Endothelial progenitor cells control the angiogenic switch in mouse lung metastasis

Angiogenesis-mediated progression of micrometastasis to lethal macrometastasis is the major cause of death in cancer patients. Here, using mouse models of pulmonary metastasis, we identify bone marrow (BM)-derived endothelial progenitor cells (EPCs) as critical regulators of this angiogenic switch. We show that tumors induce expression of the transcription factor Id1 in the EPCs and that suppression of Id1 after metastatic colonization blocked EPC mobilization, caused angiogenesis inhibition, impaired pulmonary macrometastases, and increased survival of tumor-bearing animals. These findings establish the role of EPCs in metastatic progression in preclinical models and suggest that selective targeting of EPCs may merit investigation as a therapy for cancer patients with lung metastases

Reproducible protocols for metagenomic analysis of human faecal phageomes

peer-reviewedAll sequence data used in the analyses were deposited in the Sequence read Archive (SRA) (http://www.ncbi.nlm.nih.gov/sra) under BioProject PRJNA407341. Sample IDs, meta data and corresponding accession numbers are summarised in Additional file 2: Table S2. All raw count tables, 16S taxonomic assignments, BLAST top hits for viral contigs and R code used for the analysis are available at (https://figshare.com/s/71163558b4f78e3e7ed6).Background Recent studies have demonstrated that the human gut is populated by complex, highly individual and stable communities of viruses, the majority of which are bacteriophages. While disease-specific alterations in the gut phageome have been observed in IBD, AIDS and acute malnutrition, the human gut phageome remains poorly characterised. One important obstacle in metagenomic studies of the human gut phageome is a high level of discrepancy between results obtained by different research groups. This is often due to the use of different protocols for enriching virus-like particles, nucleic acid purification and sequencing. The goal of the present study is to develop a relatively simple, reproducible and cost-efficient protocol for the extraction of viral nucleic acids from human faecal samples, suitable for high-throughput studies. We also analyse the effect of certain potential confounding factors, such as storage conditions, repeated freeze-thaw cycles, and operator bias on the resultant phageome profile. Additionally, spiking of faecal samples with an exogenous phage standard was employed to quantitatively analyse phageomes following metagenomic sequencing. Comparative analysis of phageome profiles to bacteriome profiles was also performed following 16S rRNA amplicon sequencing. Results Faecal phageome profiles exhibit an overall greater individual specificity when compared to bacteriome profiles. The phageome and bacteriome both exhibited moderate change when stored at + 4 °C or room temperature. Phageome profiles were less impacted by multiple freeze-thaw cycles than bacteriome profiles, but there was a greater chance for operator effect in phageome processing. The successful spiking of faecal samples with exogenous bacteriophage demonstrated large variations in the total viral load between individual samples. Conclusions The faecal phageome sequencing protocol developed in this study provides a valuable additional view of the human gut microbiota that is complementary to 16S amplicon sequencing and/or metagenomic sequencing of total faecal DNA. The protocol was optimised for several confounding factors that are encountered while processing faecal samples, to reduce discrepancies observed within and between research groups studying the human gut phageome. Rapid storage, limited freeze-thaw cycling and spiking of faecal samples with an exogenous phage standard are recommended for optimum results

'Turning the tide' on hyperglycemia in pregnancy : insights from multiscale dynamic simulation modeling

INTRODUCTION: Hyperglycemia in pregnancy (HIP, including gestational diabetes and pre-existing type 1 and type 2 diabetes) is increasing, with associated risks to the health of women and their babies. Strategies to manage and prevent this condition are contested. Dynamic simulation models (DSM) can test policy and program scenarios before implementation in the real world. This paper reports the development and use of an advanced DSM exploring the impact of maternal weight status interventions on incidence of HIP. METHODS: A consortium of experts collaboratively developed a hybrid DSM of HIP, comprising system dynamics, agent-based and discrete event model components. The structure and parameterization drew on a range of evidence and data sources. Scenarios comparing population-level and targeted prevention interventions were simulated from 2018 to identify the intervention combination that would deliver the greatest impact. RESULTS: Population interventions promoting weight loss in early adulthood were found to be effective, reducing the population incidence of HIP by 17.3% by 2030 (baseline ('business as usual' scenario)=16.1%, 95% CI 15.8 to 16.4; population intervention=13.3%, 95% CI 13.0 to 13.6), more than targeted prepregnancy (5.2% reduction; incidence=15.3%, 95% CI 15.0 to 15.6) and interpregnancy (4.2% reduction; incidence=15.5%, 95% CI 15.2 to 15.8) interventions. Combining targeted interventions for high-risk groups with population interventions promoting healthy weight was most effective in reducing HIP incidence (28.8% reduction by 2030; incidence=11.5, 95% CI 11.2 to 11.8). Scenarios exploring the effect of childhood weight status on entry to adulthood demonstrated significant impact in the selected outcome measure for glycemic regulation, insulin sensitivity in the short term and HIP in the long term. DISCUSSION: Population-level weight reduction interventions will be necessary to 'turn the tide' on HIP. Weight reduction interventions targeting high-risk individuals, while beneficial for those individuals, did not significantly impact forecasted HIP incidence rates. The importance of maintaining interventions promoting healthy weight in childhood was demonstrated

Epidemiology and outcomes from out-of-hospital cardiac arrests in England

Introduction This study reports the epidemiology and outcomes from out-of-hospital cardiac arrest (OHCA) in England during 2014. Methods Prospective observational study from the national OHCA registry. The incidence, demographic and outcomes of patients who were treated for an OHCA between 1st January 2014 and 31st December 2014 in 10 English ambulance service (EMS) regions, serving a population of almost 54 million, are reported in accordance with Utstein recommendations. Results 28,729 OHCA cases of EMS treated cardiac arrests were reported (53 per 100,000 of resident population). The mean age was 68.6 (SD = 19.6) years and 41.3% were female. Most (83%) occurred in a place of residence, 52.7% were witnessed by either the EMS or a bystander. In non-EMS witnessed cases, 55.2% received bystander CPR whilst public access defibrillation was used rarely (2.3%). Cardiac aetiology was the leading cause of cardiac arrest (60.9%). The initial rhythm was asystole in 42.4% of all cases and was shockable (VF or pVT) in 20.6%. Return of spontaneous circulation at hospital transfer was evident in 25.8% (n = 6302) and survival to hospital discharge was 7.9%. Conclusion Cardiac arrest is an important cause of death in England. With less than one in ten patients surviving, there is scope to improve outcomes. Survival rates were highest amongst those who received bystander CPR and public access defibrillation

Why is it difficult to implement e-health initiatives? A qualitative study

<b>Background</b> The use of information and communication technologies in healthcare is seen as essential for high quality and cost-effective healthcare. However, implementation of e-health initiatives has often been problematic, with many failing to demonstrate predicted benefits. This study aimed to explore and understand the experiences of implementers - the senior managers and other staff charged with implementing e-health initiatives and their assessment of factors which promote or inhibit the successful implementation, embedding, and integration of e-health initiatives.<p></p> <b>Methods</b> We used a case study methodology, using semi-structured interviews with implementers for data collection. Case studies were selected to provide a range of healthcare contexts (primary, secondary, community care), e-health initiatives, and degrees of normalization. The initiatives studied were Picture Archiving and Communication System (PACS) in secondary care, a Community Nurse Information System (CNIS) in community care, and Choose and Book (C&B) across the primary-secondary care interface. Implementers were selected to provide a range of seniority, including chief executive officers, middle managers, and staff with 'on the ground' experience. Interview data were analyzed using a framework derived from Normalization Process Theory (NPT).<p></p> <b>Results</b> Twenty-three interviews were completed across the three case studies. There were wide differences in experiences of implementation and embedding across these case studies; these differences were well explained by collective action components of NPT. New technology was most likely to 'normalize' where implementers perceived that it had a positive impact on interactions between professionals and patients and between different professional groups, and fit well with the organisational goals and skill sets of existing staff. However, where implementers perceived problems in one or more of these areas, they also perceived a lower level of normalization.<p></p> <b>Conclusions</b> Implementers had rich understandings of barriers and facilitators to successful implementation of e-health initiatives, and their views should continue to be sought in future research. NPT can be used to explain observed variations in implementation processes, and may be useful in drawing planners' attention to potential problems with a view to addressing them during implementation planning

Clinical care of pregnant and postpartum women with COVID-19: Living recommendations from the National COVID-19 Clinical Evidence Taskforce

To date, 18 living recommendations for the clinical care of pregnant and postpartum women with COVID-19 have been issued by the National COVID-19 Clinical Evidence Taskforce. This includes recommendations on mode of birth, delayed umbilical cord clamping, skin-to-skin contact, breastfeeding, rooming-in, antenatal corticosteroids, angiotensin-converting enzyme inhibitors, disease-modifying treatments (including dexamethasone, remdesivir and hydroxychloroquine), venous thromboembolism prophylaxis and advanced respiratory support interventions (prone positioning and extracorporeal membrane oxygenation). Through continuous evidence surveillance, these living recommendations are updated in near real-time to ensure clinicians in Australia have reliable, evidence-based guidelines for clinical decision-making. Please visit https://covid19evidence.net.au/ for the latest recommendation updates

A survey of the anti-apoptotic Bcl-2 subfamily expression in cancer types provides a platform to predict the efficacy of Bcl-2 antagonists in cancer therapy

We investigated the mRNA expression levels of all six antiapoptotic Bcl-2 subfamily members in 68 human cancer cell lines using qPCR techniques and measured the ability of known Bcl-2 inhibitors to induce cell death in 36 of the studied tumor cell lines. Our study reveals that Mcl-1 represents the anti-apoptotic Bcl-2 subfamily member with the highest mRNA levels in the lung, prostate, breast, ovarian, renal, and glioma cancer cell lines. In leukemia/lymphoma and melanoma cancer cell lines, Bcl-2 and Bfl-1 had the highest levels of mRNA, respectively. The observed correlation between the cell killing properties of known Bcl-2 inhibitors and the relative mRNA expression levels of anti-apoptotic Bcl-2 proteins provide critical insights into apoptosis-based anticancer strategies that target Bcl-2 proteins. Our data may explain current challenges of selective Bcl-2 inhibitors in the clinic, given that severe expression of Bcl-2 seems to be limited to leukemia cell lines. Furthermore, our data suggest that in most cancer types a strategy targeted to Mcl-1 inhibition, or combination of Bfl-1 and Mcl-1 inhibition for melanoma, may prove to be more successful than therapies targeting only Bcl-2

Investigation of inter- and intraspecies variation through genome sequencing of Aspergillus section Nigri

Aspergillus section Nigri comprises filamentous fungi relevant to biomedicine, bioenergy, health, and biotechnology. To learn more about what genetically sets these species apart, as well as about potential applications in biotechnology and biomedicine, we sequenced 23 genomes de novo, forming a full genome compendium for the section (26 species), as well as 6 Aspergillus niger isolates. This allowed us to quantify both inter-and intraspecies genomic variation. We further predicted 17,903 carbohydrateactive enzymes and 2,717 secondary metabolite gene clusters, which we condensed into 455 distinct families corresponding to compound classes, 49% of which are only found in single species. We performed metabolomics and genetic engineering to correlate genotypes to phenotypes, as demonstrated for the metabolite aurasperone, and by heterologous transfer of citrate production to Aspergillus nidulans. Experimental and computational analyses showed that both secondary metabolism and regulation are key factors that are significant in the delineation of Aspergillus species.Peer reviewe

Intraperitoneal drain placement and outcomes after elective colorectal surgery: international matched, prospective, cohort study

Despite current guidelines, intraperitoneal drain placement after elective colorectal surgery remains widespread. Drains were not associated with earlier detection of intraperitoneal collections, but were associated with prolonged hospital stay and increased risk of surgical-site infections.Background Many surgeons routinely place intraperitoneal drains after elective colorectal surgery. However, enhanced recovery after surgery guidelines recommend against their routine use owing to a lack of clear clinical benefit. This study aimed to describe international variation in intraperitoneal drain placement and the safety of this practice. Methods COMPASS (COMPlicAted intra-abdominal collectionS after colorectal Surgery) was a prospective, international, cohort study which enrolled consecutive adults undergoing elective colorectal surgery (February to March 2020). The primary outcome was the rate of intraperitoneal drain placement. Secondary outcomes included: rate and time to diagnosis of postoperative intraperitoneal collections; rate of surgical site infections (SSIs); time to discharge; and 30-day major postoperative complications (Clavien-Dindo grade at least III). After propensity score matching, multivariable logistic regression and Cox proportional hazards regression were used to estimate the independent association of the secondary outcomes with drain placement. Results Overall, 1805 patients from 22 countries were included (798 women, 44.2 per cent; median age 67.0 years). The drain insertion rate was 51.9 per cent (937 patients). After matching, drains were not associated with reduced rates (odds ratio (OR) 1.33, 95 per cent c.i. 0.79 to 2.23; P = 0.287) or earlier detection (hazard ratio (HR) 0.87, 0.33 to 2.31; P = 0.780) of collections. Although not associated with worse major postoperative complications (OR 1.09, 0.68 to 1.75; P = 0.709), drains were associated with delayed hospital discharge (HR 0.58, 0.52 to 0.66; P < 0.001) and an increased risk of SSIs (OR 2.47, 1.50 to 4.05; P < 0.001). Conclusion Intraperitoneal drain placement after elective colorectal surgery is not associated with earlier detection of postoperative collections, but prolongs hospital stay and increases SSI risk