COMPRIME - COnhecer Mais PaRa Intervir MElhor: Preliminary Mapping of Municipal Level Determinants of COVID-19 Transmission in Portugal at Different Moments of the 1st Epidemic Wave

The role of demographic and socio-economic determinants of COVID-19 transmission is still unclear and is expected to vary in different contexts and epidemic periods. Exploring such determinants may generate a hypothesis about transmission and aid the definition of prevention strategies. Objectives: To identify municipality-level demographic and socio-economic determinants of COVID-19 in Portugal. Methods: We assessed determinants of COVID-19 daily cases at 4 moments of the first COVID-19 epidemic wave in Portugal, related with lockdown and post-lockdown measures. We selected 60 potential determinants from 5 dimensions: population and settlement, disease, economy, social context, and mobility. We conducted a multiple linear regression (MLR) stepwise analysis (p < 0.05) and an artificial neural network (ANN) analysis with the variables to identify predictors of the number of daily cases. Results: For MLR, some of the identified variables were: resident population and population density, exports, overnight stays in touristic facilities, the location quotient of employment in accommodation, catering and similar activities, education, restaurants and lodging, some industries and building construction, the share of the population working outside the municipality, the net migration rate, income, and renting. In ANN, some of the identified variables were: population density and resident population, urbanization, students in higher education, income, exports, social housing buildings, production services employment, and the share of the population working outside the municipality of residence. Conclusions: Several factors were identified as possible determinants of COVID- 19 transmission at the municipality level. Despite limitations to the study, we believe that this information should be considered to promote communication and prevention approaches. Further research should be conducted.info:eu-repo/semantics/publishedVersio

Desenvolvimento de novos catalisadores de metais de transição : catálise de reacções de carbonilação conducentes à obtenção de produtos de valor acrescentado

Tese de Doutoramento em Química, apresentada à Faculdade de Ciências e Tecnologia da Universidade de Coimbra.A reacção de hidroformilação de olefinas catalisada por complexos de ródio permite obter, num só passo, aldeídos que podem ser convertidos, posteriormente ou in situ, numa grande diversidade de outros produtos de valor acrescentado com especial interesse no domínio da química fina. Um dos objectivos fulcrais do trabalho apresentado nesta dissertação centrava-se no desenvolvimento de catalisadores activos e selectivos para promover a carbonilação de produtos naturais, nomeadamente esteróides, terpenos e quinolinas, tendo em vista a preparação de novos compostos com potencial interesse para a indústria farmacêutica e de perfumaria. Os estudos foram iniciados com optimização de sistemas catalíticos para promover a reacção de hidroformilação de diterpenos (extraídos directamente de plantas) utilizando catalisadores de ródio (Rh/CO, Rh/PPh3 e Rh/P(O-o-tBuC6H4)3). Os sistemas catalíticos seleccionados revelaram ser activos e selectivos para a formação de um par de aldeídos diastereoisoméricos. A diastereosselectividade, apesar de tendencialmente controlada pelo substrato é também dependente do sistema catalítico utilizado. O sistema Rh/CO foi o que conduziu sempre a uma maior diastereosselectividade (~80/20). Os estudos cinéticos realizados, no decorrer das duas primeiras horas de reacção, permitiram estabelecer que o processo de -eliminação do intermediário metal--alquilo conduz a uma maior a diastereosselectividade e que portanto o catalisador com maior tendência para promover a -eliminação é também o mais diastereosselectivo. O catalisador Rh/P(O-o-tBuC6H4)3, foi seleccionado para promover a reacção de hidroformilação do monorterpeno acetato de (1R)-(-)-mirtenilo e de 3-acetoxi-esteróides, uma vez que é conhecida a sua capacidade para promover a hidroformilação de duplas ligações internas e estereoquimicamente mais impedidas. Este sistema catalítico mostrou ser eficaz na transformação das duplas ligações do acetato de (1R)-(-)-mirtenol, obtendo-se uma mistura de aldeídos com um rendimento de 65% e uma relação diastereoisomérica de 71/28. A reacção de hidrofomilação do 3-acetoxicolest-4-eno com o mesmo sistema catalítico, permitiu obter conversões e quimiosselectividades >98 % e uma relação diastereoisomérica de 60/40. A caracterização dos aldeídos formados, recorrendo a técnicas de RMN bidimensional completada com estudos de deuterioformilação dos dois substratos permitiu propor o mecanismo da reacções que justifica a formação dos produtos obtidos. Para além da aplicação da reacção de hidroformilação aos produtos naturais referidos anteriormente, era também nosso objectivo promover a funcionalização de quinolinas recorrendo à reacção de carbonilação, tendo em conta as potencialidades destes compostos. A aminocarbonilação da 5,7-diiodo-8-benziloxiquinolina conduziu à formação de carboxamidas e ceto-carboxamidas cuja selectividade depende da pressão de CO usada. Por outro lado, quando se aplicou as condições de aminocarbonilação à 5,7-diiodo-8-hidroxiquinolina verificou-se que a presença do grupo hidroxilo da posição 8 é responsável pela hidrodesiodação do substrato. Tendo em conta a diversidade de produtos que é possível sintetizar a partir da função aldeído, um outro objectivo deste trabalho consistia em combinar a reacção de hidroformilação com outras reacções, no mesmo vaso de reacção, no sentido de sintetizar novos produtos de valor acrescentado, evitando os isolamentos dos intermediários formados e tornando os processos ambientalmente mais sustentáveis. Neste sentido, efectuou-se uma reacção sequencial “tandem” de hidroaminometilação para sintetizar directamente aminas terciárias a partir do caurenato de metilo, tendo-se obtido conversões de 79 % e uma relação diastereoisomérica de 61/39 resultante do processo de hidroformilação. Além disso, recorreu-se à reacção sequencial tipo “dominó” para promover “in situ” a síntese de -aminonitrilos derivados do éter de trimetilsililcaurenol e do colest-4-eno e a mistura dos aminonitrilos foi obtida com rendimentos de 65% e 95 %, respectivamente. A reacção sequencial “dominó” foi ainda aplicada à síntese de -aminoácidos lipídicos partindo de olefinas alquílicas de cadeias variáveis. Em primeiro lugar foi efectuado um estudo sistemático do efeito da estrutura do ligando na regiosselectividade do processo para aldeído terminal, tendo-se obtido os melhores resultados com o catalisador Rh/Xantphos, conversões de 98% e regiosselectividades para os aldeídos lineares (>95 %) elevadas. Por fim, os -aminoácidos de cadeias carbonadas variáveis (n= 8-16) foram obtidos por hidrólise ácida dos correspondentes -aminonitrilos com bons rendimentos (63-92 %). Os foram isolados e caracterizados por RMN 1H e 13C e por EM. Tendo em conta a crescente aplicação da reacção de hidroformilação na preparação de aldeídos enantiomericamente puros, com especial interesse para o desenvolvimento da química fina, continua a ser relevante a procura de novos ligandos, que combinados com as condições de reacção ideais formem sistemas catalíticos mais activos e selectivos. Com base neste importante propósito, um outro objectivo deste trabalho, centrava-se no desenvolvimento de uma estratégia para se sintetizar novos ligandos ditópicos do tipo piridina-bis-BINOL-fosfito. O efeito da estrutura do ligando nos complexos de ródio foi avaliado na reacção de hidroformilação do estireno. Foi ainda estudado o efeito da adição de sais de lítio ao catalisador observando-se um aumento de 25% da regiosselectividade em alguns casos. Com base nos resultados experimentais obtidos para a reacção de hidroformilação do estireno foi desenvolvido, com um dos sistemas Rh/piridina-bis-BINOL-fosfito, um planeamento factorial 23 no sentido de racionalizar os efeitos dos factores pressão, temperatura e relação Li/Rh na regiosselectividade global do processo e prever as condições óptimas de reacção para obter uma resposta de 100% (regiosselectividade para aldeído ramificado). Foram também efectuados estudos de RMN em solução dos complexos e cálculos teóricos de estrutura dos complexos no sentido de interpretar os resultados catalíticos da reacção de hidroformilação obtidos com estes sistemas catalíticos.Olefin hydroformylation is a one-step reaction catalysed by transition metals which permits to obtain aldehydes that can be further converted, subsequently and “in situ”, into a diversity of other added value products, with special interest in Fine Chemistry domain. The key objective of the work presented in this dissertation is centred on the development of active and selective catalysts, in order to promote hydroformylation of natural products, namely, steroids, terpenes and quinolines in sighting the preparation of new potentially interesting compounds for pharmaceutical and cosmetic industry. For that reason, selection studies on rhodium catalysts (Rh/CO, Rh/PPh3 and Rh/P(O-o-tBuC6H4)3.) were firstly carried out, as well as activity and selectivity optimization of the catalytic systems, on hydroformylation reactions of plant extracted diterpenes. The three systems allowed converting the substrates into two diastereoisomeric aldehydes, with very dependent selectivity upon the used system. Independently of the substrate, the greatest diastereoselectivities (80/20) were obtained with Rh/CO system. From the performed kinetic studies, in the course of the two first reaction hours, was possible to conclude that diastereoselectivity is not only controlled by the substrate structure, but also the -elimination process that may occurs from the metal--alkyl intermediate. The Rh/P(O-o-tBuC6H4)3 catalyst was the selected one to promote the hydroformylation reaction of substrates with endocyclic double bonds and sterically crowded, belonging to a monoterpene 3-acetoxy type steroids. This catalytic system showed high activity and chemoselectivity for aldehyde formation starting from (1R)-(−)-myrtenyl acetate and 3-acetoxycolest-4-ene with diastereoisomeric ratio of 71/28 and 60/40, respectively. The deuterohydroformylation studies of these two substrates, complemented with full characterisation of the aldehyde mixture obtained in each case, supported by 2D NMR techniques, allowed the characterization of the products and a reaction mechanism proposed to justify the obtained products. Taking into account the high interest in developing alternative methods for alkoxyquinoline derivatives synthesis, due to its increasing demand (potential biological activity as PDE4 inhibitors and as LED electroluminescent materials), the aminocarbonilation reaction in the presence of a Pd catalyst was applied, as synthetic method for the preparation of carboxamide and keto-carboxamide from 5,7-iodo-8-benzyloxyquinoline. The unprotected 5,7-diiodo-8-hydroxyquinoline underwent dehydroiodination resulting in 8-hydroxyquinoline as the major product. Taking into account the product assortment that is possible to synthesise from the aldehyde organic function, another objective of this dissertation is the report of the combination of hydroformylation reaction with other type reactions in an in situ fashion, with the synthetic purpose of obtaining other added value products, avoiding complicated intermediary product isolations, turning the processes into more environmentally friendly ones. Therefore, “tandem” type sequential hydroaminomethylation reactions were performed, to allow the direct synthesis of tertiary amines based on methyl kaurenate with conversions of 79 % to the diastereisomeric aldehydes (61/39), resulting from the hydroformylation process. Besides that, “domino” type sequential reactions were also carried out, in order to promote the synthesis of -aminonitriles derived from trimethylsilylkaurenol ether and colest-4-ene, with 65 and 95 % yield, respectively. The “domino” sequential reaction was still applies to the synthesis of -aminoacids, starting from several sized alkyl chain olefins. Firstly, a systematic study on the phosphine structure on the terminal aldehyde regiosselectivity was carried out, where the best results were obtained with the catalytic system Rh/Xantphos, obtaining conversions of 98% and regioselectivity for the linear aldehyde >95 %. The resulting -aminonitriles from the “domino” sequential hydroformylation-Strecker reactions were isolated and characterised by 1H and 13C NMR and mass spectrometry techniques. The ending -aminoacids were finally obtained by acidic hydrolysis of the previous -aminonitriles in 63-92 % yields. With the growing interest in the application of the hydroformylation reaction in the preparation of enantiomerically pure aldehydes, with special importance for Fine Chemistry, we consider pertinent the continuous search for new ligands, that when combined with ideal reaction conditions, can form more active and selective catalytic systems. Sighting this purpose, we also developed a strategy to synthesise new ditopic ligands like piridina-bis-BINOL-phosphite. The ligand structural effect on the Rh/bis-BINOL-phosphite complexes was evaluated in styrene hydroformylation reaction. Lithium salt addition to the catalytic system was also tested, and a 25% increase on regiosselectivity was attained in some cases. Based on these experimental results a 23 factorial design was developed, in a way of rationalizing the effect of factors like pressure, temperature and Li/Rh ratio on the global process regiosselectivity in order to predict the optimal reaction conditions, with a lower number of experiments, to obtain an 100% response (regiosselectivity for the branched aldehyde). For the interpretation of the catalytic results obtained in the hydroformylation reaction with the Rh/bis-BINOL-phosphite complexes, both NMR studies, in solution, and structural theoretical calculations were performed

An In Vitro Evaluation of the Potential Neuroprotective Effects of Intranasal Lipid Nanoparticles Containing Astaxanthin Obtained from Different Sources: Comparative Studies

The intranasal route has been suggested as a promising alternative to improve the direct transport of molecules to the brain, avoiding the need to cross the blood–brain barrier (BBB). In this area, the use of lipid nanoparticles, namely solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC), has been highlighted as a promising strategy to improve the treatment of neurodegenerative diseases. In this work, formulations containing SLN and NLC that were loaded with astaxanthin that was obtained from different sources (astaxanthin extract (AE) from the algae Haematococcus pluvialis and pure astaxanthin (PA) from the fungi Blakeslea trispora) were prepared for nose-to-brain administration, and comparative in vitro experiments were performed to evaluate the biocompatibility of the formulations with nasal (RPMI 2650) and neuronal (SH-SY5Y) cells. Afterwards, the antioxidant activity of the formulations was evaluated for its potential neuroprotective effects, using different chemical aggressors. Finally, the cellular uptake of the astaxanthin was evaluated for the formulations that showed the greatest neuroprotection of the neuronal cells against chemical-induced damage. On the production day, all the formulations showed a particle size, a high encapsulation efficiency (EE), the presence of nanoparticles with a typical spherical shape, and a polydispersity index (PDI) and zeta potential (ZP) that are suitable for nose-to-brain administration. After three months of storage at room temperature, no significant changes were observed in the characterization parameters, predicting a good long-term stability. Furthermore, these formulations were shown to be safe with concentrations of up to 100 µg/mL in differentiated SH-SY5Y and RPMI 2650 cells. Regarding neuroprotection studies, the PA-loaded SLN and NLC formulations showed an ability to counteract some mechanisms of neurodegeneration, including oxidative stress. Moreover, when compared with the PA-loaded SLN, the PA-loaded NLC showed greater neuroprotective effects against the cytotoxicity induced by aggressors. In contrast, the AE-loaded SLN and NLC formulations showed no significant neuroprotective effects. Although further studies are needed to confirm these neuroprotective effects, the results of this study suggest that the intranasal administration of PA-loaded NLC may be a promising alternative to improve the treatment of neurodegenerative diseases

High zirconium loads in Zr-SBA-15 mesoporous materials prepared by direct-synthesis and pH-adjusting approaches

SBA-15 is a material with interesting characteristics associated with the size, order, uniformity, and pores distribution. However, the absence of acidity in SBA-15 restricts its applications as a potential acid catalyst in the industry for the large-scale production of fuels and chemicals. Mesoporous SBA-15 modified by the incorporation of heteroatomic species can be a good strategy to include acidity and prepare an efficient catalyst. In this work, we present a comparative study in the preparation of SBA-15 and Zr-SBA-15 mesoporous materials with high zirconium loads (Si/Zr ¿= ¿10, 5, and 2) using direct-synthesis and pH-adjusting approaches with a low crystallization temperature of 60 ¿°C. The materials were characterized using XRPD, HRTEM, ICP, SEM-EDS, XPS, DRS UV-VIS, FT-IR, NH3-TPD, in situ FT-IR with pyridine probe, and N2-physisorption. Characterization by ICP and SEM-EDS indicated that the Si/Zr molar ratio of Zr-materials prepared by the pH adjustment better matched the nominal values. N2-physisorption showed that the mesoporosity of the materials was preserved even at the high Zr load. XRPD and HRTEM pointed out that Zr-SBA-15 materials prepared by the pH adjustment showed a higher level of ordering in the porous network. Regardless of the synthesis approach, the presence of a higher Zr load caused a loss in the structural ordering. It must be highlighted that the high-resolution XPS spectra of Zr 3d suggested the formation of Si–O–Zr bonds giving some indication of Zr incorporation into the SBA-15 framework. The formation of Si–O–Zr linkage in the Zr-materials was also corroborated by DRS UV-VIS due to the presence of a blue shift in the absorption edge for both series of the Zr-SBA-15 materials. NH3-TPD and in-situ FT-IR spectroscopy with pyridine probe showed that the presence of Zr species introduces acidity in the SBA-15 and at higher Zr load the Brønsted acidity increased particularly for the Zr-materials prepared by pH adjustment. In conclusion, this study evidences that the pH-adjusting approach improves structural, textural, morphological, and acidic properties in SBA-15 and Zr-SBA-15 materials compared to the direct-synthesis approach.Peer ReviewedPostprint (author's final draft

Revealing the effects of high Al loading incorporation in the SBA-15 silica mesoporous material

High aluminum loading incorporation in the SBA-15 silica structure was investigated. Different Si/Al molar ratios (15, 10, and 2) were evaluated. The SBA-15 and the aluminum-containing materials (Al-SBA-15) were prepared by the “pH adjusting” method with modifications. The mesoporous structure of the materials was demonstrated by the type IV isotherms. The SBA-15 pore changed from a cylindrical to a slit-like structure in the presence of higher aluminum content. X-ray diffraction (XRD) and high-resolution transmission electron microscopy (HRTEM) pointed out that the structural order is compromised in the presence of a higher aluminum load in the Al-SBA-15 materials, although the mesoporous structure was preserved. Higher Al loading increases the total quantity of Lewis acid sites as well as generates Brönsted acid sites. CO adsorption FTIR spectroscopy suggests aluminum incorporation into the SBA-15 and generation of acid sites. The Si–O–Al linkage in the aluminum-containing materials was corroborated by UV–Vis DRS due to the presence of a peak centered at 241 nm related to the Al-O bond, which is ascribed to four-coordinated framework aluminum in the SBA-15 structure. XPS spectra of Al 2p suggested that the Al species are less oxidized than the Al2O3 phase giving some indication of Al incorporation into the SBA-15 framework. 27Al MAS NMR results revealed that the aluminum species are in a tetrahedral oxygen coordination environment for Al-SBA-15 with Si/Al molar ratios of 15 and 10. Aluminum species in both tetrahedral and octahedral environments were evidenced for Al-SBA-15 with a Si/Al molar ratio of 2.Peer ReviewedPostprint (author's final draft

Characterisation of microbial attack on archaeological bone

As part of an EU funded project to investigate the factors influencing bone preservation in the archaeological record, more than 250 bones from 41 archaeological sites in five countries spanning four climatic regions were studied for diagenetic alteration. Sites were selected to cover a range of environmental conditions and archaeological contexts. Microscopic and physical (mercury intrusion porosimetry) analyses of these bones revealed that the majority (68%) had suffered microbial attack. Furthermore, significant differences were found between animal and human bone in both the state of preservation and the type of microbial attack present. These differences in preservation might result from differences in early taphonomy of the bones. © 2003 Elsevier Science Ltd. All rights reserved

Management of coronary disease in patients with advanced kidney disease

BACKGROUND Clinical trials that have assessed the effect of revascularization in patients with stable coronary disease have routinely excluded those with advanced chronic kidney disease. METHODS We randomly assigned 777 patients with advanced kidney disease and moderate or severe ischemia on stress testing to be treated with an initial invasive strategy consisting of coronary angiography and revascularization (if appropriate) added to medical therapy or an initial conservative strategy consisting of medical therapy alone and angiography reserved for those in whom medical therapy had failed. The primary outcome was a composite of death or nonfatal myocardial infarction. A key secondary outcome was a composite of death, nonfatal myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. RESULTS At a median follow-up of 2.2 years, a primary outcome event had occurred in 123 patients in the invasive-strategy group and in 129 patients in the conservative-strategy group (estimated 3-year event rate, 36.4% vs. 36.7%; adjusted hazard ratio, 1.01; 95% confidence interval [CI], 0.79 to 1.29; P=0.95). Results for the key secondary outcome were similar (38.5% vs. 39.7%; hazard ratio, 1.01; 95% CI, 0.79 to 1.29). The invasive strategy was associated with a higher incidence of stroke than the conservative strategy (hazard ratio, 3.76; 95% CI, 1.52 to 9.32; P=0.004) and with a higher incidence of death or initiation of dialysis (hazard ratio, 1.48; 95% CI, 1.04 to 2.11; P=0.03). CONCLUSIONS Among patients with stable coronary disease, advanced chronic kidney disease, and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of death or nonfatal myocardial infarction

Health status after invasive or conservative care in coronary and advanced kidney disease

BACKGROUND In the ISCHEMIA-CKD trial, the primary analysis showed no significant difference in the risk of death or myocardial infarction with initial angiography and revascularization plus guideline-based medical therapy (invasive strategy) as compared with guideline-based medical therapy alone (conservative strategy) in participants with stable ischemic heart disease, moderate or severe ischemia, and advanced chronic kidney disease (an estimated glomerular filtration rate of &lt;30 ml per minute per 1.73 m2 or receipt of dialysis). A secondary objective of the trial was to assess angina-related health status. METHODS We assessed health status with the Seattle Angina Questionnaire (SAQ) before randomization and at 1.5, 3, and 6 months and every 6 months thereafter. The primary outcome of this analysis was the SAQ Summary score (ranging from 0 to 100, with higher scores indicating less frequent angina and better function and quality of life). Mixed-effects cumulative probability models within a Bayesian framework were used to estimate the treatment effect with the invasive strategy. RESULTS Health status was assessed in 705 of 777 participants. Nearly half the participants (49%) had had no angina during the month before randomization. At 3 months, the estimated mean difference between the invasive-strategy group and the conservative-strategy group in the SAQ Summary score was 2.1 points (95% credible interval, 120.4 to 4.6), a result that favored the invasive strategy. The mean difference in score at 3 months was largest among participants with daily or weekly angina at baseline (10.1 points; 95% credible interval, 0.0 to 19.9), smaller among those with monthly angina at baseline (2.2 points; 95% credible interval, 122.0 to 6.2), and nearly absent among those without angina at baseline (0.6 points; 95% credible interval, 121.9 to 3.3). By 6 months, the between-group difference in the overall trial population was attenuated (0.5 points; 95% credible interval, 122.2 to 3.4). CONCLUSIONS Participants with stable ischemic heart disease, moderate or severe ischemia, and advanced chronic kidney disease did not have substantial or sustained benefits with regard to angina-related health status with an initially invasive strategy as compared with a conservative strategy