Epidemic history of hepatitis C virus genotypes and subtypes in Portugal

Any successful strategy to prevent and control HCV infection requires an understanding of the epidemic behaviour among the different genotypes. Here, we performed the first characterization of the epidemic history and transmission dynamics of HCV subtypes in Portugal. Direct sequencing of NS5B was performed on 230 direct-acting antiviral drugs (DAA)-treatment naïve patients in Lisbon. Phylogenetic analysis was used for subtyping and transmission cluster identification. Bayesian methods were used to reconstruct the epidemic history of HCV subtypes. Sequences were analysed for resistance-associated substitutions (RAS). The majority of strains were HCV-GT1 (62.6%), GT3 (18.3%, all subtype 3a) and GT4 (16.1%). Among GT1, the most frequent were subtypes 1a (75.5%) and 1b (24.5%). Polyphyletic patterns were found in all but 12 lineages suggesting multiple introductions of the different subtypes in this population. Five distinct epidemics were identified. The first significant HCV epidemic in Portugal occurred between 1930s and 1960s, was caused almost exclusively by GT1b and was likely associated with blood transfusions. Rapid expansion of GT3a occurred in the 1960s and GT1a in the 1980s, associated with intravenous drug use. The most recent epidemics were caused by GT4a and GT4d and seem to be associated with the resurgence of opioid use. The C316N substitution was found in 31.4% of GT1b-patients. Close surveillance of patients bearing this mutation and undergoing dasabuvir-based regimens will be important to determine its impact on treatment outcome.publishersversionpublishe

What clinicians who practice in countries reaching malaria elimination should be aware of: lessons learnt from recent experience in Sri Lanka

Following progressive reduction in confirmed cases of malaria from 2002 to 2007 (41,411 cases in 2002, 10,510 cases in 2003, 3,720 cases in 2004, 1,640 cases in 2005, 591 cases in 2006, and 198 cases in 2007). Sri Lanka entered the pre-elimination stage of malaria in 2008. One case of indigenous malaria and four other cases of imported malaria are highlighted here, as the only patients who presented to the Professorial Medical Unit, Colombo North Teaching Hospital, Ragama, Sri Lanka over the past eight years, in contrast to treating several patients a week about a decade ago. Therefore, at the eve of elimination of malaria from Sri Lanka, it is likely that the infection is mostly encountered among travellers who return from endemic areas, or among the military who serve in un-cleared areas of Northern Sri Lanka. They may act as potential sources of introducing malaria as until malaria eradication is carried out. These cases highlight that change in the symptomatology, forgetfulness regarding malaria as a cause of acute febrile illness and deterioration of the competency of microscopists as a consequence of the low disease incidence, which are all likely to contribute to the delay in the diagnosis. The importance regarding awareness of new malaria treatment regimens, treatment under direct observation, prompt notification of suspected or diagnosed cases of malaria and avoiding blind use of anti-malarials are among the other responsibilities expected of all clinicians who manage patients in countries reaching malaria elimination

Rate-Induced Transitions in Networked Complex Adaptive Systems: Exploring Dynamics and Management Implications Across Ecological, Social, and Socioecological Systems

Complex adaptive systems (CASs), from ecosystems to economies, are open systems and inherently dependent on external conditions. While a system can transition from one state to another based on the magnitude of change in external conditions, the rate of change -- irrespective of magnitude -- may also lead to system state changes due to a phenomenon known as a rate-induced transition (RIT). This study presents a novel framework that captures RITs in CASs through a local model and a network extension where each node contributes to the structural adaptability of others. Our findings reveal how RITs occur at a critical environmental change rate, with lower-degree nodes tipping first due to fewer connections and reduced adaptive capacity. High-degree nodes tip later as their adaptability sources (lower-degree nodes) collapse. This pattern persists across various network structures. Our study calls for an extended perspective when managing CASs, emphasizing the need to focus not only on thresholds of external conditions but also the rate at which those conditions change, particularly in the context of the collapse of surrounding systems that contribute to the focal system's resilience. Our analytical method opens a path to designing management policies that mitigate RIT impacts and enhance resilience in ecological, social, and socioecological systems. These policies could include controlling environmental change rates, fostering system adaptability, implementing adaptive management strategies, and building capacity and knowledge exchange. Our study contributes to the understanding of RIT dynamics and informs effective management strategies for complex adaptive systems in the face of rapid environmental change.Comment: 25 pages, 4 figures, 1 box, supplementary informatio

Facile discovery of surrogate cytokine agonists

Cytokines are powerful immune modulators that initiate signaling through receptor dimerization, but natural cytokines have structural limitations as therapeutics. We present a strategy to discover cytokine surrogate agonists by using modular ligands that exploit induced proximity and receptor dimer geometry as pharmacological metrics amenable to high-throughput screening. Using VHH and scFv to human interleukin-2/15, type-I interferon, and interleukin-10 receptors, we generated combinatorial matrices of single-chain bispecific ligands that exhibited diverse spectrums of functional activities, including potent inhibition of SARS-CoV-2 by surrogate interferons. Crystal structures of IL-2R:VHH complexes revealed that variation in receptor dimer geometries resulted in functionally diverse signaling outputs. This modular platform enabled engineering of surrogate ligands that compelled assembly of an IL-2R/IL-10R heterodimer, which does not naturally exist, that signaled through pSTAT5 on T and natural killer (NK) cells. This “cytokine med-chem” approach, rooted in principles of induced proximity, is generalizable for discovery of diversified agonists for many ligand-receptor systems

Improved functionalization of oleic acid-coated iron oxide nanoparticles for biomedical applications

Superparamagnetic iron oxide nanoparticles can providemultiple benefits for biomedical applications in aqueous environments such asmagnetic separation or magnetic resonance imaging. To increase the colloidal stability and allow subsequent reactions, the introduction of hydrophilic functional groups onto the particles’ surface is essential. During this process, the original coating is exchanged by preferably covalently bonded ligands such as trialkoxysilanes. The duration of the silane exchange reaction, which commonly takes more than 24 h, is an important drawback for this approach. In this paper, we present a novel method, which introduces ultrasonication as an energy source to dramatically accelerate this process, resulting in high-quality waterdispersible nanoparticles around 10 nmin size. To prove the generic character, different functional groups were introduced on the surface including polyethylene glycol chains, carboxylic acid, amine, and thiol groups. Their colloidal stability in various aqueous buffer solutions as well as human plasma and serum was investigated to allow implementation in biomedical and sensing applications.status: publishe

The global burden of cancer attributable to risk factors, 2010-19 : a systematic analysis for the Global Burden of Disease Study 2019

Background Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally. Methods The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk-outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented. Findings Globally, in 2019, the risk factors included in this analysis accounted for 4.45 million (95% uncertainty interval 4.01-4.94) deaths and 105 million (95.0-116) DALYs for both sexes combined, representing 44.4% (41.3-48.4) of all cancer deaths and 42.0% (39.1-45.6) of all DALYs. There were 2.88 million (2.60-3.18) risk-attributable cancer deaths in males (50.6% [47.8-54.1] of all male cancer deaths) and 1.58 million (1.36-1.84) risk-attributable cancer deaths in females (36.3% [32.5-41.3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20.4% (12.6-28.4) and DALYs by 16.8% (8.8-25.0), with the greatest percentage increase in metabolic risks (34.7% [27.9-42.8] and 33.3% [25.8-42.0]). Interpretation The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.Peer reviewe

Association of whole-genome and NETRIN1 signaling pathway-derived polygenic risk scores for Major Depressive Disorder and white matter microstructure in UK Biobank

Background: Major depressive disorder is a clinically heterogeneous psychiatric disorder with a polygenic architecture. Genome-wide association studies have identified a number of risk-associated variants across the genome and have reported growing evidence of NETRIN1 pathway involvement. Stratifying disease risk by genetic variation within the NETRIN1 pathway may provide important routes for identification of disease mechanisms by focusing on a specific process, excluding heterogeneous risk-associated variation in other pathways. Here, we sought to investigate whether major depressive disorder polygenic risk scores derived from the NETRIN1 signaling pathway (NETRIN1-PRSs) and the whole genome, excluding NETRIN1 pathway genes (genomic-PRSs), were associated with white matter microstructure. Methods: We used two diffusion tensor imaging measures, fractional anisotropy (FA) and mean diffusivity (MD), in the most up-to-date UK Biobank neuroimaging data release (FA: n = 6401; MD: n = 6390). Results: We found significantly lower FA in the superior longitudinal fasciculus (β = −.035, p =.029) and significantly higher MD in a global measure of thalamic radiations (β =.029, p =.021), as well as higher MD in the superior (β =.034, p =.039) and inferior (β =.029, p =.043) longitudinal fasciculus and in the anterior (β =.025, p =.046) and superior (β =.027, p =.043) thalamic radiation associated with NETRIN1-PRS. Genomic-PRS was also associated with lower FA and higher MD in several tracts. Conclusions: Our findings indicate that variation in the NETRIN1 signaling pathway may confer risk for major depressive disorder through effects on a number of white matter tracts

A political economy of non-governmental organizations in Bangladesh and Sri Lanka

This dissertation explores the agency of Non-governmental Organizations (NGOs) in social change in Bangladesh and Sri Lanka. The roots of organizations similar to contemporary NGOs are traced to Christian missionary organizations in the early Nineteenth Century. Since then, NGOs have been engaged in a diverse array of activities. They gained a high level of social visibility during periods in which a given State formation faced a serious legitimacy crisis and showed signs of fundamental change. I have identified four such \u27moments\u27 during which NGOs acted as arenas for debate on social change. NGO activities during these periods have contributed to the centralization and domestication of State power. In other words, once the State consolidates its hegemonic position the vitality of NGOs fade until the next legitimacy crisis emerges. While aspects of evangelism, nationalism, democracy, and development have interactively shaped the agency of NGOs, what transcends these social processes is the continuous expansion and consolidation of capitalist development. NGO activities have contributed to this evolutionary process. The impact of micro-credit on the empowerment of women demonstrates that the counter-hegemonic agendas of the NGOs that have voiced the interests of subordinate groups have failed. NGOs do not reach the poorest of the poor and their systems of management are bureaucratic and top-down. These failures are attributed to; first, the institutional identity and legal boundaries for NGO activities are defined and legitimated by the State. Second, NGOs do not advocate nor have a mandate to work towards a form of the State fundamentally different from the one that characterizes emerging neo-liberal political economy. Third, NGOs\u27 reliance on local institutions, authority and power relations to ensure the financial self-sufficiency of micro-credit programs do not provide much space for NGOs to transform the institutions that are oppressive to women. Instead, they further strengthen them. Fourth, whatever influence NGOs have on the State is derived from the support received from their international donors, rather than from a social base comprised of their members. In the final analysis the autonomy and capacity of NGOs to challenge State power has progressively declined since the Nineteenth Century. They have become the means through which state-society relations are disciplined to facilitate capitalist development on a global scale

Dynamics of essentialist representations of nationhood and the politics of interpretation : the role of religion in the making and unmaking of the Sri Lankan nation-state

THESIS 8554Sometimes the impression given of the Lankan conflict by both the local and mainstream media is that the conflict has been caused by primordial or perennial antagonisms that existed between the parties involved. Such a projection adds evidence to the unchecked hypothesis of a ?clash of civilisations? that is supposed to be gaining ground in the emerging world order. In my study of the Lankan conflict I argue that it is mainly a modern conflict which has its roots in the colonial and postcolonial state-building