Therapeutic Advancements: the role of SGLT1 inhibitors in the current management of type 2 Diabetes

Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2021, Universidade de Lisboa, Faculdade de Farmácia.Os co-transportadores de Na+-glucose, SGLT1 e SGLT2, transportam a glucose através das membranas epiteliais. A maior parte da captação intestinal da glucose proveniente da dieta é mediada pelos SGLT1, e como tal, os indivíduos com mutações neste gene apresentam má absorção de glucose/galactose. Ambos os transportadores, SGLT1 e SGLT2, estão presentes no rim, e estudos recentes indicam que os SGLT2 medeiam até 97% da reabsorção da glucose, pelo que humanos com mutações no gene SGLT2 têm glicosúria renal familiar. Surpreendentemente, o knock-out dos SGLT2 ou a terapia com inibidores seletivos dos SGLT2 resulta numa excreção fracionada de glucose de apenas 60%, um efeito mediado pela sobre regulação renal de SGLT1. Como a inibição dos SGLT1 reduz os níveis de glucose no sangue através da inibição da absorção de glucose no intestino e a sua reabsorção renal, foi proposto que a inibição dupla SGLT1/2 poderia melhorar ainda mais o controle glicémico, tendo como alvo os órgãos que expressam SGLT1: o intestino e o rim. Além disso, os fármacos que inibem o transporte de glucose mediado por SGLT1 podem proteger o tecido cardíaco, reduzindo a acumulação de glicogénio e a formação de espécies reativas de oxigénio. Porém, modelos genéticos mostram que a inibição dos SGLT1 pode ter um impacto negativo em vários órgãos. Esta abordagem pode causar diarreia, depleção de volume, interferir na correção da hipoglicemia pela administração oral de carbohidratos e predispor o desenvolvimento de cetoacidose diabética euglicémica. Como resultado, a inibição SGLT1 parece ser uma faca de dois gumes. Vários inibidores seletivos SGLT2, assim como os inibidores seletivos SGLT1 e duplos SGLT1/2, foram desenvolvidos com base na estrutura da florizina, uma molécula natural que atua como um inibidor duplo do SGLT1/2. Esta revisão irá abordar as manifestações clínicas e o diagnóstico de diabetes, a gestão farmacológica da glucose na diabetes tipo 2, com foco no racional para o desenvolvimento de inibidores seletivos SGLT1 e inibidores duplos SGLT1/2, enquanto avalia os potenciais benefícios em comparação com a inibição seletiva SGLT2, pesando a evidências sobre os efeitos benéficos versus prejudiciais que a inibição SGLT1 pode ter.Na+-glucose co-transporters, SGLT1 and SGLT2, transport glucose across epithelial membranes. The bulk of dietary glucose uptake in the intestine is mediated by SGLT1, and for that, individuals with SGLT1 gene mutations have glucose/galactose malabsorption. Both transporters, SGLT1 and SGLT2, are present in the kidney, and new research indicates that SGLT2 mediates up to 97% of glucose reabsorption, for that, humans with mutations in the SGLT2 gene have familial renal glucosuria. Surprisingly, SGLT2 knock-out or therapy with SGLT2 selective inhibitors only results in a fractional glucose excretion of 60%, an effect mediated by renal SGLT1 up-regulation. Since inhibiting SGLT1 reduces blood glucose levels via inhibiting glucose absorption in the intestine and renal reabsorption, it was proposed that dual SGLT1/2 inhibition might enhance glycaemic control even further by targeting these separate organs that express SGLT1: the intestine and the kidney. Furthermore, medications that inhibit SGLT1-mediated glucose transport may protect cardiac tissue by lowering glycogen accumulation and the generation of reactive oxygen species. Yet, genetic models of SGLT1 inactivation show that the failure of these transporters might have a negative impact on a variety of organs. This method may cause diarrhoea, volume depletion, interfere with the correction of hypoglycaemia by oral carbohydrate delivery, and predispose to the development of euglycemic diabetic ketoacidosis. As a result, SGLT1 inhibition appears to be a two-edged sword. Several SGLT2 inhibitors, as well as SGLT1 and dual SGLT1/2 inhibitors, have been developed based on the structure of phlorizin, a natural molecule that acts as a dual SGLT1/2 inhibitor. This review will address the clinical manifestations and diagnosis of diabetes, the pharmacological management of glucose in type 2 diabetes, focusing on the rationale for the development of SGLT1 and dual SGLT1/2 inhibitors, while evaluating potential benefits compared to sole SGLT2 inhibition and weighting evidence on the beneficial versus detrimental effects that SGLT1inhibition might have

Interdisciplinaridade no Ensino Superior: uma experiência na licenciatura em Educação Básica

[PT] Nesta comunicação, apresentamos resultados de uma experiência implementada no 2.º ano da Licenciatura em Educação Básica (LEB) de uma instituição de Ensino Superior do Nordeste de Portugal, que teve como objetivos: (i) promover a articulação e a interdisciplinaridade entre duas unidades curriculares (UCs) desta licenciatura e, consecutivamente, o desenvolvimento de competências transversais a ambas, através de um trabalho conjunto dos estudantes e dos docentes envolvidos; (ii) perceber de que forma os alunos envolvidos avaliam este tipo de articulação entre diferentes unidades curriculares. Tendo por base a obra literária de potencial receção infantojuvenil de Richard Zimmler intitulada:“Maria e Danilo e o mágico perdido”, os alunos envolvidos, num primeiro momento leram, interpretaram e transformaram em texto dramático o texto narrativo original. Posteriormente, encenaram-no e apresentaram-no à comunidade. No final os alunos da LEB avaliaram a sua perceção desta experiência de articulação entre as UCs. Apresentamos os resultados preliminares, obtidos a partir dos dados analisados, resultantes das ações reflexivas, exploratórias, formativas e expressivas trabalhadas com os alunos diretamente envolvidos.Do Espírito Santo Guerreiro, CA.; Fortunato Vaz, PM.; Marques Gomes, JL.; Pereira Da Costa, MA. (2020). Interdisciplinaridade no Ensino Superior: uma experiência na licenciatura em Educação Básica. Editorial Universitat Politècnica de València. 999-1005. https://doi.org/10.4995/INN2019.2019.10100OCS999100

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

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

NEOTROPICAL ALIEN MAMMALS: a data set of occurrence and abundance of alien mammals in the Neotropics

Biological invasion is one of the main threats to native biodiversity. For a species to become invasive, it must be voluntarily or involuntarily introduced by humans into a nonnative habitat. Mammals were among first taxa to be introduced worldwide for game, meat, and labor, yet the number of species introduced in the Neotropics remains unknown. In this data set, we make available occurrence and abundance data on mammal species that (1) transposed a geographical barrier and (2) were voluntarily or involuntarily introduced by humans into the Neotropics. Our data set is composed of 73,738 historical and current georeferenced records on alien mammal species of which around 96% correspond to occurrence data on 77 species belonging to eight orders and 26 families. Data cover 26 continental countries in the Neotropics, ranging from Mexico and its frontier regions (southern Florida and coastal-central Florida in the southeast United States) to Argentina, Paraguay, Chile, and Uruguay, and the 13 countries of Caribbean islands. Our data set also includes neotropical species (e.g., Callithrix sp., Myocastor coypus, Nasua nasua) considered alien in particular areas of Neotropics. The most numerous species in terms of records are from Bos sp. (n = 37,782), Sus scrofa (n = 6,730), and Canis familiaris (n = 10,084); 17 species were represented by only one record (e.g., Syncerus caffer, Cervus timorensis, Cervus unicolor, Canis latrans). Primates have the highest number of species in the data set (n = 20 species), partly because of uncertainties regarding taxonomic identification of the genera Callithrix, which includes the species Callithrix aurita, Callithrix flaviceps, Callithrix geoffroyi, Callithrix jacchus, Callithrix kuhlii, Callithrix penicillata, and their hybrids. This unique data set will be a valuable source of information on invasion risk assessments, biodiversity redistribution and conservation-related research. There are no copyright restrictions. Please cite this data paper when using the data in publications. We also request that researchers and teachers inform us on how they are using the data

Respiratory support in patients with severe COVID-19 in the International Severe Acute Respiratory and Emerging Infection (ISARIC) COVID-19 study: a prospective, multinational, observational study

Background: Up to 30% of hospitalised patients with COVID-19 require advanced respiratory support, including high-flow nasal cannulas (HFNC), non-invasive mechanical ventilation (NIV), or invasive mechanical ventilation (IMV). We aimed to describe the clinical characteristics, outcomes and risk factors for failing non-invasive respiratory support in patients treated with severe COVID-19 during the first two years of the pandemic in high-income countries (HICs) and low middle-income countries (LMICs). Methods: This is a multinational, multicentre, prospective cohort study embedded in the ISARIC-WHO COVID-19 Clinical Characterisation Protocol. Patients with laboratory-confirmed SARS-CoV-2 infection who required hospital admission were recruited prospectively. Patients treated with HFNC, NIV, or IMV within the first 24 h of hospital admission were included in this study. Descriptive statistics, random forest, and logistic regression analyses were used to describe clinical characteristics and compare clinical outcomes among patients treated with the different types of advanced respiratory support. Results: A total of 66,565 patients were included in this study. Overall, 82.6% of patients were treated in HIC, and 40.6% were admitted to the hospital during the first pandemic wave. During the first 24 h after hospital admission, patients in HICs were more frequently treated with HFNC (48.0%), followed by NIV (38.6%) and IMV (13.4%). In contrast, patients admitted in lower- and middle-income countries (LMICs) were less frequently treated with HFNC (16.1%) and the majority received IMV (59.1%). The failure rate of non-invasive respiratory support (i.e. HFNC or NIV) was 15.5%, of which 71.2% were from HIC and 28.8% from LMIC. The variables most strongly associated with non-invasive ventilation failure, defined as progression to IMV, were high leukocyte counts at hospital admission (OR [95%CI]; 5.86 [4.83-7.10]), treatment in an LMIC (OR [95%CI]; 2.04 [1.97-2.11]), and tachypnoea at hospital admission (OR [95%CI]; 1.16 [1.14-1.18]). Patients who failed HFNC/NIV had a higher 28-day fatality ratio (OR [95%CI]; 1.27 [1.25-1.30]). Conclusions: In the present international cohort, the most frequently used advanced respiratory support was the HFNC. However, IMV was used more often in LMIC. Higher leucocyte count, tachypnoea, and treatment in LMIC were risk factors for HFNC/NIV failure. HFNC/NIV failure was related to worse clinical outcomes, such as 28-day mortality. Trial registration This is a prospective observational study; therefore, no health care interventions were applied to participants, and trial registration is not applicable

Respiratory support in patients with severe COVID-19 in the International Severe Acute Respiratory and Emerging Infection (ISARIC) COVID-19 study: a prospective, multinational, observational study

Background: Up to 30% of hospitalised patients with COVID-19 require advanced respiratory support, including high-flow nasal cannulas (HFNC), non-invasive mechanical ventilation (NIV), or invasive mechanical ventilation (IMV). We aimed to describe the clinical characteristics, outcomes and risk factors for failing non-invasive respiratory support in patients treated with severe COVID-19 during the first two years of the pandemic in high-income countries (HICs) and low middle-income countries (LMICs). Methods: This is a multinational, multicentre, prospective cohort study embedded in the ISARIC-WHO COVID-19 Clinical Characterisation Protocol. Patients with laboratory-confirmed SARS-CoV-2 infection who required hospital admission were recruited prospectively. Patients treated with HFNC, NIV, or IMV within the first 24 h of hospital admission were included in this study. Descriptive statistics, random forest, and logistic regression analyses were used to describe clinical characteristics and compare clinical outcomes among patients treated with the different types of advanced respiratory support. Results: A total of 66,565 patients were included in this study. Overall, 82.6% of patients were treated in HIC, and 40.6% were admitted to the hospital during the first pandemic wave. During the first 24 h after hospital admission, patients in HICs were more frequently treated with HFNC (48.0%), followed by NIV (38.6%) and IMV (13.4%). In contrast, patients admitted in lower- and middle-income countries (LMICs) were less frequently treated with HFNC (16.1%) and the majority received IMV (59.1%). The failure rate of non-invasive respiratory support (i.e. HFNC or NIV) was 15.5%, of which 71.2% were from HIC and 28.8% from LMIC. The variables most strongly associated with non-invasive ventilation failure, defined as progression to IMV, were high leukocyte counts at hospital admission (OR [95%CI]; 5.86 [4.83–7.10]), treatment in an LMIC (OR [95%CI]; 2.04 [1.97–2.11]), and tachypnoea at hospital admission (OR [95%CI]; 1.16 [1.14–1.18]). Patients who failed HFNC/NIV had a higher 28-day fatality ratio (OR [95%CI]; 1.27 [1.25–1.30]). Conclusions: In the present international cohort, the most frequently used advanced respiratory support was the HFNC. However, IMV was used more often in LMIC. Higher leucocyte count, tachypnoea, and treatment in LMIC were risk factors for HFNC/NIV failure. HFNC/NIV failure was related to worse clinical outcomes, such as 28-day mortality. Trial registration This is a prospective observational study; therefore, no health care interventions were applied to participants, and trial registration is not applicable

Thrombotic and hemorrhagic complications of COVID-19 in adults hospitalized in high-income countries compared with those in adults hospitalized in low- and middle-income countries in an international registry

Background: COVID-19 has been associated with a broad range of thromboembolic, ischemic, and hemorrhagic complications (coagulopathy complications). Most studies have focused on patients with severe disease from high-income countries (HICs). Objectives: The main aims were to compare the frequency of coagulopathy complications in developing countries (low- and middle-income countries [LMICs]) with those in HICs, delineate the frequency across a range of treatment levels, and determine associations with in-hospital mortality. Methods: Adult patients enrolled in an observational, multinational registry, the International Severe Acute Respiratory and Emerging Infections COVID-19 study, between January 1, 2020, and September 15, 2021, met inclusion criteria, including admission to a hospital for laboratory-confirmed, acute COVID-19 and data on complications and survival. The advanced-treatment cohort received care, such as admission to the intensive care unit, mechanical ventilation, or inotropes or vasopressors; the basic-treatment cohort did not receive any of these interventions. Results: The study population included 495,682 patients from 52 countries, with 63% from LMICs and 85% in the basic treatment cohort. The frequency of coagulopathy complications was higher in HICs (0.76%-3.4%) than in LMICs (0.09%-1.22%). Complications were more frequent in the advanced-treatment cohort than in the basic-treatment cohort. Coagulopathy complications were associated with increased in-hospital mortality (odds ratio, 1.58; 95% CI, 1.52-1.64). The increased mortality associated with these complications was higher in LMICs (58.5%) than in HICs (35.4%). After controlling for coagulopathy complications, treatment intensity, and multiple other factors, the mortality was higher among patients in LMICs than among patients in HICs (odds ratio, 1.45; 95% CI, 1.39-1.51). Conclusion: In a large, international registry of patients hospitalized for COVID-19, coagulopathy complications were more frequent in HICs than in LMICs (developing countries). Increased mortality associated with coagulopathy complications was of a greater magnitude among patients in LMICs. Additional research is needed regarding timely diagnosis of and intervention for coagulation derangements associated with COVID-19, particularly for limited-resource settings

Characteristics and outcomes of an international cohort of 600 000 hospitalized patients with COVID-19

Background: We describe demographic features, treatments and clinical outcomes in the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) COVID-19 cohort, one of the world's largest international, standardized data sets concerning hospitalized patients. Methods: The data set analysed includes COVID-19 patients hospitalized between January 2020 and January 2022 in 52 countries. We investigated how symptoms on admission, co-morbidities, risk factors and treatments varied by age, sex and other characteristics. We used Cox regression models to investigate associations between demographics, symptoms, co-morbidities and other factors with risk of death, admission to an intensive care unit (ICU) and invasive mechanical ventilation (IMV). Results: Data were available for 689 572 patients with laboratory-confirmed (91.1%) or clinically diagnosed (8.9%) SARS-CoV-2 infection from 52 countries. Age [adjusted hazard ratio per 10 years 1.49 (95% CI 1.48, 1.49)] and male sex [1.23 (1.21, 1.24)] were associated with a higher risk of death. Rates of admission to an ICU and use of IMV increased with age up to age 60 years then dropped. Symptoms, co-morbidities and treatments varied by age and had varied associations with clinical outcomes. The case-fatality ratio varied by country partly due to differences in the clinical characteristics of recruited patients and was on average 21.5%. Conclusions: Age was the strongest determinant of risk of death, with a ∼30-fold difference between the oldest and youngest groups; each of the co-morbidities included was associated with up to an almost 2-fold increase in risk. Smoking and obesity were also associated with a higher risk of death. The size of our international database and the standardized data collection method make this study a comprehensive international description of COVID-19 clinical features. Our findings may inform strategies that involve prioritization of patients hospitalized with COVID-19 who have a higher risk of death