Clonal Strain Persistence of Candida albicans Isolates from Chronic Mucocutaneous Candidiasis Patients

Funding: The study was supported by the MRC for a PhD studentship for AM and the Wellcome Trust for funding (086827, 075470, 097377 & 101873). Acknowledgments We thank Professor Frank Odds for MLST central database curation and useful discussions.Peer reviewedPublisher PD

ABC Transporter Genes Show Upregulated Expression in Drug Resistant Clinical Isolates of Candida auris : a Genome-Wide Characterization of ATP-Binding Cassette (ABC) Transporter Genes

Funding This work was supported by the ICMR (AMR/149/2018-ECD-II) and DBT (BT/PR14117/BRB/10/1420/2015) to RP. AKM appreciates the support by research grant EMR/2016/001927 and DST PURSE II from the Department of Science and Technology (IN). MW was grateful for a Senior Research Fellowship from the University Grant Commission. NG acknowledges the Wellcome Trust support of a Senior Investigator (101873/Z/13/Z), Collaborative (200208/A/15/Z), and Strategic Awards (097377/Z11/Z), and the MRC Centre for Medical Mycology (MR/N006364/1). AJM was supported by the University of Aberdeen studentship. Work in AL’s laboratory was supported by the Wellcome Trust (212524/Z/18/Z) and the Medical Research Council (MRC) Centre for Medical Mycology at the University of Aberdeen (MR/P501955/1 and MR/N006364/1). Acknowledgments We thank the Centre for Genome Enabled Biology and Medicine at the University of Aberdeen (E. Collie-Duguid and S. Shaw) for sequencing and support with genome analysis.Peer reviewedPublisher PD

River bank burrowing by invasive crayfish: Spatial distribution, biophysical controls and biogeomorphic significance

Invasive species generate significant global environmental and economic costs and represent a particularly potent threat to freshwater systems. The biogeomorphic impacts of invasive aquatic and riparian species on river processes and landforms remain largely unquantified, but have the potential to generate significant sediment management issues within invaded catchments. Several species of invasive (non-native) crayfish are known to burrow into river banks and visual evidence of river bank damage is generating public concern and media attention. Despite this, there is a paucity of understanding of burrow distribution, biophysical controls and the potential significance of this problem beyond a small number of local studies at heavily impacted sites. This paper presents the first multi-catchment analysis of this phenomenon, combining existing data on biophysical river properties and invasive crayfish observations with purpose-designed field surveys across 103 river reaches to derive key trends. Crayfish burrows were observed on the majority of reaches, but burrowing tended to be patchy in spatial distribution, concentrated in a small proportion (< 10%) of the length of rivers surveyed. Burrow distribution was better explained by local bank biophysical properties than by reach-scale properties, and burrowed banks were more likely to be characterised by cohesive bank material, steeper bank profiles with large areas of bare bank face, often on outer bend locations. Burrow excavation alone has delivered a considerable amount of sediment to invaded river systems in the surveyed sites (3 t km− 1 impacted bank) and this represents a minimum contribution and certainly an underestimate of the absolute yield (submerged burrows were not recorded). Furthermore, burrowing was associated with bank profiles that were either actively eroding or exposed to fluvial action and/or mass failure processes, providing the first quantitative evidence that invasive crayfish may cause or accelerate river bank instability and erosion in invaded catchments beyond the scale of individual burro

The Concise Guide to PHARMACOLOGY 2013/14: overview.

The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties of over 2000 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties from the IUPHAR database. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.12444/full. This compilation of the major pharmacological targets is divided into seven areas of focus: G protein-coupled receptors, ligand-gated ion channels, ion channels, catalytic receptors, nuclear hormone receptors, transporters and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. A new landscape format has easy to use tables comparing related targets. It is a condensed version of material contemporary to late 2013, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in previous Guides to Receptors & Channels. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and GRAC and provides a permanent, citable, point-in-time record that will survive database updates

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Amido analogues of zincocenes and cadmocenes

The synthesis and characterisation of low-coordinate zinc and cadmium complexes of the sterically demanding 1,3,6,8-tetra-tert-butylcarbazol-9-yl ligand (tBu4carb−) are reported. (tBu4carb)2M (M = Zn 1; M = Cd 2) are the first examples of formally two-coordinate bis-carbazol-9-yl complexes of the Group 12 metals and 2 is the first crystallographically characterised two-coordinate amido complex of cadmium. The structure and bonding within these complexes are explored via a combination of X-ray crystallography and DFT calculations. The solid state structures for these zinc and cadmium complexes differ greatly from each other; not only do the steric demands of the peripheral tert-butyl substituents in these systems act to inhibit solvent coordination, but they also influence the coordination geometry around the metal centres

No evidence of increased mutations in the germline of a group of British nuclear test veterans.

The potential germline effects of radiation exposure to military veterans present at British nuclear tests in Australia and the South Pacific is of considerable interest. We analyzed germline mutations in 60 families of UK military personnel comprising 30 control and 30 nuclear test veterans (NTV). Using whole-genome sequencing we studied the frequency and spectra of de novo mutations to investigate the transgenerational effect of veterans' (potential) exposure to radiation at nuclear bomb test sites. We find no elevation in total de novo single nucleotide variants, small insertion-deletions, structural variants or clustered mutations among the offspring of nuclear test veterans compared to those of control personnel. We did observe an elevated occurrence of single base substitution mutations within mutation signature SBS16, due to a subset of NTV offspring. The relevance of this elevation to potential exposure of veteran fathers and, future health risks, require further investigation. Overall, we find no evidence of increased mutations in the germline of a group of British nuclear test veterans. ISRCTN Registry 17461668

A systematic review of human evidence for the intergenerational effects of exposure to ionizing radiation

To provide a synthesis of the published evidence pertaining to the intergenerational health effects of parental preconceptional exposure to ionizing radiation in humans. The study populations are the descendants of those who were exposed to ionizing radiation prior to conception. A Boolean search identified publications for review in accordance with Office of Health Assessment and Translation guidelines. Initially, a risk of bias assessment was conducted for each published study and relevant data extracted. Information was organized into adverse health outcome groups and exposure situations. To make an assessment from the body of evidence within each group, an initial confidence rating was assigned, before factors including inconsistencies between studies, magnitude of effect, dose response and confounders were considered. From this, ‘an effect’, ‘no effect’ or whether the evidence remained ‘inadequate’ to determine either effect or no effect, was ascertained. This assessment was based primarily upon the author’s conclusions within that evidence-base and, by binomial probability testing of the direction of effect reported. 2441 publications were identified for review which after screening was reduced to 127. For the majority of the adverse health groups, we find there to be inadequate evidence from which to determine whether the health effect was, or was not, associated with parental preconceptional radiation exposure. This was largely due to heterogeneity between individual study’s findings and conclusions within each group and, the limited number of studies within each group. We did observe one health grouping (congenital abnormalities) in occupationally exposed populations, where an increase in effect relative to their controls or large magnitude of effects, were reported, although it is noted that the authors of these studies interpreted their findings as most likely not to be associated with parental radiation exposure. We find there to be a lack of evidence to enable the formal assessment of radiation-related adverse effects in offspring of exposed humans. This is not the same as there being no clear evidence that effects may occur but does infer that if adverse health effects do arise in children of exposed parents, then these effects are small and difficult to reproducibly measure. Inconsistencies in designing studies are unavoidable, however we highlight the need for an element of standardization and, more sharing of primary datasets as part of open access initiatives, in order for future reviews to make reasonable conclusions. Overall, there is a need for future work to ensure comparable measures between studies where possible.</p

Patient clinical data.

<p>Flucon = fluconazole, itracon = itraconazole, amph sus = amphotericin suspension (10 mg/ml swirl and swallow 4x daily). All swabs were taken for routine Dg purposes. Ethical approval was obtained under the Newcastle Autoimmune Inflammatory Rheumatic Disease Research Biobank (NAIRB) Ref No NAIRB-DL-01 dx obtained from the Southwest 3 Research Ethics Committee (Ref. 10/H0106/30) to perform research on samples collected as part of the NAIRB by researchers based at Newcastle University. Pts 1–5 had primary CMC; whole exome sequencing confirmed gain-of-function STAT1 mutations in 3 while no mutation was identified in 2 patients; P4 had candida granuloma of soft palate. P6 had 2oCMC due to steroid inhalers (asthma). Swabs were processed in the Department of Microbiology, Newcastle upon Tyne Hospitals NHS Trust (NUTH): Mohammad Raza, Consultant Microbiologist (<a href="mailto:[email protected]" target="_blank">[email protected]</a>) and Claire Rennison, Senior BMS (now retired).</p