An economic evaluation of the randomized controlled trial of topical corticosteroid and home-based narrowband ultraviolet B for active and limited vitiligo (the HI-Light Vitiligo Trial)

Background: Economic evidence for vitiligo treatments is absent. Objectives: To determine the cost-effectiveness of (i) handheld narrowband ultraviolet B (NB-UVB) and (ii) a combination of topical corticosteroid (TCS) and NB-UVB compared with TCS alone for localized vitiligo. Methods: Cost-effectiveness analysis alongside a pragmatic, three-arm, placebo-controlled randomized controlled trial with 9 months’ treatment. In total 517 adults and children (aged ≥ 5 years) with active vitiligo affecting < 10% of skin were recruited from secondary care and the community and were randomized 1: 1: 1 to receive TCS, NB-UVB or both. Cost per successful treatment (measured on the Vitiligo Noticeability Scale) was estimated. Secondary cost–utility analyses measured quality-adjusted life-years using the EuroQol 5 Dimensions 5 Levels for those aged ≥ 11 years and the Child Health Utility 9D for those aged 5 to < 18 years. The trial was registered with number ISRCTN17160087 on 8 January 2015. Results: The mean ± SD cost per participant was £775 ± 83·7 for NB-UVB, £813 ± 111.4 for combination treatment and £600 ± 96·2 for TCS. In analyses adjusted for age and target patch location, the incremental difference in cost for combination treatment compared with TCS was £211 (95% confidence interval 188–235), corresponding to a risk difference of 10·9% (number needed to treat = 9). The incremental cost was £1932 per successful treatment. The incremental difference in cost for NB-UVB compared with TCS was £173 (95% confidence interval 151–196), with a risk difference of 5·2% (number needed to treat = 19). The incremental cost was £3336 per successful treatment. Conclusions: Combination treatment, compared with TCS alone, has a lower incremental cost per additional successful treatment than NB-UVB only. Combination treatment would be considered cost-effective if decision makers are willing to pay £1932 per additional treatment success

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Musculoskeletal injury rates in Thoroughbred racehorses following local corticosteroid injection

A retrospective cohort study was performed to compare the rates of musculoskeletal injury (MSI) in horses receiving local corticosteroid injection (LCI) with those that were untreated and those prior to treatment. Of the 1911 study horses, 392 had been treated. A LCI was defined as any injection of corticosteroid into or adjacent to a synovial structure, muscle, or tendon/ligament. A MSI was defined as any limb injury identified by a veterinarian, following which the horse did not race for at least 6 months, or was retired. Hazard ratios (HR) comparing hazard of injury following injection to that in non-injected horses and prior to injection were calculated using Cox proportional hazards models.&lt;p&gt;&lt;/p&gt; At least one LCI was administered to 392 horses (20.5%; median 2, range 1–16). Most LCIs were performed bilaterally (70.9%) and intra-articularly into the carpal (49.7%) or fore fetlock (29.3%) joints. There were 219 MSIs of which carpal injuries (47%), fore fetlock (22%) and forelimb tendon injuries (16%) were the most common. The incidence rate of MSI in untreated horses and those prior to injection was 1.22 (95% CI 1.04–1.44) injuries/100 horse-months, and following LCI the hazard of MSI was greater (HR 4.83, 3.54–6.61, P &#60; 0.001). The hazard ratio returned to levels indistinguishable from before treatment after 49 days. The hazard of MSI in horses following second and subsequent LCIs in the data collection period was greater than in horses following their first LCI (HR 2.10, 1.31–3.36, P = 0.002).&lt;p&gt;&lt;/p&gt; There was a positive association between LCI and subsequent musculoskeletal injury rates which was most likely due to progression of the musculoskeletal condition which prompted treatment. Assuming horses that received LCI were at increased risk of MSI subsequently, any beneficial effects of the LCI were insufficient to counter this increased risk for at least 49 days after the injection

Construction of bacterial artificial chromosome libraries from the parasitic nematode Brugia malayi and physical mapping of the genome of its Wolbachia endosymbiont

The parasitic nematode, Brugia malayi, causes lymphatic filariasis in humans, which in severe cases leads to the condition known as elephantiasis. The parasite contains an endosymbiotic α-proteobacterium of the genus Wolbachia that is required for normal worm development and fecundity and is also implicated in the pathology associated with infections by these filarial nematodes. Bacterial artificial chromosome libraries were constructed from B. malayi DNA and provide over 11-fold coverage of the nematode genome. Wolbachia genomic fragments were simultaneously cloned into the libraries giving over 5-fold coverage of the 1.1 Mb bacterial genome. A physical framework for the Wolbachia genome was developed by construction of a plasmid library enriched for Wolbachia DNA as a source of sequences to hybridise to high-density bacterial artificial chromosome colony filters. Bacterial artificial chromosome end sequencing provided additional Wolbachia probe sequences to facilitate assembly of a contig that spanned the entire genome. The Wolbachia sequences provided a marker approximately every 10 kb. Four rare-cutting restriction endonucleases were used to restriction map the genome to a resolution of approximately 60 kb and demonstrate concordance between the bacterial artificial chromosome clones and native Wolbachia genomic DNA. Comparison of Wolbachia sequences to public databases using BLAST algorithms under stringent conditions allowed confident prediction of 69 Wolbachia peptide functions and two rRNA genes. Comparison to closely related complete genomes revealed that while most sequences had orthologs in the genome of the Wolbachia endosymbiont from Drosophila melanogaster, there was no evidence for long-range synteny. Rather, there were a few cases of short-range conservation of gene order extending over regions of less than 10 kb. The molecular scaffold produced for the genome of the Wolbachia from B. malayi forms the basis of a genomic sequencing effort for this bacterium, circumventing the difficult challenge of purifying sufficient endosymbiont DNA from a tropical parasite for a whole genome shotgun sequencing strategy

Enhancing the analysis of complex lipid samples through developments in chromatography and chemical derivatization

Lipids are one of the main building blocks of cellular life and represent the most abundant class of biomolecule by weight. Some of their most obvious roles include providing a source of energy storage within cells and creating barriers to compartmentalize cells by forming boundaries between cells and organelles. More recently, the roles that lipids and lipid metabolites play in cellular signaling have been increasingly revealed by the scientific community, fueling interest in this field. Chromatography coupled to mass spectrometry has emerged as an eminent analytical tool with which to study lipids, however not without challenges along the way. This chapter first summarizes some of the recent developments in the use of chromatography to separate complex lipid samples in an efficacious manner including the presentation of new techniques to increase precision and avoid sample carryover. The latter part of the chapter details recent strategies to chemically derivatize lipids to enhance their analytical characteristics for separation and analysis by mass spectrometry with the aim to gain greater insight into the roles that these biomolecules play in living systems