Biomechanical and clinical evaluation of minimal invasive plate osteosynthesis for two-part clavicle shaft fractures.

BACKGROUND: Many surgical treatment methods exist for clavicle shaft fractures. A locking compression plate (LCP) fixation with three screws per fracture side is commonly used. For certain fractures a stabilization with 2 screws per side is potentially suitable, offering the advantage of reduced soft tissue approach, while avoiding the disadvantages of minimally-invasive nailing at the same time. This hypothesis was evaluated biomechanically and clinically. METHODS: Four treatment procedures were investigated biomechanically using composite human clavicle specimens. A load-to-failure test was performed using a three-point cantilever test. In group 1, a simple shaft fracture was simulated and stabilized with 2 screws per fracture side (5-hole LCP). In the second group 3 screws per side (7-hole LCP) were used. In group 3, a non-reduced fracture zone was simulated and treated with 3 screws per side (7-hole LCP). In group 4, an anatomically reduced fracture zone was simulated and treated with 3 screws per side (7-hole LCP). Furthermore 27 patients treated with a short plate and 2 screws per side (similar to group 1) were assessed after a minimum follow-up of 12 months (Constant and DASH Score). RESULTS: The maximum load-to-failure of group 1 was 367N. We observed the highest load-to-failure in group 2 with 497N and the lowest in group 3 with 90N. In group 4 a maximum load-to-failure of 298N could be evaluated. There was no significant difference in load-to-failure between the treatment of a simple clavicle fracture using 5- or 7-hole LCP (p = 0.121). However, we found a significant difference of load-to-failure between the simple and anatomically reduced fracture using a 7-hole plate (p = 0.014). The mean constant score of the surgically treated patients was 95 and the DASH score 3.0. Fracture consolidation was observed in 96.3%. CONCLUSIONS: For certain non-fragmented and well interlocking 2-part fractures, a plate osteosynthesis fixed with only 2 screws per fracture side might offer sufficient biomechanical stability, better soft tissue preservation and comparable fusion rates compared to the operative treatment with 3 screws per side. However, the maximum load-to-failure of the 7-hole LCP was higher than of the 5-hole LCP, but this difference was not statistically significant. TRIAL REGISTRATION: Approval from the ethics committee of the Technical University of Dresden was retrospectively obtained (EK 588122019).

Treatment of critical bone defects using calcium phosphate cement and mesoporous bioactive glass providing spatiotemporal drug delivery.

Calcium phosphate cements (CPC) are currently widely used bone replacement materials with excellent bioactivity, but have considerable disadvantages like slow degradation. For critical-sized defects, however, an improved degradation is essential to match the tissue regeneration, especially in younger patients who are still growing. We demonstrate that a combination of CPC with mesoporous bioactive glass (MBG) particles led to an enhanced degradation in vitro and in a critical alveolar cleft defect in rats. Additionally, to support new bone formation the MBG was functionalized with hypoxia conditioned medium (HCM) derived from rat bone marrow stromal cells. HCM-functionalized scaffolds showed an improved cell proliferation and the highest formation of new bone volume. This highly flexible material system together with the drug delivery capacity is adaptable to patient specific needs and has great potential for clinical translation.

Composites consisting of calcium phosphate cements and mesoporous bioactive glasses as a 3D plottable drug delivery system.

Calcium phosphate cements (CPC) and mesoporous bioactive glasses (MBG) are two well studied biomaterial groups widely under investigation on their applicability to treat bone defects in orthopaedics and maxillofacial surgery. Recently the extrusion properties of CPC-MBG composites using a pasty CPC based on a hydrophobic carrier-liquid were studied in our group demonstrating that such composites are suitable for low temperature 3D plotting. Based on this work, we show in this study that by variation of the MBG content in the composite the degradation of the final scaffolds can be influenced. Furthermore, by modifying the cement phase and/or the MBG with therapeutically active ions like strontium, the released ion concentration can be varied over a wide range. In a second step the MBG was functionalized exploiting the high specific surface area of the glass as a carrier system for proteins like lysozyme or grow factors. We developed a protocol that allows the incorporation of protein-laden MBG in CPC pastes without impairing the extrudability of the CPC-MBG composites. Additionally, we found that released proteins from pure MBG or 3D plotted composite-scaffolds maintained their biological activity. Therefore, the combination of CPC and MBG allows the creation of a highly flexible composite system making it a promising candidate for bone tissue engineering. STATEMENT OF SIGNIFICANCE: Calcium phosphate cements and mesoporous bioactive glasses are two promising degradable biomaterials for the regenerative treatment of bone defects. The combination of both materials to a 3D printable composite enables the creation of implants with patient specific geometry. By varying the composition of the composite, the degradation behaviour can be influenced and especially the release of therapeutically active ions is tailorable over a wide range. We demonstrated this for strontium, as it has been shown to stimulate bone formation. Moreover, the bioactive glass can be used as a carrier system for drugs or growth factors and we show the successful combination of such functionalised glass particles and a cement paste without affecting the printability.

Bayesian Strategies in Rare Diseases.

Bayesian strategies for planning and analyzing clinical trials have become a viable choice, especially in rare diseases where drug development faces many challenges and stakeholders are interested in innovations that may help overcome them. Disease natural history and clinical outcomes occurrence and variability are often poorly understood. Standard trial designs are not optimized to obtain adequate safety and efficacy data from small numbers of patients. Bayesian methods are well-suited for adaptive trials, with an accelerated learning curve. Using Bayesian statistics can be advantageous in that design choices and their consequences are considered carefully, continuously monitored, and updated where necessary, which ultimately provides a natural and principled way of seamlessly combining prior clinical information with data, within a solid decision theoretical framework. In this article, we introduce the Bayesian option in the rare disease context to support clinical decision-makers in selecting the best choice for their drug development project. Many researchers in drug development show reluctance to using Bayesian statistics, and the top-two reported barriers are insufficient knowledge of Bayesian approaches and a lack of clarity or guidance from regulators. Here we introduce concepts of borrowing, extrapolation, adaptation, and modeling and illustrate them with examples that have been discussed or developed with regulatory bodies to show how Bayesian strategies can be applied to drug development in rare diseases.

Low transmission rates of Equine infectious anemia virus (EIAV) in foals born to seropositive feral mares inhabiting the Amazon delta region despite climatic conditions supporting high insect vector populations.

BACKGROUND: Marajó Island, within in the Amazon River Delta, supports numerous bands of feral equids including the genetically distinct Marajoara horses. Approximately 40% of the equids on the island are infected with Equine infectious anemia virus (EIAV). This high seropositivity rate coupled with the need to preserve rare breeds such as the Marajoara horse precludes euthanasia as the primary means for controlling EIAV in this region. In the absence of iatrogenic transmission, spread of this lentivirus is mediated primarily by hematophagous insects, whose year-round prevalence on the island is supported by favorable climatic conditions. In addition, cases of vertical EIAV transmission have been observed suggesting inclusion of seropositive mares in restorative breeding programs could result in their progeny becoming infected with this virus either pre-parturition or post-partum via hematophagous insects. Therefore, the aim of this study was to evaluate EIAV vertical and post-partum insect-mediated transmission rates among foals born to seropositive feral mares until natural weaning. Serum samples from foals born to seropositive feral mares within the Soure municipality, of Marajó Island, were collected to investigate their serological status, using an indirect ELISApgp45, with positive samples confirmed using the classical agar gel immunodiffusion (AGID) assay. RESULTS: The serological status of 28 foals were monitored over a 2-year period with some subjects, depending on their date of birth, being sampled up to six times. All foals remained with their respective mares until fully weaned at approximately 10 months of age. Only 2 foals (7.14%) in the study group became seropositive against EIAV. CONCLUSION: The results demonstrate that in most cases it is possible to obtain seronegative foals born to and eventually weaned by EIA positive mares, even in equatorial regions where substantial rainfall and high temperatures favor the proliferation of insect vectors.

Oral ferroportin inhibitor vamifeport for improving iron homeostasis and erythropoiesis in ß-thalassemia: current evidence and future clinical development.

INTRODUCTION: In ß-thalassemia, imbalanced globin synthesis causes reduced red blood cell survival and ineffective erythropoiesis. Suppressed hepcidin levels increase ferroportin-mediated iron transport in enterocytes, causing increased iron absorption and potentially iron overload. Low hepcidin also stimulates ferroportin-mediated iron release from macrophages, increasing transferrin saturation (TSAT), potentially forming non-transferrin-bound iron, which can be toxic. Modulating the hepcidin-ferroportin axis is an attractive strategy to improve ineffective erythropoiesis and limit the potential tissue damage resulting from iron overload. There are no oral ß-thalassemia treatments that consistently ameliorate anemia and prevent iron overload. AREAS COVERED: The preclinical and clinical development of vamifeport (VIT-2763), a novel ferroportin inhibitor, was reviewed. PubMed, EMBASE and ClinicalTrials.gov were searched using the search term 'VIT-2763'. EXPERT OPINION: Vamifeport is the first oral ferroportin inhibitor in clinical development. In healthy volunteers, vamifeport had comparable safety to placebo, was well tolerated and rapidly decreased iron levels and reduced TSAT, consistent with observations in preclinical models. Data from ongoing/planned Phase II studies are critical to define its potential in ß-thalassemia and other conditions associated with iron overabsorption and/or ineffective erythropoiesis. If vamifeport potentially increases hemoglobin and reduces iron-related parameters, it could be a suitable treatment for non-transfusion-dependent and transfusion-dependent ß-thalassemia.

Tailorable Zinc-Substituted Mesoporous Bioactive Glass/Alginate-Methylcellulose Composite Bioinks.

Bioactive glasses have been used for bone regeneration applications thanks to their excellent osteoconductivity, an osteostimulatory effect, and high degradation rate, releasing biologically active ions. Besides these properties, mesoporous bioactive glasses (MBG) are specific for their highly ordered mesoporous channel structure and high specific surface area, making them suitable for drug and growth factor delivery. In the present study, calcium (Ca) (15 mol%) in MBG was partially and fully substituted with zinc (Zn), known for its osteogenic and antimicrobial properties. Different MBG were synthesized, containing 0, 5, 10, or 15 mol% of Zn. Up to 7 wt.% of Zn-containing MBG could be mixed into an alginate-methylcellulose blend (algMC) while maintaining rheological properties suitable for 3D printing of scaffolds with sufficient shape fidelity. The suitability of these composites for bioprinting applications has been demonstrated with immortalized human mesenchymal stem cells. Uptake of Ca and phosphorus (P) (phosphate) ions by composite scaffolds was observed, while the released concentration of Zn2+ corresponded to the initial amount of this ion in prepared glasses, suggesting that it can be controlled at the MBG synthesis step. The study introduces a tailorable bioprintable material system suitable for bone tissue engineering applications.

Toward Biofabrication of Resorbable Implants Consisting of a Calcium Phosphate Cement and Fibrin-A Characterization In Vitro and In Vivo.

Cleft alveolar bone defects can be treated potentially with tissue engineered bone grafts. Herein, we developed novel biphasic bone constructs consisting of two clinically certified materials, a calcium phosphate cement (CPC) and a fibrin gel that were biofabricated using 3D plotting. The fibrin gel was loaded with mesenchymal stromal cells (MSC) derived from bone marrow. Firstly, the degradation of fibrin as well as the behavior of cells in the biphasic system were evaluated in vitro. Fibrin degraded quickly in presence of MSC. Our results showed that the plotted CPC structure acted slightly stabilizing for the fibrin gel. However, with passing time and fibrin degradation, MSC migrated to the CPC surface. Thus, the fibrin gel could be identified as cell delivery system. A pilot study in vivo was conducted in artificial craniofacial defects in Lewis rats. Ongoing bone formation could be evidenced over 12 weeks but the biphasic constructs were not completely osseous integrated. Nevertheless, our results show that the combination of 3D plotted CPC constructs and fibrin as suitable cell delivery system enables the fabrication of novel regenerative implants for the treatment of alveolar bone defects.

Frequency of Attendance at Religious Services and Exposure to Environmental Tobacco Smoke.

Exposure to environmental tobacco smoke (ETS) is associated with increased risk of disease and death. Reports on ETS and religion are lacking. Data from the National Health and Nutrition Examination Survey were used to test this association. In 4,712 nonsmokers, serum cotinine level of 0.05-3.99 ng/mL indicated ETS exposure. Frequency of attendance at religious services was categorized as > = weekly or less. In bivariate analysis, ETS exposure occurred in 28.6% of those with > = weekly attendance but 36.4% of less frequent attenders (p = 0.0004). In logistic regression controlling for multiple confounders OR = 0.72, 95%CI 0.61-0.85. ETS exposure was negatively associated with religion.

Use, Persistence, Efficacy, and Safety of Apixaban in Patients with Non-Valvular Atrial Fibrillation in Unselected Patients in Germany. Results of the Prospective Apixaban in Atrial Fibrillation (APAF) Registry.

INTRODUCTION: Apixaban has been shown to be superior to warfarin in patients with non-valvular atrial fibrillation in the randomized ARISTOTLE trial and its use is recommended in current guidelines. There are only scarce data about its use, efficacy, and safety in unselected patients in Germany. METHODS AND RESULTS: The APAF registry is a prospective non-interventional study enrolling 5015 patients with non-valvular atrial fibrillation. Of these, 1349 (26.9%) patients were initially treated with apixaban and followed up at 3 and 12 months. The dose of apixaban used was 1 × 2.5 mg in 1.6%, 2 × 2.5 mg in 30.4%, and 2 × 5 mg daily in 68.0% of patients, respectively. Inappropriate underdosing of apixaban was observed in 22.3%, mostly in elderly patients with higher HAS-BLED Score and a history of bleeding. Persistence to apixaban after 1 year was 88.6%, while the dose was changed in 3.7% of patients. Switching to other NOACs or VKAs occurred in 5.1%. After 12 months, all-cause mortality was 5.0%, non-fatal stroke occurred in 0.4%, non-fatal myocardial infarction in 0.6%, ISTH major bleeding in 0.8%, moderate or minor bleeding in 4.3% of patients, respectively. CONCLUSIONS: In this prospective experience in unselected patients with atrial fibrillation, persistence to apixaban was high, and efficacy and safety were comparable to the results in clinical trials, supporting its use in clinical practice.

Oral ferroportin inhibitor VIT-2763: First-in-human, phase 1 study in healthy volunteers.

Restriction of iron availability by ferroportin inhibition is a novel approach to treating non-transfusion-dependent thalassemia (ß-thalassemia intermedia). This first-in-human, Phase I study (https://www.clinicaltrialsregister.eu; EudraCT no. 2017-003395-31) assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of single- and multiple-ascending doses (SAD and MAD) of the oral ferroportin inhibitor, VIT-2763, in healthy volunteers. Participants received VIT-2763 5/15/60/120/240 mg or placebo in the SAD phase and VIT-2763 60/120 mg once daily, VIT-2763 60/120 mg twice daily, or placebo for 7 days in the MAD phase. Seventy-two participants completed treatment. VIT-2763 was well tolerated and demonstrated a similar safety profile to the placebo. There were no serious or severe adverse events, or discontinuations due to adverse events. VIT-2763 absorption was relatively fast, with detectable levels 15 to 30 minutes post-dose. Following multiple dosing there was no apparent change in absorption and accumulation was minimal. Mean elimination half-life was 1.9 to 5.3 hours following single dosing, and 2.1 to 3.8 hours on Day 1 and 2.6 to 5.3 hours on Day 7, following repeated dosing. There was a temporary decrease in mean serum iron levels with VIT-2763 single doses ≥60 mg and all multiple doses; mean calculated transferrin saturation (only assessed following multiple dosing) also temporarily decreased. A shift in mean serum hepcidin peaks followed administration of all iron-lowering doses of VIT-2763. This effect was less pronounced after 7 days of multiple dosing (aside from with 120 mg once daily). These results support the initiation of clinical studies in patients with non-transfusion-dependent thalassemia and documented iron overload due to ineffective erythropoiesis.

Development and Characterization of Composites Consisting of Calcium Phosphate Cements and Mesoporous Bioactive Glass for Extrusion-Based Fabrication.

Calcium phosphate cements (CPC) and mesoporous bioactive glasses (MBG) are two degradable biomaterial groups widely under investigation concerning their applicability to treat bone defects. MBG-CPC composites were recently shown to possess enhanced degradation properties in comparison to pure CPC. In addition, modification of MBG allows an easy incorporation of therapeutically effective ions. Additive manufacturing of such composites enables the fabrication of patient-specific geometries with further improved degradation behavior due to control over macroporosity. In this study, we developed composites prepared from a non-aqueous carrier-liquid (cl) based CPC paste and MBG particles suitable for extrusion-based additive manufacturing (3D plotting). CPC with the addition of up to 10 wt % MBG were processible by adjusting the amount of cl. Scaffolds consisting of a 4, 6 and 8%-MBG-CPC composite were successfully manufactured by 3D plotting. While mechanically characterization of the scaffolds showed an influence of the MBG, no changes of microstructure were observed. During degradation of the composite, the release of Ca2+ and Sr2+ ions could be controlled by the MBG composition and plotted scaffolds with macropores showed a significant higher release than bulk samples of comparable mass. These findings demonstrate a high flexibility regarding ion release of the developed composites and suggest utilizing the drug binding capacities of MBG as a prospective delivery system for biologically active proteins.

Safety and Tolerability of the Chymase Inhibitor Fulacimstat in Patients With Left Ventricular Dysfunction After Myocardial Infarction-Results of the CHIARA MIA 1 Trial.

The chymase inhibitor fulacimstat is developed as a first-in-class treatment option for the inhibition of adverse cardiac remodeling in patients with left ventricular dysfunction (LVD) after acute myocardial infarction (MI). The aim of the study was to examine the safety and tolerability of fulacimstat in patients with LVD after remote MI. A multicenter, multinational randomized, placebo-controlled study was performed in clinically stable patients (40-79 years of age, left ventricular ejection fraction ≤ 45% because of MI in medical history) who were on stable evidence-based standard-of-care therapies for LVD post-MI including an angiotensin converting enzyme inhibitor or angiotensin receptor blocker at doses of at least half the recommended target dose. Patients were treated for 2 weeks with either placebo (n = 12) or 4 different doses of fulacimstat (5 mg twice daily, n = 9; 10 mg twice daily, n = 9; 25 mg twice daily, n = 10; 50 mg once daily, n = 9). Fulacimstat was safe and well tolerated at all examined doses. There were no clinically relevant effects on vital signs or potassium levels compared with placebo treatment. Mean plasma concentrations of fulacimstat increased with the administered dose and reached exposures predicted to be therapeutically active. The safety profile and the absence of effects on blood pressure or heart rate in a chronic patient population having similar comorbidities and receiving similar comedication as patients after acute MI support future clinical trials with fulacimstat in patients after acute MI.

Effect of tiotropium on COPD exacerbations: A systematic review.

BACKGROUND: Exacerbation frequency is related to disease progression, quality of life, and prognosis in COPD. Earlier diagnosis, along with interventions aimed at preventing exacerbations and delaying progression, may help reduce the global burden of disease. Long-acting inhaled bronchodilators are effective at maintaining symptom relief and are recommended as first-choice therapy for more symptomatic patients and those at risk of exacerbation. METHODS: As prevention of exacerbations is a priority goal in COPD management and a number of different long-acting bronchodilators are available, we conducted a systematic review of exacerbation data from randomized controlled trials (published January 2000 to May 2014) comparing the effect of tiotropium versus placebo and/or other maintenance therapies. RESULTS: Exacerbations were a primary endpoint in 12 publications (five studies: four comparing tiotropium with placebo; one with active comparator) and a secondary endpoint in 17 publications (seven studies: six comparing tiotropium with placebo; one with active comparator). Overall, tiotropium was associated with a longer time to first exacerbation event and fewer exacerbations (including severe exacerbations/hospitalizations) compared with placebo and long-acting ß2-agonists. Tiotropium also showed similar efficacy to glycopyrronium and a fixed long-acting muscarinic antagonist/long-acting ß2-agonist combination (glycopyrronium/indacaterol), although not all studies were powered to demonstrate differences in exacerbation outcomes. Exacerbation outcomes were comparable with both formulations of tiotropium (HandiHaler(®) 18 µg/Respimat(®) 5 µg). CONCLUSIONS: The results of this comprehensive systematic review demonstrate tiotropium is beneficial in reducing exacerbation risk versus placebo or other maintenance treatments.

Tiotropium Respimat(®) Versus HandiHaler(®): Comparison of Bronchodilator Efficacy of Various Doses in Clinical Trials.

INTRODUCTION: The long-acting muscarinic antagonist tiotropium bromide is approved in many countries as maintenance therapy for chronic obstructive pulmonary disease (COPD). Tiotropium is available as a dry-powder formulation delivered via HandiHaler(®) (18 µg once daily) and is now also approved as an aqueous solution delivered via the Respimat(®) Soft Mist™ Inhaler (5 µg once daily, 2 puffs of 2.5 µg). Several studies have compared the efficacy of tiotropium HandiHaler (18 µg once daily) with different doses of Respimat. We aimed to compare available bronchodilator efficacy data of once-daily Respimat 1.25, 2.5, 5, 10, 20 µg, and HandiHaler 18 µg to investigate which dose of tiotropium delivered by Respimat is the closest match to tiotropium HandiHaler. METHODS: Evaluation of six clinical trials (duration from 3 weeks to 2-3 years) that included lung function measures (trough forced expiratory volume in 1 s and trough forced vital capacity) as key outcomes. RESULTS: In the six trials, bronchodilator efficacy of Respimat 5 µg and HandiHaler 18 µg was similar; however, reduced bronchodilator efficacy was observed with lower doses of Respimat (1.25 and 2.5 µg). CONCLUSION: These findings support the use of the marketed once-daily dose of Respimat 5 µg for the maintenance treatment of patients with COPD. FUNDING: Boehringer Ingelheim.

A cross-sectional study to assess inhalation device handling and patient satisfaction in COPD.

Delivery of inhaled medications via an inhaler device underpins the effectiveness of treatment for patients with chronic obstructive pulmonary disease (COPD). Correct inhaler technique among patients is also a predictor of achieving treatment compliance and adherence. Reporting of patient satisfaction with inhalers is therefore gaining increasing attention and is now recognized as an important patient-reported outcome in clinical trials involving patients with COPD or asthma. In this cross-sectional study, we use the validated Patient Satisfaction and Preference Questionnaire (PASAPQ) to assess the handling and satisfaction for Respimat(®) Soft Mist™ Inhaler (SMI) compared with the Breezhaler(®) dry powder inhaler (DPI) among patients with COPD in Spain. Patients were already assigned to therapy with either SPIRIVA(®) (tiotropium) Respimat(®) or with Hirobriz(®)/Onbrez(®)/Oslif(®) (indacaterol) Breezhaler(®) for at least 3 but not more than 6 months before completing the PASAPQ at a single visit to the study site. The primary endpoint of the trial was the mean total PASAPQ score. Secondary endpoints were the performance score domain of the PASAPQ, the convenience score domain of the PASAPQ, and the overall satisfaction score of the PASAPQ. For the primary endpoint, the mean PASAPQ total score in the Respimat(®) and Breezhaler(®) groups was 80.7 and 79.9, respectively (difference of 0.8, 95% confidence interval [CI] -2.9 to 4.5; P=0.67). The mean total performance scores were 82.5 and 78.2 (difference of 4.3, 95% CI -0.3 to 8.9; P=0.06), and the mean total convenience scores were 78.6 and 81.9 (difference of -3.3, 95% CI -7.0 to 0.4; P=0.08) for the Respimat(®) and Breezhaler(®) groups, respectively. Patients gave the Respimat(®) SMI and the Breezhaler(®) DPI overall satisfaction PASAPQ scores of 6.0 and 5.9, respectively, which shows that patients were satisfied with these inhalers.

Roflumilast combined with montelukast versus montelukast alone as add-on treatment in patients with moderate-to-severe asthma.

BACKGROUND: Roflumilast, a selective phosphodiesterase 4 inhibitor, has been shown to provide modest improvements in lung function in patients with mild-to-moderate asthma, but its efficacy in patients with moderate-to-severe asthma has not been assessed. We hypothesized that this drug might provide benefit if combined with montelukast, a leukotriene receptor antagonist, in patients whose symptoms are uncontrolled by inhaled corticosteroids and long-acting ß-agonists. OBJECTIVE: We sought to examine the efficacy, safety, and mode of action of the addition of roflumilast and montelukast versus montelukast alone in patients with moderate-to-severe asthma. METHODS: In a phase 2, randomized, double-blind, placebo-controlled, multiple-dose, 2-sequence, crossover study, 64 patients were randomized to receive 500 µg of roflumilast plus montelukast followed by placebo plus 10 mg of montelukast (sequence AB) or placebo plus 10 mg of montelukast followed by 500 µg of roflumilast plus 10 mg of montelukast (sequence BA). All patients had a diagnosis of bronchial asthma inadequately controlled by at least a medium-dose inhaled corticosteroid plus a long-acting ß-agonist. RESULTS: The analysis of FEV1 change from baseline to week 4 showed a statistically significant and clinically meaningful treatment difference of 100 mL for roflumilast plus montelukast versus placebo plus montelukast. Also, improvements in patient-reported outcomes and a reduction in urinary leukotriene E4 levels were observed during roflumilast plus montelukast treatment compared with placebo plus montelukast treatment. Adverse events were consistent with the known safety profile of roflumilast. CONCLUSION: The combination of roflumilast with montelukast compared with montelukast alone improved lung function and asthma control in patients with moderate-to-severe asthma and deserves further study for this indication.

Roflumilast for the treatment of COPD in an Asian population: a randomized, double-blind, parallel-group study.

BACKGROUND: Roflumilast is the only oral phosphodiesterase 4 inhibitor indicated for use in the treatment of COPD. Previous studies of roflumilast have predominantly involved European and North American populations. A large study was necessary to determine the efficacy and safety of roflumilast in a predominantly ethnic Chinese population. METHODS: In a placebo-controlled, double-blind, parallel-group, multicenter, phase 3 study, patients of Chinese, Malay, and Indian ethnicity (N = 626) with severe to very severe COPD were randomized 1:1 to receive either roflumilast 500 µg once daily or placebo for 24 weeks. The primary end point was change in prebronchodilator FEV1 from baseline to study end. RESULTS: Three hundred thirteen patients were assigned to each treatment. Roflumilast provided a sustained increase over placebo in mean prebronchodilator FEV1 (0.071 L; 95% CI, 0.046, 0.095 L; P < .0001). Similar improvements were observed in the secondary end points of postbronchodilator FEV1 (0.068 L; 95% CI 0.044, 0.092 L; P < .0001) and prebronchodilator and postbronchodilator FVC (0.109 L; 95% CI, 0.061, 0.157 L; P < .0001 and 0.101 L; 95% CI, 0.055, 0.146 L; P < .0001, respectively). The adverse event profile was consistent with previous roflumilast studies. The most frequently reported treatment-related adverse event was diarrhea (6.0% and 1.0% of patients in the roflumilast and placebo groups, respectively). CONCLUSIONS: Roflumilast plays an important role in lung function improvement and is well tolerated in an Asian population. It provides an optimal treatment choice for patients with severe to very severe COPD.

Distinguishing source of autonomy support in relation to workers' motivation and self-efficacy.

The purpose was to investigate the relationship between autonomy support by managers and co-workers and employees' work motivation and self-efficacy in two studies. In Study 1, a sample of 343 Swedish workers completed surveys, and in Study 2, we followed up with a subsample of 98 workers one year later. As in previous studies, managers support of autonomy was significantly positively related to workers' outcomes. However, the results of Study 1 also showed that co-worker autonomy support was related to these outcomes over and above the effects of manager support. Study 2 showed that changes in autonomy support from co-workers during one year significantly predicted motivation and self-efficacy one year later, while change in support from managers was unrelated to outcomes later. These findings provide evidence for the importance of both vertical and horizontal sources of support.

Childhood epilepsy recorded in primary care in the UK.

OBJECTIVE: To examine temporal trends in the incidence of epilepsy recorded in UK primary care and to evaluate the impact of recent efforts to improve the specificity of diagnosis in children. DESIGN: Birth cohort study using primary care data from The Health Improvement Network, which includes a representative sample of the UK population of approximately 5%. METHODS: We identified epilepsy recorded in primary care using relatively specific through to relatively sensitive indicators to identify epilepsy. Incidence estimates were based on 344 718 children aged 0-14 years with 1 447 760 years' follow-up between 1994 and 2008. Trends in cumulative incidence were explored with stratified analysis by year-of-birth. Trends in annual incidence were investigated using Poisson regression with adjustment for age, gender and deprivation. RESULTS: Cumulative incidence of recorded epilepsy at age 5 years ranged from 0.38% to 0.68% and annual incidence ranged from 71 to 116/100 000 person-years-at-risk, depending on the indicator used to identify epilepsy. With the most specific indicator for epilepsy, cumulative incidence was 33% lower among children born in 2003-2005 than in children born in 1994-1996, and annual incidence declined by 4% per annum between 2001 and 2008, after adjusting for age, gender and deprivation. Using a more sensitive indicator for epilepsy, the equivalent declines were 47% in cumulative incidence and 9% in annual incidence. CONCLUSIONS: The decline since the mid-1990s in epilepsy recorded in primary care may be due to more specific diagnosis, cessation of treatment for some forms of epilepsy, reduced exposure to risk factors or all of these factors.