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Over a period of 3 years, the European Union’s Innovative Medicines Initiative WEB-RADR (Recognising Adverse Drug Reactions; https://web-radr.eu/ ) project explored the value of two digital tools for pharmacovigilance (PV): mobile applications (apps) for reporting the adverse effects of drugs and social media data for its contribution to safety signalling. The ultimate intent of WEB-RADR was to provide policy, technical and ethical recommendations on how to develop and implement such digital tools to enhance patient safety. Recommendations relating to the use of mobile apps for PV are summarised in this paper. There is a presumption amongst at least some patients and healthcare professionals that information ought to be accessed and reported from any setting, including mobile apps. WEB-RADR has focused on the use of such technology for reporting suspected adverse drug reactions and for broadcasting safety information to its users, i.e. two-way risk communication. Three apps were developed and publicly launched within Europe as part of the WEB-RADR project and subsequently assessed by a range of stakeholders to determine their value as effective tools for improving patient safety; a fourth generic app was later piloted in two African countries. The recommendations from the development and evaluation of the European apps are presented here with supporting considerations, rationales and caveats as well as suggested areas for further research.

Over a period of 3 years, the European Union’s Innovative Medicines Initiative WEB-RADR project has explored the value of social media (i.e., information exchanged through the internet, typically via online social networks) for identifying adverse events as well as for safety signal detection. Many patients and clinicians have taken to social media to discuss their positive and negative experiences of medications, creating a source of publicly available information that has the potential to provide insights into medicinal product safety concerns. The WEB-RADR project has developed a collaborative English language workspace for visualising and analysing social media data for a number of medicinal products. Further, novel text and data mining methods for social media analysis have been developed and evaluated. From this original research, several recommendations are presented with supporting rationale and consideration of the limitations. Recommendations for further research that extend beyond the scope of the current project are also presented.

Introduction Spontaneous reporting of suspected adverse drug reactions is key for efficient post-marketing safety surveillance. To increase usability and accessibility of reporting tools, the Web-Recognising Adverse Drug Reactions (WEB-RADR) consortium developed a smartphone application (app) based on a simplified reporting form. Objective The objective of this study was to evaluate the characteristics, quality and contribution to signals of reports submitted via the WEB-RADR app. Methods The app was launched in the UK, the Netherlands and Croatia between July 2015 and May 2016. Spontaneous reports submitted until September 2016 with a single reporter were included. For each country, app reports and reports received through conventional means in the same time period were compared to identify characteristic features. A random subset of reports was assessed for clinical quality and completeness. The contribution to signal detection was assessed by a descriptive analysis. Results Higher proportions of app reports were submitted by patients in the UK (28 vs. 18%) and Croatia (32 vs. 7%); both p  < 0.01. In the Netherlands, the difference was small (60 vs. 57%; p  = 0.5). The proportion of female patients and the median patient ages in app reports submitted by patients were similar to the reference. The proportion of reports of at least moderate quality was high in both samples (app: 78–85%, reference: 78–98%), for all countries. App reports contributed to detecting eight potential safety signals at the national level, four of which were eventually signalled. Conclusion The WEB-RADR app offers a new route of spontaneous reporting that shows promise in attracting reports from patients and that could become an important tool in the future. Patient demographics are similar to conventional routes, report quality is sufficient despite a simplified reporting form, and app reports show potential in contributing to signal detection.

Introduction Spontaneous reporting of suspected adverse drug reactions is key for efficient post-marketing safety surveillance. To increase usability and accessibility of reporting tools, the Web-Recognising Adverse Drug Reactions (WEB-RADR) consortium developed a smartphone application (app) based on a simplified reporting form. Objective The objective of this study was to evaluate the characteristics, quality and contribution to signals of reports submitted via the WEB-RADR app. Methods The app was launched in the UK, the Netherlands and Croatia between July 2015 and May 2016. Spontaneous reports submitted until September 2016 with a single reporter were included. For each country, app reports and reports received through conventional means in the same time period were compared to identify characteristic features. A random subset of reports was assessed for clinical quality and completeness. The contribution to signal detection was assessed by a descriptive analysis. Results Higher proportions of app reports were submitted by patients in the UK (28 vs. 18%) and Croatia (32 vs. 7%); both p < 0.01. In the Netherlands, the difference was small (60 vs. 57%; p = 0.5). The proportion of female patients and the median patient ages in app reports submitted by patients were similar to the reference. The proportion of reports of at least moderate quality was high in both samples (app: 78-85%, reference: 78-98%), for all countries. App reports contributed to detecting eight potential safety signals at the national level, four of which were eventually signalled. Conclusion The WEB-RADR app offers a new route of spontaneous reporting that shows promise in attracting reports from patients and that could become an important tool in the future. Patient demographics are similar to conventional routes, report quality is sufficient despite a simplified reporting form, and app reports show potential in contributing to signal detection.

OBJECTIVE:Myxomatous mitral valve disease (MMVD) is the most frequent acquired cardiac disease in dogs and echocardiography is the gold standard for its diagnosis. Radiographic evaluation is a valuable toll to evaluate left atrial dimensions when echocardiography is not available. The aim of the present study was to evaluate the diagnostic potential of the vertebral heart score (VHS), radiographic left atrial dimensions(RLAD) and vertebral left atrial size (VLAS) for the detection of left atrium enlargement(LAE) in dogs with MMVD. MATERIALS AND METHODS:In this prospective study measurements of VHS, RLAD, VLAS and echocardiographic left atrium-to-aorta ratio (LA/Ao) were performed and RLADand VLAS were correlated with LA/Ao. Concerning radiographic measurements, the influence of the lateral decubitus side was also evaluated (right lateral recumbency (RLR) vs. left lateral recumbency (LLR)). The diagnostic accuracy was evaluated for LAE prediction. RESULTS:Differences between recumbencies were statistically different for VHS(p<0.001) and RLAD (p=0.031). A positive correlation was found between LA/Ao and RLAD (r = 0.41, p=0.004 for the RLR and r = 0.57, p<0.0001 for the LLR) and between VLAS and LA/Ao (r = 0.47, p=0.0008 for the RLR and r = 0.50, p=0.0002 for the LLR). The diagnostic accuracy of the three techniques was moderate (area under the curve [AUC] of 0.833/0.771 for VHS in the RLR/LLR, respectively; 0.824/0.772 for VLAS in the RLR/LLR, respectively;0.745/0.788 for RLAD in the RLR/LLR, respectively), although not statistically different between techniques for the detection of LAE (p>0.05). CONCLUSION:All 3 techniques are useful for the detection of LAE in canine MMVD, showing similar diagnostic potential. The optimal cut-off for RLAD showed maximum specificity, which represents a clinical advantage. The differences between recumbencies warrant standardization, and the same recumbency should be used when sequential measurements are intended.

A Lei 11.340 de 07.08.2006, conhecida como Lei Maria da Penha, criou mecanismos para coibir e prevenir a violência doméstica e familiar contra a mulher, nos termos do § 8o do art. 226 da Constituição Federal, da Convenção sobre a Eliminação de Todas as Formas de Discriminação contra as Mulheres e da Convenção Interamericana para Prevenir, Punir e Erradicar a Violência contra a Mulher, oportunidade em que introduziu no ordenamento jurídico brasileiro as medidas protetivas de urgência, instrumentos para pedidos de proteção pelas vítimas. A publicação da Lei Maria da Penha coincidiu com a queda das ocorrências de crimes contra mulheres no ano subsequente (2007), entretanto, a partir de 2008, as taxas de homicídio feminino seguiram crescendo no Brasil. Na busca de respostas sobre como dar melhor prestação jurisdicional à sociedade no combate ao fenômeno da violência, efetuou-se estudo da doutrina e legislação relativa à violência doméstica e familiar contra a mulher, cotejando-se com informações coletadas em pesquisa empírica previamente realizada na Vara Especial da Mulher de Imperatriz no ano de 2009, analisando-se o procedimento das medidas protetivas de urgência, observando-se os manejos adotados pelos órgãos envolvidos. Realizou-se estudo do direito comparado, a respeito do procedimento das medidas de proteção em outros países, tais como Paraguai, Uruguai, Chile e Argentina, da América Latina, e Espanha e Portugal, na Europa. Utilizou-se a metodologia exploratória, tendo como fontes de informações, além da bibliografia sobre o tema, documentos e banco de dados públicos. Os dados foram analisados visando-se encontrar sugestões para garantir resultados mais eficazes na proteção das mulheres, no sentido de otimizar o alcance do efetivo acesso à justiça, com sugestões quanto ao procedimento das medidas protetivas de urgência. Realizou-se apontamentos quanto à natureza jurídica das medidas e consequente procedimento, quanto à finalidade protetiva desses instrumentos para com as vítimas e seus familiares, bem como, situações passíveis de ensejar revitimização no campo institucional, levando-se a um descrédito social quanto às instituições envolvidas e crença na impunidade, elevando-se os números da violência. Tratou-se, outrossim, da atuação integrada dos órgão da rede de proteção, como o serviço médico de atendimento e a importância da realização da notificação compulsória prevista na Lei Federal n. 10.788/2003, nos casos de violência contra a mulher, tendo em vista sua finalidade informativa, preventiva e viabilizadora de uma maior repressão a este fenômeno a ser combatido em rede, cujas informações deveriam constar num banco de dados acessível ao Poder Judiciário. Propõe-se um procedimento judicial simplificado e específico para as medidas de urgência, com base em princípios da Lei Maria da Penha, visando torná-las mais céleres e efetivas, menos formais, usando como analogia, porém de forma adaptada, o procedimento das tutelas de urgência do Código de Processo Civil, nos moldes do art. 305 e seguinte do CPC, tendo em vista a omissão quanto ao procedimento das medidas na Lei Maria da Penha, utilizando-se os princípios constitucionais e ditames contidos nos tratados internacionais dos quais o Brasil é signatário.

An important area of e-government research is how different stakeholders perceive the impact and the use of e-government systems on the different channels of governmental services. The objective of this article is to examine the perceived effectiveness of local e-government systems through a survey of directors in different Egyptian cities. The approach to accomplish this objective is to conduct exploratory factor analysis and regression analysis to determine what factors explain e-government effectiveness. This research adopts a model that uses the citizen-initiated contacts with government literature as a way for understanding e-government effectiveness. Results of an exploratory factor analysis reveal that e-government effectiveness is explained by management capacity, security and privacy, and collaboration. These factors were then analyzed through regression models that indicated that management capacity and security and privacy influenced e-government effectiveness. However, there was no evidence that collaboration had a statistically significant impact on e-government effectiveness. This paper fits into the theme of the special issue since it suggests strategies to better design e-government technology for local governments in Egypt through changes in security, privacy, and management capacity.

The SUMO-targeted E3 ubiquitin ligase RNF4 plays an important role in safeguarding genome and proteome integrity. RNF4 recognizes polySUMO modified proteins and induces their proteolytic or non-proteolytic ubiquitylation. Given the key function of RNF4 in maintaining proteome and genome stability, we explored its role in cancer cell survival and as a potential cancer drug target. We found that RNF4 is overexpressed in acute myeloid leukemia and high expression levels correlate with poor survival of patients. Depletion of RNF4 exerts antiproliferative effects in AML cells and increased their sensitivity towards antileukemic drugs thus validating RNF4 as a potential vulnerability in AML. To develop PROTACs for targeted degradation of RNF4, we aimed to exploit the recently described cysteine-reactive RNF4 ligand CCW16, and synthesized a set of CCW16-derived degrader molecules using established VHL- and CRBN-E3 ligands. We validated covalent binding of CCW16 and CCW16-derived PROTACs to cysteine residues outside the RING domain of RNF4 using recombinant protein. However, none of the synthesized PROTACs were active in degrading RNF4 in a panel of different cell lines. Consistent with the high reactivity of the chosen electrophile, we detected in the cellular context covalent attachment of CCW16 to accessible cysteines in a large number of proteins including covalent linkage with the catalytic residues in members of the peroxiredoxin family. Furthermore, exposure of cells to CCW16-derived PROTACs induced upregulation of heme oxygenase 1, a ferroptosis marker and impaired cell viability in a distinct, RNF4-independent, ferroptotic cell death pathway.Competing Interest StatementThe authors have declared no competing interest.

O transporte público tem perdido importância nas escolhas pessoais do modo de transporte a utilizarnas diversas deslocações diárias. Esta mudança deve-se, parcialmente, à melhoria do nível de vida dapopulação que favoreceu a aquisição de automóveis, e à incapacidade dos sistemas de transportescolectivos existentes competirem com a flexibilidade e comodidade do transporte individual.Este aumento do uso do automóvel tem reflexos no congestionamento dos aglomerados populacionais,na qualidade ambiental e na segurança das populações. Assim, tendo em vista o desenvolvimentosustentável e a mobilidade sustentável dos cidadãos, é importante investir num sistema de transportespúblicos eficiente, seguro, amigo do ambiente, capaz de competir com transporte individual e as suasvantagens.Dentro do sector, os autocarros e as camionetas, juntamente com os táxis, são os únicos modos detransporte que conseguem competir com o automóvel particular e oferecer uma alternativa sustentável,garantindo ainda elevados níveis de flexibilidade.Neste contexto, as infra-estruturas de acesso ao transporte colectivo surgem como elementofundamental para o adequado funcionamento do sistema de transporte público, como nós de ligaçãoentre os diferentes transportes disponíveis e locais onde os condutores de automóveis ou os peões sãoconvertidos em passageiros.A presente dissertação tem como finalidade analisar as infra-estruturas de acesso ao transporterodoviário e procurar perceber quais são as características fundamentais que influenciam a utilizaçãodas mesmas e, consequentemente, o aumento do uso do transporte público. Esta análise incideespecificamente nas Estações Centrais de Camionagem ou Centros Coordenadores de Transportes,Terminais Rodoviários e Pontos de Chegada e Correspondência, e divide-se em duas partes.Na primeira parte fez-se uma caracterização da situação existente e uma avaliação das estaçõescentrais de camionagem, de acordo com alguns indicadores definidos. Assim, foi possível identificaros bons exemplos e boas práticas, bem como as maiores debilidades e deficiências que estas infraestruturas apresentam e que devem ser acauteladas.A segunda parte resume-se à apresentação de um conjunto de recomendações sobre as principaiscaracterísticas que uma infra-estrutura de apoio ao transporte rodoviário colectivo deve possuir, tendoem conta as situações mais comuns em Portugal, nomeadamente o tipo de infra-estrutura, a dimensão,a localização, os serviços disponíveis, entre outros.Concluiu-se que as maiores debilidades destas infra-estruturas em Portugal relacionam-se com aligação a outros modos de transporte, informação ao público e serviços disponibilizados aos utentes.Por sua vez verificou-se uma falta de informação organizada e informatizada das questõesrelacionadas com estas infra-estruturas por parte das entidades responsáveis, nomeadamente a falta deinformação detalhada quanto ao movimento de passageiros e autocarros, fundamental para seaveriguar os níveis de utilização e o grau de utilidade das mesmas. Assim, observou-se que estas infraestruturas não se encontram reguladas e não existe um acompanhamento do seu funcionamento.

Parkinson’s disease (PD) is characterized by severe motor symptoms, and currently there is no treatment that retards disease progression or reverses damage prior to the time of clinical diagnosis. Tauroursodeoxycholic acid (TUDCA) is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD; however, its effect in PD motor symptoms has never been addressed. In the present work, an extensive behavior analysis was performed to better characterize the MPTP model of PD and to evaluate the effects of TUDCA in the prevention/improvement of mice phenotype. MPTP induced significant alterations in general motor performance paradigms, including increased latency in the motor swimming, adhesive removal and pole tests, as well as altered gait, foot dragging, and tremors. TUDCA administration, either before or after MPTP, significantly reduced the swimming latency, improved gait quality, and decreased foot dragging. Importantly, TUDCA was also effective in the prevention of typical parkinsonian symptoms such as spontaneous activity, ability to initiate movement and tremors. Accordingly, TUDCA prevented MPTP-induced decrease of dopaminergic fibers and ATP levels, mitochondrial dysfunction and neuroinflammation. Overall, MPTP-injected mice presented motor symptoms that are aggravated throughout time, resembling human parkinsonism, whereas PD motor symptoms were absent or mild in TUDCA-treated animals, and no aggravation was observed in any parameter. The thorough demonstration of improvement of PD symptoms together with the demonstration of the pathways triggered by TUDCA supports a subsequent clinical trial in humans and future validation of the application of this bile acid in PD.