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RESUMENEsta investigación asumió como propósito la determinación de problemas y sus factores, y las estrategias o medidas implementadas a nivel mundial respecto al tratamiento de la brecha de recursos humanos en salud y su distribución, además de la forma en cómo esto influye en la calidad del servicio sanitario; todo esto se realizó por medio de un proceso de revisión sistemático con validez científica que hizo posible la obtención de datos, enfoques, estrategias y requerimientos, los mismos que fueron filtrados a través de una fase de análisis que permitió el desarrollo de un criterio para la discriminación de información relevante y la adaptación de aquellos estudios más relacionados con el tópico principal de este documento. La metodología empleada consistió en la recolección de distintos artículos de varios países con problemas en el recurso humano en salud, medidas de estado para corregir la brecha, estrategias de formación y evaluaciones de satisfacción del usuario externo.PALABRAS CLAVE: brecha; recursos humanos; calidad; servicios sanitarios.Human resources gap and the quality of care in health servicesABSTRACTThe purpose of this research was to determine problems and their factors, and the strategies or measures implemented worldwide regarding the treatment of the gap in human resources in health and its distribution, as well as the way in which this influences the quality of service. sanitary; all this was done through a systematic review process with scientific validity that made it possible to obtain data, approaches, strategies, and requirements, which were filtered through an analysis phase that allowed the development of a criterion for the discrimination of relevant information and the adaptation of those studies most related to the main topic of this document. The methodology used consisted of the collection of different articles from several countries with problems in human resources in health, state measures to correct the gap, training strategies and evaluations of external user satisfaction. KEYWORDS: gap; human resources; quality; health services.

Pancreatic ductal adenocarcinoma (PDAC) is expected to be the second-leading cause of cancer deaths by 2030. This is related to the incidence increment, latter diagnosis, and absence of therapies with efficacy. Imaging techniques are the standard for monitoring the therapy response in PDAC, but these techniques have considerable limits, including delayed disease progression detection and difficulty in distinguishing benign from malignant lesions. The use of CA19.9 as tumor marker is validated in clinical, but also present some limitations (is not expressed in up to 20% of patients and can be increased in several benign conditions including biliary tree complications). The study of new biomarkers, especially with the use of technologies associated with liquid biopsies, has been used to try to solve the limitations. Extracellular vesicle (EV) liquid biopsy is an emerging diagnosis modality. Still, most research on EV-based diagnosis is based on point analyses of EVs at certain times. Longitudinal studies of EV populations before and during therapeutic interventions are still largely unexplored. We analyzed plasma EV protein composition at diagnosis and throughout PDAC therapy using mass spectrometry (MS). Using flow cytometry, we validated the previous result and explored the evolution of the population of EVs expressing the identified protein in MS in patients with metastatic PDAC in accordance with the chemotherapy treatment results. We found that IgG is linked to the diagnosis of PDAC and the patient’s response to therapy, and that IgG+ EV population increases with disease progression and reduces with treatment response. Importantly, this covers PDAC patients devoid of the standard PDAC serum marker CA19.9 expression. We also observed that IgG is bound to EVs via the tumor antigen MAGE B1, and that this is independent of the patient’s inflammatory condition and IgG serum levels. With these results, we propose that a population analysis of IgG+ EVs in PDAC plasma could represent a novel method to supplement the monitoring of the treatment response of patients with metastatic PDAC. Resumo As projeções indicam que em 2030 a segunda causa de morte associada a tumores será o adenocarcinoma ductal do pâncreas. As razões para estas projeções devem-se a um incremento da sua incidência, diagnósticos em estádios avançados e poucas opções terapêuticas de eficácia prolongada disponíveis. Em doentes com doença metastizada a avaliação da resposta à quimioterapia em curso baseia-se na utilização de métodos imagiológicos e do marcador sérico CA19.9. A avaliação imagiológica tem como limitações o possível atraso na deteção da progressão e a dificuldade de distinguir entre lesões benignas e malignas, nomeadamente se estas forem de dimensões reduzidas. O marcador CA19.9 não é expresso em cerca de 20% dos doentes e pode estar elevado devido a outras circunstâncias clínicas, nomeadamente alterações benignas, como infeções do trato biliar. A investigação de novos biomarcadores, nomeadamente com o uso de biopsias líquidas tem tentado ajudar a ultrapassar essas limitações. A utilização de vesículas extracelulares como ferramenta de biopsia líquida tem sido explorada; no entanto, a maioria dos estudos focam-se no diagnóstico ou avaliações isoladas de amostras de doentes, tendo os estudos longitudinais sido muito pouco explorados. Neste trabalho foi realizada a análise de proteínas presentes em vesículas extracelulares isoladas de plasma de doentes com adenocarcinoma ductal de pâncreas ao diagnóstico e após tratamento de quimioterapia, através de espectrometria de massa. As proteínas identificadas como elevadas na população em estudo foram posteriormente validadas por citometria de fluxo das vesículas extracelulares e analisadas longitudinalmente em doentes sob tratamento de quimioterapia. Foi possível identificar que a presença de IgG em vesículas extracelulares se associava ao diagnóstico de adenocarcinoma ductal do pâncreas e à resposta dos doentes à terapêutica de quimioterapia em curso. O aumento da população IgG + EV foi associado a progressão da doença e a sua redução à resposta à terapêutica. Este achado ocorreu também em doentes sem expressão de CA19.9. Esta associação foi independente da quantidade de IgGs séricas e de marcadores de inflamação. A avaliação das proteínas associadas às IgG presentes nas vesículas extracelulares permitiu identificar o antigénio tumoral MAGE B1 justificando uma ligação das IgGs presentes na superfície das vesículas extracelulares à carga nessas vesículas por parte das células tumorais de proteínas com potencial antigénico. Com estes resultados, propõe-se que a análise da população de vesículas extracelulares com IgGs na sua superfície presentes em plasma de doentes com adenocarcinoma ductal do pâncreas possa ser utilizada como complemento na monitorização de resposta à terapêutica de quimioterapia de doentes com adenocarcinoma ductal do pâncreas metastizado.

Introduction Telemedicine applications, including teleconsultations, can potentially improve patient health outcomes, access to health care and to reduce health care costs. “Telemedicine” means “medicine delivered at a distance”, and the exchange of information can occur synchronously (when interactions happen in real time) or asynchronously (when there is a lag between the clinical information being transmitted and the response), and through different channels, including videoconferencing, mobile applications, and secure messaging. It is also possible that one telemedicine service has a store-andforward as well as a realtime component. Although telemedicine and telehealth have been conceptualised separately, with the latter being a broader term that also incorporates activities such as patient and provider education, they are often used synonymously. Also, the terms ehealth and telehealth are most often used interchangeably. Semantically, the difference between these two concepts is that ehealth applications are not limited to health care over a distance, as is the case with telehealth. Given continuing technological innovation and the emergence of a new generation of people in a digital world, it must be emphasised the importance of studying both patients and doctors perceptions on the impact of these changes in the doctor-patient relationship. The general aim of this thesis is to explore patients’ and physicians’ perceptions of the impact of teleconsultations on clinical practice and the organisation of care of a pilot project of interactive telecardiology in the Portuguese national health system (NHS). The specific objectives are to identify the facilitators and barriers to the uptake of teleconsultations; to explore the perceptions of participants on the doctorpatient relationship and the inter-professional collaboration in health care; and to assess the effects of mobile-based technologies versus usual care for supporting communication and consultations between health care providers on their performance, acceptability and satisfaction, health care use, patient health outcomes, costs, and technical difficulties. Methods The thesis contains four research manuscripts, divided in two parts. The first group includes a Cochrane systematic review of randomised trials developed in collaboration with the Nuffield Department of Population Health, University of Oxford. We searched CENTRAL, MEDLINE, Embase and three other databases from 1 January 2000 to 22 July 2019. We searched clinical trials registries, checked references of relevant systematic reviews and included studies, and contacted topic experts. For the data collection and analysis we followed standard methodological procedures expected by Cochrane and the EPOC group. We used the GRADE approach to assess the certainty of the body of evidence for the most important outcomes. The second group includes three qualitative studies embedded in a case study of the rollout of a new service model of teleconsultations between the primary and the secondary care levels. Semi-structured interviews to patients and physicians were transcribed, stored, coded and analysed following the steps for conventional content analysis. This type of study design facilitates the understanding of the phenomenon of teleconsultations that is both context-dependent and influenced by the individual’s characteristics. We reflected on the dynamics and process of introducing teleconsultations into health care with two of the most frequently used theories in telemedicine research, namely, normalisation process theory and the diffusion of innovations, although there is scarce integration of constructs belonging to different theories found in the literature. Both of these theories highlight that the ongoing use of technology is linked to flexibility to enable care models to meet end-users’ needs and expectations, which in turn will evolve as new challenges appear. We chose qualitative methods because they may help to identify unexpected experiences, or provide in-depth understandings of how participants’ interactions with interventions produce change. The Medical Research Council (MRC) emphasises the need for qualitative exploration of participant responses, during and after intervention, to understand how change is produced in the short and longer term. Exploring the way in which this intervention is implemented can provide insight into why it has unexpected consequences, or why it works and how it can be optimised. Results The systematic review included 19 trials (5766 participants), most were conducted in high-income countries. The most frequently used mobile technology was a mobile phone, often accompanied by training if it was used to transfer digital images. Trials recruited participants with different conditions, and interventions varied in delivery, components, and frequency of contact. We judged most trials to have high risk of performance bias, and approximately half had a high risk of detection, attrition, and reporting biases. Two studies reported data on technical problems, reporting few difficulties. The qualitative studies included a total of 29 participants interviewed between September 2019 and January 2020. The first qualitative study found that patients and physicians merged in their views on ‘process’ issues, i.e., those concerning a better prioritisation of patients and an improved collaborative practice, albeit with possible technological constraints. Physicians recognised that teleconsultations presented an educational opportunity for managing patients’ health problems. Our findings suggest that not all patients would require equally intensive collaborative activities across the health system. The barriers described included difficulties using the system (technical issues) and concerns about workload as a consequence of the disruption of traditional clinical routines. Increasing the range of collaborative strategies available to health care providers may require a broader assessment of the way that care processes are structured between levels of care. Patients revealed strong support for teleconsultation on the grounds of interprofessional collaboration and avoidance of unnecessary hospital visits. The second qualitative study found that patients and physicians presented clear views about the role of the general practitioner (GP) and the cardiologist and their function in overall structure of health care. GPs felt their role was to bring expertise in the patient which could supplement the cardiologists’ expertise on the condition. However, GPs had to renegotiate roles in the teleconsultations when they saw themselves in a new situation, together with another physician and the patient. The third qualitative study found that GPs and cardiologists recognised that telemedicine between levels of care could act as a continuing medical education tool (CME). Although they departed with different expectations, telemedicine helped them collaborate as a multidisciplinary team, exchanging feedback about clinical decisions, and constructing knowledge collaboratively. Telemedicine also supplemented existing learning meetings. Conclusions Interventions including a mobile technology component to support communication among health care providers may reduce the time between presentation and management of the health condition when primary care providers or emergency physicians use them to consult with specialists, and may increase the likelihood of receiving a clinical examination among participants with diabetes and those who required an ultrasound. They may decrease the number of people attending primary care who are referred to secondary or tertiary care in some conditions, such as some skin conditions and chronic kidney disease. The implementation of teleconsultations between levels of care may be facilitated when patients, caregivers and physicians see the added value of this service, that adequate resources are put in place and that there is flexible implementation. This work adds an in-depth understanding of participants’ perceptions of this intervention in a case study. Teleconsultations can promote continuity of care for patients in the primary-secondary care interface. Active coordination between physicians with delineation of roles throughout primary-secondary care interface is needed to manage selected patients who may benefit the most from shared care. Our findings suggest that, in the context of the Portuguese NHS, telemedicine as a CME tool helped to build multidisciplinary teams which exchanged feedback and constructed shared knowledge to improve patients’ outcomes. It also helped to identify practice-changing contents to be included in faceto-face educational meetings. Adequate organisational and financial support are necessary for this new collaborative practice to succeed.

Objetivos: Con la meta de contribuir al desarrollo del servicio pericial, se pone a prueba la confiabilidad de la “Guía para Comprender y Valorar la Calidad de la Formulación en Salud Mental Forense – TECF”. Método: Doce profesionales de la salud mental de diversas tradiciones latinoamericanas valoraron la calidad de diez informes periciales internacionales, psicológicos y psiquiátricos, utilizando la TECF. La guía cuenta con manual que describe dimensiones, criterios e indicadores para apreciar la calidad de la formulación forense. Resultados: Los indicadores de congruencia interna tuvieron rango 0,34-0,81 para las dimensiones y valor de 0,85 para el total de la TECF. El coeficiente de correlación intraclase de acuerdo absoluto entre evaluadores con similar tradición alcanzó valores de 0,72; 0,52; 0,76 y 0,77 para las dimensiones, y de 0,84 para el total. El acuerdo entre evaluadores con tradiciones disímiles fue menor. Conclusiones: La TECF resulta un instrumento promisorio para guiar la apreciación de la calidad y estimular el perfeccionamiento de las formulaciones periciales. Desde la métrica tradicional se recomienda cautela por el efecto de tradiciones prácticas diversas., Facultad de Ciencias Médicas

La poliquistosis renal autosómica dominante (PQRAD) es la causa más frecuente de nefropatía genética y representa entre el 6 y el 10% de los pacientes en terapia de reemplazo renal (TRR). Muy pocos ensayos prospectivos, aleatorizados o estudios clínicos abordan el diagnóstico y el tratamiento de este trastorno relativamente frecuente. No hay guías clínicas disponibles hasta la fecha. Este es un documento de consenso revisada de la versión anterior del 2014, que presenta las recomendaciones del Grupo de Trabajo Español de Enfermedades Renales Hereditarias, acordadas tras la búsqueda bibliográfica y discusiones. Los niveles de evidencia en su mayoría son C y D según el Centro de Medicina Basada en Evidencia (Universidad de Oxford). Las recomendaciones se relacionan, entre otros temas, con el uso de diagnóstico por imágenes y genético, el manejo de la hipertensión, el dolor, las infecciones y el sangrado quístico, la afectación extrarrenal, incluida la enfermedad poliquística hepática y los aneurismas craneales, el manejo de la enfermedad renal crónica y el TRR, así como el seguimiento de niños con PQRAD. Se proporcionan recomendaciones sobre terapias específicas para la PQRAD, así como la recomendación para evaluar la rápida progresión. Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent cause of genetic renal disease and accounts for 6–10% of patients on kidney replacement therapy (KRT). Very few prospective, randomized trials or clinical studies address the diagnosis and management of this relatively frequent disorder. No clinical guidelines are available to date. This is a revised consensus statement from the previous 2014 version, presenting the recommendations of the Spanish Working Group on Inherited Kidney Diseases, which were agreed to following a literature search and discussions. Levels of evidence mostly are C and D according to the Centre for Evidence-Based Medicine (University of Oxford). The recommendations relate to, among other topics, the use of imaging and genetic diagnosis, management of hypertension, pain, cyst infections and bleeding, extra-renal involvement including polycystic liver disease and cranial aneurysms, management of chronic kidney disease and KRT and management of children with ADPKD. Recommendations on specific ADPKD therapies are provided as well as the recommendation to assess rapid progression. Sin financiación 0.252 SJR (2021) Q3, 1824/2489 Medicine (Miscellaneous) No data IDR 2021 3.084 JCR (2021) Q2, 40/90 Urology & Nephrology 0.252 SJR (2021) Q3, 49/72 Nephrology No data IDR 2021 UEM

Pigments are among the most fascinating molecules found in nature and used by human civilizations since the prehistoric ages. Although most of the bio-dyes reported in the literature were discovered around the eighties, the necessity to explore novel compounds for new biological applications has made them resurface as potential alternatives. Prodigiosin (PG) is an alkaloid red bio-dye produced by diverse microorganisms and composed of a linear tripyrrole chemical structure. PG emerges as a really interesting tool since it shows a wide spectrum of biological activities, such as antibacterial, antifungal, algicidal, anti-Chagas, antiamoebic, antimalarial, anticancer, antiparasitic, antiviral, and/or immunosuppressive. However, PG vehiculation into different delivery systems has been proposed since possesses low bioavailability because of its high hydrophobic character (XLogP3-AA = 4.5). In the present review, the general aspects of the PG correlated with synthesis, production process, and biological activities are reported. Besides, some of the most relevant PG delivery systems described in the literature, as well as novel unexplored applications to potentiate its biological activity in biomedical applications, are proposed., Centro de Investigación y Desarrollo en Fermentaciones Industriales, Instituto de Investigaciones Bioquímicas de La Plata

Learning is a key process allowing individuals to adapt to the environment. It is now well accepted that information stored in the form of long-term memories (LTM) involves a process of consolidation, in which labile memories are stabilized as longlasting traces. Although one can consider each learning event as the acquisition of a “new” memory, considerable evidence indicates that new memories are formed in an interleaved fashion upon a large network of pre-existing knowledge. This implies that learning is highly influenced by previous experience and that previously consolidated memories can be reactivated during new learning. Once active, a previously acquired memory can be strengthened by the following event, by cooperation, or can be lost, by competition. The rules by which memory cooperation and competition are orchestrated and what determines which trace is stored as longterm memory, are completely unknown. To tackle these questions, we have studied the rules of synaptic cooperation and competition in the lateral amygdala (LA). The LA circuitry is very well characterized from the anatomical and behavioural point of view, with the possibility of linking cellular physiology with behaviour. We found that cortical and thalamic inputs into the amygdala engage in synaptic cooperation leading to the maintenance of transient forms of long-term potentiation (LTP) induced by either weak stimulation of thalamic or cortical synapses. Interestingly, the cooperation between cortical and thalamic inputs is bi-directional but asymmetric. We found that thalamic capture of plasticity-related proteins (PRPs) occurs in a time window that is much shorter than the cortical capture of PRPs. This suggests a restriction mechanism in thalamic cooperation, which we found to be due to an activity-dependent release of endocannabinoids. Cortical and thalamic synapses also engage in competition when the availability of PRPs is limited. Interestingly, inhibition of the endocannabinoid signaling favors competition. Additionally, we found that the time of thalamic and cortical activation is a crucial parameter for synaptic cooperation and competition. Our current hypothesis is that endocannabinoid signaling controls negatively the thalamic activity limiting the time of association with the cortical activation. Thalamic time restriction can be particularly relevant in the acquisition of discriminative forms of fear-learning. To test this hypothesis, we developed a behaviour protocol designed to probe memory cooperation and competition. Animals were exposed to two auditory stimuli one unpaired (CS-) and one paired with a footshock (CS+) separated by different time intervals. In our paradigm, during training, each stimulus is presented in blocks, in two different contexts representing two different events. We found, similarly to what we described at the synaptic level, that animals’ associate events if the time interval is less than 30 minutes, showing that memory cooperation follows the same temporal rule as synaptic cooperation. Interestingly, we also found that introducing a third stimulus, during training induces a form of memory competition that destabilizes the acquisition of a fear response to both events. Memory competition is also sensitive to the time at which the third stimulus is introduced. Taken together, we found that memory cooperation and competition follow the same temporal rules as synaptic competition in the lateral amygdala. It remains to be explored whether the same rules apply to remote versus recent events and whether different sensory modalities and/or neuronal circuits show different temporal rules. RESUMO A aprendizagem é um processo chave na adaptação dos indivíduos ao ambiente. Actualmente sabe-se que a informação armazenada na forma de memórias de longo prazo (LTM) envolve um processo de consolidação, no qual as memórias “voláteis” são estabilizadas como “traços” de longa duração. Embora se possa considerar cada evento de aprendizagem como a aquisição de uma “nova” memória, várias evidências indicam que as novas memórias são formadas de forma intercalada sobre uma grande rede de conhecimento pré-existente. Isso implica que a aprendizagem seja altamente influenciada pela experiência anterior e, que memórias previamente consolidadas possam ser reativadas durante a nova aprendizagem. Uma vez ativa, uma memória previamente adquirida pode ser fortalecida pelo evento seguinte, por cooperação, ou pode ser perdida, por competição. As regras pelas quais a cooperação e a competição de memórias são orquestradas e o que determina qual é o “traço” que é armazenado como memória de longo prazo são completamente desconhecidos. De forma a resolver estas questões, estudámos as regras de cooperação e competição sináptica na amígdala lateral. O circuito da amígdala está muito bem caracterizado do ponto de vista anatómico e comportamental, oferecendo a possibilidade de vincular a fisiologia celular ao comportamento. Descobrimos que as projecções corticais e talâmicas na amígdala interagem através de mecanismos de cooperação sináptica, levando à manutenção de formas transitórias de potenciação de longo prazo (LTP) induzidas por estimulação fraca de sinapses talâmicas ou corticais. Curiosamente, a cooperação entre as projecções corticais e talâmicas é bidirecional, mas assimétrica. Por outro lado, descobrimos que a captura de proteínas relacionadas com a plasticidade (em inglês: “plasticity-related proteins – PRPs”), por parte da projecção talâmica, ocorre numa janela temporal muito menor do que a captura cortical de PRPs. Estes resultados sugerem um mecanismo de restrição na cooperação talâmica, o qual se deve a uma liberação dependente da atividade de endocanabinóides. Por outro lado, as sinapses corticais e talâmicas também interagem através de mecanismos de competição quando a disponibilidade de PRPs é limitada. Neste caso, a inibição da sinalização dos endocanabinóides favorece a competição. Para além disso, descobrimos que o tempo de ativação talâmica e cortical é um parâmetro crucial para a cooperação e competição sinápticas. A nossa hipótese atual é que a sinalização através dos endocanabinóides controla negativamente a atividade talâmica, limitando o tempo de associação. A restrição de tempo talâmica pode ser particularmente relevante na aquisição de formas discriminativas de aprendizagem pelo medo. Para testar essa hipótese, desenvolvemos um protocolo de comportamento projetado para estudar a cooperação e a competição entre memórias. Os animais foram expostos a dois estímulos auditivos, um não emparelhado (CS-) e outro emparelhado com um choque (CS+), separados por diferentes intervalos de tempo. No nosso modelo, durante o treino, cada estímulo é apresentado em blocos em dois contextos diferentes, representando dois eventos diferentes. À semelhança do que descrevemos ao nível sináptico, descobrimos que os animais associam eventos se o intervalo de tempo for inferior a 30 minutos, mostrando que a cooperação de memórias segue a mesma regra temporal que a cooperação sináptica. Curiosamente, também descobrimos que a introdução de um terceiro estímulo, durante o treino, induz uma forma de competição de memória que desestabiliza a aquisição de uma resposta ao medo a ambos os eventos. Mais ainda, a competição de memória também é sensível ao momento em que o terceiro estímulo é introduzido. Em suma, mostrámos que a cooperação e a competição de memória seguem as mesmas regras temporais que a competição sináptica na amígdala lateral. No futuro, será interessante explorar se as mesmas regras se aplicam a eventos remotos versus eventos recentes e se diferentes modalidades sensoriais e/ou circuitos neuronais apresentam diferentes regras temporais.