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Abstract Our aim was to explore if different exposure windows for sunshine or temperature are associated with increased suicidal behaviour among people starting antidepressant treatment. 307 completed and 1674 attempted suicides were included as cases in the conditional logistic regression analyses, while controlling for potential confounders, including season, as well as temperature and hours of sunshine when these variables were not the main exposure variable. Ten controls were matched to each case using risk-set sampling. The role of season, age, and sex was examined with likelihood ratio tests (LRTs) with and without the respective interaction terms and with stratified analyses. There was no overall association between temperature or sunshine with suicidal behaviour. Age was a significant effect modifier for suicide and suicide attempt for both sunshine and temperature exposure. In stratified analyses, an increase of one degree Celsius in the average daily temperature during the last 4 weeks was associated, in the unadjusted model, with a 3% increase in the rate of suicide (p = 0.023) amongst older patients (65+). In the same age group, an increase of 1 h in the average daily sunshine during the last 4 weeks was associated with an 8% increase in the rate of suicide attempt (p = 0.002), while the respective increase for the exposure period of 5–8 weeks was 7% (p = 0.007). An increase of one degree Celsius in the average daily temperature during the last 4 weeks was associated with a 3% increase in the rate of suicide attempt (p = 0.007). These associations did not retain statistical significance in the adjusted models. No associations were found in the other age groups. Our results point to a possible effect modification by age, with higher risk of suicidal behavior associated with an increase in sunshine and temperature found in the older age groups.

Abstract Background Successful treatment of latent tuberculosis infection (LTBI) is essential to reduce tuberculosis (TB) incidence rates in low-burden countries. This study measures treatment completion and determinants of non-completion of LTBI treatment in Norway in 2016. Methods This prospective cohort study included all individuals notified with LTBI treatment to the Norwegian Surveillance System for Infectious Diseases (MSIS) in 2016. We obtained data from MSIS and from a standardized form that was sent to health care providers at the time of patient notification to MSIS. We determined completion rates. Pearson’s chi squared test was used to study associations between pairs of categorical variables and separate crude and multivariable logistic regression models were used to identify factors associated with treatment completion and adverse drug effects. Results We obtained information on treatment completion from 719 of the 726 individuals notified for LTBI treatment in 2016. Overall, 91% completed treatment. Treatment completion was highest in the foreign-born group [foreign-born, n = 562 (92%) vs Norwegian-born, n = 115 (85%), p = 0.007]. Treatment completion did not differ significantly between prescribed regimens (p = 0.124). Adverse events were the most common reason for incomplete treatment. We found no significant differences in adverse events when comparing weekly rifapentine (3RPH) with three months daily isoniazid and rifampicin (3RH). However, there were significantly fewer adverse events with 3RPH compared to other regimens (p = 0.037). Age over 35 years was significantly associated with adverse events irrespective of regimen (p = 0.024), whereas immunosuppression was not significantly associated with adverse events after adjusting for other variables (p = 0.306). Treatment under direct observation had a significant effect on treatment completion for foreign-born (multivariate Wald p-value = 0.017), but not for Norwegian-born (multivariate Wald p-value = 0.408) individuals. Conclusions We report a very high treatment completion rate, especially among individuals from countries with high TB incidence. The follow-up from tuberculosis-coordinators and the frequent use of directly observed treatment probably contributes to this. Few severe adverse events were reported, even with increased age and in individuals that are more susceptible. While these results are promising, issues of cost-effectiveness and targeting treatment to individuals at highest risk of TB are important components of public health impact.

Abstract Protists are less studied for their role and diversity in ecosystems. Notably, protists have played and still play an important role in microbialites. Microbialites, or lithified microbial mats, represent the oldest evidence of fossil biofilms (~3.5 Gyr). Modern microbialites may offer a unique proxy to study the potential role of protists within a geological context. We examined protist diversity in freshwater (Kelly and Pavilion Lake in British Columbia, Canada) and marine (Highborne Cay, Bahamas) to hypersaline (Shark Bay, Australia) microbialites to decipher their geomicrobiological role. The freshwater microbialite communities were clearly distinct from their marine and hypersaline counterparts. Chlorophytes had higher numerical abundance in freshwater microbialites; whereas pennate diatoms dominated numerically in marine microbialites. Despite the differences, protists across ecosystems may have adopted similar roles and functions. We suggest a consistent biogeochemical role of protists across microbialites globally; but that salinity may shape protist composition and evolution in these ecosystems.

Abstract Background The delivery of safe drinking water has high public health relevance, as reflected in the Sustainable Development Goals (SDG6). Several precautionary actions have reduced the burden associated with infectious diseases in high-income countries; however, pollution in source waters, inadequate disinfection, and premise plumbing, along with an increased awareness that intrusion in the drinking water distribution system, represents risk factors for gastrointestinal illness linked to consume of drinking water. Sporadic cases of waterborne infections are expected to be underreported since a sick person is less likely to seek healthcare for a self-limiting gastrointestinal infection. Hence, knowledge on the true burden of waterborne diseases is scarce. The primary aim with the present study was to estimate the risk of gastrointestinal illness associated with drinking tap water in Norway. Methods We conducted a 12-month prospective cohort study where participants were recruited by telephone interview after invitation based on randomised selection. A start up e-survey were followed by 12 monthly SMS questionnaires to gather information on participants characteristics and drinking tap water (number of 0.2L glasses per day), incidence, duration and symptoms associated with gastrointestinal illness. Associations between the exposure of drinking tap water and the outcome of risk of acute gastrointestinal illness (AGI) were analysed with linear mixed effects models. Age, sex, education level and size of the drinking water supply were identified as potential confounders and included in the adjusted model. Results In total, 9,946 persons participated in this cohort study, accounting for 11.5% of all invited participants. According to the data per person and month (99,446 monthly submissions), AGI was reported for 5,508 person-months (5.5 per 100 person-months). Severe AGI was reported in 819 person-months (0.8 per 100 person-months). Our study estimates that 2–4% of AGI in Norway is attributable to drinking tap water. Conclusions This is the largest cohort study in Norway estimating the burden of self-reported gastrointestinal infections linked to the amount of tap water drunk in Norway. The data indicate that waterborne AGI is not currently a burden in Norway, but the findings need to be used with caution. The importance of continued efforts and investments in the maintenance of drinking water supplies in Norway to address the low burden of sporadic waterborne cases and to prevent future outbreaks needs to be emphasised.

New tuberculosis (TB) drugs with little existing antimicrobial resistance enable a pan-TB treatment regimen, intended for universal use without prior drug-susceptibility testing. However, widespread use of such a regimen could contribute to an increasing prevalence of antimicrobial resistance, potentially rendering the pan-TB regimen ineffective or driving clinically problematic patterns of resistance. We developed a model of multiple sequential TB patient cohorts to compare treatment outcomes between continued use of current standards of care (guided by rifampin-susceptibility testing) and a hypothetical pan-TB approach. A pan-TB regimen that met current target profiles was likely to initially outperform the standard of care; however, a rising prevalence of transmitted resistance to component drugs could make underperformance likely among subsequent cohorts. Although the pan-TB approach led to an increased prevalence of resistance to novel drugs, it was unlikely to cause accumulation of concurrent resistance to novel drugs and current first-line drugs.

We read with great interest the recent paper by Lo et al., who argue that there is an urgent need to ensure the quality of modelling evidence used to support international and national guideline development. Here we outline efforts by the Tuberculosis Modelling and Analysis Consortium, together with the World Health Organization Global Task Force on Tuberculosis Impact Measurement, to develop material to improve the quality and transparency of country-level tuberculosis modelling to inform decision-making.

Past anti-bacterial use of bacteriophages (phage therapy) is already well reviewed as a potential therapeutic response to the emergence of multidrug-resistant, pathogenic bacteria. Phage therapy has been limited by the following. (1) The success rate is too low for routine use and Food and Drug Administration (FDA) approval. (2) Current strategies of routine phage characterization do not sufficiently improve the success rate of phage therapy. (3) The stability of many phages at ambient temperature is not high enough to routinely store and transport phages at ambient temperature. In the present communication, we present new and previous data that we interpret as introductory to biophysically and efficiently transforming phage therapy to the needed level of effectiveness. Included are (1) procedure and preliminary data for the use of native gel electrophoresis (a low-cost procedure) for projecting the therapy effectiveness of a newly isolated phage, (2) data that suggest a way to achieve stabilizing of dried, ambient-temperature phages via polymer embedding, and (3) data that suggest means to increase the blood persistence, and therefore the therapy effectiveness, of what would otherwise be a relatively low-persistence phage.

Understanding the evolution of the solid electrolyte-electrode interface is currently one of the most challenging obstacles in the development of solid-state batteries (SSBs). Here, we develop an X-ray Photoelectron Spectroscopy (XPS) that allows for operando measurement during cycling. Based on theoretical analysis and the modulated electrode and detector co-grounding mode, the displacement of binding energy can be correlated with the surface electrostatic potential of the material, revealing the charge distribution and composition evolution of the space charge layer between the cathode and the electrolyte. In the investigation of typical LiCoO2 (LCO)/Li6PS5Cl (LPSC)/Li–In batteries, we observed the static potential difference and oxidative decomposition between LPSC and LCO, and the effectiveness of the LiNbO3 coating in reducing potential difference and inhibiting the diffusion of Co and oxidation of S species. Furthermore, our study also revealed that the potential drop between LiNi0·8Co0·1Mn0·1O2 and LPSC is smaller than that of LCO, whilst that between Li3InCl6 and LCO remains near zero. The proposed operando XPS method offers a novel approach for real-time monitoring of interface potential and species formation, providing rational guidance for the interface engineering in SSBs.

Abstract Background Colistin is one of the last resort therapeutic options for treating carbapenemase-producing Enterobacterales, which are resistant to a broad range of beta-lactam antibiotics. However, the increased use of colistin in clinical and livestock farming settings in Thailand and China, has led to the inevitable emergence of colistin resistance. To better understand the rise of colistin-resistant strains in each of these settings, we characterized colistin-resistant Enterobacterales isolated from farmers, swine, and hospitalized patients in Thailand. Methods Enterobacterales were isolated from 149 stool samples or rectal swabs collected from farmers, pigs, and hospitalized patients in Thailand between November 2014–December 2017. Confirmed colistin-resistant isolates were sequenced. Genomic analyses included species identification, multilocus sequence typing, and detection of antimicrobial resistance determinants and plasmids. Results The overall colistin-resistant Enterobacterales colonization rate was 26.2% (n = 39/149). The plasmid-mediated colistin-resistance gene (mcr) was detected in all 25 Escherichia coli isolates and 9 of 14 (64.3%) Klebsiella spp. isolates. Five novel mcr allelic variants were also identified: mcr-2.3, mcr-3.21, mcr-3.22, mcr-3.23, and mcr-3.24, that were only detected in E. coli and Klebsiella spp. isolates from farmed pigs. Conclusion Our data confirmed the presence of colistin-resistance genes in combination with extended spectrum beta-lactamase genes in bacterial isolates from farmers, swine, and patients in Thailand. Differences between the colistin-resistance mechanisms of Escherichia coli and Klebsiella pneumoniae in hospitalized patients were observed, as expected. Additionally, we identified mobile colistin-resistance mcr-1.1 genes from swine and patient isolates belonging to plasmids of the same incompatibility group. This supported the possibility that horizontal transmission of bacterial strains or plasmid-mediated colistin-resistance genes occurs between humans and swine.

Abstract Background India had an estimated 2.9 million tuberculosis cases and 506 thousand deaths in 2021. Novel vaccines effective in adolescents and adults could reduce this burden. M72/AS01E and BCG-revaccination have recently completed phase IIb trials and estimates of their population-level impact are needed. We estimated the potential health and economic impact of M72/AS01E and BCG-revaccination in India and investigated the impact of variation in vaccine characteristics and delivery strategies. Methods We developed an age-stratified compartmental tuberculosis transmission model for India calibrated to country-specific epidemiology. We projected baseline epidemiology to 2050 assuming no-new-vaccine introduction, and M72/AS01E and BCG-revaccination scenarios over 2025–2050 exploring uncertainty in product characteristics (vaccine efficacy, mechanism of effect, infection status required for vaccine efficacy, duration of protection) and implementation (achieved vaccine coverage and ages targeted). We estimated reductions in tuberculosis cases and deaths by each scenario compared to the no-new-vaccine baseline, as well as costs and cost-effectiveness from health-system and societal perspectives. Results M72/AS01E scenarios were predicted to avert 40% more tuberculosis cases and deaths by 2050 compared to BCG-revaccination scenarios. Cost-effectiveness ratios for M72/AS01E vaccines were around seven times higher than BCG-revaccination, but nearly all scenarios were cost-effective. The estimated average incremental cost was US$190 million for M72/AS01E and US$23 million for BCG-revaccination per year. Sources of uncertainty included whether M72/AS01E was efficacious in uninfected individuals at vaccination, and if BCG-revaccination could prevent disease. Conclusions M72/AS01E and BCG-revaccination could be impactful and cost-effective in India. However, there is great uncertainty in impact, especially given the unknowns surrounding the mechanism of effect and infection status required for vaccine efficacy. Greater investment in vaccine development and delivery is needed to resolve these unknowns in vaccine product characteristics.

Abstract Melanoma exhibits numerous transcriptional cell states including neural crest-like cells as well as pigmented melanocytic cells. How these different cell states relate to distinct tumorigenic phenotypes remains unclear. Here, we use a zebrafish melanoma model to identify a transcriptional program linking the melanocytic cell state to a dependence on lipid droplets, the specialized organelle responsible for lipid storage. Single-cell RNA-sequencing of these tumors show a concordance between genes regulating pigmentation and those involved in lipid and oxidative metabolism. This state is conserved across human melanoma cell lines and patient tumors. This melanocytic state demonstrates increased fatty acid uptake, an increased number of lipid droplets, and dependence upon fatty acid oxidative metabolism. Genetic and pharmacologic suppression of lipid droplet production is sufficient to disrupt cell cycle progression and slow melanoma growth in vivo. Because the melanocytic cell state is linked to poor outcomes in patients, these data indicate a metabolic vulnerability in melanoma that depends on the lipid droplet organelle.

Background: Individuals with bacteriologically confirmed pulmonary tuberculosis (TB) disease who do not report symptoms (subclinical TB) represent around half of all prevalent cases of TB, yet their contribution to Mycobacterium tuberculosis (Mtb) transmission is unknown, especially compared to individuals who report symptoms at the time of diagnosis (clinical TB). Relative infectiousness can be approximated by cumulative infections in household contacts, but such data are rare. Methods: We reviewed the literature to identify studies where surveys of Mtb infection were linked to population surveys of TB disease. We collated individual-level data on representative populations for analysis and used literature on the relative durations of subclinical and clinical TB to estimate relative infectiousness through a cumulative hazard model, accounting for sputum-smear status. Relative prevalence of subclinical and clinical disease in high-burden settings was used to estimate the contribution of subclinical TB to global Mtb transmission. Results: We collated data on 414 index cases and 789 household contacts from three prevalence surveys (Bangladesh, the Philippines, and Viet Nam) and one case-finding trial in Viet Nam. The odds ratio for infection in a household with a clinical versus subclinical index case (irrespective of sputum smear status) was 1.2 (0.6–2.3, 95% confidence interval). Adjusting for duration of disease, we found a per-unit-time infectiousness of subclinical TB relative to clinical TB of 1.93 (0.62–6.18, 95% prediction interval [PrI]). Fourteen countries across Asia and Africa provided data on relative prevalence of subclinical and clinical TB, suggesting an estimated 68% (27–92%, 95% PrI) of global transmission is from subclinical TB. Conclusions: Our results suggest that subclinical TB contributes substantially to transmission and needs to be diagnosed and treated for effective progress towards TB elimination. Funding: JCE, KCH, ASR, NS, and RH have received funding from the European Research Council (ERC) under the Horizon 2020 research and innovation programme (ERC Starting Grant No. 757699) KCH is also supported by UK FCDO (Leaving no-one behind: transforming gendered pathways to health for TB). This research has been partially funded by UK aid from the UK government (to KCH); however, the views expressed do not necessarily reflect the UK government’s official policies. PJD was supported by a fellowship from the UK Medical Research Council (MR/P022081/1); this UK-funded award is part of the EDCTP2 programme supported by the European Union. RGW is funded by the Wellcome Trust (218261/Z/19/Z), NIH (1R01AI147321-01), EDTCP (RIA208D-2505B), UK MRC (CCF17-7779 via SET Bloomsbury), ESRC (ES/P008011/1), BMGF (OPP1084276, OPP1135288 and INV-001754), and the WHO (2020/985800-0).

For vaccine development and adoption decisions, the ‘Full Value of Vaccine Assessment’ (FVVA) framework has been proposed by the WHO to expand the range of evidence available to support the prioritization of candidate vaccines for investment and eventual uptake by low- and middle-income countries. Recent applications of the FVVA framework have already shown benefits. Building on the success of these applications, we see important new opportunities to maximize the future utility of FVVAs to country and global stakeholders and provide a proof-of-concept for analyses in other areas of disease control and prevention. These opportunities include the following: (1) FVVA producers should aim to create evidence that explicitly meets the needs of multiple key FVVA consumers, (2) the WHO and other key stakeholders should develop standardized methodologies for FVVAs, as well as guidance for how different stakeholders can explicitly reflect their values within the FVVA framework, and (3) the WHO should convene experts to further develop and prioritize the research agenda for outcomes and benefits relevant to the FVVA and elucidate methodological approaches and opportunities for standardization not only for less well-established benefits, but also for any relevant research gaps. We encourage FVVA stakeholders to engage with these opportunities.

Abstract Early trials of novel vaccines against tuberculosis (TB) in adults have suggested substantial protection against TB. However, little is known about the feasibility and affordability of rolling out such vaccines in practice. We conducted expert interviews to identify plausible vaccination implementation strategies for the novel M72/AS01E vaccine candidate. The strategies were defined in terms of target population, coverage, vaccination schedule and delivery mode. We modelled these strategies to estimate long-term resource requirements and health benefits arising from vaccination over 2025–2050. We presented these to experts who excluded strategies that were deemed infeasible, and estimated cost-effectiveness and budget impact for each remaining strategy. The four strategies modelled combined target populations: either everyone aged 18–50, or all adults living with HIV, with delivery strategies: either a mass campaign followed by routine vaccination of 18-year olds, or two mass campaigns 10 years apart. Delivering two mass campaigns to all 18–50-year olds was found to be the most cost-effective strategy conferring the greatest net health benefit of 1.2 million DALYs averted having a probability of being cost-effective of 65–70%. This strategy required 38 million vaccine courses to be delivered at a cost of USD 507 million, reducing TB-related costs by USD 184 million while increasing ART costs by USD 79 million. A suitably designed adult TB vaccination programme built around novel TB vaccines is likely to be cost-effective and affordable given the resource and budget constraints in South Africa.

Abstract Background A previous study found that circulating angiopoietin-1 (angpt-1) concentrations were significantly lower in patients who had a recent ischaemic stroke compared to healthy controls. The primary aim of this study was to assess whether serum angpt-1 could be used as a diagnostic test of ischemic stroke in patients presenting to hospital as an emergency. Exploratory analyses investigated the association of proteins functionally related to angpt-1 (angpt-2, Tie-2, matrix metalloproteinase-9 and vascular endothelial growth factors A, C and D) with ischaemic stroke diagnosis. Methods Patients presenting to Townsville University Hospital for emergency assessment of stroke-like symptoms were consecutively recruited and provided a blood sample. After assessment by a consultant neurologist, patients were grouped into those who did, or did not have ischaemic stroke. The potential for serum angpt-1 to diagnose ischaemic stroke was assessed using receiver operator characteristic (ROC) curves. Cross-sectional analyses appraised inter-group differences in the serum concentration of other proteins. Results One-hundred and twenty-six patients presenting to Townsville University Hospital for emergency assessment of stroke-like symptoms were recruited (median time from symptom onset to hospital presentation: 2.6 (inter-quartile range: 1.2–4.6) hours). Serum angpt-1 had poor ability to diagnose ischaemic stroke in analyses using the whole cohort, or in sensitivity analyses (area under the ROC curve 0.51 (95% CI: 0.41–0.62) and 0.52 (95% CI: 0.39–0.64), respectively). No associations of serum angpt-1 concentration with ischaemic stroke severity, symptom duration or aetiology were observed. Serum concentrations of the other assessed proteins did not differ between patient groups. Conclusions Serum angpt-1 concentration is unlikely to be useful for emergency diagnosis of ischaemic stroke.

Data on social contact patterns are widely used to parameterize age-mixing matrices in mathematical models of infectious diseases. Most studies focus on close contacts only (i.e., persons spoken with face-to-face). This focus may be appropriate for studies of droplet and short-range aerosol transmission but neglects casual or shared air contacts, who may be at risk from airborne transmission. Using data from 2 provinces in South Africa, we estimated age mixing patterns relevant for droplet transmission, nonsaturating airborne transmission, and Mycobacterium tuberculosis transmission, an airborne infection where saturation of household contacts occurs. Estimated contact patterns by age did not vary greatly between the infection types, indicating that widespread use of close contact data may not be resulting in major inaccuracies. However, contact in persons >50 years of age was lower when we considered casual contacts, and therefore the contribution of older age groups to airborne transmission may be overestimated.

BackgroundMost individuals developing tuberculosis (TB) are working age adults living in low- and middle-income countries (LMICs). The resulting disability and death impact economic productivity and burden health systems. New TB vaccine products may reduce this burden. In this study, we estimated the impact of introducing novel TB vaccines on gross domestic product (GDP) growth in 105 LMICs.Methods and findingsWe adapted an existing macroeconomic model to simulate country-level GDP trends between 2020 and 2080, comparing scenarios for introduction of hypothetical infant and adolescent/adult vaccines to a no-new-vaccine counterfactual. We parameterized each scenario using estimates of TB-related mortality, morbidity, and healthcare spending from linked epidemiological and costing models. We assumed vaccines would be introduced between 2028 and 2047 and estimated incremental changes in GDP within each country from introduction to 2080, in 2020 US dollars. We tested the robustness of results to alternative analytic specifications. Both vaccine scenarios produced greater cumulative GDP in the modeled countries over the study period, equivalent to $1.6 (95% uncertainty interval: $0.8, 3.0) trillion for the adolescent/adult vaccine and $0.2 ($0.1, 0.4) trillion for the infant vaccine. These GDP gains were substantially lagged relative to the time of vaccine introduction, particularly for the infant vaccine. GDP gains resulting from vaccine introduction were concentrated in countries with higher current TB incidence and earlier vaccine introduction. Results were sensitive to secular trends in GDP growth but relatively robust to other analytic assumptions. Uncertain projections of GDP could alter these projections and affect the conclusions drawn by this analysis.ConclusionsUnder a range of assumptions, introducing novel TB vaccines would increase economic growth in LMICs.

Introduction Decisions regarding the optimal vascular access for haemodialysis patients are becoming increasingly complex, and the provision of vascular access is open to variations in systems of care as well as surgical experience and practice. Two main surgical options are recognised: arteriovenous fistula and arteriovenous graft (AVG). All recommendations regarding AVG are based on a limited number of randomised controlled trials (RCTs). It is essential that when considering an RCT of a surgical procedure, an appropriate definition of quality assurance (QA) is made for both the new approach and the comparator, otherwise replication of results or implementation into clinical practice may differ from published results. The aim of this systematic review will be to assess the methodological quality of RCT involving AVG, and the QA measures implemented in delivering interventions in these trials.Methods and analysis The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines will be followed. A systematic search will be performed of the MEDLINE, Embase and Cochrane databases to identify relevant literature. Studies will be selected by title and abstract review, followed by a full-text review using inclusion and exclusion criteria. Data collected will pertain to generic measures of QA, credentialing of investigators, procedural standardisation and performance monitoring. Trial methodology will be compared against a standardised template developed by a multinational, multispecialty review body with experience in vascular access. A narrative approach will be taken to synthesise and report data.Ethics and dissemination Ethical approval is not required as it is a protocol for a systematic review. Findings will be disseminated through peer-reviewed publications and conference presentations, with the ultimate aim of providing recommendations for future RCT of AVG design.

Introduction One in two patients developing tuberculosis (TB) in low-income and middle-income countries (LMICs) faces catastrophic household costs. We assessed the potential financial risk protection from introducing novel TB vaccines, and how health and economic benefits would be distributed across income quintiles.Methods We modelled the impact of introducing TB vaccines meeting the World Health Organization preferred product characteristics in 105 LMICs. For each country, we assessed the distribution of health gains, patient costs and household financial vulnerability following introduction of an infant vaccine and separately for an adolescent/adult vaccine, compared with a ‘no-new-vaccine’ counterfactual. Patient-incurred direct and indirect costs of TB disease exceeding 20% of annual household income were defined as catastrophic.Results Over 2028–2050, the health gains resulting from vaccine introduction were greatest in lower income quintiles, with the poorest 2 quintiles in each country accounting for 56% of total LMIC TB cases averted. Over this period, the infant vaccine was estimated to avert US$5.9 (95% uncertainty interval: US$5.3–6.5) billion in patient-incurred total costs, and the adolescent/adult vaccine was estimated to avert US$38.9 (US$36.6–41.5) billion. Additionally, 3.7 (3.3–4.1) million fewer households were projected to face catastrophic costs with the infant vaccine and 22.9 (21.4–24.5) million with the adolescent/adult vaccine, with 66% of gains accruing in the poorest 2 income quintiles.Conclusion Under a range of assumptions, introducing novel TB vaccines would reduce income-based inequalities in the health and household economic outcomes of TB in LMICs.

Background: COVID-19 vaccine hesitancy in the United States is high, with at least 63 million unvaccinated individuals to date. Socioeconomically disadvantaged populations experience lower COVID-19 vaccination rates despite facing a disproportionate COVID-19 burden. Objective: To assess the factors associated with COVID-19 vaccine acceptance among under-resourced, adult patients. Methods: Participants were patients receiving care at a Federally Qualified Health Center (FQHC) in St. Paul, Minnesota. Data were collected via multiple modes over 2 phases in 2020 (self-administered electronic survey) and 2021 (study team-administered survey by telephone, self-administered written survey) to promote diversity and inclusion for study participation. The primary outcome was COVID-19 vaccine acceptance. Using logistic regression analysis, associations between vaccine acceptance and factors including risk perception, concerns about the COVID-19 vaccine, social determinants of health (SDOH), co-morbidities, pandemic-induced hardships, and stress were assessed by adjusted odds ratios (AORs) and 95% confidence intervals (CI). Results: One hundred sixty-eight patients (62.5% female; mean age [SD]: 49.9 [17.4] years; 32%

Infectious disease models are widely used by epidemiologists to improve the understanding of transmission dynamics and disease natural history, and to predict the possible effects of interventions. As the complexity of such models increases, however, it becomes increasingly challenging to robustly calibrate them to empirical data. History matching with emulation is a calibration method that has been successfully applied to such models, but has not been widely used in epidemiology partly due to the lack of available software. To address this issue, we developed a new, user-friendly R package hmer to simply and efficiently perform history matching with emulation. In this paper, we demonstrate the first use of hmer for calibrating a complex deterministic model for the country-level implementation of tuberculosis vaccines to 115 low- and middle-income countries. The model was fit to 9–13 target measures, by varying 19–22 input parameters. Overall, 105 countries were successfully calibrated. Among the remaining countries, hmer visualisation tools, combined with derivative emulation methods, provided strong evidence that the models were misspecified and could not be calibrated to the target ranges. This work shows that hmer can be used to simply and rapidly calibrate a complex model to data from over 100 countries, making it a useful addition to the epidemiologist’s calibration tool-kit.

We have used the Dark Energy Camera (DECam) on the CTIO Blanco 4 m telescope to perform a new emission-line survey of the Large Magellanic Cloud (LMC) using narrowband H α and [S ii ] filters in addition to a continuum band to create pure emission-line images. We refer to this new survey as DeMCELS, to distinguish it from the earlier Magellanic Cloud Emission-line Survey (MCELS). DeMCELS covers ∼54 deg ^2 , encompassing most of the bright optical disk of the LMC. With DECam's pixel size of only 0.″27, our DeMCELS survey provides a seeing-limited improvement of 3–5 times over MCELS and is comparable in depth, with surface brightness limits of $3.3\times \,{10}^{-17}\mathrm{erg}\ {\mathrm{cm}}^{-2}\ {{\rm{s}}}^{-1}\,{\mathrm{arcsec}}^{-2}$ and $2.9\times \,{10}^{-17}\mathrm{erg}\ {\mathrm{cm}}^{-2}\ {{\rm{s}}}^{-1}\,{\mathrm{arcsec}}^{-2}$ in H α and [S ii ], respectively. DeMCELS provides detailed morphological information on nebulae of all scales, from the largest supershells to individual H ii regions and supernova remnants, to bubbles of emission surrounding individual stars, and even to faint structures in the diffuse ionized gas of the LMC. Many complex regions of emission show significant variations in the ratio of [S ii ] to H α —a sign of a mixture of shocks from stellar winds and/or supernovae with photoionization by embedded hot, young stars. We present the details of the observing strategy and data processing for this survey, and show selected results in comparison with previous data. A companion project for the Small Magellanic Cloud is in progress and will be reported separately. We are making these new data available to the community at large via NOIRLab’s Data Lab site.

Abstract Background Respirable mineral particles represent a potential health hazard in occupational settings and ambient air. Previous studies show that mineral particles may induce cytotoxicity and inflammatory reactions in vitro and in vivo and that the potency varies between samples of different composition. However, the reason for these differences is largely unknown and the impact of mineralogical composition on the biological effects of mineral dust remains to be determined. Methods We have assessed the cytotoxic and pro-inflammatory effects of ten mineral particle samples of different composition in human bronchial epithelial cells (HBEC3-KT) and THP-1-derived macrophages, as well as their membranolytic properties in erythrocytes. Moreover, the results were compiled with the results of recently published experiments on the effects of stone particle exposure and analysed using linear regression models to elucidate which mineral components contribute most to the toxicity of mineral dust. Results While all mineral particle samples were more cytotoxic to HBEC3-KT cells than THP-1 macrophages, biotite and quartz were among the most cytotoxic in both cell models. In HBEC3-KT cells, biotite and quartz also appeared to be the most potent inducers of pro-inflammatory cytokines, while the quartz, Ca-feldspar, Na-feldspar and biotite samples were the most potent in THP-1 macrophages. All particle samples except quartz induced low levels of membranolysis. The regression analyses revealed associations between particle bioactivity and the content of quartz, muscovite, plagioclase, biotite, anorthite, albite, microcline, calcite, chlorite, orthopyroxene, actinolite and epidote, depending on the cell model and endpoint. However, muscovite was the only mineral consistently associated with increased cytotoxicity and cytokine release in both cell models. Conclusions The present study provides further evidence that mineral particles may induce cytotoxicity and inflammation in cells of the human airways and that particle samples of different mineralogical composition differ in potency. The results show that quartz, while being among the most potent samples, does not fully predict the toxicity of mineral dust, highlighting the importance of other particle constituents. Moreover, the results indicate that the phyllosilicates muscovite and biotite may be more potent than other minerals assessed in the study, suggesting that this group of sheet-like minerals may warrant further attention.

Abstract Background Majority of research and commercial efforts have focussed on use of artificial intelligence (AI) for fracture detection in adults, despite the greater long-term clinical and medicolegal implications of missed fractures in children. The objective of this study was to assess the available literature regarding diagnostic performance of AI tools for paediatric fracture assessment on imaging, and where available, how this compares with the performance of human readers. Materials and methods MEDLINE, Embase and Cochrane Library databases were queried for studies published between 1 January 2011 and 2021 using terms related to ‘fracture’, ‘artificial intelligence’, ‘imaging’ and ‘children’. Risk of bias was assessed using a modified QUADAS-2 tool. Descriptive statistics for diagnostic accuracies were collated. Results Nine eligible articles from 362 publications were included, with most (8/9) evaluating fracture detection on radiographs, with the elbow being the most common body part. Nearly all articles used data derived from a single institution, and used deep learning methodology with only a few (2/9) performing external validation. Accuracy rates generated by AI ranged from 88.8 to 97.9%. In two of the three articles where AI performance was compared to human readers, sensitivity rates for AI were marginally higher, but this was not statistically significant. Conclusions Wide heterogeneity in the literature with limited information on algorithm performance on external datasets makes it difficult to understand how such tools may generalise to a wider paediatric population. Further research using a multicentric dataset with real-world evaluation would help to better understand the impact of these tools.

The SARS-CoV-2 variant XBB.1.5 is of concern as it has high transmissibility. XBB.1.5 currently accounts for upwards of 30% of new infections in the United States. One year after our group published the predicted structure of the Omicron (B.1.1.529) variant’s receptor binding domain (RBD) and antibody binding affinity, we return to investigate the new mutations seen in XBB.1.5 which is a descendant of Omicron. Using in silico modeling approaches against newer neutralizing antibodies that are shown effective against B.1.1.529, we predict the immune consequences of XBB.1.5’s mutations and show that there is no statistically significant difference in overall antibody evasion when comparing to the B.1.1.529 and other related variants (e.g., BJ.1 andBM.1.1.1). However, noticeable changes in antibody binding affinity were seen due to specific amino acid changes of interest in the newer variants.

Introduction Nosocomial Mycobacterium tuberculosis (Mtb) transmission substantially impacts health workers, patients and communities. Guidelines for tuberculosis infection prevention and control (TB IPC) exist but implementation in many settings remains suboptimal. Evidence is needed on cost-effective investments to prevent Mtb transmission that are feasible in routine clinic environments.Methods A set of TB IPC interventions was codesigned with local stakeholders using system dynamics modelling techniques that addressed both core activities and enabling actions to support implementation. An economic evaluation of these interventions was conducted at two clinics in KwaZulu-Natal, employing agent-based models of Mtb transmission within the clinics and in their catchment populations. Intervention costs included the costs of the enablers (eg, strengthened supervision, community sensitisation) identified by stakeholders to ensure uptake and adherence.Results All intervention scenarios modelled, inclusive of the relevant enablers, cost less than US$200 per disability-adjusted life-year (DALY) averted and were very cost-effective in comparison to South Africa’s opportunity cost-based threshold (US$3200 per DALY averted). Two interventions, building modifications to improve ventilation and maximising use of the existing Central Chronic Medicines Dispensing and Distribution system to reduce the number of clinic attendees, were found to be cost saving over the 10-year model time horizon. Incremental cost-effectiveness ratios were sensitive to assumptions on baseline clinic ventilation rates, the prevalence of infectious TB in clinic attendees and future HIV incidence but remained highly cost-effective under all uncertainty analysis scenarios.Conclusion TB IPC interventions in clinics, including the enabling actions to ensure their feasibility, afford very good value for money and should be prioritised for implementation within the South African health system.

A primary new capability of JWST is the ability to penetrate the dust in star-forming galaxies to identify and study the properties of young star clusters that remain embedded in dust and gas. In this Letter we combine new infrared images taken with JWST with our optical Hubble Space Telescope (HST) images of the starbursting barred (Seyfert2) spiral galaxy NGC 1365. We find that this galaxy has the richest population of massive young clusters of any known galaxy within 30 Mpc, with ∼30 star clusters that are more massive than 10 ^6 M _⊙ and younger than 10 Myr. Sixteen of these clusters are newly discovered from our JWST observations. An examination of the optical images reveals that 4 of 30 (∼13%) are so deeply embedded that they cannot be seen in the Hubble I band ( A _V ≳ 10 mag), and that 11 of 30 (∼37%) are missing in the HST B band, so age and mass estimates from optical measurements alone are challenging. These numbers suggest that massive clusters in NGC 1365 remain completely obscured in the visible for ∼1.3 ± 0.7 Myr and are either completely or partially obscured for ∼3.7 ± 1.1 Myr. We also use the JWST observations to gain new insights into the triggering of star cluster formation by the collision of gas and dust streamers with gas and dust in the bar. The JWST images reveal previously unknown structures (e.g., bridges and overshoot regions from stars that form in the bar) that help us better understand the orbital dynamics of barred galaxies and associated star-forming rings. Finally, we note that the excellent spatial resolution of the NIRCAM F200W filter provides a better way to separate barely resolved compact clusters from individual stars based on their sizes.

BackgroundTuberculosis (TB) is preventable and curable but eliminating it has proven challenging. Safe and effective TB vaccines that can rapidly reduce disease burden are essential for achieving TB elimination. We assessed future costs, cost-savings, and cost-effectiveness of introducing novel TB vaccines in low- and middle-income countries (LMICs) for a range of product characteristics and delivery strategies.Methods and findingsWe developed a system of epidemiological and economic models, calibrated to demographic, epidemiological, and health service data in 105 LMICs. For each country, we assessed the likely future course of TB-related outcomes under several vaccine introduction scenarios, compared to a "no-new-vaccine" counterfactual. Vaccine scenarios considered 2 vaccine product profiles (1 targeted at infants, 1 at adolescents/adults), both assumed to prevent progression to active TB. Key economic inputs were derived from the Global Health Cost Consortium, World Health Organization (WHO) patient cost surveys, and the published literature. We estimated the incremental impact of vaccine introduction for a range of health and economic outcomes. In the base-case, we assumed a vaccine price of $4.60 and used a 1× per-capita gross domestic product (GDP) cost-effectiveness threshold (both varied in sensitivity analyses). Vaccine introduction was estimated to require substantial near-term resources, offset by future cost-savings from averted TB burden. From a health system perspective, adolescent/adult vaccination was cost-effective in 64 of 105 LMICs. From a societal perspective (including productivity gains and averted patient costs), adolescent/adult vaccination was projected to be cost-effective in 73 of 105 LMICs and cost-saving in 58 of 105 LMICs, including 96% of countries with higher TB burden. When considering the monetized value of health gains, we estimated that introduction of an adolescent/adult vaccine could produce $283 to 474 billion in economic benefits by 2050. Limited data availability required assumptions and extrapolations that may omit important country-level heterogeneity in epidemiology and costs.ConclusionsTB vaccination would be highly impactful and cost-effective in most LMICs. Further efforts are needed for future development, adoption, and implementation of novel TB vaccines.

La pandemia de la enfermedad por coronavirus 2019 (COVID-19) fue una de las principales causas de muerte en todo el mundo en 2020. La enfermedad es causada por el coronavirus 2 (SARS-CoV-2), un virus de ARN de la subfamilia Orthocoronavirinae relacionado con otros 2 coronavirus clínicamente relevantes, SARS-CoV y MERS-CoV. Al igual que otros coronavirus y varios otros virus, el SARS-CoV-2 se originó en los murciélagos. Sin embargo, a diferencia de otros coronavirus, el SARS-CoV-2 resultó en una pandemia devastadora. La pandemia de SARS-CoV-2 continúa, debido a la evolución viral que conduce a variantes más transmisibles e inmunes evasivas. Tecnologías como la secuenciación genómica, ha impulsado el cambio de la epidemiología sindrómica a la molecular, y promete una mejor comprensión de las variantes. La pandemia de COVID-19 ha expuesto obstáculos críticos que deben abordarse para desarrollar la ciencia de las pandemias. Gran parte del progreso se está aplicando en el mundo desarrollado. Sin embargo, persisten las barreras para el uso de la epidemiología molecular en los países de ingresos bajos y medianos (LMIC), incluida la falta de logística para equipos y reactivos y la falta de capacitación en análisis. Revisamos la literatura de epidemiología molecular para comprender sus orígenes desde la epidemia de SARS (2002-2003) hasta los eventos de influenza y la pandemia actual de COVID-19. Abogamos por una mejor vigilancia genómica del SARS-CoV y por comprender la diversidad de patógenos en posibles huéspedes zoonóticos. Este trabajo requerirá capacitación en computación filogenética y de alto rendimiento para mejorar los análisis del origen y la propagación de patógenos. Los objetivos generales son comprender y reducir el riesgo de zoonosis a través de la colaboración interdisciplinaria y la reducción de las barreras logísticas.

Cancer cells exist in a complex ecosystem with numerous other cell types in the tumor microenvironment (TME). The composition of this tumor/TME ecosystem will vary at each anatomic site and affects phenotypes such as initiation, metastasis, and drug resistance. A mechanistic understanding of the large number of cell-cell interactions between tumor and TME requires models that allow us to both characterize as well as genetically perturb this complexity. Zebrafish are a model system optimized for this problem, because of the large number of existing cell-type-specific drivers that can label nearly any cell in the TME. These include stromal cells, immune cells, and tissue resident normal cells. These cell-type-specific promoters/enhancers can be used to drive fluorophores to facilitate imaging and also CRISPR cassettes to facilitate perturbations. A major advantage of the zebrafish is the ease by which large numbers of TME cell types can be studied at once, within the same animal. While these features make the zebrafish well suited to investigate the TME, the model has important limitations, which we also discuss. In this review, we describe the existing toolset for studying the TME using zebrafish models of cancer and highlight unique biological insights that can be gained by leveraging this powerful resource.

The COVID-19 pandemic profoundly disrupted, and, out of necessity, accelerated innovation of research and development of medical countermeasures to combat COVID-19. Although countermeasures were developed with unprecedented speed as a result of decades of long-term Federal investments in platform technologies and existing partnerships, the pandemic also revealed gaps in our preparedness and response capabilities that threaten our readiness posture. Challenges include limited federal funding that hinders sustainable development and manufacturing of, and equitable access to, medical countermeasures. Here we discuss lessons learned from the development and production efforts of medical countermeasures, such as vaccines and immunotherapeutics, to combat COVID-19. This commentary highlights some of the key gaps and challenges that must be addressed to ensure preparation for future outbreaks caused by viruses of pandemic potential.

Abstract Background South Africa implemented rapid and strict physical distancing regulations to minimize SARS-CoV-2 epidemic spread. Evidence on the impact of such measures on interpersonal contact in rural and lower-income settings is limited. Methods We compared population-representative social contact surveys conducted in the same rural KwaZulu-Natal location once in 2019 and twice in mid-2020. Respondents reported characteristics of physical and conversational (‘close interaction’) contacts over 24 hours. We built age-mixing matrices and estimated the proportional change in the SARS-CoV-2 reproduction number (R0). Respondents also reported counts of others present at locations visited and transport used, from which we evaluated change in potential exposure to airborne infection due to shared indoor space (‘shared air’). Results Respondents in March–December 2019 (n = 1704) reported a mean of 7.4 close interaction contacts and 196 shared air person-hours beyond their homes. Respondents in June-July 2020 (n = 216), as the epidemic peaked locally, reported 4.1 close interaction contacts and 21 shared air person-hours outside their home, with significant declines in others’ homes and public spaces. Adults aged over 50 had fewer close contacts with others over 50, but little change in contact with 15–29 year olds, reflecting ongoing contact within multigenerational households. We estimate potential R0 fell by 42% (95% plausible range 14–59%) between 2019 and June-July 2020. Conclusions Extra-household social contact fell substantially following imposition of Covid-19 distancing regulations in rural South Africa. Ongoing contact within intergenerational households highlighted a potential limitation of social distancing measures in protecting older adults.

Switchgrass (Panicum virgatum L.) remains the preeminent American perennial (C4) bioenergy crop for cellulosic ethanol, that could help displace over a quarter of the US current petroleum consumption. Intriguingly, there is often little response to nitrogen fertilizer once stands are established. The rhizosphere microbiome plays a critical role in nitrogen cycling and overall plant nutrient uptake. We used high-throughput metagenomic sequencing to characterize the switchgrass rhizosphere microbial community before and after a nitrogen fertilization event for established stands on marginal land. We examined community structure and bulk metabolic potential, and resolved 29 individual bacteria genomes via metagenomic de novo assembly. Community structure and diversity were not significantly different before and after fertilization; however, the bulk metabolic potential of carbohydrate-active enzymes was depleted after fertilization. We resolved 29 metagenomic assembled genomes, including some from the ‘most wanted’ soil taxa such as Verrucomicrobia, Candidate phyla UBA10199, Acidobacteria (rare subgroup 23), Dormibacterota, and the very rare Candidatus Eisenbacteria. The Dormibacterota (formally candidate division AD3) we identified have the potential for autotrophic CO utilization, which may impact carbon partitioning and storage. Our study also suggests that the rhizosphere microbiome may be involved in providing associative nitrogen fixation (ANF) via the novel diazotroph Janthinobacterium to switchgrass.

Abstract Background Gestational diabetes mellitus (GDM) is a metabolic disease that occurs in pregnant women and increases the risk for the development of diabetes. The relationship between GDM and meconium microbiota and metabolome remains incompletely understood. Methods Four hundred eighteen mothers (147 women with GDM and 271 normal pregnant women) and their neonates from the GDM Mother and Child Study were included in this study. Meconium microbiota were profiled by 16S rRNA gene sequencing. Meconium and maternal serum metabolome were examined by UPLC-QE. Results Microbial communities in meconium were significantly altered in neonates from the GDM mothers. A reduction in alpha diversity was observed in neonates of GDM mothers. At the phylum level, the abundance of Firmicutes and Proteobacteria changed significantly in neonates of GDM mothers. Metabolomic analysis of meconium showed that metabolic pathways including taurine and hypotaurine metabolism, pyrimidine metabolism, beta-alanine metabolism, and bile acid biosynthesis were altered in GDM subjects. Several changed metabolites varying by the similar trend across the maternal serum and neonatal meconium were observed. Conclusion Altogether, these findings suggest that GDM could alter the serum metabolome and is associated with the neonatal meconium microbiota and metabolome, highlighting the importance of maternal factors on early-life metabolism.