Clinical and cost-effectiveness of PCF versus ACD in the treatment of cervical brachialgia (FORVAD trial).

BACKGROUND: Cervical radiculopathy occurs when a nerve root is compressed in the spine, if symptoms fail to resolve after 6 weeks surgery may be indicated. Anterior Cervical Discectomy (ACD) is the commonest procedure, Posterior Cervical Foraminotomy (PCF) is an alternative that avoids the risk of damage to anterior neck structures. This prospective, Phase III, UK multicentre, open, individually randomised controlled trial was performed to determine whether PCF is superior to ACD in terms of improving clinical outcome as measured by the Neck Disability Index (NDI) 52 weeks post-surgery. METHOD: Following consent to participate and collection of baseline data, subjects with cervical brachialgia were randomised to ACD or PCF in a 1:1 ratio on the day of surgery. Clinical outcomes were assessed on day 1 and patient reported outcomes on day 1 and weeks 6, 12, 26, 39 and 52 post-operation. A total of 252 participants were planned to be randomised. Statistical analysis was limited to descriptive statistics. Health economic outcomes were also described. RESULTS: The trial was closed early (n = 23). Compared to baseline, the median (interquartile range (IQR)) NDI score at 52 weeks reduced from 44.0 (36.0, 62.0) to 25.3 (20.0, 42.0) in the PCF group and increased from 35.6 (34.0, 44.0) to 45.0 (20.0, 57.0) in the ACD group. ACD may be associated with more swallowing, voice and other complications and was more expensive; neck and arm pain scores were similar. CONCLUSIONS: The trial was closed early, therefore no definitive conclusions on clinical or cost-effectiveness could be made.

Effectiveness of oral care interventions on malodour in dogs.

BACKGROUND: Oral malodour is identified by pet owners as an unpleasant inconvenience, but they may not recognise this likely indicates underlying disease. The primary cause of oral malodour relates to the presence of bacteria in the oral cavity often associated with gingivitis and periodontitis. The purpose of this study was to determine the effect of feeding two oral care chews with different textural properties on oral malodour and the proportion of bacterial species involved in the production of volatile sulphur compounds (VSCs). METHODS: Fourteen dogs (9 Petit Basset Griffon Vendéen (PBGV) and 5 Beagle dogs) participated in the randomised cross-over study for a total of 14 weeks. The cohort was divided into four groups with each exposed to a different intervention per week: chew A, chew B, tooth brushing control or a no intervention control. An induced malodour method was used to assess VSCs in breath samples using a portable gas chromatograph (OralChroma™). Microbiological samples (supragingival plaque and tongue coating scrapes) were analysed for VSC-producing bacteria using Oral Hydrogen Sulfide agar with lead acetate. RESULTS: VSCs were detected in the dogs' breath samples and levels of hydrogen sulphide and methyl mercaptan were found to be reduced following an intervention. Chew B significantly reduced the levels of both hydrogen sulphide (p < 0.001) and methyl mercaptan (p < 0.05) compared to no intervention. Reductions in methyl mercaptan were also observed for chew A and tooth brushing but these were not statistically significant. When compared to no intervention, all interventions significantly reduced the total bacterial load and VSC producing bacterial load in plaque (p < 0.001). For tongue samples, only chew B significantly reduced the total bacterial load and VSC-producing bacterial load (p < 0.001) compared to no intervention. CONCLUSIONS: By inducing oral malodour and subsequently applying the one-time interventions, significant reductions in the levels of VSCs were observed. The use of oral care chews texturally designed to deliver a deep, all-round cleaning action can be particularly effective at managing oral malodour in dogs, likely through an enhanced ability to remove bacteria.

The Incidence of Low Anterior Resection Syndrome as Assessed in an International Randomized Controlled Trial (MRC/NIHR ROLARR).

OBJECTIVE: To investigate the incidence of LARS in patients undergoing elective anterior resection within the MRC/NIHR ROLARR trial and to explore perioperative variables that might be associated with major LARS. SUMMARY BACKGROUND DATA: Sphincter-preserving rectal cancer surgery is frequently accompanied by defaecatory dysfunction known as Low anterior resection syndrome (LARS). This is distressing for patients and is an unmet clinical challenge. METHODS: An international, retrospective cohort study of patients undergoing anterior resection within the ROLARR trial was undertaken. Trial participants with restoration of gastrointestinal continuity and free from disease recurrence completed the validated LARS questionnaire between August 2015 and April 2017. The primary outcome was the incidence of LARS and secondary outcome was severity (minor versus major). RESULTS: LARS questionnaires were received from 132/155 (85%) eligible patients. The median time from surgery to LARS assessment was 1065 days (range 174-1655 d). The incidence of LARS was 82.6% (n = 109/132), which was minor in 26/132 (19.7%) and major in 83/132 (62.9%). The most common symptoms were incontinence to flatus (n = 86/132; 65.2%) and defaecatory clustering (88/132; 66.7%). In a multivariate model, predictors of major LARS were: 1 cm decrease in tumor height above the anal verge (OR = 1.290, 95% CI: 1.101,1.511); and an ASA grade greater than 1 (OR = 2.920, 95% CI: 1.239, 6.883). Treatment allocation (laparoscopic vs robotic) did not predict major LARS. CONCLUSIONS: LARS is a common after rectal cancer surgery and patients should be appropriately counselled preoperatively, particularly before surgery for low tumors or in comorbid populations.

Effect of Robotic-Assisted vs Conventional Laparoscopic Surgery on Risk of Conversion to Open Laparotomy Among Patients Undergoing Resection for Rectal Cancer: The ROLARR Randomized Clinical Trial.

Importance: Robotic rectal cancer surgery is gaining popularity, but limited data are available regarding safety and efficacy. Objective: To compare robotic-assisted vs conventional laparoscopic surgery for risk of conversion to open laparotomy among patients undergoing resection for rectal cancer. Design, Setting, and Participants: Randomized clinical trial comparing robotic-assisted vs conventional laparoscopic surgery among 471 patients with rectal adenocarcinoma suitable for curative resection conducted at 29 sites across 10 countries, including 40 surgeons. Recruitment of patients was from January 7, 2011, to September 30, 2014, follow-up was conducted at 30 days and 6 months, and final follow-up was on June 16, 2015. Interventions: Patients were randomized to robotic-assisted (n = 237) or conventional (n = 234) laparoscopic rectal cancer resection, performed by either high (upper rectum) or low (total rectum) anterior resection or abdominoperineal resection (rectum and perineum). Main Outcomes and Measures: The primary outcome was conversion to open laparotomy. Secondary end points included intraoperative and postoperative complications, circumferential resection margin positivity (CRM+) and other pathological outcomes, quality of life (36-Item Short Form Survey and 20-item Multidimensional Fatigue Inventory), bladder and sexual dysfunction (International Prostate Symptom Score, International Index of Erectile Function, and Female Sexual Function Index), and oncological outcomes. Results: Among 471 randomized patients (mean [SD] age, 64.9 [11.0] years; 320 [67.9%] men), 466 (98.9%) completed the study. The overall rate of conversion to open laparotomy was 10.1%: 19 of 236 patients (8.1%) in the robotic-assisted laparoscopic group and 28 of 230 patients (12.2%) in the conventional laparoscopic group (unadjusted risk difference = 4.1% [95% CI, -1.4% to 9.6%]; adjusted odds ratio = 0.61 [95% CI, 0.31 to 1.21]; P = .16). The overall CRM+ rate was 5.7%; CRM+ occurred in 14 (6.3%) of 224 patients in the conventional laparoscopic group and 12 (5.1%) of 235 patients in the robotic-assisted laparoscopic group (unadjusted risk difference = 1.1% [95% CI, -3.1% to 5.4%]; adjusted odds ratio = 0.78 [95% CI, 0.35 to 1.76]; P = .56). Of the other 8 reported prespecified secondary end points, including intraoperative complications, postoperative complications, plane of surgery, 30-day mortality, bladder dysfunction, and sexual dysfunction, none showed a statistically significant difference between groups. Conclusions and Relevance: Among patients with rectal adenocarcinoma suitable for curative resection, robotic-assisted laparoscopic surgery, as compared with conventional laparoscopic surgery, did not significantly reduce the risk of conversion to open laparotomy. These findings suggest that robotic-assisted laparoscopic surgery, when performed by surgeons with varying experience with robotic surgery, does not confer an advantage in rectal cancer resection. Trial Registration: isrctn.org Identifier: ISRCTN80500123.

SaFaRI: sacral nerve stimulation versus the FENIX magnetic sphincter augmentation for adult faecal incontinence: a randomised investigation.

PURPOSE: Faecal incontinence is a physically, psychologically and socially disabling condition. NICE guidance (2007) recommends surgical intervention, including sacral nerve stimulation (SNS), after failed conservative therapies. The FENIX magnetic sphincter augmentation (MSA) device is a novel continence device consisting of a flexible band of interlinked titanium beads with magnetic cores that is placed around the anal canal to augment anal sphincter tone through passive attraction of the beads. Preliminary studies suggest the FENIX MSA is safe, but efficacy data is limited. Rigorous evaluation is required prior to widespread adoption. METHOD AND DESIGN: The SaFaRI trial is a National Institute of Health Research (NIHR) Health Technology Assessment (HTA)-funded UK multi-site, parallel group, randomised controlled, unblinded trial that will investigate the use of the FENIX MSA, as compared to SNS, for adult faecal incontinence resistant to conservative management. Twenty sites across the UK, experienced in the treatment of faecal incontinence, will recruit 350 patients randomised equally to receive either SNS or FENIX MSA. Participants will be followed-up at 2 weeks post-surgery and at 6, 12 and 18 months post-randomisation. The primary endpoint is success, as defined by device in use and ≥50 % improvement in the Cleveland Clinic Incontinence Score (CCIS) at 18 months post-randomisation. Secondary endpoints include complications, quality of life and cost effectiveness. DISCUSSION: SaFaRI will rigorously evaluate a new technology for faecal incontinence, the FENIX™ MSA, allowing its safe and controlled introduction into current clinical practice. These results will inform the future surgical management of adult faecal incontinence.

'The unexpected journey': a qualitative interview study exploring patient and health professionals experiences of participating in the knee arthroplasty versus joint distraction study (KARDS).

OBJECTIVE: The aim of the knee arthroplasty versus joint distraction (KARDS) randomised trial was to investigate whether knee joint distraction (KJD) is non-inferior to knee arthroplasty, also known as knee replacement (KR). Here we report the findings from qualitative interviews that were part of the planned KARDS process evaluation. DESIGN AND METHODS: Semi-structured qualitative interviews with staff and participants in secondary care. Data were analysed using thematic content analysis. FINDINGS: We were unable to complete the full-planned KARDS process evaluation as recruitment to the trial was closed early but key common themes emerged.Eleven members of staff were interviewed from two KARDS sites (eight initial interviews just after site opening and three follow-up interviews at 12 months). Eleven KARDS participants (six KR and five KJD) were interviewed. One overarching theme emerged: 'An unexpected journey'. This incorporated subthemes including 'an important research question', 'a roller coaster ride', 'lessons learnt', 'managing expectations' and 'a slow recovery'. These encapsulate experiences of both staff and participants. CONCLUSION: The information that we were able to collect highlights that providing adequate and comprehensive information about all aspects of treatment including estimated timelines of recovery are essential in clinical trials of novel interventions. Incorporating a comprehensive rehabilitation package following KJD was a key learning. Process evaluations in these complex trials are essential to determine issues as early as possible so appropriate changes can be made to ensure participants have a smooth journey through the trial experience. TRIAL REGISTRATION NUMBER: ISRCTN14879004.

Pathway Of Low Anterior Resection syndrome relief after Surgery (POLARiS) feasibility trial protocol: a multicentre, feasibility cohort study with embedded randomised control trial to compare sacral neuromodulation and transanal irrigation to optimised conservative management in the management of major low anterior resection syndrome following rectal cancer treatment.

INTRODUCTION: Rectal cancer is common with a 60% 5-year survival rate. Treatment usually involves surgery with or without neoadjuvant chemoradiotherapy or adjuvant chemotherapy. Sphincter saving curative treatment can result in debilitating changes to bowel function known as low anterior resection syndrome (LARS). There are currently no clear guidelines on the management of LARS with only limited evidence for different treatment modalities. METHODS AND ANALYSIS: Patients who have undergone an anterior resection for rectal cancer in the last 10 years will be approached for the study. The feasibility trial will take place in four centres with a 9-month recruitment window and 12 months follow-up period. The primary objective is to assess the feasibility of recruitment to the POLARiS trial which will be achieved through assessment of recruitment, retainment and follow-up rates as well as the prevalence of major LARS.Feasibility outcomes will be analysed descriptively through the estimation of proportions with confidence intervals. Longitudinal patient reported outcome measures will be analysed according to scoring manuals and presented descriptively with reporting graphically over time. ETHICS AND DISSEMINATION: Ethical approval has been granted by Wales REC1; Reference 22/WA/0025. The feasibility study is in the process of set up. The results of the feasibility trial will feed into the design of an expanded, international trial. TRIAL REGISTRATION NUMBER: CT05319054.

Posterior cervical foraminotomy versus anterior cervical discectomy for Cervical Brachialgia: the FORVAD RCT.

Background: Posterior cervical foraminotomy and anterior cervical discectomy are routinely used operations to treat cervical brachialgia, although definitive evidence supporting superiority of either is lacking. Objective: The primary objective was to investigate whether or not posterior cervical foraminotomy is superior to anterior cervical discectomy in improving clinical outcome. Design: This was a Phase III, unblinded, prospective, United Kingdom multicentre, parallel-group, individually randomised controlled superiority trial comparing posterior cervical foraminotomy with anterior cervical discectomy. A rapid qualitative study was conducted during the close-down phase, involving remote semistructured interviews with trial participants and health-care professionals. Setting: National Health Service trusts. Participants: Patients with symptomatic unilateral cervical brachialgia for at least 6 weeks. Interventions: Participants were randomised to receive posterior cervical foraminotomy or anterior cervical discectomy. Allocation was not blinded to participants, medical staff or trial staff. Health-care use from providing the initial surgical intervention to hospital discharge was measured and valued using national cost data. Main outcome measures: The primary outcome measure was clinical outcome, as measured by patient-reported Neck Disability Index score 52 weeks post operation. Secondary outcome measures included complications, reoperations and restricted American Spinal Injury Association score over 6 weeks post operation, and patient-reported Eating Assessment Tool-10 items, Glasgow-Edinburgh Throat Scale, Voice Handicap Index-10 items, PainDETECT and Numerical Rating Scales for neck and upper-limb pain over 52 weeks post operation. Results: The target recruitment was 252 participants. Owing to slow accrual, the trial closed after randomising 23 participants from 11 hospitals. The qualitative substudy found that there was support and enthusiasm for the posterior cervical FORaminotomy Versus Anterior cervical Discectomy in the treatment of cervical brachialgia trial and randomised clinical trials in this area. However, clinical equipoise appears to have been an issue for sites and individual surgeons. Randomisation on the day of surgery and processes for screening and approaching participants were also crucial factors in some centres. The median Neck Disability Index scores at baseline (pre surgery) and at 52 weeks was 44.0 (interquartile range 36.0-62.0 weeks) and 25.3 weeks (interquartile range 20.0-42.0 weeks), respectively, in the posterior cervical foraminotomy group (n = 14), and 35.6 weeks (interquartile range 34.0-44.0 weeks) and 45.0 weeks (interquartile range 20.0-57.0 weeks), respectively, in the anterior cervical discectomy group (n = 9). Scores appeared to reduce (i.e. improve) in the posterior cervical foraminotomy group, but not in the anterior cervical discectomy group. The median Eating Assessment Tool-10 items score for swallowing was higher (worse) after anterior cervical discectomy (13.5) than after posterior cervical foraminotomy (0) on day 1, but not at other time points, whereas the median Glasgow-Edinburgh Throat Scale score for globus was higher (worse) after anterior cervical discectomy (15, 7, 6, 6, 2, 2.5) than after posterior cervical foraminotomy (3, 0, 0, 0.5, 0, 0) at all postoperative time points. Five postoperative complications occurred within 6 weeks of surgery, all after anterior cervical discectomy. Neck pain was more severe on day 1 following posterior cervical foraminotomy (Numerical Rating Scale - Neck Pain score 8.5) than at the same time point after anterior cervical discectomy (Numerical Rating Scale - Neck Pain score 7.0). The median health-care costs of providing initial surgical intervention were £2610 for posterior cervical foraminotomy and £4411 for anterior cervical discectomy. Conclusions: The data suggest that posterior cervical foraminotomy is associated with better outcomes, fewer complications and lower costs, but the trial recruited slowly and closed early. Consequently, the trial is underpowered and definitive conclusions cannot be drawn. Recruitment was impaired by lack of individual equipoise and by concern about randomising on the day of surgery. A large prospective multicentre trial comparing anterior cervical discectomy and posterior cervical foraminotomy in the treatment of cervical brachialgia is still required. Trial registration: This trial is registered as ISRCTN10133661. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 21. See the NIHR Journals Library website for further project information.

Cervical brachialgia is pain that starts in the neck and passes down into the arm. Although most people with cervical brachialgia recover quickly, in some patients pain persists, and in 15% of patients pain is so severe that they are unable to work. In the posterior cervical FORaminotomy Versus Anterior cervical Discectomy in the treatment of cervical brachialgia trial, we investigated two neck surgeries used to treat this problem: posterior cervical foraminotomy (surgery from the back of the neck) and anterior cervical discectomy (surgery from the front of the neck). This trial aimed to find out if one of them is better than the other at relieving pain and more cost-effective for the National Health Service. We assessed patients' quality of life 1 year after their surgery and how their pain changed over the course of the year. We also measured the number of complications patients had in the first 6 weeks after their operation. Recruitment was slow and so the trial was stopped early, after only 23 patients from 11 hospitals had been randomly allocated to the two surgery groups. We had planned to recruit 252 participants to the trial; the number of participants we were able to recruit in practice was too small to enable us to determine which surgery is better at relieving pain. To find out why the trial had struggled to recruit, we asked hospital staff and participants about their experiences. We found that hospital staff sometimes struggled to organise everything needed to randomise patients on the day of surgery. Some staff also found it difficult to randomise patients as they had an opinion on which surgery they thought the patient should receive. The data collected in the trial will still be useful to help design future research. Finding out which surgery is better at relieving pain remains important, and the data we have collected will support answering this question in future.

Recruiting to surgical trials in the emergency setting: using a mixed methods study to understand clinician and patient perspectives.

BACKGROUND: Undertaking randomized clinical trials (RCTs) in emergency surgical settings is associated with methodological and practical challenges. This study explored patients' and clinicians' perspectives associated with the conduct of an RCT comparing laparoscopic and open colorectal surgery in the acute setting. METHODS: All eligible patients screened and enrolled for the 'Laparoscopic versus open colorectal surgery in the acute setting (LaCeS)' multicentre, randomized clinical feasibility trial in five UK NHS Trusts were invited to respond to a survey. Patients and healthcare professionals were also invited to take part in semi-structured interviews. Survey and interviews explored the acceptability of the feasibility trial. Interviews were audio recorded, transcribed verbatim, and analysed using thematic analysis. Survey data were analysed descriptively to assess patient views of the trial and intervention. RESULTS: Out of 72 patients enrolled for the LaCeS RCT, survey data were collected from 28 patients (38.9 per cent), and interviews were conducted with 16 patients and 14 healthcare professionals. Thirteen out of 28 patients (46 per cent) had treatment preferences but these were not strong enough to deter participation. Twelve of the patients interviewed believed that their surgeon preferred laparoscopic surgery, but this did not deter them from participating in the trial. Half of the surgeons interviewed expressed the view that laparoscopic surgery was of benefit in this setting, but recognized that the need for research evidence outweighed their personal treatment preferences. Eight of the 14 recruiters reported that the emergency setting affected recruitment, especially in centres with fewer recruiting surgeons. Interviewees reported that recruitment was helped significantly by using surgical trainees to consent patients. CONCLUSION: This study identified specific challenges for the LaCeS trial design to address and adds significant insights to our understanding of recruiting to emergency surgical trials more broadly.

Clinical and cost-effectiveness of Knee Arthroplasty versus Joint Distraction for Osteoarthritis (KARDS): protocol for a multicentre, phase III, randomised control trial.

INTRODUCTION: Knee replacement (KR) is a clinically proven procedure typically offered to patients with severe knee osteoarthritis (OA) to relieve pain and improve quality of life. However, artificial joints fail over time, requiring revision associated with higher mortality and inferior outcomes. With more young people presenting with knee OA and increasing life expectancy, there is an unmet need to postpone time to first KR. Knee joint distraction (KJD), the practice of using external fixators to open up knee joint space, is proposed as potentially effective to preserve the joint following initial studies in the Netherlands, however, has not been researched within an NHS setting. The KARDS trial will investigate whether KJD is non-inferior to KR in terms of patient-reported postoperative pain 12 months post-surgery. METHODS AND ANALYSIS: KARDS is a phase III, multicentre, pragmatic, open-label, individually randomised controlled non-inferiority trial comparing KJD with KR in patients with severe knee OA, employing a hybrid-expertise design, with internal pilot phase and process evaluation. 344 participants will be randomised (1:1) to KJD or KR. The primary outcome measure is the Knee Injury and Osteoarthritis Outcomes Score (KOOS) pain domain score at 12 months post-operation. Secondary outcome measures include patient-reported overall KOOS, Pain Visual Analogue Scale and Oxford Knee Scores, knee function assessments, joint space width, complications and further interventions over 24 months post-operation. Per patient cost difference between KR and KJD and cost per quality-adjusted life year (QALY) gained over 24 months will be estimated within trial, and incremental cost per QALY gained over 20 years by KJD relative to KR predicted using decision analytic modelling. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Research Ethics Committee (REC) and Health Research Authority (HRA). Trial results will be disseminated at clinical conferences, through relevant patient groups and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN14879004; recruitment opened April 2021.

Radical Cystectomy Against Intravesical BCG for High-Risk High-Grade Nonmuscle Invasive Bladder Cancer: Results From the Randomized Controlled BRAVO-Feasibility Study.

PURPOSE: High-grade nonmuscle invasive bladder cancer (HRNMIBC) is a heterogeneous disease. Treatments include intravesical maintenance Bacillus Calmette-Guerin (mBCG) and radical cystectomy (RC). We wanted to understand whether a randomized trial comparing these options was possible. MATERIALS AND METHODS: We conducted a two-arm, prospective multicenter randomized study to determine the feasibility in Bacillus Calmette-Guerin-naive patients. Participants had new high-risk HRNMIBC suitable for both treatments. Random assignment was stratified by age, sex, center, stage, presence of carcinoma in situ, and prior low-risk bladder cancer. Qualitative work investigated how to maintain equipoise. The primary outcome was the number of patients screened, eligible, recruited, and randomly assigned. RESULTS: We screened 407 patients, approached 185, and obtained consent from 51 (27.6%) patients. Of these, one did not proceed and therefore 50 were randomly assigned (1:1). In the mBCG arm, 23/25 (92.0%) patients received mBCG, four had nonmuscle invasive bladder cancer (NMIBC) after induction, three had NMIBC at 4 months, and four received RC. At closure, two patients had metastatic BC. In the RC arm, 20 (80.0%) participants received cystectomy, including five (25.0%) with no tumor, 13 (65.0%) with HRNMIBC, and two (10.0%) with muscle invasion in their specimen. At follow-up, all patients in the RC arm were free of disease. Adverse events were mostly mild and equally distributed (15/23 [65.2%] patients with mBCG and 13/20 [65.0%] patients with RC). The quality of life (QOL) of both arms was broadly similar at 12 months. CONCLUSION: A randomized controlled trial comparing mBCG and RC will be challenging to recruit into. Around 10% of patients with high-risk HRNMIBC have a lethal disease and may be better treated by primary radical treatment. Conversely, many are suitable for bladder preservation and may maintain their prediagnosis QOL.

Sacral nerve stimulation versus the magnetic sphincter augmentation device for adult faecal incontinence: the SaFaRI RCT.

BACKGROUND: Preliminary studies using the FENIX™ (Torax Medical, Minneapolis, MN, USA) magnetic sphincter augmentation device suggest that it is safe to use for the treatment of adult faecal incontinence, but efficacy data are limited. OBJECTIVE: To compare FENIX with sacral nerve stimulation for the treatment of adult faecal incontinence in terms of safety, efficacy, quality of life and cost-effectiveness. DESIGN, SETTING AND PARTICIPANTS: Multicentre, parallel-group, unblinded, randomised trial comparing FENIX with sacral nerve stimulation in participants suffering moderate to severe faecal incontinence. INTERVENTIONS: Participants were randomised on an equal basis to either sacral nerve stimulation or FENIX. Follow-up occurred 2 weeks postoperatively and at 6, 12 and 18 months post randomisation. MAIN OUTCOME AND MEASURE: The primary outcome was success, defined as device in use and ≥ 50% improvement in Cleveland Clinic Incontinence Score at 18 months post randomisation. Secondary outcomes included complication rates, quality of life and cost-effectiveness. Between 30 October 2014 and 23 March 2017, 99 participants were randomised across 18 NHS sites (50 participants to FENIX vs. 49 participants to sacral nerve stimulation). The median time from randomisation to FENIX implantation was 57.0 days (range 4.0-416.0 days), and the median time from randomisation to permanent sacral nerve stimulation was 371.0 days (range 86.0-918.0 days). A total of 45 out of 50 participants underwent FENIX implantation and 29 out of 49 participants continued to permanent sacral nerve stimulation. The following results are reported, excluding participants for whom the corresponding outcome was not evaluable. Overall, there was success for 10 out of 80 (12.5%) participants, with no statistically significant difference between the two groups [FENIX 6/41 (14.6%) participants vs. sacral nerve stimulation 4/39 (10.3%) participants]. At least one postoperative complication was experienced by 33 out of 45 (73.3%) participants in the FENIX group and 9 out of 40 (22.5%) participants in the sacral nerve stimulation group. A total of 15 out of 50 (30%) participants in the FENIX group ultimately had to have their device explanted. Slightly higher costs and quality-adjusted life-years (incremental = £305.50 and 0.005, respectively) were observed in the FENIX group than in the sacral nerve stimulation group. This was reversed over the lifetime horizon (incremental = -£1306 and -0.23 for costs and quality-adjusted life-years, respectively), when sacral nerve stimulation was the optimal option (net monetary benefit = -£3283), with only a 45% chance of FENIX being cost-effective. LIMITATIONS: The SaFaRI study was terminated in 2017, having recruited 99 participants of the target sample size of 350 participants. The study is, therefore, substantially underpowered to detect differences between the treatment groups, with significant uncertainty in the cost-effectiveness analysis. CONCLUSIONS: The SaFaRI study revealed inefficiencies in the treatment pathways for faecal incontinence, particularly for sacral nerve stimulation. The success of both FENIX and sacral nerve stimulation was much lower than previously reported, with high postoperative morbidity in the FENIX group. FUTURE WORK: Further research is needed to clarify the treatment pathways for sacral nerve stimulation and to determine its true clinical and cost-effectiveness. TRIAL REGISTRATION: Current Controlled Trials ISRCTN16077538. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 18. See the NIHR Journals Library website for further project information.

Faecal incontinence is a distressing condition for patients, and surgery is recommended if symptoms are having an effect on quality of life. One of the treatments recommended for faecal incontinence by the National Institute for Health and Care Excellence is sacral nerve stimulation, which aims to improve continence by stimulating the nerves to the back passage. A newer treatment involves surgery to implant a string of magnetic beads around the anal canal using the FENIX™ device (Torax Medical, Minneapolis, MN, USA). The aim of this study was to assess the benefits and risks of the FENIX device compared with sacral nerve stimulation. The SaFaRI study aimed to recruit 350 participants with faecal incontinence, but was stopped early because of the manufacturer withdrawing the FENIX device for strategic reasons. In total, we recruited 99 participants. Fifty participants were allocated to receive the FENIX device and 49 participants were allocated to receive sacral nerve stimulation. The observed success rates with both devices were low: at 18 months following their entry into the study, 6 out of 41 (14.6%) participants in the FENIX group and 4 out of 39 (10.3%) participants in the sacral nerve stimulation group had the device both in use and producing a benefit. A total of 5 out of 50 (10.0%) participants allocated to receive the FENIX device did not have a device implanted, and 15 out of 45 (33.3%) participants who did have the FENIX device implanted needed to have it removed because of complications during the 18-month follow-up period. A total of 21 out of 49 (42.9%) participants allocated to receive sacral nerve stimulation did not have a permanent sacral nerve stimulation device implanted, and 0 of the 28 who did have a permanent sacral nerve stimulation device implanted needed to have it removed during the 18-month follow-up period. The costs associated with the FENIX device were higher because of a greater number of participants experiencing complications, meaning that the FENIX device is unlikely to be cost-effective in the treatment of faecal incontinence compared with sacral nerve stimulation.

Liver resection surgery compared with thermal ablation in high surgical risk patients with colorectal liver metastases: the LAVA international RCT.

BACKGROUND: Although surgical resection has been considered the only curative option for colorectal liver metastases, thermal ablation has recently been suggested as an alternative curative treatment. There have been no adequately powered trials comparing surgery with thermal ablation. OBJECTIVES: Main objective - to compare the clinical effectiveness and cost-effectiveness of thermal ablation versus liver resection surgery in high surgical risk patients who would be eligible for liver resection. Pilot study objectives - to assess the feasibility of recruitment (through qualitative study), to assess the quality of ablations and liver resection surgery to determine acceptable standards for the main trial and to centrally review the reporting of computed tomography scan findings relating to ablation and outcomes and recurrence rate in both arms. DESIGN: A prospective, international (UK and the Netherlands), multicentre, open, pragmatic, parallel-group, randomised controlled non-inferiority trial with a 1-year internal pilot study. SETTING: Tertiary liver, pancreatic and gallbladder (hepatopancreatobiliary) centres in the UK and the Netherlands. PARTICIPANTS: Adults with a specialist multidisciplinary team diagnosis of colorectal liver metastases who are at high surgical risk because of their age, comorbidities or tumour burden and who would be suitable for liver resection or thermal ablation. INTERVENTIONS: Thermal ablation conducted as per local policy (but centres were encouraged to recruit within Cardiovascular and Interventional Radiological Society of Europe guidelines) versus surgical liver resection performed as per centre protocol. MAIN OUTCOME MEASURES: Pilot study - patients' and clinicians' acceptability of the trial to assist in optimisation of recruitment. Primary outcome - disease-free survival at 2 years post randomisation. Secondary outcomes - overall survival, timing and site of recurrence, additional therapy after treatment failure, quality of life, complications, length of hospital stay, costs, trial acceptability, and disease-free survival measured from end of intervention. It was planned that 5-year survival data would be documented through record linkage. Randomisation was performed by minimisation incorporating a random element, and this was a non-blinded study. RESULTS: In the pilot study over 1 year, a total of 366 patients with colorectal liver metastases were screened and 59 were considered eligible. Only nine participants were randomised. The trial was stopped early and none of the planned statistical analyses was performed. The key issues inhibiting recruitment included fewer than anticipated patients eligible for both treatments, misconceptions about the eligibility criteria for the trial, surgeons' preference for one of the treatments ('lack of clinical equipoise' among some of the surgeons in the centre) with unconscious bias towards surgery, patients' preference for one of the treatments, and lack of dedicated research nurses for the trial. CONCLUSIONS: Recruitment feasibility was not demonstrated during the pilot stage of the trial; therefore, the trial closed early. In future, comparisons involving two very different treatments may benefit from an initial feasibility study or a longer period of internal pilot study to resolve these difficulties. Sufficient time should be allowed to set up arrangements through National Institute for Health Research (NIHR) Research Networks. TRIAL REGISTRATION: Current Controlled Trials ISRCTN52040363. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 21. See the NIHR Journals Library website for further project information.

In about 50% of people with bowel cancer, cancer spreads to the liver (colorectal liver metastases) within 5 years of detection and treatment. Liver resection (i.e. surgical removal of a portion of the liver) is the standard treatment in people below 70 years of age who are otherwise well, provided that the liver cancer is confined to a limited part of the liver. Such patients are considered 'low-risk' patients. Older patients and those with major medical problems or extensive cancers are considered 'high-risk' patients, as they are at a higher risk of developing complications following liver resection. Thermal ablation destroys the liver cancers using a needle that heats the cancer deposits until they are destroyed. There is significant uncertainty as to whether or not ablation can offer equivalent survival compared with surgery for 'high-risk' patients. We planned and conducted a randomised controlled trial comparing ablation with surgery to resolve this uncertainty. In this trial, some patients received ablation and others received surgery. The treatment was allocated at random with neither patients nor the study organisers choosing the treatment. The trial had an internal pilot (i.e. a smaller version of the full trial to resolve any 'teething problems' and ensure that a sufficient number of participants can be included in the full trial). Only nine patients were recruited in the 1-year internal pilot, compared with the anticipated recruitment of 45 patients. Therefore, the trial closed early as a result of poor recruitment, and the uncertainty about the best treatment for high-risk patients with colorectal liver metastases continues. The main reasons for the poor recruitment included fewer than anticipated eligible participants, clinicians' unconscious bias towards surgery, and patients' preference for one treatment or the other. In the future, comparisons involving two very different treatments may benefit from a feasibility study or a longer period of pilot study to resolve any difficulties.

Exploring and adjusting for potential learning effects in ROLARR: a randomised controlled trial comparing robotic-assisted vs. standard laparoscopic surgery for rectal cancer resection.

BACKGROUND: Commonly in surgical randomised controlled trials (RCT) the experimental treatment is a relatively new technique which the surgeons may still be learning, while the control is a well-established standard. This can lead to biased comparisons between treatments. In this paper we discuss the implementation of approaches for addressing this issue in the ROLARR trial, and points of consideration for future surgical trials. METHODS: ROLARR was an international, randomised, parallel-group trial comparing robotic vs. laparoscopic surgery for the curative treatment of rectal cancer. The primary endpoint was conversion to open surgery (binary). A surgeon inclusion criterion mandating a minimum level of experience in each technique was incorporated. Additionally, surgeon self-reported data were collected periodically throughout the trial to capture the level of experience of every participating surgeon. Multi-level logistic regression adjusting for operating surgeon as a random effect is used to estimate the odds ratio for conversion to open surgery between the treatment groups. We present and contrast the results from the primary analysis, which did not account for learning effects, and a sensitivity analysis which did. RESULTS: The primary analysis yields an estimated odds ratio (robotic/laparoscopic) of 0.614 (95% CI 0.311, 1.211; p = 0.16), providing insufficient evidence to conclude superiority of robotic surgery compared to laparoscopic in terms of the risk of conversion to open. The sensitivity analysis reveals that while participating surgeons in ROLARR were expert at laparoscopic surgery, some, if not all, were still learning robotic surgery. The treatment-effect odds ratio decreases by a factor of 0.341 (95% CI 0.121, 0.960; p = 0.042) per unit increase in log-number of previous robotic operations performed by the operating surgeon. The odds ratio for a patient whose operating surgeon has the mean experience level in ROLARR - 152.46 previous laparoscopic, 67.93 previous robotic operations - is 0.40 (95% CI 0.168, 0.953; p = 0.039). CONCLUSIONS: In this paper we have demonstrated the implementation of approaches for accounting for learning in a practical example of a surgery RCT analysis. The results demonstrate the value of implementing such approaches, since we have shown that without them the ROLARR analysis would indeed have been confounded by the learning effects. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number (ISRCTN) registry, ID: ISRCTN80500123. Registered on 27 May 2010.

Liver resection surgery versus thermal ablation for colorectal LiVer MetAstases (LAVA): study protocol for a randomised controlled trial.

BACKGROUND: Although surgical resection has been considered the only curative option for colorectal liver metastases (CLM), thermal ablation has recently been suggested as an alternative curative treatment. A prospective randomised trial is required to define the efficacy of resection vs ablation for the treatment of colorectal liver metastases. METHODS: Design and setting: This is a multicentre, open, randomised controlled non-inferiority trial design with internal pilot and will be performed in tertiary liver centres in UK and The Netherlands. PARTICIPANTS: Eligible patients will be those with colorectal liver metastases at high surgical risk because of their age, co-morbidities or tumour burden and who would be suitable for liver resection or thermal ablation. INTERVENTION: Thermal ablation as per local policy. CONTROL: Surgical liver resection performed as per centre protocol. Co-interventions: Further chemotherapy will be offered to patients as per current practice. Outcomes Pilot study: Same as main study and in addition patients and clinicians' acceptability of the trial to assist in optimisation of recruitment. PRIMARY OUTCOME: Disease-free survival (DFS) at two years post randomisation. SECONDARY OUTCOMES: Overall survival, timing and site of recurrence, additional therapy after treatment failure, quality of life, complications, length of hospital stay, costs, trial acceptability, DFS measured from end of intervention. FOLLOW-UP: 24 months from randomisation; five-year follow-up for overall survival. SAMPLE SIZE: 330 patients to demonstrate non-inferiority of thermal ablation. DISCUSSION: This trial will determine the effectiveness and cost-effectiveness of thermal ablation vs surgical resection for high-risk people with colorectal liver metastases, and guide the optimal treatment for these patients. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN52040363 . Registered on 9 March 2016.

Effects of Lactobacillus acidophilus DSM13241 as a probiotic in healthy adult cats.

OBJECTIVE: To evaluate the effect of dietary supplementation with the probiotic strain Lactobacillus acidophilus DSM13241 in healthy adult cats. ANIMALS: 15 adult cats. PROCEDURES: Cats were fed a nutritionally complete dry food for 5 weeks. Fecal character was assessed daily, and a single fecal sample and 3-mL blood sample were collected for bacterial enumeration and hematologic analysis, respectively. Cats were then fed the same diet supplemented with L acidophilus DSM13241 (2 x 10(8) CFU/d) for 4.5 weeks. Repeat fecal and hematologic measurements were taken prior to the return to control diet for a 4-week period. RESULTS: The probiotic species was recovered from feces, demonstrating survival through the feline gastrointestinal tract. Probiotic supplementation was associated with increased numbers of beneficial Lactobacillus and L acidophilus groups in feces and decreased numbers of Clostridium spp and Enterococcus faecalis, indicating an altered bacterial balance in the gastrointestinal tract microflora. Fecal pH was also decreased suggesting a colonic environment selective for the beneficial lactic acid bacterial population. Systemic and immunomodulatory effects were associated with administration of L acidophilus DSM13241 including altered cell numbers within WBC subsets and enhanced phagocytic capacity in the peripheral granulocyte population. In addition, plasma endotoxin concentrations were decreased during probiotic feeding, and RBCs had a decreased susceptibility to osmotic pressure. CONCLUSIONS AND CLINICAL RELEVANCE: Probiotic strain L acidophilus DSM13241 fed at 2 x 10(8) CFU/d can alter the balance of gastrointestinal microflora in healthy cats. Furthermore, administration of this probiotic results in beneficial systemic and immunomodulatory effects in cats.

A Pyrosequencing Investigation of Differences in the Feline Subgingival Microbiota in Health, Gingivitis and Mild Periodontitis.

Periodontitis is the most frequently diagnosed health problem in cats yet little is known about the bacterial species important for the disease. The objective of this study was to identify bacterial species associated with health, gingivitis or mild periodontitis (<25% attachment loss) in feline plaque. Knowledge of these species is a first step in understanding the potential for improving oral health of cats via dietary interventions that alter the proportions of influential species. Subgingival plaque samples were collected from 92 cats with healthy gingiva, gingivitis or mild periodontitis. Pyrosequencing of the V1-V3 region of the 16S rDNA from these plaque samples generated more than one million reads and identified a total of 267 operational taxonomic units after bioinformatic and statistical analysis. Porphyromonas was the most abundant genus in all gingival health categories, particularly in health along with Moraxella and Fusobacteria. The Peptostreptococcaceae were the most abundant family in gingivitis and mild periodontitis. Logistic regression analysis identified species from various genera that were significantly associated with health, gingivitis or mild periodontitis. The species identified were very similar to those observed in canine plaque in the corresponding health and disease states. Such similarities were not observed between cat and human at the bacterial species level but with disease progression similarities did emerge at the phylum level. This suggests that interventions targeted at human pathogenic species will not be effective for use in cats but there is more potential for commonalities in interventions for cats and dogs.

The feline oral microbiome: a provisional 16S rRNA gene based taxonomy with full-length reference sequences.

The human oral microbiome is known to play a significant role in human health and disease. While less well studied, the feline oral microbiome is thought to play a similarly important role. To determine roles oral bacteria play in health and disease, one first has to be able to accurately identify bacterial species present. 16S rRNA gene sequence information is widely used for molecular identification of bacteria and is also useful for establishing the taxonomy of novel species. The objective of this research was to obtain full 16S rRNA gene reference sequences for feline oral bacteria, place the sequences in species-level phylotypes, and create a curated 16S rRNA based taxonomy for common feline oral bacteria. Clone libraries were produced using "universal" and phylum-selective PCR primers and DNA from pooled subgingival plaque from healthy and periodontally diseased cats. Bacteria in subgingival samples were also cultivated to obtain isolates. Full-length 16S rDNA sequences were determined for clones and isolates that represent 171 feline oral taxa. A provisional curated taxonomy was developed based on the position of each taxon in 16S rRNA phylogenetic trees. The feline oral microbiome curated taxonomy and 16S rRNA gene reference set will allow investigators to refer to precisely defined bacterial taxa. A provisional name such as "Propionibacterium sp. feline oral taxon FOT-327" is an anchor to which clone, strain or GenBank names or accession numbers can point. Future next-generation-sequencing studies of feline oral bacteria will be able to map reads to taxonomically curated full-length 16S rRNA gene sequences.

Integration of robotic surgery into routine practice and impacts on communication, collaboration, and decision making: a realist process evaluation protocol.

BACKGROUND: Robotic surgery offers many potential benefits for patients. While an increasing number of healthcare providers are purchasing surgical robots, there are reports that the technology is failing to be introduced into routine practice. Additionally, in robotic surgery, the surgeon is physically separated from the patient and the rest of the team, with the potential to negatively impact teamwork in the operating theatre. The aim of this study is to ascertain: how and under what circumstances robotic surgery is effectively introduced into routine practice; and how and under what circumstances robotic surgery impacts teamwork, communication and decision making, and subsequent patient outcomes. METHODS AND DESIGN: We will undertake a process evaluation alongside a randomised controlled trial comparing laparoscopic and robotic surgery for the curative treatment of rectal cancer. Realist evaluation provides an overall framework for the study. The study will be in three phases. In Phase I, grey literature will be reviewed to identify stakeholders' theories concerning how robotic surgery becomes embedded into surgical practice and its impacts. These theories will be refined and added to through interviews conducted across English hospitals that are using robotic surgery for rectal cancer resection with staff at different levels of the organisation, along with a review of documentation associated with the introduction of robotic surgery. In Phase II, a multi-site case study will be conducted across four English hospitals to test and refine the candidate theories. Data will be collected using multiple methods: the structured observation tool OTAS (Observational Teamwork Assessment for Surgery); video recordings of operations; ethnographic observation; and interviews. In Phase III, interviews will be conducted at the four case sites with staff representing a range of surgical disciplines, to assess the extent to which the results of Phase II are generalisable and to refine the resulting theories to reflect the experience of a broader range of surgical disciplines. The study will provide (i) guidance to healthcare organisations on factors likely to facilitate successful implementation and integration of robotic surgery, and (ii) guidance on how to ensure effective communication and teamwork when undertaking robotic surgery.

Early development and quorum sensing in bacterial biofilms.

We develop mathematical models to examine the formation, growth and quorum sensing activity of bacterial biofilms. The growth aspects of the model are based on the assumption of a continuum of bacterial cells whose growth generates movement, within the developing biofilm, described by a velocity field. A model proposed in Ward et al. (2001) to describe quorum sensing, a process by which bacteria monitor their own population density by the use of quorum sensing molecules (QSMs), is coupled with the growth model. The resulting system of nonlinear partial differential equations is solved numerically, revealing results which are qualitatively consistent with experimental ones. Analytical solutions derived by assuming uniform initial conditions demonstrate that, for large time, a biofilm grows algebraically with time; criteria for linear growth of the biofilm biomass, consistent with experimental data, are established. The analysis reveals, for a biologically realistic limit, the existence of a bifurcation between non-active and active quorum sensing in the biofilm. The model also predicts that travelling waves of quorum sensing behaviour can occur within a certain time frame; while the travelling wave analysis reveals a range of possible travelling wave speeds, numerical solutions suggest that the minimum wave speed, determined by linearisation, is realised for a wide class of initial conditions.