From single to multivariable exposure models to translate climatic and air pollution effects into mortality risk. A customized application to the city of Rome, Italy.

This study presents an approach developed to derive a Delayed-Multivariate Exposure-Response Model (D-MERF) useful to assess the short-term influence of temperature on mortality, accounting also for the effect of air pollution (O3 and PM10). By using Distributed, lag non-linear models (DLNM) we explain how city-specific exposure-response functions are derived for the municipality of Rome, which is taken as an example. The steps illustrated can be replicated to other cities while the statistical model presented here can be further extended to other exposure variables. We derive the mortality relative-risk (RR) curve averaged over the period 2004-2015, which accounts for city-specific climate and pollution conditions. Key aspects of customization are as follows: This study reports the steps followed to derive a combined, multivariate exposure-response model aimed at translating climatic and air pollution effects into mortality risk. Integration of climate and air pollution parameters to derive RR values. A specific interest is devoted to the investigation of delayed effects on mortality in the presence of different exposure factors.

Climate change and air pollution: Translating their interplay into present and future mortality risk for Rome and Milan municipalities.

Heat and cold temperatures associated with exposure to poor air quality lead to increased mortality. Using a generalized linear model with Poisson regression for overdispersion, this study quantifies the natural-caused mortality burden attributable to heat/cold temperatures and PM10 and O3 air pollutants in Rome and Milan, the two most populated Italian cities. We calculate local-specific mortality relative risks (RRs) for the period 2004-2015 considering the overall population and the most vulnerable age category (≥85 years). Combining a regional climate model with a chemistry-transport model under future climate and air pollution scenarios (RCP2.6 and RCP8.5), we then project mortality to 2050. Results show that for historical mortality the burden is much larger for cold than for warm temperatures. RR peaks during wintertime in Milan and summertime in Rome, highlighting the relevance of accounting for the effects of air pollution besides that of climate, in particular PM10 for Milan and O3 for Rome. Overall, Milan reports higher RRs while, in both cities, the elderly appear more susceptible to heat/cold and air pollution events than the average population. Two counterbalancing effects shape mortality in the future: an increase associated with higher and more frequent warmer daily temperatures - especially in the case of climate inaction - and a decrease due to declining cold-mortality burden. The outcomes highlight the urgent need to adopt more stringent and integrated climate and air quality policies to reduce the temperature and air pollution combined effects on health.

Gestational age limits for abortion and cross-border reproductive care in Europe: a mixed-methods study.

OBJECTIVES: Little is known about the experiences of women who travel within Europe for abortion care from countries with relatively liberal laws. This paper aims to assess the primary reasons for travel among a sample of women who travelled from European countries with relatively liberal abortion laws to obtain abortion care mainly in the UK and the Netherlands. DESIGN: Multi-country, 5-year mixed methods study on barriers to legal abortion and travel for abortion. SETTING: UK, the Netherlands and Spain. POPULATION OR SAMPLE: We present quantitative data from 204 surveys, and qualitative data from 30 in-depth interviews with pregnant people who travelled to the UK, the Netherlands and Spain from countries where abortion is legal on broad grounds within specific gestational age (GA) limits. METHODS: Mixed-methods. MAIN OUTCOME MEASURES: GA when presenting at abortion clinic, primary reason for abortion-related travel. RESULTS: Study participants overwhelmingly reported travelling for abortion because they had exceeded GA limits in their country of residence. Participants also reported numerous delays and barriers to receiving care. CONCLUSIONS: Our findings highlight the need for policies that support access to abortion throughout pregnancy and illustrate that early access to it is necessary but not sufficient to meet people's reproductive health needs. FUNDING: This study is funded by the European Research Council (ERC). TWEETABLE ABSTRACT: This study shows that GA limits drive women from EU countries where abortion is legal to seek abortions abroad.

Air pollution and childhood leukaemia: a nationwide case-control study in Italy.

OBJECTIVES: Leukaemia is the most common cancer in children, but its aetiology is still poorly understood. We tested the hypothesis that traffic-related air pollution is associated with paediatric leukaemia because of chronic exposure to several potential carcinogens. METHODS: The Italian SETIL study (Study on the aetiology of lymphohematopoietic malignancies in children) was conducted in 14 Italian regions. All incident cases of leukaemia in children aged ≤10 years from these regions (period 1998-2001) were eligible for enrolment. Two controls per case, matched on birth date, gender and region of residence were randomly selected from the local population registries. Exposure assessment at birth residence included traffic indicators (distance to main roads and length of main roads within 100 m) and estimates of pollutants concentrations (particulate matter -PM2.5 and PM10- and gases -NO2 and O3-) from national dispersion model and land use regression models. The association between the exposure variables and leukaemia was assessed by logistic regression analyses. RESULTS: Participation rates were 91.4% among cases and 69.2% in controls; 620 cases (544 acute lymphocytic and 76 acute non-lymphocytic leukaemia) and 957 controls were included. Overall, when considering the residence at birth, 35.6% of cases and 42.4% of controls lived along busy roads, and the mean annual PM10 levels were 33.3 (SD=6.3) and 33.4 µg/m(3) (SD=6.5), respectively. No association was found, and all ORs, independent of the method of assessment and the exposure windows, were close to the null value. CONCLUSIONS: Using various exposure assessment strategies, air pollution appears not to affect the incidence of childhood leukaemia.

Stem cells and repair of the heart: cell-releasing epicardial scaffolds.

Cell transplantation represents the last frontier within the treatment of cardiac diseases. From the first paper published in 1992 that has documented the potentials of the transplantation of autologous skeletal muscle cells to treat the damage induced by acute myocardial infarction, innumerable techniques of implantation and types of cells used has been reported, greatly expanding this innovative and appealing field of search in cardiovascular medicine. Despite original promises and expectations, current evidences of stem cell transplantation are still weak and controversial. Therefore, alternative line of research are being explored, particularly in the field of techniques of cell implantation and engraftment. Besides direct implantation or myocardial colonization by bone marrow stimulation, epicardial application of cell-delivering systems (scaffold and patches) have gained popularity due to the possibility to apply selectively a cell-containing device which may gradually release the chosen cell type, alone or in combination with trophic substances. The scaffolds have proven to be successful in this respect and may represent a valid alternative to coronary, intra-myocardial, or venous injection of stem cells, or to stem cell stimulating factors. Finally these systems may be applied through minimally invasive procedures and act as external constraint to enhance ventricular reverse remodelling or limit further cardiac dilatation.

Artemether and artesunate show the highest efficacies in rescuing mice with late-stage cerebral malaria and rapidly decrease leukocyte accumulation in the brain.

The murine model of cerebral malaria (ECM) caused by Plasmodium berghei ANKA (PbA) infection in susceptible mice has been extensively used for studies of pathogenesis and identification of potential targets for human CM therapeutics. However, the model has been seldom explored to evaluate adjunctive therapies for this malaria complication. A first step toward this goal is to define a treatment protocol with an effective antimalarial drug able to rescue mice presenting late-stage ECM. We evaluated the efficacy of artemisinin, artemether, artesunate, and quinine given intraperitoneally once a day, and combinations with mefloquine, in suppressing PbA infection in mice with moderate parasitemia. Artemether, artesunate, and quinine were then evaluated for efficacy in rescuing PbA-infected mice with ECM, strictly defined by using objective criteria based on the presentation of clinical signs of neurological involvement, degree of hypothermia, and performance in a set of six motor behavior tests. Artemether at 25 mg/kg presented the fastest parasite killing ability in 24 h and fully avoided recrudescence in a 5-day treatment protocol. Artemether and artesunate were equally effective in rescuing mice with late-stage ECM (46 and 43% survival, respectively), whereas quinine had a poor performance (12.5% survival). Artemether caused a marked decrease in brain leukocyte accumulation 24 h after the first dose. In conclusion, artemether and artesunate are effective in rescuing mice with late-stage ECM and decrease brain inflammation. In addition, the described protocols for more strict clinical evaluation and for rescue treatment provide a framework for studies of CM adjunctive therapies using this mouse model.

Tako-tsubo-like left ventricular dysfunction: transient left ventricular apical ballooning syndrome.

AIMS/OBJECTIVES: This review examines the 'tako-tsubo-like' syndrome or transient left ventricular apical ballooning. The aim of this review is a complete evaluation of epidemiology, clinical and instrumental features, pathophysiological mechanisms, therapy and prognosis of this syndrome. METHODS: We have evaluated the data from literature for a comprehensive consideration of multiple aspects of this syndrome. RESULTS/FINDINGS: Transient left ventricular apical ballooning typically affects women, and the clinical presentation is comparable to acute coronary syndrome with chest pain or sudden dyspnoea, changes in ECG and elevated cardiac enzymes in the absence of significant coronary stenosis, with complete resolution of wall-motion abnormalities in a period of days or weeks. This syndrome is triggered by marked psychological or physiological stress. Several pathophysiological mechanisms have been proposed, such as cathecolamine-mediated cardiotoxicity, abnormalities in coronary microvascular function and multivessel coronary vasospasm. The highest incidence of transient left ventricular apical ballooning is in the Japanese population, but it has been recently identified also in the USA and Europe. Treatment is empirical and supportive. The prognosis is generally favourable, although some deaths have been reported, usually the result of irreversible cardiogenic shock, refractory ventricular arrhythmias, or other catastrophic cardiovascular event. CONCLUSIONS/INTERPRETATIONS: We conclude by emphasising the importance of a more deeper knowledge of this syndrome for general physicians and cardiologists and it should be often considered as a possible diagnosis occurring in emergency department and in patients admitted in the Chest Pain Units with a diagnosis of coronary acute syndrome.

[Homocysteine: a casual link with heart failure?]. / Omocisteina e scompenso cardiaco: un'associazione casuale?

Several studies and recent patents have demonstrated that hyperhomocysteinemia (HHCY) is an independent risk factor for congestive heart failure (CHF); it is also correlated to the severity of the disease. In literature there are some data about effects of HHCY on myocardial structure and function in animal models. These studies indicate a direct effect of HCY in promoting reactive myocardial fibrosis and systolic dysfunction, promoting miocardial redox state, endothelial and mithocondryal dysfunction, negative inotropic effect. According to some authors the HHCY is a potential ethiological factor for heart failure while according to others it is just an epiphenomenon without direct effects on myocardium. Nevertheless the literature studies show the relevant involvement of HHCY in CHF and the strong relations between HHCY plasma levels and the severity and prognosis of the disease. Regarding the potential mechanistic role of HHCY in CHF, all of these studies do not provide any mechanistic insights because of their epidemiological nature. Future studies need to explore the exact pathomechanisms of HHCY in CHF.

Coronary artery fistula: diagnostic role of transthoracic and transesophageal echocardiography.

Congenital coronary artery fistulas (CAFs) are rare. Some patients develop symptoms of congestive heart failure secondary to a large left-to-right shunt or myocardial ischemia from coronary artery steal in the first few years after birth. After the second decade the frequency of symptoms and complications increase. We report a case of CAF originating from the circumflex artery and draining into the coronary sinus, associated with left main coronary aneurysm. Transtho-racic and transesophageal echocardiography approach showed the origin, course, and drainage site of the CAF. This case represents a typical sample of this rare anomaly and puts into evidence the essential role of echocardiography to define and complete the angiographic diagnosis.

An evaluation of particle deposition fluxes to cultural heritage sites in Florence, Italy.

The pernicious effects of deposition of airborne particles on monumental stones have been widely demonstrated, but estimates of deposition fluxes on historic buildings remain a hard task because of the lack of careful experiments and modelling. AERBOX is a new box model developed by ENVIROWARE and ENEA, simulating the whole life cycle of aerosols. AERBOX takes into account all the relevant chemical and physical processes involved: emission, chemical reactions in gas and in gas-liquid phases, deposition, entrainment, condensation and nucleation. Concentration and deposition rates of 52 species of gaseous pollutants and 14 species of particulate pollutants are calculated on hourly basis. A modelling system composed by AERBOX and the emission pre-processor Tool for Hourly Speciation of CORINAIR Annual Emissions (THOSCANE) has been applied to estimate the flux of particulate matter deposited on the monumental area of Florence downtown starting from a CORINAIR emission inventory developed by the Tuscany Region including the industrial and mobile sources in the area of Florence and Prato counties. The time and chemical profiles of the emissions have been adapted to the Tuscany region from the reference profiles given by both the California Air Resource Board and EPA and meteorological inputs were given by the Tuscany Meteorological Centre. Concentrations and deposition fluxes were compared with field measurements available in the open literature.

Immunization of Saimiri sciureus monkeys with Plasmodium falciparum merozoite surface protein-3 and glutamate-rich protein suggests that protection is related to antibody levels.

The immunogenicity and protective efficacy of various antigen-adjuvant formulations derived either from the merozoite-surface protein-3 (MSP-3) or the glutamate-rich protein (GLURP) of Plasmodium falciparum were evaluated in Saimiri sciureus monkeys. These proteins were selected for immunogenicity studies based primarily on their capacity of inducing an antibody-dependent cellular inhibition effect on parasite growth. Some of the S. sciureus monkeys immunized with MSP-3(212-380)-AS02 or GLURP(27-500)-alum were able to fully or partially control parasitaemia upon an experimental P. falciparum [Falciparum Uganda Palo Alto (FUP-SP) strain] blood-stage infection, and this protection was related to the prechallenge antibody titres induced. The data are indicative that MSP-3 and GLURP can induce protective immunity against an experimental P. falciparum infection using adjuvants that are acceptable for human use and this should trigger further studies with those new antigens.

Inactivation of infective larvae of Angiostrongylus costaricensis with short time incubations in 1.5% bleach solution, vinegar or saturated cooking salt solution.

Angiostrongylus costaricensis is a nematode parasite of wild rodents in the Americas. Man may become infected accidentally and, sometimes, suffers a very severe abdominal disease. Ingestion of raw vegetables has been proven to be a risk factor for the acquisition of A. costaricensis and, therefore, prophylaxis should include food disinfection. The larvicidal effect of wine vinegar, saturated cooking salt (SS) and a 1.5% bleach solution (BW) were compared with a 1-h-incubation period, at room temperature. Larval viability was tested through inoculation in Swiss mice. Only one out of 560 larvae treated with BW (97.3% of the animals were uninfected) was recovered as an adult worm, while 90/336 and 29/512 larvae treated, respectively, with SS and WV were recovered as adult worms. This larvicidal effect of BW was seen also in incubation times as short as 15 min. In conclusion, the 1.5% bleach solution may be helpful for prophylaxis of human abdominal angiostrongyliasis through disinfection of raw vegetables and unpeeled fruits.

Autoimmunity and malaria: what are they doing together?

A common feature of autoimmunity is the presence of autoantibodies (AAb). Two types of AAb have been described: the 'pathogenic' AAb, associated with autoimmune diseases (AID), and the so-called 'natural' AAb. The latter are present in all normal individuals and have been postulated to play a major role as a first defensive barrier of the organism. Both the 'pathogenic' and the 'natural' AAb can be detected at higher frequencies among individuals exposed to viral, bacterial and parasitic infections. The malaria associated AAb do not seem to result from a generalised polyclonal B-cell activation (PBA), have specificities that may differ according to the degree of clinical immunity and do not seem to be pathogenic. Malaria may offer a protective effect against AID, by diminishing its severity or by either preventing or retarding its expression. AAb could also participate in the immune protection against malaria, and this could happen in several ways: (i) AAb directed to modified Ag expressed on the red blood cell (RBC) membrane during parasitisation and (ii) AAb reactive with crypto- or neo-Ag revealed on both normal and infected RBC membranes, by destroying infected, and also normal, erythrocytes; (iii) anti-idiotype AAb specific of the binding site of anti-merozoite Ab, which would mimic the parasite ligand for the RBC receptor, by competing with parasites and blocking RBC invasion; (iv) AAb cross-reactive with parasite material - such as nuclear or cytoskeleton Ag - having a direct parasiticide activity; (v) the natural AAb network, through its 'anti-bacterial first defense barrier'; and finally (vi) anti-phospholipid (PL) AAb, by neutralizing the pathogenic properties of parasite-derived PL. Finally, in view of currently available knowledge, it is concluded that, since AAb are not always pathogenic, the price for an 'autoimmunity-mediated' protection in malaria would not necessarily be immunopathology and clinical autoimmunity, and a protective role of AAb could be exerted with no danger to the host.

The physician-patient relationship in amyotrophic lateral sclerosis.

The principal models of the physician-patient relationship are analysed in terms of their historical development. An outline is given of the clinical, psychological and ethical particularities of the approach to patients with amyotrophic lateral sclerosis. The peculiarities of this disease are so exclusive that they do not resemble other progressive diseases with a negative prognosis, and therefore require an equally exclusive approach to the physician-patient relationship. This approach should not only be informative, scientific and interpretative-deliberative, but must simultaneously be founded on a solid therapeutic alliance aimed at seeking the best interests of the patients while respecting their autonomy as well as their "good" (not only in the sense of physical well-being, but also in terms of respect for their personal values). This is the only way to confront the conflicts that inevitably arise (especially in advanced stages of the disease) without the risks associated with a desire to escape or to adopt extreme solutions (such as euthanasia and therapeutic insistence) and without the risk of burn-out.

Swiss regulations for controlling clinical trials.

Switzerland has recently issued regulations designed to control all trials with drugs in human subjects, namely the 'Regolamento dell'Ufficio Intercantonale per il controllo dei medicamenti in fase di studio clinico' (Intercantonal Regulations Controlling Drugs used in Clinical Trials), which have been operating since 1st January 1995. These new regulations are generally consistent with other international regulations and have introduced the concept of good clinical practice (GCP) into Switzerland. There are other regulations in Switzerland, such as Federal regulations on immunobiological products, special rules governing the administration of radiolabelled drugs to humans, drugs of abuse and medical devices. Any gap in the central regulations must be filled by cantonal regulations, where they exist. This is a comprehensive review of the regulations governing clinical trials in Switzerland, with special attention being devoted to trials with therapeutic compounds and to compatibility between Swiss and international procedures.