Physcion and Physcion 8-O-β-D-glucopyranoside: Natural Anthraquinones with Potential Anti-cancer Activities.

Nature has provided prodigious reservoirs of pharmacologically active compounds for drug development since times. Physcion and physcion 8-O-β-D-glucopyranoside (PG) are bioactive natural anthraquinones which exert anti-inflammatory and anti-cancer properties with minimum or no adverse effects. Moreover, physcion also exhibits anti-microbial and hepatoprotective properties while PG is known to have anti-sepsis as well as ameliorative activities against dementia. This review aims to highlight the natural sources and anti-cancer activities of physcion and PG along with asso-ciated mechanisms of actions. On the basis of the literature, physcion and PG regulate multitudinous cell signaling path-ways through the modulation of various regulators of cell cycle, protein kinases, microRNAs, transcriptional factors, and apoptosis linked proteins resulting in the effective killing of cancerous cells in vitro as well as in vivo. Both compounds effectively suppress metastasis, furthermore, physcion acts as inhibitor of 6PGD and also play an important role in chemosensitization. This review article suggests that physcion and PG are potent anti-cancer drug candidates but further investigations on their mechanism of action and pre-clinical trials are mandatory in order to comprehend the full potential of these natural cancer killers in anti-cancer remedies

Development and validation of Videogame Addiction Scale for Children (VASC)

The aim of the present study was to develop a valid and reliable Videogame Addiction Scale for Children (VASC). The data were derived from 780 children who completed the Videogame Addiction Scale (405 girls and 375 boys; 48.1% ranging in age from 9 to 12 years). The sample was randomly split into two different sub-samples (sample 1, n=400; sample 2, n= 380). Sample 1 was used to perform exploratory factor analysis (EFA) to define the factorial structure of VASC. As a result of EFA, a four-factor structure comprising 21 items was obtained and explained 55% of the total variance (the four factors being "self-control," "reward/reinforcement", "problems," and "involvement"). The internal consistency reliability of VASC has found 0.89. Confirmatory factor analysis (CFA) was performed to confirm the factorial structure obtained by EFA in the remaining half of sample (n= 390). The obtained fit indices from the CFA confirmed the structure of the EFA. The 21-item VASC has good psychometric properties that can be used among Turkish schoolchildren populations

Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci

Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations withP <5 x 10(-8)in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P <5 x 10(-8)) in the discovery samples. Ten novel SNVs, including rs12616219 nearTMEM182, were followed-up and five of them (rs462779 inREV3L, rs12780116 inCNNM2, rs1190736 inGPR101, rs11539157 inPJA1, and rs12616219 nearTMEM182) replicated at a Bonferroni significance threshold (P <4.5 x 10(-3)) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, inCCDC141and two low-frequency SNVs inCEP350andHDGFRP2. Functional follow-up implied that decreased expression ofREV3Lmay lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.Peer reviewe

Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy

Background The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89.6 per cent) compared with that in countries with a middle (753 of 1242, 60.6 per cent; odds ratio (OR) 0.17, 95 per cent c.i. 0.14 to 0.21, P <0001) or low (363 of 860, 422 per cent; OR 008, 007 to 010, P <0.001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -94 (95 per cent c.i. -11.9 to -6.9) per cent; P <0001), but the relationship was reversed in low-HDI countries (+121 (+7.0 to +173) per cent; P <0001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0.60, 0.50 to 073; P <0.001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries. Conclusion Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.Peer reviewe

Phase 1 clinical study of an embryonic stem cell-derived retinal pigment epithelium patch in age-related macular degeneration

Age-related macular degeneration (AMD) remains a major cause of blindness, with dysfunction and loss of retinal pigment epithelium (RPE) central to disease progression. We engineered an RPE patch comprising a fully differentiated, human embryonic stem cell (hESC)-derived RPE monolayer on a coated, synthetic basement membrane. We delivered the patch, using a purpose-designed microsurgical tool, into the subretinal space of one eye in each of two patients with severe exudative AMD. Primary endpoints were incidence and severity of adverse events and proportion of subjects with improved best-corrected visual acuity of 15 letters or more. We report successful delivery and survival of the RPE patch by biomicroscopy and optical coherence tomography, and a visual acuity gain of 29 and 21 letters in the two patients, respectively, over 12 months. Only local immunosuppression was used long-term. We also present the preclinical surgical, cell safety and tumorigenicity studies leading to trial approval. This work supports the feasibility and safety of hESC-RPE patch transplantation as a regenerative strategy for AMD

Evaluation of appendicitis risk prediction models in adults with suspected appendicitis

Background Appendicitis is the most common general surgical emergency worldwide, but its diagnosis remains challenging. The aim of this study was to determine whether existing risk prediction models can reliably identify patients presenting to hospital in the UK with acute right iliac fossa (RIF) pain who are at low risk of appendicitis. Methods A systematic search was completed to identify all existing appendicitis risk prediction models. Models were validated using UK data from an international prospective cohort study that captured consecutive patients aged 16–45 years presenting to hospital with acute RIF in March to June 2017. The main outcome was best achievable model specificity (proportion of patients who did not have appendicitis correctly classified as low risk) whilst maintaining a failure rate below 5 per cent (proportion of patients identified as low risk who actually had appendicitis). Results Some 5345 patients across 154 UK hospitals were identified, of which two‐thirds (3613 of 5345, 67·6 per cent) were women. Women were more than twice as likely to undergo surgery with removal of a histologically normal appendix (272 of 964, 28·2 per cent) than men (120 of 993, 12·1 per cent) (relative risk 2·33, 95 per cent c.i. 1·92 to 2·84; P < 0·001). Of 15 validated risk prediction models, the Adult Appendicitis Score performed best (cut‐off score 8 or less, specificity 63·1 per cent, failure rate 3·7 per cent). The Appendicitis Inflammatory Response Score performed best for men (cut‐off score 2 or less, specificity 24·7 per cent, failure rate 2·4 per cent). Conclusion Women in the UK had a disproportionate risk of admission without surgical intervention and had high rates of normal appendicectomy. Risk prediction models to support shared decision‐making by identifying adults in the UK at low risk of appendicitis were identified

Global variation in anastomosis and end colostomy formation following left-sided colorectal resection

Background End colostomy rates following colorectal resection vary across institutions in high-income settings, being influenced by patient, disease, surgeon and system factors. This study aimed to assess global variation in end colostomy rates after left-sided colorectal resection. Methods This study comprised an analysis of GlobalSurg-1 and -2 international, prospective, observational cohort studies (2014, 2016), including consecutive adult patients undergoing elective or emergency left-sided colorectal resection within discrete 2-week windows. Countries were grouped into high-, middle- and low-income tertiles according to the United Nations Human Development Index (HDI). Factors associated with colostomy formation versus primary anastomosis were explored using a multilevel, multivariable logistic regression model. Results In total, 1635 patients from 242 hospitals in 57 countries undergoing left-sided colorectal resection were included: 113 (6·9 per cent) from low-HDI, 254 (15·5 per cent) from middle-HDI and 1268 (77·6 per cent) from high-HDI countries. There was a higher proportion of patients with perforated disease (57·5, 40·9 and 35·4 per cent; P < 0·001) and subsequent use of end colostomy (52·2, 24·8 and 18·9 per cent; P < 0·001) in low- compared with middle- and high-HDI settings. The association with colostomy use in low-HDI settings persisted (odds ratio (OR) 3·20, 95 per cent c.i. 1·35 to 7·57; P = 0·008) after risk adjustment for malignant disease (OR 2·34, 1·65 to 3·32; P < 0·001), emergency surgery (OR 4·08, 2·73 to 6·10; P < 0·001), time to operation at least 48 h (OR 1·99, 1·28 to 3·09; P = 0·002) and disease perforation (OR 4·00, 2·81 to 5·69; P < 0·001). Conclusion Global differences existed in the proportion of patients receiving end stomas after left-sided colorectal resection based on income, which went beyond case mix alone

Design-for-Cost – An Approach for Distributed Manufacturing Cost Estimation

Part 9: Collaborative Product DevelopmentInternational audienceResearch has shown that design changes cost more in later stages of product development. Therefore, companies adopt Design-for-X methods to optimize product designs for many aspects in the early design stage. Despite such efforts, products often encounter several design changes during the commission of the production, a principal reason being failure to meet target costs. Accurately estimating cost in the early design stage is difficult due to insufficient information. In particular, as production becomes more distributed cost estimation is also more difficult because information is more distributed. This paper introduces a cost estimation method to address this problem. It describes a distributed manufacturing situation and a cost breakdown framework. A use case is provided to illustrate how the framework allows for supply-chain cost negotiation and design adjustments in the early design stage

Extracellular CIRP and TREM‐1 axis promotes ICAM‐1‐Rho‐mediated NETosis in sepsis

© 2020 Federation of American Societies for Experimental Biology Extracellular cold-inducible RNA-binding protein (eCIRP) is a damage-associated molecular pattern (DAMP). Intercellular adhesion molecule-1 (ICAM-1) expressing neutrophils produce excessive amounts of neutrophil extracellular traps (NETs). We reveal that eCIRP generates ICAM-1+ neutrophils through triggering receptor expressed on myeloid cells-1 (TREM-1) and the ICAM-1+ neutrophils involve Rho GTPase to promote NETosis. Treatment of BMDN with rmCIRP increased the frequency of ICAM-1+ BMDN, while rmCIRP-treated TREM-1−/− BMDN or pretreatment of BMDN with TREM-1 inhibitor LP17 significantly decreased the frequency of ICAM-1+ neutrophils. The frequencies of ICAM-1+ neutrophils in blood and lungs were markedly decreased in rmCIRP-injected mice or septic mice treated with LP17. Coculture of ICAM-1−/− neutrophils or wild-type (WT) neutrophils with WT macrophages in the presence of a peptidylarginine deiminase 4 (PAD4) inhibitor reduced TNF-α and IL-6 compared to WT neutrophils treated with rmCIRP. Treatment of ICAM-1−/− neutrophils with rmCIRP resulted in reduced quantities of NETs compared to WT rmCIRP-treated neutrophils. Treatment of BMDN with rmCIRP-induced Rho activation, while blockade of ICAM-1 significantly decreased Rho activation. Inhibition of Rho significantly decreased rmCIRP-induced NET formation in BMDN. TREM-1 plays a critical role in the eCIRP-mediated increase of ICAM-1 expression in neutrophils, leading to the increased NET formation via Rho activation to exaggerate inflammation