Identification of a novel class of autotaxin inhibitors through cross-screening

Three novel series were generated in order to mimic the pharmacophoric features displayed by lead compound AM095, a Lysophosphatidic acid (LPA1) receptor antagonist. Biological evaluation of this array of putative LPA1 antagonists led us to the discovery of three novel series of inhibitors of the ecto-enzyme Autotaxin (ATX), responsible for LPA production in blood, with potencies in the range 1 – 4 μM accompanied with good (> 100 μg/mL) solubility

Adaptation of the WHO Essential Medicines List for national antibiotic stewardship policy in England: being AWaRe.

OBJECTIVES:Appropriate use of and access to antimicrobials are key priorities of global strategies to combat antimicrobial resistance (AMR). The WHO recently classified key antibiotics into three categories (AWaRe) to improve access (Access), monitor important antibiotics (Watch) and preserve effectiveness of 'last resort' antibiotics (Reserve). This classification was assessed for antibiotic stewardship and quality improvement in English hospitals. METHODS:Using an expert elicitation exercise, antibiotics used in England but not included in the WHO AWaRe index were added to an appropriate category following a workshop consensus exercise with national experts. The methodology was tested using national antibiotic prescribing data and presented by primary and secondary care. RESULTS:In 2016, 46/108 antibiotics included within the WHO AWaRe index were routinely used in England and an additional 25 antibiotics also commonly used in England were not included in the WHO AWaRe index. WHO AWaRe-excluded and -included antibiotics were reviewed and reclassified according to the England-adapted AWaRE index with the justification by experts for each addition or alteration. Applying the England-adapted AWaRe index, Access antibiotics accounted for the majority (60.9%) of prescribing, followed by Watch (37.9%) and Reserve (0.8%); 0.4% of antibiotics remained unclassified. There was unexplained 2-fold variation in prescribing between hospitals within each AWaRe category, highlighting the potential for quality improvement. CONCLUSIONS:We have adapted the WHO AWaRe index to create a specific index for England. The AWaRe index provides high-level understanding of antibiotic prescribing. Subsequent to this process the England AWaRe index is now embedded into national antibiotic stewardship policy and incentivized quality improvement schemes

A large-scale and PCR-referenced vocal audio dataset for COVID-19

The UK COVID-19 Vocal Audio Dataset is designed for the training and evaluation of machine learning models that classify SARS-CoV-2 infection status or associated respiratory symptoms using vocal audio. The UK Health Security Agency recruited voluntary participants through the national Test and Trace programme and the REACT-1 survey in England from March 2021 to March 2022, during dominant transmission of the Alpha and Delta SARS-CoV-2 variants and some Omicron variant sublineages. Audio recordings of volitional coughs, exhalations, and speech were collected in the 'Speak up to help beat coronavirus' digital survey alongside demographic, self-reported symptom and respiratory condition data, and linked to SARS-CoV-2 test results. The UK COVID-19 Vocal Audio Dataset represents the largest collection of SARS-CoV-2 PCR-referenced audio recordings to date. PCR results were linked to 70,794 of 72,999 participants and 24,155 of 25,776 positive cases. Respiratory symptoms were reported by 45.62% of participants. This dataset has additional potential uses for bioacoustics research, with 11.30% participants reporting asthma, and 27.20% with linked influenza PCR test results.Comment: 37 pages, 4 figure

SARS-CoV-2 infection in UK university students: lessons from September-December 2020 and modelling insights for future student return.

Funder: Isaac Newton Institute for Mathematical Sciences; Id: http://dx.doi.org/10.13039/501100005347Funder: Wellcome Trust; Id: http://dx.doi.org/10.13039/100004440Funder: Medical Research Council; Id: http://dx.doi.org/10.13039/501100000265Funder: UKRIFunder: University of Nottingham; Id: http://dx.doi.org/10.13039/501100000837In this paper, we present work on SARS-CoV-2 transmission in UK higher education settings using multiple approaches to assess the extent of university outbreaks, how much those outbreaks may have led to spillover in the community, and the expected effects of control measures. Firstly, we found that the distribution of outbreaks in universities in late 2020 was consistent with the expected importation of infection from arriving students. Considering outbreaks at one university, larger halls of residence posed higher risks for transmission. The dynamics of transmission from university outbreaks to wider communities is complex, and while sometimes spillover does occur, occasionally even large outbreaks do not give any detectable signal of spillover to the local population. Secondly, we explored proposed control measures for reopening and keeping open universities. We found the proposal of staggering the return of students to university residence is of limited value in terms of reducing transmission. We show that student adherence to testing and self-isolation is likely to be much more important for reducing transmission during term time. Finally, we explored strategies for testing students in the context of a more transmissible variant and found that frequent testing would be necessary to prevent a major outbreak.This work was supported by EPSRC grant no EP/R014604/1. The authors would also like to thank the Virtual Forum for Knowledge Exchange in Mathematical Sciences (V-KEMS) for the support during the workshop Unlocking higher education Spaces – What Might Mathematics Tell Us? where work on this paper was undertaken. K.J.B. acknowledges support from a University of Nottingham Anne McLaren Fellowship. E.L.F. acknowledges support via K.J.B.’s fellowship and the Nottingham BBSRC Doctoral Training Partnership. M.L.T. was supported by the UK Engineering and Physical Sciences Research Council (grant no. EP/N509620/1). E.B.-P., E.J.N., L.D., J.R.G. and M.J.T. were supported by UKRI through the JUNIPER modelling consortium (grant no. MR/V038613/1). E.M.H., L.D. and M.J.T. were supported by the Medical Research Council through the COVID-19 Rapid Response Rolling Call (grant no. MR/V009761/1). H.B.S. is funded by the Wellcome Trust and the Royal Society (grant no. 202562/Z/16/Z). J.E. is partially funded by the UK Engineering and Physical Sciences Research Council (grant no. EP/T004878/1)

Parental influences on children's eating behaviour and characteristics of successful parent-focussed interventions

Parental reports suggest that difficulties related to child-feeding and children's eating behaviour are extremely common. While 'fussy eating' does not pose an immediate threat to health, over the long-term, consumption of a poor diet can contribute to the development of a range of otherwise preventable diseases. In addition, the stress and anxiety that can surround difficult mealtimes can have a detrimental impact upon both child and parental psychological wellbeing. Since parents have a great influence over what, when, and how much food is offered, feeding difficulties may be preventable by better parental awareness. The aim of this review is to describe how parental factors contribute to the development of common feeding problems, and to discuss the merits of existing interventions aimed at parents/primary caregivers to improve child-feeding and children's eating behaviour. The potential for different technologies to be harnessed in order to deliver interventions in new ways will also be discussed

Megakaryocytes possess a functional intrinsic apoptosis pathway that must be restrained to survive and produce platelets

Deletion of Bak and Bax, the effectors of mitochondrial apoptosis, does not affect platelet production, however, loss of prosurvival Bcl-xL results in megakaryocyte apoptosis and failure of platelet shedding

Human and mouse mutations in WDR35 cause short-rib polydactyly syndromes due to abnormal ciliogenesis

Defects in cilia formation and function result in a range of human skeletal and visceral abnormalities. Mutations in several genes have been identified to cause a proportion of these disorders, some of which display genetic (locus) heterogeneity. Mouse models are valuable for dissecting the function of these genes, as well as for more detailed analysis of the underlying developmental defects. The short-rib polydactyly (SRP) group of disorders are among the most severe human phenotypes caused by cilia dysfunction. We mapped the disease locus from two siblings affected by a severe form of SRP to 2p24, where we identified an in-frame homozygous deletion of exon 5 in WDR35. We subsequently found compound heterozygous missense and nonsense mutations in WDR35 in an independent second case with a similar, severe SRP phenotype. In a mouse mutation screen for developmental phenotypes, we identified a mutation in Wdr35 as the cause of midgestation lethality, with abnormalities characteristic of defects in the Hedgehog signaling pathway. We show that endogenous WDR35 localizes to cilia and centrosomes throughout the developing embryo and that human and mouse fibroblasts lacking the protein fail to produce cilia. Through structural modeling, we show that WDR35 has strong homology to the COPI coatamers involved in vesicular trafficking and that human SRP mutations affect key structural elements in WDR35. Our report expands, and sheds new light on, the pathogenesis of the SRP spectrum of ciliopathies

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707