A motion-corrected deep-learning reconstruction framework for accelerating whole-heart magnetic resonance imaging in patients with congenital heart disease.

BACKGROUND: Cardiovascular magnetic resonance (CMR) is an important imaging modality for the assessment and management of adult patients with congenital heart disease (CHD). However, conventional techniques for three-dimensional (3D) whole-heart acquisition involve long and unpredictable scan times and methods that accelerate scans via k-space undersampling often rely on long iterative reconstructions. Deep-learning-based reconstruction methods have recently attracted much interest due to their capacity to provide fast reconstructions while often outperforming existing state-of-the-art methods. In this study, we sought to adapt and validate a non-rigid motion-corrected model-based deep learning (MoCo-MoDL) reconstruction framework for 3D whole-heart MRI in a CHD patient cohort. METHODS: The previously proposed deep-learning reconstruction framework MoCo-MoDL, which incorporates a non-rigid motion-estimation network and a denoising regularization network within an unrolled iterative reconstruction, was trained in an end-to-end manner using 39 CHD patient datasets. Once trained, the framework was evaluated in eight CHD patient datasets acquired with seven-fold prospective undersampling. Reconstruction quality was compared with the state-of-the-art non-rigid motion-corrected patch-based low-rank reconstruction method (NR-PROST) and against reference images (acquired with three-or-four-fold undersampling and reconstructed with NR-PROST). RESULTS: Seven-fold undersampled scan times were 2.1 ± 0.3 minutes and reconstruction times were ∼30 seconds, approximately 240 times faster than an NR-PROST reconstruction. Image quality comparable to the reference images was achieved using the proposed MoCo-MoDL framework, with no statistically significant differences found in any of the assessed quantitative or qualitative image quality measures. Additionally, expert image quality scores indicated the MoCo-MoDL reconstructions were consistently of a higher quality than the NR-PROST reconstructions of the same data, with the differences in 12 of the 22 scores measured for individual vascular structures found to be statistically significant. CONCLUSION: The MoCo-MoDL framework was applied to an adult CHD patient cohort, achieving good quality 3D whole-heart images from ∼2-minute scans with reconstruction times of ∼30 seconds.

IgG glycosylation associates with risk of progression from latent to active tuberculosis.

OBJECTIVES: Glycosylation motifs shape antibody structure, stability and antigen affinity and play an important role in antibody localization and function. Serum IgG glycosylation profiles are significantly altered in infectious diseases, including tuberculosis (TB), but have not been studied in the context of progression from latent to active TB. METHODS: We performed a longitudinal study of paired bulk IgG glycosylation and transcriptomic profiling in blood from individuals with active TB (ATB) or latent TB infection (LTBI) before and after treatment. RESULTS: We identified that a combination of two IgG1 glycosylation traits were sufficient to distinguish ATB from LTBI with high specificity and sensitivity, prior to, and after treatment. Importantly, these two features positively correlated with previously defined cellular and RNA signatures of ATB risk in LTBI, namely monocyte to lymphocyte ratio and the expression of interferon (IFN)-associated gene signature of progression (IFN-risk signature) in blood prior to treatment. Additional glycosylation features at higher prevalence in LTBI individuals with high expression of the IFN-risk signature prior to treatment included fucosylation on IgG1, IgG2 and IgG3. CONCLUSIONS: Together, our results demonstrate that bulk IgG glycosylation features could be useful in stratifying the risk of LTBI reactivation and progression to ATB.

Gastrointestinal parasite infections in Nepalese Gurkha recruits arriving in the United Kingdom from 2012-2020.

BACKGROUND: Gastrointestinal parasite (GIP) infections are a major cause of global morbidity, infecting hundreds of millions of people each year and potentially leading to lifelong infection and serious complications. Few data exist on screening for GIP infections in migrants entering the UK or on the current performance of different traditional diagnostic approaches. This study aimed to describe the prevalence of GIP infections in Nepalese Gurkha recruits screened on arrival in the UK. METHODOLOGY/PRINCIPAL FINDINGS: We present a retrospective analysis of data from screening male adults (18-21 years) who arrived in the UK from Nepal between 2012 and 2020. Three separate faecal samples were obtained from participants at weekly intervals and processed for formalin-ethyl acetate (FEA) concentration/light microscopy and charcoal culture. Serum samples were analysed for IgG antibodies to Strongyloides stercoralis by ELISA. Results were available from 2,263 participants, of whom 463 (20.5%, 95% CI 18.8%-22.2%) had a positive diagnostic test for at least one GIP infection. A total of 525 potential infections were identified. Giardia duodenalis was most common (231/2263, 10.2%), followed by S. stercoralis (102/2263, 4.5%), and hookworm species (86/2263, 3.8%). Analysis (microscopy and culture) of the initial stool sample diagnosed only 244/427 (57.1%) faecally identified pathogens, including 41/86 (47.7%) hookworm infections. The proportion of participants infected with any GIP showed a downward trend over the study period. Log-binomial regression showed risk of infection decreasing by 6.1% year-on-year (95% CI 3.2% - 9.0%). This was driven predominantly by a fall in hookworm, S. stercoralis and Trichuris trichiura prevalence. CONCLUSIONS/SIGNIFICANCE: The level of potentially pathogenic GIP infection in young Nepalese men migrating to the UK is high (20.5%) and requires a combined diagnostic approach including serology and analysis of multiple stool samples incorporating specialised parasitological methods. Advances in molecular approaches may optimise and simplify the intensive screening strategy required.

Outbreak of Diarrhea Caused by a Novel Cryptosporidium hominis Subtype During British Military Training in Kenya.

Background: We report clinical, epidemiological, and laboratory features of a large diarrhea outbreak caused by a novel Cryptosporidium hominis subtype during British military training in Kenya between February and April 2022. Methods: Data were collated from diarrhea cases, and fecal samples were analyzed on site using the multiplex polymerase chain reaction (PCR) BioFire FilmArray. Water was tested using Colilert kits (IDEXX, UK). DNA was extracted from feces for molecular characterization of Cryptosporidium A135, Lib13, ssu rRNA, and gp60 genes. Results: One hundred seventy-two of 1200 (14.3%) personnel at risk developed diarrhea over 69 days. One hundred six primary fecal samples were tested, and 63/106 (59.4%; 95% CI, 0.49%-0.69%) were positive for Cryptosporidium spp. Thirty-eight had Cryptosporidium spp. alone, and 25 had Cryptosporidium spp. with ≥1 other pathogen. A further 27/106 (25.5%; 95% CI, 0.18%-0.35%) had non-Cryptosporidium pathogens only, and 16/106 (15.1%; 95% CI, 0.09%-0.23%) were negative. C. hominis was detected in 58/63 (92.1%) Cryptosporidium spp.-positive primary samples, but the others were not genotypable. Twenty-seven C. hominis specimens were subtypable; 1 was gp60 subtype IeA11G3T3, and 26 were an unusual subtype, ImA13G1 (GenBank accession OP699729), supporting epidemiological evidence suggesting a point source outbreak from contaminated swimming water. Diarrhea persisted for a mean (SD) of 7.6 (4.6) days in Cryptosporidium spp. cases compared with 2.3 (0.9) days in non-Cryptosporidium cases (P = .001). Conclusions: Real-time multiplex PCR fecal testing was vital in managing this large cryptosporidiosis outbreak. The etiology of a rare C. hominis gp60 subtype emphasizes the need for more genotypic surveillance to identify widening host and geographic ranges of novel C. hominis subtypes.

Molnupiravir versus placebo in unvaccinated and vaccinated patients with early SARS-CoV-2 infection in the UK (AGILE CST-2): a randomised, placebo-controlled, double-blind, phase 2 trial.

BACKGROUND: The antiviral drug molnupiravir was licensed for treating at-risk patients with COVID-19 on the basis of data from unvaccinated adults. We aimed to evaluate the safety and virological efficacy of molnupiravir in vaccinated and unvaccinated individuals with COVID-19. METHODS: This randomised, placebo-controlled, double-blind, phase 2 trial (AGILE CST-2) was done at five National Institute for Health and Care Research sites in the UK. Eligible participants were adult (aged ≥18 years) outpatients with PCR-confirmed, mild-to-moderate SARS-CoV-2 infection who were within 5 days of symptom onset. Using permuted blocks (block size 2 or 4) and stratifying by site, participants were randomly assigned (1:1) to receive either molnupiravir (orally; 800 mg twice daily for 5 days) plus standard of care or matching placebo plus standard of care. The primary outcome was the time from randomisation to SARS-CoV-2 PCR negativity on nasopharyngeal swabs and was analysed by use of a Bayesian Cox proportional hazards model for estimating the probability of a superior virological response (hazard ratio [HR]>1) for molnupiravir versus placebo. Our primary model used a two-point prior based on equal prior probabilities (50%) that the HR was 1·0 or 1·5. We defined a priori that if the probability of a HR of more than 1 was more than 80% molnupiravir would be recommended for further testing. The primary outcome was analysed in the intention-to-treat population and safety was analysed in the safety population, comprising participants who had received at least one dose of allocated treatment. This trial is registered in ClinicalTrials.gov, NCT04746183, and the ISRCTN registry, ISRCTN27106947, and is ongoing. FINDINGS: Between Nov 18, 2020, and March 16, 2022, 1723 patients were assessed for eligibility, of whom 180 were randomly assigned to receive either molnupiravir (n=90) or placebo (n=90) and were included in the intention-to-treat analysis. 103 (57%) of 180 participants were female and 77 (43%) were male and 90 (50%) participants had received at least one dose of a COVID-19 vaccine. SARS-CoV-2 infections with the delta (B.1.617.2; 72 [40%] of 180), alpha (B.1.1.7; 37 [21%]), omicron (B.1.1.529; 38 [21%]), and EU1 (B.1.177; 28 [16%]) variants were represented. All 180 participants received at least one dose of treatment and four participants discontinued the study (one in the molnupiravir group and three in the placebo group). Participants in the molnupiravir group had a faster median time from randomisation to negative PCR (8 days [95% CI 8-9]) than participants in the placebo group (11 days [10-11]; HR 1·30, 95% credible interval 0·92-1·71; log-rank p=0·074). The probability of molnupiravir being superior to placebo (HR>1) was 75·4%, which was less than our threshold of 80%. 73 (81%) of 90 participants in the molnupiravir group and 68 (76%) of 90 participants in the placebo group had at least one adverse event by day 29. One participant in the molnupiravir group and three participants in the placebo group had an adverse event of a Common Terminology Criteria for Adverse Events grade 3 or higher severity. No participants died (due to any cause) during the trial. INTERPRETATION: We found molnupiravir to be well tolerated and, although our predefined threshold was not reached, we observed some evidence that molnupiravir has antiviral activity in vaccinated and unvaccinated individuals infected with a broad range of SARS-CoV-2 variants, although this evidence is not conclusive. FUNDING: Ridgeback Biotherapeutics, the UK National Institute for Health and Care Research, the Medical Research Council, and the Wellcome Trust.

Characterisation of SARS-CoV-2 genomic variation in response to molnupiravir treatment in the AGILE Phase IIa clinical trial.

Molnupiravir is an antiviral, currently approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA) for treating at-risk COVID-19 patients, that induces lethal error catastrophe in SARS-CoV-2. How this drug-induced mechanism of action might impact the emergence of resistance mutations is unclear. To investigate this, we used samples from the AGILE Candidate Specific Trial (CST)-2 (clinical trial number NCT04746183). The primary outcomes of AGILE CST-2 were to measure the drug safety and antiviral efficacy of molnupiravir in humans (180 participants randomised 1:1 with placebo). Here, we describe the pre-specified exploratory virological endpoint of CST-2, which was to determine the possible genomic changes in SARS-CoV-2 induced by molnupiravir treatment. We use high-throughput amplicon sequencing and minor variant analysis to characterise viral genomics in each participant whose longitudinal samples (days 1, 3 and 5 post-randomisation) pass the viral genomic quality criteria (n = 59 for molnupiravir and n = 65 for placebo). Over the course of treatment, no specific mutations were associated with molnupiravir treatment. We find that molnupiravir significantly increased the transition:transversion mutation ratio in SARS-CoV-2, consistent with the model of lethal error catastrophe. This study highlights the utility of examining intra-host virus populations to strengthen the prediction, and surveillance, of potential treatment-emergent adaptations.

Artificial intelligence in cardiac magnetic resonance fingerprinting.

Magnetic resonance fingerprinting (MRF) is a fast MRI-based technique that allows for multiparametric quantitative characterization of the tissues of interest in a single acquisition. In particular, it has gained attention in the field of cardiac imaging due to its ability to provide simultaneous and co-registered myocardial T1 and T2 mapping in a single breath-held cardiac MRF scan, in addition to other parameters. Initial results in small healthy subject groups and clinical studies have demonstrated the feasibility and potential of MRF imaging. Ongoing research is being conducted to improve the accuracy, efficiency, and robustness of cardiac MRF. However, these improvements usually increase the complexity of image reconstruction and dictionary generation and introduce the need for sequence optimization. Each of these steps increase the computational demand and processing time of MRF. The latest advances in artificial intelligence (AI), including progress in deep learning and the development of neural networks for MRI, now present an opportunity to efficiently address these issues. Artificial intelligence can be used to optimize candidate sequences and reduce the memory demand and computational time required for reconstruction and post-processing. Recently, proposed machine learning-based approaches have been shown to reduce dictionary generation and reconstruction times by several orders of magnitude. Such applications of AI should help to remove these bottlenecks and speed up cardiac MRF, improving its practical utility and allowing for its potential inclusion in clinical routine. This review aims to summarize the latest developments in artificial intelligence applied to cardiac MRF. Particularly, we focus on the application of machine learning at different steps of the MRF process, such as sequence optimization, dictionary generation and image reconstruction.

Pharmacokinetics of ß-d-N4-Hydroxycytidine, the Parent Nucleoside of Prodrug Molnupiravir, in Nonplasma Compartments of Patients With Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

ß-d-N4-hydroxycytidine (NHC), the parent nucleoside of molnupiravir, a COVID-19 antiviral, was quantified at SARS-CoV-2 transmission sites in 12 patients enrolled in AGILE Candidate-Specific Trial-2. Saliva, nasal, and tear NHC concentrations were 3%, 21%, and 22% that of plasma. Saliva and nasal NHC were significantly correlated with plasma (P < .0001). Clinical Trials Registration. NCT04746183.

An Open Label, Adaptive, Phase 1 Trial of High-Dose Oral Nitazoxanide in Healthy Volunteers: An Antiviral Candidate for SARS-CoV-2.

Repurposing approved drugs may rapidly establish effective interventions during a public health crisis. This has yielded immunomodulatory treatments for severe coronavirus disease 2019 (COVID-19), but repurposed antivirals have not been successful to date because of redundancy of the target in vivo or suboptimal exposures at studied doses. Nitazoxanide is a US Food and Drug Administration (FDA) approved antiparasitic medicine, that physiologically-based pharmacokinetic (PBPK) modeling has indicated may provide antiviral concentrations across the dosing interval, when repurposed at higher than approved doses. Within the AGILE trial platform (NCT04746183) an open label, adaptive, phase I trial in healthy adult participants was undertaken with high-dose nitazoxanide. Participants received 1,500 mg nitazoxanide orally twice-daily with food for 7 days. Primary outcomes were safety, tolerability, optimum dose, and schedule. Intensive pharmacokinetic (PK) sampling was undertaken day 1 and 5 with minimum concentration (Cmin ) sampling on days 3 and 7. Fourteen healthy participants were enrolled between February 18 and May 11, 2021. All 14 doses were completed by 10 of 14 participants. Nitazoxanide was safe and with no significant adverse events. Moderate gastrointestinal disturbance (loose stools or diarrhea) occurred in 8 participants (57.1%), with urine and sclera discoloration in 12 (85.7%) and 9 (64.3%) participants, respectively, without clinically significant bilirubin elevation. This was self-limiting and resolved upon drug discontinuation. PBPK predictions were confirmed on day 1 but with underprediction at day 5. Median Cmin was above the in vitro target concentration on the first dose and maintained throughout. Nitazoxanide administered at 1,500 mg b.i.d. with food was safe with acceptable tolerability a phase Ib/IIa study is now being initiated in patients with COVID-19.

COVID-19 risk, attitudes and behaviour study (CRAB study): A knowledge, attitudes, and practise qualitative study of COVID-19 in the Royal Navy.

Introduction: Outbreaks of SARS-CoV-2 onboard maritime platforms spread rapidly and have high attack rates. The aim of the COVID-19 Risk, Attitudes and Behaviour (CRAB) study was to investigate the knowledge, attitudes, and practises in the Royal Navy in relation to COVID-19 prevention. Methods: The CRAB study was a cross-sectional survey, using a census sampling method, conducted in May and June 2021. An online questionnaire was distributed to all serving Royal Navy regular personnel using either the MyNavy application or via a QR code through email for a continuous 14 day period. The questionnaire was based on an existing validated questionnaire used for avian influenza epidemics. Questions investigated individual perceptions of COVID-19 seriousness, compliance with prevention methods, explored vaccination intention and vaccine hesitancy (unvaccinated individuals who declined or were unsure about receiving a COVID-19 vaccine). The chi-squared test of best fit was used to compare the demographic responses against the whole organisation, with p-value < 0.05 deemed significant. Odds ratios were used to investigate associations between demographic groups and responses to questions, with an odds ratio crossing 1.0 deemed non-significant. Results: The response rate was 6% (2,080/33,200), with 315 responses collated in the pilot phase and 1,765 in the main study phase. Male participants were less likely to rate COVID-19 as serious (OR 0.34; 95% CI: 0.23-0.49). BAME ethnicity (OR 2.41; 95% CI: 1.12-5.17) rated it as more serious. At the time of the study 62% of respondents had received one dose of a COVID-19 vaccine. In the 797 unvaccinated personnel, vaccine hesitancy accounted for 24.2% (193/797), of whom 136 were white males. Those who had a higher COVID-19 serious rating, the most significant factor for non-adherence to COVID-19 prevention measures in both vaccinated (OR 1.61 [95%CI: 1.20-2.17]) and vaccine-hesitant (OR 3.24 [95%CI: 1.63-6.41]) individuals was colleagues' non-adherence. The most trusted source of information on vaccines was provided by the Defence Medical Services (77.2% [1,606/2,080]). Conclusion: This study has identified reasons for COVID-19 protective measure adherence, sources of information trusted by respondents and vaccine hesitancy, in the Royal Navy. The questionnaire can be used to investigate attitudes and behaviours in future emerging infectious diseases.

Distinct blood transcriptomic signature of treatment in latent tuberculosis infected individuals at risk of developing active disease.

Although only a small fraction will ever develop the active form of tuberculosis (ATB) disease, chemoprophylaxis treatment in latent TB infected (LTBI) individuals is an effective strategy to control pathogen transmission. Characterizing immune responses in LTBI upon chemoprophylactic treatment is important to facilitate treatment monitoring, and thus improve TB control strategies. Here, we studied changes in the blood transcriptome in a cohort of 42 LTBI and 8 ATB participants who received anti-TB therapy. Based on the expression of previously published gene signatures of progression to ATB, we stratified the LTBI cohort in two groups and examined if individuals deemed to be at elevated risk of developing ATB before treatment (LTBI-Risk) differed from others (LTBI-Other). We found that LTBI-Risk and LTBI-Other groups were associated with two distinct transcriptomic treatment signatures, with the LTBI-Risk signature resembling that of treated ATB patients. Notably, overlapping genes between LTBI-Risk and ATB treatment signatures were associated with risk of progression to ATB and interferon (IFN) signaling, and were selectively downregulated upon treatment in the LTBI-Risk but not the LTBI-Other group. Our results suggest that transcriptomic reprogramming following treatment of LTBI is heterogeneous and can be used to distinguish LTBI-Risk individuals from the LTBI cohort at large.

Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a Phase I, open-label, dose-escalating, randomized controlled study.

OBJECTIVES: AGILE is a Phase Ib/IIa platform for rapidly evaluating COVID-19 treatments. In this trial (NCT04746183) we evaluated the safety and optimal dose of molnupiravir in participants with early symptomatic infection. METHODS: We undertook a dose-escalating, open-label, randomized-controlled (standard-of-care) Bayesian adaptive Phase I trial at the Royal Liverpool and Broadgreen Clinical Research Facility. Participants (adult outpatients with PCR-confirmed SARS-CoV-2 infection within 5 days of symptom onset) were randomized 2:1 in groups of 6 participants to 300, 600 and 800 mg doses of molnupiravir orally, twice daily for 5 days or control. A dose was judged unsafe if the probability of 30% or greater dose-limiting toxicity (the primary outcome) over controls was 25% or greater. Secondary outcomes included safety, clinical progression, pharmacokinetics and virological responses. RESULTS: Of 103 participants screened, 18 participants were enrolled between 17 July and 30 October 2020. Molnupiravir was well tolerated at 300, 600 and 800 mg doses with no serious or severe adverse events. Overall, 4 of 4 (100%), 4 of 4 (100%) and 1 of 4 (25%) of the participants receiving 300, 600 and 800 mg molnupiravir, respectively, and 5 of 6 (83%) controls, had at least one adverse event, all of which were mild (≤grade 2). The probability of ≥30% excess toxicity over controls at 800 mg was estimated at 0.9%. CONCLUSIONS: Molnupiravir was safe and well tolerated; a dose of 800 mg twice daily for 5 days was recommended for Phase II evaluation.

Did Covid-19 hit harder in peripheral areas? The case of Italian municipalities.

The first wave of Covid-19 pandemic had a geographically heterogeneous impact even within the most severely hit regions. Exploiting a triple-differences methodology, we find that in Italy Covid-19 hit relatively harder in peripheral areas: the excess mortality in peripheral areas was almost double that of central ones in March 2020 (1.2 additional deaths every 1000 inhabitants). We leverage a rich dataset on Italian municipalities to explore mechanisms behind this gradient. We first show that socio-demographic and economic features at municipal level are highly collinear, making it hard to identify single-variable causal relationships. Using Principal Components Analysis we model excess mortality and show that areas with higher excess mortality have lower income, lower education, larger households, lower trade and higher industrial employments, and older population. Our findings highlight a strong centre-periphery gradient in the harshness of Covid-19, which we believe is also highly relevant from a policy-making standpoint.

Hydrodynamic efficiency in sharks: the combined role of riblets and denticles.

We investigate the influence of smooth and ribletted shark skin on a turbulent boundary layer flow. Through laser Doppler anemometry (LDA) the role of riblets in combination with the shark skin denticle is established for the first time. Our results show that smooth denticles behave like a typical rough surface when exposed to an attached boundary layer. Drag is increased for the full range of tested dimensionless denticle widths,w+≈ 25-80, wherew+is the denticle width,w, scaled by the friction velocity,uτ, and the kinematic viscosity,ν. However, when riblets are added to the denticle crown we demonstrate there is a significant reduction in drag, relative to the smooth denticles. We obtain a modest maximum drag reduction of 2% for the ribletted denticles when compared to the flat plate, but when compared to the smooth denticles the difference in drag is in excess of 20% forw+≈ 80. This study enables a new conclusion that riblets have evolved as a mechanism to reduce or eliminate the skin friction increase due to the presence of scales (denticles). The combination of scales and riblets is hydrodynamically efficient in terms of skin-friction drag, while also acting to maintain flow attachment, and providing the other advantages associated with scales, e.g. anti-fouling, abrasion resistance, and defence against parasites.

Chemical and Thermal Sintering of Supported Metals with Emphasis on Cobalt Catalysts During Fischer-Tropsch Synthesis.

This comprehensive critical review combines, for the first time, recent advances in nanoscale surface chemistry, surface science, DFT, adsorption calorimetry, and in situ XRD and TEM to provide new insights into catalyst sintering. This work provides qualitative and quantitative estimates of the extent and rate of sintering as functions of nanocrystal (NC) size, temperature, and atmosphere. This review is unique in that besides summarizing important, useful data from previous studies, it also advances the field through addition of (i) improved or new models, (ii) new data summarized in original tables and figures, and (iii) new fundamental perspectives into sintering of supported metals and particularly of chemical sintering of supported Co during Fischer-Tropsch synthesis. We demonstrate how the two widely accepted sintering mechanisms are largely sequential with some overlap and highly NC-size dependent, i.e., generally, small NCs sinter rapidly by Ostwald ripening, while larger NCs sinter slowly by crystallite migration and coalescence. In addition, we demonstrate how accumulated knowledge, principles, and recent advances, discussed in this review, can be utilized in the design of supported metal NCs highly resistant to sintering. Recommendations for improving the design of sintering experiments and for new research are addressed.

Immunological correlates of mycobacterial growth inhibition describe a spectrum of tuberculosis infection.

A major contribution to the burden of Tuberculosis (TB) comes from latent Mycobacterium tuberculosis infections (LTBI) becoming clinically active. TB and LTBI probably exist as a spectrum and currently there are no correlates available to identify individuals with LTBI most at risk of developing active disease. We set out to identify immune parameters associated with ex vivo mycobacterial growth control among individuals with active TB disease or LTBI to define the spectrum of TB infection. We used a whole blood mycobacterial growth inhibition assay to generate a functional profile of growth control among individuals with TB, LTBI or uninfected controls. We subsequently used a multi-platform approach to identify an immune signature associated with this profile. We show, for the first time, that patients with active disease had the greatest control of mycobacterial growth, whilst there was a continuum of responses among latently infected patients, likely related to the degree of immune activation in response to bacillary load. Control correlated with multiple factors including inflammatory monocytes, activated and atypical memory B cells, IgG1 responses to TB-specific antigens and serum cytokines/chemokines. Our findings offer a method to stratify subclinical TB infections and the future potential to identify individuals most at risk of progressing to active disease and benefit from chemoprophylaxis.

The onset of star formation 250 million years after the Big Bang.

A fundamental quest of modern astronomy is to locate the earliest galaxies and study how they influenced the intergalactic medium a few hundred million years after the Big Bang1-3. The abundance of star-forming galaxies is known to decline4,5 from redshifts of about 6 to 10, but a key question is the extent of star formation at even earlier times, corresponding to the period when the first galaxies might have emerged. Here we report spectroscopic observations of MACS1149-JD1 6 , a gravitationally lensed galaxy observed when the Universe was less than four per cent of its present age. We detect an emission line of doubly ionized oxygen at a redshift of 9.1096 ± 0.0006, with an uncertainty of one standard deviation. This precisely determined redshift indicates that the red rest-frame optical colour arises from a dominant stellar component that formed about 250 million years after the Big Bang, corresponding to a redshift of about 15. Our results indicate that it may be possible to detect such early episodes of star formation in similar galaxies with future telescopes.

Comparison of non-contact infrared skin thermometers.

Non-contact infra-red skin thermometers (NCITs) are becoming more prevalent for use in medical diagnostics. Not only are they used as an alternative means of estimating core body temperature but also to assess the diabetic foot for signs of inflammation prior to ulceration. Previous investigations have compared the performance of NCITs in a clinical setting against other gold standard methods. However, there have been no previous investigations comparing the performance of NCITs in assessing temperature measurement capability traceable to the International Temperature Scale of 1990 (ITS-90). A metrological assessment of nine common NCITs was carried out over the temperature range of 15-45 °C using the National Physical Laboratory's blackbody reference sources to identify their accuracy, repeatability, size-of-source and distance effects. The results are concerning in that five of the NCITs fell far outside the accuracy range stated by their manufacturers as well as the medical standard to which the NCITs are supposed to adhere. Furthermore, a 6 °C step change in measurement error over the temperature range of interest for the diabetic foot was found for one NCIT. These results have implications for all clinicians using NCITs for temperature measurement and demonstrate the need for traceable calibration to ITS-90.

Development of bioreactors for comparative study of natural attenuation, biostimulation, and bioaugmentation of petroleum-hydrocarbon contaminated soil.

Bioremediation of soil and groundwater sites contaminated by petroleum hydrocarbons is known as a technically viable, cost-effective, and environmentally sustainable technology. The purpose of this study is to investigate laboratory-scale bioremediation of petroleum-hydrocarbon contaminated soil through development of eight bioreactors, two bioreactors for each bioremediation mode. The modes were: (1) natural attenuation (NA); (2) biostimulation (BS) with oxygen and nutrients; (3) bioaugmentation (BA) with hydrocarbon degrading isolates; (4) a combination of biostimulation and bioaugmentation (BS-BA). Total petroleum hydrocarbons (TPH) mass balance over the bioreactors showed about 2% of initial 20,000mgkg-soil-1 TPH was removed by advection due to synthetic groundwater which was flowing through the soil, and the rest of decrease in TPH was caused by biodegradation. The BS-BA mode showed the highest TPH biodegradation percentage (89.7±0.3%) compared to the NA (51.4±0.6%), BS (81.9±0.3%) and BA (62.9±0.5%) modes. Furthermore, an increase in microbial population was another evidence of TPH biodegradation by microorganism. Reaction rate data from each bioremediation mode were fitted with a first-order reaction rate model. The Monod kinetic constants including maximum specific growth rate of microorganisms (µmax) and substrate concentration at half-velocity constant (Ks) were estimated for each bioremediation modes.

Human Hookworm Infection Enhances Mycobacterial Growth Inhibition and Associates With Reduced Risk of Tuberculosis Infection.

Soil-transmitted helminths and Mycobacterium tuberculosis frequently coincide geographically and it is hypothesized that gastrointestinal helminth infection may exacerbate tuberculosis (TB) disease by suppression of Th1 and Th17 responses. However, few studies have focused on latent TB infection (LTBI), which predominates globally. We performed a large observational study of healthy adults migrating from Nepal to the UK (n = 645). Individuals were screened for LTBI and gastrointestinal parasite infections. A significant negative association between hookworm and LTBI-positivity was seen (OR = 0.221; p = 0.039). Hookworm infection treatment did not affect LTBI conversions. Blood from individuals with hookworm had a significantly greater ability to control virulent mycobacterial growth in vitro than from those without, which was lost following hookworm treatment. There was a significant negative relationship between mycobacterial growth and eosinophil counts. Eosinophil-associated differential gene expression characterized the whole blood transcriptome of hookworm infection and correlated with improved mycobacterial control. These data provide a potential alternative explanation for the reduced prevalence of LTBI among individuals with hookworm infection, and possibly an anti-mycobacterial role for helminth-induced eosinophils.