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Gallbladder carriage generates genetic variation and genome degradation in Salmonella Typhi
No full textDespite recent advances in typhoid fever control, asymptomatic carriage of Salmonella Typhi in the gallbladder remains poorly understood. Aiming to understand if S. Typhi becomes genetically adapted for long-term colonisation in the gallbladder, we performed whole genome sequencing on a collection of S. Typhi isolated from the gallbladders of typhoid carriers. These sequences were compared to contemporaneously sampled sequences from organisms isolated from the blood of acute patients within the same population. We found that S. Typhi carriage was not restricted to any particular genotype or conformation of antimicrobial resistance genes, but was largely reflective of S. Typhi circulating in the general population. However, gallbladder isolates showed a higher genetic variability than acute isolates, with median pairwise SNP distances of 21 and 13 SNPs (p = 2.8x10-9), respectively. Within gallbladder isolates of the predominant H58 genotype, variation was associated with a higher prevalence of nonsense mutations. Notably, gallbladder isolates displayed a higher frequency of non-synonymous mutations in genes encoding hypothetical proteins, membrane lipoproteins, transport/binding proteins, surface antigens, and carbohydrate degradation. Specifically, we identified several gallbladder-specific non-synonymous mutations involved in LPS synthesis and modification, with some isolates lacking the Vi capsular polysaccharide vaccine target due to the 134Kb deletion of SPI-7. S. Typhi is under strong selective pressure in the human gallbladder, which may be reflected phylogenetically by long terminal branches that may distinguish organisms from chronic and acute infections. Our work shows that selective pressures asserted by the hostile environment of the human gallbladder generate new antigenic variants and raises questions regarding the role of carriage in the epidemiology of typhoid fever
Introduction & overview
No full textThis brief introduction presents the structure and contents of the current issue and links the various contributions to events or very recent discoveries that were reported in the press in the period immediately before its completion in September. It also offers an overview (not meant to be exhaustive) of archaeological activity in Greece over the past 12 months, focusing on major exhibitions and important recent publications
Crystal structure and interaction studies of human DHTKD1 provide insight into a mitochondrial megacomplex in lysine catabolism
No full textDHTKD1 is a lesser-studied E1 enzyme among the family of 2-oxoacid dehydrogenases. In complex with E2 (dihydrolipoamide succinyltransferase, DLST) and E3 (dihydrolipoamide dehydrogenase, DLD) components, DHTKD1 is involved in lysine and tryptophan catabolism by catalysing the oxidative decarboxylation of 2-oxoadipate (2OA) in mitochondria. Here, the 1.9 Å resolution crystal structure of human DHTKD1 is solved in complex with the thiamine diphosphate co-factor. The structure reveals how the DHTKD1 active site is modelled upon the well characterized homologue 2-oxoglutarate (2OG) dehydrogenase but engineered specifically to accommodate its preference for the longer substrate of 2OA over 2OG. A 4.7 Å resolution reconstruction of the human DLST catalytic core is also generated by single-particle electron microscopy, revealing a 24-mer cubic scaffold for assembling DHTKD1 and DLD protomers into a megacomplex. It is further demonstrated that missense DHTKD1 variants causing the inborn error of 2-aminoadipic and 2-oxoadipic aciduria impact on the complex formation, either directly by disrupting the interaction with DLST, or indirectly through destabilizing the DHTKD1 protein. This study provides the starting framework for developing DHTKD1 modulators to probe the intricate mitochondrial energy metabolism
Boundary spike‐layer solutions of the singular Keller–Segel system: existence and stability
No full textWe explore the existence and nonlinear stability of boundary spike‐layer solutions of the Keller–Segel system with logarithmic singular sensitivity in the half space, where the physical zero‐flux and Dirichlet boundary conditions are prescribed. We first prove that, under above boundary conditions, the Keller–Segel system admits a unique boundary spike‐layer steady state where the first solution component (bacterial density) of the system concentrates at the boundary as a Dirac mass and the second solution component (chemical concentration) forms a boundary layer profile near the boundary as the chemical diffusion coefficient tends to zero. Then we show that this boundary spike‐layer steady state is asymptotically nonlinearly stable under appropriate perturbations. As far as we know, this is the first result obtained on the global well‐posedness of the singular Keller–Segel system with nonlinear consumption rate. We introduce a novel strategy of relegating the singularity, via a Cole–Hopf type transformation, to a nonlinear nonlocality which is resolved by the technique of ‘taking anti‐derivatives’, that is, working at the level of the distribution function. Then, we carefully choose weight functions to prove our main results by suitable weighted energy estimates with Hardy's inequality that fully captures the dissipative structure of the system
Chronic obstructive pulmonary disease – management of chronic disease
No full textChronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide, affecting an estimated 1.2 million people in the UK. The most common cause is tobacco smoke. Patients with COPD experience a high symptom burden, worsened during periods of disease instability (termed exacerbations or ‘lung attacks’). Diagnosis requires clinical, laboratory and functional assessment to tailor treatments towards symptoms and exacerbation risk. To date, smoking cessation is the single most important intervention in delaying disease progression and should be a focus at every patient interaction. Diagnosing and managing co-morbidities is also an important part of managing a patient with COPD. COPD is managed using a combination of pharmacological and non-pharmacological treatments, including pulmonary rehabilitation and self-management plans, allowing control over some of the symptom burden and a reduction in exacerbations. Holistic management of COPD requires effective communication between all those involved in patient care, crossing secondary and primary care boundaries. At all stages a multidisciplinary approach should be adopted to manage this chronic lung disease
Compassionate drug (mis)use during pandemics: lessons for COVID-19 from 2009.
No full textBACKGROUND:New emerging infections have no known treatment. Assessing potential drugs for safety and efficacy enables clinicians to make evidence-based treatment decisions and contributes to overall outbreak control. However, it is difficult to launch clinical trials in the unpredictable environment of an outbreak. We conducted a bibliometric systematic review for the 2009 influenza pandemic to determine the speed and quality of evidence generation for treatments. This informs approaches to high-quality evidence generation in this and future pandemics. METHODS:We searched PubMed for all clinical data (including clinical trial, observational and case series) describing treatment for patients with influenza A(H1N1)pdm09 and ClinicalTrials.gov for research that aimed to enrol patients with the disease. RESULTS:Thirty-three thousand eight hundred sixty-nine treatment courses for patients hospitalised with A(H1N1)pdm09 were detailed in 160 publications. Most were retrospective observational studies or case series. Five hundred ninety-two patients received treatment (or placebo) as participants in a registered interventional clinical trial with results publicly available. None of these registered trial results was available during the timeframe of the pandemic, and the median date of publication was 213 days after the Public Health Emergency of International Concern ended. CONCLUSION:Patients were frequently treated for pandemic influenza with drugs not registered for this indication, but rarely under circumstances of high-quality data capture. The result was a reliance on use under compassionate circumstances, resulting in continued uncertainty regarding the potential benefits and harms of anti-viral treatment. Rapid scaling of clinical trials is critical for generating a quality evidence base during pandemics
Investigator-initiated randomized controlled trials in infectious diseases: better value for money for registration trials of new antimicrobials
No full textRandomized controlled trials (RCTs) conducted by the industry are expensive, especially trials conducted for registration of new drugs for multidrug-resistant (MDR) bacteria. Lower-cost investigator-initiated trials have recently been successful in recruiting patients with severe infections caused by MDR bacteria. In this personal viewpoint, we contrast the aims, methods and resulting costs of industry-led and investigator-initiated trials and ask whether contemporary registration trial costs are justified. Contract research organizations, delivering and monitoring industry-sponsored trials at a significant cost, have little incentive to make trials more efficient or less expensive. The value of universal monitoring of all trial data is questionable. We propose that clinical trial networks play a more influential role in RCT design and planning, lead adaptive risk-based trial monitoring, and work with the industry to maximize efficient recruitment and lower costs in registration trials for the approval of new antimicrobials
Accounting for care within human geography
No full textHuman geography has experienced a burgeoning interest in care. Despite this, the more radical potentials of thinking with, and through, care remain largely unexplored. In this paper, we critically examine one such potential, asking how care might facilitate a substantial rethinking of practices of research and analysis within human geography. We argue that care does not simply name practices of social reproduction or emotional attachment, but is a distinct mode of ethics, both visible in the social world and capable of informing academic practice. We ask what it means to recognise everyday accounts as acts of care, and to analyse these same accounts through an ethic of care where knowledge, action, relating to others, and the shaping of ethical commitment are inextricably intertwined. While, typically, everyday accounts are seen as about some sort of underlying meaning or dynamic, we suggest that such accounts need to be understood as parts of efforts to navigate and re‐make social worlds. We unfold our argument by first tracing how care has been understood and analysed within human geography as a shifting and situated social practice. Building on, but moving beyond, such approaches, we examine social worlds as “matters of care,” where everyday understandings and the potential for action and ethical commitment are not only continually negotiated but are also staunchly kept open to new possibilities. Through the close reading of extracts from in‐depth interviews with first‐time parents in the city of Oxford, UK, we illustrate how care offers a committed practice of knowing and relating within research. We argue this approach provides new ways of thinking about geographical research, where primary research, analysis, and scholarly narratives are all implicated in the remaking of everyday worlds that, in turn, reveal a new terrain of political potentiality
Modelling and mapping the intra-urban spatial distribution of Plasmodium falciparum parasite rate using very-high-resolution satellite derived indicators
No full textBACKGROUND:The rapid and often uncontrolled rural-urban migration in Sub-Saharan Africa is transforming urban landscapes expected to provide shelter for more than 50% of Africa's population by 2030. Consequently, the burden of malaria is increasingly affecting the urban population, while socio-economic inequalities within the urban settings are intensified. Few studies, relying mostly on moderate to high resolution datasets and standard predictive variables such as building and vegetation density, have tackled the topic of modeling intra-urban malaria at the city extent. In this research, we investigate the contribution of very-high-resolution satellite-derived land-use, land-cover and population information for modeling the spatial distribution of urban malaria prevalence across large spatial extents. As case studies, we apply our methods to two Sub-Saharan African cities, Kampala and Dar es Salaam. METHODS:Openly accessible land-cover, land-use, population and OpenStreetMap data were employed to spatially model Plasmodium falciparum parasite rate standardized to the age group 2-10 years (PfPR2-10) in the two cities through the use of a Random Forest (RF) regressor. The RF models integrated physical and socio-economic information to predict PfPR2-10 across the urban landscape. Intra-urban population distribution maps were used to adjust the estimates according to the underlying population. RESULTS:The results suggest that the spatial distribution of PfPR2-10 in both cities is diverse and highly variable across the urban fabric. Dense informal settlements exhibit a positive relationship with PfPR2-10 and hotspots of malaria prevalence were found near suitable vector breeding sites such as wetlands, marshes and riparian vegetation. In both cities, there is a clear separation of higher risk in informal settlements and lower risk in the more affluent neighborhoods. Additionally, areas associated with urban agriculture exhibit higher malaria prevalence values. CONCLUSIONS:The outcome of this research highlights that populations living in informal settlements show higher malaria prevalence compared to those in planned residential neighborhoods. This is due to (i) increased human exposure to vectors, (ii) increased vector density and (iii) a reduced capacity to cope with malaria burden. Since informal settlements are rapidly expanding every year and often house large parts of the urban population, this emphasizes the need for systematic and consistent malaria surveys in such areas. Finally, this study demonstrates the importance of remote sensing as an epidemiological tool for mapping urban malaria variations at large spatial extents, and for promoting evidence-based policy making and control efforts
Chariotry and prone burials: reassessing late Shang China's relationship with its northern neighbours
No full textIn place of the traditional view that raids and invasion from the north introduced new weapons and chariots to the Shang (c. 1200 BC), we argue that archaeological evidence illustrates the presence of several regional groups at or near the late Shang centre, Anyang. Here we review burial practices at Anyang dating to the late second millennium BC, and describe a substantial group of prone burials that reflect a ritual practice contrasting with that of the predominant Shang elite. Such burials occur at all social levels, from victims of sacrifice to death attendants, and include members of lower and higher elites. Particularly conspicuous are chariot drivers in some chariot pits. An elite-level link with chariots is confirmed by the burial of a military leader in tomb M54 at Huayuanzhuang at Anyang, with tools that match exactly those of chariot drivers. Given that prone burial is known to the north, in the Mongolian region that provided chariots and horses to the Shang, a route can be traced eastwards and southwards, down the Yellow River, and then through mountain basins to Anyang. Our inference is that a group originally from outside the Central Plains can be identified in these distinctive burials. This marks a first step towards understanding the heterogeneity in the central population of the late Shang