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The aim of this study was to evaluate the pharmacokinetics, safety, and tolerability of aclidinium bromide/formoterol fumarate in patients from China with moderate-to-severe chronic obstructive pulmonary disease (COPD).In this open-label, repeat-dose, 5-day pharmacokinetic study (NCT03276078) of inhaled aclidinium bromide/formoterol fumarate 400/12 µg twice daily, plasma concentrations of aclidinium, formoterol, and two aclidinium metabolites (LAS34823, LAS34850) were assessed (days 1 and 5). Adverse event (AE) data were collected.Twenty patients (15 [75%] males) with a mean age of 59.2 years were included. Median (range) time to maximum concentration on days 1 and 5 was 0.08 (0.08-0.50) and 0.08 (0.08-0.50) h, respectively, for aclidinium; and 1.00 (0.08-3.00) and 0.08 (0.08-1.50) h, respectively, for formoterol. Mean elimination half-life and accumulation ratio for area under the concentration-time curve during a dosage interval (AUCAclidinium/formoterol 400/12 µg twice daily was well-tolerated in patients from China with moderate-to-severe COPD. Safety findings were consistent with the known safety profile.ClinicalTrials.gov, NCT03276078.

Robert A Wise,1 Kenneth R Chapman,2 Benjamin M Scirica,3,4 Sami Z Daoud,5 Dan Lythgoe,6 Esther Garcia-Gil7 1Medicine, Pulmonary and Critical Care, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2Department of Medicine, University of Toronto, Toronto, ON, Canada; 3Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA, USA; 4Department of Medicine, Harvard Medical School, Boston, MA, USA; 5Late-Stage Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA; 6Statistics, Phastar, Chiswick, London, UK; 7Respiratory & Immunology, BioPharmaceuticals Medical, AstraZeneca, Barcelona, SpainCorrespondence: Robert A WiseMedicine, Pulmonary and Critical Care, Johns Hopkins University School of Medicine, 5501 Hopkins Bayview Circle, Baltimore, MD, 21224, USAEmail rwise@jhmi.eduPurpose: Chronic obstructive pulmonary disease (COPD) exacerbations are associated with increased risk of major adverse cardiovascular events (MACE) and mortality. Here, we investigate whether the safety and efficacy of aclidinium bromide differ due to exacerbation history in patients with COPD and increased cardiovascular risk.Patients and Methods: ASCENT-COPD was a Phase 4, multicenter, double-blind, randomized, placebo-controlled, parallel-group study of patients with moderate-to-very severe COPD and increased cardiovascular risk. Patients were randomized 1:1 to receive aclidinium or placebo twice daily for up to 3 years. Outcomes included time to first MACE and all-cause mortality over 3 years, exacerbation rate during the first year on-treatment, and change in baseline pre-dose forced expiratory volume in 1 second (FEV1) over 3 years. This pre-specified subgroup analysis compared outcomes in patients receiving aclidinium vs placebo. The comparison of patients with vs without an exacerbation history was added following a protocol amendment to increase enrollment in the primary study.Results: Of 3589 patients, 2156 (60.1%) had ≥ 1 moderate or severe exacerbations in the prior year, compared with 1433 (39.9%) without prior exacerbations. Although patients with an exacerbation history had numerically higher rates of MACE and mortality regardless of treatment, aclidinium did not increase risk of MACE (≥ 1: hazard ratio [HR] 0.79, 95% confidence interval [CI]: 0.54– 1.16; none: HR 1.27, 95% CI: 0.65– 2.47; interaction P=0.233) or all-cause mortality (≥ 1: HR 1.08, 95% CI: 0.81– 1.43; none: HR 0.66, 95% CI: 0.36– 1.22; interaction P=0.154), regardless of exacerbation history. Aclidinium reduced the exacerbation rate vs placebo irrespective of exacerbation history (≥ 1: rate ratio [RR] 0.80, 95% CI: 0.68– 0.94; none: RR 0.69, 95% CI: 0.54– 0.89; interaction P=0.340) and improved FEV1 (interaction P=0.633).Conclusion: In patients with moderate-to-very severe COPD and increased cardiovascular risk, aclidinium did not increase risk of MACE or mortality and reduced exacerbation rate vs placebo, regardless of exacerbation history.Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT01966107.Keywords: COPD, COPD exacerbation, aclidinium, MACE, mortality

Resume But de l’etude Le but principal de ce travail est d’etudier la population a risque, d’evaluer le taux de sauvetage des membres superieurs et de determiner les eventuels facteurs predictifs de perte de membre. Methodes Il s’agissait d’une etude retrospective, colligeant 128 patients, victimes de traumatismes arteriels du membre superieur, entre le 1er janvier 2006 et 30 juin 2017. Les criteres d’exclusion etaient la ligature arterielle, l’amputation primaire et les lesions iatrogenes. Les resultats ont ete juges sur le succes technique immediat, la permeabilite primaire, le taux de sauvetage de membre. Resultats La moyenne d’âge etait de 27 ans avec une predominance masculine (sexe-ratio H/F = 41). Les lesions etaient majoritairement consecutives a des plaies par automutilation (51 %), puis par les agressions (23 %), des accidents de la voie publique (10 %), des accidents de travail (9 %) et des accidents domestiques (7 %). Les arteres touchees etaient principalement l’artere humerale (66,5 %) suite aux automutilations ; puis, les arteres de l’avant-bras (31 %) et l’artere axillaire (2,5 %). Les modalites de reparation etaient le pontage veineux (52 %), la suture bout a bout (23 %), la suture laterale (20 %) et un patch veineux (4 %). Nous avons observe 8 thromboses aigues durant la premiere semaine (6,25 %). Quatre patients ont necessite une amputation secondaire et le taux de sauvetage etait de 96,8 %. Le recul moyen etait de 62 jours, seulement 21 % des patients etait suivis a 3 mois. Les facteurs, influencant le taux de sauvetage de membre releve, etaient l’energie du mecanisme, la perte de substance importante et la thrombose aigue. Un deces a ete releve a j14 postoperatoire dans les suites d’un polytraumatisme a multiples composantes. Conclusion Le traitement chirurgical des traumatismes arteriels du membre superieur donne de bons resultats a court et a long terme, moyennant une prise en charge rapide et multidisciplinaire. La perte de substance importante est un facteur de mauvais pronostic de sauvetage de membre.

Resume Introduction Malgre le succes de l’angioplastie de l’artere iliaque, cette technique reste associee a des taux d’amputation non negligeables. Le but de cette etude etait d’identifier les facteurs predictifs d’amputation de membre inferieur apres angioplastie iliaque chez les patients en ischemie critique. Methodes Il s’agit d’une etude retrospective incluant les patients ayant beneficie avec succes d’une angioplastie de l’artere iliaque entre 2014 et 2018. Le critere de jugement principal etait le sauvetage de membre a 1 mois. Les variables etaient etudiees en analyse univariee et multivariee. Resultats Notre etude a inclus 86 patients. L’âge median etait de 57 ans ± 10 et le sexe-ratio Homme/Femme etait de 4,7. Les facteurs de risque cardiovasculaire etaient representes par le tabagisme dans 14 cas (16,3 %), le diabete dans 25 cas (29,1 %), l’hypertension arterielle dans 2 cas (2,3 %) et la dyslipidemie dans 2 cas (2,3 %). Soixante-dix patients (81,3 %) etaient classes stade 4 selon la classification de Leriche et Fontaine et 16 patients (18,7 %) etaient classes stade 3. Les lesions etaient stenosantes dans 48 cas (55,8 %) et occlusives dans 38 cas (44,2 %). Ces lesions etaient classees selon la classification de TASC « Trans-Atlantic-Society-Consensus » en TASC A-B dans 61 cas (70,9 %) et TASC C-D dans 35 cas (29,1 %). Une arterite distale a ete retrouvee dans 8 cas (9,3 %). Une angioplastie par ballon a ete realisee dans 36 cas (41,8 %) et d’une angioplastie stenting dans 50 cas (58,2 %). A 1 mois, le taux d’amputation etait de 9,3 %. L’analyse univariee a montre que le diabete et le tabagisme etaient les facteurs les plus associes a l’amputation (respectivement p = 0,007 ; OR = 9,31 ; IC 95 % = [7,13–50][1,73–50,07] et p = 0,022 ; OR = 6,8 ; IC 95 % = [1,46–31,61]). L’analyse multivariee a montre que le diabete et l’arterite distale etaient les facteurs predictifs d’amputation (respectivement p = 0,034 ; OR = 21,06 ; IC 95 % = [1,25 a 354,46] et p = 0,008 ; OR = 11,61 ; IC 95 % = [1,88 a 71,69]). Conclusion Le diabete et l’arterite distale sont les facteurs predictifs d’amputation du membre inferieur apres angioplastie iliaque.

Background Beta-blocker therapies for cardiovascular comorbidities are often withheld in patients with chronic obstructive pulmonary disease (COPD) due to potential adverse effects on airway obstruction. We carried out a post hoc analysis to determine the efficacy and safety of aclidinium in patients with moderate-to-very severe COPD and increased cardiovascular risk receiving beta-blockers at baseline versus non-users. Methods ASCENT-COPD was a Phase 4, multicenter, double-blind, randomized, placebo-controlled, parallel-group study. Patients were randomized 1:1 to aclidinium or placebo twice-daily for up to 3 years. Outcomes included risk of (time to first) major adverse cardiovascular events (MACE), all-cause mortality, and lung function over 3 years, and exacerbations over 1 year. Results Of 3589 patients, 1269 (35.4%) used beta-blockers and 2320 (64.6%) were non-users at baseline. Aclidinium did not statistically increase the risk of MACE (beta-blocker user: hazard ratio 1.01 [95% CI 0.62–1.64]; non-user: 0.80 [0.51–1.24]; interaction P = 0.48) or all-cause mortality (beta-blocker user: 1.13 [0.78–1.64]; non-user: 0.89 [0.62–1.26]; interaction P = 0.35), in patients using beta-blockers. Aclidinium reduced annualized rate of moderate-to-severe COPD exacerbation (beta-blocker user: rate ratio 0.75 [95% CI 0.60–0.94, P = 0.013]; non-user: 0.79 [0.67–0.93, P = 0.005]), delayed time to first exacerbation, and improved lung function versus placebo. There was greater trough FEV1 benefit in beta-blocker users versus non-users (least squares mean difference at 52 weeks: 111 mL [95% CI 74 mL–147 mL] versus 69 mL [42 mL–97 mL]; interaction P = 0.041). Conclusions This post hoc analysis supports long-acting anti-muscarinic use with concomitant beta-blockers in patients with moderate-to-very severe COPD and cardiovascular comorbidity. Trial registration: ClinicalTrials.gov, NCT01966107, Registered 16 October 2013, https://clinicaltrials.gov/ct2/show/NCT01966107.

Cristina Rebordosa, 1 Estel Plana, 1 Annalisa Rubino, 2 Jaume Aguado, 1 Alejhandra Lei, 3 Sami Daoud, 4 Nuria Saigi-Morgui, 1 Susana Perez-Gutthann, 1 Elena Rivero-Ferrer 1 1RTI Health Solutions, Barcelona, Spain; 2Epidemiology, Respiratory and Immunology, AstraZeneca, Cambridge, UK; 3Patient Safety Biopharma, AstraZeneca, Barcelona, Spain; 4BioPharmaceuticals Research and Development, Late-Stage Development Research and Innovation, AstraZeneca, Gaithersburg, MD, USACorrespondence: Cristina RebordosaRTI Health Solutions, Av. Diagonal, 605, 9-1, Barcelona, 08028, SpainTel +34 93 241 7766Fax +34 93 760 8507Email crebordosa@rti.orgBackground: The long-acting anticholinergic (LAMA) aclidinium was approved in Europe in 2012 to relieve symptoms in adults with chronic obstructive pulmonary disease (COPD). A Post-Authorisation Safety Study (PASS) was initiated to assess potential cardiovascular safety concerns for aclidinium.Objective: To estimate the adjusted incidence rate ratio (IRR) for hospitalisation for heart failure in patients with COPD who were new users of aclidinium, tiotropium, other LAMA, long-acting beta-agonists/inhaled corticosteroids (LABA/ICS), and LAMA/LABA were compared with initiators of LABA.Methods: This population-based cohort study included patients with COPD aged ≥ 40 years initiating COPD medications in the Clinical Practice Research Datalink (CPRD) GOLD in the United Kingdom from 2012 to 2017. Medications were identified via general practice prescriptions. The first-ever hospitalisations for heart failure were identified in the Hospital Episode Statistics, and general practitioner records from the CPRD. Poisson regression models were used to estimate the IRR for hospitalisation for heart failure in users of COPD medications versus LABA, adjusting for clinically relevant covariates.Results: The study included 4350 new users of aclidinium, 23,405 of tiotropium, 6977 of other LAMAs, 3122 of LAMA/LABA, 26,093 of LABA/ICS, and 5678 of LABA. Mean age was 69– 70 years across medication groups. Aclidinium users had the highest proportion of severe COPD, and LABA users had the lowest (35% vs 19%, respectively). Crude incidence rates per 1000 person-years for the first-ever hospitalisation for heart failure ranged from 6.9 in LABA to 9.5 in aclidinium. Using LABA as reference, adjusted IRRs (95% confidence interval) for first-ever hospitalisation for heart failure were 0.90 (0.53– 1.53) for aclidinium, 1.02 (0.69– 1.51) for tiotropium, 0.86 (0.50– 1.47) for other LAMAs, 1.09 (0.41– 2.92) for LAMA/LABA, and 1.01 (0.69, 1.48) for LABA/ICS.Conclusion: The study did not find increased risks of hospitalisations for heart failure in new users of aclidinium, tiotropium, other LAMAs, LAMA/LABA, and LABA/ICS compared with LABA.Keywords: aclidinium, LAMA, heart failure, United Kingdom

Introduction Long-acting muscarinic antagonists (LAMAs), long-acting β2-agonists (LABAs), inhaled corticosteroids (ICS), and their combinations, are recommended for the treatment of chronic obstructive pulmonary disease (COPD). This study aimed to determine whether the safety and efficacy of aclidinium bromide differs by baseline maintenance LABA and ICS therapies. Methods ASCENT-COPD was a phase 4, multicenter, double-blind, randomized, placebo-controlled, parallel-group study of patients with moderate-to-very severe COPD and increased cardiovascular risk. Patients were randomized 1:1 to receive aclidinium 400 μg or placebo twice daily, via a multidose dry-powder inhaler for up to 3 years. Outcomes included time to first major adverse cardiovascular events (MACE), all-cause mortality, change from baseline in trough forced expiratory volume in 1 s (FEV1), and COPD assessment test (CAT) total score over 3 years, and annual moderate-to-severe COPD exacerbation rate in patients receiving aclidinium or placebo with maintenance LABA monotherapy, ICS monotherapy, LABA + ICS (fixed/free), or no maintenance therapy (neither LABA nor ICS) at baseline. Results A total of 3589 patients were included (LABA, n = 227; ICS, n = 290; LABA + ICS, n = 2058; no maintenance, n = 1130). Aclidinium did not increase the risk of MACE or all-cause mortality versus placebo, regardless of baseline maintenance treatment. Reductions in moderate-to-severe exacerbation rates were observed with aclidinium versus placebo in all subgroups [LABA 43% (P = 0.046); ICS 25% (P = 0.202); LABA + ICS 22% (P = 0.003); no maintenance 18% (P = 0.130)]. Aclidinium improved morning trough FEV1 irrespective of baseline therapy and CAT total scores, except for LABA and ICS subgroups, versus placebo at several time points. Conclusion In patients with moderate-to-severe COPD and CV risk factors, the addition of aclidinium to maintenance therapy with LABA or LABA + ICS provided further benefit. Trial Registration ClinicalTrials.gov identifier NCT01966107. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01878-5.

Background: Use of aclidinium bromide (AB) and aclidinium/formoterol (AB/FF) in the real world is not fully characterized in Europe. Aim: To describe characteristics of new users of AB, AB/FF, and other COPD medications in the United Kingdom (UK), Denmark, and Germany. Methods: Cohorts in the UK Clinical Practice Research Datalink GOLD (2015-2017), the Danish National Health Databases (2015-2017), and the German Pharmacoepidemiological Research Database (2015) included new users of long-acting muscarinic antagonists (LAMA) (AB, AB/FF, tiotropium, other LAMA), long-acting beta2-agonists (LABA), or LABA/inhaled corticosteroids (LABA/ICS). New users were characterized according to age, sex, lifestyle factors, comorbidity, COPD and asthma diagnoses, comedications, and COPD severity. Results: The study included 17,668 new users of AB and 14,808 new users of AB/FF. New users of LAMA medications were older (median range, 69-71 years) than users of LABA or LABA/ICS (median range, 53-67 years). Smoking was more frequent in LAMA users (20.1% to 39.9%) than in LABA or LABA/ICS users (7.9% to 26.8%). Hypertension, depressive disorders, urinary tract infections, and diabetes were frequent comorbidities. COPD diagnosis was more frequent in LAMA (46.8% to 92.8%) than in LABA or LABA/ICS (24.2% to 65.5%) users. In the UK, AB users had a higher proportion of severe COPD than AB/FF users; the opposite applied to the other countries. Conclusion: AB, AB/FF users showed similar characteristics to those of other LAMA users. Compared with LABA and LABA/ICS users, AB and AB/FF users were older, had a higher frequency of severe COPD, chronic comorbidities, and use of COPD comedications.

Summary Introduction Conventional open repair of a traumatic aortic isthmic rupture is associated with a significantly high mortality and morbidity rates. Thoracic endovascular aortic repair (TEVAR) is currently often performed because it is a less invasive treatment than surgery. The aim of this study was to evaluate short and mid-term results of TEVAR in traumatic aortic isthmic rupture. Methods This is a retrospective study conducted between 2010 and 2018 including patients who underwent TEVAR for traumatic aortic isthmic rupture. Results Thirty-six consecutive patients were included. All patients had sustained a violent blunt chest trauma after a sudden deceleration with associated injuries. The injury severity score (ISS) was 40 (14–66). All patients were hemodynamically stable at admission. We deployed thoracic aorta stent grafts with a mean diameter of 26 mm (18–36). The procedural success rate was 100%. We reported one intra-operative complication which was a distal migration of the graft, managed by an implantation of an aortic extension graft. On the first postoperative day, one patient presented an acute lower limb ischemia, probably due to the surgical femoral access, treated with an embolectomy with a Fogarty catheter with satisfactory results. The mean follow-up was 40.41 months (6.5–96). The mortality and paraplegia rates were 0% at one month and during the follow-up period. We reported a case of kinking of the graft that occurred at 6 months. No cases of endoleak neither re-intervention were reported. Conclusion TEVAR is a safe and a reliable method for the treatment of sub-acute traumatic thoracic aortic injuries.

A severe lack of early diagnosis coupled with resistance to most available therapeutic options renders pancreatic cancer as a major clinical concern. The limited efficacy of current treatments necessitates the development of novel therapeutic strategies that are based on an understanding of the molecular mechanisms involved in pancreatic cancer progression. MicroRNAs (miRNAs) are non-coding small RNAs that regulate the expression of multiple proteins in the post-translation process and thus have promise as biomarkers, prognostic agents, and as advanced pancreatic therapies.Profiling of deregulated miRNAs in pancreatic cancer can correlate to diagnosis, indicate optimal treatment and predict response to therapy. Furthermore, understanding the main effector genes in pancreatic cancer along with downstream pathways can identify possible miRNAs as therapeutic candidates. Additionally, obstacles to the translation of miRNAs into the clinic are also considered.Distinct miRNA expression profiles can correlate to stages of malignant pancreatic disease, and hold potential as biomarkers, prognostic markers and clinical targets. However, a limited understanding and validation of the specific role of such miRNAs stunts clinical application. Target prediction using algorithms provides a wide range of possible targets, but these miRNAs still require validation through pre-clinical studies to determine the knock-on genetic effects.Graphical abstract

Despite the success of angioplasty of the iliac artery, this technique remains associated with significant amputation rates. The purpose of this study was to identify predictive factors for lower limb amputation after iliac angioplasty in patients with critical ischemia.We reported a retrospective study including patients who successfully underwent angioplasty of the iliac artery between 2014 and 2018. The primary endpoint was limb salvage at 1 month. The variables were studied in univariate and multivariate analysis.Our study included 86 patients. The median age was 57±10 and the sex ratio was 4.7. Cardiovascular risk factors were represented by smoking in 14 cases (16.3%), diabetes in 25 cases (29.1%), arterial hypertension in 2 cases (2.3%) and dyslipidemia in 2 cases (2.3%). Seventy patients (81.3%) were classified as stage 4 according to the Leriche and Fontaine classification and 16 patients (18.7%) were classified as stage 3. The lesions were stenosing in 48 cases (55.8%) and occlusive in 38 cases (44.2%). These lesions were classified according to the TASC classification "Trans-Atlantic-Society-Consensus" in TASC A-B in 61 cases (70.9%) and TASC C-D in 35 cases (29.1%). Distal arteritis was found in 8 cases (9.3%). Balloon angioplasty was performed in 36 cases (41.8%) and angioplasty stenting in 50 cases (58.2%). At 1 month, the amputation rate was 9.3%. Univariate analysis showed that diabetes and smoking were the most important factors associated with amputation (respectively P=0.007, OR=9.31, 95% CI=[1.73-50.07] and P=0.022; OR=6.8; 95% CI=[1.46 to 31.61]). Multivariate analysis showed that diabetes and distal arteritis were the predictive factors for amputation (respectively P=0.034, OR=21.06, 95% CI=[1.25 to 354.46] and P=0.008, OR=11,61, 95% CI=[1.88 to 71.69]).Diabetes and distal arteritis are the predictive factors for lower limb amputation after iliac angioplasty.

The purpose of our study was to review the population at risk of upper limb arterial injury, to determinate the rate of upper limb salvage and the predictive factors of limb loss.This was a retrospective study, involving 128 patients with upper extremity arterial trauma operated between January first, 2006 and June 30, 2017. Exclusion criteria were arterial ligation, primary limb amputation and arterial iatrogenic injuries. End points were immediate technical success, primary patency and limb salvage rate.The average age was 27.7 years with a sex ratio M/F=41, causes of trauma were self-inflicted wounds (51%), assaults (23%), road traffic accidents (10%), work accidents (9%) and domestic accidents (7%). Injured arteries were brachial (66.5%) usually because of self-inflicted injuries; arteries of the forearm (31%) and axillery arteries (2.5%). The techniques of arterial repair were vein graft interposition in 52% of cases, end-to-end anastomosis in 23%, primary arterial repair in 21% and venous patch in 4%. Eight reconstructions occluded during the first week (6.25%). Four patients required secondary amputation and limb salvage rate was 96.8%. After a median follow-up time of 62 days, only 21% were followed at 3 months. Mechanism of injury, soft tissue loss and arterial reconstruction thromboses were selected as factors influencing the rate of limb salvage. One death occurred at day 14 secondary to multi-component poly-trauma.Prompt diagnosis, appropriate multidisciplinary management of the upper extremity arterial trauma and a readiness to revise the vascular repair early in the event of failure will maximize patient survival and upper extremity salvage. Associated soft tissue injury is a poor limb salvage factor.

IMPORTANCE: There is concern that long-acting muscarinic antagonists increase cardiovascular morbidity or mortality in patients with chronic obstructive pulmonary disease (COPD). OBJECTIVE: To determine the cardiovascular safety (noninferiority) and efficacy (superiority) of aclidinium bromide, 400 μg twice daily, in patients with COPD and cardiovascular disease or risk factors. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, randomized, placebo-controlled, double-blind, parallel-design study conducted at 522 sites in North America. A total of 3630 patients with moderate to very severe COPD and either a history of cardiovascular disease or at least 2 atherothrombotic risk factors were randomized; follow-up occurred for up to 3 years until at least 122 major adverse cardiovascular events (MACE) occurred. The first patient was enrolled on October 16, 2013 and the last on August 22, 2016. The final patient completed follow-up on September 21, 2017. INTERVENTIONS: Patients were randomized to receive aclidinium (n = 1812) or placebo (n = 1818) by dry-powder inhaler, twice daily for up to 3 years. MAIN OUTCOMES AND MEASURES: The primary safety end point was time to first MACE over up to 3 years (hazard ratio [HR] 1-sided 97.5% CI noninferiority margin = 1.8). The primary efficacy end point was the annual COPD exacerbation rate during the first year of treatment. Secondary outcomes included an expanded MACE definition (time to first MACE or serious cardiovascular event of interest) and annual rate of exacerbations requiring hospitalization. RESULTS: Among 3589 patients analyzed (mean age, 67.2 years; 58.7% male), 2537 (70.7%) completed the study. Of these, 69 (3.9%) aclidinium and 76 (4.2%) placebo patients had a MACE (HR, 0.89; 1-sided 97.5% CI, 0-1.23); the expanded MACE definition included 168 (9.4%) aclidinium vs 160 (8.9%) placebo patients with events (HR, 1.03; 1-sided 97.5% CI, 0-1.28). Annual moderate to severe exacerbation rates (aclidinium, 0.44; placebo, 0.57; rate ratio, 0.78; 2-sided 95% CI, 0.68-0.89; P

We herein describe the case of a 38-year-old patient with congenital agammaglobulinemia who presented with community-acquired pneumonia; acute respiratory failure with sepsis ensued requiring ICU admission, mechanical ventilation and vasopressors administration. The causative organism was identified as Acinetobacter calcoaceticus, sensitive to multiple agents. Stewardship was effectively applied; clinical, biologic and radiologic improvement resulted, and the patient was later discharged on ciprofloxacin therapy; improvement being maintained thereafter. This is the first reported case of community-acquired Acinetobacter pneumonia in our region.

Introduction: Chronic obstructive pulmonary disease (COPD) is a heterogeneous illness characterized by persistent airflow obstruction and exacerbations. Patients typically experience a decline in lung function, increasingly impaired health-related quality of life, and high mortality. Poor lung function and exacerbations are associated with an increased risk of cardiovascular (CV) and cerebrovascular events, and approximately 30% of patients with COPD die from CV‑related disease. Treatment with inhaled long-acting bronchodilators, such as long-acting muscarinic antagonists (LAMAs), is recommended; however, some studies have suggested that LAMAs may increase the risk of CV events. As patients with CV and cerebrovascular conditions are often excluded from clinical trials, an evaluation of the safety of COPD treatments in an at-risk population is vital. Aclidinium bromide is a LAMA approved for the long-term maintenance treatment of COPD. Methods and Objectives: The Phase 4, multicenter, double-blind, randomized, placebo-controlled, parallel-group Aclidinium Bromide on Long-Term Cardiovascular Safety and COPD Exacerbations in PatieNTs with Moderate to Very Severe COPD (ASCENT COPD) study ({"type":"clinical-trial","attrs":{"text":"NCT01966107","term_id":"NCT01966107"}}NCT01966107) is being conducted at 500 sites in the United States and Canada. The primary objectives are to evaluate the long-term effects of twice-daily aclidinium bromide 400 µg on CV safety and exacerbations in patients with moderate to very severe COPD with a history of cerebrovascular, coronary, or peripheral artery disease, or the presence of ≥2 atherothrombotic risk factors. The primary safety and efficacy variables are time to first major adverse CV event (MACE) (on-study analysis) and rate of moderate to severe COPD exacerbations during the first year of treatment (on-treatment analysis), respectively. The study will be terminated after approximately 122 MACE have occurred.

New therapies are being developed to target proinflammatory mediators thought to be involved in the pathophysiology of severe asthma. Tralokinumab is an investigational fully human monoclonal antibody that specifically blocks binding of IL-13 to its receptors. Here, we describe the background leading to the design of two Phase III trials, STRATOS 1 and 2 (NCT02161757 and NCT02194699), which aim to provide confirmatory evidence of the efficacy and safety of tralokinumab in patients with asthma that is uncontrolled despite treatment with inhaled corticosteroids and long-acting β2-agonists. These trials will also confirm the validity of periostin and DPP-4, identified in a prior Phase IIb study (NCT01402986), as predictors of an enhanced response to tralokinumab.

Invasive fungal infections (IFI) are a major cause of morbidity and mortality in immunocompromised adults and children. The purpose of this review was to update the epidemiological, clinical and therapeutic options in children, and to compare them with the adult population. Although there are important differences, the epidemiology, clinical features and risk factors for IFI have many similarities. Patient at risk include neutropenic hematology children, in whom Candida spp. y Aspergillus spp. predominate; primary immunodeficiencies, particularly chronic granulomatous disease with high susceptibility for Aspergillus spp.; and extremely premature infants, in whom C. albicans y C. parapsilosis are more prevalent. Premature babies are prone to dissemination, including the central nervous system. There are peculiarities in radiology and diagnostic biomarkers in children. In pulmonary aspergillosis, clasical signs in CT are usually absent. There is scant information on PCR and beta-D-glucan in children, and more limited on the performance of galactomannan enzyme immunoassay, that does not appear to be much different in neutropenic patients. There is a delay in the development of antifungals, limiting their use in children. Most azoles require therapeutic drug monitoring in children to optimize its safety and effectiveness. Pediatric treatment recommendations are mainly extrapolated from results of clinical trials performed in adults. There is no evidence for the benefit of preemptive therapy in children. It is necessary to foster specific pediatric studies with current and new antifungals to evaluate their pharmacokinetics, safety, and effectiveness at different ages in the pediatric population.

Susceptibility patterns of Streptococcus pneumoniae and Haemophilus influenzae collected over a 5-year period in a Beirut general university hospital were studied. Only 40.6–50% of S. pneumoniae isolates were susceptible to penicillin G. Susceptibility to clindamycin and erythromycin decreased from 94.1% and 89.7%, respectively, in 2000 to 75% and 71.9%, respectively, in 2004. All isolates were susceptible to ceftriaxone, ciprofloxacin and vancomycin. For H. influenzae , no resistance was observed to amoxycillin-clavulanate, ceftriaxone, ciprofloxacin and rifampicin, with >92% of isolates showing susceptibility to cefuroxime, chloramphenicol, erythromycin and tetracycline. The proportion of β-lactamase-positive isolates varied between 22.7 and 30.8%.

This study investigated the effect of refined rosemary extract on lipid oxidation in frozen, precooked beef patties (FBP) stored at −18.0C (0.4F) for 12 weeks. Samples were analyzed for peroxide value (PV) levels, 2-thiobarbituric acid (TBA) values and sensory characteristics on 0 day and after 4, 8, and 12 weeks. Samples with rosemary extract showed lower PV and TBA values. Sensory evaluations of precooked patties with rosemary extract were not significantly different in scores on color, smell/odor, appearance, texture and overall acceptability. Samples with refined rosemary extract reported a significantly higher liking score for flavor (P

A large set of 10-day, quasi-two-dimensional atmospheric trajectory model data is used to compute Lagrangian autocorrelation functions for horizontal velocity components and to determine their integral timescale TL. The objectives of the study are to investigate the seasonal, interannual, and altitudinal behavior of TL and to present the Lagrangian autocorrelation functions corresponding to synoptic-scale flow. Results indicate that the integral timescale TL ranges from 15 to 24 h, with values for the meridional velocity component that are 10%‐25% less than values for the zonal velocity component. The Lagrangian autocorrelation functions are modeled using Gaussian and second-order autoregressive autocorrelation models. The model fits to the observed autocorrelation functions were found to be of similar form to those determined for a 1-yr set of three-dimensional trajectory data, suggesting that these functions are robust with respect to synoptic-scale, tropospheric flow.

Background Accidental intrathecal injection of bupivacaine during epidural analgesia in labour remains a hazard, with the potential to cause total spinal anaesthesia and maternal collapse. Sacral block appears early after intrathecal injections compared with epidural ones, and we therefore used SI motor block to determine a safe and reliable test dose for epidural catheter misplacement. Methods Mothers booked for elective Caesarean section were given various intrathecal doses of bupivacaine with fentanyl during routine combined spinal-epidural anaesthesia. Results Using sequential allocation we found that the ED50 for SI motor block 10 min after intrathecal injection was bupivacaine 7 mg with fentanyl 14 μg (95% CI, 6.2–7.8 mg). We then used intrathecal bupivacaine 13 mg to look for the ED95. We found the calculated ED97.5 to be bupivacaine 9.7 mg with fentanyl 19.4 μg (95% CI, 8.7–1 1.4). Conclusion We conclude that testing for SI motor block 10 min after epidural injection of bupivacaine 10 mg is a reliable test to detect accidental intrathecal injection in the obstetric population.

The purpose of this study was to evaluate the functional state of glutamatergic neurons in the cerebellar cortex of patients with schizophrenia.The authors measured messenger ribonucleic acid (mRNA) levels of three activity-dependent genes expressed by glutamatergic neurons in the cerebellar cortex (GAP-43, BDNF, and GABA OLE_LINK2(A)-delta subunit) in the tissues of 14 patients with schizophrenia and 14 matched nonpsychiatric comparison subjects. Since its level of expression does not change in response to neuronal activity, gamma-aminobutyric acid(A)-alpha6 subunit mRNA was used as a control.The levels of GAP-43 and BDNF mRNAs were significantly elevated in patients with schizophrenia, and a similar finding was observed for GABA(A)-delta mRNA. In contrast, the levels of the GABA(A)-alpha6 subunit mRNA, which is expressed in cerebellar granule cells in an activity-independent manner, did not differ from comparison subjects.These results suggest that glutamatergic neurons may be hyperactive in the cerebellar cortices of patients with schizophrenia.

From January 2003 to December 2005, 5091 susceptibility test results from invasive isolates of Escherichia coli, collected from blood cultures and cerebrospinal fluid routinely processed within 58 participating laboratories, were investigated. These laboratories in turn serviced 64 hospitals in Algeria, Cyprus, Egypt, Jordan, Lebanon, Malta, Morocco, Tunisia and Turkey. The median proportion of resistance to third-generation cephalosporins for the duration of the project was 18.9% (interquartile range (IQR): 12.5–30.8%), and for fluoroquinolones 21.0% (IQR: 7.7–32.6%). A substantial proportion of strains reported by laboratories in countries east of the Mediterranean exhibited evidence of multiresistance, the highest proportion being from Egypt (31%). There is clearly a need for further investigation of potential causes of the significant resistance identified, as well as for strengthening of national and international surveillance initiatives within this region.‘, peer-reviewed

An interactive IC design methodology aimed at making designs less sensitive to manufacturing variations is presented, as well as a CAD tool to support it. The methodology, based on Taguchi's Robust Design Method, is shown to improve the performance and robustness of basic analog circuits. >

Accidental intrathecal injection of bupivacaine during epidural analgesia in labour remains a hazard, with the potential to cause total spinal anaesthesia and maternal collapse. Sacral block appears early after intrathecal injections compared with epidural ones, and we therefore used SI motor block to determine a safe and reliable test dose for epidural catheter misplacement.Mothers booked for elective Caesarean section were given various intrathecal doses of bupivacaine with fentanyl during routine combined spinal-epidural anaesthesia.Using sequential allocation we found that the ED50 for SI motor block 10 min after intrathecal injection was bupivacaine 7 mg with fentanyl 14 micrograms (95% CI, 6.2-7.8 mg). We then used intrathecal bupivacaine 13 mg to look for the ED95. We found the calculated ED97.5 to be bupivacaine 9.7 mg with fentanyl 19.4 micrograms (95% CI, 8.7-11.4).We conclude that testing for SI motor block 10 min after epidural injection of bupivacaine 10 mg is a reliable test to detect accidental intrathecal injection in the obstetric population.