Ironing out sex differences in tuberculosis prevalence

Last year, two striking studies focused attention on sex differences in tuberculosis (TB) epidemiology. Katherine Horton and team’s metaanalysis of 56 prevalence surveys undertaken in low- and middle-income countries found that adult men had 2.21 (95% CI, 1.92–2.54) times more bacteriologically confirmed TB than adult women. The equivalent ratio for smear-positive TB (reported in 40 surveys), was 2.51 (95%CI 2.07–3.04). A male preponderance of prevalent TB was observed in all World Health Organization geographical regions that contributed sufficient data to draw meaningful conclusions. In the second study, Pete Dodd and colleagues utilised data on adult TB prevalence, the incidence of Mycobacterium tuberculosis infection in children, and data on social contact patterns from communities in Zambia and the Western Cape of South Africa, to produce modelled estimates of the incidence of M. tuberculosis infection, by age and sex. Whilst men and women had similar numbers of social contacts, contact patterns were strongly age and sex assortative. A key finding was that 66% (95%CI 64–67, Zambia) and 57% (95%CI 56–58, Western Cape) of incident M. tuberculosis infections were attributable to contact with adult men. The authors commented that this ‘was largely because tuberculosis prevalence was higher in male interviewees’

Mycobacterium tuberculosis infection in Southern Africa – exploring patterns, locating transmission

Tuberculosis is a major cause of premature mortality. Communities in Southern Africa are disproportionately affected. A growing body of evidence suggests that recent transmission within households can explain only a limited proportion of tuberculosis disease. However, our understanding of where transmission between households occurs is limited. I undertook a systematic review and meta-analysis of molecular epidemiology studies that described rates of strain discordance in co-prevalent cases of tuberculosis resident in the same household. I also conducted a tuberculin school survey in 6-8 year old children in a rural community in Northern KwaZulu-Natal. These children were all registered in a household surveillance programme operated by the Africa Centre for Population Health. I found that, across a range of both high and low burden countries, co-prevalent cases of tuberculosis in the same household often have different strains of Mycobacterium tuberculosis. These molecular epidemiological data suggest, at least in some settings, that recent transmission within households may explain a modest proportion of tuberculosis disease. I estimated the annual risk of tuberculous infection to be approximately two percent in the community around the Africa Centre. I found weak evidence that exposure to HIV positive adults in the household was associated with Mycobacterium tuberculosis infection in children. I found no strong evidence associating use of specific indoor public spaces with Mycobacterium tuberculosis infection. Transmission between households is likely an important determinant of tuberculosis disease. Further research locating Mycobacterium tuberculosis transmission might enable TB control interventions to be better targeted

A photodissociation region study of NGC 4038

We present a model of the photodissociation regions of NGC 4038, which is part of the Antennae galaxies. We have considered one-dimensional slabs of uniform density, all having a maximum AV = 10 mag, interacting with plane-parallel radiation. The density range in our simulations spans four orders of magnitude (100 ≤ n ≤ 106 cm−3) and the UV field strength spans more than three orders of magnitude (10 ≤ χ ≤ 104.5 multiples of the Draine field), from which we generated a grid of about 1400 simulations. We compare our results with Herschel SPIRE-FTS, CSO and ISO-LWS observations of eight CO transition lines (J = 1-0 to 8-7) and the [C I] 609 μm and [O I] 146 μm fine-structure lines. We find that the molecular and atomic emission lines trace different gas components of NGC 4038; thus, single emission models are insufficient to reproduce the observed values. In general, low-J CO transition lines correspond to either low-density regions interacting with low UV field strengths, or high-density regions interacting with high UV field strengths. Higher J CO transition lines are less dependent on the UV field strength and are fitted by gas with density n ∼ 104.5-105.2 cm− 3. We find that the observed fine-structure line ratio of [C I] 609 μm/[O I] 146 μm is reproduced by clouds subject to weaker UV fields compared to the CO lines. We make estimates of the XCO factor which relates the CO emission with the column density of molecular hydrogen, and find that it is less than the canonical Milky Way value

Reconstruction of the yeast Snf1 kinase regulatory network reveals its role as a global energy regulator

Highly conserved among eukaryotic cells, the AMP-activated kinase (AMPK) is a central regulator of carbon metabolism. To map the complete network of interactions around AMPK in yeast (Snf1) and to evaluate the role of its regulatory subunit Snf4, we measured global mRNA, protein and metabolite levels in wild type, Δsnf1, Δsnf4, and Δsnf1Δsnf4 knockout strains. Using four newly developed computational tools, including novel DOGMA sub-network analysis, we showed the benefits of three-level ome-data integration to uncover the global Snf1 kinase role in yeast. We for the first time identified Snf1's global regulation on gene and protein expression levels, and showed that yeast Snf1 has a far more extensive function in controlling energy metabolism than reported earlier. Additionally, we identified complementary roles of Snf1 and Snf4. Similar to the function of AMPK in humans, our findings showed that Snf1 is a low-energy checkpoint and that yeast can be used more extensively as a model system for studying the molecular mechanisms underlying the global regulation of AMPK in mammals, failure of which leads to metabolic diseases

Tuberculosis from transmission in clinics in high HIV settings may be far higher than contact data suggest.

BACKGROUND: In South Africa, it is generally estimated that only 0.5-0.6% of people's contacts occur in clinics. Both people with infectious tuberculosis and people with increased susceptibility to disease progression may spend more time in clinics, however, increasing the importance of clinic-based transmission to overall disease incidence.METHODS: We developed an illustrative mathematical model of Mycobacterium tuberculosis transmission in clinics and other settings. We assumed that 1% of contact time occurs in clinics. We varied the ratio of clinic contact time of human immunodeficiency virus (HIV) positive people compared to HIV-negative people, and of people with infectious TB compared to people without TB, while keeping the overall proportion of contact time occurring in clinics, and each person's total contact time, constant.RESULTS: With clinic contact rates respectively 10 and 5 times higher in HIV-positive people and people with TB, 10.7% (plausible range 8.5-13.4%) of TB resulted from transmission in clinics. With contact rates in HIV-positive people and people with TB respectively 5 and 2 times higher, 5.3% (plausible range 4.3-6.3%) of all TB was due to transmission in clinics.CONCLUSION: The small amount of contact time that generally occurs in clinics may greatly underestimate their contribution to TB disease in high TB-HIV burden settings

The STELLAR trial protocol: a prospective multicentre trial for Richter’s syndrome consisting of a randomised trial investigation CHOP-R with or without acalabrutinib for newly diagnosed RS and a single-arm platform study for evaluation of novel agents in relapsed disease

Background Transformation of chronic lymphocytic leukaemia (CLL) to diffuse large B-cell lymphoma (DLCBL) type Richter’s syndrome (RS) carries a dismal prognosis. Standard-of-care chemoimmunotherapy for de novo RS is inadequate with median survival of less than one year. Patients are frequently elderly or have co-morbidities limiting dose-intense chemotherapy. Treatment of relapsed/refractory (R/R) RS and RS emerging after CLL-directed therapy represent urgent unmet clinical needs. Agents targeting Bruton’s tyrosine kinase (BTK) deliver improved outcomes for patients with high-risk CLL and expand effective treatments to frailer patients. Acalabrutinib is an oral, second-generation BTK inhibitor with a favourable toxicity profile and demonstrated activity in CLL and B-cell lymphomas. Combination of acalabrutinib with standard-of-care CHOP-R chemoimmunotherapy offers a sound rationale to test in a prospective trial for de novo RS. Methods The prospective multicentre STELLAR study is designed in two elements, consisting of a randomised study to evaluate the safety and activity of CHOP-R chemoimmunotherapy in combination with acalabrutinib in newly diagnosed RS and single-arm studies of novel agents for other RS patient cohorts. Eligible patients with newly diagnosed DLBCL-type RS are randomised between six cycles of CHOP-R therapy and six cycles CHOP-R plus acalabrutinib, followed by acalabrutinib maintenance. The primary endpoint of the randomised component is progression free survival (PFS). Cohort 1 enrols RS patients with progressive disease following chemoimmunotherapy for acalabrutinib monotherapy. Patients with RS diagnosed while on ibrutinib may enrol in Cohort 2, a single-arm study of CHOP-R plus acalabrutinib. The primary endpoint for the single-arm studies is overall response rate (ORR). Secondary endpoints for all cohorts are overall survival (OS), quality of life and proportion of patients proceeding to stem cell transplantation. The study will be accompanied by exploratory analysis of the mutational landscape of RS and the relationship between dynamic changes in sequential circulating tumour DNA samples and clinical outcomes. Discussion The STELLAR randomised trial evaluates the role of CHOP-R plus acalabrutinib in newly diagnosed RS patients. The single-arm platform studies enable the incorporation of promising novel therapies into the protocol. The STELLAR study has potential to identify novel biomarkers of treatment response in this high-risk malignancy. Trial registration EudraCT: 2017–004401-40, registered on the 31-Oct-2017. IRSCTN: https://www.isrctn.com/ISRCTN52839057, registered on the 04-Mar-2019. ClinicalTrials.gov: NCT03899337, registered on 02-April-2019