In the fight against COVID-19, vaccination is vital in achieving herd immunity. Many Asian countries are starting to vaccinate frontline workers; however, expedited vaccine development has led to ...hesitancy among the general population. We evaluated the willingness of healthcare workers to receive the COVID-19 vaccine.
From 12 to 21 December 2020, we recruited 1720 healthcare workers from 6 countries: China, India, Indonesia, Singapore, Vietnam and Bhutan. The self-administrated survey collected information on willingness to vaccinate, perception of COVID-19, vaccine concerns, COVID-19 risk profile, stigma, pro-socialness scale, and trust in health authorities.
More than 95% of the healthcare workers surveyed were willing to vaccinate. These respondents were more likely to perceive the pandemic as severe, consider the vaccine safe, have less financial concerns, less stigmatization regarding the vaccine, higher pro-socialness mindset and trust in health authorities. A high perceived pandemic risk index, low vaccine harm index and high pro-socialness index were independent predictors in multivariable analysis.
The majority of healthcare workers in Asia are willing to receive COVID-19 vaccination. Perceived COVID-19 susceptibility, low potential risk of vaccine harm and pro-socialness are the main drivers. These findings may help formulate vaccination strategies in other countries.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Arthropod-borne flaviviruses cause life-threatening diseases associated with endothelial hyperpermeability and vascular leak. We recently found that vascular leak can be triggered by dengue virus ...(DENV) non-structural protein 1 (NS1) via the disruption of the endothelial glycocalyx-like layer (EGL). However, the molecular determinants of NS1 required to trigger EGL disruption and the cellular pathway(s) involved remain unknown. Here we report that mutation of a single glycosylated residue of NS1 (N207Q) abolishes the ability of NS1 to trigger EGL disruption and induce endothelial hyperpermeability. Intriguingly, while this mutant bound to the surface of endothelial cells comparably to wild-type NS1, it was no longer internalized, suggesting that NS1 binding and internalization are distinct steps. Using endocytic pathway inhibitors and gene-specific siRNAs, we determined that NS1 was endocytosed into endothelial cells in a dynamin- and clathrin-dependent manner, which was required to trigger endothelial dysfunction in vitro and vascular leak in vivo. Finally, we found that the N207 glycosylation site is highly conserved among flaviviruses and is also essential for West Nile and Zika virus NS1 to trigger endothelial hyperpermeability via clathrin-mediated endocytosis. These data provide critical mechanistic insight into flavivirus NS1-induced pathogenesis, presenting novel therapeutic and vaccine targets for flaviviral diseases.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Severe falciparum malaria is a medical emergency characterised by potentially lethal vital organ dysfunction. Patient fatality rates even with parenteral artesunate treatment remain high. Despite ...considerable research into adjuvant therapies targeting organ and tissue dysfunction, none have shown efficacy apart from renal replacement therapy. Understanding the causal contributions of clinical and laboratory abnormalities to mortality is essential for the design and evaluation of novel therapeutic interventions.
We used a structural model causal inference approach to investigate causal relationships between epidemiological, laboratory, and clinical variables in patients with severe falciparum malaria enrolled in clinical trials and their in-hospital mortality. Under this causal model, we analysed records from 9,040 hospitalised children (0-12 years, n = 5,635) and adults (n = 3,405, 12-87 years) with severe falciparum malaria from 15 countries in Africa and Asia who were studied prospectively over the past 35 years. On admission, patient covariates associated with increased in-hospital mortality were severity of acidosis (odds ratio OR 2.10 for a 7-mEq/L increase in base deficit 95% CI 1.93-2.28), renal impairment (OR 1.71 for a 2-fold increase in blood urea nitrogen 95% CI 1.58, 1.86), coma (OR 3.59 95% CI 3.07-4.21), seizures (OR 1.40 95% CI 1.16-1.68), shock (OR 1.51 95% CI 1.14-1.99), and presumed pulmonary oedema (OR 1.58 95% CI 1.04-2.39). Lower in-hospital mortality was associated with moderate anaemia (OR 0.87 for a decrease of 10 percentage points in haematocrit 95% CI 0.80-0.95). Circulating parasite density was not associated with mortality (OR 1.02 for a 6-fold increase 95% CI 0.94-1.11), so the pathological effects of parasitaemia appear to be mediated entirely by the downstream effects of sequestration. Treatment with an artemisinin derivative decreased mortality compared with quinine (OR 0.64 95% CI 0.56-0.74). These estimates were consistent across children and adults (mainly representing African and Asian patients, respectively). Using inverse probability weighting, transfusion was not estimated to be beneficial in children with admission haematocrit values between 15% and 25% (OR 0.99 95% CI 0.97-1.02). Except for the effects of artemisinin treatment and transfusion, causal interpretations of these estimates could be biased by unmeasured confounding from severe bacterial sepsis, immunity, and duration of illness.
These data suggest that moderate anaemia is associated with a reduced risk of death in severe falciparum malaria. This is possibly a direct causal association. The severe anaemia threshold criteria for a definition of severe falciparum malaria should be reconsidered.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The discovery of a new physical process in manganese metal is reported. This process will also be present for all manganese‐containing materials in condensed matter. The process was discovered by ...applying our new technique of XR‐HERFD (extended‐range high‐energy‐resolution fluorescence detection), which was developed from the popular high‐resolution RIXS (resonant inelastic X‐ray scattering) and HERFD approaches. The acquired data are accurate to many hundreds of standard deviations beyond what is regarded as the criterion for `discovery'. Identification and characterization of many‐body processes can shed light on the X‐ray absorption fine‐structure spectra and inform the scientist on how to interpret them, hence leading to the ability to measure the dynamical nanostructures which are observable using the XR‐HERFD method. Although the many‐body reduction factor has been used universally in X‐ray absorption spectroscopy in analysis over the past 30 years (thousands of papers per year), this experimental result proves that many‐body effects are not representable by any constant reduction factor parameter. This paradigm change will provide the foundation for many future studies and X‐ray spectroscopy.
A new physical process in manganese, present for manganese‐containing materials and materials science, has been discovered by applying our new technique – XR‐HERFD (extended‐range high‐energy‐resolution fluorescence detection) – developed from high‐resolution RIXS (resonant inelastic X‐ray scattering) and HERFD (high‐energy‐resolution fluorescence detection).
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract
Rickettsia
species of the spotted fever group are arthropod-borne obligate intracellular bacteria that can cause mild to severe human disease. These bacteria invade host cells, replicate in ...the cell cytosol, and spread from cell to cell. To access the host cytosol and avoid immune detection, they escape membrane-bound vacuoles by expressing factors that disrupt host membranes. Here, we show that a patatin-like phospholipase A2 enzyme (Pat1) facilitates
Rickettsia parkeri
infection by promoting escape from host membranes and cell-cell spread. Pat1 is important for infection in a mouse model and, at the cellular level, is crucial for efficiently escaping from single and double membrane-bound vacuoles into the host cytosol, and for avoiding host galectins that mark damaged membranes. Pat1 is also important for avoiding host polyubiquitin, preventing recruitment of autophagy receptor p62, and promoting actin-based motility and cell-cell spread.
A multidrug-resistant co-lineage of Plasmodium falciparum malaria, named KEL1/PLA1, spread across Cambodia in 2008–13, causing high rates of treatment failure with the frontline combination therapy ...dihydroartemisinin-piperaquine. Here, we report on the evolution and spread of KEL1/PLA1 in subsequent years.
For this genomic epidemiology study, we analysed whole genome sequencing data from P falciparum clinical samples collected from patients with malaria between 2007 and 2018 from Cambodia, Laos, northeastern Thailand, and Vietnam, through the MalariaGEN P falciparum Community Project. Previously unpublished samples were provided by two large-scale multisite projects: the Tracking Artemisinin Resistance Collaboration II (TRAC2) and the Genetic Reconnaissance in the Greater Mekong Subregion (GenRe-Mekong) project. By investigating genome-wide relatedness between parasites, we inferred patterns of shared ancestry in the KEL1/PLA1 population.
We analysed 1673 whole genome sequences that passed quality filters, and determined KEL1/PLA1 status in 1615. Before 2009, KEL1/PLA1 was only found in western Cambodia; by 2016–17 its prevalence had risen to higher than 50% in all of the surveyed countries except for Laos. In northeastern Thailand and Vietnam, KEL1/PLA1 exceeded 80% of the most recent P falciparum parasites. KEL1/PLA1 parasites maintained high genetic relatedness and low diversity, reflecting a recent common origin. Several subgroups of highly related parasites have recently emerged within this co-lineage, with diverse geographical distributions. The three largest of these subgroups (n=84, n=79, and n=47) mostly emerged since 2016 and were all present in Cambodia, Laos, and Vietnam. These expanding subgroups carried new mutations in the crt gene, which arose on a specific genetic background comprising multiple genomic regions. Four newly emerging crt mutations were rare in the early period and became more prevalent by 2016–17 (Thr93Ser, rising to 19·8%; His97Tyr to 11·2%; Phe145Ile to 5·5%; and Ile218Phe to 11·1%).
After emerging and circulating for several years within Cambodia, the P falciparum KEL1/PLA1 co-lineage diversified into multiple subgroups and acquired new genetic features, including novel crt mutations. These subgroups have rapidly spread into neighbouring countries, suggesting enhanced fitness. These findings highlight the urgent need for elimination of this increasingly drug-resistant parasite co-lineage, and the importance of genetic surveillance in accelerating malaria elimination efforts.
Wellcome Trust, Bill & Melinda Gates Foundation, UK Medical Research Council, and UK Department for International Development.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The pathogenesis of coma in severe Plasmodium falciparum malaria remains poorly understood. Obstruction of the brain microvasculature because of sequestration of parasitized red blood cells (pRBCs) ...represents one mechanism that could contribute to coma in cerebral malaria. Quantitative postmortem microscopy of brain sections from Vietnamese adults dying of malaria confirmed that sequestration in the cerebral microvasculature was significantly higher in patients with cerebral malaria (CM; n = 21) than in patients with non-CM (n = 23). Sequestration of pRBCs and CM was also significantly associated with increased microvascular congestion by infected and uninfected erythrocytes. Clinicopathological correlation showed that sequestration and congestion were significantly associated with deeper levels of premortem coma and shorter time to death. Microvascular congestion and sequestration were highly correlated as microscopic findings but were independent predictors of a clinical diagnosis of CM. Increased microvascular congestion accompanies coma in CM, associated with parasite sequestration in the cerebral microvasculature.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
This randomized trial in 383 children in Vietnam who had moderately severe dengue shock syndrome compared the use of Ringer's lactate, 6 percent dextran 70, and 6 percent hydroxyethyl starch after ...initial resuscitation with colloid. The primary clinical outcomes were similar with the three solutions. The trial provides strong evidence that in moderately severe dengue shock syndrome the outcomes are as good with the use of Ringer's lactate as with either of the more expensive colloid solutions.
This trial provides strong evidence that in moderately severe dengue shock syndrome the outcomes are as good with Ringer's lactate as with either of the more expensive colloid solutions.
Dengue shock syndrome is the most serious manifestation of dengue hemorrhagic fever, a relatively new disease entity that has spread progressively throughout Asia and South America since its first appearance in Bangkok, Thailand, in the 1950s.
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Dengue hemorrhagic fever is characterized by systemic vascular leakage and disordered hemostasis and may develop after infection with any of four dengue viral serotypes.
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,
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Between 250,000 and 500,000 cases of dengue hemorrhagic fever, mainly in children, are reported to the World Health Organization (WHO) annually, with mortality rates of 1 to 5 percent among patients with shock.
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The pathophysiological mechanisms underlying the . . .
Initially multiple independent Kelch mutations were observed,1 but in a recent sinister development, a single dominant artemisinin-resistant P falciparum C580Y mutant lineage has arisen in western ...Cambodia, outcompeted the other resistant malaria parasites, and subsequently acquired resistance to piperaquine.2 Cambodia had adopted dihydroartemisinin-piperaquine as first-line antimalarial treatment, but has now been forced to switch its first line artemisinin combination treatment back to artesunate-mefloquine as a consequence3. 1 EA Ashley, M Dhorda, RM Fairhurst, Plasmodium falciparum, malaria, N Engl J Med, Vol. 371, 2014, 411-423 2 M Imwong, K Suwannasin, C Kunasol, Plasmodium falciparum, in the Greater Mekong Subregion: a molecular epidemiology observational study, Lancet Infect Dis, Vol. 17, 2017, 491-497 3 World Health Organization, Status report on artemisinin and ACT resistance (April 2017), (accessed July 11, 2017).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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