Tackling TB in migrants arriving at Europe’s southern border

Over a quarter of the individuals diagnosed with tuberculosis [TB] in the European Union region are born outside of the area and the proportion has been increasing steadily. Italy is a low TB incidence country with over 50% of TB cases in the foreign-born population primarily due to the high numbers of migrants entering the country via land or sea. As a case study to evaluate the value of screening in newly arrived migrants, the EDETECT-TB project in Italy implemented and evaluated active TB screening in the migrant population at first reception centres to ensure early diagnosis to avoid further spread. Based on a cost-effectiveness analysis from a program provider perspective, a decision tree model allowed the assessment of the value for money of case finding by estimating the cost per case of active TB detected compared with the status quo of no screening. The analysis confirmed that early case detection is a cost-effective intervention in areas with migrants arriving from high TB risk settings. Targeted post-arrival early screening of high TB risk vulnerable new entrants to Italy has a potential role in reducing the spread of TB among migrants

The Tuberculosis Network European Trials group (TBnet) ERS Clinical Research Collaboration: addressing drug-resistant tuberculosis through European cooperation

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Clinical and operational value of the extensively drug-resistant tuberculosis definition.

Currently, no information is available on the effect of resistance/susceptibility to first-line drugs different from isoniazid and rifampicin in determining the outcome of extensively drug-resistant tuberculosis (XDR-TB) patients, and whether being XDR-TB is a more accurate indicator of poor clinical outcome than being resistant to all first-line anti-tuberculosis (TB) drugs. To investigate this issue, a large series of multidrug-resistant TB (MDR-TB) and XDR-TB cases diagnosed in Estonia, Germany, Italy and the Russian Federation during the period 1999-2006 were analysed. Drug-susceptibility testing for first- and second-line anti-TB drugs, quality assurance and treatment delivery was performed according to World Health Organization recommendations in all study sites. Out of 4,583 culture-positive TB cases analysed, 361 (7.9%) were MDR and 64 (1.4%) were XDR. XDR-TB cases had a relative risk (RR) of 1.58 to have an unfavourable outcome compared with MDR-TB cases resistant to all first-line drugs (isoniazid, rifampicin ethambutol, streptomycin and, when tested, pyrazinamide), and an RR of 2.61 compared with "other" MDR-TB cases (those susceptible to at least one first-line anti-TB drug among ethambutol, pyrazinamide and streptomycin, regardless of resistance to the second-line drugs not defining XDR-TB). The emergence of extensively drug-resistant tuberculosis confirms that problems in tuberculosis management are still present in Europe. While waiting for new tools which will facilitate management of extensively drug-resistant tuberculosis, accessibility to quality diagnostic and treatment services should be urgently ensured and adequate public health policies should be rapidly implemented to prevent further development of drug resistance

Tocolytic effect of a selective FP receptor antagonist in rodent models reveals an innovative approach to the treatment of preterm labor

<p>Abstract</p> <p>Background</p> <p>Management of preterm labor by tocolysis remains an unmet medical need. Prostaglandins play a major role in regulation of uterine activity and in molecular mechanisms of human labor and parturition. There is some circumstantial evidence that prostaglandin F2α by action through the prostaglandin receptor subtype FP is effective in key events during labor uterine contraction, rupture of membranes and cervical dilation. This role of FP is briefly reviewed. In this study, we tested the hypothesis that an orally active and selective FP antagonist may arrest labor and delay parturition in animal models.</p> <p>Methods</p> <p>We examined the effects of a small molecule selective antagonist of the FP receptor (AS604872) in inhibition of spontaneous uterine contraction in pregnant rat near term. We tested AS604872 for its ability to delay preterm birth in a mouse model in which the anti-progestin agent RU486 triggered parturition.</p> <p>Results</p> <p>By oral or intravenous dosing AS604872 reduced markedly and dose-dependently the spontaneous uterine contractions in late-term pregnant rats at gestational days 19–21. In pregnant mice, AS604872 delayed the preterm birth caused by RU486 administration. The effect was dose-dependent with a significant increase in the mean delivery time of 16 and 33 hours at oral doses of 30 mg/kg and 100 mg/kg, respectively, in the case of labor triggered at gestational day 14. In both models AS604872 appeared more effective than the β-agonist ritodrine.</p> <p>Conclusion</p> <p>The tocolytic activity displayed by a selective FP receptor antagonist supports a key role for the FP receptor in the pathophysiology of premature birth and demonstrates the therapeutic potential of an FP antagonist for the treatment of preterm labor cases in which uterine hyperactivity plays a dominant role.</p

Choice of Bacterial Growth Medium Alters the Transcriptome and Phenotype of Salmonella enterica Serovar Typhimurium

The type of bacterial culture medium is an important consideration during design of any experimental protocol. The aim of this study was to understand the impact of medium choice on bacterial gene expression and physiology by comparing the transcriptome of Salmonella enterica SL1344 after growth in the widely used LB broth or the rationally designed MOPS minimal medium. Transcriptomics showed that after growth in MOPS minimal media, compared to LB, there was increased expression of 42 genes involved in amino acid synthesis and 23 genes coding for ABC transporters. Seven flagellar genes had decreased expression after growth in MOPS minimal medium and this correlated with a decreased motility. In both MOPS minimal medium and MEM expression of genes from SPI-2 was increased and the adhesion of S. Typhimurium to intestinal epithelial cells was higher compared to the levels after growth in LB. However, SL1344 invasion was not significantly altered by growth in either MOPs minimal media or MEM. Expression of SPI-2 was also measured using chromosomal GFP reporter fusions followed by flow cytometry which showed, for the first time, that the reduction in SPI-2 transcript after growth in different media related to a reduction in the proportion of the bacterial population expressing SPI-2. These data highlight the profound differences in the global transcriptome after in vitro growth in different media and show that choice of medium should be considered carefully during experimental design, particularly when virulence related phenotypes are being measured

App-based symptoms screening with Xpert MTB/RIF Ultra assay used for active tuberculosis detection in migrants at point of arrivals in Italy: The E-DETECT TB intervention analysis

BACKGROUND: From 2014 to 2017, the number of migrants who came to Italy via the Mediterranean route has reached an unprecedented level. The majority of refugees and migrants were rescued in the Central Mediterranean and disembarked at ports in the Sicily region. Rapid on-spot active TB screening intervention at the point of arrival will cover most migrants arriving in EU and by detecting TB prevalent cases will limit further transmission of the disease. // MATERIAL AND METHODS: Between November 2016 and December 2017 newly arrived migrants at point of arrivals in Sicily, were screened for active Tuberculosis using a smartphone application, followed in symptomatic individuals by fast molecular test, Xpert MTB/RIF Ultra, on collected sputum samples. // RESULTS: In the study period 3787 migrants received a medical evaluation. Eight hundred and ninety-one (23.5%) reported at least one protocol-defined Tuberculosis symptom. Fifteen (2.7%) were positive to at least one microbiological test revealing a post-entry screening prevalence rate of 396 per 100.000 individuals screened (95% CI: 2.22-6.53). In logistic regression analysis, those with cough and at least one other symptom had an increased probability of testing positive compared to persons with symptoms other than cough. Whole-genome-sequencing demonstrate two separate cases of transmission. // DISCUSSION: To our knowledge this study reports first-time results of an active TB case finding strategy based on on-spot symptom screening using a smartphone application, followed by fast molecular test on collected sputum samples. Our preliminary findings reveal a post-entry screening prevalence rate of 396 per 100.000 individuals screened (95% CI: 2.22-6.53)

Neutralising reactivity against SARS-CoV-2 delta and omicron variants by vaccination and infection history.

BACKGROUND: The continuous emergence of SARS-CoV-2 variants of concern (VOC) with immune escape properties, such as Delta (B.1.617.2) and Omicron (B.1.1.529), questions the extent of the antibody-mediated protection against the virus. Here we investigated the long-term antibody persistence in previously infected subjects and the extent of the antibody-mediated protection against B.1, B.1.617.2 and BA.1 variants in unvaccinated subjects previously infected, vaccinated naïve and vaccinated previously infected subjects. METHODS: Blood samples collected 15 months post-infection from unvaccinated (n=35) and vaccinated (n=41) previously infected subjects (Vo' cohort) were tested for the presence of antibodies against the SARS-CoV-2 spike (S) and nucleocapsid (N) antigens using the Abbott, DiaSorin, and Roche immunoassays. The serum neutralising reactivity was assessed against B.1, B.1.617.2 (Delta), and BA.1 (Omicron) SARS-CoV-2 strains through micro-neutralisation. The antibody titres were compared to those from previous timepoints, performed at 2- and 9-months post-infection on the same individuals. Two groups of naïve subjects were used as controls, one from the same cohort (unvaccinated n=29 and vaccinated n=20) and a group of vaccinated naïve healthcare workers (n=61). RESULTS: We report on the results of the third serosurvey run in the Vo' cohort. With respect to the 9-month time point, antibodies against the S antigen significantly decreased (P=0.0063) among unvaccinated subjects and increased (P<0.0001) in vaccinated individuals, whereas those against the N antigen decreased in the whole cohort. When compared with control groups (naïve Vo' inhabitants and naïve healthcare workers), vaccinated subjects that were previously infected had higher antibody levels (P<0.0001) than vaccinated naïve subjects. Two doses of vaccine elicited stronger anti-S antibody response than natural infection (P<0.0001). Finally, the neutralising reactivity of sera against B.1.617.2 and BA.1 was 4-fold and 16-fold lower than the reactivity observed against the original B.1 strain. CONCLUSIONS: These results confirm that vaccination induces strong antibody response in most individuals, and even stronger in previously infected subjects. Neutralising reactivity elicited by natural infection followed by vaccination is increasingly weakened by the recent emergence of VOCs. While immunity is not completely compromised, a change in vaccine development may be required going forward, to generate cross-protective pan-coronavirus immunity in the global population

Antibiotic resistance prediction for Mycobacterium tuberculosis from genome sequence data with Mykrobe [version 1; peer review: 2 approved, 1 approved with reservations]

Two billion people are infected with Mycobacterium tuberculosis, leading to 10 million new cases of active tuberculosis and 1.5 million deaths annually. Universal access to drug susceptibility testing (DST) has become a World Health Organization priority. We previously developed a software tool, Mykrobe predictor, which provided offline species identification and drug resistance predictions for M. tuberculosis from whole genome sequencing (WGS) data. Performance was insufficient to support the use of WGS as an alternative to conventional phenotype-based DST, due to mutation catalogue limitations. Here we present a new tool, Mykrobe, which provides the same functionality based on a new software implementation. Improvements include i) an updated mutation catalogue giving greater sensitivity to detect pyrazinamide resistance, ii) support for user-defined resistance catalogues, iii) improved identification of non-tuberculous mycobacterial species, and iv) an updated statistical model for Oxford Nanopore Technologies sequencing data. Mykrobe is released under MIT license at https://github.com/mykrobe-tools/mykrobe. We incorporate mutation catalogues from the CRyPTIC consortium et al. (2018) and from Walker et al. (2015), and make improvements based on performance on an initial set of 3206 and an independent set of 5845 M. tuberculosis Illumina sequences. To give estimates of error rates, we use a prospectively collected dataset of 4362 M. tuberculosis isolates. Using culture based DST as the reference, we estimate Mykrobe to be 100%, 95%, 82%, 99% sensitive and 99%, 100%, 99%, 99% specific for rifampicin, isoniazid, pyrazinamide and ethambutol resistance prediction respectively. We benchmark against four other tools on 10207 (=5845+4362) samples, and also show that Mykrobe gives concordant results with nanopore data. We measure the ability of Mykrobe-based DST to guide personalized therapeutic regimen design in the context of complex drug susceptibility profiles, showing 94% concordance of implied regimen with that driven by phenotypic DST, higher than all other benchmarked tools