Changes in neuromuscular structure and functions of human colon during ageing are region-dependent.

OBJECTIVE: To determine if human colonic neuromuscular functions decline with increasing age. DESIGN: Looking for non-specific changes in neuromuscular function, a standard burst of electrical field stimulation (EFS) was used to evoke neuronally mediated (cholinergic/nitrergic) contractions/relaxations in ex vivomuscle strips of human ascending and descending colon, aged 35-91 years (macroscopically normal tissue; 239 patients undergoing cancer resection). Then, to understand mechanisms of change, numbers and phenotype of myenteric neurons (30 306 neurons stained with different markers), densities of intramuscular nerve fibres (51 patients in total) and pathways involved in functional changes were systematically investigated (by immunohistochemistry and use of pharmacological tools) in elderly (≥70 years) and adult (35-60 years) groups. RESULTS: With increasing age, EFS was more likely to evoke muscle relaxation in ascending colon instead of contraction (linear regression: n=109, slope 0.49%±0.21%/year, 95% CI), generally uninfluenced by comorbidity or use of medications. Similar changes were absent in descending colon. In the elderly, overall numbers of myenteric and neuronal nitric oxide synthase-immunoreactive neurons and intramuscular nerve densities were unchanged in ascending and descending colon, compared with adults. In elderly ascending, not descending, colon numbers of cell bodies exhibiting choline acetyltransferase immunoreactivity increased compared with adults (5.0±0.6 vs 2.4±0.3 neurons/mm myenteric plexus, p=0.04). Cholinergically mediated contractions were smaller in elderly ascending colon compared with adults (2.1±0.4 and 4.1±1.1 g-tension/g-tissue during EFS; n=25/14; p=0.04); there were no changes in nitrergic function or in ability of the muscle to contract/relax. Similar changes were absent in descending colon. CONCLUSION: In ascending not descending colon, ageing impairs cholinergic function.

Remodelling of microRNAs in colorectal cancer by hypoxia alters metabolism profiles and 5-fluorouracil resistance.

Solid tumours have oxygen gradients and areas of near and almost total anoxia. Hypoxia reduces sensitivity to 5-fluorouracil (5-FU)-chemotherapy for colorectal cancer (CRC). MicroRNAs (miRNAs) are hypoxia sensors and were altered consistently in six CRC cell lines (colon cancer: DLD-1, HCT116 and HT29; rectal cancer: HT55, SW837 and VACO4S) maintained in hypoxia (1 and 0.2% oxygen) compared with normoxia (20.9%). CRC cell lines also showed altered amino acid metabolism in hypoxia and hypoxia-responsive miRNAs were predicted to target genes in four metabolism pathways: beta-alanine; valine, leucine, iso-leucine; aminoacyl-tRNA; and alanine, aspartate, glutamate. MiR-210 was increased in hypoxic areas of CRC tissues and hypoxia-responsive miR-21 and miR-30d, but not miR-210, were significantly increased in 5-FU resistant CRCs. Treatment with miR-21 and miR-30d antagonists sensitized hypoxic CRC cells to 5-FU. Our data highlight the complexity and tumour heterogeneity caused by hypoxia. MiR-210 as a hypoxic biomarker, and the targeting of miR-21 and miR-30d and/or the amino acid metabolism pathways may offer translational opportunities.

Ex vivo study of human visceral nociceptors.

OBJECTIVE: The development of effective visceral analgesics free of deleterious gut-specific side effects is a priority. We aimed to develop a reproducible methodology to study visceral nociception in human tissue that could aid future target identification and drug evaluation. DESIGN: Electrophysiological (single unit) responses of visceral afferents to mechanical (von Frey hair (VFH) and stretch) and chemical (bradykinin and ATP) stimuli were examined. Thus, serosal afferents (putative nociceptors) were used to investigate the effect of tegaserod, and transient receptor potential channel, vanilloid 4 (TRPV4) modulation on mechanical responses. RESULTS: Two distinct afferent fibre populations, serosal (n=23) and muscular (n=21), were distinguished based on their differences in sensitivity to VFH probing and tissue stretch. Serosal units displayed sensitivity to key algesic mediators, bradykinin (6/14 units tested) and ATP (4/10), consistent with a role as polymodal nociceptors, while muscular afferents are largely insensitive to bradykinin (0/11) and ATP (1/10). Serosal nociceptor mechanosensitivity was attenuated by tegaserod (-20.8±6.9%, n=6, p<0.05), a treatment for IBS, or application of HC067047 (-34.9±10.0%, n=7, p<0.05), a TRPV4 antagonist, highlighting the utility of the preparation to examine the mechanistic action of existing drugs or novel analgesics. Repeated application of bradykinin or ATP produced consistent afferent responses following desensitisation to the first application, demonstrating their utility as test stimuli to evaluate analgesic activity. CONCLUSIONS: Functionally distinct subpopulations of human visceral afferents can be demonstrated and could provide a platform technology to further study nociception in human tissue.

Interventions for promoting habitual exercise in people living with and beyond cancer.

BACKGROUND: This is an updated version of the original Cochrane Review published in the Cochrane Library 2013, Issue 9. Despite good evidence for the health benefits of regular exercise for people living with or beyond cancer, understanding how to promote sustainable exercise behaviour change in sedentary cancer survivors, particularly over the long term, is not as well understood. A large majority of people living with or recovering from cancer do not meet current exercise recommendations. Hence, reviewing the evidence on how to promote and sustain exercise behaviour is important for understanding the most effective strategies to ensure benefit in the patient population and identify research gaps. OBJECTIVES: To assess the effects of interventions designed to promote exercise behaviour in sedentary people living with and beyond cancer and to address the following secondary questions: Which interventions are most effective in improving aerobic fitness and skeletal muscle strength and endurance? Which interventions are most effective in improving exercise behaviour amongst patients with different cancers? Which interventions are most likely to promote long-term (12 months or longer) exercise behaviour? What frequency of contact with exercise professionals and/or healthcare professionals is associated with increased exercise behaviour? What theoretical basis is most often associated with better behavioural outcomes? What behaviour change techniques (BCTs) are most often associated with increased exercise behaviour? What adverse effects are attributed to different exercise interventions? SEARCH METHODS: We used standard methodological procedures expected by Cochrane. We updated our 2013 Cochrane systematic review by updating the searches of the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, Embase, AMED, CINAHL, PsycLIT/PsycINFO, SportDiscus and PEDro up to May 2018. We also searched the grey literature, trial registries, wrote to leading experts in the field and searched reference lists of included studies and other related recent systematic reviews. SELECTION CRITERIA: We included only randomised controlled trials (RCTs) that compared an exercise intervention with usual care or 'waiting list' control in sedentary people over the age of 18 with a homogenous primary cancer diagnosis. DATA COLLECTION AND ANALYSIS: In the update, review authors independently screened all titles and abstracts to identify studies that might meet the inclusion criteria, or that could not be safely excluded without assessment of the full text (e.g. when no abstract is available). We extracted data from all eligible papers with at least two members of the author team working independently (RT, LS and RG). We coded BCTs according to the CALO-RE taxonomy. Risk of bias was assessed using the Cochrane's tool for assessing risk of bias. When possible, and if appropriate, we performed a fixed-effect meta-analysis of study outcomes. If statistical heterogeneity was noted, a meta-analysis was performed using a random-effects model. For continuous outcomes (e.g. cardiorespiratory fitness), we extracted the final value, the standard deviation (SD) of the outcome of interest and the number of participants assessed at follow-up in each treatment arm, to estimate the standardised mean difference (SMD) between treatment arms. SMD was used, as investigators used heterogeneous methods to assess individual outcomes. If a meta-analysis was not possible or was not appropriate, we narratively synthesised studies. The quality of the evidence was assessed using the GRADE approach with the GRADE profiler. MAIN RESULTS: We included 23 studies in this review, involving a total of 1372 participants (an addition of 10 studies, 724 participants from the original review); 227 full texts were screened in the update and 377 full texts were screened in the original review leaving 35 publications from a total of 23 unique studies included in the review. We planned to include all cancers, but only studies involving breast, prostate, colorectal and lung cancer met the inclusion criteria. Thirteen studies incorporated a target level of exercise that could meet current recommendations for moderate-intensity aerobic exercise (i.e.150 minutes per week); or resistance exercise (i.e. strength training exercises at least two days per week).Adherence to exercise interventions, which is crucial for understanding treatment dose, is still reported inconsistently. Eight studies reported intervention adherence of 75% or greater to an exercise prescription that met current guidelines. These studies all included a component of supervision: in our analysis of BCTs we designated these studies as 'Tier 1 trials'. Six studies reported intervention adherence of 75% or greater to an aerobic exercise goal that was less than the current guideline recommendations: in our analysis of BCTs we designated these studies as 'Tier 2 trials.' A hierarchy of BCTs was developed for Tier 1 and Tier 2 trials, with programme goal setting, setting of graded tasks and instruction of how to perform behaviour being amongst the most frequent BCTs. Despite the uncertainty surrounding adherence in some of the included studies, interventions resulted in improvements in aerobic exercise tolerance at eight to 12 weeks (SMD 0.54, 95% CI 0.37 to 0.70; 604 participants, 10 studies; low-quality evidence) versus usual care. At six months, aerobic exercise tolerance was also improved (SMD 0.56, 95% CI 0.39 to 0.72; 591 participants; 7 studies; low-quality evidence). AUTHORS' CONCLUSIONS: Since the last version of this review, none of the new relevant studies have provided additional information to change the conclusions. We have found some improved understanding of how to encourage previously inactive cancer survivors to achieve international physical activity guidelines. Goal setting, setting of graded tasks and instruction of how to perform behaviour, feature in interventions that meet recommendations targets and report adherence of 75% or more. However, long-term follow-up data are still limited, and the majority of studies are in white women with breast cancer. There are still a considerable number of published studies with numerous and varied issues related to high risk of bias and poor reporting standards. Additionally, the meta-analyses were often graded as consisting of low- to very low-certainty evidence. A very small number of serious adverse effects were reported amongst the studies, providing reassurance exercise is safe for this population.

P2Y Receptors Sensitize Mouse and Human Colonic Nociceptors.

Activation of visceral nociceptors by inflammatory mediators contributes to visceral hypersensitivity and abdominal pain associated with many gastrointestinal disorders. Purine and pyrimidine nucleotides (e.g., ATP and UTP) are strongly implicated in this process following their release from epithelial cells during mechanical stimulation of the gut, and from immune cells during inflammation. Actions of ATP are mediated through both ionotropic P2X receptors and metabotropic P2Y receptors. P2X receptor activation causes excitation of visceral afferents; however, the impact of P2Y receptor activation on visceral afferents innervating the gut is unclear. Here we investigate the effects of stimulating P2Y receptors in isolated mouse colonic sensory neurons, and visceral nociceptor fibers in mouse and human nerve-gut preparations. Additionally, we investigate the role of Nav1.9 in mediating murine responses. The application of UTP (P2Y2 and P2Y4 agonist) sensitized colonic sensory neurons by increasing action potential firing to current injection and depolarizing the membrane potential. The application of ADP (P2Y1, P2Y12, and P2Y13 agonist) also increased action potential firing, an effect blocked by the selective P2Y1 receptor antagonist MRS2500. UTP or ADP stimulated afferents, including mouse and human visceral nociceptors, in nerve-gut preparations. P2Y1 and P2Y2 transcripts were detected in 80% and 56% of retrogradely labeled colonic neurons, respectively. Nav1.9 transcripts colocalized in 86% of P2Y1-positive and 100% of P2Y2-positive colonic neurons, consistent with reduced afferent fiber responses to UTP and ADP in Na(v)1.9(-/-) mice. These data demonstrate that P2Y receptor activation stimulates mouse and human visceral nociceptors, highlighting P2Y-dependent mechanisms in the generation of visceral pain during gastrointestinal disease.

Sacral nerve stimulation for faecal incontinence and constipation in adults.

BACKGROUND: Faecal incontinence (FI) and constipation are both socially-embarrassing and physically-disabling conditions that impair quality of life. For both, surgery may be required in a minority of people when more conservative measures fail. However, the invasiveness and irreversible nature of direct surgery on bowel and sphincter muscles, poor long-term outcomes and well-established compIications makes such procedures unappealing for these benign conditions. A less-invasive surgical option to treat faecal incontinence and constipation is direct, low-voltage stimulation of the sacral nerve roots, termed sacral nerve stimulation (SNS). SNS has become the first line surgical treatment for FI in people failing conservative therapies. Its value in the treatment of constipation is less clear. OBJECTIVES: To assess the effects of sacral nerve stimulation using implanted electrodes for the treatment of faecal incontinence and constipation in adults. SEARCH METHODS: We searched the Cochrane Incontinence Group Specialised Register, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE In-Process, ClinicalTrials.gov, the World Health Organization (WHO) ICTRP and handsearched journals and conference proceedings (searched 5 February 2015), EMBASE (1 January 1947 to 2015 Week 5), and the reference lists of retrieved relevant articles. SELECTION CRITERIA: All randomised or quasi-randomised trials assessing the effects of SNS for faecal incontinence or constipation in adults. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results, assessed the methodological quality of the included trials, and undertook data extraction. MAIN RESULTS: Six crossover trials and two parallel group trials were included.Six trials assessed the effects of SNS for FI. In the parallel group trial conducted by Tjandra, 53 participants with severe FI in the SNS group experienced fewer episodes of faecal incontinence compared to the control group who received optimal medical therapy (mean difference (MD) -5.20, 95% confidence interval (CI) -9.15 to -1.25 at 3 months; MD -6.30, 95% CI -10.34 to -2.26 at 12 months). Adverse events were reported in a proportion of participants: pain at implant site (6%), seroma (2%) and excessive tingling in the vaginal region (9%).In the parallel group trial carried out by Thin, 15 participants with FI in the SNS group experienced fewer episodes of FI compared with the percutaneous tibial nerve stimulation (PTNS) group (MD -3.00, 95% CI -6.61 to 0.61 at 3 months; MD -3.20, 95% CI -7.14 to 0.74 at 12 months). Adverse events were reported in three participants: mild ipsilateral leg pain during temporary testing (n = 1); and stimulator-site pain following insertion of neurostimulator (n = 2).In the crossover trial by Leroi 7 of 34 recruited participants were excluded from the crossover due mainly to complications or immediate device failure. Twenty-four of the remaining 27 participants while still blinded chose the period of stimulation they had preferred. Outcomes were reported separately for 19 participants who preferred the 'on' and five who preferred the 'off' period. For the group of 19, the median (range) episodes of faecal incontinence per week fell from 1.7 (0 to 9) during the 'off' period to 0.7 (0 to 5) during the 'on' period; for the group of five, however, the median (range) rose from 1.7 (0 to 11) during the 'off' period compared with 3.7 (0 to 11) during the 'on' period. Four of 27 participants experienced an adverse event resulting in removal of the stimulator.In the crossover trial by Sørensen and colleagues, participants did not experience any FI episodes in either the one-week 'on' or 'off' periods.In the crossover trial by Vaizey, participants reported an average of six, and one, episodes of faecal incontinence per week during the 'off' and 'on' periods respectively in two participants with FI. Neither study reported adverse events.In the crossover trial by Kahlke, 14 participants with FI experienced significantly lower episodes of FI per week during the stimulator 'on' (1 (SD, 1.7)) compared with the 'off' period (8.4 (SD, 8.7)). Adverse events reported include: haematoma formation (n = 3); misplacement of tined lead (1); and pain at stimulator site (n = 1).Two trials assessed SNS for constipation. In the Kenefick trial, the two participants experienced an average of two bowel movements per week during the 'off' crossover period, compared with five during the 'on' period. Abdominal pain and bloating occurred 79% of the time during the 'off' period compared with 33% during the 'on' period. No adverse events occurred. In contrast, in the trial by Dinning with 59 participants, SNS did not improve frequency of bowel movements and 73 adverse events were reported, which included pain at site of the implanted pulse generator (32), wound infection (12), and urological (17) events. AUTHORS' CONCLUSIONS: The limited evidence from the included trials suggests that SNS can improve continence in a proportion of patients with faecal incontinence. However, SNS did not improve symptoms in patients with constipation. In addition, adverse events occurred in some patients where these were reported. Rigorous high quality randomised trials are needed to allow the effects of SNS for these conditions to be assessed with more certainty.

A review of modeling and control of remote-controlled capsule endoscopes.

INTRODUCTION: The significance of this review lies in addressing the limitations of passive locomotion in capsule endoscopes, hindering their widespread use in medical applications. The research focuses on evaluating existing miniature in vivo remote-controlled capsule endoscopes, examining their locomotion designs, and working theories to pave the way for overcoming challenges and enhancing their applicability in diagnostic and treatment settings. AREAS COVERED: This paper explores control methods and dynamic system modeling in the context of self-propelled remote-controlled capsule endoscopes with a two-mass arrangement. The literature search, conducted at Queen Mary University of London Library from 2000 to 2022, utilized a systematic approach starting with the broad keyword 'Capsule Endoscope' and progressively narrowing down to specific aspects such as 'Capsule Endoscope Control' and 'Self-propelled Capsule Endoscope' using various criteria. EXPERT OPINION: Efficiently driving and controlling remote-controlled capsule endoscopes have the potential to overcome the current limitations in medical technology, offering a viable solution for diagnosing and treating gastrointestinal diseases. Successful control of the remote-controlled capsule endoscope, as demonstrated in this review paper, will lead to a step change in medical engineering, establishing the remote-controlled capsule endoscope as a swift standard in the field.

Study protocol for a pragmatic randomised controlled trial of comparing enhanced acceptance and commitment therapy plus (+) added to usual aftercare versus usual aftercare only, in patients living with or beyond cancer: SUrvivors' Rehabilitation Evaluation after CANcer (SURECAN) trial.

BACKGROUND: Two million people in the UK are living with or beyond cancer and a third of them report poor quality of life (QoL) due to problems such as fatigue, fear of cancer recurrence, and concerns about returning to work. We aimed to develop and evaluate an intervention based on acceptance and commitment therapy (ACT), suited to address the concerns of cancer survivors and in improving their QoL. We also recognise the importance of exercise and vocational activity on QoL and therefore will integrate options for physical activity and return to work/vocational support, thus ACT Plus (+). METHODS: We will conduct a multi-centre, pragmatic, theory driven, randomised controlled trial. We will assess whether ACT+ including usual aftercare (intervention) is more effective and cost-effective than usual aftercare alone (control). The primary outcome is QoL of participants living with or beyond cancer measured using the Functional Assessment of Cancer Therapy: General scale (FACT-G) at 52 weeks. We will recruit 344 participants identified from secondary care sites who have completed hospital-based treatment for cancer with curative intent, with low QoL (determined by the FACT-G) and randomise with an allocation ratio of 1:1 to the intervention or control. The intervention (ACT+) will be delivered by NHS Talking Therapies, specialist services, and cancer charities. The intervention consists of up to eight sessions at weekly or fortnightly intervals using different modalities of delivery to suit individual needs, i.e. face-to-face sessions, over the phone or skype. DISCUSSION: To date, there have been no robust trials reporting both clinical and cost-effectiveness of an ACT based intervention for people with low QoL after curative cancer treatment in the UK. We will provide high quality evidence of the effectiveness and cost-effectiveness of adding ACT+ to usual aftercare provided by the NHS. If shown to be effective and cost-effective then commissioners, providers and cancer charities will know how to improve QoL in cancer survivors and their families. TRIAL REGISTRATION: ISRCTN: ISRCTN67900293 . Registered on 09 December 2019. All items from the World Health Organization Trial Registration Data Set for this protocol can be found in Additional file 2 Table S1.

Analysis of colorectal cancers in British Bangladeshi identifies early onset, frequent mucinous histotype and a high prevalence of RBFOX1 deletion.

BACKGROUND: Prevalence of colorectal cancer (CRC) in the British Bangladeshi population (BAN) is low compared to British Caucasians (CAU). Genetic background may influence mutations and disease features. METHODS: We characterized the clinicopathological features of BAN CRCs and interrogated their genomes using mutation profiling and high-density single nucleotide polymorphism (SNP) arrays and compared findings to CAU CRCs. RESULTS: Age of onset of BAN CRC was significantly lower than for CAU patients (p=3.0 x 10-5) and this difference was not due to Lynch syndrome or the polyposis syndromes. KRAS mutations in BAN microsatellite stable (MSS) CRCs were comparatively rare (5.4%) compared to CAU MSS CRCs (25%; p=0.04), which correlates with the high percentage of mucinous histotype observed (31%) in the BAN samples. No BRAF mutations was seen in our BAN MSS CRCs (CAU CRCs, 12%; p=0.08). Array data revealed similar patterns of gains (chromosome 7 and 8q), losses (8p, 17p and 18q) and LOH (4q, 17p and 18q) in BAN and CAU CRCs. A small deletion on chromosome 16p13.2 involving the alternative splicing factor RBFOX1 only was found in significantly more BAN (50%) than CAU CRCs (15%) cases (p=0.04). Focal deletions targeting the 5' end of the gene were also identified. Novel RBFOX1 mutations were found in CRC cell lines and tumours; mRNA and protein expression was reduced in tumours. CONCLUSIONS: KRAS mutations were rare in BAN MSS CRC and a mucinous histotype common. Loss of RBFOX1 may explain the anomalous splicing activity associated with CRC.

Interventions for promoting habitual exercise in people living with and beyond cancer.

BACKGROUND: The beneficial effects of regular exercise for people living with or beyond cancer are becoming apparent. However, how to promote exercise behaviour in sedentary cancer cohorts is not as well understood. A large majority of people living with or recovering from cancer do not meet exercise recommendations. Hence, reviewing the evidence on how to promote and sustain exercise behaviour is important. OBJECTIVES: To assess the effects of interventions to promote exercise behaviour in sedentary people living with and beyond cancer and to address the following questions: Which interventions are most effective in improving aerobic fitness and skeletal muscle strength and endurance? What adverse effects are attributed to different exercise interventions? Which interventions are most effective in improving exercise behaviour amongst patients with different cancers? Which interventions are most likely to promote long-term (12 months or longer) exercise behaviour? What frequency of contact with exercise professionals is associated with increased exercise behaviour? What theoretical basis is most often associated with increased exercise behaviour? What behaviour change techniques are most often associated with increased exercise behaviour? SEARCH METHODS: We searched the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 8, 2012), MEDLINE, EMBASE, AMED, CINAHL, PsycLIT/PsycINFO, SportDiscus and PEDro from inception to August 2012. We also searched the grey literature, wrote to leading experts in the field, wrote to charities and searched reference lists of other recent systematic reviews. SELECTION CRITERIA: We included only randomised controlled trials (RCTs) that compared an exercise intervention with a usual care approach in sedentary people over the age of 18 with a homogenous primary cancer diagnosis. DATA COLLECTION AND ANALYSIS: Two review authors working independently (LB and KH) screened all titles and abstracts to identify studies that might meet the inclusion criteria, or that cannot be safely excluded without assessment of the full text (e.g. when no abstract is available). All eligible papers were formally abstracted by at least two members of the review author team working independently (LB and KH) and using the data collection form. When possible, and if appropriate, we performed a fixed-effect meta-analysis of study outcomes. For continuous outcomes (e.g. cardiorespiratory fitness), we extracted the final value, the standard deviation of the outcome of interest and the number of participants assessed at follow-up in each treatment arm, to estimate standardised mean difference (SMD) between treatment arms. SMD was used, as investigators used heterogeneous methods to assess individual outcomes. If a meta-analysis was not possible or was not appropriate, we synthesised studies as a narrative. MAIN RESULTS: Fourteen trials were included in this review, involving a total of 648 participants. Only studies involving breast, prostate or colorectal cancer were identified as eligible. Just six trials incorporated a target level of exercise that could meet current recommendations. Only three trials were identified that attempted to objectively validate independent exercise behaviour with accelerometers or heart rate monitoring. Adherence to exercise interventions, which is crucial for understanding treatment dose, is often poorly reported. It is important to note that the fundamental metrics of exercise behaviour (i.e. frequency, intensity and duration, repetitions, sets and intensity of resistance training), although easy to devise and report, are seldom included in published clinical trials.None of the included trials reported that 75% or greater adherence (the stated primary outcome for this review) of the intervention group met current aerobic exercise recommendations at any given follow-up. Just two trials reported six weeks of resistance exercise behaviour that would meet the guideline recommendations. However, three trials reported adherence of 75% or greater to an aerobic exercise goal that was less than the current guideline recommendation of 150 minutes per week. All three incorporated both supervised and independent exercise components as part of the intervention, and none placed restrictions on the control group in terms of exercise behaviour. These three trials shared programme set goals and the following behaviour change techniques: generalisation of a target behaviour; prompting of self-monitoring of behaviour; and prompting of practise. Despite the uncertainty surrounding adherence in many of the included trials, interventions caused improvements in aerobic exercise tolerance at 8 to 12 weeks (from 7 studies, SMD 0.73, 95% confidence interval (CI) 0.51 to 0.95) in intervention participants compared with controls. At six months, aerobic exercise tolerance was also improved (from 5 studies, SMD 0.70, 95% CI 0.45 to 0.94), but it should be noted that four of the five trials used in this analysis had a high risk of bias, hence caution is warranted in interpretation of results. Attrition over the course of these interventions is typically low (median 6%). AUTHORS' CONCLUSIONS: Interventions to promote exercise in cancer survivors who report better levels of adherence share some common behaviour change techniques. These involve setting programme goals, prompting practise and self-monitoring and encouraging participants to attempt to generalise behaviours learned in supervised exercise environments to other, non-supervised contexts. However, expecting most sedentary survivors to achieve current guideline recommendations of at least 150 minutes per week of aerobic exercise is likely to be unrealistic. As with all well-designed exercise programmes in any context, prescriptions should be designed around individual capabilities, and frequency, duration and intensity or sets, repetitions, intensity or resistance training should be generated on this basis.

Anterior resection syndrome.

Up to 80% of patients with rectal cancer undergo sphincter-preserving surgery. It is widely accepted that up to 90% of such patients will subsequently have a change in bowel habit, ranging from increased bowel frequency to faecal incontinence or evacuatory dysfunction. This wide spectrum of symptoms after resection and reconstruction of the rectum has been termed anterior resection syndrome. Currently, no precise definition or causal mechanisms have been established. This disordered bowel function has a substantial negative effect on quality of life. Previous reviews have mainly focused on different colonic reconstructive configurations and their comparative effects on daily function and quality of life. The present Review explores the potential mechanisms underlying disturbed functions, as well as current, novel, and future treatment options.

Introducing a structured daily multidisciplinary board round to safely enhance surgical ward patient flow in the bed shortage era: a quality improvement research report.

Hospital bed shortage is a worldwide concern. Their unavailability has caused elective surgery cancellations at our hospital peaking in spring 2016 at over 50%. This is often due to difficult patient step-down from intensive care (ICU) and high-dependency units (HDU). In our general/digestive surgery service admitting approximately 1000 patients yearly, ward rounds were run on a consultant firm basis.We report quality improvement (ISRCTN13976096) after we introduced a structured daily multidisciplinary board round framework (SAFER Surgery R2G) adapted from the 'SAFER patient flow bundle' and the 'Red to Green days' approaches to enhance flow. We compare 2016-2017, when our framework was applied for 12 months.We used a Plan-Do-Study-Act (PDSA) methodology. Our intervention consisted in (1) systematically communicating the key care plan after the afternoon ward rounds to the nurse in charge; (2) 30' 10:00 hours Monday-to-Friday multidisciplinary board rounds, attended daily by the senior team and weekly by hospital and site managers, revising the key care plan to aim at safe, early discharges, assessing the appropriateness of each inpatient day and tackling any cause of delay. We measured patient flow by average length of stay (LOS), ICU/HDU step-downs and operation cancellations count, monitoring safety through early 30-day readmissions. Compliance was assessed by board round attendance and staff satisfaction rate surveys.After 12 months of intervention (PDSA-1-2, N=1032), compared with baseline (PDSA-0, N=954) average LOS significantly decreased from 7.2 (8.9) to 6.3 (7.4) days (p=0.003); ICU/HDU bed step-down flow increased by 9.3% from 345 to 375 (p=0.197), surgery cancellations dropped from 38 to 15 (p=0.100). 30-day readmissions increased from 0.9% (N=9) to 1.3% (N=14)(p=0.390). Average cross-specialty attendance was 80%. Satisfaction rates were >75%, regarding enhanced teamwork and faster decisions.The SAFER Surgery R2G framework has increased patient flow in the context of an enhanced multidisciplinary approach, requiring senior staff commitment to remain sustainable.

Percutaneous tibial nerve stimulation for fecal incontinence: a video demonstration.

BACKGROUND: Fecal incontinence is an increasingly common condition with significant negative impact on quality on life and health care resources. It frequently presents a therapeutic challenge to clinicians. Emerging evidence suggests that percutaneous tibial nerve stimulation is an effective treatment for fecal incontinence with the added benefit of being minimally invasive and cost effective. METHOD: Pursuant to the preliminary report of our early experience of percutaneous tibial nerve stimulation in patients with fecal incontinence published in this journal in 2010, in this dynamic article, we now describe and demonstrate the actual technique that can be performed in a nurse-led clinic or outpatient or community setting. CONCLUSION: Percutaneous tibial nerve stimulation is a technically simple procedure that can potentially be performed in an outpatient or community setting. The overall early success rate of 68% following its use reported by our unit compares favorably with the success rate following other forms of neuromodulation, including sacral nerve stimulation. When completed, our long-term outcome data will provide further information on the efficacy of tibial nerve stimulation in a larger cohort of patients (n > 100). Future studies, including our currently planned randomized controlled trial of percutaneous tibial nerve stimulation vs sham stimulation, will provide controlled efficacy data and may provide information on its exact mechanism of action.

Grey-box modelling and fuzzy logic control of a Leader-Follower robot manipulator system: A hybrid Grey Wolf-Whale Optimisation approach.

This study presents the development of a grey-box modelling approach and fuzzy logic control for real time trajectory control of an experimental four degree-of-freedom Leader-Follower​ Robot (LFR) manipulator system using a hybrid optimisation algorithm, known as Grey Wolf Optimiser (GWO) - Whale Optimisation Algorithm (WOA). The approach has advantages in achieving an accurate model of the LFR manipulator system, and together with a better trajectory tracking performance. In the first instance, the white box model is formed by modelling the dynamics of the follower manipulator using the Euler-Lagrange formulation. This white-box model is then improved upon by re-tuning the model's parameters using GWO-WOA and experimental data from the real LFR manipulator system, thus forming the grey-box model. A minimum improvement of 73.9% is achieved by the grey-box model in comparison to the white-box model. In the latter part of this investigation, the developed grey-box model is used for the design, tuning and real-time implementation of a fuzzy PD＋I controller on the experimental LFR manipulator system. A 78% improvement in the total mean squared error is realised after tuning the membership functions of the fuzzy logic controller using GWO-WOA. Experimental results show that the approach significantly improves the trajectory tracking performance of the LFR manipulator system in terms of mean squared error, steady state error and time delay.

Splenic parenchymal complications in pancreatitis.

CONTEXT: The close proximity of splenic hilum to the tail of pancreas makes it vulnerable to complications in both acute and chronic pancreatitis. In this article, we examine the clinical course of these potentially fatal complications. CASE REPORTS: Citing three clinical cases, we present the spectrum of splenic complications in pancreatitis and explore the anatomical causal relationships and pathological basis of such complications. A literature review was carried out to inform on the incidence, morbidity and mortality rates, and clinical course especially diagnostic and management options for these patients. The spectrum of splenic complications in pancreatitis is wide ranging from pseudo cysts to haematomas, haemorrhages, infarctions and life threatening splenic rupture. Although a contrast enhanced helical CT scan is the investigation of choice a high index of clinical suspicion is essential in their early identification. Splenic complications in pancreatitis incur a high morbidity (79%) and a significant mortality (8%). CONCLUSIONS: Splenic parenchymal complications in pancreatitis are an increasingly recognised entity and should be suspected in patients with inflammation and or necrosis involving the tail of pancreas. Conservative management is feasible with close radiological monitoring for most patients in a tertiary referral centre with appropriate expertise and surgery may be reserved for haemodynamically unstable patients.

In silico and in vivo investigations using an endocavitary photoplethysmography sensor for tissue viability monitoring.

SIGNIFICANCE: Colorectal cancer is one of the major causes of cancer-related deaths worldwide. Surgical removal of the cancerous growth is the primary treatment for this disease. A colorectal cancer surgery, however, is often unsuccessful due to the anastomotic failure that may occur following the surgical incision. Prevention of an anastomotic failure requires continuous monitoring of intestinal tissue viability during and after colorectal surgery. To date, no clinical technology exists for the dynamic and continuous monitoring of the intestinal perfusion. AIM: A dual-wavelength indwelling bowel photoplethysmography (PPG) sensor for the continuous monitoring of intestinal viability was proposed and characterized through a set of in silico and in vivo investigations. APPROACH: The in silico investigation was based on a Monte Carlo model that was executed to quantify the variables such as penetration depth and detected intensity with respect to the sensor-tissue separations and tissue perfusion. Utilizing the simulated information, an indwelling reflectance PPG sensor was designed and tested on 20 healthy volunteers. Two sets of in vivo studies were performed using the driving current intensities 20 and 40 mA for a comparative analysis, using buccal tissue as a proxy tissue-site. RESULTS: Both simulated and experimental results showed the efficacy of the sensor to acquire good signals through the "contact" to a "noncontact" separation of 5 mm. A very slow wavelength-dependent variation was shown in the detected intensity at the normal and hypoxic states of the tissue, whereas a decay in the intensity was found with the increasing submucosal-blood volume. The simulated detected-to-incident-photon-ratio and the experimental signal-to-noise ratio exhibited strong positive correlations, with the Pearson product-moment correlation coefficient R ranging between 0.65 and 0.87. CONCLUSIONS: The detailed feasibility analysis presented will lead to clinical trials utilizing the proposed sensor.

Diagnostic accuracy of whole-body MRI versus standard imaging pathways for metastatic disease in newly diagnosed colorectal cancer: the prospective Streamline C trial.

BACKGROUND: Whole-body MRI (WB-MRI) could be an alternative to multimodality staging of colorectal cancer, but its diagnostic accuracy, effect on staging times, number of tests needed, cost, and effect on treatment decisions are unknown. We aimed to prospectively compare the diagnostic accuracy and efficiency of WB-MRI-based staging pathways with standard pathways in colorectal cancer. METHODS: The Streamline C trial was a prospective, multicentre trial done in 16 hospitals in England. Eligible patients were 18 years or older, with newly diagnosed colorectal cancer. Exclusion criteria were severe systemic disease, pregnancy, contraindications to MRI, or polyp cancer. Patients underwent WB-MRI, the result of which was withheld until standard staging investigations were complete and the first treatment decision made. The multidisciplinary team recorded its treatment decision based on standard investigations, then on the WB-MRI staging pathway (WB-MRI plus additional tests generated), and finally on all tests. The primary outcome was difference in per-patient sensitivity for metastases between standard and WB-MRI staging pathways against a consensus reference standard at 12 months, in the per-protocol population. Secondary outcomes were difference in per-patient specificity for metastatic disease detection between standard and WB-MRI staging pathways, differences in treatment decisions, staging efficiency (time taken, test number, and costs), and per-organ sensitivity and specificity for metastases and per-patient agreement for local T and N stage. This trial is registered with the International Standard Randomised Controlled Trial registry, number ISRCTN43958015, and is complete. FINDINGS: Between March 26, 2013, and Aug 19, 2016, 1020 patients were screened for eligibility. 370 patients were recruited, 299 of whom completed the trial; 68 (23%) had metastasis at baseline. Pathway sensitivity was 67% (95% CI 56 to 78) for WB-MRI and 63% (51 to 74) for standard pathways, a difference in sensitivity of 4% (-5 to 13, p=0·51). No adverse events related to imaging were reported. Specificity did not differ between WB-MRI (95% [95% CI 92-97]) and standard pathways (93% [90-96], p=0·48). Agreement with the multidisciplinary team's final treatment decision was 96% for WB-MRI and 95% for the standard pathway. Time to complete staging was shorter for WB-MRI (median, 8 days [IQR 6-9]) than for the standard pathway (13 days [11-15]); a 5-day (3-7) difference. WB-MRI required fewer tests (median, one [95% CI 1 to 1]) than did standard pathways (two [2 to 2]), a difference of one (1 to 1). Mean per-patient staging costs were £216 (95% CI 211-221) for WB-MRI and £285 (260-310) for standard pathways. INTERPRETATION: WB-MRI staging pathways have similar accuracy to standard pathways and reduce the number of tests needed, staging time, and cost. FUNDING: UK National Institute for Health Research.

The effects of optical sensor-tissue separation in endocavitary photoplethysmography.

OBJECTIVE: Intestinal anastomotic failure that occurs mainly due to ischaemia is a serious risk in colorectal cancer patients undergoing surgery. Surgeons continue to rely on subjective methods such as visual inspection to assess intestinal viability during surgery and there are no clinical tools to directly monitor viability postoperatively. A dual-wavelength reflectance optical sensor has been developed for continuous and dynamic monitoring of intestinal viability via the intestinal lumen. Maintaining direct contact between the sensor and the inner intestinal wall can be difficult in an intraluminal design, therefore impacting on signal acquisition and quality. This paper investigates the effect of direct contact versus variable distances between the sensor and the tissue surface of the buccal mucosa as a surrogate. APPROACH: The in vivo study involved 20 healthy volunteers to measure the effect of optical sensor-tissue distances on the ability to acquire photoplethysmography signals and their quality. Signals were acquired from the buccal mucosa at five optical sensor-tissue distances. MAIN RESULTS: Distances between 0 mm (contact) to 5 mm were the most optimal, producing signals of high quality and signal-to-noise ratio, resulting in reliable estimations of the blood oxygen saturation. Distances exceeding 5 mm compromised the acquired signals, and were of poor quality, thereby unreliably estimating the blood oxygen saturation. SIGNIFICANCE: The developed optical sensor proved to be reliable for acquiring photoplethysmography signals for cases where distances between the optical sensor-tissue may arise during the assessment of intraluminal intestinal viability.

Development of an intraluminal intestinal photoplethysmography sensor.

Intestinal ischemia is a serious medical condition and can lead to life threatening sepsis. Currently, there are no reliable techniques available for directly monitoring intestinal viability for prolonged periods of time, and intraoperatively, the majority of the surgeons still rely on subjective methods, such as visual inspection to assess viability of the intestine. The development of an intraluminal optical sensor for monitoring intestinal viability is being proposed. The sensor will continuously monitor changes in blood volume and oxygen saturation. The developed reflectance photoplethysmography/pulse oximetry sensor comprises of two emitters (red and infrared) and a photodiode. A photoplethysmography processing and data acquisition system was also utilized. The prototype sensor was evaluated in a pilot study in the buccal mucosa of 12 healthy volunteers, given the locations similarity to the intestinal mucosa and its easy accessibility. Good quality photoplethysmography signals with high signal-to-noise ratio were acquired from the buccal mucosa in all the volunteers. Preliminary blood oxygen saturation values from the intraluminal sensor were in broad agreement with the standard finger pulse oximeter probes.

Methylation of HPV and a tumor suppressor gene reveals anal cancer and precursor lesions.

We studied DNA methylation patterns of human papillomavirus (HPV) and tumor suppressor gene EPB41L3 in 148 anal and perianal biopsies to determine whether high levels of methylation would be associated with anal intraepithelial neoplasia (AIN). The most prevalent HPV type was HPV16, detected in 54% of the 30 benign biopsies, 33% of the 43 low-grade AIN (lgAIN), 82% of the 59 high grade AIN (hgAIN) and 4 of the 5 anal cancers. A methylation score was developed (0.561*HPV16me+0.439*EPB41L3) which had increasing values with severity of disease: the mean was 8.1% in benign, 13.2% in lgAIN, 22.3% in hgAIN and 49.3% in cancers (p < 0.0001). The methylation score as a triage classifier at a cut-off of 8.8 gave a sensitivity of 90.6% (95% CI: 82.8, 96.9), specificity of 50.7% (95% CI: 39.7, 61.6) and area under the curve of 0.82 (95% CI: 0.75-0.89) for separating hgAIN and cancer from benign and lgAIN biopsies. We conclude that methylation of HPV16 and EPB41L3 show highly significant association with increasing severity of AIN and cancer and may be useful as biomarkers in anal disease.