Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. © 2021, The Author(s)

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Trick or treat: the relationship between destabilisation, aid and government development policies in Mozambique 1975-1990

A ajuda, a desestabilização e as políticas de desenvolvimento do governo são companheiros incômodos. Os esforços para correlacioná-los são considerados uma tentativa de misturar óleo e água. A ajuda externa é geralmente vista como um fluxo altruísta de recursos; a desestabilização como uma conspiração e as estratégias de desenvolvimento do governo como um esforço positivo para mudar para melhor a realidade socioeconômica e política de um país. Os resultados da minha pesquisa sobre Moçambique. Com base no uso simultâneo de múltiplos métodos das ciências sociais, mostra que o saber convencional aborda a relação entre ajuda, estratégias de desenvolvimento e desestabilização, que vê os dois primeiros fatores como positivos e o terceiro como negativos. São simplificações que reproduzem os esquemas de responsabilização dos detentores do poder do Estado: os efeitos combinados dos três fatores no Moçambique pós-colonial convergiram para criar uma espiral viciosa de colapso social. Os desafios das diferentes forças sociais que foram afetadas fortemente pelas políticas governamentais, foram designados pelos detentores do poder estatal como desestabilizadores, considerando o assalto ao Estado um ato de bandidos coloniais ou lacaios imperialistas. A ajuda ao desenvolvimento, por outro lado, consistia não apenas na transferência de recursos, mas também de influências, medidas e funções. As estratégias de desenvolvimento e as políticas associadas são caracterizadas pela endogeneidade e heterogeneidade de valor. A chamada desestabilização teve um impacto social na economia política moçambicana e teve um impacto na sua mudança. O grupo sob ataque das políticas governamentais: capitalistas, lojistas, camponeses ricos, elites tradicionais acabou se tornando mais poderoso, às vezes até mesmo tirando proveito das mesmas políticas. Uma nova classe rica foi empregada e apoiada na mudança das estratégias de desenvolvimento e do sistema político. A natureza de classe dos membros do governo também foi alterada.Aid, destabilisation and government development policies are uneasy bedfellows. Efforts to correlate them beem considered an an attempt to mix oil and water. Foreign aid is usually seen as an altruistic flow of resources; destabilisation as a conspiracy, and goverment development strategies as a positive sffort to change the socio- economic snd political reality of a country to the better. The results of my research on Mozambique. Based on the simultaneous use of multiple methods of social science, shows that the conventional wisdom approaches to the relationship between aid, development strategies and destabilisation, which see the first two factors as positive and the third as negative. Are simplifications which reproduce the blame lying schemata of the holders of state power: the combined effects of the three factors in post colonial Mozambique converged to create a vicious spiral of social-breakdown. Challenges fron different social forces who werw nwgwtivwly afected by the government policies, were designated by the holders of state power as destabilisation, considering the assult against the state as an act of banditscolonial or imperialist lackys. Development aid, on the other hand, consisted notonly in the transfer of resources but also of influences, prssures and sanstions. Development strategies and associated policies are characterised by value endogeneity and heterogeneity. The so- called destabilisation had a social in the Mozambican political economy and had an impact on changing it. The group under attack by the goverment policies: capitalists, shop-keepers, rich peasants, tradicitional elites eventually became more powerful, sometimes even taking advantage of the same policies. A new rich class was emplowerwd and supported in changing development strategies and the political system. The class nature of the members of government was also changed

“No fim não vai ficar nada”: exploração dos recursos florestais em Cabo Delgado relatório do trabalho de campo em Namiune, Nkonga e 5º Congresso: Relatório do trabalho de campo nas concessões COMADEL e a FMJ, Cabo Delgado, Novembro de 2010

This report focuses on forest product users in the COMADEL and FMJ forest concessions, Cabo Delgado, as well as the effects of their combined strategies and activities on sustainable use of natural resources and sustainable socio-economic development of the region. The aim is to contribute to understanding the effects of these strategies and activities on forest regeneration, ecosystem services and on resource sustainability. The study examines the role played by the Committees of Natural Resources in forest exploitation. Data obtained from interviews and observations were used to complement and update a variety of existing data from oral and written sources dealing with forest regeneration in Cabo Delgado. These existing materials originate from previous studies conducted in the context of the ESAPP project that started more than two years ago. They include results from Learning for Sustainability workshops (LforS, http://www.cde.unibe.ch/Pages/Project/2/14/Learningfor- Sustainability-Extension-Approach.aspx), as well as field reports, academic studies, management plans used by concessionaires, and others. The interviews and observations took place more or less continuously from the beginning of this phase of the project in 2008. Interviews were systematically conducted with owners of concessions operating in the region, employees of logging companies, residents of villages within the existing concessions, government officials and others. It was not possible to collect information directly from poachers in part due to the illegal nature of their work. Information on these activities was obtained indirectly through members of the Committees of Natural Resources, the concessionaire, and its workers, as well as by observing the traces of extraction – traps, bones and parts of slaughtered animals, tree stumps, material ready for transportation, etc. The main results indicate that extraction by the logging company MITI Ltd. and others acting in the region, by poachers and by other actors – e.g. sawyers using manual saws – put a lot of pressure on marketable species, particularly Millettia stuhlmannii, Afzelia quanzensis and Swartzia madagascariensis. Natural regeneration of forests in northern Cabo Delgado is being compromised by the combination of various extracting activities and uncontrolled fires. MITI Ltd. continued the pattern of exploitation of forest resources that was characteristic of companies operating in the region earlier, such as COMADEL. MITI Ltd. failed to implement the broad range of development and conservation activities encouraged by the new legislation on forest concessions that was created to promote sustainable use of resources

“Se querem que façamos algo pela floresta tem que nos pagar”: As lógicas da participação dos camponeses nos Comités de Gestão dos Recursos Naturais nos distritos de Palma e Mocimboa da Praia em 2009: Relatório do trabalho de campo em Namiune, Nkonga e 5º Congresso, Maputo, Dezembro de 2010

Our study considers the natural resources of the Miombo forests in Cabo Delgado from a broad ecosystems perspective. Thus, our view goes beyond the disciplinary approaches of forestry, agronomy, biology or zoology, and also of the social sciences, namely anthropology, history, sociology, political science or economics. The present study aims to establish a dialogue and create synergies between Miti Ltd. – the logging company and owner of the forest concessions – as well as government and state structures at the various levels and the communities – through the Committees on Natural Resources – in order to promote the sustainable use of resources and ecosystems. The research methodology we used can broadly be described as moderated transdisciplinary interaction for action-research based on the approach known as Learning for Sustainability (LforS, http://www.cde.unibe.ch/Pages/Project/2/14/Learning-for-Sustainability-Extension-Approach.aspx). The research methods used include: LforS seminars; field work; forests observations focusing, among others, on ecosystems, trees, wildlife, and burned areas; visits to farms; and interviews. We conducted both collective interviews and individual interviews, including with key informants. The main results indicate that members of the Committee on Natural Resources have a dual attitude: their statements defend the paradigm of sustainable use of natural resources as well as their own immediate monetary gain. They are willing to apply the values, concepts and theories of sustainable development that underpin the establishment of Committees on Natural Resources if they are paid for their work or if they can derive direct benefits from it, i.e. if they can earn a salary or allowance. If this does not happen, however, they are willing to allow actors to engage in illegal hunting or logging activities. This dual attitude also exists in relation to forestry operators. If the concession workers pay the committee members in cash or provide goods, they can run their business even if they violate the law. Natural forest regeneration in Nkonga and Namiune already shows the impact of such use. Although there are many saplings that could basically ensure continuous regeneration under sustainable management, repeated burning is damaging the young trees, deforming them and killing a great number of them. Campaigns against uncontrolled fires are ineffective because the administrative and political authorities have a dual attitude as well and are also part of the group that uses resources to their own profit and benefit. There are institutional structures within the administration, populations, and communities to perform regulating functions, create and implement rules, punish offenders, and oversee resource use. However, they feel that since they are not paid for performing these functions, they do not have to do so. This attitude shows a lack of awareness, but also indicates a situation where everyone seeks to derive maximum benefits from existing resource use patterns. Anything goes

Forest regeneration capacity and its enhancement by forest management and silviculture in Cabo Delgado

SDC has been involved in rural development in Cabo Delgado for more than 30 years. Shortly after the independence of Mozambique, projects in water supply and integrated rural development were initiated. The silvoagropastoral project FO9 based in Mueda was a very early experience in forestry in Cabo Delgado. Andreas Kläy was responsible for the forestry sector in FO9 for 3 years in the early 1980s and had an opportunity to initiate an exchange of ideas and experience in rural development theory and approaches with Yussuf Adam, who was doing research in human anthropology and history in the province. 25 years later, the current situation of forest management in Cabo Delgado was reassessed, with a specific focus on concessions in the North. The opportunity for a partnership between the MITI SA, the University of Eduardo Mondlane, and CDE was created on the basis of this preliminary study1. The aim of this partnership is to generate knowledge and develop capacity for sustainable forest management. The preliminary study showed that “…we have to face weaknesses and would like to start a learning process with the main institutions, organisations, and stakeholder groups active in forest management and research in the North of Cabo Delgado. This learning process will involve studies supported by competent research institutions and workshops …” The specific objectives of ESAPP project Q804 are the following: 1. Contribute to understanding of the forestry sector; 2. Capacity development for professionals and academics; 3. Support for the private sector and the local forest service; 4. Support data generation at Cabo Delgado's Provincial Service; 5. Capacity development for Swiss academic institutions (CDE and ETHZ). A conceptual planning platform was elaborated as a basis for cooperation and research in the partnership (cf. Annex 1). The partners agreed to work on two lines of research: biophysical and socio-economic. In order to ensure a transdisciplinary approach, disciplinary research is anchored in common understanding in workshops based on the LforS methods. These workshops integrate the main stakeholders in the local context of the COMADEL concession in Nangade District managed by MITI SA, and take place in the village of Namiune. The research team observed that current management schemes consist mainly of strategies of nature mining by most stakeholders involved. Institutional settings - formal and informal - have little impact due to weak capacity at the local level and corruption. Local difficulties in a remote rural area facilitate external access to resources and are perpetuated by the loss of benefits. The benefits of logging remain at the top level (economic and political elites). The interests of the owners of the concession in stopping the loss of resources caused by this regime offers a unique opportunity to intervene in the logic of resource degradation and agony in rural development and forest management

The training and expectations of medical students in Mozambique

Abstract Background This paper describes the socio-economic profile of medical students in the 1998/99 academic year at the Universidade Eduardo Mondlane (UEM) Medical Faculty in Maputo. It aims to identify their social and geographical origins in addition to their expectations and difficulties regarding their education and professional future. Methods The data were collected through a questionnaire administered to all medical students at the faculty. Results Although most medical students were from outside Maputo City and Maputo Province, expectations of getting into medical school were already associated with a migration from the periphery to the capital city, even before entering medical education. This lays the basis for the concentration of physicians in the capital city once their term of compulsory rural employment as junior doctors is completed. The decision to become a doctor was taken at an early age. Close relatives, or family friends seem to have been an especially important variable in encouraging, reinforcing and promoting the desire to be a doctor. The academic performance of medical students was dismal. This seems to be related to several difficulties such as lack of library facilities, inadequate financial support, as well as poor high school preparation. Only one fifth of the students reported receiving financial support from the Mozambican government to subsidize their medical studies. Conclusion Medical students seem to know that they will be needed in the public sector, and that this represents an opportunity to contribute to the public's welfare. Nevertheless, their expectations are, already as medical students, to combine their public sector practice with private medical work in order to improve their earnings.</p

Systemic Lupus Erythematosus and Cardiovascular Diseases: A Systematic Review

Systemic lupus erythematosus (SLE) is an autoimmune condition characterized by multi-organ involvement. The clinical presentation often varies from mild to moderate to severe. The cardiovascular system may also be affected, often portending a poor prognosis for patients. Although the relationship between SLE and cardiovascular disorders has been extensively explored through case reports and literature reviews, few systematic reviews explicitly focusing on this association have been conducted. In light of this, this systematic review aims to analyze the extent of the association between SLE and cardiovascular diseases (CVDs), by exploring the risk of developing CVDs, including myocardial infarction (MI), atherosclerosis, myocarditis, pericarditis and arrhythmias, in SLE patients vs. non-SLE patients. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to perform the systematic review. A detailed search was done covering the period from March 2003 to March 2023 using three databases: PubMed, Google Scholar, and Cochrane. The PubMed search identified 597 articles, while Google Scholar and Cochrane searches yielded 559 and three articles, respectively. Of the 1159 articles retrieved, we chose eight for final consideration, after excluding papers that did not discuss the role of SLE in CVDs, papers published earlier than 2003, and papers with incomplete data. The eight studies chosen included two narrative reviews, two systematic reviews, and four observational studies. In this systematic review, SLE was proven to have a strong relationship with diverse CVDs, including rare ones scarcely discussed in the literature, such as vasculitis and aortic dissection. All eight of the final papers indicated a connection between SLE and CVDs, based on the systematic analysis of these articles, which revealed that most recent research supports a higher risk of peripheral arterial occlusive disease (PAOD), MI, pericarditis, myocarditis, and other cardiovascular disorders in individuals with SLE. These associations may have certain gray areas, as patient characteristics and comorbidities often affect the extent of illness and long-term prognosis. Larger-scale studies are required to probe this relationship further and research the etiopathogenesis involved in order to improve patient outcomes. The effects of SLE on the heart are, however, unequivocal