Medication nonadherence and psychiatry.

Nonadherence to appropriately prescribed medication for psychiatric disorders prevents patients from realizing the full benefits of their treatment and negatively impacts on individuals, their families and the healthcare system. Understanding and reducing nonadherence is therefore a key challenge to quality care for patients with psychiatric disorders. This review highlights findings regarding the prevalence and consequence of nonadherence, barriers to adherence and new intervention methods from 2012 onwards

Designing crossing and selection strategies to combine diagnostic markers and quantitative traits

Tese de doutoramento em Biociências, ramo de especialização em Toxicologia, apresentada à Faculdade de Ciências e Tecnologia da Universidade de CoimbraDoxorubicin (DOX) is one of the most potent antineoplastic drugs. Although possessing a superior anti-­‐‑cancer activity, a broader clinical use of DOX is limited by a dose-­‐‑dependent, constant and cumulative cardiomyopathy involving deterioration of mitochondrial function. Although acute effects of DOX treatment often disappear when treatment finishes, chronic effects often result in a persistent cardiotoxicity, including a progressive deterioration of mitochondrial metabolism, the development of cardiomyopathy and ultimately congestive heart failure. Important in the context of DOX-­‐‑induced cardiotoxicity, mitochondrial disruption has been observed in different models. This alteration of mitochondrial function is often sub-­‐‑clinical and is only manifested as cardiomyopathy when other factors are combined, including age or different types of cardiovascular stress. Also, metabolic alterations in the cardiac cell occur, which contribute to the ability of the heart to withstand increased workloads. Although mitochondrial disruption is an early and sensitive marker of DOX cardiotoxicity, how metabolic stress contributes to the development of cardiomyopathy remains to be determined. Because of this gap in knowledge, the objective of this work was to use of model of metabolic inhibition in perfused hearts from saline (SAL) and DOX-­‐‑ treated rats in order to identify metabolic alterations caused by an acute and sub-­‐‑ chronic treatment. Our assumption for this strategy is that a lower susceptibility to a determined inhibitor during perfusion, would be a sign of a more robust (i.e. more capacity) of the targeted pathway(s). XV For the acute treatment protocol, sixteen week-­‐‑old male Wistar rats were i.p. injected with 20mg/Kg DOX or 1mg/Kg 0.9%NaCl and sacrificed 24 hours later. For sub-­‐‑ chronic protocol, eight weeks-­‐‑old male Wistar rats received seven weekly s.c. injections with DOX(2mg/Kg) or equivalent SAL solution and sacrificed one week after the last injection. Following the protocol treatments, animals were sacrificed and hearts were removed and perfused using a Langendorff apparatus with distinct cardiac substrates (glucose, galactose plus glutamine -­‐‑ GG or octanoate plus malate – OM). Glycolytic (iodoacetate) and oxidative phosphorylation (rotenone-­‐‑ Rot or cyanide-­‐‑ KCN) inhibitors were separately added to the different metabolic perfusates, aiming to detect undercover mitochondrial defects in the DOX-­‐‑treated group. In non-­‐‑perfused hearts, or hearts perfused in the absence (time controls, TC) or presence of inhibitors, selected metabolic and mitochondrial proteins were semi-­‐‑ quantified by Western blotting, and mRNA levels were quantified by RT-­‐‑PCR. In the acute DOX treatment model, hearts perfused with glucose as substrate suffered a decline in the number of heart beat and rate pressure product (RPP) when iodoacetate was added, contrarily to Rot or KCN which had no effect. With GG, inhibitor titration decreased the heart rate, despite that the decrease in the RPP was more evident in SAL vs. DOX group with iodoacetate and KCN. Perfusion with OM resulted in decreased heart rate an RPP in the presence of the inhibitors, showing equal response between treatments. When glycolytic and mitochondrial proteins were semi-­‐‑quantified by Western blotting, alterations in proteins involved in mitochondrial biogenesis and autophagy were observed in DOX hearts perfused with inhibitors. The data from the acute protocol study, appears to suggest that hearts from DOX-­‐‑treated animals have improved function in the presence of XVI metabolic inhibitors, thus indicating that DOX triggers adaptations that allow the hearts to be less susceptible to mitochondrial and glycolytic inhibition. In the sub-­‐‑chronic model and using glucose as substrate, the DOX-­‐‑treated group showed again a better tolerability to inhibitors than SAL. With GG, titration with iodoacetate caused a decrease in heart beat and on RPP in DOX group, when rot or KCN was added the number of heart beat and RPP remains identical between the two groups. Glycolytic and mitochondrial proteins semi-­‐‑quantification suggested an impairment of autophagy in DOX perfused hearts perfused, more evident during GG perfusion. The presence of inhibitors in the perfusion also generally decreased the total amount of proteins detected by Western Blotting, although glycolytic proteins were increased when hearts were perfused with glucose, contrarily to GG perfusion. The results suggest that sub-­‐‑chronic DOX-­‐‑treated rats suffered a metabolic remodeling which is based on stronger glycolytic fluxes to maintain contractility, although no overt mitochondrial defect was uncovered. A surprising result is that regardless of the perfusion buffer used, no striking differences between SAL and DOX hearts in terms of hemodynamic parameters were found. The present work suggests that metabolic remodeling during DOX acute and sub-­‐‑ chronic treatment maintains cardiac function in the treated animals. This remodeling is apparently based in a stronger contribution of glycolysis to overall metabolism. Data from protein amount analyzed suggest that DOX treatment in both models affect important regulators of autophagy, mitochondrial biogenesis as well as the adenine nucleotide translocator. The results also suggest that a longer treatment XVII protocol or resting period should also be tested in order to uncover more profound differences.A doxorrubicina (DOX) é um dos fármacos antineoplásicos mais potentes. Apesar de possuir uma actividade anti-­‐‑cancro superior, uma mais ampla utilização clínica da DOX é limitada por uma dose-­‐‑dependente, constante e cumulativa cardiomiopatia que envolve a deterioração da função mitocondrial. Embora os efeitos agudos do tratamento DOX normalmente desaparece quando se conclui o tratamento, os efeitos crónicos resultam muitas vezes numa cardiotoxicidade persistente, incluindo a deterioração progressiva do metabolismo mitocondrial, o desenvolvimento de cardiomiopatia e por fim insuficiência cardíaca congestiva. Importante no contexto da cardiotoxicidade induzida pela DOX, perturbação mitocondrial foi observada em diferentes modelos. Esta alteração da função mitocondrial é muitas vezes sub-­‐‑clínica e só se manifesta como cardiomiopatia quando outros factores são combinados, incluindo a idade ou diferentes tipos de estresse cardiovascular. Além disso, ocorrem alterações metabólicas na célula cardíaca, o que contribui para a capacidade do coração resistir a maior demanda. Embora a perturbação mitocondrial seja um marcador precoce e sensível de DOX cardiotoxicidade, como o stress metabólico contribui para o desenvolvimento de cardiomiopatia permanece por determinar. Devido a essa lacuna no conhecimento, o objetivo deste trabalho foi a utilização de um modelo de inibição metabólica em corações perfundidos de ratos tratados com uma solução salina (SAL) e ratos tratados com DOX, a fim de identificar alterações metabólicas causadas por um tratamento agudo e sub-­‐‑crônico. XIX O nosso pressuposto para esta estratégia é que uma menor susceptibilidade a um determinado inibidor durante a perfusão, seria um sinal de uma forma mais robusta (ou seja, mais de capacidade) da via-­‐‑alvo (s). Para o protocolo de tratamento agudo, ratos machos Wistar de 16 semanas de idade foram injectados i.p. com 20 mg / kg de DOX ou de 1 mg / kg a 0,9% de NaCl e sacrificados 24 horas mais tarde. Para o protocolo sub-­‐‑crônico, ratos machos Wistar de oito semanas de idade, receberam sete injecções s.c. semanais com DOX (2 mg / kg) ou uma equivalente da solução SAL sendo sacrificados uma semana após a última injecção. Após o protocolo de tratamentos, os animais foram sacrificados e os corações foram perfundidos com um aparelho de Langendorff com substratos cardíacos distintos (glucose, galactose mais glutamina -­‐‑ GG ou octanoato mais malato -­‐‑ OM). Inibidores glicolíticos (iodoacetato) e inibidores da fosforilação oxidativa (Rot-­‐‑ rotenona ou KCN-­‐‑ cianeto) foram adicionados separadamente nos diferentes substratos metabólicos, com o objetivo de detectar defeitos mitocondriais no grupo tratado com DOX. Em corações não perfundidos, ou corações perfundidos na ausência (controlos de tempo, TC) ou na presença de inibidores, algumas proteínas metabólicas e proteínas mitocondriais foram semi-­‐‑quantificadas por Western blotting, e os níveis de mRNA foram quantificados por RT-­‐‑PCR. No modelo de tratamento agudo DOX, corações perfundidos com glucose como substrato sofreram um declínio no número de batimentos cardíacos e produto da taxa de pressão (RPP), quando iodoacetato foi adicionado, ao contrário da Rot ou KCN, que não teve nenhum efeito. Com GG, a titulação com o inibidor diminuiu a frequência cardíaca, apesar de que a diminuição da RPP foi mais evidente no grupo SAL vs. DOX com iodoacetato e KCN. Perfusão com OM resultou em diminuição da XX frequência cardíaca e do RPP na presença dos inibidores, mostrando uma resposta igual entre os tratamentos. Quando proteínas glicolíticas e mitocondriais foram semi-­‐‑ quantificadas por Western blotting, alterações de proteínas envolvidas na biogênese mitocondrial e autofagia foram observados em corações DOX perfundidos com inibidores. Os dados do protocolo de estudo agudo, parecem sugerir que os corações provenientes de animais tratados com DOX na presença de inibidores, têm a função metabólica melhorada, indicando assim que a DOX desencadeia adaptações que permitem que os corações sejam menos susceptíveis à inibição mitocondrial e glicolítica. No modelo sub-­‐‑crónica e utilizando glucose como substrato, o grupo tratado com DOX mostrou novamente um melhor tolerabilidade para inibidores que SAL. Com GG, a titulação com iodoacetato causou uma diminuição no batimento cardíaco e no RPP em grupo DOX, quando rot ou KCN foi adicionado o número de batimentos cardíacos e RPP permaneceram idênticos entre os dois grupos. A semi-­‐‑quantificação de proteínas glicolíticas e mitocondriais sugerem uma deficiência da autofagia em corações DOX perfundidos, mais evidente durante a perfusão com GG. A presença de inibidores da perfusão geralmente também reduziu a quantidade total de proteínas detectadas através de Western Blot, embora proteínas glicolíticas aumentaram quando os corações foram perfundidos com glucose, ao contrário da perfusão com GG. Os resultados sugerem que ratos tratados sub-­‐‑cronicamente com DOX sofreram uma remodelação metabólica, que é baseado em fluxos glicolíticos mais fortes para manter a contratilidade, embora nenhum defeito mitocondrial ostensivo foi descoberto. XXI Um resultado surpreendente é que, independentemente do tampão de perfusão utilizado, não foram encontradas diferenças marcantes entre SAL e DOX corações em termos de parâmetros hemodinâmicos. O presente trabalho sugere que o remodelação metabólica durante o tratamento agudo e sub-­‐‑crônico com DOX, mantém a função cardíaca nos animais tratados. Esta remodelação é, aparentemente, baseado numa contribuição mais forte da glicólise ao metabolismo geral. Os resultados de quantidade de proteína analisados sugerem que o tratamento com DOX em ambos os modelos afectam importantes reguladores da autofagia e biogénese mitocondrial, bem como o translocador de nucleótidos de adenina. Os resultados também sugerem que um protocolo de tratamento mais longo ou com um período de repouso também devem ser testados a fim de descobrir diferenças mais profundas

Erratum to: 25 Years of Self-organized Criticality: Concepts and Controversies

Introduced by the late Per Bak and his colleagues, self-organized criticality (SOC) has been one of the most stimulating concepts to come out of statistical mechanics and condensed matter theory in the last few decades, and has played a significant role in the development of complexity science. SOC, and more generally fractals and power laws, have attracted much comment, ranging from the very positive to the polemical. The other papers (Aschwanden et al. in Space Sci. Rev., 2014, this issue; McAteer et al. in Space Sci. Rev., 2015, this issue; Sharma et al. in Space Sci. Rev. 2015, in preparation) in this special issue showcase the considerable body of observations in solar, magnetospheric and fusion plasma inspired by the SOC idea, and expose the fertile role the new paradigm has played in approaches to modeling and understanding multiscale plasma instabilities. This very broad impact, and the necessary process of adapting a scientific hypothesis to the conditions of a given physical system, has meant that SOC as studied in these fields has sometimes differed significantly from the definition originally given by its creators. In Bak’s own field of theoretical physics there are significant observational and theoretical open questions, even 25 years on (Pruessner 2012). One aim of the present review is to address the dichotomy between the great reception SOC has received in some areas, and its shortcomings, as they became manifest in the controversies it triggered. Our article tries to clear up what we think are misunderstandings of SOC in fields more remote from its origins in statistical mechanics, condensed matter and dynamical systems by revisiting Bak, Tang and Wiesenfeld’s original papers

Size matters in quantitative radar monitoring of animal migration: estimating monitored volume from wingbeat frequency

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record.Quantitative radar studies are an important component of studying the movements of birds. Whether a bird, at a certain distance from the radar, is detected or not depends on its size. The volume monitored by the radar is therefore different for birds of different sizes. Consequently, an accurate quantification of bird movements recorded by small-scale radar requires an accurate determination of the monitored volume for the objects in question, although this has tended to be ignored. Here, we demonstrate the importance of sensitivity settings for echo detection on the estimated movement intensities of birds of different sizes. The amount of energy reflected from a bird and detected by the radar receiver (echo power) depends not only on the bird's size and on the distance from the radar antenna, but also on the beam shape and the bird's position within this beam. We propose a method to estimate the size of a bird based on the wingbeat frequency, retrieved from the echo-signal, independent of the absolute echo power. The estimated bird-size allows calculation of size-specific monitored volumes, allowing accurate quantification of movement intensities. We further investigate the importance of applying size-specific monitored volumes to quantify avian movements instead of using echo counts. We also highlight the importance of accounting for size-specific monitored volume of small scale radar systems, and the necessity of reporting technical information on radar parameters. Applying this framework will increase the quality and validity of quantitative radar monitoring.COST – European Cooperation in Science and Technolog

Beliefs about medication predict the misattribution of a common symptom as a medication side effect - Evidence from an analogue online study.

OBJECTIVE: Some perceived medication side effects may be 'normal' symptoms that patients misattribute to the medication. Using an analogue approach, we tested if medication beliefs predict whether participants misattribute a headache as a side effect and subsequently intend to stop medication. METHODS: We recruited 690 participants, 223 reporting a past asthma diagnosis. They received information about asthma and Molair, a fictitious asthma treatment modeled on a licensed treatment (montelukast). We varied the description of efficacy and side effects (which did not include headache). Pre-exposure to this information, participants completed the Beliefs about Medicine Questionnaire (BMQ)-General and the Perceived Sensitivity to Medicines Scale (PSM), post-exposure they completed the BMQ-Specific. Participants were asked to imagine they experienced a headache while taking Molair. Finally, they rated whether the headache was a side effect (misattribution) and if they would stop taking Molair (behavioral intention). RESULTS: Nearly a quarter (170) of participants misattributed the headache to Molair and 69 (10%) subsequently intended to stop Molair. Both outcomes were predicted by general and specific medication beliefs. Odds of misattribution (m) and behavioral intention (i) increased with higher General Harm (ORm=1.90, ORi=2.72), General Overuse (ORm=1.74, ORi=1.56) and Molair Concern beliefs (ORm=1.52, ORi=1.78, all p<.01), but decreased with General Benefit (ORm=0.72, ORi=0.53) and Molair Necessity beliefs (ORm=0.72, ORi=0.70, all p<.05). CONCLUSION: Symptom misattribution and subsequent intentions to stop Molair were predicted by pre-exposure beliefs about medicines in general and post-exposure beliefs about Molair. Patients with negative medication beliefs may be prone to misattribute symptoms and subsequently stop medication

The Galaxy Structure-Redshift Relationship

There exists a gradual, but persistent, evolutionary effect in the galaxy population such that galaxy structure and morphology change with redshift. This galaxy structure-redshift relationship is such that an increasingly large fraction of all bright and massive galaxies at redshifts 2 < z < 3 are morphologically peculiar at wavelengths from rest-frame ultraviolet to rest-frame optical. There are however examples of morphologically selected spirals and ellipticals at all redshifts up to z ~ 3. At lower redshift, the bright galaxy population smoothly transforms into normal ellipticals and spirals. The rate of this transformation strongly depends on redshift, with the swiftest evolution occurring between 1 < z < 2. This review characterizes the galaxy structure-redshift relationship, discusses its various physical causes, and how these are revealing the mechanisms responsible for galaxy formation.Comment: 20 pages, 8 figures. Invited Review to appear in "Penetrating Bars Through Masks of Cosmic Dust: The Hubble Tuning Fork Strikes A New Note", ed. D. Block et a

Evaluation of the vector competence of a native UK mosquito Ochlerotatus detritus (Aedes detritus) for dengue, chikungunya and West Nile viruses

BACKGROUND: To date there has been no evidence of mosquito-borne virus transmission of public health concern in the UK, despite the occurrence of more than 30 species of mosquito, including putative vectors of arboviruses. The saltmarsh mosquito Ochlerotatus detritus [syn. Aedes (Ochlerotatus) detritus] is locally common in parts of the UK where it can be a voracious feeder on people. METHODS: Here, we assess the competence of O. detritus for three major arboviruses: dengue virus (DENV), chikungunya virus (CHIKV) and West Nile virus (WNV) using adult mosquitoes reared from wild, field-obtained immatures. RESULTS: We demonstrate laboratory competence for WNV at 21 °C, with viral RNA detected in the mosquito’s saliva 17 days after oral inoculation. By contrast, there was no evidence of laboratory competence of O. detritus for either DENV or CHIKV. CONCLUSIONS: To our knowledge, this is the first study to demonstrate competence of a UK mosquito for WNV and confirms that O. detritus may present a potential risk for arbovirus transmission in the UK and that further investigation of its vector role in the wild is required