100 years of Mycobacterium bovis bacille Calmette-Guérin Lange, Christoph; Aaby, Peter; Behr, Marcel A ...
Lancet. Infectious diseases/The Lancet. Infectious diseases,
January 2022, 2022-01-00, 20220101, Letnik:
22, Številka:
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Journal Article
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Mycobacterium bovis bacille Calmette-Guérin (BCG), an experimental vaccine designed to protect cattle from bovine tuberculosis, was administered for the first time to a newborn baby in Paris in 1921. ...Over the past century, BCG has saved tens of millions of lives and has been given to more humans than any other vaccine. It remains the sole tuberculosis vaccine licensed for use in humans. BCG provides long-lasting strong protection against miliary and meningeal tuberculosis in children, but it is less effective for the prevention of pulmonary tuberculosis, especially in adults. Evidence mainly from the past two decades suggests that BCG has non-specific benefits against non-tuberculous infections in newborn babies and in older adults, and offers immunotherapeutic benefit in certain malignancies such as non-muscle invasive bladder cancer. However, as a live attenuated vaccine, BCG can cause localised or disseminated infections in immunocompromised hosts, which can also occur following intravesical installation of BCG for the treatment of bladder cancer. The legacy of BCG includes fundamental discoveries about tuberculosis-specific and non-specific immunity and the demonstration that tuberculosis is a vaccine-preventable disease, providing a foundation for new vaccines to hasten tuberculosis elimination.
Supply of anthropogenic nitrogen (N) to the biosphere has tripled since 1960; however, little is known of how in situ response to N fertilisation differs among phytoplankton, whether species response ...varies with the chemical form of N, or how interpretation of N effects is influenced by the method of analysis (microscopy, pigment biomarkers). To address these issues, we conducted two 21-day in situ mesocosm (3140 L) experiments to quantify the species- and genus-specific responses of phytoplankton to fertilisation of P-rich lake waters with ammonium (NH(4)(+)), nitrate (NO(3)(-)), and urea (NH(2)(2)CO). Phytoplankton abundance was estimated using both microscopic enumeration of cell densities and high performance liquid chromatographic (HPLC) analysis of algal pigments. We found that total algal biomass increased 200% and 350% following fertilisation with NO(3)(-) and chemically-reduced N (NH(4)(+), urea), respectively, although 144 individual taxa exhibited distinctive responses to N, including compound-specific stimulation (Planktothrix agardhii and NH(4)(+)), increased biomass with chemically-reduced N alone (Scenedesmus spp., Coelastrum astroideum) and no response (Aphanizomenon flos-aquae, Ceratium hirundinella). Principle components analyses (PCA) captured 53.2-69.9% of variation in experimental assemblages irrespective of the degree of taxonomic resolution of analysis. PCA of species-level data revealed that congeneric taxa exhibited common responses to fertilisation regimes (e.g., Microcystis aeruginosa, M. flos-aquae, M. botrys), whereas genera within the same division had widely divergent responses to added N (e.g., Anabaena, Planktothrix, Microcystis). Least-squares regression analysis demonstrated that changes in phytoplankton biomass determined by microscopy were correlated significantly (p<0.005) with variations in HPLC-derived concentrations of biomarker pigments (r(2) = 0.13-0.64) from all major algal groups, although HPLC tended to underestimate the relative abundance of cyanobacteria. Together, these findings show that while fertilisation of P-rich lakes with N can increase algal biomass, there is substantial variation in responses of genera and divisions to specific chemical forms of added N.
In 2011, Lake Erie experienced the largest harmful algal bloom in its recorded history, with a peak intensity over three times greater than any previously observed bloom. Here we show that long-term ...trends in agricultural practices are consistent with increasing phosphorus loading to the western basin of the lake, and that these trends, coupled with meteorological conditions in spring 2011, produced record-breaking nutrient loads. An extended period of weak lake circulation then led to abnormally long residence times that incubated the bloom, and warm and quiescent conditions after bloom onset allowed algae to remain near the top of the water column and prevented flushing of nutrients from the system. We further find that all of these factors are consistent with expected future conditions. If a scientifically guided management plan to mitigate these impacts is not implemented, we can therefore expect this bloom to be a harbinger of future blooms in Lake Erie.
Summary Tuberculous meningitis causes substantial mortality and morbidity in children and adults. More research is urgently needed to better understand the pathogenesis of disease and to improve its ...clinical management and outcome. A major stumbling block is the absence of standardised diagnostic criteria. The different case definitions used in various studies makes comparison of research findings difficult, prevents the best use of existing data, and limits the management of disease. To address this problem, a 3-day tuberculous meningitis workshop took place in Cape Town, South Africa, and was attended by 41 international participants experienced in the research or management of tuberculous meningitis. During the meeting, diagnostic criteria were assessed and discussed, after which a writing committee was appointed to finalise a consensus case definition for tuberculous meningitis for use in future clinical research. We present the consensus case definition together with the rationale behind the recommendations. This case definition is applicable irrespective of the patient's age, HIV infection status, or the resources available in the research setting. Consistent use of the proposed case definition will aid comparison of studies, improve scientific communication, and ultimately improve care.
Summary Background New drugs, but also shorter, better-tolerated regimens are needed to tackle the high global burden of tuberculosis complicated by drug resistance and retroviral disease. We ...investigated new multiple-agent combinations over the first 14 days of treatment to assess their suitability for future development. Methods In this prospective, randomised, early bactericidal activity (EBA) study, treatment-naive, drug-susceptible patients with uncomplicated pulmonary tuberculosis were admitted to hospitals in Cape Town, South Africa, between Oct 7, 2010, and Aug 19, 2011. Patients were randomised centrally by computer-generated randomisation sequence to receive bedaquiline, bedaquiline-pyrazinamide, PA-824-pyrazinamide, bedaquiline-PA-824, PA-824-moxifloxacin-pyrazinamide, or unmasked standard antituberculosis treatment as positive control. The primary outcome was the 14-day EBA assessed in a central laboratory from the daily fall in colony forming units (CFU) of M tuberculosis per mL of sputum in daily overnight sputum collections. Bilinear regression curves were fitted for each group separately and groups compared with ANOVA for ranks, followed by pair-wise comparisons adjusted for multiplicity. Clinical staff were partially masked but laboratory personnel were fully masked. This study is registered, NCT01215851. Findings The mean 14-day EBA of PA-824-moxifloxacin-pyrazinamide (n=13; 0·233 SD 0·128) was significantly higher than that of bedaquiline (14; 0·061 0·068), bedaquiline-pyrazinamide (15; 0·131 0·102), bedaquiline-PA-824 (14; 0·114 0·050), but not PA-824-pyrazinamide (14; 0·154 0·040), and comparable with that of standard treatment (ten; 0·140 0·094). Treatments were well tolerated and appeared safe. One patient on PA-824-moxifloxacin-pyrazinamide was withdrawn because of corrected QT interval changes exceeding criteria prespecified in the protocol. Interpretation PA-824-moxifloxacin-pyrazinamide is potentially suitable for treating drug-sensitive and multidrug-resistant tuberculosis. Multiagent EBA studies can contribute to reducing the time needed to develop new antituberculosis regimens. Funding The Global Alliance for TB Drug Development (TB Alliance).
Summary Background New antituberculosis regimens are urgently needed to shorten tuberculosis treatment. Following on from favourable assessment in a 2 week study, we investigated a novel regimen for ...efficacy and safety in drug-susceptible and multidrug-resistant (MDR) tuberculosis during the first 8 weeks of treatment. Methods We did this phase 2b study of bactericidal activity—defined as the decrease in colony forming units (CFUs) of Mycobacterium tuberculosis in the sputum of patients with microscopy smear-positive pulmonary tuberculosis—at eight sites in South Africa and Tanzania. We enrolled treatment-naive patients with drug-susceptible, pulmonary tuberculosis, who were randomly assigned by computer-generated sequences to receive either 8 weeks of moxifloxacin, 100 mg pretomanid (formerly known as PA-824), and pyrazinamide (MPa100Z regimen); moxifloxacin, 200 mg pretomanid, and pyrazinamide (MPa200Z regimen); or the current standard care for drug-susceptible pulmonary tuberculosis, isoniazid, rifampicin, PZA, and ethambutol (HRZE regimen). A group of patients with MDR tuberculosis received MPa200Z (DRMPa200Z group). The primary outcome was bactericidal activity measured by the mean daily rate of reduction in M tuberculosis CFUs per mL overnight sputum collected once a week, with joint Bayesian non-linear mixed-effects regression modelling. We also assessed safety and tolerability by monitoring adverse events. This study is registered with ClinicalTrials.gov , number NCT01498419. Findings Between March 24, 2012, and July 26, 2013 we enrolled 207 patients and randomly assigned them to treatment groups; we assigned 60 patients to the MPa100Z regimen, 62 to the MPa200Z regimen, and 59 to the HRZE regimen. We non-randomly assigned 26 patients with drug-resistant tuberculosis to the DRMPa200Z regimen. In patients with drug-susceptible tuberculosis, the bactericidal activity of MPa200Z (n=54) on days 0–56 (0·155, 95% Bayesian credibility interval 0·133–0·178) was significantly greater than for HRZE (n=54, 0·112, 0·093–0·131). DRMPa200Z (n=9) had bactericidal activity of 0·117 (0·070–0·174). The bactericidal activity on days 7–14 was strongly associated with bactericidal activity on days 7–56. Frequencies of adverse events were similar to standard treatment in all groups. The most common adverse event was hyperuricaemia in 59 (29%) patients (17 28% patients in MPa100Z group, 17 27% patients in MPa200Z group, 17 29% patients. in HRZE group, and 8 31% patients in DRMPa200Z group). Other common adverse events were nausea in (14 23% patients in MPa100Z group, 8 13% patients in MPa200Z group, 7 12% patients in HRZE group, and 8 31% patients in DRMPa200Z group) and vomiting (7 12% patients in MPa100Z group, 7 11% patients in MPa200Z group, 7 12% patients in HRZE group, and 4 15% patients in DRMPa200Z group). No on-treatment electrocardiogram occurrences of corrected QT interval more than 500 ms (an indicator of potential of ventricular tachyarrhythmia) were reported. No phenotypic resistance developed to any of the drugs in the regimen. Interpretation The combination of moxifloxacin, pretomanid, and pyrazinamide, was safe, well tolerated, and showed superior bactericidal activity in drug-susceptible tuberculosis during 8 weeks of treatment. Results were consistent between drug-susceptible and MDR tuberculosis. This new regimen is ready to enter phase 3 trials in patients with drug-susceptible tuberculosis and MDR-tuberculosis, with the goal of shortening and simplifying treatment. Funding Global Alliance for TB Drug Development.
Tuberculous meningitis, the most destructive form of tuberculosis, continues to be associated with considerable mortality and morbidity; among children, it is the major cause of death resulting from ...tuberculosis. The consequences of tuberculous meningitis are yet again clearly shown in the article by Heemskerk et al. in this issue of the
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This randomized, controlled study of tuberculous meningitis in Vietnamese adults, probably the largest ever undertaken, was carefully planned and executed and evaluated an intensified regimen that included both a higher dose of oral rifampin than the standard dose (15 mg per kilogram of body weight vs. 10 . . .
The effect of supplementing unscreened adults with vitamin D
on mortality is unclear. We aimed to determine whether monthly doses of vitamin D
influenced mortality in older Australians.
We did a ...randomised, double-blind, placebo-controlled trial of oral vitamin D
supplementation (60 000 IU per month) in Australians 60 years or older who were recruited across the country via the Commonwealth electoral roll. Participants were randomly assigned (1:1), using automated computer-generated permuted block randomisation, to receive one oral gel capsule of either 60 000 IU vitamin D
or placebo once a month for 5 years. Participants, staff, and investigators were blinded to study group allocation. The primary endpoint was all-cause mortality assessed in all participants who were randomly assigned. We also analysed mortality from cancer, cardiovascular disease, and other causes. Hazard ratios (HRs) and 95% CIs were generated using flexible parametric survival models. This trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000743763.
Between Feb 14, 2014, and June 17, 2015, we randomly assigned 21 315 participants, including 10 662 to the vitamin D group and 10 653 to the placebo group. In 4441 blood samples collected from randomly sampled participants (N=3943) during follow-up, mean serum 25-hydroxy-vitamin D concentrations were 77 (SD 25) in the placebo group and 115 (SD 30) nmol/L in the vitamin D group. Following 5 years of intervention (median follow-up 5·7 years IQR 5·4-6·7), 1100 deaths were recorded (placebo 538 5·1%; vitamin D 562 5·3%). 10 661 participants in the vitamin D group and 10 649 participants in the placebo group were included in the primary analysis. Five participants (one in the vitamin D group and four in the placebo group) were not included as they requested to be withdrawn and their data to be destroyed. The HR of vitamin D
effect on all-cause mortality was 1.04 95% CI 0·93 to 1·18; p=0·47)and the HR of vitamin D
effect on cardiovascular disease mortality was 0·96 (95% CI 0·72 to 1·28; p=0·77). The HR for cancer mortality was 1·15 (95% CI 0·96 to 1·39; p=0·13) and for mortality from other causes it was 0·83 (95% CI 0·65 to 1·07; p=0·15). The odds ratio for the per-protocol analysis was OR 1·18 (95% CI 1·00 to 1·40; p=0·06). In exploratory analyses excluding the first 2 years of follow-up, those randomly assigned to receive vitamin D had a numerically higher hazard of cancer mortality than those in the placebo group (HR 1·24 95% CI 1·01-1·54; p=0·05).
Administering vitamin D
monthly to unscreened older people did not reduce all-cause mortality. Point estimates and exploratory analyses excluding the early follow-up period were consistent with an increased risk of death from cancer. Pending further evidence, the precautionary principle would suggest that this dosing regimen might not be appropriate in people who are vitamin D-replete.
The D-Health Trial is funded by National Health and Medical Research Council.
Dissolved nitrogen (N) as urea (NH₂₂CO), nitrate (NO⁻₃), and ammonium (NH⁺₄) was added to naturally phosphorus (P)-rich lake water (up to 175 μg P L−1) to test the hypotheses that pollution of ...hypereutrophic lakes with N increases total algal abundance, alters community composition, and favors toxic cyanobacteria that do not fix atmospheric N₂. Monthly experiments were conducted in triplicate in polymictic Wascana Lake, Saskatchewan, Canada, during July, August, and September 2008 using large (> 3140 liters) enclosures. Addition of all forms of N added at 6 mg N L−1 increased total algal abundance (as chlorophyll a) by up to 350% relative to controls during August and September, when soluble reactive P (SRP) was > 50 μg P L−1 and dissolved N: P was < 20 : 1 by mass. In particular, NH⁺₄ and urea favored non-heterocystous cyanobacteria and chlorophytes and NO⁻₃, urea promoted chlorophytes, some cyanobacteria, and transient blooms of siliceous algae, whereas N₂-fixing cyanobacteria and dinoflagellates exhibited little response to added N. Added N also increased microcystin production by up to 13-fold in August and September, although the magnitude of response varied with N species and predominant algal taxon (Planktothrix agardhii, Microcystis spp.). These findings demonstrate that pollution with N intensifies eutrophication and algal toxicity in lakes with elevated concentrations of SRP and low N: P, and that the magnitude of these effects depends on the chemical form, and hence source, of N.
Summary Para-aminosalicylic acid (PAS) is one of the last remaining drugs available to treat extensively drug-resistant (XDR) tuberculosis. Good outcomes (81% 5 year survival) were documented when ...PAS was first used with streptomycin, yet results of PAS with remaining potentially effective drugs for the treatment of XDR tuberculosis are poor (mortality 30–90%). In this Review, we assess published work regarding recommendations for PAS dosing in relation to efficacy and tolerance. PAS 20 g daily acoompanied only by streptomycin is better in prevention of streptomycin resistance than PAS 10 g or 5 g daily. When accompanied by isonazid, a more potent drug than streptomycin, treatment success with PAS 20 g daily is similar to that of PAS 10 g daily. In contemporary, relatively weak XDR tuberculosis regimens, the recommended doseage of PAS 8–12 g in two to three doses daily is probably insufficient. Furthermore, once daily PAS could be considered, because substantial research suggests no worse intolerance than with multiple daily PAS doses. In most countries, PAS is now available in a granular, slow-release formulation that seems well tolerated, but efficacy has never been formally assessed. Once daily dosing with granular PAS might achieve high peak concentrations and a long interval above minimum inhibitory concentration, with the advantage of improved supervision of drug intake.
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