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SummaryBackgroundThe emerging threat represented by SARS-CoV-2 variants, demands the development of therapies for better clinical management of COVID-19. MAD0004J08 is an extremely potent Fc-engineered monoclonal antibody (mAb) able to neutralise in vitro all current SARS-CoV-2 variants of concern (VoCs). This ongoing study, evaluates safety, pharmacokinetics and SARS-CoV-2 sera neutralization effect of MAD0004J08 when administered as single dose intramuscularly in healthy adults.MethodWe conducted a dose escalation study with sequential enrolment of three cohorts, each with an increasing dose level of MAD0004J08 (48mg, 100mg and 400mg). Within each cohort, 10 young healthy adults were randomized with 4:1 ratio to a single intramuscular (i.m.) injection of MAD0004J08 or placebo. The primary endpoint is the proportion of subjects with severe and/or serious treatment emergent adverse events (TEAEs) within 7 days post-treatment. Secondary endpoints reported in this paper are the proportion of subjects with solicited TEAEs up 7 days post dosing, MAD0004J08 serum concentrations and neutralising activity versus the original SARS-COV-2 Wuhan virus at different timepoints post-dosing. As post-hoc analyses, we compared the sera neutralising titres of subjects who received MAD0004J08 with those of people that had received the COVID-19 BNT162b2 mRNA vaccine in the previous sixty days (n=10) and COVID-19 convalescent patients (n=20), and assessed serum neutralisation activity against the B.1.1.7 (alpha), B.1.351 (beta) and B.1.1.248 (gamma) SARS-CoV-2 variants of concern.FindingsA total of 30 subjects, 10 per cohort, were enrolled and randomized. Data up to 30 days were available and analysed in this report. No severe TEAEs were reported in any of the cohorts in the 7 days post-treatment. MAD0004J08 was detected in the sera of treated subjects within few hours post-administration and reached almost maximal levels on day 8. The geometric mean neutralising titres (GMT) assessed against the original Wuhan virus peaked on day 8 and ranged 226 – 905, 905 – 2,560, and 1,280 – 5,120 for cohort 1, 2 and 3 respectively. The sera neutralising GMT in MAD0004J08 treated subjects in all the three cohorts were found to be 1·5-54·5-fold higher compared to sera from convalescent patients and 1·83– 76·4-fold higher compared to sera from COVID-19 vaccinees. Finally, GMT in MAD0004J08 treated subjects showed high neutralising titres versus the B.1.1.7 (alpha), B.1.351 (beta) and B.1.1.248 (gamma) SARS-CoV-2 VoCs.InterpretationA single dose administration of MAD0004J08 via i.m. route is safe and well tolerated and results in a rapid systemic distribution of the MAD0004J08 and sera neutralising titres higher than COVID-19 convalescent and vaccinated subjects. A single dose administration of MAD0004J08 is also sufficient to effectively neutralise major SARS-CoV-2 variants of concern. Based on these results, a Phase 2-3 trial is ongoing to further assess the safety, dosage, and efficacy of MAD0004J08 in asymptomatic or mild-moderate symptomatic COVID-19 patients.FundingEU Malaria Fund, Ministero dello Sviluppo Economico, Ministero della Salute, Regione Toscana, Toscana Life Sciences Sviluppo and European Research Council.Research in contextEvidence before this studyWe searched PUBMED, MEDLINE and MedRxiv for clinical trials, meta-analyses and randomized controlled trials evaluating the antibody neutralization titres vs. different SARS-CoV-2 variants of concern obtained from subjects who received monoclonal antibodies for the treatment of COVID-19 using the following search terms: (“COVID-19” OR “SARS-CoV-2”) AND (“monoclonal antibody” OR “neutralising antibody”) AND (“variants” OR “variants of concern”). No relevant studies were identified.Added value of this studyThis is the first human study assessing safety, PK and neutralising potential of MAD0004J08, a monoclonal antibody against SARS-CoV-2 wild type Wuhan virus and variants of concern, administered intramuscularly at low dosages (48, 100 and 400 mg). MAD0004J08 showed to be safe and well tolerated in the tested dose range. Anti-spike antibodies were detected in the sera of tested SARS-CoV-2 negative healthy adults few hours post-injection. In addition, the sera obtained from MAD0004J08treated subjects, showed to have high neutralisation titres against the Wuhan virus, the B.1.1.7 (alpha), B.1.351 (beta) and B.1.1.248 (gamma) variants of concern.Implications of all the available evidenceA potent monoclonal antibody such as MAD0004J08, capable of neutralising multiple variants of concern of SARS-CoV-2 rapidly and long lastingly when given as a single intramuscular injection. The antibody, presently tested in a phase 2-3 efficacy trial, can be a major advancement in the prophylaxis and clinical management of COVID-19, because of its broad spectrum, ease of use in non-hospital settings and economic sustainability.

Coronavirus disease 2019 (COVID-19) outbreak is a public health emergency of international concern due to a highly pathogenic human coronavirus (HCoV), actually named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite much emerging data about the epidemiological association between cardiovascular diseases and COVID-19, little is still known atrial fibrillation (AF) and its optimal management in this clinical contest. The aim of our review is to describe the pharmacological interactions between cardiovascular drugs more commonly used in AF management and experimental COVID-19 therapies, based on European (EU) and Unites States (US) summaries of product characteristics.

Diabetes mellitus is a lifelong disease in which either the pancreas fails to produce insulin or the produced amount is insufficient to control blood sugar levels. A way to tackle this malfunctioning is to devise an artificial pancreas endowed with a personalized control algorithm able to regulate the insulin dosage. A crucial step in realizing such a device is to effectively forecast future glucose levels starting from past glucose values, the knowledge of the food intake, and of the basal and the injected insulin. The increasing availability of medical diabetes data sets is providing unprecedented opportunities to identify correlations inside these data even harnessing innovative investigation methods, such as deep learning. As an alternative to the deep learning methods successfully used as forecasting models, we exploit a neuroevolution algorithm to model and predict future personalized blood glucose levels. The discovered subjective regression model can represent the control algorithm of an artificial pancreas. This model is assessed through experiments performed on a real-world database containing data of six patients suffering from Type 1 diabetes. To further evaluate the effectiveness of the predictions derived from the proposed approach, the results are also compared against those obtained by other state-of-the-art recently proposed methods.

The management of diabetes is a very complex task, hence devising automatic procedures able to predict the glycemic level can represent a significant step towards the building of an artificial pancreas capable of providing the needed amounts of insulin boluses.This paper presents a Grammatical Evolution-based algorithm aiming at extrapolating a regression model able to estimate the blood glucose level in future instants of time through interstitial glucose measurements. The hypothesis is that the amounts of carbohydrates assumed, of basal insulin levels and of those administered with boluses are known. Experiments, performed on a real-world database made up of five patients suffering from Type 1 diabetes, are shown in terms of Clark Error Grid analysis. To evaluate the effectiveness of the predictions derived from the proposed approach, the results obtained are compared against those obtained by other state-of-the-art evolutionary-based methods very recently proposed.

Background: A two-incision technique, in association with inter-muscular positioning of the subcutaneous defibrillator (S-ICD), is now the most frequently adopted implantation approach in Europe. Ultrasound-guided serratus anterior plane block (SAPB) has been proposed to provide anesthesia/analgesia during S-ICD implantation. Objective: We performed a case-control analysis in which a standardized SAPB approach was compared with the typical local anesthesia and sedation approach. Methods: Ninety-one consecutive patients underwent implantation of an S-ICD with the SAPB approach for anesthesia/analgesia at 10 centers. The control group consisted of 55 consecutive patients who underwent S-ICD implantation with a standard local approach. Results: The mean procedure duration was 59 ± 15 minutes in the SAPB group and 76 ± 23 minutes in the control group (P

Funding Acknowledgements No Funding OnBehalf RHYTHM DETECT study group Background A two-incision technique, in association with inter-muscular positioning of the subcutaneous defibrillator (S-ICD), is now the most frequently adopted implantation approach in Europe. Ultrasound-guided serratus anterior plane block (SAPB) has been proposed in order to provide anesthesia/analgesia during S-ICD implantation. Objective We performed a case-control analysis in which a standardized SAPB approach was compared with the typical local anesthesia and sedation approach. Methods 91 consecutive patients underwent implantation of an S-ICD with the SAPB approach for anesthesia/analgesia at 10 centers. The control group consisted of 55 consecutive patients who underwent S-ICD implantation with standard local approach. Results The mean procedure duration was 59 ± 15min in the SAPB group and 76 ± 23min in the control group (p Conclusions SAPB is feasible and effective in providing anesthesia/analgesia during S-ICD implantation. The procedures were successfully accomplished and no complications occurred in either group. However, SAPB was associated with lower pain levels, enabling the need for sedation to be reduced and more patients to remain awake. Moreover, it resulted in shorter procedure durations.

Tento článek ilustruje vývoj a použitelnost Evolučního Počítání pro zlepšení léčby pacientů s diabetem typu 1, kteří léčbu inzulínem. Jelikož je takové onemocnění spojeno se špatnou funkcí slinivky břišní, která produkuje nedostatečné množství inzulínu, způsob, jak zvýšit kvalitu života těchto pacientů, je vytvořit umělou slinivku schopnou uměle regulovat dávkování inzulínu. Cílem této práce je extrapolace regresního modelu, schopného odhadnout krevní glukózu (BG) pomocí měření intersticiální glukózy (IG) a jejich prvních derivací. V této studii demonstruujeme použitelnost tohoto přístupu. Zejména s ohledem na vysokou složitost vzájemných interakcí je navržena evoluční strategie, která extrapoluje matematický vztah mezi BG a IG a jeho derivací. Vypočítané modely jsou porovnány s jinými modely během experimentů na personalizovaných a globálních datech. This paper illustrates the development and the applicability of an Evolutionary Computation approach to enhance the treatment of Type-1 diabetic patients that necessitate insulin injections. In fact, being such a disease associated to a malfunctioning pancreas that generates an insufficient amount of insulin, a way to enhance the quality of life of these patients is to implement an artificial pancreas able to artificially regulate the insulin dosage. This work aims at extrapolating a regression model, capable of estimating the blood glucose (BG) through interstitial glucose (IG) measurements and their numerical first derivatives. Such an approach represents a viable preliminary stage in building the basic component of this artificial pancreas. In particular, considered the high complexity of the reciprocal interactions, an evolutionary-based strategy is outlined to extrapolate a mathematical relationship between BG and IG and its derivative. The investigation is carried out about the accuracy of personalized models and of a global relationship model for all of the subjects under examination. The discovered models are assessed through a comparison with other models during the experiments on personalized and global data.

Deep Neural Networks (DNNs) may be very effective for the classification over highly-sized data sets, especially in the medical domain, where the recognition of the occurrence of a specific event related to a disease is of high importance. Unfortunately, DNNs suffer from the drawback that a good set of values for their configuration hyper-parameters must be found. Currently, this is done through the use of either trial-and-error methods or sampling-based ones. In this paper we propose a new approach to find the most suitable structure for a DNN used for a classification problem in terms of achievement of the highest classification accuracy. This approach is based on a distributed version of Differential Evolution (DE), a variety of an Evolutionary Algorithm. To evaluate the approach, in this paper we investigate this issue with reference to Obstructive Sleep Apnea (OSA). OSA is an important medical problem consisting of episodes taking place during night in which a subject stops breathing due to a constriction of the upper airways. This deteriorates the quality of life and may have dangerous, and even lethal, consequences on both short and long term. An accurate classification is a very crucial step for the OSA treatment, because understanding automatically that a subject is experiencing such an episode may be decisive if prompt medical action is needed. In our experiments, classification takes place on a data set in which each item contains the values of 17 Heart Rate Variability parameters, extracted from ElectroCardiography signals, and the annotation of OSA events. We have extracted this data set from the real-world Sleep Heart Health Study database. The results obtained by the distributed DE are compared against those of the Grid Search as well as against those achieved by 13 well-known classification tools. The use of a distributed DE version turns out to be very effective in automatically obtaining DNN structures with higher classification accuracy with respect to Grid Search (72.95% versus 72.61%), and allows saving a high amount of time (three hours as opposed to 65 h and 40 min). Moreover, the proposed method outperforms in terms of higher accuracy all the other classifiers investigated, as it is evidenced also by statistical analysis. Numerically, the runner-up, i.e., JRip, achieves as its best value 72.01% and 71.50% on average over 25 runs, both values being lower than 72.95% and 72.74% obtained by our dDE.

Pacienti s diabetem jsou vystaveni několika vážným zdravotním rizikům, které mohou vést k smrtelným následkům. Pro zvýšení kvality života těchto pacientů je nutné navrhnout umělou slinivku, která bude podávat inzulín v případě potřeby. Tento článek představuje algoritmus založený na genetickém programování pro extrapolaci regresního modelu schopného odhadnout hladinu glukózy v krvi (BG) pomocí měření intersticiální glukózy (IG) a jejich derivácí. Tento algoritmus představuje možný krok při budování základního prvku umělé slinivky, jmenovitě nové evoluční výpočetní metodologie pro odvození matematického vztahu mezi BG a IG. Navržený evoluční postup je vyhodnocen na základě reálné databáze, která se skládá z měření BG i IG u osob trpících diabetem 1. typu. Zjištěný model je validován porovnáním s dalšími technikami během experimentální fáze. The patients suffering from diabetes are subjected to several serious medical risks that can lead also to fatal consequences. To enhance the quality of life of these patients there is the necessity to devise an artificial pancreas able to inject an insulin bolus when needed. This paper presents a genetic-programming based algorithm to extrapolate a regression model able to estimate the blood glucose (BG) level through interstitial glucose (IG) measurements and their derivatives. This algorithm represents a possible step in building the fundamental element of such an artificial pancreas, namely a new evolutionary computation-based metodology to derive a mathematical relationship between BG and IG. The proposed evolutionary automatic procedure is evaluated on a real-world database made up of both BG and IG measurements of people suffering from Type 1 diabetes. The discovered model is validated through a comparison with other techniques during the experimental phase

A three-step approach to the early development of adjuvanted vaccine candidates is proposed, the goal of which is to allow ample space for exploratory and hypothesis-generating human experiments and to select dose(s) and dosing schedule(s) to bring into full development. Although the proposed approach is more extensive than the traditional early development program, the authors suggest that by addressing key questions upfront the overall time, size and cost of development will be reduced and the probability of public health advancement enhanced. The immunogenicity end-points chosen for early development should be critically selected: an established immunological parameter with a well characterized assay should be selected as primary end-point for dose and schedule finding; exploratory information-rich end-points should be limited in number and based on pre-defined hypothesis generating plans, including system biology and pathway analyses. Building a pharmacodynamic profile is an important aspect of early development: to this end, multiple early (within 24h) and late (up to one year) sampling is necessary, which can be accomplished by sampling subgroups of subjects at different time points. In most cases the final target population, even if vulnerable, should be considered for inclusion in early development. In order to obtain the multiple formulations necessary for the dose and schedule finding, "bed-side mixing" of various components of the vaccine is often necessary: this is a complex and underestimated area that deserves serious research and logistical support.

Mass immunization of children has the potential to decrease infection rates and prevent the transmission of influenza. We evaluated the immunogenicity, safety, and tolerability of different formulations of cell-derived MF59-adjuvanted and nonadjuvanted A/H1N1 influenza vaccine in children and adolescents. This was a randomized, single-blind, multicenter study with a total of 666 healthy subjects aged 6 months–17 y in one of 3 vaccination groups, each receiving formulations containing different amounts of influenza A/H1N1 antigen with or without MF59. A booster trivalent seasonal MF59 vaccine was administered one year after primary vaccinations. Antibody titers were assessed by hemagglutination inhibition (HI) and microneutralization assays obtained on days 1, 22, 43, 366, and 387 (3 weeks post booster). Safety was monitored throughout the study. One vaccination with 3.75 μg of A/H1N1 antigen formulated with 50% MF59 (3.75_halfMF59) or 7.5 μg of A/H1N1 antigen formulated with 100% MF59 (7.5_fullMF59) induced an HI titer ≥1:40 in >70% of children in the 1–70% while 2 doses of 3.75_halfMF59 were required to achieve this result. All vaccines were well tolerated. Our findings support the immunogenicity and safety of the 3.75_halfMF59 (2 doses for children

Aims Paroxysmal atrial arrhythmias occur in myotonic dystrophy type 1 (MD1) patients frequently. Pacemaker (PM) including detailed diagnostic functions may facilitate the diagnosis and management of frequent paroxysmal atrial tachyarrhythmias that may remain undetected during conventional clinical follow-up. Aim of our study was to evaluate the preventive effects of interatrial septum pacing in the Bachmann's Bundle region on atrial fibrillation (AF) in MD1 patients during 12 months follow up period. Methods and results Thirty MD1 patients (age 50.3 ± 7.3; 11 F) who underwent dual chamber PM implantation were randomized at implantation to receive right atrial appendage pacing (16 patients) or Bachmann's bundle pacing (14 patients). No statistically significant difference in the electrical parameters (P wave amplitude, pacing threshold and lead impedance) was found between the two groups at implantation. Patients were followed at 1 month, 3 months, and every 6 months thereafter. They underwent clinical assessment, a standard 12-lead ECG and assessment of device performance at every visit. We counted the number of episodes of atrial arrhythmia occurred during the collection period and the duration of each episode. At 12 months of follow-up, no statistically significant differences in the number of AF episodes or in AF duration were found. Lead parameters remained stable over time and there were no displacements of the electrodes after implantation. Conclusion Implantation of an atrial-active fixation lead on the atrial septum is safe and feasible. However, this study showed no significant difference between septal pacing and high atrial pacing, using the endpoints of AF duration and number of AF episodes.

Subjects suffering from Type 1 diabetes mellitus need to constantly receive insulin injections. To improve their life quality, a desirable solution is represented by the implementation of an artificial pancreas. In this paper we move a preliminary step towards this goal. Namely, we work at the knowledge base for such a device. One of the main problems is to estimate the Blood Glucose (BG) values, starting from the easily available Interstitial Glucose (IG) ones, and this is the aim of our paper. To face this regression task we avail ourselves of Genetic Programming over a real-world database containing both BG and IG measurements for several subjects suffering from Type 1 diabetes, aiming at finding an explicit relationship between BG and IG values under the form of a mathematical expression. This latter could be the core of the knowledge base part of an artificial pancreas. Experimental comparisons against the state-of-the-art models evidence the quality of the proposed approach.

Aim: We performed a two-year follow-up comparative study of long-term electrical parameters between the right atrial appendage (RAA) and Bachmann’s Bundle (BB) stimulation in myotonic dystrophy type 1 (MD1) patients. Methods: Twenty-five MD1 patients (18 men; age: 54 ± 13 years) with no difference in the electrical parameters between the RAA site and the BB region at implantation were randomized into two groups: in group I (13 patients; age: 52 ± 14 years; four women) the atrial lead was placed in the RAA and in group II (12 patients, age: 56 ± 12 years, three women) the lead was placed in the BB region. Measurements of electrical parameters were recorded at follow-up intervals of 6 weeks and then 12 and 24 months postimplant. Results: There was no statistically significant different in P-wave amplitude, pacing threshold, and impedance values between the two groups at 6 weeks. At 24 months follow-up, the intrinsic P-wave amplitude was 2.05 ± 1.45 mV in the RAA group versus 3.28 ± 1.09 mV in the BB group (P < 0.05); the pacing threshold was 1.85 ± 1.8 V in the RAA group versus 0.50 ± 0.39 V in the BB group (P = 0.03); there were no differences in the atrial impedance between the two groups during the follow-up period. Conclusions: In a direct two-year follow-up comparison between the RAA and BB atrial pacing sites, we showed a statistically significant increased pacing threshold and decreased intrinsic P-wave amplitude during RAA stimulation in MD1 patients. (PACE 2009; 32:1191–1196) Bachmann’s bundle, myotonic dystrophy, pacemaker, arrhythmias, heart block, fibrosis, sensing,pacing, impedance, atrial lead

Background: Cytotoxic regimens used in induction treatments for acute myeloid leukemia (AML) almost always include standard or high-dose cytarabine (Ara-C). During or soon after induction therapy, leukemic patients frequently develop gastroenteric complications, characterized by abdominal pain and diarrhea. The association ofthese symptoms with f and melena is typical ofnecrotizing enterocolitis (NE), a life-threathening condition that can be documented by ultrasound abdominal scan. Patients and methods: We analyzed retrospectively the clinical course of169 adult patients with AML treated by standard dose Ara-C-containing induction regimens, either by continuous venous infusion (group 1) or subcutaneous injection (group 2). Ultrasonography was employed as early diagnostic tool in a majority ofpatients with gastroenteric complications. Bowel wall thickening was accurately measured and used to confirm the diagnosis of necrotizing enterocolitis. Results: In the first group of 115 patients (median age, 51 years), gastroenteric complications were observed in 55 patients (48%), and 10 patients (9%) received diagnosis ofNE, which was fatal in four. Patients with NE had a median age older than that of patients without gastroenteric symptoms, and a more prolonged neutropenia. In the second group of54 patients (median age, 60 years), gastroenteric events were observed in 14 patients (26%), and no case of NE was recorded. Conclusions: This retrospective analysis shows that NE is a serious complication occurring mainly in patients treated by Ara-C administered as continuous i.v. infusion. The Hematology Journal (2003) 4, 346–350. doi:10.1038/sj.thj.6200304

MF59-adjuvanted trivalent influenza vaccine (Novartis Vaccines and Diagnostics, Siena, Italy) has been shown to be more effective than nonadjuvanted vaccine in the elderly population. Here we present results from a large-scale, observational, noninterventional, prospective postlicensure study that evaluated the safety of MF59-adjuvanted vaccine in elderly subjects aged 65 years or more. The study was performed in 5 northern Italian health districts during the 2006–2007, 2007–2008, and 2008–2009 influenza seasons. The choice of vaccine—either adjuvanted vaccine or a nonadjuvanted influenza vaccine—was determined by individual providers on the basis of local influenza vaccination policy. Hospitalizations for potential adverse events of special interest (AESIs) were identified from hospital databases and then reviewed against recognized case definitions to identify confirmed cases of AESI. Cumulative incidences were calculated for AESIs in predefined biologically plausible time windows, as well as in a 6-month window following vaccination. During the 3-year study period, 170,988 vaccine doses were administered to a total of 107,661 persons. Despite the large study size, cases of AESI resulting in hospitalization were rare, and risks of AESI were similar in both the MF59-adjuvanted and nonadjuvanted vaccination groups. In conclusion, similar safety profiles were observed for both nonadjuvanted and MF59-adjuvanted seasonal influenza vaccines in elderly recipients. adjuvants; elderly; influenza; influenza vaccine; MF59; vaccines; vaccine safety

Monoclonal gammopathies are characterized by serum monoclonal component (MC) plus an intact immunoglobulin and a free light chain (FLC), or a combination of both. The measurement of FLC with Freelite® is the standard practice recommended by International Myeloma Working Group guidelines. Recently, Hevylite® heavy/light chains (HLC) assays were introduced to specifically target junctional epitopes between the heavy and light chains of intact immunoglobulins, allowing the independent quantification of the involved (MC) and uninvolved (polyclonal immunoglobulin background) HLC isotype. Between January 2012 and March 2014, 90 patients were examined: 49 multiple myeloma (MM), 6 smoldering MM (SMM) and 35 monoclonal gammopathy of undetermined significance (MGUS). Of these 90 patients, 300 samples were collected at different times. The diagnostic and monitoring contribution of Hevylite A and G assays was assessed in all 90 patients examined. Additionally, 3 representative cases were selected. The Hevylite absolute values and ratio demonstrated high sensitivity and specificity with respect to serum protein electrophoresis and serum immunofixation. The combined use of Hevylite A and G with Freelite was particularly useful in dubious cases with more than one MC or with co-migrating components, as well as in the course of monitoring to assess the independent change of FLC and HLC, possibly reflecting the presence of clonal heterogeneity in the cohort. From this study, it can be concluded that FLC and HLC are independent, useful markers to monitor the MC and to assess with greater specificity and sensitivity the effect of therapy, thereby providing clinical support. Further studies are required to assess the prognostic potential of Hevylite in MGUS and SMM.

Background The potential consequences of an avian influenza pandemic warrants the development of safe, highly immunogenic pre-pandemic A/H5N1 vaccines with cross-clade protection. In this randomized, controlled study we compared the immunogenicity and safety of an MF59®-adjuvanted (Novartis Vaccines, Marburg, Germany) A/H5N1 pre-pandemic vaccine with that of a licensed, MF59-adjuvanted, seasonal influenza vaccine. Methods Healthy adult (18–60 years, n = 3372) and elderly (≥61 years, n = 275) volunteers received either an initial dose of a licensed, non-adjuvanted, trivalent, seasonal influenza vaccine (Agrippal®) on Day 1, followed by one dose of MF59-H5N1 study vaccine on Day 22 and a second dose of MF59-H5N1 on Day 43, or alternatively, placebo on Day 1 followed by one dose of MF59-adjuvanted seasonal reference vaccine on Day 22 and a second dose of reference vaccine on Day 43. Homologous and cross-reactive A/H5N1 antibody responses were analysed by haemagglutination inhibition (HI), single radial haemolysis (SRH), and microneutralization (MN) assays three weeks after each vaccination. Vaccine safety was assessed throughout the study. Results Analysis by HI assay found that two doses of MF59-H5N1 resulted in a seroconversion rate of 56% and a geometric mean ratio (GMR) of 7.1 in adult subjects. Similar results were observed on analysis by SRH (GMR 4.03; seroconversion 78% and seroprotection 91%) and MN (seroconversion 67%) assays. These data met the European licensure criteria for influenza vaccines. No significant difference in immunogenicity was detected between the adult and elderly populations. Anti-A/H5N1 cross-clade antibodies were detected by SRH, 49% of adult and 32% of elderly subjects achieved seroconversion after the second vaccine dose. Overall, MF59-H5N1 containing 7.5 μg antigen was less reactogenic than the MF59-adjuvanted trivalent seasonal vaccine which contained 15 μg antigen for each component strain. Conclusions Two doses of MF59-H5N1 vaccine were well tolerated and induced adequate levels of seroprotection against homologous and cross-clade A/H5N1 virus. These data support the suitability of MF59-adjuvanted A/H5N1 vaccine for pre-pandemic use in adults and the elderly.

Background Paroxysmal episodes of atrial fibrillation frequently occur in Emery-Dreifuss muscular dystrophy (EDMD). Although previous studies have documented a variety of electrocardiographic abnormalities in EDMD, little is still known about P-wave dispersion (PD), an independent risk factor for the development of atrial fibrillation. The aim of our study was to evaluate the P-wave duration and PD in patients with EDMD with conserved systolic and diastolic cardiac function. Methods The study involved 36 patients with EDMD (age, 20 [SD, 12] years; 26 men) and 36 healthy subjects used as controls, matched for age and sex. P-wave dispersion was carefully measured using 12-lead electrocardiogram. Compared with the healthy control group, patients with EDMD presented increased maximum P-wave duration (108.2 [SD, 22.2] vs 97.8 [SD, 11] milliseconds, P = 0.04) and PD (51.4 [SD, 12.8] vs 39.3 [SD, 9.7] milliseconds, P = 0.004) values. No statistically significant differences in left atrium diameter (37.1 [SD, 2.9] vs 34.1 [SD, 4.2] mm, P = 0.3) and maximum left atrium volume (15.2 [SD, 3.8] vs 14.1 [SD, 4.2] mL/m2, P = 0.4) were found between the 2 groups. We divided our study population into 2 subgroups, according to the different genetic diagnosis, patients with laminopathy EDMD (n = 17) or with emerinopathy EDMD (n = 19). No statistically significant differences were found in PD between the 2 subgroups (54.6 [SD, 15.6] vs 50.2 [SD, 11.5] milliseconds, P = 0.4). Conclusions Our study showed a significant increase of maximum P-wave duration and PD in patients with EDMD with conserved systolic and diastolic cardiac function.

We reviewed the safety of MF59-adjuvanted versus non-adjuvanted influenza vaccines in children and adolescents (aged 6 months-18 years) in an integrated analysis of all pediatric trials evaluating MF59-containing influenza vaccines completed to date (5 trials). In the MF59-adjuvanted group (n=1181) versus the non-adjuvanted group (n=545) there was no increase in the incidence of unsolicited adverse events and serious adverse events. As expected, solicited local or systemic reactions occurred more frequently in MF59-adjuvanted subjects; however, a majority of reactions were mild and transient. These data support the safety of MF59-adjuvanted influenza vaccines in the pediatric population.

Introduction: Our study was designed to analyze dynamic changes in autonomic tone before the onset of typical sustained atrioventricular nodal reentry tachycardia (AVNRT) in a large group of patients without structural heart disease. Materials and Methods: Twenty-four-hour Holter tapes from 42 consecutive patients (27 men and 15 women; aged 30 ± 21 years) with several episodes of sustained typical AVNRT were analyzed. The diagnosis was validated by transesophageal electrophysiological study. The time-domain calculated parameters were SDNN, SDANN, rMSSD, pNN50; the frequency-domain parameters were low-frequency power (LF, 0.04–0.15 Hz), high-frequency power (HF, 0.15–0.40 Hz), very low-frequency power (VLF, 0.008 to 0.04 Hz) and LF/HF. The mean values in the hour before the onset of sustained AVNRT were compared with the mean values of 2 hours before and 1 hour after the onset of sustained AVNRT. Results: The mean SDNN, rMSSD, pNN50, HF were significantly decreased during the hour preceding the onset of AVNRT, when compared to the mean values observed during the time periods selected. Instead, the LF values and LF/HF were increased before the onset of sustained AVNRT. No significant change in the VLF and atrial ectopic beats were observed. Conclusion: This study suggests that sustained typical AVNRT episodes are preceded by increase in adrenergic drive. Ann Noninvasive Electrocardiol 2010;15(1):49–55

Background Adding adjuvants such as MF59 ® to influenza vaccines can enhance the immune response. This analysis evaluated the safety profile of MF59-adjuvanted [(+)MF59] compared with non-adjuvanted [(−)MF59] vaccines in a large clinical database. Methods Safety data were pooled from 64 clinical trials involving (+)MF59 seasonal and pandemic influenza vaccines. Safety outcomes were analysed in the overall population and in subjects aged ≥65 years, in all clinical trials and in controlled trials only. Findings Data from 20,447 (+)MF59 and 7526 (−)MF59 subjects were analysed. Overall, (+)MF59 subjects had lower risks than (−)MF59 subjects of experiencing any unsolicited adverse event (AE) (26.8% vs 39.2%; adjusted risk ratio [ARR] 0.65; 95% CI 0.60–0.70), cardiovascular AEs (1.9% vs 5.6%; ARR 0.44; 95% CI 0.35–0.55), new onset chronic diseases (1.3% vs 1.9%; ARR 0.71; 95% CI 0.57–0.87) and death (0.8% vs 1.2%; ARR 0.67; 95% CI 0.51–0.87). Few AEs of potential autoimmune origin were reported: 0.71 and 0.67 per 1000 with (+)MF59 and (−)MF59, respectively. As expected, (+)MF59 subjects had a higher risk of solicited local or systemic reactions within 3 days of vaccination (58.5% vs 46.9%, weighted RR 1.34; 95% CI 1.28–1.40). Safety outcomes were consistent between total and elderly populations, and between all trials and controlled trials, although statistical significance was lost for some of the outcomes in the subgroups. Interpretation This large-scale analysis supports the good safety profile of (+)MF59 seasonal and pandemic influenza vaccines and suggests a clinical benefit over (−)MF59 influenza vaccines.

Bullying directly and negatively impacts millions of people across the globe each year. Bullying has traditionally been studied from perspectives other than social psychology, even though bullying is an inherently social behavior. We therefore suggest studying bullying using an adaptive ecological framework that highlights how individual and social factors interact to promote or influence bullying, particularly under conditions of high competition. Drawing inspiration from Bronfenbrenner’s (The ecology of human development: experiments by nature and design, Harvard University Press, Cambridge, MA, 2009) socioecological theory, we examine individual facts as well as an expanding ring of social factors from the immediate environment, to the neighborhood, to the broader culture, to determine how and when bullying is influenced by various social factors, and how individuals respond adaptively to these social factors. We include data on animal bullying and social factors, as well as final conclusions and recommendations for future research.

Study objectives The primary objective was to determine whether high-dose formoterol, 24 μg bid, was associated with more asthma exacerbations compared with lower formoterol doses in patients with stable persistent asthma. Serious asthma exacerbations (life threatening or requiring hospitalization) were the primary end point. Secondary end points included significant exacerbations requiring systemic corticosteroids, all exacerbations, and changes in FEV 1 . Design: In a multicenter, placebo-controlled, parallel-group study, patients were randomized to 16 weeks of treatment with formoterol, 24 μg bid; formoterol, 12 μg bid, with up to two additional 12-μg doses daily on demand for worsening symptoms (12 μg bid plus on demand); formoterol, 12 μg bid; or placebo. The formoterol 12-μg-bid plus on-demand regimen was administered open label, while the other three regimens were double blind. Setting Outpatient clinics. Patients A total of 2,085 patients aged ≥ 12 years with stable, persistent asthma were enrolled and treated; 65% (n = 1,347) received regular concomitant antiinflammatory therapy during the study. Measurements and results Nine patients had respiratory-related serious adverse events (SAEs) requiring hospitalization: two patients (0.4%) in the 24-μg-bid group; one patient (0.2%) in the 12-μg-bid plus on-demand group; five patients (0.9%) in the 12-μg-bid group; and one patient (0.2%) in the placebo group. All of these events were asthma related, except for two SAEs in the 12-μg-bid group that were later considered not to be asthma related by independent reviewers who were not associated with the conduct of the study. The proportions of patients with significant asthma exacerbations (requiring systemic corticosteroids) were similar in the 24-μg-bid group (6.3%, 33 of 527 patients), 12-μg-bid group (5.9%, 31 of 527 patients) and placebo group (8.8%, 45 of 514 patients) and lower in the 12-μg-bid plus on-demand group (4.4%, 23 of 517 patients; p=0.0057 vs placebo). All treatments were well tolerated. All formoterol treatment regimens had a significant effect on FEV 1 measured 2 h after dose during the study (p 1 measured at all visits after baseline (p Conclusions Treatment with formoterol, 24 μg bid, was not associated with an increase in serious asthma exacerbations compared with the lower formoterol doses or placebo.

Background: Patients with severe persistent asthma who are inadequately controlled despite treatment according to current asthma management guidelines have a significant unmet medical need. Such patients are at high risk of serious exacerbations and asthma-related mortality. Methods: Here, we pooled data from seven studies to determine the effect of omalizumab, an anti-immunoglobulin E (IgE) monoclonal antibody, on asthma exacerbations in patients with severe persistent asthma. Omalizumab was added to current asthma therapy and compared with placebo (in five double-blind studies) or with current asthma therapy alone (in two open-label studies). The studies included 4308 patients (2511 treated with omalizumab), 93% of whom had severe persistent asthma according to the Global Initiative for Asthma (GINA) 2002 classification. Using the Poisson regression model, results were calculated as the ratio of treatment effect (omalizumab : control) on the standardized exacerbation rate per year. Results: Omalizumab significantly reduced the rate of asthma exacerbations by 38% (P

The Certihaler is a new multi-dose dry powder inhaler for the delivery of formoterol (Foradil), a long-acting beta(2)-agonist. This dose-ranging study compared the efficacy and safety of formoterol 5, 10, 15 and 30 microg and placebo administered via the Certihaler or formoterol 12 microg via a single-dose dry powder inhaler (Aerolizer) in children with persistent asthma. This was a randomized, placebo-controlled, double-blind, double-dummy, incomplete block crossover, dose-finding and pharmacokinetic study. Children (5-12 years, n = 77) received four of the active treatments twice weekly (BID) for 1 week separated by 1-week single-blind washouts. The primary efficacy variable was 12-h AUC of FEV(1) after 1 week's treatment. Secondary variables included serial 12-h FEV(1). A subset of patients (n = 37) participated in a pharmacokinetic analysis. All formoterol doses resulted in significant increases in 12-h AUC of FEV(1) compared with placebo, and there was no difference between active treatments. The onset of action of formoterol was3 min for all active treatments. Doses of formoterolor =10 microg via the Certihaler increased FEV(1) significantly for up to 12 h compared with placebo. The 5 microcg dose via the Certihaler and 12 microg dose via the Aerolizer had a significant effect up to 8 and 7 h post-dose, respectively. Urinary excretion of formoterol via the Certihaler increased in a dose-proportional manner. All formoterol doses were well tolerated, but some patients experienced tremor at the 15 and 30 microg doses. Despite the lack of significant differences between the active doses in the overall bronchodilation, formoterol 10 microg BID via the Certihaler was the dose that provided the best balance between efficacy and tolerability: its duration of action was sustained over 12 h, contrary to that the lower dose (5 microg BID), whereas its tolerability, especially with regard to tremor, was better than the higher doses (15 and 30 microg BID). Overall, Certihaler 10 microg BID was not significantly different from formoterol 12 microg BID via Aerolizer.

AIMS: Atrial Preference Pacing (APP) is a pacemaker (PM) algorithm that supports a continuous atrial stimulation instead of a spontaneous atrial rhythm to prevent supraventricular tachyarrhythmias. The role of the APP in the prevention of atrial fibrillation (AF) is still controversial. The aim of our study was to evaluate the effect of preventive atrial pacing on AF incidence in myotonic dystrophy type I patients during a 12-month follow-up period. METHODS AND RESULTS: We studied 40 patients with myotonic dystrophy type 1 (MD1) who underwent dual-chamber PM implantation for first- and second-degree atrioventricular block. After a 1-month stabilization period, they were randomized to APP algorithm programmed OFF or ON for 6 months each, using a cross-over design. The number of AF episodes during active treatment (APP ON phases) was lower than those registered during no treatment (APP OFF phases). No statistically significant difference was found in AF episodes duration between the two phases. During the APP OFF phases and APP ON phases, the atrial pacing percentage was 0 and 98%, respectively, while the ventricular pacing percentage did not show statistically significant difference (10 vs. 8%, P =0.2). Atrial premature beats count was significantly greater during APP OFF phases than during APP ON phases. Lead parameters remained stable over time and there were no lead-related complications. CONCLUSIONS: Based on these 12-month follow-up data, it is concluded that APP is an efficacy algorithm for preventing paroxysmal AF in MD1 patients who underwent dual-chamber PM implantation for atrioventricular conduction disorders.

Summary Evaluation of patients with chronic obstructive pulmonary disease (COPD) often includes the use of post-bronchodilator reversibility testing to guide treatment decisions. Recommendations for reversibility testing differ and there is no universally accepted method or outcome criterion. A survey of recent clinical trials with β2-agonists in COPD illustrates the diversity of methods used to assess reversibility and highlights the difficulty of comparing data from such trials. Two recent studies demonstrated the benefits of treatment with the long-acting β2-agonist bronchodilator formoterol (Foradil® Aerolizer®) in patients with COPD. When patients were classified according to their degree of reversibility as partially or poorly reversible, improvements were observed in both groups irrespective of the definition applied. These results suggest that bronchodilator reversibility testing should not be used as a rigid basis for treatment decisions with β2-agonists in COPD patients. There is a pressing need for the role of reversibility testing to be clearly defined.

Recent studies suggest that inspiratory capacity (IC) measured at rest can be used to predict improvements in dyspnea and exercise tolerance in chronic obstructive pulmonary disease (COPD) patients. In this study we compared the effect of formoterol (Foradil, Aerolizer) and salmeterol (Serevent, Diskus) in terms of IC in patients with COPD.This was a multicentre, randomized, placebo-controlled, single-dose, double-dummy, crossover study conducted in five secondary care centres in four European countries. A total of 47 patients with Stage II and III COPD, as defined by ATS criteria, with an increase in forced expiratory volume in 1s (FEV(1)) ofor= 12% from the patient's predicted normal value after salbutamol inhalation were included. Patients inhaled single doses of formoterol (12 and 24 microg), salmeterol (50 and 100 microg) or matching placebo. IC was recorded before dosing and at 5, 10, 15 and 30 min and 1, 2, 3 and 4 h post-dose.Formoterol was significantly superior to salmeterol during the first hour post-dose as indicated by notable differences at all times during the first hour post-dose and by the ANCOVA analysis of the Area Under the IC Curve (AUC(0-1 h)).Both formoterol and salmeterol increase IC in patients with COPD, with formoterol 12 microg showing a significantly greater increase in IC over the first hour post-dose than salmeterol 50 microg, consistent with a more rapid onset of action.

Objective: Atrioventricular nodal reentrant tachycardia (AVNRT) accounts for about 60% of the patients presenting with paroxysmal supraventricular tachycardia. The radiofrequency (RF) catheter ablation of the slow atrioventricular (AV) node pathway is the preferred therapeutic approach in patients with AV node reentrant tachycardia. The aim of our study was describe the electrophysiological properties of successful slow pathway RF ablation in patients with common atrioventricular nodal reentrant tachycardia. Methods: The study design was a retrospective analysis involving fifty consecutive patients (18 males; mean age of 39±22 years) who underwent slow pathway ablation because of AVNRT. Results: Slow junctional beats with a cycle length longer than 550 ms were observed in 39 patients (79%); the presence of rapid junctional beats with a cycle length less than 550 ms was showed in 5 patients (10%). Moreover, in 32 of 50 patients (65%) duration of atrial electrogram more than 40 ms was noticed. Analyzing data reported, we found the statistically significant presence of slow junctional beats (p40 ms (p40 ms and slow junctional beats with cycle length >550 ms during the application of RF energy describe the electrophysiological properties of successful slow pathway RF ablation. (Anadolu Kardiyol Derg 2010; 10: 126-9) © Telif Hakki 2010 AVES Yayincilik Ltd. Sti.

Inhaled short-acting beta(2)-adrenoceptor agonists are the most commonly used treatment for the prevention of exercise-induced bronchoconstriction (EIB). Formoterol, a long-acting beta(2)-adrenoceptor agonist, has been demonstrated to provide protection from EIB, although the onset and duration of this protection have not been defined.The purpose of this study was to determine the onset and duration of the protective effect of a single dose of inhaled formoterol powder against EIB, comparing them with the effect of a single dose of placebo and albuterol administered via metered-dose inhaler (MDI).In this double-dummy, 4-way crossover study, patients received single doses of formoterol (12 and 24 microg) via a powder inhaler, albuterol by MDI (180 microg), and placebo. Exercise challenge tests (ECTs) were conducted at 15 minutes and at 4, 8, and 12 hours postdose. Pulmonary function studies (forced expiratory volume in 1 second [FEV(1)] and peak expiratory flow rate) were performed before and after each exercise challenge.Twenty adolescent and adult patients (mean age, 23.8 years; range, 13-41 years; 9 male, 11 female) with asthma were enrolled in the study, and 17 completed all 4 treatment sequences. Compared with placebo, both doses of formoterol produced significantly greater inhibition of FEV(1) decreases at all time points (P0.01). There were no significant differences in efficacy measures between the 2 formoterol doses throughout the study. The exercise-induced decrease in FEV(1) after albuterol treatment was significantly reduced compared with placebo only at 15 minutes after dosing (P0.05). Formoterol and albuterol exhibited a similar rapid onset of action (15 minutes), but formoterol continued to protect patients against EIB for at least 12 hours (P0.01), whereas albuterol was no longer clinically effective by the 4-hour ECT.Formoterol and albuterol, given as single-dose inhalations, both provided protection from EIB within 15 minutes in this group of patients. The bronchoprotection afforded by formoterol lasted up to 12 hours, whereas that of albuterol was no longer significant by 4 hours.

The long-term efficacy and safety of formoterol dry powder capsules for inhalation in pediatric asthma have not previously been evaluated.We examined the effectiveness of inhaled formoterol over a period of 12 months in asthmatic children who were still symptomatic despite anti-inflammatory treatment.After a run-in period, 518 patients (5 to 12 years old) were randomized in a double-blind manner to receive 12 or 24 microg formoterol dry powder (Foradil, Novartis Pharma AG, Basel, Switzerland) or placebo twice daily for 12 months. The drug was administered by inhaler (Aerolizer, Novartis Pharma AG) and was given in addition to their anti-inflammatory treatment. The primary variable was the area under the curve for forced expiratory volume in 1 second measured over 12 hours after the morning dose of study medication.The area under the curve for forced expiratory volume in 1 second after the first dose of treatment and after 3 and 12 months of treatment was significantly greater for patients receiving formoterol 12 microg and 24 microg than for patients receiving placebo (all Por = 0.0062). Compared with placebo, both doses of formoterol significantly improved morning and evening premedication peak expiratory flow rate (all P0.001). In the group treated with formoterol 24 microg, median symptom score and median dose of rescue medication at night were lower than during the run-in period, whereas the opposite occurred in the placebo group. The incidence of hospitalizations for asthma was higher in the formoterol groups than in the placebo group.Our results indicate that, in asthmatic children who are still symptomatic despite anti-inflammatory therapy, the addition of formoterol consistently improves airflow obstruction and nocturnal symptoms and reduces the use of rescue medication. However, this treatment requires close disease monitoring to detect early signs of acute exacerbation.

To compare the efficacy, tolerability, and safety of therapy with formoterol and oral slow-release theophylline (THEO) in patients with COPD.A randomized, parallel-group study, with double-blind arms for formoterol and placebo (PL) and an open arm for oral slow-release THEO administered in individual doses on the basis of plasma concentrations.Eighty-one centers worldwide.Eight hundred fifty-four patients with symptomatic COPD.Comparison of twice-daily inhaled formoterol dry powder (12 or 24 microg), PL, and THEO (individualized doses) over 12 months.Compared to PL, doses of formoterol and THEO both significantly improved the area under the curve for FEV(1) measured over a period of 12 h following the morning dose of study medication at 3 and 12 months (p0.001 for all comparisons). Therapy with formoterol, 12 microg, was significantly more effective than that with THEO (por = 0.026). Formoterol significantly reduced the percentage of "bad days" (i.e., days with at least two individual symptom scoresor = 2 and/or a reduction in peak expiratory flow from a baseline of20%; por = 0.035 vs. PL and THEO), and the use of salbutamol rescue medication (por = 0.003 vs PL) over the whole treatment period, while the effect of THEO was similar to that of PL. Therapy with formoterol and THEO was more effective than PL at improving quality of life for12 months (por = 0.030). Treatment-related adverse events and discontinuations were more frequent among patients receiving THEO than among those receiving formoterol.Long-term treatment with inhaled formoterol dry powder is more effective and better tolerated than treatment with therapeutically appropriate doses of oral slow-release THEO in symptomatic patients with COPD.

A potentially deadly A/H7N9 avian-origin influenza virus is currently the cause of an ongoing outbreak in China. Preparedness plans have thus been initiated to preempt the spread of this virus, which appears to have substantial pandemic potential. To effectively prevent a pandemic from unfolding, rapid production of an immunogenic vaccine with an acceptable safety profile is critical. Given the significance to public health, we are reporting immunogenicity and safety results from a phase 1 study in healthy adults administered one of four inactivated A/H7N9 vaccine formulations. Three formulations contained increasing quantities of antigen and of an oil-in-water adjuvant, MF59, and one formulation contained only the maximum dose of antigen without adjuvant. All vaccine formulations were derived using a synthetic virus seed technology in combination with a cell culture approach; together, these techniques have been shown to expedite vaccine production compared to conventional methods. Higher responses were seen with the MF59-adjuvanted versus the nonadjuvanted A/H7N9 vaccine, with significant and potentially protective immune responses after two doses in most subjects with no preexisting immunity to the H7N9 virus. Further, despite increased injection site pain and other mild effects with MF59, all formulations were well tolerated. These encouraging immunogenicity and safety data on the A/H7N9 vaccine provide a strong rationale for further clinical development. By also using synthetic seed/cell culture technology, we are now one step closer to being able to rapidly and reliably respond to a potential H7N9 pandemic using a clinically tested A/H7N9 vaccine.

This study was designed to identify the optimal dose of an MF59-adjuvanted, monovalent, A/H1N1 influenza vaccine in healthy paediatric subjects.Subjects aged 3-8 years (n=194) and 9-17 years (n=160) were randomized to receive two primary doses of A/H1N1 vaccine containing either 3.75 μg antigen with half a standard dose of MF59 adjuvant, 7.5 μg antigen with a full dose of MF59, or (children 3-8 years only), a non-adjuvanted 15 μg formulation. A booster dose of MF59-adjuvanted seasonal influenza vaccine including homologous A/H1N1 strain was given one year after priming. Immunogenicity was assessed by haemagglutination inhibition (HI) and microneutralization assays. Vaccine safety was assessed throughout the study (up to 18 months).A single priming dose of either MF59-adjuvanted formulation was sufficient to meet the European licensure criteria for pandemic influenza vaccines (HI titres ≥1:4070%; seroconversion40%; and GMR2.5). Two non-adjuvanted vaccine doses were required to meet the same licensure criteria. After first and second doses, percentage of subjects with HI titres ≥1:40 were between 97% and 100% in the adjuvanted vaccine groups compared with 68% and 91% in the non-adjuvanted group, respectively. Postvaccination seroconversion rates ranged from 91% to 98% in adjuvanted groups and were 68% (first dose) and 98% (second dose) in the non-adjuvanted group. HI titres ≥1:330 after primary doses were achieved in 69% to 90% in adjuvanted groups compared with 41% in the non-adjuvanted group. Long-term antibody persistence after priming and a robust antibody response to booster immunization were observed in all vaccination groups. All A/H1N1 vaccine formulations were generally well tolerated. No vaccine-related serious adverse events occurred, and no subjects were withdrawn from the study due to an adverse event.An MF59-adjuvanted influenza vaccine containing 3.75 μg of A/H1N1 antigen was well tolerated and sufficiently immunogenic to meet all the European licensure criteria after a single dose in healthy children 3-17 years old.

Non-adjuvanted seasonal influenza vaccines show only modest efficacy in young children. This study compared the immunogenicity, reactogenicity and safety of the MF59-adjuvanted trivalent subunit vaccine (aTIV) with two non-adjuvanted trivalent vaccines, TIV-1, the non-adjuvanted version of aTIV, and TIV-2, a split virion vaccine.6078 children received two doses of aTIV (n=3125), TIV-1 (n=1479), or TIV-2 (n=1474) four weeks apart (Days 1 and 29). Children aged 6 to36 months and 36 to72 months received 0.25 mL and 0.50 mL doses, respectively. Immunogenicity was assessed by hemagglutination inhibition (HI) assay (n=2435) on Days 1, 29, 50 and 209. Safety was assessed up to Day 394.After the second vaccination (Day 50), the aTIV group showed significantly higher geometric mean HI titers and seroconversion rates than the TIV-1 or TIV-2 groups against all homologous and heterologous strains. The difference was enhanced at HI titers ≥110. aTIV elicited a faster, more persistent antibody response, with significantly higher titers in the aTIV group after one vaccination (Day 29) and after six months (Day 209) than in either TIV group. aTIV was more reactogenic than were TIV-1 and TIV-2 but rates of severe adverse events were very low for all three vaccines.In infants and young children, the MF59-adjuvanted vaccine induced substantially faster (after one dose), higher, persistent HI titers than the non-adjuvanted vaccines, with consistently higher seroprotection rates at increased threshold HI titers. This trial is registered at clinicaltrials.gov: NCT01346592.

Background: Vaccines against pandemic A/H1N1 influenza should provide protective immunity in children, because they are at greater risk of disease than adults. This study was conducted to identify the optimal dose of an MF59 (R)-adjuvanted, egg-derived, A/H1N1 influenza vaccine for young children. Methods: Children 6-11 months (N = 144) and 12-35 months (N = 186) of age received vaccine formulations containing either 3.75 mu g antigen with half the standard dose of MF59 or 7.5 mu g antigen with a standard dose of MF59, or a nonadjuvanted formulation containing 15 mu g antigen (children 12-35 months only). Participants were given 2 primary vaccine doses 3 weeks apart, followed by 1 booster dose of MF59-adjuvanted seasonal influenza vaccine 1 year later. Immunogenicity was assessed by hemagglutination inhibition and microneutralization assays. Results: All vaccine formulations were highly immunogenic and met all 3 European licensure criteria after 2 doses. MF59-adjuvanted vaccines met all licensure criteria after 1 dose in both age cohorts, while nonadjuvanted vaccine did not meet all criteria after 1 dose in children 12-35 months. A single booster dose was highly immunogenic, and stable antibody persistence was observed in response to all vaccines. All vaccines were well tolerated. Conclusions: In this study, a single dose of 3.75 mu g antigen with half the standard dose of MF59 was shown to be optimal, providing adequate levels of immediate and long-term antibodies in pediatric subjects 6-35 months of age. These data demonstrated that MF59 adjuvant allowed for reduced antigen content and promoted significant long-term antibody persistence in children, with a satisfactory safety profile.

The clinical benefit and steroid-sparing effect of treatment with the anti-immunoglobulin-E (IgE) antibody, omalizumab, was assessed in patients with moderate-to-severe allergic asthma.After a run-in period, 546 allergic asthmatics (aged 12–76 yrs), symptomatic despite inhaled corticosteroids (500–1,200 µg daily of beclomethasone dipropionate), were randomized to receive double-blind either placebo or omalizumab every 2 or 4 weeks (depending on body weight and serum total IgE) subcutaneously for 7 months. A constant beclomethasone dose was maintained during a 16-week stable-steroid phase and progressively reduced to the lowest dose required for asthma control over the following 8 weeks. The latter dose was maintained for the next 4 weeks. Asthma exacerbations represented the primary variable.Compared to the placebo group, the omalizumab group showed 58% fewer exacerbations per patient during the stable-steroid phase (pversusthe placebo group (pThese results indicate that omalizumab therapy safely improves asthma control in allergic asthmatics who remain symptomatic despite regular use of inhaled corticosteroids and simultaneous reduction in corticosteroid requirement.

Background Formoterol is a β 2 -adrenergic agent which, when inhaled, produces rapid and long-lasting bronchodilatation. Objective The aim of this study was to compare the efficacy, safety, and tolerability of formoterol powder for inhalation delivered via the Aerolizer device with placebo and with albuterol delivered via metered-dose inhaler in patients with mild to moderate persistent asthma. Methods In a multicenter, double-blind, parallel-group study, 541 patients were randomized at 26 trial sites to receive either formoterol, 12 μg twice daily; formoterol, 24 μg twice daily; albuterol, 180 μg four times daily; or a placebo for 12 weeks. The effects of each treatment on lung function, asthma symptoms, and frequency of rescue albuterol use were evaluated. Adverse effects and clinical laboratory parameters were also evaluated. Results The bronchodilatory effects of formoterol were rapid in onset and persisted for 12 hours. Both formoterol doses were more effective than placebo and albuterol for objective measures of lung function. Morning and evening peak expiratory flow rates were more improved with formoterol, and formoterol provided significantly greater improvements in asthma symptom scores compared with both albuterol and placebo. Overall, patients taking formoterol used significantly less rescue medication than did those taking albuterol or placebo. Nocturnal awakenings occurred less often with formoterol than with placebo or albuterol. The therapeutic effects of formoterol were maintained over the entire 12 weeks of treatment. Adverse events were similar for all treatment groups, and clinical laboratory data were unremarkable. Conclusions Rapid-onset, long-acting formoterol, administered via the Aerolizer inhaler, is an effective and safe treatment for patients with mild to moderate persistent asthma.

We report the case of 14-year-old boy with X-linked Emery-Dreifuss muscular dystrophy who developed sick sinus syndrome and required placement of an implantable intracardiac cardioverter-defibrillator (ICD) to prevent sudden death. He demonstrated no significant risk factors for sudden death such as depressed left ventricular ejection fraction, or spontaneous or inducible ventricular tachycardia. One month after implantation, the patient experienced one appropriate ICD discharge.

Background: Allergic rhinitis is a common condition often requiring treatment. Objective: We evaluated whether recombinant humanized (rhu)mAb-E25, a recombinant humanized construct of a murine antibody that binds to circulating IgE, could control symptoms and reduce intake of concomitant medication in seasonal allergic rhinitis (SAR) induced by birch pollen if given subcutaneously in a dose schedule predicted to reduce serum free IgE levels below 25 ng/mL. Methods: We randomly assigned 251 adult subjects with a history of SAR and a positive skin test response to birch pollen to receive 300 mg of rhumAb-E25 or placebo given 2 or 3 times during the season, depending on baseline IgE levels. The primary efficacy variable was the subject's average daily nasal symptom severity score (sneezing, itching, runny, and stuffy nose) from diary data collected over the double-blind treatment period. Secondary efficacy variables included the average number of rescue antihistamine tablets per day, the proportion of days with any SAR medication use, and rhinoconjunctivitis-specific quality of life (QOL). Results: Significant between-treatment differences in favor of rhumAb-E25 were observed in average daily nasal symptom severity scores, the average number of tablets of rescue antihistamines per day, the proportion of days with any SAR medication use, and all domains of QOL. Serum-free IgE levels were markedly lower in rhumAb-E25-treated subjects and were associated with clinical effectiveness. Recombinant humanized mAb-E25 was well tolerated. No anti-rhumAb-E25 antibodies were detected. Conclusion: Compared with placebo, rhumAb-E25 was safe and effective in controlling birch pollen-induced SAR symptoms, with less concomitant medication use and improved QOL. This study shows the therapeutic potential of anti-IgE antibody in SAR.

We investigated bone marrow (BM) and circulating (PB) hematopoietic progenitor cells in 37 normal donors and in 25 patients 1 to 8 years after successful allogeneic bone marrow transplant. At the time of testing, transplanted patients had normal blood counts and bone marrow cellularity. By flow cytometry, BM CD34+ cells were found to be three- to four-fold decreased in transplanted patients compared to normal donors, while the number of PB CD34+ cells was the same as in normal donors. Using a methylcellulose colony assay, primary BM colony-forming cells (CFU-GM) were decreased 2.1-fold, whereas PB CFU-GM were only marginally decreased. In a long-term culture initiating cell (LTC-IC) assay, an eight-fold decrease of early progenitor cells was observed in the marrow of transplanted patients compared to normal donors, and a five-fold decrease was documented in peripheral blood. We found that the BM LTC-IC cell number correlated with concurrently determined BM CD34+ cells and committed progenitor cell number (measured as CFU-GM) and with PB LTC-IC number, but not with PB CFU-GM and CD34+ cells. We conclude that marrow and circulating early stem cell compartments, as measured by the LTC-IC assay, are greatly and permanently depressed following bone marrow transplant. The correlation between BM and PB LTC-IC indicates that the enumeration of circulating LTC-IC can be used as a measure of the stem cell compartment in the bone marrow after transplant. It seems that the deficiency of the most immature progenitor cells persists forever after successful bone marrow transplant; this means that a complete hematopoietic reconstitution can be sustained by a reduced stem cell pool.

The present study was designed to observe the effects of 8 wk of treatment with formoterol (Foradil) 24 microgram, budesonide 400 microgram, and matched placebo inhaled twice a day on inflammatory indices in the bronchial mucosa of 64 patients with mild atopic asthma. Biopsies were obtained at the start and 1 wk before stopping a 9-wk period of treatment, and inflammatory cell numbers were assessed in the submucosa and epithelium by immunohistochemistry. Regular formoterol significantly reduced the number of submucosal mast cells, with a similar trend for eosinophils but not activated T cells. A subgroup analysis conducted in biopsies with >= 10 eosinophils per mm2 revealed a significant reduction in eosinophil numbers when compared with both pretreatment baseline (p < 0.01) and changes after placebo (p < 0.01). Parallel, but less pronounced, effects were observed on mast cell but not on CD25(+) T cell numbers. There was no effect of any of the three treatments on BAL levels of mast cell or eosinophil mediators. We conclude that regular treatment with inhaled formoterol reduces rather than increases inflammatory cells in the mucosa of asthmatic patients. It is possible that these cellular effects of formoterol may contribute to the therapeutic efficacy of this drug when used regularly in the treatment

Objectives: To examine the potential of a new matrix system developed for estradiol delivery to cause microbial proliferation under the occluded site or to cause acute phototoxicity reactions. Methods: Twenty healthy postmenopausal women participated in a microbial proliferation study and 11 in a phototoxicity study. Both studies were single centre, single blind and placebo controlled. Microbial proliferation was assessed by quantitative counts of the total aerobic bacterial population and of eight individual species before patch application and after removal following a 4 day application period on the abdomen. Acute phototoxicity potential was assessed following an 8 h application period on the abdomen by irradiating the application site after patch removal with ultra violet A radiation and visible light and evaluating the sites for up to 48 h post irradiation. Non-irradiated active and placebo patches on the other side of the abdomen served as controls. Results: Total aerobic bacterial populations both before and after the matrix patch application period were low as expected for dry skin. Separate counts of microbial species were also low and did not change in any meaningful or consistent manner after patch application. In the phototoxicity study, mild erythema was observed in some patients at 0, 0.5 and 24 h post patch removal with no differences between irradiated and non-irradiated sites. Conclusions: These two studies demonstrate that a new matrix patch developed for estradiol delivery does not promote microbial proliferation under the occluded patch site or cause acute phototoxicity following removal.

Aflunov is an egg-derived, subunit vaccine from Novartis Vaccines and Diagnostics containing 7.5 μg of hemagglutinin (HA) from the avian A/H5N1 virus and the oil-in-water adjuvant MF59.Aflunov behaves as a pre-pandemic vaccine. It has a good safety profile at all ages. At all ages, it induces high and persisting antibody titers and activation of HA-specific Th0/Th1 CD4(+) T cells, the levels of which correlate with the neutralizing antibody titers after a booster dose 6 months later. Aflunov triggers strong immunological memory, which persists for at least 6 - 8 years and can be rapidly boosted with a heterovariant vaccine strain, inducing very high neutralizing antibody titers within one week. These antibodies broadly and strongly cross-react with drifted H5N1 virus strains from various clades. Finally, the MF59 changes the pattern of HA recognition by antibodies that react with the HA1 more than with the HA2 region.The available data show that Aflunov is a pre-pandemic vaccine suitable not only for stockpiling in case of a pandemic, but also before a pandemic is declared, with the ultimate objective of preventing the onset of an influenza pandemic.

MF59-adjuvanted influenza vaccines have superior immunogenicity in older adults compared with non-adjuvanted vaccines. We assessed whether changing formulation (i.e., increasing H3N2 antigen or decreasing the quantity of adjuvant) of the licensed, MF59-adjuvanted trivalent influenza subunit vaccine Fluad (®) (Novartis Vaccines and Diagnostics) improves the risk-benefit profile in vaccinees aged ≥ 65 years.A significant dose-response relationship was observed between antibody levels and MF59 dose; full dose formulations elicited the strongest immune responses, meeting immunogenicity licensure criteria by Day 8. Doubling H3N2 antigen content did not increase the response to this antigen. Increased frequency of circulating CD4+ T-cells specific for vaccine antigens were detected by Day 8; magnitude and functional profile of the CD4+ T-cell response was comparable across the different vaccination groups. Mild to moderate solicited local reactions were more common with vaccines formulated with higher doses of MF59 (®) , but there were no MF59- or antigen dose-related increase in the frequency of solicited systemic reactions or unsolicited adverse events and serious adverse events.We report on 357 subjects who received one of eight intramuscular vaccine formulations. Hemagglutination-inhibiting antibodies were assayed on Days 1, 8 and 22; magnitude and functional profile of CD4+ T-cell responses to vaccine antigens were assessed in subsets. Solicited adverse reactions were reported via diary cards for seven days after vaccination and spontaneous adverse events were monitored throughout the study.This study confirms that the current formulation is the optimal one for MF59-adjuvanted influenza vaccine for use in older adults.

BACKGROUND: Modern cell-culture production techniques and the use of adjuvants helps to ensure that the global demand for pandemic influenza vaccine can be met. This study aimed to assess the immunogenicty and safety profiles of various cell-culture-derived A/H1N1 pandemic vaccine formulations in healthy adult and elderly subjects. METHODS: Adult (18-60 years) subjects (n=544) received vaccine either containing 3.75mug of antigen with half the standard dose of MF59((R)) (Novartis Vaccines and Diagnostics) adjuvant, 7.5mug antigen with a full dose of MF59, or a non-adjuvanted vaccine containing 15mug of antigen. Elderly (

INTRODUCTION The hemagglutination inhibition (HI) titer of 1:40, which has been recognized as an immunologic correlate corresponding to a 50% reduction in the risk of contracting influenza, is based on studies in adults. Neither seasonal nor challenge-based correlates have been evaluated in children. METHODS A total of 4707 influenza vaccine-naive healthy children 6 to 72 months old were randomized in a ratio of 2:2:1 to receive 2 doses of MF-59-adjuvanted influenza vaccine (Novartis Vaccines), trivalent inactivated influenza vaccine subunit (trivalent inactivated influenza vaccine control, GSK), or a saline placebo during the 2007 to 2008 and 2008 to 2009 influenza seasons. The second dose was given 30 days after dose 1. Clinical influenza-like illnesses cases identified by active surveillance were confirmed by reverse transcription polymerase chain reaction testing for influenza. Vaccine immunogenicity 50 days after dose 1 was evaluated in a subset of 777 children. RESULTS Immunogenicity and efficacy results for H3N2 were evaluated against the Prentice criteria, which confirmed that the immunogenicity results warranted estimation of an immunologic correlate. We then used the Dunning model fitting the H3N2 antibody titers at day 50 and the influenza cases observed in the immunogenicity subset to estimate a correlate of protection. This analysis revealed that a cutoff HI titer of 1:110 was associated with the conventional 50% clinical protection rate against infection during the entire season, and titers of 1:215, 1:330, and 1:629 predicated protection rates of 70%, 80%, and 90%, respectively. The conventional adult HI titer of 1:40 was only associated with 22% protection. CONCLUSIONS The use of the 1:40 HI adult correlate of protection is not appropriate when evaluating influenza vaccines in children. Although a cutoff of 1:110 may be used to predict the conventional 50% clinical protection rate, a titer of 1:330 would predict an 80% protective level, which would seem to be more desirable from a public health perspective.

Sudden death is a possible occurrence for newborns younger than 1 year with severe aortic coarctation (CoA) before surgical correction. Basic research and animal experiments have shown electrophysiologic changes during mechanical ventricular pressure overload. The current study aimed to evaluate the effect of severe CoA on the heterogeneity of ventricular repolarization by examining corrected QT and JT interval dispersion (respectively, QTc-D and JTc-D) and electrocardiographic parameters of spatial heterogeneity of ventricular repolarization in newborns with no associated congenital cardiac malformations. The study enrolled 30 isolated severe CoA neonates (age, 45 ± 15 days; 17 males) with normal size and wall thickness of the left ventricle before surgical correction and 30 age- and sex-matched healthy newborns used as control subjects. Heart rate, QRS duration, maximum and minimum QT and JT intervals, and QTc-D and JTc-D measurements were performed. The healthy control group did not significantly differ from the CoA group in terms of heart rate, weight, height, and echocardiographic parameters. Compared with the healthy control group, the CoA group presented significantly increased values of QTc-D (109.7 ± 43.4 vs. 23 ± 15 ms; P = 0.03) and JTc-D (99.1 ± 43.3 vs. 65.8 ± 24.1 ms; P = 0.04). A statistically significant correlation was found between the Doppler peak pressure gradient across the coarctation site and the values of QTc-D (r = 0.48; P = 0.03) and JTc-D (r = 0.42; P = 0.04). Our study showed significantly increased QTc-D and JTc-D in isolated CoA newborns with normal left ventricular geometry. © Springer Science+Business Media, LLC 2011.