Drug-Resistant Tuberculosis--Current Dilemmas, Unanswered Questions, Challenges and Priority Needs

Tuberculosis was declared a global emergency by the World Health Organization (WHO) in 1993. Following the declaration and the promotion in 1995 of directly observed treatment short course (DOTS), a cost-effective strategy to contain the tuberculosis epidemic, nearly 7 million lives have been saved compared with the pre-DOTS era, high cure rates have been achieved in most countries worldwide, and the global incidence of tuberculosis has been in a slow decline since the early 2000s. However, the emergence and spread of multidrug-resistant (MDR) tuberculosis, extensively drug-resistant (XDR) tuberculosis, and more recently, totally drug-resistant tuberculosis pose a threat to global tuberculosis control. Multidrug-resistant tuberculosis is a man-made problem. Laboratory facilities for drug susceptibility testing are inadequate in most tuberculosis-endemic countries, especially in Africa; thus diagnosis is missed, routine surveillance is not implemented, and the actual numbers of global drug-resistant tuberculosis cases have yet to be estimated. This exposes an ominous situation and reveals an urgent need for commitment by national programs to health system improvement because the response to MDR tuberculosis requires strong health services in general. Multidrug-resistant tuberculosis and XDR tuberculosis greatly complicate patient management within resource-poor national tuberculosis programs, reducing treatment efficacy and increasing the cost of treatment to the extent that it could bankrupt healthcare financing in tuberculosis-endemic areas. Why, despite nearly 20 years of WHO-promoted activity and >12 years of MDR tuberculosis–specific activity, has the country response to the drug-resistant tuberculosis epidemic been so ineffectual? The current dilemmas, unanswered questions, operational issues, challenges, and priority needs for global drug resistance screening and surveillance, improved treatment regimens, and management of outcomes and prevention of DR tuberculosis are discussed

Major Histocompatibility Complex Class I- And II-Deficient Knock-Out Mice Are Resistant to Primary but Susceptible to Secondary Eimeria Papillata Infections

Two distinct mechanisms seem to function in reducing oocyst output during Eimeria papillata infections in mice. For naive mice, immunity was afforded by a T-cell-independent gamma-interferon (IFN-γ) response mediated by natural killer (NK) cells. On reinfection, resistance was associated with T-cells and, to a lesser extent, perforin. To determine if antigen presentation with major histocompatibility complex (MHC) molecules was required to control oocyst production by NK cells during primary infection or by T-cells during secondary infection, mutant mice that lacked H2-IAβb (Aβb(-/-)) or β2-microglobulin (β2m(-/-)) were used. Since MHC molecules are required for the maturation of αβ T-cells, Aβb(-/-) and β2m(-/-) mutant mice are also deficient in functional αβ+ CD4+ or αβ+ CD8+ T-cells, respectively. As compared with wild-type control mice, oocyst output by mutant mice was not significantly affected during primary infection, suggesting that the ability of NK cells to control parasite replication is not dependent on the expression of MHC molecules. On reinfection, differences were observed for mutant mice as compared with controls. Aβb(-/-) mice were found to be more susceptible than β2m(-/-) mice, suggesting that the αβ+ CD4+ T-cell subset plays a greater role in resistance to reinfection than does the αβ+ CD8+ T-cell subset. The mechanism of resistance depends on the immune status of the host and requires the coordinated interaction of both αβ+ T-cell, subsets for optimal parasite control during subsequent infections

Drug-Resistant Tuberculosis—Current Dilemmas, Unanswered Questions, Challenges, and Priority Needs

Tuberculosis was declared a global emergency by the World Health Organization (WHO) in 1993. Following the declaration and the promotion in 1995 of directly observed treatment short course (DOTS), a cost-effective strategy to contain the tuberculosis epidemic, nearly 7 million lives have been saved compared with the pre-DOTS era, high cure rates have been achieved in most countries worldwide, and the global incidence of tuberculosis has been in a slow decline since the early 2000s. However, the emergence and spread of multidrug-resistant (MDR) tuberculosis, extensively drug-resistant (XDR) tuberculosis, and more recently, totally drug-resistant tuberculosis pose a threat to global tuberculosis control. Multidrug-resistant tuberculosis is a man-made problem. Laboratory facilities for drug susceptibility testing are inadequate in most tuberculosis-endemic countries, especially in Africa; thus diagnosis is missed, routine surveillance is not implemented, and the actual numbers of global drug-resistant tuberculosis cases have yet to be estimated. This exposes an ominous situation and reveals an urgent need for commitment by national programs to health system improvement because the response to MDR tuberculosis requires strong health services in general. Multidrug-resistant tuberculosis and XDR tuberculosis greatly complicate patient management within resource-poor national tuberculosis programs, reducing treatment efficacy and increasing the cost of treatment to the extent that it could bankrupt healthcare financing in tuberculosis-endemic areas. Why, despite nearly 20 years of WHO-promoted activity and >12 years of MDR tuberculosis-specific activity, has the country response to the drug-resistant tuberculosis epidemic been so ineffectual? The current dilemmas, unanswered questions, operational issues, challenges, and priority needs for global drug resistance screening and surveillance, improved treatment regimens, and management of outcomes and prevention of DR tuberculosis are discusse

Tuberculosis diagnostics and biomarkers: needs, challenges, recent advances, and opportunities

Tuberculosis is unique among the major infectious diseases in that it lacks accurate rapid point-of-care diagnostic tests. Failure to control the spread of tuberculosis is largely due to our inability to detect and treat all infectious cases of pulmonary tuberculosis in a timely fashion, allowing continued Mycobacterium tuberculosis transmission within communities. Currently recommended gold-standard diagnostic tests for tuberculosis are laboratory based, and multiple investigations may be necessary over a period of weeks or months before a diagnosis is made. Several new diagnostic tests have recently become available for detecting active tuberculosis disease, screening for latent M. tuberculosis infection, and identifying drug-resistant strains of M. tuberculosis. However, progress toward a robust point-of-care test has been limited, and novel biomarker discovery remains challenging. In the absence of effective prevention strategies, high rates of early case detection and subsequent cure are required for global tuberculosis control. Early case detection is dependent on test accuracy, accessibility, cost, and complexity, but also depends on the political will and funder investment to deliver optimal, sustainable care to those worst affected by the tuberculosis and human immunodeficiency virus epidemics. This review highlights unanswered questions, challenges, recent advances, unresolved operational and technical issues, needs, and opportunities related to tuberculosis diagnostics

Critical Path to Tuberculosis Drug Regimens: Global collaboration to accelerate development of novel drug regimens and rapid drug susceptibility tests for tuberculosis

The Critical Path to Tuberculosis Drug Regimens (CPTR) initiative aims to support the rational deployment of new tuberculosis (TB) therapies by speeding the development and impact of new and markedly improved drug regimens as well as rapid drug susceptibility tests. Co-founded by the Bill & Melinda Gates Foundation, the Critical Path Institute, and the TB Alliance in 2010, CPTR is a coalition comprising the world’s leading pharmaceutical companies, product development sponsors, diagnostic companies, regulatory agencies, and civil society organizations which support and catalyze advances in regulatory science, the development of infrastructure, and other progress needed to accelerate the pace of development and introduction of novel regimens and rapid drug susceptibility tests. This manuscript summarizes the work of two subgroups within CPTR, the Regulatory Sciences and Rapid Drug Susceptibility Test consortia, and their efforts to drive innovation. These consortia are supported by a robust TB clinical data platform, which continues to evolve through contributions of contemporary TB clinical trial data sets as well as whole genome sequence level data from isolates across the globe. Examples of innovation are described and include a recently-qualified drug development tool and emerging programs to support the development of clinical trial simulation tools

Tuberculosis Diagnostics and Biomarkers: Needs, Challenges, Recent Advances, and Opportunities

Tuberculosis is unique among the major infectious diseases in that it lacks accurate rapid point-of-care diagnostic tests. Failure to control the spread of tuberculosis is largely due to our inability to detect and treat all infectious cases of pulmonary tuberculosis in a timely fashion, allowing continued Mycobacterium tuberculosis transmission within communities. Currently recommended gold-standard diagnostic tests for tuberculosis are laboratory based, and multiple investigations may be necessary over a period of weeks or months before a diagnosis is made. Several new diagnostic tests have recently become available for detecting active tuberculosis disease, screening for latent M. tuberculosis infection, and identifying drug-resistant strains of M. tuberculosis. However, progress toward a robust point-of-care test has been limited, and novel biomarker discovery remains challenging. In the absence of effective prevention strategies, high rates of early case detection and subsequent cure are required for global tuberculosis control. Early case detection is dependent on test accuracy, accessibility, cost, and complexity, but also depends on the political will and funder investment to deliver optimal, sustainable care to those worst affected by the tuberculosis and human immunodeficiency virus epidemics. This review highlights unanswered questions, challenges, recent advances, unresolved operational and technical issues, needs, and opportunities related to tuberculosis diagnostic

Paleo‐thermal constraints on the origin of native diagenetic sulfur in the Messinian evaporites : The Northern Apennines foreland basin case study (Italy)

This work has benefited from the equipment and frame-work of the COMP- HUB Initiative (University of Parma), funded by the Department of Excellence programme of the Italian Ministry for Education, University and Research (MIUR, 2018- 2022). This work has benefited from University of Roma Tre MIUR funds for the Department of Excellence. This work has benefited from the University of Parma FIL2016- 2018 responsible Professor Marco Roveri, University of Parma FIL2016- 2018 responsible Professor Vinicio Manzi, MIUR PhD scholarship 2016- 2019. Platte River Associates, Inc is kindly acknowledged for providing BasinMod2D® software for research purposes. Massimo Rossi (ENI S.p.A., Milano, Italy) is kindly acknowledged for his review of the manuscriptPeer reviewedPublisher PD

Chronic diseases are strongly associated with sickness absences in a sample of Italian public employees

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Host-Directed Therapies for tackling Multi-Drug Resistant TB – learning from the Pasteur-Bechamp debates

Tuberculosis (TB) remains a global emergency causing an estimated 1.5 million deaths annually. For several decades the major focus of TB treatment has been on antibiotic development targeting Mycobacterium tuberculosis (M.tb). The lengthy TB treatment duration and poor treatment outcomes associated with multi-drug resistant TB (MDR-TB) are of major concern. The sparse new TB drug pipeline and widespread emergence of MDR-TB signal an urgent need for more innovative interventions to improve treatment outcomes. Building on the historical Pasteur-Bechamp debates on the role of the ‘microbe’ versus the ‘host internal milieu’ in disease causation, we make the case for parallel investments into host-directed therapies (HDTs). A range of potential HDTs are now available which require evaluation in randomized controlled clinical trials as adjunct therapies for shortening the duration of TB therapy and improving treatment outcomes for drug-susceptible TB and MDR-TB. Funder initiatives that may enable further research into HDTs are described

Barriers to Physical Activity in Chronic Hemodialysis Patients: A Single-Center Pilot Study in an Italian Dialysis Facility

Background/Aims: In patients on chronic dialysis a sedentary lifestyle is a strong, yet potentially modifiable, predictor of mortality. The present single-center pilot study evaluated social, psychological and clinical barriers that may hinder physical activity in this population. Methods: We explored the association between barriers to physical activity and sedentarism in adult patients at a chronic dialysis facility in Parma, Italy. We used different questionnaries exploring participation in physical activity, physical functioning, patient attitudes and preferences, and barriers to physical activity perceived by either patients or dialysis doctors and nurses. Results: We enrolled 104 patients, (67 males, 65%), mean age 69 years (79% of patients older than 60 years); median dialysis vintage 60 months (range 8-440); mean Charlson score 5.55, ADL (Activities of Daily Living) score 5.5. Ninety-two participants (88.5%) reported at least one barrier to physical activity. At multivariable analysis, after adjusting for age and sex, feeling to have too many medical problems (OR 2.99, 95% CI 1.27 to 7.07; P=0.012), chest pain (OR 10.78, 95% CI 1.28 to 90.28; P=0.029) and sadness (OR 2.59, 95% CI 1.10 to 6.09; P=0.030) were independently associated with physical inactivity. Lack of time for exercise counseling and the firm belief about low compliance/interest by the patients toward exercise were the most frequent barriers reported by doctors and nurses. Conclusion: We identified a number of patient-related and health personnel-related barriers to physical activity in patients on chronic dialysis. Solutions for these barriers should be addressed in future studies aimed at increasing the level of physical activity in this population