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Background Therapeutic options are limited in patients with unresectable metastatic colorectal cancer (mCRC) ineligible for intensive chemotherapy. The use of trifluridine/tipiracil plus bevacizumab (TT-B) in this setting was evaluated in the TASCO1 trial; here, we present the final overall survival (OS) results. Methods TASCO1 was an open-label, non-comparative phase II trial. Patients (n = 153) were randomised 1:1 to TT-B (trifluridine/tipiracil 35 mg/m2 orally twice daily on days 1–5 and 8–12, and bevacizumab intravenously 5 mg/kg on days 1 and 15 of each 28-day cycle) or capecitabine plus bevacizumab (C-B; capecitabine, 1250 mg/m2 orally twice daily on days 1–14 and bevacizumab 7.5 mg/kg intravenously on day 1 of each 21-day cycle). Final OS was analysed when all patients had either died or withdrawn from the study. Adjusted multivariate regression was used to investigate the effects of pre-specified variables on OS. Results At 1 September 2020, median OS was 22.3 months (95% CI: 18.0–23.7) with TT-B and 17.7 months (95% CI: 12.6–19.8) with C-B (adjusted HR 0.78; 95% CI: 0.55–1.10). No variables negatively affected OS with TT-B. Safety results were consistent with prior findings. Conclusions TT-B is a promising therapeutic regimen in mCRC patients ineligible for intensive chemotherapy. Clinical trial information NCT02743221 (clinicaltrials.gov)

This article describes the incorporation of an evidence-based mental health intervention, the Youth Readiness Intervention (YRI), into a youth entrepreneurship training program in Sierra Leone. A collaborative team approach (CTA) was used as the implementation strategy to address the human resource shortage and related challenges associated with capacity and access to care.A cluster randomized quasi-experimental pilot trial (N=175) was conducted in one rural district of Sierra Leone. Pilot data assessed implementation feasibility and clinical effectiveness when using a CTA. A larger hybrid type-2 effectiveness-implementation cluster randomized trial is underway (N=1,151) in three rural districts. Findings on feasibility and fidelity, barriers and facilitators influencing the integration of the YRI into the entrepreneurship program, and clinical effectiveness of the YRI are of interest.Findings from the pilot study indicated that the YRI can be implemented within a youth entrepreneurship program and provide mental health benefits to youths at high risk of emotion dysregulation and interpersonal deficits. Pilot findings informed the ongoing, larger hybrid type-2 trial to understand barriers and facilitators of the CTA and clinical effectiveness of the YRI within youth employment programming.In fragile postconflict settings, innovative approaches are needed to address the mental health treatment gap. Findings from this study will support efforts by the government of Sierra Leone and its partners to address human resource challenges and increase access to evidence-based mental health services.

The development in the past decade of Industry 4.0 technologies has brought many new opportunities to manufacturers. The increased digitization of manufacturing operations has led to new modes of production and product development. This digitization has also increased the quantity of sensorial data which is easily available and which can be used to support real-time decision making. That said, with the oppor– tunities come as well a number of challenges. Principally amongst these is a skills gap within the workforce. Without the required knowledge organisations will find it difficult and complex not only to employ these technologies, but also to develop the new manufacturing paradigms of tomorrow. Hence an innovative and effective training methodology is required to address this skills and knowledge gap. As part of the development of this methodology, this paper presents the finding of a study carried out to analyse the knowledge and skills gap, preferred learning methods and styles of trainers, current and past students in engineering Higher Education Institutions. This requirements analysis has led to the specifications for a Digital Training Toolbox, which can be utilised to support the implementation of Inudstry 4.0 technologies and organisational concepts., peer-reviewed

With design methodologies, as Integrated Product Development, industry is continuously looking to improve their product development processes. Staying ahead concurrence forces them to deliver new and more complex products in shorter time. When it comes to fast delivery and requirement changes, product development can be inspired by agile methods. Although the application is difficult, the idea to implement these methods for development of products other than software comes out. To ease its implementation, this paper proposes to use IPD as a framework for agile product development.

Hip joint arthroplasty is considered to be a safe, successful and cost-effective procedure to restore hip joint functionality. However, a successful hip joint arthroplasty affects different stakeholders e.g. patient and surgeon and depends on various influencing factors within the product life cycle as well as the applied technological opportunities. Due to the complex dependencies between influencing factors, technological opportunities and stakeholders, this contribution introduces an IPD-based approach to improve the quality of total hip arthroplasties.

Introduction\ud \ud Patients with cancer who develop small bowel obstruction are at high risk of malnutrition and morbidity following compromise of gastrointestinal tract continuity. This study aimed to characterise current management and outcomes following malignant small bowel obstruction.\ud \ud \ud \ud Methods\ud \ud A prospective, multicentre cohort study of patients with small bowel obstruction who presented to UK hospitals between 16th January and 13th March 2017. Patients who presented with small bowel obstruction due to primary tumours of the intestine (excluding left-sided colonic tumours) or disseminated intra-abdominal malignancy were included. Outcomes included 30-day mortality and in-hospital complications. Cox-proportional hazards models were used to generate adjusted effects estimates, which are presented as hazard ratios (HR) alongside the corresponding 95% confidence interval (95% CI). The threshold for statistical significance was set at the level of P ≤ 0.05 a-priori.\ud \ud \ud \ud Results\ud \ud 205 patients with malignant small bowel obstruction presented to emergency surgery services during the study period. Of these patients, 50 had obstruction due to right sided colon cancer, 143 due to disseminated intraabdominal malignancy, 10 had primary tumours of the small bowel and 2 patients had gastrointestinal stromal tumours. In total 100 out of 205 patients underwent a surgical intervention for obstruction. 30-day in-hospital mortality rate was 11.3% for those with primary tumours and 19.6% for those with disseminated malignancy. Severe risk of malnutrition was an independent predictor for poor mortality in this cohort (adjusted HR 16.18, 95% CI 1.86 to 140.84, p = 0.012). Patients with right-sided colon cancer had high rates of morbidity.\ud \ud \ud \ud Conclusions\ud \ud Mortality rates were high in patients with disseminated malignancy and in those with right sided colon cancer. Further research should identify optimal management strategy to reduce morbidity for these patient groups.

Therapeutic options are limited in patients with unresectable metastatic colorectal cancer (mCRC) ineligible for intensive chemotherapy. The use of trifluridine/tipiracil plus bevacizumab (TT-B) in this setting was evaluated in the TASCO1 trial; here, we present the final overall survival (OS) results.TASCO1 was an open-label, non-comparative phase II trial. Patients (n = 153) were randomised 1:1 to TT-B (trifluridine/tipiracil 35 mg/mAt 1 September 2020, median OS was 22.3 months (95% CI: 18.0-23.7) with TT-B and 17.7 months (95% CI: 12.6-19.8) with C-B (adjusted HR 0.78; 95% CI: 0.55-1.10). No variables negatively affected OS with TT-B. Safety results were consistent with prior findings.TT-B is a promising therapeutic regimen in mCRC patients ineligible for intensive chemotherapy.NCT02743221 (clinicaltrials.gov).

Background Youth Functioning and Organizational Success for West African Regional Development (Youth FORWARD) was launched as an implementation science collaboration focused on scaling out evidence-based mental health interventions for youth exposed to war and other adversities through novel delivery platforms. This implementation science case study examines the use of a collaborative team approach (CTA) as a scale-out strategy to foster the integration of an evidence-based group mental health intervention, the Youth Readiness Intervention, into youth employment programs tied to regional economic development in Sierra Leone. Methods A case study methodology is used to explore the feasibility and acceptability of integrating an evidence-based intervention, the Youth Readiness Intervention (YRI), into youth entrepreneurship programs (ENTR) in Sierra Leone, facilitated by the CTA. The authors analyzed field notes logged during program implementation, 8 weeks of supervision notes, 20 interviews with agency leaders and front-line staff delivering the YRI within this alternate delivery platform. Quantitative dissemination and implementation interviews administered to youth, facilitators, and agency leaders were analyzed using descriptive statistics and mixed linear models. A linked Hybrid Type II effectiveness-implementation cluster randomized trial is evaluating the clinical effectiveness of the YRI within this delivery platform. Results Extant data indicate the strong feasibility and acceptability of integrating the YRI into the ENTR program. Facilitators of integration of the YRI into the ENTR include mission alignment of the organizations with the delivery of psychosocial interventions, shared commitment to serving vulnerable youth, support from local District Youth Councils, and high interest from the youth served. Barriers include perceived competition between frontline organizations seeking funding for psychosocial interventions, and challenges in flexibility between donors and implementation partners operating in a fragile/post-conflict setting. The CTA was a feasible and acceptable strategy to support fidelity and quality improvement while scaling out the YRI. Conclusions Youth entrepreneurship and livelihood programs offer a promising mechanism for expanding the reach of evidence-based interventions to youth in fragile and post-conflict settings. Quality improvement and sustainment of evidence-based interventions are novel concepts in such settings. The CTA strategy institutionalizes the integration of an evidence-based intervention into youth entrepreneurship programs. Trial registration NCT03603613 (phase 1 pilot, registered May 18, 2018) and NCT03542500 (phase 2 scale-out study, registered May 18, 2018).

Background Although bariatric surgery is well established as an effective treatment for patients with obesity and type 2 diabetes mellitus (T2DM), there exists reluctance to increase its availability for patients with severe T2DM. The aims of this study were to examine the impact of bariatric surgery on T2DM resolution in patients with obesity and T2DM requiring insulin (T2DM-Ins) using data from a national database and to develop a health economic model to evaluate the cost-effectiveness of surgery in this cohort when compared to best medical treatment (BMT). Methods and findings Clinical data from the National Bariatric Surgical Registry (NBSR), a comprehensive database of bariatric surgery in the United Kingdom, were extracted to analyse outcomes of patients with obesity and T2DM-Ins who underwent primary bariatric surgery between 2009 and 2017. Outcomes for this group were combined with data sourced from a comprehensive literature review in order to develop a state-transition microsimulation model to evaluate cost-effectiveness of bariatric surgery versus BMT for patients over a 5-year time horizon. The main outcome measure for the clinical study was insulin cessation at 1-year post-surgery: relative risks (RR) summarising predictive factors were determined, unadjusted, and after adjusting for variables including age, initial body mass index (BMI), duration of T2DM, and weight loss. Main outcome measures for the economic evaluation were total costs, total quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER) at willingness-to-pay threshold of GBP£20,000. A total of 2,484 patients were eligible for inclusion, of which 1,847 had 1-year follow-up data (mean age of 51 years, mean initial BMI 47.2 kg/m2, and 64% female). 67% of patients no longer required insulin at 1-year postoperatively: these rates persisted for 4 years. Roux-en-Y gastric bypass (RYGB) was associated with a higher rate of insulin cessation (71.7%) than sleeve gastrectomy (SG; 64.5%; RR 0.92, confidence interval (CI) 0.86–0.99) and adjustable gastric band (AGB; 33.6%; RR 0.45, CI 0.34–0.60; p < 0.001). When adjusted for percentage total weight loss and demographic variables, insulin cessation following surgery was comparable for RYGB and SG (RR 0.97, CI 0.90–1.04), with AGB having the lowest cessation rates (RR 0.55, CI 0.40–0.74; p < 0.001). Over 5 years, bariatric surgery was cost saving compared to BMT (total cost GBP£22,057 versus GBP£26,286 respectively, incremental difference GBP£4,229). This was due to lower treatment costs as well as reduced diabetes-related complications costs and increased health benefits. Limitations of this study include loss to follow-up of patients within the NBSR dataset and that the time horizon for the economic analysis is limited to 5 years. In addition, the study reflects current medical and surgical treatment regimens for this cohort of patients, which may change. Conclusions In this study, we observed that in patients with obesity and T2DM-Ins, bariatric surgery was associated with high rates of postoperative cessation of insulin therapy, which is, in turn, a major driver of overall reductions in direct healthcare cost. Our findings suggest that a strategy utilising bariatric surgery for patients with obesity and T2DM-Ins is cost saving to the national healthcare provider (National Health Service (NHS)) over a 5-year time horizon., Emma Rose McGlone and colleagues report the clinical and cost- effectiveness of bariatric surgery for patients with Type 2 diabetes., Author summary Why was this study done? Bariatric or weight loss surgery can dramatically improve type 2 diabetes mellitus (T2DM) in patients with obesity, allowing many patients to stop medicines for T2DM completely. Unfortunately, there are limited resources for performing bariatric surgery. Patients with severe T2DM, who require daily insulin injections, are at risk of being considered lower priority than those with T2DM managed by tablet medications. This is because some small studies have suggested that T2DM requiring insulin (T2DM-Ins) is too advanced to be reversed by surgery. The aims of this study were to see how effective bariatric surgery is in patients with obesity and T2DM-Ins, as well as to determine if performing surgery in this group is cost-effective over a 5-year period. What did the researchers do and find? We used data from a nationwide registry of patients undergoing bariatric surgery in the UK to examine the effect of surgery on patients that require insulin for T2DM. We found that certain types of procedure (Roux en Y gastric bypass (RYGB) and sleeve gastrectomy (SG)) were associated with excellent rates of stopping insulin (approximately two-thirds of patients). We then devised an economic model to compare the costs of this type of surgery with the costs of treating patients using optimal medicines for T2DM. We found that performing surgery was less costly and more effective for the national healthcare provider (National Health Service (NHS)), over a 5-year timeline. What do these findings mean? These findings are important because they suggest that patients with obesity and T2DM-Ins are good candidates for bariatric surgery. Offering bariatric surgery to such patients could improve their health and provide cost savings to national healthcare payers.

Increasingly competitive markets are putting pressure on product development teams to design products which exploit an emotional connection to users in order to distinguish them from their competitors. Researchers at the University of Malta have been engaged in understanding the challenges of designing emotionally pleasing products by studying the product development process of a number of artefacts ranging from cosmetic packaging for the make-up sector, camera enclosures to hand prosthesis. Based on the experience garnered from these case studies the researchers have been able to generalize an approach they term Engustrial design that systematically merges industrial and engineering design. This paper explains this innovative approach by applying it to the design of a camera case enclosure and further argues that a new educational approach is required to help minimize such diverse designer mindsets.

HLA antibody detection with single antigen flow beads (SAFB) assays is impaired by complement interference whose frequency, predictability and distribution among HLA antigens have not been analyzed in large cohorts. We compared in two patients' cohorts the routine follow-up SAFB profiles obtained in class I (n = 129) and class II (n = 85) with and without ethylenediaminetetraacetic acid (EDTA)-treatment. The presence of complement interference was defined according to the reproducibility of the SAFB assays evaluated with our class I and II routine positive control sera. Interference occurred in 29.5% and 45.9% of patients in class I and II, respectively. In the untreated condition, at serum level, neither the number of positive beads, the highest bead mean fluorescence intensity (MFI) nor MFI at bead level, satisfactorily predicted interference. HLA-C were the least affected among class I beads. HLA-DQ beads were the most affected in class II. At least one antibody specificity was falsely negative without EDTA for about 3% of sera in class I and 9% in class II. EDTA-treatment did not significantly modify the low-MFI strengths (500-3000 range). This study emphasizes the high frequency of complement interference and the importance and advantages of systematically pretreating sera with EDTA before performing SAFB assays.