In silico evaluation of WHO-endorsed molecular methods to detect drug resistant tuberculosis

Universal drug susceptibility testing (DST) for tuberculosis is a major goal of the END TB strategy. PCR-based molecular diagnostic tests have been instrumental in increasing DST globally and several assays have now been endorsed by the World Health Organization (WHO) for use in the diagnosis of drug resistance. These endorsed assays, however, each interrogate a limited number of mutations associated with resistance, potentially limiting their sensitivity compared to sequencing-based methods. We applied an in silico method to compare the sensitivity and specificity of WHO-endorsed molecular based diagnostics to the mutation set identified by the WHO mutations catalogue using phenotypic DST as the reference. We found that, in silico, the mutation sets used by probe-based molecular diagnostic tests to identify rifampicin, isoniazid, pyrazinamide, levofloxacin, moxifloxacin, amikacin, capreomycin and kanamycin resistance produced similar sensitivities and specificities to the WHO mutation catalogue. PCR-based diagnostic tests were most sensitive for drugs where mechanisms of resistance are well established and localised to small genetic regions or a few prevalent mutations. Approaches using sequencing technologies can provide advantages for drugs where our knowledge of resistance is limited, or where complex resistance signatures exist

Alternative splicing regulates stochastic NLRP3 activity

Leucine-rich repeat (LRR) domains are evolutionarily conserved in proteins that function in development and immunity. Here we report strict exonic modularity of LRR domains of several human gene families, which is a precondition for alternative splicing (AS). We provide evidence for AS of LRR domain within several Nod-like receptors, most prominently the inflammasome sensor NLRP3. Human NLRP3, but not mouse NLRP3, is expressed as two major isoforms, the full-length variant and a variant lacking exon 5. Moreover, NLRP3 AS is stochastically regulated, with NLRP3. exon 5 lacking the interaction surface for NEK7 and hence loss of activity. Our data thus reveals unexpected regulatory roles of AS through differential utilization of LRRs modules in vertebrate innate immunity

PRex: an experiment to investigate detection of near-field particulate deposition from a simulated underground nuclear weapons test vent

A radioactive particulate release experiment to produce a near-field ground deposition representative of small-scale venting from an underground nuclear test was conducted to gather data in support of treaty capability development activities. For this experiment, aCO₂‐driven “air cannon” was used to inject ¹⁴⁰La, a radioisotope of lanthanum with 1.7‐d half-life and strong gamma-ray emissions, into the lowest levels of the atmosphere at ambient temperatures.Witness plates and air samplers were laid out in an irregular grid covering the area where the plume was anticipated to deposit based on climatological wind records. This experiment was performed at the Nevada National Security Site, where existing infrastructure, radiological procedures, and support personnel facilitated planning and execution of the work. A vehicle-mounted NaI(Tl) spectrometer and a polyvinyl toluene-based backpack instrument were used to survey the deposited plume. Hand-held instruments, including NaI(Tl) and lanthanum bromide scintillators and high purity germanium spectrometers, were used to take in situ measurements. Additionally, three soil sampling techniques were investigated and compared. The relative sensitivity and utility of sampling and survey methods are discussed in the context of on-site inspection.Keywords: environmental transport, airborne, radioactivity, atomic bomb, accidents, transpor

Description and consequences of sexual violence in Ituri province, Democratic Republic of Congo

ABSTRACT: BACKGROUND: The war in eastern Democratic Republic of Congo has been the subject of numerous studies related to the problem of sexual violence. Historically, such violence is known to be part of strategic war plans to conquer and destroy communities, but it is now unfortunately prevalent in times of relative calm. METHODS: We describe the characteristics and consequences of sexual violence in Ituri province of Democratic Republic of Congo through the retrospective analysis of 2,565 patients who received medical care in the Medecins Sans Frontieres sexual violence clinic in the capital of Ituri province, Bunia, between September 2005 and December 2006. Using a standardised questionnaire, we report patients' demographics, number and status of aggressor(s), forced detention and violent threats among other variables for all patients presenting for medical consultation after a sexually violent event during this period. RESULTS: Ninety-six percent of our cohort were female and 29.3% minors, 18-29 years was the most represented age group. Acts of sexual violence (n= 2,565) were reported to be mainly perpetrated by men with military affiliations (73%), although civilians were implicated in 21% of crimes. The attack was perpetrated by two or more persons in over 74% of cases and most commonly perpetrators were unknown armed males, (87.2%). Male victims accounted for 4% (n=103) of our cohort. Forty-eight percent of our patients reported being attacked whilst performing daily domestic duties outside the home and 18% of victims being detained by their perpetrators, the majority of whom were held for less than 2 weeks (61.6%). CONCLUSIONS: The characteristics of sexually violent acts in Ituri province during this period cannot be simply explained as a 'weapon of war' as described in the literature, meaning the use of sexual violence within a military strategy where it is employed under the orders of a commander to harm a particular community. Whilst the majority of aggressions were by armed men there was an important proportion in which civilian perpetrators were implicated. This type of violence has become part of the general characteristics of violence in this war-torn population. Sometimes, as a means for some military factions to acquire remuneration with impunity and for some civilians, a means to counteract confronting, changing social norms occurring during chronic conflict

The future of zoonotic risk prediction

In the light of the urgency raised by the COVID-19 pandemic, global investment in wildlife virology is likely to increase, and new surveillance programmes will identify hundreds of novel viruses that might someday pose a threat to humans. To support the extensive task of laboratory characterization, scientists may increasingly rely on data-driven rubrics or machine learning models that learn from known zoonoses to identify which animal pathogens could someday pose a threat to global health. We synthesize the findings of an interdisciplinary workshop on zoonotic risk technologies to answer the following questions. What are the prerequisites, in terms of open data, equity and interdisciplinary collaboration, to the development and application of those tools? What effect could the technology have on global health? Who would control that technology, who would have access to it and who would benefit from it? Would it improve pandemic prevention? Could it create new challenges? This article is part of the theme issue 'Infectious disease macroecology: parasite diversity and dynamics across the globe'.Peer reviewe

A Strategic Orientation Model for the Turkish Local e-Governments

Increased environmental uncertainty and complexity along with budget constraints requires public organizations to manage strategically as never before. The environments of public organizations have become increasingly turbulent and more firmly interconnected. During the past two decades, governments have innovated new management tools such as strategic planning, outsourcing, and performance measurement to deal with complex governance and networks to provide their public services. Meanwhile, the drive to implement e-government has resulted in the formulation of many e-government visions and strategies, driven by their own sets of political, economic, and social factors and requirements. With this regard, recent developments in e-service provision of Turkish Local e-Governments deserve empirical and well-structured research. Building on the recent literature, this study draws a strategic orientation framework and tests it by analyzing the contents of strategic documents of 114 Turkish Local e-Governments

Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine

The future of zoonotic risk prediction

In the light of the urgency raised by the COVID-19 pandemic, global investment in wildlife virology is likely to increase, and new surveillance programmes will identify hundreds of novel viruses that might someday pose a threat to humans. To support the extensive task of laboratory characterization, scientists may increasingly rely on data-driven rubrics or machine learning models that learn from known zoonoses to identify which animal pathogens could someday pose a threat to global health. We synthesize the findings of an interdisciplinary workshop on zoonotic risk technologies to answer the following questions. What are the prerequisites, in terms of open data, equity and interdisciplinary collaboration, to the development and application of those tools? What effect could the technology have on global health? Who would control that technology, who would have access to it and who would benefit from it? Would it improve pandemic prevention? Could it create new challenges? This article is part of the theme issue ‘Infectious disease macroecology: parasite diversity and dynamics across the globe’.NSF BII 2021909; the University of Toronto EEB Fellowship; the Wellcome Trust; the National Institute of Allergy and Infectious Diseases of the National Institutes of Health and the Defense Threat Reduction Agency.http://rstb.royalsocietypublishing.orgam2022Medical Virolog