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Highlights from ASCO-GI 2021 from EORTC Gastrointestinal tract cancer group
No full textLast year the field of immunotherapy was finally introduced to GI oncology, with several changes in clinical practice such as advanced hepatocellular carcinoma or metastatic colorectal MSI-H. Last month, at the virtual ASCO-GI symposium 2021, several large trial results have been reported, some leading to a change of practice. Furthermore, during ASCO-GI 2021, results from early phase trials have been presented, some with potential important implications for future treatments. We provide here an overview of these important results and their integration into routine clinical practice. <br/
Facilitators and Barriers of Co-production of Services with Children and Young People within Education, Health and Care Services
No full textAim: This systematic review of research studies published between 2014 and 2019 explores facilitators and barriers to successful co-production and its application to practice. Rationale: Through legislation, ‘co-production’ underpins practice to promote social justice for children and young people (CYP) with Special Educational Needs and Disability (SEND). Yet little is known about how to engage in co-production successfully. Method: Through systematic searching of research databases, a total of 21 papers was found, seven of which met inclusion criteria and were found to be of at least medium level methodological quality and relevance. Findings: The included research papers highlight the importance of leadership support for co-production to enable CYP to really ‘be heard’, as well as practical considerations around transport and support to attend co-production meetings. Creative methods chosen by CYP, flexibility to the needs of CYP and valuing CYP’s time and views were significant factors in creating change through co-production. Implications: A lack of funding, commitment and awareness by leaders and organisations to ensure that CYP can participate over time, often however, led to unsustainable co-production endeavours. Limitations: A significant gap was identified within the co-production of Education services, with the majority of research papers developing co-production and social justice practice within Health and Social Care organisations. Conclusions: Implications for development of practice and further research are considered. <br/
Randomized phase 2 study of the addition of ramucirumab or merestinib to standard first line therapy for advanced or metastatic biliary tract cancer
No full textBackground: Biliary tract cancers (BTC) are aggressive, rare GI malignancies with poor outcomes; approximately half of patients succumb to disease within 1 year. We evaluated the efficacy and safety of ramucirumab or merestinib with first-line cisplatin-gemcitabine in patients with advanced BTC.Methods: This global, double-blind, phase 2 study was carried out in 81 sites across 18 countries. Eligible patients who were treatment naïve, ≥18 years, with non-resectable, recurrent or metastatic biliary tract adenocarcinoma, an ECOG performance status of 0 or 1, received cisplatin-gemcitabine (25mg/m2-1000mg/m2) (day-1 and day-8, every 21-days, 8-cycles) and were randomized 2:1:2:1 to receive either intravenous (IV) ramucirumab 8mg/kg/placebo (same cycle) or oral merestinib 80mg/oral placebo (daily) until disease progression. Randomization was done by an interactive web response system; stratified by primary tumor site, geographic region and metastatic disease. Primary objective was investigator-assessed PFS (intention-to-treat population). This study, registered at ClinicalTrials.gov, NCT02711553, is ongoing for long-term follow-up.Findings: 309 patients were randomized (25-May-2016 through 08-August-2017); 106 to the RAM arm, 102 to the MER arm and 101 to the placebo arm; 306 received ≥1 treatment dose. Median PFS (80% CI) was 6.47 (5.7-7.1) months in ramucirumab arm (n=106), 6.97 (6.2-7.1) months in merestinib arm (n=102), and 6.64 (5.6-6.8) months in pooled placebo arm (n=101) (ramucirumab vs placebo: HR 1.12, 80% CI 0.90-1.40; merestinib vs placebo: HR 0.92, 80% CI 0.73-1.15). Median follow-up time (IQR) (data cutoff 16-February-2018.) was 10.9 (8.1-14.1) months. Grade ≥3 adverse events (AEs) occurred in 90 (86.5%) of 104 patients in ramucirumab, 87 (85.3%) of 102 in merestinib, compared to 81 (81.0%) of 100 patients in placebo; most commonly neutropenia (ramucirumab: 51 [49.0%]; merestinib: 48 [47.1%]; placebo: 33 [33.0%]), thrombocytopenia (ramucirumab: 36 [34.6%]; merestinib: 19 [18.6%]; placebo: 17 [17.0%]) and anemia (ramucirumab: 28 [26.9%]; merestinib: 16 [15.7%]; placebo: 19 [19.0%]). Approximately half the patients reported serious AEs (ramucirumab: 53 [51.0%]; merestinib: n=56 [54.9%]; placebo: n=48 [48.0%]). Treatment-related deaths, deemed related by the investigator, occurred in 1 patient in RAM arm (cardiac arrest) and 2 patients in MER arm (1 pulmonary embolism and 1 sepsis). Interpretation: Adding ramucirumab or merestinib to first-line cisplatin-gemcitabine was well-tolerated, with no new safety signals but did not improve PFS in patients with molecularly-unselected advanced BTC. The role of these targeted inhibitors remains investigational, highlighting the need for further understanding of biliary tract malignancies and the contribution of molecular selection
Wayfinder: Towards Automatically Deriving Optimal OS Configurations
No full textTuning operating systems configuration in order to obtain the maximum application performance is a hard problem. This is due to the extremely large size of the configuration space offered by modern OSes, and to the fact that it is generally explored manually. To address that issue, we propose to bring automation to the OS configuration space exploration process, in order to derive effortlessly and as quickly as possible optimal OS configurations for a given use case. We present Wayfinder, a generic OS performance evaluation platform. Wayfinder is fully automated and ensures both the accuracy and reproducibility of results, all the while speeding up how fast tests are run on a system. Wayfinder is easily extensible and offers convenient APIs to (1) implement custom configuration space exploration techniques, (2) add new benchmarks and (3) support additional OS projects. We demonstrate Wayfinder’s capacity to automatically and efficiently explore a LibOS’ networking configuration space; as well as its ability to efficiently isolate parallel experiments to avoid noisy neighbours
Risk of suicide in patients who present to hospital after self-cutting according to site of injury: findings from the Multicentre Study of Self-harm in England
No full textBackground: We compared the risk of death by suicide following hospital presentation for self-harm according to site of self-cut/stab.Method: We included 54,999 self-harm presentations (involving 31,419 individuals) to hospitals in the Multicentre Study of Self-harm in England (1/1/2004-31/12/2014), with mortality follow-up to 31/12/2019. Information on method of self-harm was obtained through monitoring in hospitals. Information about mortality was obtained through linkage with NHS Digital. We assessed the association of site of self-cut with death by suicide using mixed effect models. Results: 10,790 (19.6%) hospital presentations involved self-cutting/stabbing, 7,489 of which (69.4%) were due to laceration to the arm/wrist alone, 1,846 episodes (17.1%) involved cutting elsewhere on the body, and 1,455 (13.5%) were due to laceration to unknown site. Controlling for confounders, presentation to hospital following self-cut/stab to bodily parts other than wrist/arm was associated with greater chance of subsequent suicide relative to presentation after self-poisoning alone [adjusted odds ratio (aOR) 1.75, 95% confidence interval (CI) 1.03-2.96, P=0.038]. The likelihood of suicide after presentation for cutting/stabbing the wrist/arm alone was comparable to that of patients who had self-poisoned alone. Presentations after laceration involving the neck were associated with a 4-fold greater chance of subsequent suicide relative to self-poisoning (aOR 4.09, 95% CI 1.80-9.30, p=0.001). Conclusions: Patients who attend hospital after self-cutting/stabbing are a heterogeneous group in terms of characteristics, methods of cutting/stabbing and risk of subsequent suicide. Risk of suicide is greater in individuals who self-cut/stab to parts of the body other than the wrist or arm, especially the neck
Service learning in pharmacy: An effective pedagogical approach to undergraduate education
No full textMaster of Pharmacy (MPharm) students at the University of Manchester experience service learning during the third year of the course. The students put their academic learning into practice and develop many professional skills whilst teaching and enthusing local high school pupils about various public health topics. This article explores how this example of service learning helps prepare the next generation of pharmacists for their future roles and summarises the practical aspects of the project and its success
In vivo investigation of 3D printed polycaprolactone/graphene electro-active bone scaffolds
No full textAdditive manufactured scaffolds are widely used as 3D support structures for tissue engineering. This paper investigates the mechanisms behind bone regeneration due to the combined use of 3D printed poly(ɛ-caprolactone)/graphene (PCL/G) electro-active scaffolds and electrical stimulation. A comprehensive in vivo study was conducted to assess the proposed approach, using a rat model. Results show that the combined use of electro-active scaffolds and electrical stimulation therapy accelerates the bone regeneration process and the formation of more organised new bone, through fast angiogenesis, and a rapid transition to the mineralisation and bone remodelling phase. The mechanism is investigated and explained
Development of an energy-efficient single mixed refrigerant cycle for small scale LNG production
No full textEnergy-intensive single mixed refrigerant (SMR) cycles are employed to produce liquefied natural gas (LNG) at small scale. The energy required for refrigerant compression (shaft work) dominates the overall operating costs of the LNG plant. While current methods to minimize shaft work demand (e.g. exergy analysis) focus on the PRICO cycle, this paper shows that structurally modifying the configuration of SMR cycles can yield significant savings in shaft work demand with low added complexity. The novel SMR cycle developed in this work is based on the CryoMan SMR cycle; its benefits, in terms of energy savings, are demonstrated through a case study for natural gas liquefaction at small scale. The shaft work demand of the PRICO, CryoMan and the novel SMR cycles are minimized using a genetic algorithm and nonlinear optimization. The structural modifications applied tailor the refrigerant composition and exploit complex trade-offs between the operating variables to enhance the energy-efficiency of the SMR cycles. The results from the case study demonstrate that the novel SMR cycle achieves 10% savings in shaft work demand in comparison with the PRICO SMR cycle
Cyclic Ether Triggers for Polymeric Frustrated Lewis Pair Gels
No full textSterically hindered Lewis acid and base centers are unable to form Lewis adducts, instead forming frustrated Lewis pairs (FLPs), where latent reactivity can be utilized for the activation of small molecules. Applying FLP chemistry into polymeric frameworks transforms this chemistry into responsive and functional materials. Here, we report a versatile synthetic strategy for the preparation of macromolecular FLPs and explore its potential with the ring-opening reactions of cyclic ethers. Addition of the cyclic substrates triggered polymer network formation, where the extent of cross-linking, strength of network, and reactivity are tuned by the steric and electronic properties of the ethers. The resultant networks behave like covalently cross-linked polymers, demonstrating the versatility of FLPs to simultaneously tune both small molecule capture and mechanical properties of materials
Prevalence and predictors of adverse events with methotrexate mono- and combination- therapy for rheumatoid arthritis: a systematic review
No full textObjectivesThis systematic review aims to summarise rates of adverse events (AEs) in patients with rheumatoid arthritis (RA) or inflammatory arthritis starting methotrexate (MTX) as monotherapy or in combination with other csDMARDs, and to identify reported predictors of AEs. MethodsThree databases were searched for studies reporting AEs in MTX-naïve patients with RA. Randomised controlled trials (RCTs) and observational cohort studies were included. Prevalence rates of AEs were pooled using random effects meta-analysis, stratified by study design.Results46 articles (34 RCTs and 12 observational studies) were identified. The pooled prevalence of total AEs was 80.1% in RCTs [95% CI 73.5, 85.9], compared to 23.1% in observational studies [95% CI 12.3, 36.0]. The pooled prevalence of serious AEs was 9.5% in RCTs [95% CI 7.4, 11.7], and 2.1% in observational studies [95% CI 1.0, 3.4]. MTX discontinuation due to AEs was higher in observational studies (15.5% [95% CI 9.6, 22.3]) compared to RCTs (6.7% [95% CI 4.7, 8.9]). Gastrointestinal events were the most commonly reported AEs (pooled prevalence: 32.7% [95% CI 18.5, 48.7]).Five studies examined predictors of AEs. Rheumatoid factor status, body mass index and HAQ score were associated with MTX discontinuation due to AEs; anti-citrullinated protein antibody negativity, smoking and elevated creatinine were associated with increased risk of elevated liver enzymes.ConclusionThe review provides an up-to-date overview of the prevalence of AEs associated with MTX in patients with RA. The findings should be communicated to patients to help them make informed choices prior to commencing MTX.<br/