient care., Conclusions: Information about service provision in Europe for women with urinary incontinence is limited and makes it difficult to understand barriers to treatment seeking. A broad European perspective may promote optimised treatment access in the future for this widespread and under-recognised condition.

Objectives: To describe the patient-reported impact of urinary incontinence (UI) in treatment-seeking women in Europe., Design: PURE was a non-interventional, observational study, which aimed to describe the direct costs of treatment for European women seeking treatment for UI. A secondary study objective was to describe the impact of UI on health-related quality of life (HRQoL) by UI subtype and severity of disease. This paper presents the results from quality of life assessments as well as bothersomeness and interference with daily activities from the first study observation., Subjects: Nine thousand four hundred and eighty-seven European women who had UI symptoms in the last 12 months were enrolled. Their UI symptoms were frequently those defined as mixed urinary incontinence (MUI) and were moderate to severe in nature., Measurements: HRQoL was assessed at the first observation using the urinary Incontinence-specific Quality of Life Questionnaire (I-QOL) and the EQ-5D, a generic quality of life questionnaire. Data collected from EQ-5D provided insight into the patients' general health perception, while the I-QOL data indicated how affected the women were about their UI symptoms. Higher EQ-5D and I-QOL scores represent better quality of life. Patients were asked to indicate how much UI symptoms limited selected activities and to indicate the degree to which they found their symptoms to be bothersome., Results: Overall, the median self-rated health status on the EQ-5D visual analogue scale (VAS) was 70.0 and the median EQ-5D health state index was 0.85, with small but noticeable differences observed between countries. Of the five health dimensions of the EQ-5D, patients' self-care appeared to be the least affected by UI, with fewer than 10% of the women reporting that they had some problems. Between 20 and 40% of patients had some problems with their mobility and usual activities, or had pain/discomfort or anxiety/depression. However, the impact of existing co-morbidity was not assessed and may have affected some women's scoring of the EQ-5D domains. The mean total I-QOL score overall was 57.7 and of the three subscales of the I-QOL, psychosocial impact had the highest overall scores, representing fewer problems, with lower scores observed for the avoidance and limiting behaviour subscale, and even lower scores for the social embarrassment subscale. The greatest patient-reported impact of UI symptoms on activities was on exercise, with more than 45% of patients moderately to totally limited in this activity. In most of the countries, more than 60% of the women reported that they were moderately to extremely bothered by their UI symptoms., Conclusions: There was considerable impact of UI on HRQoL in a treatment seeking population, as demonstrated by the disease-specific quality of life scale and by the high percentage of patients who were bothered by their symptoms.

Human colon adenocarcinoma cells WiDr were cultured as monolayers or multicellular spheroids in 5% or 20% (v/v) oxygen and in various external lactate concentrations of 0-20 mM. Doubling times and H-3-thymidine labeling indices of exponential monolayer cells indicated that there was no difference in growth behavior between the two oxygen environments, yet these parameters reflected a growth retardation upon elevation of lactate. Growth of WiDr spheroids was retarded in both low oxygen and high lactate concentrations. There was a tendency towards a decrease in the thickness of the viable cell rim with increasing lactate in 20% O-2, whereas the width of the viable rim increased significantly as a function of external lactate in 5% O-2. Intraspheroidal oxygen tensions (Po-2) measured with microelectrodes were less in 5% O-2 than in 20% O-2, yet did not vary systematically as a function of external lactate. Po-2 values in the spheroid center dropped to 0 mm Hg prior to the emergence of central necrosis under all conditions investigated. Unlike numerous other spheroid types investigated up to now, WiDr spheroids mimic tumor microregions with hypoxia-induced necrosis and with nonproliferating cells at very low oxygen pressure.