The Genetics of Susceptibility to Leprosy

There is strong evidence that genetic factors play a role in susceptibility to leprosy. Although the major histocompatibility complex is known to play a part, it does not account for the whole picture. Recent advances in genetic technology have made it possible to identify loci involved in complex traits. In this thesis I discuss two contrasting approaches: a genome-wide search for the detection of major genes, and candidate gene association studies capable of detecting smaller genetic effects. 242 affected sibling pairs with leprosy were identified in Tamil Nadu in South India. DNA extracted from their blood was used to perform a two-stage genome wide search. Initially 92 families were screened using 293 polymorphic microsatellite markers. A further 96 families were then used to rescreen the markers that showed lod scores suggestive of linkage. Markers on chromosomes 2, 6, 10, 16 and 17 showed increased sharing which could be consistent with the presence of minor genes. These regions include some interesting candidate genes that warrant further investigation. Association studies were performed on 5 candidate gaies using cases and controls from South India, Bengal, and Mali: Interleukins-4 and —10, tumour necrosis factor (INF), vitamin D receptor, and the natural resistance associated macrophage protein 1 (NRAMP1). An association was found between the NRAMP1 1729+55del4 polymorphism and leprosy type in a population from Mali, mutant homozygotes being susceptible to paucibacillary leprosy whilst heterozygotes were susceptible to multibacillary leprosy (x2 =8.88, p=0.00288 OR=5.79{CI 1.46-24.61}). These findings persisted after logistic regression to allow for region and ethnicity. This association was not observed in the South Indian cases and controls. A borderline association was found between the TNF — 238 polymorphism and susceptibility to leprosy in a South Indian population, cases having an excess of the common allele compared to controls (2x2 x2 = 4.12, p=0.042 OR=1.68{CI 0.98-2.87})

Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia (ARREST): study protocol for a randomised controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common and serious infection, with an associated mortality of ~25%. Once in the blood, S. aureus can disseminate to infect almost any organ, but bones, joints and heart valves are most frequently affected. Despite the infection's severity, the evidence guiding optimal antibiotic therapy is weak: fewer than 1,500 patients have been included in 16 randomised controlled trials investigating S. aureus bacteraemia treatment. It is uncertain which antibiotics are most effective, their route of administration and duration, and whether antibiotic combinations are better than single agents. We hypothesise that adjunctive rifampicin, given in combination with a standard first-line antibiotic, will enhance killing of S. aureus early in the treatment course, sterilise infected foci and blood faster, and thereby reduce the risk of dissemination, metastatic infection and death. Our aim is to determine whether adjunctive rifampicin reduces all-cause mortality within 14 days and bacteriological failure or death within 12 weeks from randomisation. METHODS: We will perform a parallel group, randomised (1:1), blinded, placebo-controlled trial in NHS hospitals across the UK. Adults (≥ 18 years) with S. aureus (meticillin-susceptible or resistant) grown from at least one blood culture who have received ≤ 96 h of active antibiotic therapy for the current infection and do not have contraindications to the use of rifampicin will be eligible for inclusion. Participants will be randomised to adjunctive rifampicin (600-900 mg/day; orally or intravenously) or placebo for the first 14 days of therapy in combination with standard single-agent antibiotic therapy. The co-primary outcome measures will be all-cause mortality up to 14 days from randomisation and bacteriological failure/death (all-cause) up to 12 weeks from randomisation. 940 patients will be recruited, providing >80% power to detect 45% and 30% reductions in the two co-primary endpoints of death by 14 days and bacteriological failure/death by 12 weeks respectively. DISCUSSION: This pragmatic trial addresses the long-standing hypothesis that adjunctive rifampicin improves outcome from S. aureus bacteraemia through enhanced early bacterial killing. If proven correct, it will provide a paradigm through which further improvements in outcome from S. aureus bacteraemia can be explored.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

WISEA J083011.95+283716.0: A Missing Link Planetary-Mass Object

We present the discovery of WISEA J083011.95+283716.0, the first Y dwarf candidate identified through the Backyard Worlds: Planet 9 citizen science project. We identified this object as a red, fast-moving source with a faint $W2$ detection in multi-epoch \textit{AllWISE} and unWISE images. We have characterized this object with Spitzer Space Telescope and \textit{Hubble Space Telescope} follow-up imaging. With mid-infrared detections in \textit{Spitzer}'s \emph{ch1} and \emph{ch2} bands and flux upper limits in Hubble Space Telescope $F105W$ and $F125W$ filters, we find that this object is both very faint and has extremely red colors ($ch1-ch2 = 3.25\pm0.23$ mag, $F125W-ch2 \geq 9.36$ mag), consistent with a T$_{eff}\sim300$ K source, as estimated from the known Y dwarf population. A preliminary parallax provides a distance of $11.1^{+2.0}_{-1.5}$ pc, leading to a slightly warmer temperature of $\sim350$ K. The extreme faintness and red Hubble Space Telescope and Spitzer Space Telescope colors of this object suggest it may be a link between the broader Y dwarf population and the coldest known brown dwarf WISE J0855$-$0714, and highlight our limited knowledge of the true spread of Y dwarf colors. We also present four additional Backyard Worlds: Planet 9 late-T brown dwarf discoveries within 30 pc.Comment: 13 pages, 6 figures, 5 table

WISEA J083011.95+283716.0: A Missing Link Planetary-mass Object

We present the discovery of WISEA J083011.95+283716.0, the first Y-dwarf candidate identified through the "Backyard Worlds: Planet 9" citizen science project. We identified this object as a red, fast-moving source with a faint W2 detection in multiepoch AllWISE and unWISE images. We have characterized this object with Spitzer and Hubble Space Telescope's (HST) follow-up imaging. With mid-infrared detections in Spitzer's ch1 and ch2 bands and flux upper limits in HST F105W and F125W filters, we find that this object is both very faint and has extremely red colors (ch1 − ch2 = 3.25 ± 0.23 mag, F125W − ch2 ≥ 9.36 mag), consistent with a T_(eff) ~ 300 K source, as estimated from the known Y-dwarf population. A preliminary parallax provides a distance of 11.1_(-1.5)^(+2.0) pc, leading to a slightly warmer temperature of ~350 K. The extreme faintness and red HST and Spitzer colors of this object suggest that it may be a link between the broader Y-dwarf population and the coldest known brown dwarf WISE J0855−0714, and may highlight our limited knowledge of the true spread of Y-dwarf colors. We also present four additional "Backyard Worlds: Planet 9" late-T brown dwarf discoveries within 30 pc

Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia: the ARREST RCT.

BACKGROUND: Staphylococcus aureus bacteraemia is a common and frequently fatal infection. Adjunctive rifampicin may enhance early S. aureus killing, sterilise infected foci and blood faster, and thereby reduce the risk of dissemination, metastatic infection and death. OBJECTIVES: To determine whether or not adjunctive rifampicin reduces bacteriological (microbiologically confirmed) failure/recurrence or death through 12 weeks from randomisation. Secondary objectives included evaluating the impact of rifampicin on all-cause mortality, clinically defined failure/recurrence or death, toxicity, resistance emergence, and duration of bacteraemia; and assessing the cost-effectiveness of rifampicin. DESIGN: Parallel-group, randomised (1 : 1), blinded, placebo-controlled multicentre trial. SETTING: UK NHS trust hospitals. PARTICIPANTS: Adult inpatients (≥ 18 years) with meticillin-resistant or susceptible S. aureus grown from one or more blood cultures, who had received < 96 hours of antibiotic therapy for the current infection, and without contraindications to rifampicin. INTERVENTIONS: Adjunctive rifampicin (600-900 mg/day, oral or intravenous) or placebo for 14 days in addition to standard antibiotic therapy. Investigators and patients were blinded to trial treatment. Follow-up was for 12 weeks (assessments at 3, 7, 10 and 14 days, weekly until discharge and final assessment at 12 weeks post randomisation). MAIN OUTCOME MEASURES: The primary outcome was all-cause bacteriological (microbiologically confirmed) failure/recurrence or death through 12 weeks from randomisation. RESULTS: Between December 2012 and October 2016, 758 eligible participants from 29 UK hospitals were randomised: 370 to rifampicin and 388 to placebo. The median age was 65 years [interquartile range (IQR) 50-76 years]. A total of 485 (64.0%) infections were community acquired and 132 (17.4%) were nosocomial; 47 (6.2%) were caused by meticillin-resistant S. aureus. A total of 301 (39.7%) participants had an initial deep infection focus. Standard antibiotics were given for a median of 29 days (IQR 18-45 days) and 619 (81.7%) participants received flucloxacillin. By 12 weeks, 62 out of 370 (16.8%) patients taking rifampicin versus 71 out of 388 (18.3%) participants taking the placebo experienced bacteriological (microbiologically confirmed) failure/recurrence or died [absolute risk difference -1.4%, 95% confidence interval (CI) -7.0% to 4.3%; hazard ratio 0.96, 95% CI 0.68 to 1.35; p = 0.81]. There were 4 (1.1%) and 5 (1.3%) bacteriological failures (p = 0.82) in the rifampicin and placebo groups, respectively. There were 3 (0.8%) versus 16 (4.1%) bacteriological recurrences (p = 0.01), and 55 (14.9%) versus 50 (12.9%) deaths without bacteriological failure/recurrence (p = 0.30) in the rifampicin and placebo groups, respectively. Over 12 weeks, there was no evidence of differences in clinically defined failure/recurrence/death (p = 0.84), all-cause mortality (p = 0.60), serious (p = 0.17) or grade 3/4 (p = 0.36) adverse events (AEs). However, 63 (17.0%) participants in the rifampicin group versus 39 (10.1%) participants in the placebo group experienced antibiotic or trial drug-modifying AEs (p = 0.004), and 24 (6.5%) participants in the rifampicin group versus 6 (1.5%) participants in the placebo group experienced drug-interactions (p = 0.0005). Evaluation of the costs and health-related quality-of-life impacts revealed that an episode of S. aureus bacteraemia costs an average of £12,197 over 12 weeks. Rifampicin was estimated to save 10% of episode costs (p = 0.14). After adjustment, the effect of rifampicin on total quality-adjusted life-years (QALYs) was positive (0.004 QALYs), but not statistically significant (standard error 0.004 QALYs). CONCLUSIONS: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S. aureus bacteraemia. FUTURE WORK: Given the substantial mortality, other antibiotic combinations or improved source management should be investigated. TRIAL REGISTRATIONS: Current Controlled Trials ISRCTN37666216, EudraCT 2012-000344-10 and Clinical Trials Authorisation 00316/0243/001. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 59. See the NIHR Journals Library website for further project information.NIHR HTA Programm

WISEA J041451.67–585456.7 and WISEA J181006.18–101000.5: The First Extreme T-type Subdwarfs?

We present the discoveries of WISEA J041451.67−585456.7 and WISEA J181006.18−101000.5, two low-temperature (1200–1400 K), high proper motion T-type subdwarfs. Both objects were discovered via their high proper motion (>0".5 yr⁻¹); WISEA J181006.18−101000.5 as part of the NEOWISE proper motion survey and WISEA J041451.67−585456.7 as part of the citizen science project Backyard Worlds; Planet 9. We have confirmed both as brown dwarfs with follow-up near-infrared spectroscopy. Their spectra and near-infrared colors are unique among known brown dwarfs, with some colors consistent with L-type brown dwarfs and other colors resembling those of the latest-type T dwarfs. While no forward model consistently reproduces the features seen in their near-infrared spectra, the closest matches suggest very low metallicities ([Fe/H] ⩽ −1), making these objects likely the first examples of extreme subdwarfs of the T spectral class (esdT). WISEA J041451.67−585456.7 and WISEA J181006.18−101000.5 are found to be part of a small population of objects that occupy the "substellar transition zone," and have the lowest masses and effective temperatures of all objects in this group

DESI Survey Validation Spectra Reveal an Increasing Fraction of Recently Quenched Galaxies at z∼1z\sim1

We utilize $\sim17000$ bright Luminous Red Galaxies (LRGs) from the novel Dark Energy Spectroscopic Instrument Survey Validation spectroscopic sample, leveraging its deep ($\sim2.5$ hour/galaxy exposure time) spectra to characterize the contribution of recently quenched galaxies to the massive galaxy population at $0.4<z<1.3$. We use Prospector to infer non-parametric star formation histories and identify a significant population of post-starburst galaxies that have joined the quiescent population within the past $\sim1$ Gyr. The highest redshift subset (277 at $z>1$) of our sample of recently quenched galaxies represents the largest spectroscopic sample of post-starburst galaxies at that epoch. At $0.4<z<0.8$, we measure the number density of quiescent LRGs, finding that recently quenched galaxies constitute a growing fraction of the massive galaxy population with increasing lookback time. Finally, we quantify the importance of this population amongst massive ($\mathrm{log}(M_\star/M_\odot)>11.2$) LRGs by measuring the fraction of stellar mass each galaxy formed in the Gyr before observation, $f_{\mathrm{1 Gyr}}$. Although galaxies with $f_{\mathrm{1 Gyr}}>0.1$ are rare at $z\sim0.4$ ($\lesssim 0.5\%$ of the population), by $z\sim0.8$ they constitute $\sim3\%$ of massive galaxies. Relaxing this threshold, we find that galaxies with $f_\mathrm{1 Gyr}>5\%$ constitute $\sim10\%$ of the massive galaxy population at $z\sim0.8$. We also identify a small but significant sample of galaxies at $z=1.1-1.3$ that formed with $f_{\mathrm{1 Gyr}}>50\%$, implying that they may be analogues to high-redshift quiescent galaxies that formed on similar timescales. Future analysis of this unprecedented sample promises to illuminate the physical mechanisms that drive the quenching of massive galaxies after cosmic noon.Comment: Submitted to ApJ Letters after DESI Collaboration Review. 14 pages, 5 figures, comments welcome

WISEA J041451.67–585456.7 and WISEA J181006.18–101000.5: The First Extreme T-type Subdwarfs?

We present the discoveries of WISEA J041451.67−585456.7 and WISEA J181006.18−101000.5, two low-temperature (1200–1400 K), high proper motion T-type subdwarfs. Both objects were discovered via their high proper motion (>0".5 yr⁻¹); WISEA J181006.18−101000.5 as part of the NEOWISE proper motion survey and WISEA J041451.67−585456.7 as part of the citizen science project Backyard Worlds; Planet 9. We have confirmed both as brown dwarfs with follow-up near-infrared spectroscopy. Their spectra and near-infrared colors are unique among known brown dwarfs, with some colors consistent with L-type brown dwarfs and other colors resembling those of the latest-type T dwarfs. While no forward model consistently reproduces the features seen in their near-infrared spectra, the closest matches suggest very low metallicities ([Fe/H] ⩽ −1), making these objects likely the first examples of extreme subdwarfs of the T spectral class (esdT). WISEA J041451.67−585456.7 and WISEA J181006.18−101000.5 are found to be part of a small population of objects that occupy the "substellar transition zone," and have the lowest masses and effective temperatures of all objects in this group