Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer (TOPAZ-1): patient-reported outcomes from a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: In the ongoing, randomised, double-blind phase 3 TOPAZ-1 study, durvalumab, a PD-L1 inhibitor, plus gemcitabine and cisplatin was associated with significant improvements in overall survival compared with placebo, gemcitabine, and cisplatin in people with advanced biliary tract cancer at the pre-planned intermin analysis. In this paper, we present patient-reported outcomes from TOPAZ-1. METHODS: In TOPAZ-1 (NCT03875235), participants aged 18 years or older with previously untreated, unresectable, locally advanced, or metastatic biliary tract cancer with an Eastern Cooperative Oncology Group performance status of 0 or 1 and one or more measurable lesions per Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) were randomly assigned (1:1) to the durvalumab group or the placebo group using a computer-generated randomisation scheme. Participants received 1500 mg durvalumab or matched placebo intravenously every 3 weeks (on day 1 of the cycle) for up to eight cycles in combination with 1000 mg/m2 gemcitabine and 25 mg/m2 cisplatin intravenously on days 1 and 8 every 3 weeks for up to eight cycles. Thereafter, participants received either durvalumab (1500 mg) or placebo monotherapy intravenously every 4 weeks until disease progression or other discontinuation criteria were met. Randomisation was stratified by disease status (initially unresectable vs recurrent) and primary tumour location (intrahepatic cholangiocarcinoma vs extrahepatic cholangiocarcinoma vs gallbladder cancer). Patient-reported outcomes were assessed as a secondary outcome in all participants who completed the European Organisation for Research and Treatment of Cancer's 30-item Quality of Life of Cancer Patients questionnaire (QLQ-C30) and the 21-item Cholangiocarcinoma and Gallbladder Cancer Quality of Life Module (QLQ-BIL21). We calculated time to deterioration-ie, time from randomisation to an absolute decrease of at least 10 points in a patient-reported outcome that was confirmed at a subsequent visit or the date of death (by any cause) in the absence of deterioration-and adjusted mean change from baseline in patient-reported outcomes. FINDINGS: Between April 16, 2019, and Dec 11, 2020, 685 participants were enrolled and randomly assigned, 341 to the durvalumab group and 344 to the placebo group. Overall, 345 (50%) of participants were male and 340 (50%) were female. Data for the QLQ-C30 were available for 318 participants in the durvalumab group and 328 in the placebo group (median follow-up 9·9 months [IQR 6·7 to 14·1]). Data for the QLQ-BIL21 were available for 305 participants in the durvalumab group and 322 in the placebo group (median follow-up 10·2 months [IQR 6·7 to 14·3]). The proportions of participants in both groups who completed questionnaires were high and baseline scores were mostly similar across treatment groups. For global health status or quality of life, functioning, and symptoms, we noted no difference in time to deterioration or adjusted mean changes from baseline were observed between groups. Median time to deterioration of global health status or quality of life was 7·4 months (95% CI 5·6 to 8·9) in the durvalumab group and 6·7 months (5·6 to 7·9) in the placebo group (hazard ratio 0·87 [95% CI 0·69 to 1·12]). The adjusted mean change from baseline was 1·23 (95% CI -0·71 to 3·16) in the durvalumab group and 0·35 (-1·63 to 2·32) in the placebo group. INTERPRETATION: The addition of durvalumab to gemcitabine and cisplatin did not have a detrimental effect on patient-reported outcomes. These results suggest that durvalumab, gemcitabine, and cisplatin is a tolerable treatment regimen in patients with advanced biliary tract cancer. FUNDING: AstraZeneca.

A Critical Appraisal of a University's Response to a Campus Mass Shooting: Perspectives from Public Health Students and Researchers at Michigan State University.

Mass shootings are a public health crisis and have become more frequent on U.S. university campuses over the past decade, with the number doubling since 2000. Due to this alarming trend, many institutions have developed response strategies for active shooting events. Yet, the extent to which these response strategies address the needs and minimize harm for students, faculty, and staff has not been evaluated critically after a campus mass shooting. Michigan State University (MSU) experienced a mass shooting on February 13, 2023. Before, during, and 6 months following this tragedy, the university employed an estimated 18 strategies to inform, support, and protect its students, faculty, and staff. While MSU continues to address concerns and roll out programs related to this event, here we aimed to (1) create a timeline of resources and communication provided by MSU from the event to 6 months post-event; (2) critically evaluate the extent to which these resources met the needs of students, faculty, and staff through a survey among persons involved in public health research; and (3) identify potential areas for improvement in the university's responses. We used an online survey where participants (n = 10) rated the university responses and provided additional comments. From our survey, we recommend that, in the event of a campus shooting, other universities are attentive to re-engaging with the community within which the university is situated, holding communal events on campus, offering pauses in classes, and enhancing mental health services. These responses were seen as crucial to re-establish campus life and learning.

Unraveling the leptospirosis epidemic: tales from the Philippine outbreak - a short communication.

Leptospirosis, also known as Weil's disease, is an emerging zoonotic infection that occurs worldwide but is particularly common in the tropics. There has been an increasing trend of leptospirosis in the Philippines since the outbreak occurred in 2020. The number of reported cases was 182 in 2020, 1661 in 2021, and 2794 in 2022. This present article aimed to access previously published studies on the prevalence, implications, and efforts to combat leptospirosis worldwide, with a particular focus on the Philippines from 2001 to 2023. In writing this article, we conducted a thorough search of databases such as PubMed, Researchgate, Web of Science, Scopus, and Google Scholar within 20 years. This present article found that more than 810 cases were reported from 1 January to 4 March 2023. The Cagayan Valley Region has 103 cases, the Zamboanga Peninsula has 77 cases, and the Western Visayas Region has 176 cases, making them the worst-hit areas. The increase in leptospirosis cases in the Philippines is primarily attributed to several factors. Firstly, the country is prone to natural disasters such as typhoons, floods, and landslides, which increase the risk of water sources and the environment being contaminated with Leptospira bacteria. To address the menace of leptospirosis in the Philippines, we urge the Philippine government to focus on improving healthcare infrastructure, providing swift, reliable, and effective treatments, implementing safety regulations, supplying personal protective equipment to medical authorities, and taking strict actions to improve water sanitation.

Particle breakability assessment using an Aero S disperser.

Milling is widely used in various industries to tailor the particle size distribution for desired attributes. The ability to predict milling behaviour by testing the breakability of a small quantity of material is of great interest. In this paper, a widely available aerodynamic dispersion method, i.e. the Aero S disperser of Malvern Mastersizer 3000 has been evaluated for this purpose. This device is commonly used for dispersion of fine and cohesive powders, as the particles are accelerated and impacted at a bend, but here its use for assessing particle breakability is explored. The fluid flow field is modelled using one-way coupled Computational Fluid Dynamics approach, as the particle concentration is low, following which the particle impact velocity is calculated by Lagrangian tracking and used in the analysis of particle breakage. Experimental work on the breakability is carried out using aspirin, paracetamol, sucrose and α-lactose monohydrate particles. The relative shift in the specific surface area is determined and together with the calculated particle impact velocity and physical properties, they are used to calculate the breakability index. A good agreement is obtained with the single particle impact testing and aerodynamic dispersion by Scirocco disperser, indicating the breakability could also be inferred from this method.

Bleeding complications in patients with squamous cell carcinoma of the head and neck.

Hemorrhage in recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) may be attributed to chemotherapy and local tumor irradiation. Evidence of the relationship between hemorrhage in R/M HNSCC and targeted therapies, including epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) inhibitors, or immune checkpoint inhibitors, is limited. We aimed to identify epidemiological and clinical data related to the occurrence of hemorrhage in R/M HNSCC and to explore its relationship with various therapies. We describe information obtained from literature searches as well as data extracted from a commercial database and a database from the author's institution (Istituto Nazionale dei Tumori of Milan). Evidence suggests that most bleeding events in R/M HNSCC are minor. Clinical trial safety data do not identify a causal association between hemorrhage and anti-EGFR agents or immune checkpoint inhibitors. In contrast, anti-VEGF agents are associated with increased, and often severe/fatal, hemorrhagic complications.

Assessment of impact breakage of carbamazepine dihydrate due to aerodynamic dispersion.

Acicular crystals are very common in pharmaceutical manufacturing. They are very prone to breakage, causing unwanted particle size degradation and problems such as segregation and lump formation. We investigate the breakage pattern of carbamazepine dihydrate, an acicular and platy crystal with cleavage planes. It readily undergoes attrition during isolation and drying stage, causing processing difficulties. We use the aerodynamic dispersion of a very small quantity of powder sample to induce breakage by applying a pulse of pressurised air. The dispersion unit of Morphologi G3 is used for this purpose. The broken particles settle in a chamber and are subsequently analysed using the built-in image analysis software. The shift in the particle size and shape distributions is quantified through which the extent of breakage is determined as a function of the dispersion pressure. The analysis reveals a change of breakage mechanism as the dispersion pressure is increased from primarily snapping along the crystal length to one in which chipping has also a notable contribution. The breakage data are analysed using a modified impact-based breakage model and the breakability index of the carbamazepine dihydrate is determined for the two breakage regimes. The method provides a quick and easy testing of particle breakability, a useful tool for assessing attrition in process plant and grindability in milling operations.

Safety and Effectiveness of 177Lu-DOTATATE Peptide Receptor Radionuclide Therapy After Regional Hepatic Embolization in Patients With Somatostatin-Expressing Neuroendocrine Tumors.

PURPOSE: Peptide receptor radionuclide therapy (PRRT) with Lu-DOTATATE is shown to be an effective therapeutic option for somatostatin-expressing neuroendocrine neoplasms. Some concerns are raised over safety of this modality in patients with a history of regional chemoembolization and radionuclide hepatic embolization (CRHE) and is cause of reluctance among some physicians for suggesting Lu-DOTATATE in this patient population. METHODS: We retrospectively reviewed 143 patients with somatostatin-expressing neuroendocrine tumors who underwent Lu-DOTATATE PRRT. Statistical analysis was performed on effect of Lu-DOTATATE in patients with and without prior CRHE using resampling procedures and correlation coefficient (r). RESULTS: Proportion of toxicity in patients with and without CRHE was comparable (P = 0.246). No statistically significant correlation (r) found between any toxicity and prior CRHE (r = -0.3 to -0.03) or time elapsed between embolization and the first cycle of PRRT (r = -0.59 to 0.17). Following PRRT, 76.5% of patients with CRHE experienced benefit (partial response + stable disease), whereas 23.4% experienced progressive disease. Patients with CRHE showed more stable disease (P = 0.048) and less progressive disease (P = 0.046) following PRRT compared with no CRHE. The CRHE and no-CRHE status shared same probability for developing partial response/complete response following PRRT (P = 0.50). CONCLUSIONS: Treatment with Lu-DOTATATE did not show clinically or statistically significant toxicity in CRHE patients regardless of frequency of embolization or time interval between embolization and first PRRT. Results suggested a statistically significant higher response rate in patients with a history of CRHE. A prior history of CRHE is not a contraindication to subsequent PRRT.

Peptide Receptor Radionuclide Therapy With 177Lu-Octreotate in Patients With Somatostatin Receptor Expressing Neuroendocrine Tumors: Six Years' Assessment.

OBJECTIVES: Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogues is a promising treatment for patients with inoperable, well to moderately differentiated metastatic neuroendocrine tumors (NETs). In continuation of our novel study with the radionuclide lutetium Lu, we now present further results of Lu DOTATATE therapy in managing NETs and other somatostatin receptor-expressing tumors in a larger and more diverse patient group. PATIENTS AND METHODS: One hundred forty-four consecutive patients (85 men and 59 women; age range, 11-87 years; mean age, 58.5 years) with histologically confirmed NET were enrolled. One hundred forty-three patients received at least 1 cycle of treatment. Among them, 132 were deemed evaluable by having at least 1 cycle of treatment and a posttreatment MRI or CT scan for assessment based on modified Response Evaluation Criteria in Solid Tumors. Response to therapy was evaluated in terms of progression-free survival, overall survival, as well as radiologic, biochemical, and clinical responses. Further, analysis of symptoms was reviewed during therapy and also in subsequent follow-ups for safety evaluation. Renal, gastrointestinal (GI), hepatic, and hematological adverse events were evaluated using National Cancer Institute common toxicities criteria V4.03, through full blood panels, as well as consultation with patients for any symptoms and/or adverse events. RESULTS: As of July 2016, median progression-free survival was about to be reached. Of 28 patients who have completed Lu DOTATATE therapy (completion of 4 or more cycles of treatment and all designated follow-ups), no patient showed complete response (CR), 8 patients (28.57%) showed partial response (PR), 16 patients (57.14%) showed stable disease (SD), and progressive disease (PD) was observed in 4 patients (14.28%). The objective response rate (CR + PR) of this group was 28.57% (n = 8) with a cumulative disease control (CR + PR + SD) of 85.71% (n = 24).Among 132 evaluable patients, assessment of treatment response using modified Response Evaluation Criteria in Solid Tumors criteria revealed CR in none of the patients, PR in 12 patients (9.09%), SD in 66 patients (50%), whereas PD, which included patients who passed away, was observed in 54 patients (40.90%), yielding an objective response rate of 9.09% (n = 12) and a cumulative disease control rate of 59.09% (n = 78).Symptoms including abdominal pain, diarrhea, flushing, and fatigue improved in over 50% of the patients, whereas weight loss improved in 28.26% of the patients. No grade 3 or grade 4 renal toxicities were found, though eleven grade 3 and five grade 4 hematological as well as three grade 3 hepatotoxicities were reported. Grade 3 hematotoxicity lasted an average of 2.7 months, and grade 4 lasted for only 0.9 months, whereas grade 3 hepatotoxicity lasted an average of 3.1 months. CONCLUSIONS: Lu-octreotate peptide receptor radionuclide therapy has shown promising potential as a safe and effective targeted therapy in inoperable, well to moderately differentiated metastatic neuroendocrine cancers. The results of the multicenter randomized clinical trial conducted in United States and Europe are concordant with current study.

A method for grindability testing using the Scirocco disperser.

In the early stages of development of a new Active Pharmaceutical Ingredient (API), insufficient material quantity is available for addressing processing issues, and it is highly desirable to be able to assess processability issues using the smallest possible powder sample quantity. A good example is milling of new active pharmaceutical ingredients. For particle breakage that is sensitive to strain rate, impact testing is the most appropriate method. However, there is no commercially available single particle impact tester for fine particulate solids. In contrast, dry powder dispersers, such as the Scirocco disperser of the Malvern Mastersizer 2000, are widely available, and can be used for this purpose, provided particle impact velocity is known. However, the distance within which the particles can accelerate before impacting on the bend is very short and different particle sizes accelerate to different velocities before impact. As the breakage is proportional to the square of impact velocity, the interpretation of breakage data is not straightforward and requires an analysis of particle velocity as a function of size, density and shape. We report our work using an integrated experimental and CFD modelling approach to evaluate the suitability of this device as a grindability testing device, with the particle sizing being done immediately following dispersion by laser diffraction. Aspirin, sucrose and α-lactose monohydrate are tested using narrow sieve cuts in order to minimise variations in impact velocity. The tests are carried out at eight different air nozzle pressures. As intuitively expected, smaller particles accelerate faster and impact the wall at a higher velocity compared to the larger particles. However, for a given velocity the extent of breakage of larger particles is larger. Using a numerical simulation based on CFD, the relationship between impact velocity and particle size and density has been established assuming a spherical shape, and using one-way coupling, as the particle concentration is very low. Taking account of these dependencies, a clear unification of the change in the specific surface area as a function of particle size, density and impact velocity is observed, and the slope of the fitted line gives a measure of grindability for each material. The trend of data obtained here matches the one obtained by single particle impact testing. Hence aerodynamic dispersion of solids by the Scirocco disperser can be used to evaluate the ease of grindability of different materials.

Long-acting muscarinic antagonist use in adults with asthma: real-life prescribing and outcomes of add-on therapy with tiotropium bromide.

BACKGROUND: Randomized controlled trials indicate that addition of a long-acting muscarinic antagonist (LAMA) such as tiotropium may improve asthma control and reduce exacerbation risk in patients with poorly controlled asthma, but broader clinical studies are needed to investigate the effectiveness of LAMA in real-life asthma care. METHODS: Medical records of adults with asthma (aged ≥18 years) prescribed tiotropium were obtained from the UK Optimum Patient Care Research Database for the period 2001-2013. Patients diagnosed with chronic obstructive pulmonary disease were excluded, but no other clinical exclusions were applied. Two primary outcomes were compared in the year before (baseline) and the year after (outcome) addition of tiotropium: exacerbations (asthma-related hospital emergency department attendance or inpatient admission, or acute oral corticosteroid course) and acute respiratory events (exacerbation or antibiotic prescription with lower respiratory consultation). Secondary outcomes included lung function test results and short-acting ß2 agonist usage. The Wilcoxon signed-rank test was used for variables measured on the interval scale, the marginal homogeneity test for categorized variables, and the paired t-test for lung function indices. RESULTS: Of the 2,042 study patients, 83% were prescribed an inhaled corticosteroid and 68% a long-acting ß2 agonist during the baseline year; 67% were prescribed both. Comparing baseline and outcome years, the percentage of patients having at least one exacerbation decreased from 37% to 27% (P<0.001) and the percentage having at least one acute respiratory event decreased from 58% to 47% (P<0.001). There were no significant changes in lung function, and usage of short-acting ß2 agonists (in salbutamol/albuterol equivalents) increased from a median (interquartile range) of 274 (110, 548) to 329 (110, 603) µg/day (P=0.01). CONCLUSION: In this real-life asthma population, addition of LAMA therapy was associated with significant decreases in the incidence of exacerbations and antibiotic prescriptions for lower respiratory tract infections in the following year.

Adjunctive treatment with oral AKL1, a botanical nutraceutical, in chronic obstructive pulmonary disease.

PURPOSE: The objective of this pilot trial was to evaluate the safety and efficacy of AKL1, a patented botanical formulation containing extracts of Picrorhiza kurroa, Ginkgo biloba, and Zingiber officinale, as add-on therapy for patients with chronic obstructive pulmonary disease (COPD) and chronic cough. PATIENTS AND METHODS: This randomized, double-blind, placebo-controlled trial enrolled male and female patients >18 years old with COPD and Leicester Cough Questionnaire (LCQ) score of <18. The 10-week study period comprised a 2-week single-blind placebo run-in period followed by add-on treatment with AKL1 or placebo twice daily for 8 weeks. The primary study endpoint was the change from week 0 to week 8 in cough-related health status, as assessed by the LCQ. RESULTS: Of 33 patients enrolled, 20 were randomized to AKL1 and 13 to placebo. Patients included 19 (58%) men and 14 (42%) women of mean (standard deviation [SD]) age of 67 (9.4) years; 15 (45%) patients were smokers and 16 (49%) were ex-smokers. The mean (SD) change from baseline in LCQ score at 8 weeks was 2.3 (4.9) in the AKL1 group and 0.6 (3.7) in the placebo group, with mean difference in change of 1.8 (95% confidence interval: -1.5 to 5.1; P=0.28). The St George's Respiratory Questionnaire score improved substantially in the AKL1 treatment group by a mean (SD) of -7.7 (11.7) versus worsening in the placebo group (+1.5 [9.3]), with mean difference in change of -9.2 (95% confidence interval: -19.0 to 0.6; P=0.064). There were no significant differences between treatment groups in change from baseline to week 8 in other patient-reported measures, lung function, or the 6-minute walk distance. CONCLUSION: Further study is needed with a larger patient population and over a longer duration to better assess the effects of add-on therapy with AKL1 in COPD.

Effectiveness of same versus mixed asthma inhaler devices: a retrospective observational study in primary care.

PURPOSE: Correct use of inhaler devices is fundamental to effective asthma management but represents an important challenge for patients. The correct inhalation manoeuvre differs markedly for different inhaler types. The objective of this study was to compare outcomes for patients prescribed the same inhaler device versus mixed device types for asthma controller and reliever therapy. METHODS: This retrospective observational study identified patients with asthma (ages 4-80 years) in a large primary care database who were prescribed an inhaled corticosteroid (ICS) for the first time. We compared outcomes for patients prescribed the same breath-actuated inhaler (BAI) for ICS controller and salbutamol reliever versus mixed devices (BAI for controller and pressurised metered-dose inhaler [pMDI] for reliever). The 2-year study included 1 baseline year before the ICS prescription (to identify and correct for confounding factors) and 1 outcome year. Endpoints were asthma control (defined as no hospital attendance for asthma, oral corticosteroids, or antibiotics for lower respiratory tract infection) and severe exacerbations (hospitalisation or oral corticosteroids for asthma). RESULTS: Patients prescribed the same device (n=3,428) were significantly more likely to achieve asthma control (adjusted odds ratio, 1.15; 95% confidence interval [CI], 1.02-1.28) and recorded significantly lower severe exacerbation rates (adjusted rate ratio, 0.79; 95% CI, 0.68-0.93) than those prescribed mixed devices (n=5,452). CONCLUSIONS: These findings suggest that, when possible, the same device should be prescribed for both ICS and reliever therapy when patients are initiating ICS.

Inhibition of MLC phosphorylation restricts replication of influenza virus--a mechanism of action for anti-influenza agents.

Influenza A viruses are a severe threat worldwide, causing large epidemics that kill thousands every year. Prevention of influenza infection is complicated by continuous viral antigenic changes. Newer anti-influenza agents include MEK/ERK and protein kinase C inhibitors; however, the downstream effectors of these pathways have not been determined. In this study, we identified a common mechanism for the inhibitory effects of a significant group of anti-influenza agents. Our studies showed that influenza infection activates a series of signaling pathways that converge to induce myosin light chain (MLC) phosphorylation and remodeling of the actin cytoskeleton. Inhibiting MLC phosphorylation by blocking RhoA/Rho kinase, phospholipase C/protein kinase C, and HRas/Raf/MEK/ERK pathways with the use of genetic or chemical manipulation leads to the inhibition of influenza proliferation. In contrast, the induction of MLC phosphorylation enhances influenza proliferation, as does activation of the HRas/Raf/MEK/ERK signaling pathway. This effect is attenuated by inhibiting MLC phosphorylation. Additionally, in intracellular trafficking studies, we found that the nuclear export of influenza ribonucleoprotein depends on MLC phosphorylation. Our studies provide evidence that modulation of MLC phosphorylation is an underlying mechanism for the inhibitory effects of many anti-influenza compounds.

Effectiveness of inhaler types for real-world asthma management: retrospective observational study using the GPRD.

PURPOSE: Results of randomized controlled trials may not predict effectiveness of inhaled corticosteroids (ICS) in real-world clinical practice, where inhaler technique and device characteristics can influence effectiveness. We compared asthma outcomes for ICS delivered via three different inhaler devices: pressurized metered-dose inhaler (pMDI), breath-actuated MDI (BAI), and dry powder inhaler (DPI). PATIENTS AND METHODS: This retrospective database study evaluated 1-year outcomes for primary care patients with asthma aged 5-60 years prescribed their first ICS (initiation population) by pMDI (n = 39,746), BAI (n = 9809), or DPI (n = 6792), or their first ICS dose increase (step-up population) by pMDI (n = 6245), BAI (n = 1388), or DPI (n = 1536). Co-primary outcome measures were composite proxy measures of asthma control (no hospital attendance for asthma, oral corticosteroids, or antibiotics for lower respiratory infection) and severe exacerbations (unscheduled hospital admission, emergency room attendance, or oral corticosteroids). Outcomes were adjusted for potential confounding factors identified during a baseline year. RESULTS: In the initiation population, adjusted odds ratios (95% confidence intervals [CI]) for asthma control, as compared with pMDIs, were significantly better for BAIs (1.08 [1.02-1.14]) and DPIs (1.13 [1.06-1.21]), while adjusted exacerbation rate ratios (95% CI) were 1.00 (0.93-1.08) and 0.88 (0.81-0.95), respectively. In the step-up population, adjusted odds of asthma control were 1.21 (1.05-1.39) for BAIs and 1.13 (0.99-1.29) for DPIs; adjusted exacerbation rate ratios were 0.83 (0.71-0.98) for BAIs and 0.85 (0.74-0.98) for DPIs, compared with pMDIs. CONCLUSION: Inhaler device selection may have a bearing on clinical outcomes. Differences in real-world effectiveness among these devices require closer evaluation in well-designed prospective trials.

Device type and real-world effectiveness of asthma combination therapy: an observational study.

BACKGROUND: Selection of inhaler device type appears to influence real-world effectiveness of inhaled corticosteroids (ICS), but data are lacking on the role of inhaler device in ICS and long-acting ß2-agonist (LABA) combination therapy for asthma. METHODS: This retrospective matched cohort study compared 1-year asthma outcomes for UK patients initiating fixed-dose combination (FDC) fluticasone-salmeterol delivered by pressurised metered-dose inhaler (pMDI) versus dry powder inhaler (DPI). Patients with asthma aged 4-80 years receiving a first prescription for FDC fluticasone-salmeterol by pMDI or DPI were matched on baseline demographic and asthma severity measures. Co-primary outcomes were asthma control (a composite measure comprising no recorded hospital attendance for asthma, oral corticosteroids, or antibiotics for lower respiratory infection) and exacerbation rate. RESULTS: Compared with the DPI cohort (n = 1567), patients in the pMDI cohort (n = 1567) had significantly greater odds of achieving asthma control during the outcome year (odds ratio [OR] 1.19; 95% confidence interval [CI] 1.01 to 1.40). Exacerbation rate was lower but not significantly in the pMDI cohort (adjusted rate ratio for pMDI cohort, 0.82; 95% CI 0.66 to 1.00). The odds of treatment success (defined as no exacerbations and no change in asthma therapy) was significantly greater in the pMDI cohort (OR 1.23; 95% CI, 1.07 to 1.42). CONCLUSIONS: For UK primary care patients, pMDIs appear to achieve better asthma control outcomes than DPIs for delivery of FDC fluticasone-salmeterol. Pragmatic trials are needed to further investigate real-world outcomes with different inhaler devices for combination therapy.

Lipoprotein-associated phospholipase A2 as a novel risk marker for cardiovascular disease: a systematic review of the literature.

We sought to critically assess the role of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) in the prediction of cardiovascular events in primary and secondary prevention settings. The inclusion criteria for our study included population-based epidemiologic studies and the presence of clinical outcomes of interest, including atherosclerotic disease, coronary events, stroke, and cardiovascular death. Studies that lacked clinical outcomes or that involved animals were excluded. We included primary and secondary prevention studies of subjects in all ethnic groups and of either sex, with no age limitation. We searched MEDLINE, Google Scholar, and the Cochrane Library for studies with publication dates from January 1970 through July 2009, and we searched major cardiology meeting abstracts from 2000 through 2009. From each study, we used predictive ability-including relative risk, hazard ratio, odds ratio, and prevalence of high Lp-PLA(2) levels, with adjustment-along with baseline population characteristics.Of 33 studies that met our inclusion criteria, 30 showed a significant association between Lp-PLA(2) and cardiovascular events. Most of the studies had been adjusted for major Framingham risk factors and other variables that might influence the effect under question. After multivariate adjustments in cohort and nested case-control studies, increased levels of Lp-PLA(2) remained a significant predictor of cardiovascular events. The available body of evidence suggests that Lp-PLA(2) is a reliable marker of risk for cardiovascular events.

Oligonol a low molecular weight polyphenol of lychee fruit extract inhibits proliferation of influenza virus by blocking reactive oxygen species-dependent ERK phosphorylation.

The emergence of resistance to anti-influenza drugs calls for the search for new antiviral molecules with different resistance profiles. Polyphenolic compounds are found in various plants and have antiviral and antioxidative properties. We tested the hypothesis that oligonol, a lychee fruit-derived low molecular weight polyphenol, possesses anti-influenza effects by inhibiting phosphorylation of extracellular-signal-regulated kinases (ERK). Real time PCR, plaque assay, and immunofluorescence techniques were used to study the effects of oligonol on proliferation of influenza virus. Oligonol inhibits influenza virus proliferation by blocking attachment of the virus to MDCK cells and by suppression of nuclear export of influenza virus ribonucleoprotein (RNP). Infection of MDCK cells with influenza virus leads to an increase in production of reactive oxygen species (ROS) and induction of a ROS-dependent ERK phosphorylation. Inhibition of ERK activation by a dominant negative mutant of ERK or N-acetyl-cysteine (NAC) leads to inhibition of influenza RNP nuclear export. Phorbol 12-myristate 13-acetate (PMA) induces ROS production, ERK phosphorylation and enhances influenza proliferation in MDCK cells. Oligonol and NAC inhibit PMA-induced ERK phosphorylation and ROS production. Our studies suggest that the underlying mechanism for the inhibitory effect of oligonol on influenza virus RNP nuclear export is blocking of ROS-dependent induction of ERK phosphorylation.

Influenza virus directly infects, inflames, and resides in the arteries of atherosclerotic and normal mice.

OBJECTIVE: Influenza can trigger heart attacks, and vaccination against influenza reduces the risk of cardiovascular events. Currently, it is believed that influenza virus in general does not disseminate to extra-pulmonary tissues. We assessed the vascular effects of influenza infection and whether the virus can directly infect atherosclerotic arteries in mice. METHODS/RESULTS: We intranasally infected 4 different types of mice--atherosclerotic apo E-deficient (our primary model), LDL receptor knockout, C57BL/6, and outbred Swiss--with influenza A/HK (H3/N2) virus. On day 7 after infection, we cultured viable virus from lung, aorta, and heart tissue, but not from the blood of apo E-deficient mice. Immunofluorescence studies showed influenza A virus NP1 protein and real time polymerase chain reaction (PCR) assay showed RNA in the aorta of infected apo E-deficient mice. Infected mice had significantly higher blood levels of chemokines and cytokines than control mice. At the local level, gene expression for several chemokines and cytokines was increased and eNOS expression was decreased. Infected mice had a higher density of macrophages in plaque than did control mice. CONCLUSIONS: We have shown for the first time that influenza virus can directly infect and reside in atherosclerotic arteries and that infection was associated with systemic and arterial-level pro-inflammatory changes.

Increased oxidative stress in atherosclerosis-predisposed regions of the mouse aorta.

AIMS: The localization of atherosclerotic lesions to predictable regions in mammalian arteries has been recognized for over a century. We sought to investigate the association between oxidative stress and regional susceptibility of the mouse aorta to atherosclerosis. MAIN METHODS: En face confocal microscopy was employed to assess oxidative stress in the aortic intima of atherosclerosis-susceptible and protected regions of wild-type C57BL/6 mouse. Expression of reactive oxygen species and antioxidant producing genes were compared in endothelial cells from the susceptible and protected regions. KEY FINDINGS: In vivo administration of redox-sensitive fluorescent dyes revealed an increase in the production of reactive oxygen species (ROS) in the atherosclerosis-susceptible regions relative to the protected regions. In contrast, Hoechst a redox-insensitive dye distributed evenly in the susceptible and protected regions. Accumulation of superoxide in the susceptible regions of the aorta was significantly blocked by the administration of Diphenyleneiodonium, a flavoprotein inhibitor. mRNA levels of superoxide-producing and scavenging enzymes were significantly increased in the regions predisposed to atherosclerosis. The regional difference in oxidative stress was at a lesser magnitude in BALB/c than the atherosclerosis-susceptible mouse (C57BL/6). SIGNIFICANCE: Our study for the first time demonstrated an augmented oxidative stress in atherosclerosis-susceptible regions of the normal mouse aorta.

Lipoprotein-associated phospholipase A2: a cardiovascular risk predictor and a potential therapeutic target.

Lipoprotein-associated phospholipase A2 (Lp-PLA2), present in the circulation and in atherosclerotic plaque, is an inflammatory marker with potential use as a predictor of cardiovascular risk and as a therapeutic target. Although Lp-PLA2 is associated with both LDL and HDL, it is important to determine whether Lp-PLA2 has a predominantly pro- or anti-atherogenic effect. Increasing evidence suggests a proatherogenic role for Lp-PLA2. Epidemiologic and clinical evidence suggests Lp-PLA2 is an independent predictor of risk and may be superior to other inflammatory markers owing to its specificity and minimal biovariation. Lp-PLA2 inhibitors currently being investigated in clinical trials are promising novel anti-inflammatory agents with a specificity for the vascular bed and a potential for decreasing plaque vulnerability.