To end the global tuberculosis epidemic, latent tuberculosis infection needs to be addressed. All standard treatments for latent tuberculosis contain drugs to which multidrug-resistant (MDR) ...Mycobacterium tuberculosis is resistant. We aimed to estimate the global burden of multidrug-resistant latent tuberculosis infection to inform tuberculosis elimination policy.
By fitting a flexible statistical model to tuberculosis drug resistance surveillance and survey data collated by WHO, we estimated national trends in the proportion of new tuberculosis cases that were caused by MDR strains. We used these data as a proxy for the proportion of new infections caused by MDR M tuberculosis and multiplied trends in annual risk of infection from previous estimates of the burden of latent tuberculosis to generate trends in the annual risk of infection with MDR M tuberculosis. These estimates were used in a cohort model to estimate changes in the global and national prevalence of latent infection with MDR M tuberculosis. We also estimated recent infection levels (ie, in 2013 and 2014) and made predictions for the future burden of MDR tuberculosis in 2035 and 2050.
19·1 million (95% uncertainty interval UI 16·4 million–21·7 million) people were latently infected with MDR tuberculosis in 2014—a global prevalence of 0·3% (95% UI 0·2–0·3). MDR strains accounted for 1·2% (95% UI 1·0–1·4) of the total latent tuberculosis burden overall, but for 2·9% (95% UI 2·6–3·1) of the burden among children younger than 15 years (risk ratio for those younger than 15 years vs those aged 15 years or older 2·65 95% UI 2·11–3·25). Recent latent infection with MDR M tuberculosis meant that 1·9 million (95% UI 1·7 million–2·3 million) people globally were at high risk of active MDR tuberculosis in 2015.
We estimate that three in every 1000 people globally carry latent MDR tuberculosis infection, and prevalence of MDR M tuberculosis in those with latent tuberculosis infection is more than double among those younger than 15 years. If current trends continue, the proportion of latent tuberculosis caused by MDR strains will increase, which will pose serious challenges for management of latent tuberculosis—a cornerstone of tuberculosis elimination strategies.
UK Medical Research Council, Bill & Melinda Gates Foundation, and European Research Council.
Large experimental programmes in the fields of nuclear and particle physics search for evidence of physics beyond that explained by current theories. The observation of the Higgs boson completed the ...set of particles predicted by the standard model, which currently provides the best description of fundamental particles and forces. However, this theory's limitations include a failure to predict fundamental parameters, such as the mass of the Higgs boson, and the inability to account for dark matter and energy, gravity, and the matter-antimatter asymmetry in the Universe, among other phenomena. These limitations have inspired searches for physics beyond the standard model in the post-Higgs era through the direct production of additional particles at high-energy accelerators, which have so far been unsuccessful. Examples include searches for supersymmetric particles, which connect bosons (integer-spin particles) with fermions (half-integer-spin particles), and for leptoquarks, which mix the fundamental quarks with leptons. Alternatively, indirect searches using precise measurements of well predicted standard-model observables allow highly targeted alternative tests for physics beyond the standard model because they can reach mass and energy scales beyond those directly accessible by today's high-energy accelerators. Such an indirect search aims to determine the weak charge of the proton, which defines the strength of the proton's interaction with other particles via the well known neutral electroweak force. Because parity symmetry (invariance under the spatial inversion (x, y, z) → (-x, -y, -z)) is violated only in the weak interaction, it provides a tool with which to isolate the weak interaction and thus to measure the proton's weak charge
. Here we report the value 0.0719 ± 0.0045, where the uncertainty is one standard deviation, derived from our measured parity-violating asymmetry in the scattering of polarized electrons on protons, which is -226.5 ± 9.3 parts per billion (the uncertainty is one standard deviation). Our value for the proton's weak charge is in excellent agreement with the standard model
and sets multi-teraelectronvolt-scale constraints on any semi-leptonic parity-violating physics not described within the standard model. Our results show that precision parity-violating measurements enable searches for physics beyond the standard model that can compete with direct searches at high-energy accelerators and, together with astronomical observations, can provide fertile approaches to probing higher mass scales.
Highlights • A GABAA receptor-active neurosteroid analog, ganaxolone, reinstated ethanol seeking in mice. • An extrasynaptic GABAA receptor agonist, gaboxadol (THIP), did not reinstate ethanol ...seeking. • Direct extrasynaptic GABAA receptor activation is not sufficient to reinstate ethanol seeking.
We present an analysis of high-precision pulsar timing data taken as part of the North American Nanohertz Observatory for Gravitational Waves (NANOGrav) project. We have observed 17 pulsars for a ...span of roughly five years using the Green Bank and Arecibo radio telescopes. We analyze these data using standard pulsar timing models, with the addition of time-variable dispersion measure and frequency-variable pulse shape terms. Sub-microsecond timing residuals are obtained in nearly all cases, and the best rms timing residuals in this set are ~30-50 ns. We present methods for analyzing post-fit timing residuals for the presence of a gravitational wave signal with a specified spectral shape. These optimally take into account the timing fluctuation power removed by the model fit, and can be applied to either data from a single pulsar, or to a set of pulsars to detect a correlated signal. We apply these methods to our data set to set an upper limit on the strength of the nHz-frequency stochastic supermassive black hole gravitational wave background of h sub(c)(1 yr super(-1)) < 7 x 10 super(-15) (95%). This result is dominated by the timing of the two best pulsars in the set, PSRs J1713+0747 and J1909-3744.
The European Society for Medical Oncology (ESMO) held a virtual consensus-building process on epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer in 2021. The consensus included ...a multidisciplinary panel of 34 leading experts in the management of lung cancer. The aim of the consensus was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where the available evidence is either limited or conflicting. The main topics identified for discussion were: (i) tissue and biomarkers analyses; (ii) early and locally advanced disease; (iii) metastatic disease and (iv) clinical trial design, patient’s perspective and miscellaneous. The expert panel was divided into four working groups to address questions relating to one of the four topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the recommendations developed, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation.
•A virtual consensus on the management of EGFR-mutant NSCLC was organized by the ESMO, including 34 experts from 18 countries.•The experts compiled recommendations with supporting evidence on controversial topics about the EGFR-mutant lung cancer.•Recommendations were formulated for tissue and biomarkers analyses; early, locally advanced and metastatic disease; miscellaneous.
The Gene Ontology (GO) is a comprehensive resource of computable knowledge regarding the functions of genes and gene products. As such, it is extensively used by the biomedical research community for ...the analysis of -omics and related data. Our continued focus is on improving the quality and utility of the GO resources, and we welcome and encourage input from researchers in all areas of biology. In this update, we summarize the current contents of the GO knowledgebase, and present several new features and improvements that have been made to the ontology, the annotations and the tools. Among the highlights are 1) developments that facilitate access to, and application of, the GO knowledgebase, and 2) extensions to the resource as well as increasing support for descriptions of causal models of biological systems and network biology. To learn more, visit http://geneontology.org/.
An interesting and so far unexplained feature of chronic pain in autoimmune disease is the frequent disconnect between pain and inflammation. This is illustrated well in rheumatoid arthritis (RA) ...where pain in joints (arthralgia) may precede joint inflammation and persist even after successful anti-inflammatory treatment. In the present study, we have addressed the possibility that autoantibodies against citrullinated proteins (ACPA), present in RA, may be directly responsible for the induction of pain, independent of inflammation.
Antibodies purified from human patients with RA, healthy donors and murinised monoclonal ACPA were injected into mice. Pain-like behaviour was monitored for up to 28 days, and tissues were analysed for signs of pathology. Mouse osteoclasts were cultured and stimulated with antibodies, and supernatants analysed for release of factors. Mice were treated with CXCR1/2 (interleukin (IL) 8 receptor) antagonist reparixin.
Mice injected with either human or murinised ACPA developed long-lasting pronounced pain-like behaviour in the absence of inflammation, while non-ACPA IgG from patients with RA or control monoclonal IgG were without pronociceptive effect. This effect was coupled to ACPA-mediated activation of osteoclasts and release of the nociceptive chemokine CXCL1 (analogue to human IL-8). ACPA-induced pain-like behaviour was reversed with reparixin.
The data suggest that CXCL1/IL-8, released from osteoclasts in an autoantibody-dependent manner, produces pain by activating sensory neurons. The identification of this new pain pathway may open new avenues for pain treatment in RA and also in other painful diseases associated with autoantibody production and/or osteoclast activation.
Skill decay is a recognised problem in resuscitation training. Spaced learning has been proposed as an intervention to optimise resuscitation skill performance compared to traditional massed ...learning. A systematic review was performed to answer ‘In learners taking resuscitation courses, does spaced learning compared to massed learning improve educational outcomes and clinical outcomes?’
This systematic review followed the PRISMA guidelines. We searched bibliographic databases (Embase, MEDLINE and the Cochrane Library (CENTRAL)) from inception to 2 December 2019. Randomised controlled trials and non-randomised studies were eligible for inclusion. Two reviewers independently scrutinized studies for relevance, extracted data and assessed quality of studies. Risk of bias of studies and quality of evidence were assessed using RoB, ROBINS-I tool and GRADEpro respectively. Educational outcomes studied were skill retention and performance 1 year after completion of training; skill performance between completion of training and 1 year; and knowledge at course conclusion. Clinical outcomes were skill performance at actual resuscitation, patient survival to discharge with favourable neurological outcome. This systematic review was registered in PROSPERO (CRD42019150358).
From 2,042 references, we included data from 17 studies (13 randomised studies, 4 cohort studies) in courses with manikins and simulation in the narrative synthesis. Eight studies reported results from basic life support training (with or without automatic external defibrillator); three studies reported from paediatric life support training; five were in neonatal resuscitation and one study reported results from a bespoke emergency medicine course which included resuscitation teaching. Fifteen out of seventeen studies reported improved performance with the use of spaced learning. The overall certainty of evidence was rated as very low for all outcomes primarily due to a very serious risk of bias. Heterogeneity across studies precluded any meta-analyses. There was a lack of data on the effectiveness of spaced learning on skill acquisition compared to maintaining skill performance and/or preventing skill decay. There was also insufficient data to examine the effectiveness of spaced learning on laypeople compared to healthcare providers.
Despite the very low certainty of evidence this systematic review suggests that spaced learning can improve skill performance at 1 year post course conclusion and skill performance between course conclusion and 1 year. There is a lack of data from this educational intervention on skill performance in clinical resuscitation and patient survival at discharge with favourable neurological outcomes.
•Numerical noise is studied in a finite particle number system, by kernel density estimation.•Ornstein-Uhlenbeck bridge describes the electric field correlations.•Optimal kernel width minimizes the ...error by bias-variance optimization.•Particle shapes of arbitrary width are possible, and partition of unity gives charge conservation on the grid.•Results apply to particle-in-cell (PIC), delta-f, and hybrid methods.
In this paper we analyze the noise in macro-particle methods used in plasma physics and fluid dynamics, leading to approaches for minimizing the total error, focusing on electrostatic models in one dimension. We begin by describing kernel density estimation for continuous values of the spatial variable x, expressing the kernel in a form in which its shape and width are represented separately. The covariance matrix C(x,y) of the noise in the density is computed, first for uniform true density. The bandwidth of the covariance matrix is related to the width of the kernel. A feature that stands out is the presence of constant negative terms in the elements of the covariance matrix both on and off-diagonal. These negative correlations are related to the fact that the total number of particles is fixed at each time step; they also lead to the property ∫C(x,y)dy=0. We investigate the effect of these negative correlations on the electric field computed by Gauss's law, finding that the noise in the electric field is related to a process called the Ornstein-Uhlenbeck bridge, leading to a covariance matrix of the electric field with variance significantly reduced relative to that of a Brownian process.
For non-constant density, ρ(x), still with continuous x, we analyze the total error in the density estimation and discuss it in terms of bias-variance optimization (BVO). For some characteristic length l, determined by the density and its second derivative, and kernel width h, having too few particles within h leads to too much variance; for h that is large relative to l, there is too much smoothing of the density. The optimum between these two limits is found by BVO. For kernels of the same width, it is shown that this optimum (minimum) is weakly sensitive to the kernel shape.
We repeat the analysis for x discretized on a grid. In this case the charge deposition rule is determined by a particle shape. An important property to be respected in the discrete system is the exact preservation of total charge on the grid; this property is necessary to ensure that the electric field is equal at both ends, consistent with periodic boundary conditions. We find that if the particle shapes satisfy a partition of unity property, the particle charge deposited on the grid is conserved exactly. Further, if the particle shape is expressed as the convolution of a kernel with another kernel that satisfies the partition of unity, then the particle shape obeys the partition of unity. This property holds for kernels of arbitrary width, including widths that are not integer multiples of the grid spacing.
We show results relaxing the approximations used to do BVO optimization analytically, by doing numerical computations of the total error as a function of the kernel width, on a grid in x. The comparison between numerical and analytical results shows good agreement over a range of particle shapes.
We discuss the practical implications of our results, including the criteria for design and implementation of computationally efficient particle shapes that take advantage of the developed theory.
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