Global burden of drug-resistant tuberculosis in children: a mathematical modelling study

Background: After infection with Mycobacterium tuberculosis, children are at an increased risk of progression to tuberculosis disease; a condition that can be challenging to diagnose. New estimation approaches for children have highlighted the gap between incidence and notifications of M tuberculosis, and suggest there are more cases of isoniazid-resistant and multidrug-resistant (MDR) disease than are identified. No work has yet quantified the burden of drug-resistant infection, or accounted for other types of drug resistance or sampling uncertainty. Methods: We combined a mathematical model of tuberculosis in children with an analysis of drug-resistance patterns to produce country-level, regional, and global estimates of drug-resistant infection and disease. We determined drug resistance using data from the Global Project on Antituberculosis Drug Resistance Surveillance at WHO, from surveys and surveillance reported between 1988 and 2014. We combined 1000 sampled proportions for each country from a Bayesian approach with 10 000 sampled country estimates of tuberculosis disease incidence and M tuberculosis infection prevalence. We estimated the proportions of tuberculosis cases at a country level with isoniazid monoresistance, rifampicin monoresistance, multidrug resistance (MDR), fluoroquinolone-resistant multidrug resistance, second-line injectable-resistant multidrug resistance, and extensive multidrug resistance with resistance to both a fluoroquinolone and a second-line injectable (XDR). Findings: We estimated that 850 000 children developed tuberculosis in 2014; 58 000 with isoniazid-monoresistant tuberculosis, 25 000 with MDR tuberculosis, and 1200 with XDR tuberculosis. We estimate 67 million children are infected with M tuberculosis; 5 million with isoniazid monoresistance, 2 million with MDR, and 100 000 with XDR. Africa and southeast Asia have the highest numbers of children with tuberculosis, but the WHO Eastern Mediterranean region, European region, and Western Pacific region also contribute substantially to the burden of drug-resistant tuberculosis because of their much higher proportions of resistance. Interpretation: Far more drug-resistant tuberculosis occurs in children than is diagnosed, and there is a large pool of drug-resistant infection. This finding has implications for approaches to empirical treatment and preventive therapy in some regions of the world

The global impact of household contact management for children on multidrug-resistant and rifampicin-resistant tuberculosis cases, deaths, and health-system costs in 2019: a modelling study

Background: Estimates suggest that at least 30 000 children develop multidrug-resistant or rifampicin-resistant tuberculosis each year. Despite household contact management (HCM) being widely recommended, it is rarely done. Methods: We used mathematical modelling to evaluate the potential country-level and global effects and cost-effectiveness of multidrug-resistant or rifampicin-resistant tuberculosis HCM for children younger than 15 years who are living with a person with newly diagnosed multidrug-resistant or rifampicin-resistant tuberculosis. We compared a baseline of no HCM with several HCM strategies and tuberculosis preventive therapy regimens, calculating the effect on multidrug-resistant or rifampicin-resistant tuberculosis cases, deaths, and health-system costs. All HCM strategies involved the screening of children for prevalent tuberculosis disease but with tuberculosis preventive therapy either not given or targeted dependent on age, HIV status, and result of tuberculin skin test. We evaluated the use of fluoroquinolones (ie, levofloxacin and moxifloxacin), delamanid, and bedaquiline as tuberculosis preventive therapy. Findings: Compared with a baseline without HCM, HCM for all adults diagnosed with multidrug-resistant or rifampicin-resistant tuberculosis in 2019 would have entailed screening 227 000 children (95% uncertainty interval [UI]: 205 000–252 000) younger than 15 years globally, and averted 2350 tuberculosis deaths (1940–2790), costing an additional US$63 million (74–95 million). If all the children within the household who had been in contact with the person with multidrug-resistant or rifampicin-resistant tuberculosis received tuberculosis preventive therapy with levofloxacin, 5620 incident tuberculosis cases (95% UI 4540–6890) and an additional 1240 deaths (970–1540) would have been prevented. Incremental cost-effectiveness ratios were lower than half of per-capita gross domestic product for most interventions in most countries. Targeting only children younger than 5 years and those living with HIV reduced the number of incident cases and deaths averted, but improved cost-effectiveness. Tuberculosis preventive therapy with delamanid increased the effect, in terms of reduced incidence and mortality, compared with levofloxacin. Interpretation: HCM for patients with multidrug-resistant or rifampicin-resistant tuberculosis is cost-effective in most settings and could avert a substantial proportion of multidrug-resistant or rifampicin-resistant tuberculosis cases and deaths in children globally. Funding: UK Medical Research Council

Magnetic susceptibilities, specific heat, and crystal structure of four S = 3/2, three-dimensional antiferromagnets

The zero-field, ac magnetic susceptibilities of single crystals of four S=3/2 trigonal salts containing the tris(1,2-diaminoethane)chromium(III) cation, [Cr(en)3]3+, and heat-capacity measurements on one of them, [Na(OH2)6][Cr(en)3]2Cl7, are reported. The crystal structures of two of them, [Na(OH2)6][Cr(en3]2Cl7 and [Na(OH)2)6][Cr(en)3]2Br6Cl, have been determined. They both belong to the trigonal P3¯cl space group, with a=11.513(2), c=15.566(6) Å; Z=2; and a=11.740(5), c=16.008(9) Å; Z=2, respectively, and contain discrete octahedral hexaquasodium (i) cations. The salt [K(OH2)6][Cr(en)3]2Cl7 appears to be isomorphous with its sodium analog, and [Cr(en)3]Cl3·3H2O belongs to the same space group. The magnetic measurements on the four salts extend over the temperature interval 60 mK to 4.2 K, and antiferromagnetic ordering is found in all of them. The zero-field-splitting energy is of the same order of magnitude as the magnetic exchange energy. The susceptibility data have been fitted with the parameters 2D/kB=-0.091(8) K, g?=1.994, g¿=1.988, and zJ/kB=-0.061(2) K for [Cr(en)3]Cl3·3H2O; 2D/kB=-0.058(8) K, g?=2.01, g¿=2.00, and zJ/kB=-0.068(4) K for [Na(OH2)6][Cr(en)3]2Cl7; 2D/kB =-0.060(8) K, g?=1.993, g¿=1.951, and zJ/kB=-0.046(4) K for [K(OH2)6][Cr(en)3]2Cl7; and 2D/kB=+0.064(8) K, g?=2.001, g¿=1.991, and zJ/kB=-0.066(4) K for [Na(OH2)6][Cr(en)3]2Br6Cl, where longitudinal (¿) and transverse (¿) refer to the unique threefold crystallographic axis. The ordering temperatures are 0.124(5), 0.116(5), 0.093(5), and 0.112(5) K, respectively. The easy axis for the chloride compounds lies parallel to the longitudinal axis, whereas the easy axis for the bromide lies in the transverse plane. Heat-capacity measurements on [Na(OH2)6][Cr(en)3]2Cl7 confirm that magnetic ordering takes place at 0.112(5) K. The heat-capacity curve and magnetic entropy calculations agree with the three-dimensional character of the ordering of an S=3/2, effective bcc magnetic lattice

Global impact of COVID-19 on childhood tuberculosis: an analysis of notification data

Background There is concern that the COVID-19 pandemic has damaged global childhood tuberculosis management. Quantifying changes in childhood tuberculosis notifications could support more targeted interventions to restore childhood tuberculosis services. We aimed to use time-series modelling to evaluate the impact of COVID-19 on child tuberculosis notifications. Methods Annual tuberculosis case notification data reported to WHO by 215 countries were used to calculate annual notification counts for the years 2014–20, stratified by age groups (0–4, 5–14, and ≥15 years) and sex. We used time-series modelling to predict notification counts for 2020, and calculated differences between these predictions and observed notifications in 2020 for each of the six WHO regions and at the country level for 30 countries with high tuberculosis burden. We assessed associations between these differences and the COVID-19 stringency index, a measure of COVID-19 social impact. Findings From 2014 to 2019, annual tuberculosis notification counts increased across all age groups and WHO regions. More males than females in the 0–4 years age group and ≥15 years age group had notifications in all years from 2014 to 2020 and in all WHO regions. In the 5–14 years age group, more females than males were notified globally in all years, although some WHO regions had higher notifications from males than females. In 2020, global notifications were 35·4% lower than predicted (95% prediction interval –30·3 to –39·9; 142 525 observed vs 220 794 predicted notifications [95% prediction interval 204 509 to 237 078]) for children aged 0–4 years, 27·7% lower (–23·4 to –31·5; 256 398 vs 354 578 [334 724 to 374 431]) in children aged 5–14 years, and 18·8% lower (–15·4 to –21·9; 5 391 753 vs 6 639 547 [6 375 086 to 6 904 007]) for people aged 15 years or older. Among those aged 5–14 years, the reduction in observed relative to predicted notifications for 2020 was greater in males (–30·9% [–24·8 to –36·1]) than females (–24·5% [–18·1 to –29·9]). Among 28 countries with high tuberculosis burden, no association was observed between the stringency of COVID-19 restrictions and the relative difference in observed versus predicted notifications. Interpretation Our findings suggest that COVID-19 has substantially affected childhood tuberculosis services, with the youngest children most affected. Although children have mostly had fewer severe health consequences from COVID-19 than have adults, they have been disproportionately affected by the effects of the pandemic on tuberculosis care. Observed sex differences suggest that targeted interventions might be required. As countries rebuild health systems following the COVID-19 pandemic, it is crucial that childhood tuberculosis services are placed centrally within national strategic plans

Counting children with tuberculosis: why numbers matter.

In the last 5 years, childhood tuberculosis (TB) has received increasing attention from international organisations, national TB programmes and academics. For the first time, a number of different groups are developing techniques to estimate the burden of childhood TB. We review the challenges in diagnosing TB in children and the reasons why cases in children can go unreported. We discuss the importance of an accurate understanding of burden for identifying problems in programme delivery, targeting interventions, monitoring trends, setting targets, allocating resources appropriately and providing strong advocacy. We briefly review the estimates produced by new analytical methods, and outline the reasons for recent improvements in our understanding and potential future directions. We conclude that while innovation, collaboration and better data have improved our understanding of the childhood TB burden, it remains substantially incomplete

Looking forward through the past: identification of 50 priority research questions in palaeoecology

1. Priority question exercises are becoming an increasingly common tool to frame future agendas in conservation and ecological science. They are an effective way to identify research foci that advance the field and that also have high policy and conservation relevance. 2. To date, there has been no coherent synthesis of key questions and priority research areas for palaeoecology, which combines biological, geochemical and molecular techniques in order to reconstruct past ecological and environmental systems on time-scales from decades to millions of years. 3. We adapted a well-established methodology to identify 50 priority research questions in palaeoecology. Using a set of criteria designed to identify realistic and achievable research goals, we selected questions from a pool submitted by the international palaeoecology research community and relevant policy practitioners. 4. The integration of online participation, both before and during the workshop, increased international engagement in question selection. 5. The questions selected are structured around six themes: human–environment interactions in the Anthropocene; biodiversity, conservation and novel ecosystems; biodiversity over long time-scales; ecosystem processes and biogeochemical cycling; comparing, combining and synthesizing information from multiple records; and new developments in palaeoecology. 6. Future opportunities in palaeoecology are related to improved incorporation of uncertainty into reconstructions, an enhanced understanding of ecological and evolutionary dynamics and processes and the continued application of long-term data for better-informed landscape management

Search for Darkonium in e+e- Collisions

Collider searches for dark sectors, new particles interacting only feebly with ordinary matter, have largely focused on identifying signatures of new mediators, leaving much of dark sector structures unexplored. In particular, the existence of dark matter bound states (darkonia) remains to be investigated. This possibility could arise in a simple model in which a dark photon (A0 ) is light enough to generate an attractive force between dark fermions. We report herein a search for a JPC ¼ 1−− darkonium state, the ϒD, produced in the reaction eþe− → γϒD, ϒD → A0 A0 A0 , where the dark photons subsequently decay into pairs of leptons or pions, using 514 fb−1 of data collected with the BABAR detector. No significant signal is observed, and we set bounds on the γ − A0 kinetic mixing as a function of the dark sector coupling constant for 0.001 < mA0 < 3.16 GeV and 0.05 < mϒD < 9.5 GeV.publishedVersio

Building a tuberculosis-free world: The Lancet Commission on tuberculosis

___Key messages___ The Commission recommends five priority investments to achieve a tuberculosis-free world within a generation. These investments are designed to fulfil the mandate of the UN High Level Meeting on tuberculosis. In addition, they answer