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Rationale: Emerging data demonstrate that the smallest conducting airways, terminal bronchioles, are the early site of tissue destruction in chronic obstructive pulmonary disease (COPD) and are reduced by as much as 41% by the time someone is diagnosed with mild (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 1) COPD. Objectives: To develop a single-cell atlas that describes the structural, cellular, and extracellular matrix alterations underlying terminal bronchiole loss in COPD. Methods: This cross-sectional study of 262 lung samples derived from 34 ex-smokers with normal lung function ( n  = 10) or GOLD stage 1 ( n  = 10), stage 2 ( n  = 8), or stage 4 ( n  = 6) COPD was performed to assess the morphology, extracellular matrix, single-cell atlas, and genes associated with terminal bronchiole reduction using stereology, micro-computed tomography, nonlinear optical microscopy, imaging mass spectrometry, and transcriptomics. Measurements and Main Results: The lumen area of terminal bronchioles progressively narrows with COPD severity as a result of the loss of elastin fibers within alveolar attachments, which was observed before microscopic emphysematous tissue destruction in GOLD stage 1 and 2 COPD. The single-cell atlas of terminal bronchioles in COPD demonstrated M1-like macrophages and neutrophils located within alveolar attachments and associated with the pathobiology of elastin fiber loss, whereas adaptive immune cells (naive, CD4, and CD8 T cells, and B cells) are associated with terminal bronchiole wall remodeling. Terminal bronchiole pathology was associated with the upregulation of genes involved in innate and adaptive immune responses, the interferon response, and the degranulation of neutrophils. Conclusions: This comprehensive single-cell atlas highlights terminal bronchiole alveolar attachments as the initial site of tissue destruction in centrilobular emphysema and an attractive target for disease modification.

Lymph nodes (LNs) are frequently the first sites of metastasis. Currently, the only prognostic LN assessment is determining metastatic status. However, there is evidence suggesting that LN metastasis is facilitated by the formation of a pre-metastatic niche induced by tumour derived extracellular vehicles (EVs). Therefore, it is important to detect and modify the LN environmental changes. Earlier work has demonstrated that neutrophil extracellular traps (NETs) can sequester and promote distant metastasis. Here, we first confirmed that LN NETs are associated with reduced patient survival. Next, we demonstrated that NETs deposition precedes LN metastasis and NETs inhibition diminishes LN metastases in animal models. Furthermore, we discovered that EVs are essential to the formation of LN NETs. Finally, we showed that lymphatic endothelial cells secrete CXCL8/2 in response to EVs inducing NETs formation and the promotion of LN metastasis. Our findings reveal the role of EV-induced NETs in LN metastasis and provide potential immunotherapeutic vulnerabilities that may occur early in the metastatic cascade., (© 2023 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.)

Targeting the dynamic tumor immune microenvironment (TIME) can provide effective therapeutic strategies for cancer. Neutrophils are the predominant leukocyte population in mice and humans, and mounting evidence implicates these cells during tumor growth and metastasis. Neutrophil extracellular traps (NETs) are networks of extracellular neutrophil DNA fibers that are capable of binding tumor cells to support metastatic progression. Here we demonstrate for the first time that circulating NET levels are elevated in advanced esophageal, gastric and lung cancer patients compared to healthy controls. Using pre-clinical murine models of lung and colon cancer in combination with intravital video microscopy, we show that NETs functionally regulate disease progression and that blocking NETosis through multiple strategies significantly inhibits spontaneous metastasis to the lung and liver. Further, we visualize how inhibiting tumor-induced NETs decreases cancer cell adhesion to liver sinusoids following intrasplenic injection - a mechanism previously thought to be driven primarily by exogenous stimuli. Thus, in addition to neutrophil abundance, the functional contribution of NETosis within the TIME has critical translational relevance and represents a promising target to impede metastatic dissemination.

The aim of treatment of depression is remission of symptoms and functioning. Although there is a relationship between remission of symptoms and remission of functioning, it is not known how individual residual symptoms are related to functioning. Here we report a post-hoc analysis of two studies which treated depressed patients with duloxetine in an open fashion for 10-12 weeks. We evaluated the association of individual residual symptoms and functional impairment in patients who remitted or partially remitted after acute treatment. Logistic regression was used to investigate residual symptoms associated with functional impairment at endpoint. Our results suggest that in partial remitters, the only residual symptom associated with a reduction in the risk of having impaired function was the resolution of painful physical symptoms (PPS). In patients who remitted, the presence of residual core mood symptoms (CMS), particularly in patients without any anxiety, predicted impaired functioning. The resolution of PPS in the presence of residual CMS was associated with less risk of impaired functioning. Our results contribute to understand better the role of specific residual symptoms on functional impairment. To achieve normal functioning, intervention on specific residual symptoms is recommended., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

The objective of this study is to identify prognostic factors of treatment response to atomoxetine in improvement of health-related quality of life (HR-QoL), measured by the Child Health and Illness Profile-Child Edition Parent Report Form (CHIP-CE PRF) Achievement and Risk Avoidance domains, in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Pooled data from 3 placebo-controlled trials and separate data from 3 open-label trials of atomoxetine in children and adolescents with ADHD were analyzed using logistic regression methods. Based on baseline impairment in the Achievement and/or Risk Avoidance domains (CHIP-CE PRF < 40 points), 2 subsamples of subjects were included. Treatment outcome was categorized as <5 points or ≥5 points increase in the CHIP-CE PRF Achievement and Risk Avoidance domains. Data of 190 and 183 subjects from the pooled sample, and 422 and 355 subjects from the open-label trials were included in the analysis of Achievement and Risk Avoidance domains. Baseline CHIP-CE subdomain scores proved to be the most robust prognostic factors for treatment outcome in both domains, based on data from the pooled sample of double-blind studies and from the individual open-label studies (odds ratios [OR] 0.74-1.56, p < 0.05; OR < 1, indicating a worse baseline score associated with worse odds of responding). Initial treatment response (≥25 % reduction in ADHD Rating Scale scores in the first 4-6 weeks) was another robust prognostic factor, based on data from the open-label studies (OR 2.99-6.19, p < 0.05). Baseline impairment in HR-QoL and initial treatment response can be early prognostic factors of atomoxetine treatment outcome in HR-QoL in children and adolescents with ADHD.

Psychopharmacological agents were shown to be important for improving the quality of life (QoL) of patients with attention-deficit/hyperactivity disorder (ADHD). A short-term, 10-week study found atomoxetine (ATX) to be effective in improving QoL of ADHD patients. We compared, for the first time, long-term treatment outcomes of ATX and other early standard therapy (OEST, any pharmacological ADHD treatment except ATX) in QoL and functional impairment in pharmacologically naive children/ adolescents in a randomized, controlled, open-label study at 6 and 12 months. Patients received ATX (0.5-1.8 mg/kg per day) or OEST (mainly methylphenidate). Quality of life and functioning were assessed by the Child Health and Illness Profile-Child Edition, Parent Rating Form and the Weiss Functional Impairment Rating Scale-Parent Report. Three hundred ninety-eight patients (79.4% male; mean age, 9.3 years) received study treatment. The Child Health and Illness Profile-Child Edition, Parent Rating Form achievement domain t scores significantly improved from baseline to 6 months from means of 28.0 to 37.1 for ATX and from 28.3 to 40.7 for OEST. Mean t scores at 12 months were 40.0 for ATX and 41.0 for OEST. The Weiss Functional Impairment Rating Scale-Parent Report total score improved from baseline to 6 months in both groups (ATX: mean 1.02 to 0.63; OEST: 0.96 to 0.59). Both treatments were safe with no statistically significant difference in the overall rate of adverse events. Overall, the improvements in QoL and functional impairment observed over time for ATX and OEST were meaningful and stable over the study period of 12 months. Between-group differences were small but sometimes statistically significant, providing the first-time long-term comparative symptomatic and QoL analysis between ATX and OEST.

Purpose: The speed of onset of depressive episodes is a clinical aspect of affective disorders that has not been sufficiently investigated. Thus, we aimed to explore whether patients with fast onset of the full-blown depressive symptomatology (≤7 days) differ from those with slow onset (>7 days) with regard to demographic and clinical aspects., Subjects and Methods: Data were obtained within an observational study conducted in outpatients with major depression who were treated with duloxetine (30-120 mg/day). Onset of depression (without any preceding critical life event) was fast in 416 (less than one week) and slower in 2220 patients., Results: Compared to patients with slow onset, those with fast onset of depression had more suicide attempts in the previous 12 months (2.7% versus 1.3%, P=0.046) and less somatic comorbidity (61.7% versus 74.1%, P<0.0001). In addition, they were slightly younger at onset of depression (mean±SD 40.2±14.6 versus 42.8±14.2 years, P<0.001) and used analgesics at baseline significantly less frequently (22.8% versus 33.4%, P<0.0001)., Discussion and Conclusion: The speed of onset of depression has to be regarded as a relevant clinical characteristic in patients with unipolar depression., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Objective: To compare fast versus slow switching from stimulants to atomoxetine (ATX) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD)., Methods: This was a randomized, controlled, open-label study in 6-16-year-old ADHD patients, previously treated with stimulants and cross-titrated (fast switch, over 2 weeks, or slow switch, over 10 weeks) to ATX because of unsatisfactory response and/or adverse events. Study duration was 14 weeks with an ATX standard target dose of 1.2 mg/kg/day. Primary measure was the change from baseline in the investigator-rated ADHD-Rating Scale (ADHD-RS) at weeks 2 and 10. Secondary measures included Global Impression of Perceived Difficulties (GIPD) and Child Health and Illness Profile-Child Edition (CHIP-CE)., Results: The majority of the 111 patients were male (83.8%, n=93) and mean (SD) age was 11.5 (2.38) years. Mean baseline ADHD-RS total score was 36.0 in the fast and 38.0 in the slow group. Adjusted mean change after 2 weeks was -8.1 (-10.1; -6.1) in the fast and -8.0 (-9.9;-6.0) in the slow group (p=0.927), and after 10 weeks -15.0 (-17.4;-12.6) and -14.3 (-16.7;-12.0), respectively, (p=0.692). GIPD scores did not show differences between groups. Significant differences at week 10 were found in the CHIP-CE achievement domain favoring slow (p=0.036) and the comfort domain favoring fast cross-titration (p=0.030). No significant differences were found for adverse events, and differences for systolic blood pressure (BP) and weight were not considered clinically relevant., Conclusions: ADHD-RS and GIPD scores improved in both switching groups. No clinically relevant differences between fast and slow switching from stimulants to ATX were found.

Objectives: To describe health-related quality of life (HRQoL), pain, clinical outcomes and treatment patterns in French patients with depression treated by general practitioners and psychiatrists., Methods: Factors Influencing Depression Endpoints Research (FINDER) is a European longitudinal observational, naturalistic, multicentre study to determine the HRQoL (SF-36 and EQ-5D) and to assess outcomes of depression and anxiety (Hospital Anxiety and Depression Scale [HADS]), and pain (VAS) in a population of depressed patients initiating antidepressant treatment. Clinical diagnosis of depression was based on physician's clinical judgment. Physicians decided at their own discretion and clinical practice to initiate pharmacological treatment for depression. Adult patients with a first or new episode of depression were enrolled between May 2004 and September 2005, and followed up for 6 months. Across Europe, 437 physicians observed 3468 patients., Results: In France, 606 patients (approximately 17% of the whole sample) were enrolled by 57 psychiatrists and 46 general practitioners. These patients were (mean ± SD) 45.6 ± 13.0 years old, 69% female and 39% having had a previous depressive episode in the last 2 years. According to the patient-rated HADS score greater or equal to 11, most patients (75%) were classified as cases of depression as well as cases of anxiety (84%); 51% of patients rated their overall pain severity (based on VAS cut-off of 30 mm) as moderate/severe, with 65% of these patients reporting no medical explanation for their pain. The majority (81%) of the patients were prescribed selective serotonin reuptake inhibitors (SSRI). During the 6-month follow-up, the majority of the patients (73%) remained on the same antidepressant at the same dose during the course of treatment. Between baseline and 6-month endpoint, French patients improved their mean scores (SD) on the SF-36 physical score by+3.5 (9.0) (P<0.001) and mental score by+20.6 (14.2) (P<0.001); on the EQ-5D Health State Index by+0.37 (0.32) (P<0.001) and the EQ-5D VAS by+32.3 (25.0) (P<0.001); on the HADS depression score by-8.1 (6.0) (P<0.001) and HADS anxiety score by-6.9 (5.0) (P<0.001). Patients with moderate/severe pain at baseline improved their overall pain on a mean VAS score by-34.1 (28.7) (P<0.001)., Conclusions: More than half of the French patients enrolled in the study experienced pain associated with depression. During follow-up, patients improved all of their outcome measurements (physical and mental SF-36 scores, depression and anxiety HADS scores, pain VAS, EQ-5D Health State Index and VAS) and most patients remained on the same antidepressant at the same dose., (Copyright © 2012 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.)

Aims: To evaluate the safety and tolerability of duloxetine during routine clinical care in women with stress urinary incontinence (SUI) in Germany, and in particular, to identify previously unrecognized safety issues as uncommon adverse reactions, and the influence of confounding factors present in clinical practice on the safety profile of duloxetine., Methods: Office-based urologists, gynaecologists and primary care physicians were asked to document women newly started on treatment for moderate to severe symptoms of SUI. Six thousand eight hundred and fifty-four patients from urologist/gynaecologist practices and 5879 primary care patients were assessed. In a two-armed, observational study with parallel 12 week (urologists and gynaecologists) or 24 week (primary care physicians) design, patients were treated with duloxetine or other conservative treatment. The main outcome measure was the occurrence of adverse events (AEs)., Results: Baseline characteristics differed slightly between patient groups and studies. Duloxetine doses in most patients were lower than recommended. Overall, AE frequency with duloxetine was lower than in controlled studies (15.9% (95% CI 14.9, 16.9) and 9.1% (95% CI 8.2, 10.0) in the 12 and 24 week treatment groups, respectively), but exhibited a similar qualitative spectrum. In the logistic regression models, the following factors were associated with greater AE risk: investigator specialization (gynaecologist vs. urologist and primary care physician), initial duloxetine dose (80 vs. 20 mg day(-1) ) and use of any concomitant medication. Within the 24 week study, a positive screen for depressive disorder was surprisingly common, but no case of attempted suicide was reported in either study., Conclusions: Our results from German clinical practice show that women with SUI were often treated with duloxetine doses lower than recommended. This was associated with a low incidence of AEs. Suicide attempts were not reported., (© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.)

Objectives: To investigate the impact of depression and its treatment on health-related quality of life (HRQoL) in a naturalistic, primary care setting in the UK., Methods: The Factors Influencing Depression Endpoints Research (FINDER) study was a European, 6-month, prospective, observational study designed to estimate HRQoL in patients with a clinical diagnosis of depression. This paper examines primary care patients recruited in the UK. HRQoL was measured at baseline and at 3 and 6 months after starting antidepressant therapy using the Short Form 36 Health Status Survey and the European Quality of Life-5 Dimensions (EQ-5D). Regression analysis was used to identify baseline and treatment variables independently and significantly associated with HRQoL. Further analyses included the effect of caseness for depression on HRQoL, the effect of moderate/severe pain at baseline on HRQoL, changes in overall pain, pain interference scores, and the use of different antidepressants by pain cohort., Results: A total of 608 patients was recruited from 58 centres and mean HRQoL was significantly below reported population norms at baseline. Most improvement in HRQoL was seen at 3 months for EQ-5D, with small additional improvement at 6 months. Worse HRQoL outcomes at 6 months were associated with higher somatic symptoms score, duration of depression at baseline, and switching within antidepressant classes. Patients meeting the criteria for caseness for depression, or with significant pain at baseline showed less improvement in HRQoL scores at 6 months., Conclusion: Patients presenting with depression in primary care show reduced HRQoL compared to population norms. HRQoL improves during antidepressant treatment particularly within the first 3 months. Nonpainful somatic symptoms, socioeconomic factors, depression variables and switching within antidepressant class predict poor HRQoL outcome. Pain is a common symptom in depressed patients and remains after 6 months' treatment. Pain and somatic symptoms should be assessed in all patients with depression in primary care.

Objective: To develop clinical leadership among front-line public health nurses (PHNs)., Methods: This paper describes a quality improvement process to develop clinical leadership among front-line PHNs. Three activities were undertaken by a working group consisting mainly of front-line staff: engaging PHNs in an online change-readiness questionnaire, administering a survey to clients who had ever used public health services delivered by one Vancouver Community Infant, Child and Youth (ICY) program team and conducting three group interviews with public health providers. The group interviews asked about PHN practice. They were analyzed using thematic content analysis., Results: This quality improvement project suggests that PHNs (n=70) strongly believed in opportunities for system improvement. Client surveys (n=429) and community partner surveys (n=79) revealed the importance of the PHN role. Group interview data yielded three themes: PHNs were the "hub" of community care; PHNs lacked a common language to describe their work; PHNs envisioned their future practice encompassing their full scope of competencies. PHNs developed the "ICY Public Health Nursing Model," which articulates 14 public health interventions and identifies the scope of their work., Conclusion: Developing and sustaining clinical leadership in front-line PHNs was accomplished through these various quality assurance activities., (Copyright © 2013 Longwoods Publishing.)

The purpose of this work is to describe the effect of duloxetine on functioning as measured by the Sheehan disability scale (SDS) compared with placebo in patients with major depressive disorder (MDD). Pooled data from six randomized, parallel, double-blind, placebo-controlled duloxetine studies in adult MDD patients were analyzed at the short-term (7-13 weeks) and the long-term (>24 weeks) endpoint. The primary variable was the SDS total score. Secondary variables included functional remission (SDS total ≤ 6) rates, Hamilton rating scale for depression total score, and pain visual analog scale. Analysis of covariance and logistic regression methods were used to assess differences in treatment and identify prognostic baseline factors. In total, 2496 patients (1424 duloxetine; 1072 placebo) were included. The between-treatment difference of -2.52 between duloxetine and placebo in the SDS total score at the short-term endpoint was statistically significant in favor of duloxetine vs. placebo (95% confidence interval: -3.17, -1.87; P < 0.001). The endpoint functional remission rates were 39.5% with duloxetine and 28.7% with placebo. Time since first depression episode, antidepressant pretreatment (yes/no), baseline visual analog scale pain (≤30 / >30 mm), and sex were significant prognostic factors. The effect of duloxetine was maintained at the long-term endpoint. Duloxetine is effective in improving MDD patients' functioning. Further antidepressant studies focusing on functioning would be helpful.

Introduction: In depressed patients tricyclic antidepressants and selective serotonin and noradrenaline reuptake inhibitors can reduce not only depressive, but also painful physical symptoms. We investigated whether under treatment with duloxetine pain improves earlier than mood., Methods: Data were obtained within a prospective 6-month multi-centre naturalistic study in adult out-patients with depressive episodes treated with duloxetine (fl exible doses: 30-120 mg/day). Pain and mood were assessed daily by visual analogue scales. For responders (n = 622) "time to 50 % pain response" and "time to 50 % mood response" were determined by counting the earliest day between day 0 and 27, at which the patient achieved 50 % improvement., Results: Mean time to 50 % pain response (mean 6.3 days, SD 5.3) was significantly shorter than time to 50 % mood response (mean 7.6 days, SD 6.0, mean difference 1.3 days, SD 6.4; p < 0.0001)., Discussion: In duloxetine-responders to both pain and mood, self-rated pain improved slightly earlier than self-rated mood. The short temporal dissociation between pain and mood improvement might be explained by an earlier conscious perception of pain than mood changes., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: To investigate the association of the change of painful physical symptoms (PPS) after 4 weeks, with the 6-month treatment outcomes of depressive symptoms in patients treated with duloxetine in clinical practice., Methods: Multicenter, prospective, 6-month, non-interventional study in adult outpatients with a depressive episode and starting treatment with duloxetine. Depression severity was assessed by the clinician (Inventory for Depressive Symptomatology [IDS-C]) and patient (Kurz-Skala Stimmung/Aktivierung [KUSTA]). Somatic symptoms and PPS were assessed using the patient-rated Somatic Symptom Inventory (SSI) and visual analog scales (VAS) for pain items. Association of change in PPS with outcomes of depressive symptoms was analyzed based on mean KUSTA scores (mean of items mood, activity, tension/relaxation, sleep) and achievement of a 50% reduction in the total IDS-C score after 6 months using linear and logistic regression models, respectively., Results: Of the 4,517 patients enrolled (mean age: 52.2 years, 71.8% female), 3,320 patients (73.5%) completed the study. 80% of the patients had moderate to severe overall pain (VAS > 30 mm) at baseline. A 50% VAS overall pain reduction after 4 weeks was associated with a 13.32 points higher mean KUSTA score after 6 months, and a 50% pain reduction after 2 weeks with a 6.33 points improvement. No unexpected safety signals were detected in this naturalistic study., Conclusion: Pain reduction after 2 and 4 weeks can be used to estimate outcomes of long-term treatment with duloxetine. PPS associated with depression have a potential role in predicting remission of depressive symptoms in clinical practice.

Background: Patients with depression often experience pain. There is limited understanding of the relation between pain and other symptoms (depressive, anxious and non-painful somatic symptoms). This exploratory study assesses pain severity and interference of pain with functioning in a clinically depressed population and investigates the relation between the different groups of symptoms., Methods: FINDER was a 6-month prospective, observational study investigating health-related quality of life of outpatients with depression initiating antidepressant treatment. Patients completed ratings on the Hospital Anxiety and Depression Scale (HADS), Somatic Symptom Inventory (SSI-28), and overall pain severity and interference of pain with functioning using Visual Analogue Scales (VAS) at baseline and at 3 and 6 months. Regression analyses identified factors associated with overall pain severity and interference of pain with functioning, at baseline and over the observation period., Results: Of 3468 eligible patients at baseline, 56.3% experienced moderate to severe pain and 53.6% had moderate to severe pain-related interference with functioning. At 6 months of follow-up, these proportions decreased to 32.5% and 28.1%, respectively. Higher baseline SSI-somatic scores (non-painful) were strongly associated with greater pain severity and greater pain-related interference with functioning at baseline and over 6 months. Certain socio-demographic (increasing age, being unemployed) and depression-related factors (more previous episodes, longer duration of current episode) were also significantly associated with greater pain severity and interference over 6 months, while higher baseline severity of depression (HADS-D) and further education were associated with less severe pain or pain-related interference with functioning over 6 months., Conclusions: Over half of depressed patients in this study experienced moderate to severe pain. Painful somatic symptoms appear to be closely related to non-painful somatic symptoms, more than to depressive or anxious symptoms suggesting that painful and non-painful somatic symptoms can be considered as one group of 'somatic symptoms,' all of them associated with depressive and anxious symptoms., (2010. Published by Elsevier B.V.)

Objective: To assess the cost-effectiveness of duloxetine compared with conservative therapy in women with stress urinary incontinence (SUI)., Methods: Cost and outcome data were taken from the Stress Urinary Incontinence Treatment (SUIT) study, a 12-month, prospective, observational, naturalistic, multicenter, multicountry study. Costs were assessed in UK pound and outcomes in quality adjusted life years using responses to the EuroQol (EQ-5D); numbers of urine leaks were also estimated. Potential selection bias was countered using multivariate regression and propensity score analysis., Results: Duloxetine alone, duloxetine in combination with conservative treatment, and conservative treatment alone were associated with roughly two fewer leaks per week compared with no treatment. Duloxetine alone and with conservative treatment for SUI were associated with incremental quality-adjusted life-years (QALYs) of about 0.03 over a year compared with no treatment or with conservative treatment alone. Conservative treatment alone did not show an effect on QALYs. None of the interventions appeared to have marked impacts on costs over a year. Depending on the form of matching, duloxetine either dominated or had an incremental cost-effectiveness ratio (ICER) below pound900 per QALY gained compared with no treatment and with conservative treatment alone. Duloxetine plus conservative therapy had an ICER below pound5500 compared with no treatment or conservative treatment alone. Duloxetine compared with duloxetine plus conservative therapy showed similar outcomes but an additional cost for the combined intervention., Conclusions: Although the limitations of the use of SUIT's observational data for this purpose need to be acknowledged, the study suggests that initiating duloxetine therapy in SUI is a cost-effective treatment alternative.

Background: Factors Influencing Depression Endpoints Research (FINDER) is a 6-month, prospective, observational study carried out in 12 European countries aimed at investigating health-related quality of life (HRQoL) in outpatients receiving treatment for a first or new depressive episode. The Italian HRQoL data at 6 months is described in this report, and the factors associated with HRQoL changes were determined., Methods: Data were collected at baseline, 3 and 6 months of treatment. HRQoL was measured using components of the 36-item Short Form Health Survey (SF-36; mental component summary (MCS), physical component summary (PCS)) and the European Quality of Life-5 Dimensions (EQ-5D; visual analogue scale (VAS) and health status index (HSI)). The Hospital Anxiety and Depression Scale (HADS) was adopted to evaluate depressive symptoms, while somatic and painful physical symptoms were assessed by using the 28-item Somatic Symptom Inventory (SSI-28) and a VAS., Results: Of the initial 513 patients, 472 completed the 3-month observation and 466 the 6-month observation. The SF-36 and EQ-5D mean (+/- SD) scores showed HRQoL improvements at 3 months and a further smaller improvement at 6 months, with the most positive effects for SF-36 MCS (baseline 22.0 +/- 9.2, 3 months 34.6 +/- 10.0; 6 months 39.3 +/- 9.5) and EQ-5D HSI (baseline 0.4 +/- 0.3; 3 months 0.7 +/- 0.3; 6 months 0.7 +/- 0.2). Depression and anxiety symptoms (HADS-D mean at baseline 13.3 +/- 4.2; HADS-A mean at baseline 12.2 +/- 3.9) consistently decreased during the first 3 months (8.7 +/- 4.3; 7.5 +/- 3.6) and showed a further positive change at 6 months (6.9 +/- 4.3; 5.8 +/- 3.4). Somatic and painful symptoms (SSI and VAS) significantly decreased, with the most positive changes in the SSI-28 somatic item (mean at baseline 2.4 +/- 0.7; mean change at 3 months: -0.5; 95% CI -0.6 to -0.5; mean change at 6 months: -0.7; 95% CI -0.8 to -0.7); in 'interference of overall pain with daily activities' (mean at baseline 45.2 +/- 30.7; mean change at 3 months -17.4; 95% CI -20.0 to -14.8; mean change at 6 months -24.4; 95% CI -27.3 to -21.6) and in 'having pain while awake' (mean at baseline 41.1 +/- 29.0; mean change at 3 months -13.7; 95% CI -15.9 to -11.5; mean change at 6 months -20.2; 95% CI -22.8 to -17.5) domains. The results from linear regression analyses showed that the antidepressant switch within classes was consistently associated with a worsening in SF-36 MCS, EQ-5D VAS and HSI compared to non-switching treatment. Furthermore, between-group antidepressants (AD) switch was associated with a worse SF-36 MCS and EQ-5D HSI. MCS (P = 0.028), PCS (P = 0.036) and HSI (P = 0.002) were inversely related to the number of each previous additional depressive episode. PCS (P = 0.009) and HSI (P = 0.005) were also less improved in patients suffering from a chronic medical condition. Moreover, PCS (P = 0.044) and EQ-5D VAS (P < 0.0001) worsening was consistently associated with the presence of a psychiatric illness in the 24 months before baseline. For every additional point on the SSI-somatic score and on the overall pain VAS score at baseline, HSI score were on average 0.062 (P < 0.001) and 0.001 (P = 0.005) smaller, respectively., Conclusions: After starting AD treatment, HRQoL improvements at 3 and 6 months were observed. However, several factors can negatively influence HRQoL, such as the presence of somatic and painful symptoms, the presence of any chronic medical condition or previous psychiatric illness.

Aims: To determine which patient characteristics, incontinence and non-incontinence related, are associated with the symptom severity scores of the Urogenital Distress Inventory (UDI) and the International Consultation on Incontinence Questionnaire Urinary Incontinence (ICIQ-UI); and to determine the association of both patient characteristics and symptom severity scores with quality-of-life scores of the Incontinence Impact Questionnaire (IIQ) and the Incontinence-Quality of Life (I-QOL) questionnaire., Methods: Women presenting with stress urinary incontinence (SUI) symptoms in primary and secondary care entered the Stress Urinary Incontinence Treatment Study (SUIT), an observational study evaluating the cost-effectiveness of duloxetine compared to other non-surgical treatments for SUI. At enrollment patients completed the UDI-6, the short form ICIQ-UI, the IIQ-7 and the I-QOL. Multivariate linear regressions were performed with the UDI-6, ICIQ-UI SF, IIQ-7, and I-QOL as outcomes., Results: The total number of incontinence episodes is the most significant explanatory variable of the two symptom questionnaire scores, but the UDI-6 score also reflects the type of incontinence. The variability of the condition-specific quality-of-life questionnaires is primarily explained by the symptom severity questionnaire scores. Although there is a high intercorrelation, both these symptom questionnaires independently contributed significantly to the IIQ-7 and I-QOL total scores., Conclusions: The UDI-6 and ICIQ-UI SF can be regarded as scientifically sound symptom questionnaires in UI evaluation; but they have differences. Since the UDI-6 and ICIQ-UI SF independently contribute to the quality-of-life scores, this suggests that in incontinence research symptom questionnaires should not focus only on incontinence, but on a broader range of urogenital symptoms., ((c) 2009 Wiley-Liss, Inc.)

Objective: To describe the characteristics of women seeking treatment for symptoms of stress urinary incontinence (SUI) and to investigate the association of SUI symptoms with generic health-related quality of life (HRQoL) as measured by the EuroQol (EQ-5D) instrument., Methods: The Stress Urinary Incontinence Treatment (SUIT) study was a 12-month observational study in four European countries that evaluated the cost-effectiveness of duloxetine compared with other forms of nonsurgical intervention in the treatment of the symptoms of SUI. Four hundred thirty-one physicians observed women seeking treatment for their SUI, and recorded the care provided and the outcomes of that care at enrollment and at 3, 6 and 12 months afterward The impact of SUI on baseline HRQoL as expressed by the EQ-5D index score was assessed by linear and logistic regression., Results: Three thousand seven hundred sixty-two women were enrolled into SUIT, with the largest patient group from Germany. Overall, the majority of women were postmenopausal, had a mean age of 58.0 years, were not current smokers, and tended to be overweight (mean body mass index [BMI]=27.7 kg/m2), with at least one comorbidity. The health state index scores were significantly and independently influenced by the presence of comorbidity(ies) affecting quality of life, total number of stress and urge incontinence episodes, urinary incontinence subtype, comorbidity(ies) affecting incontinence, BMI, socioeconomic status, educational status, age, and country., Conclusion: This article describes the characteristics of patients at the SUIT enrollment visit, and demonstrates that the number of incontinence episodes has a significant impact on the EQ-5D index score.

Background: Duloxetine was found safe and effective in the treatment of moderate to severe female stress urinary incontinence (SUI) in controlled clinical trials; complementary data from routine clinical practice are still wanted., Objectives: To explore the use of various initial duloxetine doses by physicians in the treatment of female SUI in routine clinical practice and its implications on drug safety and patients' subjective impression of effectiveness., Methods: Adult women treated with duloxetine for SUI symptoms were documented as part of an ongoing large-scale observational study in Germany. Data collected at baseline, after 4 and 12 weeks, were evaluated by initial doses. Statistics were descriptive, 95% confidence intervals were calculated for adverse event (AE) rates., Results: A total of 7888 adult women were treated with duloxetine; their mean age was 61.4 years, body mass index 27 kg/m(2), incontinence episode frequency (IEF) 14.0 per week. Previous SUI treatments were observed in 52.2%, comorbidities in 60.4% of the patients. A total of 90.7% reported reduced frequency of SUI-episodes, 12.1% any AE; nausea (5.7%) and vertigo (1.6%) were reported most frequently. In all, 52.2% of patients were initiated on a duloxetine dose of 40 mg/day. Only minor differences in patient characteristics, effectiveness and tolerability were associated with varying initial duloxetine doses., Conclusions: Many women received lower duloxetine doses than expected based on evidence-based dosing recommendations. Although SUI patients in this study had a higher health risk because of old age and multiple comorbidities than in previous controlled clinical trials, AE rates were lower, possibly because of the observational character of the study and/or the use of rather low doses. Similar AE rates for varying initial doses possibly reflect sensible dose-adjustment to individual needs.

Background: Health-related quality of life (HRQoL) data in depression are limited. We studied the impact of antidepressant (AD) treatment on HRQoL outcomes in depressed patients and investigated factors associated with these outcomes in routine practice settings., Methods: The Factors Influencing Depression Endpoints Research (FINDER) study was a 6-month, European, prospective, observational study, designed to estimate HRQoL in 3468 adult patients with a clinically diagnosed episode of depression at baseline and at 3 and 6-months after commencing AD treatment. HRQoL was assessed by the Medical Outcome Short-Form (36) Health Survey (SF-36) and European Quality of Life-5 Dimensions (EQ-5D). Regression analysis identified baseline and treatment variables independently and significantly associated with HRQoL outcomes., Results: Most HRQoL improvement occurred within 3 months of starting treatment. Better HRQoL outcomes were strongly associated with fewer somatic symptoms at baseline, AD treatment taken and not switching within AD groups. Education and occupational status were also important. Depression variables (number of previous depressions and current episode duration) were consistently associated with worse HRQoL outcomes. Self-rated depression severity was associated with poorer outcomes on the SF-36 mental component only., Limitations: As this was an observational study, the important finding that between and within AD group switching impacted HRQoL will need to be investigated in more controlled settings., Conclusions: Receiving an AD treatment was associated with large improvements in HRQoL, but switching within AD groups was consistently associated with poorer outcomes. Somatic symptoms, including painful symptoms, are often present in depressed patients and appear to negatively impact HRQoL outcomes.

Painful physical symptoms (PPS) are common in patients with depression. Our objective was to evaluate the presence of PPS in a sample of SSRI non- or partial-responders with MDD and examine the effect of a switch to duloxetine on those PPS. Outpatients who met criteria for MDD despite having taken an SSRI antidepressant for at least 6 weeks, and who had a Hamilton depression rating scale total score of at least 15 and a clinical global impression of severity score of at least 3, were randomized to switch to duloxetine by either a direct switch or a start-taper switch method. PPS were assessed at baseline and at the study endpoint using various measures including six visual analog scales (VAS) for pain (overall pain, headache, back pain, shoulder pain, interference with daily activities, and time in pain while awake), the pain subscale of the symptom questionnaire-somatic subscale, and the bodily pain subscale of the short form-36 item health survey. Clinically significant levels of pain (mean baseline VAS scores >30 mm) were seen across all VAS pain measures prior to switching. Switch to duloxetine was associated with significant improvements on all pain measures regardless of switch method, and there was evidence for an earlier reduction in pain in the start-taper switch group. In summary, MDD patients who were non- or partial-responders to SSRI treatment were found to have clinically significant pain which improved significantly following switch to duloxetine regardless of the switch method utilized.

Objective: To examine the diagnostic status of patients enrolled in the Factors Influencing Depression Endpoints Research (FINDER) study and symptomatic outcomes and baseline characteristics associated with remission 6 months after commencing antidepressant therapy., Method: Status of clinically diagnosed depressed patients was based on self-rated Hospital Anxiety and Depression Scale (HADS) scores. Five diagnostic categories were defined: noncaseness, mixed anxiety-depression (subthreshold depressive and anxious symptomatology), caseness for depression, caseness for anxiety, and caseness for comorbid anxiety-depression. Assessments included the Somatic Symptom Inventory and health-related quality of life (HRQoL) using the Medical Outcomes Study 36-item Short-Form Health Survey. Remission rates (based on HADS noncaseness for both depression and anxiety) and their associations with baseline characteristics were investigated. Patients were enrolled between May 2004 and September 2005., Results: Of the 3,353 patients enrolled, 66.4% met the HADS criteria for probable depressive disorder and 74.1% met the HADS criteria for probable anxiety disorder. Somatic symptom severity (painful and nonpainful) was highest and HRQoL was lowest in the comorbid anxiety-depression group. After 6 months, remission rates were 50.2% for caseness for depression, 40.4% for caseness for anxiety, and 40.6% for caseness for comorbid anxiety-depression. A lower number of previous depressive episodes, shorter current episode duration, lower painful and nonpainful somatic symptom scores, being married, a higher educational level, and working for pay were most consistently associated with higher remission rates., Conclusions: Physicians do not always differentiate between anxiety and depressive symptoms when making a clinical diagnosis of depression. At baseline, most enrolled patients had significant emotional depressive and anxious symptoms, as well as significant nonpainful and painful somatic symptomatology, and these factors were associated with outcome.

Objective: We hypothesized that combining antidepressant medication with a standardized telephone adherence support intervention would lead to superior outcomes in the treatment of depression compared with antidepressant medication alone., Method: Patients with depression were randomized to receive the antidepressant duloxetine alone (DLX), or duloxetine plus a standardized telephone intervention (DLX+TI), for 12 weeks of open-label treatment. The primary outcome measure was remission (HAMD 17 total score 90% at every visit) in both groups., Conclusions: A telephone intervention in combination with antidepressant medication (duloxetine) did not improve depression outcomes compared with antidepressant alone in this clinical trial, perhaps due to high drug adherence in both treatment groups. Addition of a telephone intervention was, however, associated with increased reporting of AEs.

Objective: To investigate the relationship between the characteristics of somatic symptoms and depression severity, quality of life (QOL), and health resources utilization in patients with major depressive disorder (MDD) in primary care setting., Method: This cross-sectional, nationwide epidemiologic study, carried out in 1150 primary care patients with DSM-IV-defined MDD, evaluated the characteristics of somatic symptoms by means of the Standardized Polyvalent Psychiatric Interview. Depression severity and QOL were evaluated by means of the Zung Self-Rating Depression Scale (SDS) and the Physical and Mental Component Summaries of the Medical Outcomes Study 12-item Short-Form Health Survey. Health resources utilization was measured in terms of doctor consultations and hospitalizations. The associations were assessed by means of adjusted analyses. The study was carried out from April 2004 to July 2004., Results: Disability associated with somatic symptoms and number of somatic symptoms were strongly associated with increased depression severity (2.45 and 0.29 increase in SDS score, respectively) and health resources utilization (odds ratios of 1.42 and 1.04, respectively). Associated disability, frequency, and persistence during leisure time of somatic symptoms were strongly associated with poorer QOL. In contrast, we found a weaker relationship between duration and intensity of somatic symptoms and depression severity, QOL, and health resources utilization., Conclusions: Of the studied somatic symptom characteristics, somatic symptom-associated disability and number of somatic symptoms are strongly associated with increased depression severity and health resources utilization, as well as with decreased QOL. Our results may help physicians identify relevant characteristics of somatic symptoms to more effectively diagnose and treat depression in primary care patients.

Factors influencing outcomes of depression in clinical practice, especially health-related quality of life (HRQoL), are poorly understood. The Factors Influencing Depression Endpoints Research (FINDER) study is a European prospective, observational study designed to estimate the HRQoL of adults with a clinically diagnosed depressive episode at baseline, and 3 and 6 months after commencing antidepressant medication. We report here the study design and baseline patient characteristics. HRQoL was assessed by the 36-item Short-Form Health Survey (SF-36) and European Quality of Life-5 Dimensions (EQ-5D). Patient ratings on Hospital Anxiety and Depression Scale (HADS) and pain Visual Analogue Scale (VAS) were also obtained. Results (n=3468) showed that SF-36 mental component summary (mean 22.2) was more than two SDs below general population norms (mean 50.0) and one SD below clinical depression norms (mean 34.8); the physical component summary (mean 46.1) was similar to general population (mean 50.0) and clinical depression norms (mean 45.0). Mean EQ-5D scores were also lower than general population norms. Mean HADS-Depression and -Anxiety subscores were 12.3 and 13.0, respectively. Fifty-six percent of patients reported an overall pain VAS score of at least 30mm and 70% of these patients had no physical explanation for their pain. Further investigation into factors associated with HRQoL in depression after treatment initiation is warranted.

Antidepressant prescribing patterns and factors influencing the choice of antidepressant for the treatment of depression were examined in the Factors Influencing Depression Endpoints Research (FINDER) study, a prospective, observational study in 12 European countries of 3468 adults about to start antidepressant medication for their first episode of depression or a new episode of recurrent depression. Selective serotonin reuptake inhibitors (SSRIs) were the most commonly prescribed antidepressant (63.3% patients), followed by serotonin-norepinephrine reuptake inhibitors (SNRIs, 13.6%), but there was considerable variation across countries. Notably, tricyclic and tetracyclic antidepressants (TCAs) were prescribed for 26.5% patients in Germany. The choice of the antidepressant prescribed was strongly influenced by the previous use of antidepressants, which was significantly associated with the prescription of a SSRI (OR 0.64; 95% CI 0.54, 0.76), a SNRI (OR 1.49; 95% CI 1.18, 1.88) or a combination of antidepressants (OR 2.78; 95% CI 1.96, 3.96). Physician factors (age, gender, speciality) and patient factors (severity of depression, age, education, smoking, number of current physical conditions and functional syndromes) were associated with initial antidepressant choice in some models. In conclusion, the prescribing of antidepressants varies by country, and the type of antidepressant chosen is influenced by physician- as well as patient-related factors.

Objective: To compare 2 methods of switching selective serotonin reuptake inhibitor (SSRI) non-responders or partial responders to duloxetine., Method: Adult outpatients with DSM-IV major depressive disorder, a Hamilton Rating Scale for Depression (HAM-D(17)) total score of >or= 15, and a Clinical Global Impressions-Severity of Illness score of >or= 3 despite at least 6 weeks of SSRI treatment were randomly assigned to either abrupt discontinuation of SSRI immediately followed by initiation of duloxetine (direct switch [DS]; N = 183) or tapered discontinuation of SSRI over 2 weeks and simultaneous administration of duloxetine (start-taper switch [STS]; N = 185). Efficacy, safety, and tolerability outcomes associated with these 2 switch methods were compared following switch and after 10 weeks of duloxetine treatment. The study was conducted from August 2004 to March 2006., Results: There was a significant improvement in depressive symptom severity in both switch groups as measured by mean change in HAM-D(17) total score (p

Objective: To evaluate the relationship of the severity of restless legs syndrome (RLS) as assessed by a subjective, patient-rated scale (International RLS Study Group Rating Scale, IRLS), and of periodic leg movements in sleep (PLMS) as an objective parameter, in two different patient populations., Methods: Data of 200 unmedicated patients with idiopathic RLS were evaluated. Group 1 (n=100) consisted of selected patients participating in the Pergolide European Australian RLS (PEARLS) study. Group 2 (n=100) represented an outpatient RLS population investigated in a Sleep Disorders Center. Additionally, Group 1 was also evaluated after a 6 week double-blind treatment period, where 47 patients received pergolide and 53 patients placebo., Results: In unmedicated patients, IRLS scores correlated with the PLMS-arousal index (r=0.22, p=0.033) but not with the PLMS index in Group 1 while no correlation was found in Group 2. The change of the IRLS score under treatment in Group 1 correlated significantly both with the change of the PLMS index (r=0.42, p<0.001) and the change of the PLMS-arousal index (r=0.38, p<0.001)., Conclusions: The IRLS adequately reflects treatment changes of PLMS indices. In unmedicated patients, the IRLS correlates with PLMS indices probably only in selected RLS populations with predefined PSG criteria and high PLM activity., Significance: The IRLS is an appropriate subjective rating scale for measuring treatment effects in RLS.

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.

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.

Objective: To describe the characteristics of women seeking treatment for symptoms of urinary incontinence (UI) in European countries., Design: Prospective urinary incontinence research (PURE) was a 6-month, observational, pan-European study, primarily aimed at determining the direct costs of urinary incontinence treatment. The secondary objectives of PURE were to describe the impact of UI on health-related quality of life (HRQoL) in treatment seeking patients and to illustrate the treatment patterns for UI in Europe., Setting: One thousand and Fifty-five physicians from 14 European countries, including general practitioners (GPs), gynaecologists, urologists and geriatricians, observed women seeking treatment for their UI and recorded data at the first observation and then prospectively at 3 and 6 months after the first observation during the normal course of therapy., Subjects: Women of at least 18 years of age who had experienced urinary leakage in the 12 months prior to enrolment in the study, who were seeking treatment or under treatment for UI and who presented within the normal course of UI care were included in the 6 months study. The first observation characteristics of the patients are described here., Methods: Demographic characteristics, as well as disease and treatment status at first observation were explored using descriptive summary statistics to gain an understanding of the population studied., Results: In total, 9487 women took part in PURE, with the largest patient groups from Germany, Spain and the UK/Ireland. The majority of women were post-menopausal and had a mean age of 60.7 years, were not current smokers and tended to be overweight (BMI > 25.0). Overall, mixed UI symptoms were more common than SUI and UUI, as defined by clinical opinion (SUI 38%, MUI 42% and UUI 18%), and by a two-item questionnaire, the S/UIQ (SUI 29%, MUI 58% and UUI 13%). Around half of the patients (48%) suffered from their symptoms for less than 2 years before consulting a physician; 28% delayed seeking treatment for 3-5 years, with 13% waiting for 6-10 years and the remaining 11% waiting for 11 or more years., Conclusions: Some of the described patients' characteristics may provide important information to clinicians to enable them to take a more active approach to case-finding, which will ultimately benefit the incontinent patient.

Objectives: To review the main findings of the Euralox 1 study - a multicentre, randomised, double-blind study conducted in 1008 healthy postmenopausal women allocated to raloxifene (n = 495) or continuous combined estrogen-progestin therapy (ccEPT; n = 513) for 6 months -- and provide an overview of the risks and benefits of raloxifene and ccEPT., Methods: A review is provided of previously published findings on uterine safety (bleeding rates and changes in endometrial thickness and uterine volume), gynaecological adjudication, cardiovascular risk (lipids, fibrinogen), adverse events, compliance, treatment satisfaction and quality of life. New data on biochemical markers of bone turnover (serum N-telopeptides and C-terminal telopeptides of type I collagen; NTX and CTX) assessed before and after 6 months' treatment are presented., Results: Raloxifene caused less uterine bleeding than ccEPT and, unlike ccEPT, did not alter endometrial thickness or uterine volume. Serum CTX and NTX levels were reduced in both treatment groups, but the reduction was significantly greater with ccEPT. The two treatments had differential effects on lipids and fibrinogen levels; raloxifene had more favourable effects on serum HDL, the LDL/HDL ratio, and plasma fibrinogen. Raloxifene was associated with fewer adverse events or discontinuations, and this was associated with higher treatment satisfaction and better self-reported compliance., Conclusions: The clinical risk-benefit profile of raloxifene derived from the intermediate endpoints of this study suggests that it may be a better alternative to ccEPT for preventing long-term postmenopausal health risks in healthy postmenopausal women who are not suffering from vasomotor symptoms.

Objective: To compare the incident rate of abnormal endometrial findings in postmenopausal women receiving treatment with either 60 mg of raloxifene or a continuous combined estrogen plus progestin therapy containing 2 mg of 17 beta-estradiol plus 1 mg of norethisterone acetate for a duration of up to 12 months., Methods: One thousand eight asymptomatic postmenopausal women with osteoporosis or cardiovascular risk factors with an endometrial thickness of less than 5 mm at baseline participated in this prospective, randomized, double-blind trial that lasted 6 months; 347 of these women also participated in a 6-month extension. Women with repeated bleeding or an increase in endometrial thickness to above 5 mm were subjected to saline-infused sonohysterography or hysteroscopy with biopsy. Sonographic, histologic, and clinical findings were adjudicated by a panel of 4 experts blinded with respect to patients' treatments. All adjudicated patients were grouped into 15 diagnostic categories according to predefined criteria., Results: Three hundred thirty-four women needed adjudication during the core phase, 73 (14.7%) of those taking raloxifene and 261 (50.9%) taking continuous combined estrogen plus progestin therapy (P <.001). Compared with raloxifene, women using continuous combined estrogen plus progestin therapy had significantly higher rates of benign endometrial proliferation (8.8 versus 1.2%, P <.001), endometrial polyps (4.3 versus 2.0%, P =.048), and cystic atrophy (5.5 versus 1.2%, P <.001)., Conclusion: Women using continuous combined estrogen plus progestin therapy more often have benign endometrial pathology and, in our study, more often required the protocol-specific gynecological follow-up assessments for safety reasons, as compared with those using raloxifene. These findings are of clinical relevance when choosing the most appropriate therapy for postmenopausal health risks such as osteoporosis.

Objective: To evaluate the short- and long-term safety and efficacy of pergolide therapy for restless legs syndrome (RLS) in a double-blind, placebo-controlled, randomized trial (Pergolide European Australian RLS [PEARLS] study)., Methods: We randomized 100 patients with idiopathic RLS were randomized to pergolide, 0.25 to 0.75 mg, in the evening or placebo for 6 weeks (phase 1); thereafter, patients with response on the Patient Global Impression (PGI) scale continued on double-blind pergolide or placebo, and nonresponders received open-label pergolide up to 1.5 mg/d for 12 months of treatment (phase 2). Sleep efficiency (SE) and periodic limb movements during sleep (PLMS) arousal index were monitored by centrally evaluated polysomnography (PSG). The severity of RLS was assessed using the validated International RLS Scale (IRLS)., Results: In phase 1 (change from baseline to week 6), pergolide reduced PLMS arousal index vs placebo (mean +/- SD, -12.6 +/- 10.0 vs -3.6 +/- 15.9; p = 0.004), and SE did not improve (mean +/- SD, +11.3 +/- 11.9% vs +6.1 +/- 18.6%; p = 0.196). Pergolide improved RLS severity score (-12.2 +/- 9.9 vs -1.8 +/- 7.5 placebo; p < 0.001) and was associated with a higher PGI response (68.1% vs 15.1%; p < 0.001) and improvements in periodic limb movements (PLM) index, PGI improvement scale, Clinical Global Impression improvement, and IRLS (all p < 0.001), patient-reported SE (p = 0.019), and quality of sleep (p < 0.001). After 12 months (phase 2), double-blind pergolide maintained improvements in PLMS arousal index and PLM index. Placebo patients switched to open-label pergolide in phase 2 exhibited marked improvements in these measures that were maintained at 12 months. Pooled results from the blinded and open-label pergolide groups demonstrated improvements at 12 months in the PLMS arousal index (p = 0.028) and PLM index (p < 0.0001) compared with placebo. Nausea and headache were more frequent with pergolide than with placebo treatment., Conclusions: Pergolide substantially improves periodic limb movement measures and subjective sleep disturbance associated with restless legs syndrome. Low-dose pergolide was well tolerated and maintained its efficacy in the long term.

Raloxifene effectively reduces the incidence of vertebral fractures in patients with postmenopausal osteoporosis. Recent data suggest that low-dose monofluorophosphate (MFP) plus calcium reduces the vertebral fracture rate in postmenopausal women with moderate osteoporosis. The objective of this study was to evaluate the combination of raloxifene and MFP in the treatment of postmenopausal women with osteopenia, osteoporosis and severe osteoporosis. A total of 596 postmenopausal women with osteopenia, osteoporosis and severe osteoporosis (mean femoral neck T-score of -2.87 SD) were randomized to treatment with 60 mg/day raloxifene HCl and 20 mg/day fluoride ions (as MFP) or 20 mg/day fluoride and placebo for 18 months. All patients received calcium (1000 mg/day) and vitamin D (500 IU/day) supplements. Changes in bone mineral density (BMD), as primary endpoint, and the rate of osteoporotic fractures and biochemical markers, as secondary endpoints, were assessed. As compared with MFP, raloxifene plus MFP was associated with significantly greater mean increases in the BMD of the femoral neck (1.37% versus 0.33%; P=0.004), total hip (0.89% versus -0.42%; P<0.001) and lumbar spine (8.80% versus 5.47% P<0.001). In the raloxifene plus MFP group, 16 patients sustained 17 osteoporotic fractures, as compared with 22 patients sustaining 34 incident osteoporotic fractures in the MFP group ( P=0.313). One patient in the raloxifene plus MFP group sustained multiple osteoporotic fractures, as compared with eight patients in the MFP group ( P=0.020). MFP alone significantly increased the serum bone alkaline phosphatase (bone ALP) and the urinary C-terminal crosslinking telopeptide of type I collagene (U-CTX). The addition of raloxifene in the combination arm blunted the rise in bone ALP, which remained nevertheless significant, and abolished the increase in U-CTX. The combination of raloxifene with MFP was generally well tolerated. This study demonstrates that, in postmenopausal women with osteopenia, osteoporosis and severe osteoporosis, the combination therapy of raloxifene plus MFP favorably influences the BMD and the bone formation and resorption balance, and may reduce the risk of multiple osteoporotic fractures compared to MFP alone.

Objective: To compare the uterine effects of 60 mg of raloxifene with a continuous combined hormone replacement therapy, a preparation of 2 mg 17beta-oestradiol (E(2)) and 1 mg norethisterone acetate for a duration of 12 months., Design: A randomised, double-blind trial., Setting: Multicentre: Europe, Israel, South Africa., Population: Asymptomatic postmenopausal women with risk factors for osteoporosis or cardiovascular disease who had an endometrial thickness of less than 5 mm. One thousand and eight women were randomised for the six month core; of these 420 were invited to continue into a six month extension period., Methods: Randomisation to either raloxifene or continuous combined hormone replacement therapy. Patients, recruiters and assessors were blinded to the treatment used., Main Outcome Measures: The frequency of vaginal spotting/bleeding as recorded in a diary, endometrial thickness and uterine volume as measured by transvaginal ultrasonography at baseline and after 6 and 12 months., Results: After six months of therapy with raloxifene, the rate of women on raloxifene reporting vaginal bleeding and spotting (6.8%) was similar to the rate in the lead-in phase (8.3%) but increased from 7.0% to 55.1% in the continuous combined hormone replacement therapy group. Raloxifene treatment was not associated with a significant change from baseline to endpoint in mean endometrial thickness (P = 0.11), whereas continuous combined hormone replacement therapy treatment was associated with an increase in this value of mean (SD) of 1.2 (2.2) mm (P < 0.001). Compared with raloxifene, mean endometrial thickness for women on continuous combined hormone replacement therapy was significantly increased at endpoint [4.6 (2.1) mm vs 3.5 (1.7) mm; change from baseline P < 0.001]. In the raloxifene group, there was a trend towards a decrease from baseline in uterine volume [from 31.4 (20.3) to 30.3 (16.2) mm; P = 0.37]; in the continuous combined hormone replacement therapy group, there was a significant increase in uterine volume [from 31.3 (16.3) to 54.0 (36.1) mm; P < 0.001], and the difference in the effect of both compounds on change in uterine volume at endpoint reached statistical significance (P < 0.001). Statistically significant differences between the treatment groups were sustained for all parameters during the extension period. Early discontinuation rates, both overall and due to adverse events, were significantly lower (P < 0.001) in the raloxifene group after 6 and 12 months., Conclusion: Compared with continuous combined hormone replacement therapy, 6 and 12 months of raloxifene treatment do not lead to vaginal bleeding/spotting, are not associated with increased endometrial thickness or uterine volume and result in a significantly lower rate of early treatment discontinuations in asymptomatic women receiving treatment to prevent long term postmenopausal health risks.

Abrupt interruption or cessation of selective serotonin reuptake inhibitor (SSRI) treatment may result in discontinuation or treatment interruption symptoms. Recent reports suggested these symptoms occur more frequently with shorter half-life SSRIs. Previous studies indicated a 5-8-day treatment interruption resulted in fewer discontinuation-emergent adverse events in fluoxetine-treated patients than in paroxetine-treated patients. This study examines the effects of shorter treatment interruption (3-5 days), as would occur if patients miss just a few doses of medication. Patients successfully treated for depression with fluoxetine or paroxetine underwent treatment interruption in a double-blind fashion. Treatment interruption-emergent symptoms were assessed using the Discontinuation-Emergent Signs and Symptoms checklist. Other assessments included the Montgomery-Asberg Depression Rating Scale, Clinical Global Impressions-Severity scale and a social functioning questionnaire. Of 150 patients enrolled, 141 completed the study. Following treatment interruption, fluoxetine-treated patients experienced fewer treatment interruption-emergent events than did paroxetine-treated patients. The paroxetine treatment group also experienced significant increases in depressive symptoms, clinical global severity scores and difficulty in social functioning; the fluoxetine treatment group did not. These results are consistent with reports suggesting abrupt interruption of treatment with paroxetine is more often associated with somatic and psychological symptoms than is abrupt interruption of fluoxetine. Patients treated with fluoxetine appeared to be protected by its longer half-life.

Objective: To compare continuous combined hormone replacement therapy (ccHRT) and raloxifene with respect to compliance and quality of life, which were predefined secondary endpoints of a large, prospective study designed to investigate the uterine effects of both treatments., Design: Double-blind, randomised controlled trial of six-month duration., Setting: One hundred and twenty-nine gynaecology hospital departments, clinics or practices specialised in women's healthcare, located in Europe, South Africa and Israel., Population: Healthy postmenopausal women (n = 1008)., Main Outcome Measures: Changes in quality of life using the Women's Health Questionnaire (WHQ) and compliance using a compliance questionnaire and pill count. Adverse event and early discontinuation rates and satisfaction with treatment using a visual analogue scale (VAS)., Results: Women taking raloxifene reported greater satisfaction with their treatment as assessed on the VAS (P = 0.004), and a lower proportion, as compared with ccHRT, reported being worried by the treatment (9.6% vs 20.2%, P < 0.01). Women taking ccHRT reported greater deterioration in scores from the WHQ for depressed mood and menstrual symptoms than those taking raloxifene (P < 0.01). For memory, vasomotor symptoms and sexual behaviour, the ccHRT group reported significantly greater mean improvements (P < 0.05). Over half (58.8%) of those taking raloxifene noticed no effect, 37.7% felt better and 3.4% felt worse as measured using the compliance questionnaire. Fifty percent of the women taking ccHRT felt better, 37.8% noticed no effect but over 10% felt worse. More women on raloxifene (94.6%) than on ccHRT (85.9%) reported that they were taking their double-blinded medication regularly (P < 0.01)., Conclusions: A lower rate of adverse event-related discontinuations, the lack of negative effects on quality of life and a smaller proportion of women being worried by the drug treatment were associated with higher treatment satisfaction and better compliance in postmenopausal women taking ccHRT or raloxifene.

Objective: To compare the effects of the selective estrogen receptor modulator (SERM) raloxifene (Evista) and a continuous combined hormone replacement therapy (ccHRT) formulation containing estradiol and norethisterone acetate (Kliogest) on lipid and fibrinogen levels of postmenopausal women., Methods: Euralox 1 was a prospective, randomized, double-blind trial. After a placebo wash-out, healthy postmenopausal women (n = 1008, average age 56.1 +/- 4.9 years) with a health risk profile that suggested a potential benefit from either treatment were randomly assigned to either 60 mg raloxifene or ccHRT consisting of 2 mg estradiol and 1 mg norethisterone acetate (NETA) per day for 6 months., Measurements: Total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol with its fractions HDL2 and HDL3, the LDL/HDL ratio, triglycerides and fibrinogen were assessed at baseline and after 6 months or on early drop-out., Results: Baseline values were comparable between the two groups. Blood samples of 841 women (83.4%) were available at baseline and endpoint. Total and LDL cholesterol decreased statistically significantly from baseline to endpoint in both treatment arms (by 7.2% and 3.8% with raloxifene and by 13.0% and 8.9% with ccHRT, respectively). Raloxifene produced a statistically significant increase in HDL cholesterol by 4.2%, while ccHRT induced a decline by 9.5%. Triglycerides were moderately suppressed with raloxifene and ccHRT, by 3.6 and 5.4%, respectively. Fibrinogen fell by 7.0% with raloxifene and rose by 3.6% with ccHRT., Conclusions: Continuous combined HRT was associated with decreases in total cholesterol and LDL cholesterol about twice as large as with raloxifene, but also with a decrease in HDL cholesterol. The smaller decreases in total cholesterol and LDL cholesterol associated with raloxifene were accompanied by an increase in HDL cholesterol and a decrease in fibrinogen. In conclusion, raloxifene affects fibrinogen concentrations and the overall cholesterol profile more favorably than ccHRT; these differences may have important implications for the reduction of cardiovascular disease.

A two-centre, double-blind, placebo controlled, randomized 3-way crossover study was undertaken to assess the efficacy, tolerability and safety of celiprolol in mild to moderate essential hypertension. A 4-week single-blind placebo run-in/screening period, during which no antihypertensive medication was given, was followed by 3 consecutive 4-week treatment periods with placebo or celiprolol (200 mg or 400 mg daily). At the end of the 4-week placebo run-in/screening period, 26 hospital out-patients with a seated mean blood pressure (systolic/diastolic) of 161.4/101.7 mmHg and a mean pulse rate of 75 beats/min entered the double-blind crossover phase of the study. Results showed that there was no significant difference in seated mean systolic or diastolic blood pressure between 200 mg celiprolol daily (149.2/92.3 mmHg) and 400 mg celiprolol daily (149.1/92.5 mmHg). However, mean seated systolic and diastolic blood pressures were significantly (p less than 0.05) lower on celiprolol than on placebo (157.1/98.2 mmHg). Neither dose of celiprolol had a significant effect on seated pulse rate. No patient was withdrawn due to an adverse event and no laboratory assessment outside the normal range was reported to be of any clinical significance. It is concluded that oral celiprolol, 200 mg or 400 mg daily, is effective and well tolerated for controlling mild to moderate essential hypertension. Since both doses had very similar effects on blood pressure there is no advantage in this group of patients for the 400 mg daily dose of celiprolol.