Epigenome erosion and SOX10 drive neural crest phenotypic mimicry in triple-negative breast cancer

Intratumoral heterogeneity is caused by genomic instability and phenotypic plasticity, but how these features co-evolve remains unclear. SOX10 is a neural crest stem cell (NCSC) specifier and candidate mediator of phenotypic plasticity in cancer. We investigated its relevance in breast cancer by immunophenotyping 21 normal breast and 1860 tumour samples. Nuclear SOX10 was detected in normal mammary luminal progenitor cells, the histogenic origin of most TNBCs. In tumours, nuclear SOX10 was almost exclusive to TNBC, and predicted poorer outcome amongst cross-sectional (p = 0.0015, hazard ratio 2.02, n = 224) and metaplastic (p = 0.04, n = 66) cases. To understand SOX10’s influence over the transcriptome during the transition from normal to malignant states, we performed a systems-level analysis of co-expression data, de-noising the networks with an eigen-decomposition method. This identified a core module in SOX10’s normal mammary epithelial network that becomes rewired to NCSC genes in TNBC. Crucially, this reprogramming was proportional to genome-wide promoter methylation loss, particularly at lineage-specifying CpG-island shores. We propose that the progressive, genome-wide methylation loss in TNBC simulates more primitive epigenome architecture, making cells vulnerable to SOX10-driven reprogramming. This study demonstrates potential utility for SOX10 as a prognostic biomarker in TNBC and provides new insights about developmental phenotypic mimicry—a major contributor to intratumoral heterogeneity

High-dose antipsychotic therapy and reflective prescribing: development of an online tool for rapid, easy calculation of antipsychotic total daily dose

Safe and effective antipsychotic prescribing is a fundamental skill in psychiatric practice; however, antipsychotic medications are not without risk. These risks are increased when antipsychotics are prescribed in high doses, with or without polypharmacy. Decision-making regarding antipsychotic prescribing can be hampered by a lack of readily available or easily approachable tools for calculating and interpreting total daily doses, especially when antipsychotic polypharmacy is involved. Our objective was to create an accessible method for calculating antipsychotic total daily dosing.We have developed an online calculator for determining antipsychotic total daily dose using information on recommended maximum total daily dosing based on the British National Formulary.This calculator is free, easy to implement and allows for users to input a large variety of possible antipsychotic dosing regimens.It is hoped that this tool will allow clinicians to readily review their prescribing practice, inform decision-making and improve patient safety outcomes. Further research may be appropriate to determine the impact of this tool on these intended goals

Rumen-like methanogens identified from the crop of the folivorous South American bird, the hoatzin (Opisthocomus hoazin)

The hoatzin is the only known avian species with foregut fermentation. It is a primarily folivorous feeder and has a distended crop and lower/distal esophagus, which has evolved for the microbial fermentation of ingested feed. Crop samples collected from 10 individual animals from the Apure River area, Apure State, Venezuela were examined for the presence and density of methanogens using 16S rRNA gene clone libraries and real-time PCR prepared from pooled and individual PCR products. A total of 197 clones were examined, revealing 24 different methanogen 16S rRNA sequences, or phylotypes. Of the 24 unique phylotypes, 16 (171 of 197 clones) formed five unique clades within the genus Methanobrevibacter with the largest group of clones (118 clones) 98.7% similar to Methanobrevibacter ruminantium. The remaining eight phylotypes (26 clones) formed four unique clades that had only 94.0-96.7% identity to Methanosphaera stadtmanae. Based upon 98% sequence identity, we identified 17 of the 24 methanogen phylotypes from the hoatzin as possible new species and strains, with three phylotypes representing possible new genera (94.5% sequence identity). Although none of the hoatzin methanogen phylotypes had 100% sequence identity to any other archaeal sequences in the GenBank database, the hoatzin crop methanogen sequences formed sister groups with known rumen methanogens. Mean population densities (numbers per gram wet weight) of methanogenic archaea, rumen bacteria and ciliate protozoa, estimated using real-time PCR, were 5.80 × 10 9, 7.93 × 10 12 and 3.31 × 10 5, respectively. The crop microbial data presented here provide an excellent example of convergent evolution of foregut fermentation in the hoatzin, similar to that of ruminants

Monitoring for post-injection delirium/sedation syndrome with long-acting olanzapine during the COVID-19 pandemic.

We included all 74,960 olanzapine LAI dispensings listed in the Pharmaceutical Benefits Schedule (PBS) database from the introduction of olanzapine LAI in January 2010 until the end of January 2020. Adverse event reports for all olanzapine formulations (and the subset of olanzapine LAI) were drawn from Australian Therapeutic Goods Association Database of Adverse Event Notifications (DAEN)

Prevalence of frailty in severe mental illness: findings from the UK Biobank

Background Severe mental illness (SMI) is associated with significant morbidity. Frailty combines biological ageing, comorbidity and psychosocial factors and can predict adverse health outcomes. Emerging evidence indicates that frailty is higher in individuals with SMI than in the general population, although studies have been limited by sample size. Aims To describe the prevalence of frailty in people with SMI in a large cohort using three different frailty measures and examine the impact of demographic and sociodemographic variables. Method The UK Biobank survey data, which included individuals aged 37–73 years from England, Scotland and Wales from 2006 to 2010, with linked in-patient hospital episodes, were utilised. The prevalence of frailty in individuals with and without SMI was assessed through three frailty measures: frailty index, physical frailty phenotype (PFP) and Hospital Frailty Risk Score (HFRS). Stratified analysis and dichotomous logistic regression were conducted. Results A frailty index could be calculated for 99.5% of the 502 412 UK Biobank participants and demonstrated greater prevalence of frailty in women and an increase with age. The prevalence of frailty for those with SMI was 3.19% (95% CI 3.0–3.4), 4.2% (95% CI 3.8–4.7) and 18% (95% CI 15–23) using the frailty index, PFP and HFRS respectively. The prevalence ratio was between 3 and 18 times higher than in those without SMI. Conclusions As a measure, frailty captures the known increase in morbidity associated with SMI and may potentially allow for earlier identification of those who will benefit from targeted interventions

Impact of High-Concentrate Feeding and Low Ruminal pH on Methanogens and Protozoa in the Rumen of Dairy Cows

Non-lactating dairy cattle were transitioned to a high-concentrate diet to investigate the effect of ruminal pH suppression, commonly found in dairy cattle, on the density, diversity, and community structure of rumen methanogens, as well as the density of rumen protozoa. Four ruminally cannulated cows were fed a hay diet and transitioned to a 65% grain and 35% hay diet. The cattle were maintained on an high-concentrate diet for 3 weeks before the transition back to an hay diet, which was fed for an additional 3 weeks. Rumen fluid and solids and fecal samples were obtained prior to feeding during weeks 0 (hay), 1, and 3 (high-concentrate), and 4 and 6 (hay). Subacute ruminal acidosis was induced during week 1. During week 3 of the experiment, there was a significant increase in the number of protozoa present in the rumen fluid (P = 0.049) and rumen solids (P = 0.004), and a significant reduction in protozoa in the rumen fluid in week 6 (P = 0.003). No significant effect of diet on density of rumen methanogens was found in any samples, as determined by real-time PCR. Clone libraries were constructed for weeks 0, 3, and 6, and the methanogen diversity of week 3 was found to differ from week 6. Week 3 was also found to have a significantly altered methanogen community structure, compared to the other weeks. Twenty-two unique 16S rRNA phylotypes were identified, three of which were found only during high-concentrate feeding, three were found during both phases of hay feeding, and seven were found in all three clone libraries. The genus Methanobrevibacter comprised 99% of the clones present. The rumen fluid at weeks 0, 3, and 6 of all the animals was found to contain a type A protozoal population. Ultimately, high-concentrate feeding did not significantly affect the density of rumen methanogens, but did alter methanogen diversity and community structure, as well as protozoal density within the rumen of nonlactating dairy cattle. Therefore, it may be necessary to monitor the rumen methanogen and protozoal communities of dairy cattle susceptible to depressed pH when methane abatement strategies are being investigated