Strategies to secure surgical research funding: fellowships and grants.

Innovation and advances in surgery are entirely dependent on research. Fellowships and grants are the principal means by which surgical research projects are funded. However, these are scarce and highly competitive. This article offers guidance through the application process for the aspiring academic surgeon. Approaching the application in a timely and structured manner, seeking advice from current and previous award-holders and members of review panels, and obtaining preliminary data are key ingredients to success

Pharmacokinetic Disposition and Clinical Outcomes in Infants and Children Receiving Intravenous Busulfan for Allogeneic Hematopoietic Stem Cell Transplantation

AbstractWe conducted a retrospective pharmacokinetic analysis of i.v. busulfan in children undergoing hematopoietic stem cell transplantation (HSCT) and describe its relation to transplantation outcomes. Forty-five children (median age, 3 yr) underwent HSCT at The Hospital for Sick Children from April 2003 through January 2006 and received i.v. busulfan every 6 h as part of their conditioning regimen. Initial busulfan doses were based on actual patient weight: <9 kg, 0.95 mg/kg per dose; 9-16 kg, 1.2 mg/kg per dose; 16-23 kg, 1.1 mg/kg per dose; 24-34 kg, 0.95 mg/kg per dose; >34 kg, 0.8 mg/kg per dose. Plasma busulfan concentrations were obtained after the first dose. The fourth and subsequent busulfan doses were adjusted to achieve an area under the concentration versus time curve (AUC) of 900-1500 μM·min. Development of hepatic venous occlusive disease (HVOD; modified Baltimore criteria) and engraftment (absolute neutrophil count ≥0.5 × 109/L) were evaluated. Busulfan pharmacokinetic parameters were calculated using 1-compartment methods. Mean busulfan pharmacokinetic parameters were maximum concentration (Cmax; 4.7 ± 0.75 μM), volume of distribution at steady state (0.68 ± 0.17 L/kg), elimination rate constant (0.0051 ± 0.0010 min−1), total body clearance (3.5 ± 1.23 mL/[min·kg]), and AUC (1271 ± 280 μM·min). Mean volume of distribution at steady state was larger in children <1 yr of age (0.77 ± 0.24 vs 0.64 ± 0.11 L/kg; P = .040) and children <4 yr of age (0.73 ± 0.18 vs 0.60 ± 0.11 L/kg; P = .001) than in older children. Compared with older children, mean weight-adjusted total body clearance was higher in children <4 yr of age (3.8 ± 1.40 versus 3.0 ± 0.76 mL/[min·kg]). HVOD was diagnosed in 8 children (18%), including 4 children <1 yr of age. Children who developed HVOD achieved a lower Cmax than did those without HVOD (4.2 ± 0.68 versus 4.8 ± 0.73 μM; P = .035). Other than Cmax, no association was observed between busulfan disposition and development of HVOD in children for whom i.v. busulfan doses were adjusted to achieve a target AUC. The influence of factors other than busulfan disposition on transplantation outcomes, such as genetic polymorphisms, should be evaluated

Thrombospondin 1 is a key mediator of transforming growth factor β-mediated cell contractility in systemic sclerosis via a mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK)-dependent mechanism

BACKGROUND: The mechanism underlying the ability of fibroblasts to contract a collagen gel matrix is largely unknown. Fibroblasts from scarred (lesional) areas of patients with the fibrotic disease scleroderma show enhanced ability to contract collagen relative to healthy fibroblasts. Thrombospondin 1 (TSP1), an activator of latent transforming growth factor (TGF)β, is overexpressed by scleroderma fibroblasts. In this report we investigate whether activation of latent TGFβ by TSP1 plays a key role in matrix contraction by normal and scleroderma fibroblasts. METHODS: We use the fibroblast populated collagen lattices (FPCL) model of matrix contraction to show that interfering with TSP1/TGFβ binding and knockdown of TSP1 expression suppressed the contractile ability of normal and scleroderma fibroblasts basally and in response to TGFβ. Previously, we have shown that ras/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) mediates matrix contraction basally and in response to TGFβ. RESULTS: During mechanical stimulation in the FPCL system, using a multistation tensioning-culture force monitor (mst-CFM), TSP1 expression and p-ERK activation in fibroblasts are enhanced. Inhibiting TSP1 activity reduced the elevated activation of MEK/ERK and expression of key fibrogenic proteins. TSP1 also blocked platelet-derived growth factor (PDGF)-induced contractile activity and MEK/ERK activation. CONCLUSIONS: TSP1 is a key mediator of matrix contraction of normal and systemic sclerosis fibroblasts, via MEK/ERK

Survey to define informational needs of patients undergoing surgery for Crohn’s anal fistula

Aim There are many surgical treatments used in Crohn's anal fistula, although none is perfect. Decisions about surgery in this condition may be preference sensitive. The aim of this study was to identify what information patients would like in order to make treatment decisions and to explore experiences of making decisions in this setting. Method A survey was designed based upon qualitative interviews and input from patients and clinicians. It included a long list of informational items to be ranked on a scale of importance, a control preference scale, the decision regret scale, and items exploring preferred information formats. This was distributed through 10 English hospitals to patients with recent surgical treatment for Crohn's anal fistula. Results were analysed using principal component analysis, to identify key informational needs, and other appropriate descriptive statistics. Results In total 92 questionnaires were returned (response rate 41.8%); 48 (52.5%) respondents were women and 54 (58.7%) had undergone seton insertion. Principal component analysis identified three information needs: wound and aftercare, effect on perianal symptoms, severity of surgery. Decision-making preferences showed a desire to participate in decision-making. Median decision regret score was 25/100 (i.e., low). The preferred format for sharing information to support decision-making was from the surgeon, 80/92 (87.0%), and from a booklet, 58/92 (63.0%). Conclusion Key informational needs in this condition are wound and after care, effect on perianal symptoms, and severity of surgery. Patients would like this information to help engage in shared decision-making

Laparoscopic versus open colorectal surgery in the acute setting (LaCeS trial): a multicentre randomized feasibility trial

AbstractBackgroundApproximately 30,000 people per annum undergo major, emergency abdominal, gastrointestinal surgery, of which 36% (~10,800) are carried out for emergency colorectal pathology. Approximately 14% of all patients requiring emergency surgery undergo laparoscopic surgery. AimsThe aims of the LaCeS feasibility trial (Laparoscopic versus Open Colorectal Surgery in the Acute Setting) were to assess the feasibility, safety and acceptability of performing a large-scale definitive phase III randomised controlled trial with a comparison of emergency laparoscopic with open surgery for acute colorectal pathology. MethodsLaCeS was designed as a prospective, multicentre, single blind, parallel group, pragmatic, randomised controlled feasibility trial with an integrated qualitative study. Randomisation was performed centrally with patients being randomised on a 1:1 basis between laparoscopic or open surgery. ResultsA total of 64 patients were recruited across 5 centres. The overall average steady state recruitment rate was 1.2 patients/month. Baseline compliance for clinical and HrQoL data was 99.8% and 93.8% respectively. The conversion rate from laparoscopic to open surgery was 39.4% (95% CI 22.9% – 57.9%). The 30 day post-operative complication rate was 27.3% (95% CI 13.3- 45.5) in the laparoscopic arm and 41.9% (95% CI 24.6 – 60.9) in the open arm. DiscussionThe LaCeS feasibility trial has demonstrated that it is possible to evaluate laparoscopic surgery in the emergency colorectal setting within the context of a randomised controlled trial. LaCeS has demonstrated that it is possible to recruit to a surgical trial in the emergency setting, with good compliance to trial procedures and processes, and overall acceptability by patients and clinicians. The safety data obtained for laparoscopic emergency colorectal surgery indicate an acceptable safety profile, particularly when considering it to that observed in the open arm.Trial Registration ISRCTN15681041 https://doi.org/10.1186/ISRCTN15681041.Funding body: National Institute of Health Research – Research for Patient Benefi

Identification of Histological Patterns in Clinically Affected and Unaffected Palm Regions in Dupuytren's Disease

Dupuytren's disease is a fibro-proliferative disease characterized by a disorder of the extracellular matrix (ECM) and high myofibroblast proliferation. However, studies failed to determine if the whole palm fascia is affected by the disease. The objective of this study was to analyze several components of the extracellular matrix of three types of tissues—Dupuytren's diseased contracture cords (DDC), palmar fascia clinically unaffected by Dupuytren's disease contracture (NPF), and normal forehand fascia (NFF). Histological analysis, quantification of cells recultured from each type of tissue, mRNA microarrays and immunohistochemistry for smooth muscle actin (SMA), fibrillar ECM components and non-fibrillar ECM components were carried out. The results showed that DDC samples had abundant fibrosis with reticular fibers and few elastic fibers, high cell proliferation and myofibroblasts, laminin and glycoproteins, whereas NFF did not show any of these findings. Interestingly, NPF tissues had more cells showing myofibroblasts differentiation and more collagen and reticular fibers, laminin and glycoproteins than NFF, although at lower level than DDC, with similar elastic fibers than DDC. Immunohistochemical expression of decorin was high in DDC, whereas versican was highly expressed NFF, with no differences for aggrecan. Cluster analysis revealed that the global expression profile of NPF was very similar to DDC, and reculturing methods showed that cells corresponding to DDC tissues proliferated more actively than NPF, and NPF more actively than NFF. All these results suggest that NPF tissues may be affected, and that a modification of the therapeutic approach used for the treatment of Dupuytren's disease should be considered.This work was supported by CTS-115 (Tissue Engineering Group), University of Granada/Spain

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Developing a core outcome set for fistulising perianal Crohn's disease

OBJECTIVE: Lack of standardised outcomes hampers effective analysis and comparison of data when comparing treatments in fistulising perianal Crohn's disease (pCD). Development of a standardised set of outcomes would resolve these issues. This study provides the definitive core outcome set (COS) for fistulising pCD. DESIGN: Candidate outcomes were generated through a systematic review and patient interviews. Consensus was established via a three-round Delphi process using a 9-point Likert scale based on how important they felt it was in determining treatment success culminating in a final consensus meeting. Stakeholders were recruited nationally and grouped into three panels (surgeons and radiologists, gastroenterologists and IBD specialist nurses, and patients). Participants received feedback fromtheir panel(in the second round) andall participants(in the third round) to allow refinement of their scores. RESULTS: A total of 295 outcomes were identified from systematic reviews and interviews that were categorised into 92 domains. 187 stakeholders (response rate 78.5%) prioritised 49 outcomes through a three-round Delphi study.The final consensus meeting of 41 experts and patients generated agreement on an eight domain COS. The COS comprised three patient-reported outcome domains (quality of life, incontinence and a combined score of patient priorities) and five clinician-reported outcome domains (perianal disease activity, development of new perianal abscess/sepsis, new/recurrent fistula, unplanned surgery and faecal diversion). CONCLUSION: A fistulising pCD COS has been produced by all key stakeholders. Application of the COS will reduce heterogeneity in outcome reporting, thereby facilitating more meaningful comparisons between treatments, data synthesis and ultimately benefit patient care

Outcomes of obstructed abdominal wall hernia: results from the UK national small bowel obstruction audit

Background: Abdominal wall hernia is a common surgical condition. Patients may present in an emergency with bowel obstruction, incarceration or strangulation. Small bowel obstruction (SBO) is a serious surgical condition associated with significant morbidity. The aim of this study was to describe current management and outcomes of patients with obstructed hernia in the UK as identified in the National Audit of Small Bowel Obstruction (NASBO). Methods: NASBO collated data on adults treated for SBO at 131 UK hospitals between January and March 2017. Those with obstruction due to abdominal wall hernia were included in this study. Demographics, co-morbidity, imaging, operative treatment, and in-hospital outcomes were recorded. Modelling for factors associated with mortality and complications was undertaken using Cox proportional hazards and multivariable regression modelling. Results: NASBO included 2341 patients, of whom 415 (17·7 per cent) had SBO due to hernia. Surgery was performed in 312 (75·2 per cent) of the 415 patients; small bowel resection was required in 198 (63·5 per cent) of these operations. Non-operative management was reported in 35 (54 per cent) of 65 patients with a parastomal hernia and in 34 (32·1 per cent) of 106 patients with an incisional hernia. The in-hospital mortality rate was 9·4 per cent (39 of 415), and was highest in patients with a groin hernia (11·1 per cent, 17 of 153). Complications were common, including lower respiratory tract infection in 16·3 per cent of patients with a groin hernia. Increased age was associated with an increased risk of death (hazard ratio 1·05, 95 per cent c.i. 1·01 to 1·10; P = 0·009) and complications (odds ratio 1·05, 95 per cent c.i. 1·02 to 1·09; P = 0·001). Conclusion: NASBO has highlighted poor outcomes for patients with SBO due to hernia, highlighting the need for quality improvement initiatives in this group

Further evidence of the involvement of the Wnt signaling pathway in Dupuytren’s disease

Genetic background plays an important role in the development of Dupuytren's disease. A genome-wide association study (GWAS) showed that nine loci are associated with the disease, six of which contain genes that are involved in Wnt signaling (WNT2, WNT4, WNT7B, RSPO2, SFRP4, SULF1). To obtain insight in the role of these genes, we performed expression studies on affected and unaffected patient's tissues. Surgically obtained nodules and cords from eight Dupuytren's patients were compared to patient-matched control tissue (unaffected transverse palmar fascia). The Wnt-related genes found in the GWAS, the classical Wnt-downstream protein beta-catenin, as well as (myo) fibroblast markers were analyzed using real-time qPCR and immunohistochemical stainings for mRNA levels and protein levels, respectively. The collagen-coding genes COL1A1 and COL3A1 were highly upregulated on mRNA level, both in cords and nodules. Three Wnt-related genes were found to be differently regulated compared to control tissue: WNT2 was downregulated in nodules, WNT7B was upregulated in nodules, and SFRP4 was upregulated in nodules and cords. Immunohistochemistry revealed significantly less staining of Wnt2 in cords, but significantly more staining for Wnt7b in nodules. There was significantly more staining of alpha-SMA in nodules and cord and beta-catenin in nodules than in control tissue. We found differences in expression, both at mRNA and protein level, in several Wnt-related genes found earlier to be associated with Dupuytren's disease. Of these, Wnt7b was upregulated and found in close association with both alpha-SMA and beta-catenin expressing cells, making it a candidate pro-fibrotic mediator in Dupuytren's disease