Influenza vaccination in Brazil: rationale and caveats

Mass vaccination campaigns against influenza in the elderly have been conducted in Brazil since 1999. A search of the literature on influenza in Brazil indicated that data on disease burden are still scarce and inaccurate. Published data seem to indicate that vaccination has produced some impact in the southern and southeastern regions but not in other regions of Brazil. A discussion of the technical and scientific rationale for mass immunization against influenza is presented and it is argued that the current strategy has not taken into account potential differences in disease occurrence in different areas. It is suggested some epidemiological surveillance actions needed to address major concerns regarding mass influenza vaccination and its impact in Brazil.

Visceral leishmaniasis in Brazil: rationale and concerns related to reservoir control

The control of zoonotic visceral leishmaniasis is a challenge, particularly in Brazil, where the disease has been gradually spreading across the country over the past 30 years. Strategies employed for decreasing the transmission risk are based on the control of vector populations and reservoirs; since humans are considered unnecessary for the maintenance of transmission. Among the adopted strategies in Brazil, the sacrifice of infected dogs is commonly performed and has been the most controversial measure. In the present study, we provide the rationale for the implementation of different control strategies targeted at reservoir populations and highlight the limitations and concerns associated with each of these strategies.

Environment and Health in Children Day Care Centres (ENVIRH) - Study Rationale and Protocol

Background: Indoor air quality (IAQ) is considered an important determinant of human health. The association between exposure to volatile organic compounds, particulate matter, house dust mite, molds and bacteria in day care centers (DCC) is not completely clear. The aim of this project was to study these effects. Methods --- study design: This study comprised two phases. Phase I included an evaluation of 45 DCCs (25 from Lisbon and 20 from Oporto, targeting 5161 children). In this phase, building characteristics, indoor CO2 and air temperature/relative humidity, were assessed. A children’s respiratory health questionnaire derived from the ISAAC (International Study on Asthma and Allergies in Children) was also distributed. Phase II encompassed two evaluations and included 20 DCCs selected from phase I after a cluster analysis (11 from Lisbon and 9 from Oporto, targeting 2287 children). In this phase, data on ventilation, IAQ, thermal comfort parameters, respiratory and allergic health, airway inflammation biomarkers, respiratory virus infection patterns and parental and child stress were collected. Results: In Phase I, building characteristics, occupant behavior and ventilation surrogates were collected from all DCCs. The response rate of the questionnaire was 61.7% (3186 children). Phase II included 1221 children. Association results between DCC characteristics, IAQ and health outcomes will be provided in order to support recommendations on IAQ and children’s health. A building ventilation model will also be developed. Discussion: This paper outlines methods that might be implemented by other investigators conducting studies on the association between respiratory health and indoor air quality at DCC.

Twenty-eight years of Aedes albopictus in Brazil: a rationale to maintain active entomological and epidemiological surveillance

INTRODUCTION: Aedes albopictus was first detected in Brazil in 1986. This mosquito species presents a major threat to public health because Brazilian populations have shown substantial vector competence for arboviruses such as dengue and chikungunya. METHODS: We updated the records of Ae. albopictus in several States of Brazil, focusing on areas in which its presence had been reported after 2002. RESULTS: Twenty-eight years after its arrival in Brazil, Ae. albopictus has been detected in 24 of 27 States. CONCLUSIONS: The rapid spread of this species and its high vector competence demonstrate the danger of Ae. albopictus in Brazil.

Multi-Scale Integrated Analysis of Societal and Ecosystem Metabolism (MUSIASEM): an outline of rationale and theory

This paper presents an outline of rationale and theory of the MuSIASEM scheme (Multi-Scale Integrated Analysis of Societal and Ecosystem Metabolism). First, three points of the rationale behind our MuSIASEM scheme are discussed: (i) endosomatic and exosomatic metabolism in relation to Georgescu-Roegen’s flow-fund scheme; (2) the bioeconomic analogy of hypercycle and dissipative parts in ecosystems; (3) the dramatic reallocation of human time and land use patterns in various sectors of modern economy. Next, a flow-fund representation of the MUSIASEM scheme on three levels (the whole national level, the paid work sectors level, and the agricultural sector level) is illustrated to look at the structure of the human economy in relation to two primary factors: (i) human time - a fund; and (ii) exosomatic energy - a flow. The three levels representation uses extensive and intensive variables simultaneously. Key conceptual tools of the MuSIASEM scheme - mosaic effects and impredicative loop analysis - are explained using the three level flow-fund representation. Finally, we claim that the MuSIASEM scheme can be seen as a multi-purpose grammar useful to deal with sustainability issues.

The impact of iron supplementation efficiency in female blood donors with a decreased ferritin level and no anaemia. Rationale and design of a randomised controlled trial: a study protocol.

ABSTRACT: BACKGROUND: There is no recommendation to screen ferritin level in blood donors, even though several studies have noted the high prevalence of iron deficiency after blood donation, particularly among menstruating females. Furthermore, some clinical trials have shown that non-anaemic women with unexplained fatigue may benefit from iron supplementation. Our objective is to determine the clinical effect of iron supplementation on fatigue in female blood donors without anaemia, but with a mean serum ferritin </= 30 ng/ml. METHODS/DESIGN: In a double blind randomised controlled trial, we will measure blood count and ferritin level of women under age 50 yr, who donate blood to the University Hospital of Lausanne Blood Transfusion Department, at the time of the donation and after 1 week. One hundred and forty donors with a ferritin level </= 30 ng/ml and haemoglobin level >/= 120 g/l (non-anaemic) a week after the donation will be included in the study and randomised. A one-month course of oral ferrous sulphate (80 mg/day of elemental iron) will be introduced vs. placebo. Self-reported fatigue will be measured using a visual analogue scale. Secondary outcomes are: score of fatigue (Fatigue Severity Scale), maximal aerobic power (Chester Step Test), quality of life (SF-12), and mood disorders (Prime-MD). Haemoglobin and ferritin concentration will be monitored before and after the intervention. DISCUSSION: Iron deficiency is a potential problem for all blood donors, especially menstruating women. To our knowledge, no other intervention study has yet evaluated the impact of iron supplementation on subjective symptoms after a blood donation. TRIAL REGISTRATION: NCT00689793.

Basic biochemical investigations as rationale for the design of original antimalarial drugs. An example of phospholipid metabolism

The future of antimalarial chemotherapy is particulary alarming in view of the spread of parasite cross-resistances to drugs that are not even structurally related. Only the availability of new pharmacological models will make it possible to select molecules with novel mechanisms of action, thus delaving resistance and allowing the development of new chemotherapeutic strategies. We reached this objective in mice. Our approach is hunged on fundamental and applied research begun in 1980 to investigate to phospholipid (PL) metabolism of intraerythrocytic Plasmodium. This metabolism is abundant, specific and indispensable for the production of Plasmodium membranes. Any drug to interfere with this metabolism blocks parasitic development. The most effective interference yet found involves blockage of the choline transporter, which supplies Plasmodium with choline for the synthesis of phosphatidylcholine, its major PL, this is a limiting step in the pathway. The drug sensitivity thereshold is much lower for the parasite, which is more dependent on this metabolism than host cells. The compounds show in vitro activity against P. falciparum at 1 to 10 nM. They show a very low toxicity against a lymphblastoid cell line, demonstrating a total abscence of correlation between growth inhibition of parasites and lymphoblastoid cells. They show antimalarial activity in vivo, in the P. berghei or P. chabaudi/mouse system, at doses 20-to 100-fold lower than their in acute toxicity limit. The bioavailability of a radiolabeled form of the product seemed to be advantageous (slow blood clearance and no significant concentration in tissues). Lastly, the compounds are inexpensive to produce. They are stable and water-soluble.

The new direct oral anticoagulants in special indications: rationale and preliminary data in cancer, mechanical heart valves, anti-phospholipid syndrome, and heparin-induced thrombocytopenia and beyond.

The present review will briefly summarize the interplay between coagulation and inflammation, highlighting possible effects of direct inhibition of factor Xa and thrombin beyond anticoagulation. Additionally, the rationale for the use of the new direct oral anticoagulants (DOACs) for indications such as cancer-associated venous thromboembolism (CAT), mechanical heart valves, thrombotic anti-phospholipid syndrome (APS), and heparin-induced thrombocytopenia (HIT) will be explored. Published data on patients with cancer or mechanical heart valves treated with DOAC will be discussed, as well as planned studies in APS and HIT. Although at the present time published evidence is insufficient for recommending DOAC in the above-mentioned indications, there are good arguments in favor of clinical trials investigating their efficacy in these contexts. Direct inhibition of factor Xa or thrombin may reveal interesting effects beyond anticoagulation as well.

The Swiss cohort of elderly patients with venous thromboembolism (SWITCO65+): rationale and methodology.

Venous thromboembolism (VTE) is common and has a high impact on morbidity, mortality, and costs of care. Although most of the patients with VTE are aged ≥65 years, there is little data about the medical outcomes in the elderly with VTE. The Swiss Cohort of Elderly Patients with VTE (SWITCO65+) is a prospective multicenter cohort study of in- and outpatients aged ≥65 years with acute VTE from all five Swiss university and four high-volume non-university hospitals. The goal is to examine which clinical and biological factors and processes of care drive short- and long-term medical outcomes, health-related quality of life, and medical resource utilization in elderly patients with acute VTE. The cohort also includes a large biobank with biological material from each participant. From September 2009 to March 2012, 1,863 elderly patients with VTE were screened and 1003 (53.8 %) were enrolled in the cohort. Overall, 51.7 % of patients were aged ≥75 years and 52.7 % were men. By October 16, 2012, after an average follow-up time of 512 days, 799 (79.7 %) patients were still actively participating. SWITCO65+ is a unique opportunity to study short- and long-term outcomes in elderly patients with VTE. The Steering Committee encourages national and international collaborative research projects related to SWITCO65+, including sharing anonymized data and biological samples.

The Impact of CAROtid plaque Screening on Smoking (CAROSS) cessation and control of other cardiovascular risk factors: rationale and design of a randomized controlled trial

BACKGROUND: Screening tests for subclinical cardiovascular disease, such as markers of atherosclerosis, are increasingly used in clinical prevention to identify individuals at high cardiovascular risk. Being aware of these test results might also enhance patient motivation to change unhealthy behaviors but the effectiveness of such a screening strategy has been poorly studied. METHODS: The CAROtid plaque Screening trial on Smoking cessation (CAROSS) is a randomized controlled trial in 530 regular smokers aged 40-70 years to test the hypothesis that carotid plaque screening will influence smokers' behavior with an increased rate of smoking cessation (primary outcome) and an improved control of other cardiovascular risk factors (secondary outcomes) after 1-year follow-up. All smokers will receive a brief advice for smoking cessation,and will subsequently be randomly assigned to either the intervention group (with plaques screening) or the control group (without plaque screening). Carotid ultrasound will be conducted with a standard protocol. Smokers with at least one carotid plaque will receive pictures of their own plaques with a structured explanation on the general significance of plaques. To ensure equal contact conditions, smokers not undergoing ultrasound and those without plaque will receive a relevant explanation on the risks associated with tobacco smoking. Study outcomes will be compared between smokers randomized to plaque screening and smokers not submitted to plaque screening. SUMMARY: This will be the first trial to assess the impact of carotid plaque screening on 1-year smoking cessation rates and levels of control of other cardiovascular risk factors.

Presence of JC virus-specific CTL in the cerebrospinal fluid of PML patients: rationale for immune-based therapeutic strategies.

OBJECTIVES: There is urgent need of a treatment for progressive multifocal leukoencephalopathy (PML), caused by the polyomavirus JC (JCV). To evaluate the rationale for immunotherapy of PML, we explored whether JCV-specific cytotoxic T lymphocytes (CTL) can penetrate the central nervous system (CNS). In addition, we studied the breadth of their T-cell receptor (TCR) repertoire, and sought to establish a reliable method to expand these cells in vitro. DESIGN AND METHODS: We enrolled 18 patients in this study, including 16 with proven or possible PML (15 HIV-positive and one HIV-negative), and two HIV-positive patients with other neurological diseases. Detection of JCV-specific CTL in the blood and the cerebrospinal fluid was performed by Cr release and tetramer staining assays in 15 patients. RESULTS: Of 11 PML patients with analyzable cerebrospinal fluid (CSF), two had no detectable JCV-specific CTL in the blood and CSF and died 3.7 and 7.2 months later. The nine remaining patients had an inactive course of PML and detectable JCV-specific CTL in the blood. In addition, four of them (44%) also had detectable JCV-specific CTL in the CSF. Both HIV-positive patients with OND had detectable JCV-specific CTL in the blood and one in the CSF. Using tetramer technology, we obtained highly enriched JCV-specific CTL lines that were able to kill target cells presenting JCV peptides. The breadth of the TCR repertoire was CTL epitope dependent. CONCLUSIONS: These results indicate that JCV-specific CTL are present in the CNS of PML patients and pave the way for an immune-based therapeutic approach.

Treatment rationale and study design for a phase III, double-blind, placebo-controlled study of maintenance pemetrexed plus best supportive care versus best supportive care immediately following induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer.

BACKGROUND: To improve the efficacy of first-line therapy for advanced non-small cell lung cancer (NSCLC), additional maintenance chemotherapy may be given after initial induction chemotherapy in patients who did not progress during the initial treatment, rather than waiting for disease progression to administer second-line treatment. Maintenance therapy may consist of an agent that either was or was not present in the induction regimen. The antifolate pemetrexed is efficacious in combination with cisplatin for first-line treatment of advanced NSCLC and has shown efficacy as a maintenance agent in studies in which it was not included in the induction regimen. We designed a phase III study to determine if pemetrexed maintenance therapy improves progression-free survival (PFS) and overall survival (OS) after cisplatin/pemetrexed induction therapy in patients with advanced nonsquamous NSCLC. Furthermore, since evidence suggests expression levels of thymidylate synthase, the primary target of pemetrexed, may be associated with responsiveness to pemetrexed, translational research will address whether thymidylate synthase expression correlates with efficacy outcomes of pemetrexed. METHODS/DESIGN: Approximately 900 patients will receive four cycles of induction chemotherapy consisting of pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) on day 1 of a 21-day cycle. Patients with an Eastern Cooperative Oncology Group performance status of 0 or 1 who have not progressed during induction therapy will randomly receive (in a 2:1 ratio) one of two double-blind maintenance regimens: pemetrexed (500 mg/m2 on day 1 of a 21-day cycle) plus best supportive care (BSC) or placebo plus BSC. The primary objective is to compare PFS between treatment arms. Secondary objectives include a fully powered analysis of OS, objective tumor response rate, patient-reported outcomes, resource utilization, and toxicity. Tumor specimens for translational research will be obtained from consenting patients before induction treatment, with a second biopsy performed in eligible patients following the induction phase. DISCUSSION: Although using a drug as maintenance therapy that was not used in the induction regimen exposes patients to an agent with a different mechanism of action, evidence suggests that continued use of an agent present in the induction regimen as maintenance therapy enables the identification of patients most likely to benefit from maintenance treatment.

A clinical trial for uniform multidrug therapy for leprosy patients in Brazil: rationale and design

Leprosy will continue to be a public health problem for several decades. The World Health Organization (WHO) recommends that, for treatment purposes, leprosy cases be classified as either paucibacillary or multibacillary (MB). A uniform leprosy treatment regimen would simplify treatment and halve the treatment duration for MB patients. The clinical trial for uniform multidrug therapy (U-MDT) for leprosy patients (LPs) in Brazil is a randomised, open-label clinical trial to evaluate if the effectiveness of U-MDT for leprosy equals the regular regimen, to determine the acceptability of the U-MDT regimen and to identify the prognostic factors. This paper details the clinical trial methodology and patient enrolment data. The study enrolled 858 patients at two centres and 78.4% of participants were classified as MB according to the WHO criteria. The main difficulty in evaluating a new leprosy treatment regimen is that no reliable data are available for the current treatment regimen. Relapse, reaction and impaired nerve function rates have never been systematically determined, although reaction and impaired nerve function are the two major causes of nerve damage that lead to impairments and disabilities in LPs. Our study was designed to overcome the need for reliable data about the current treatment and to compare its efficacy with that of a uniform regimen.

Genetics and molecular epidemiology of multiple myeloma: the rationale for the IMMEnSE consortium (review).

There is strong evidence suggesting the presence of a genetic component in the aetiology of multiple myeloma (MM). However no genetic risk factors have been unequivocally established so far. To further our understanding of the genetic determinants of MM risk, a promising strategy is to collect a large set of patients in a consortium, as successfully done for other cancers. In this article, we review the main findings in the genetic susceptibility and pharmacogenetics of MM and present the strategy of the IMMEnSE (International Multiple Myeloma rESEarch) consortium in contributing to determine the role of genetic variation in pharmacogenetics and in MM risk.