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Objective Small molecule inhibitors able to bind to gp120 and prevent CD4-induced HIV-1 envelope conformational change provide an important class of inhibitors. Currently, only Fostemsavir is approved for HAART, which makes this class of inhibitors attractive candidates for prevention. We assessed the activity of DS003 (BMS-599793), an analogue of BMS-378806, in different mucosal tissues and elucidated its mechanism of action. Design Pre-clinical analysis was performed with human mucosal tissue models as surrogates of in vivo activity. Methods Antiviral efficacy of DS003 was assessed in mucosal tissue explants (ecto-cervical, penile and colorectal) and in trans-infection models (co-cultures of dendritic or mucosal migratory cells with CD4+T cells) with several dosing times (2 h, 24 h and sustained) and in combination with a fusion inhibitor. Binding of DS003 to gp120 was assessed by flow cytometry and bio-layer interferometry and further probed in competitive studies using soluble CD4 (sCD4) and an anti-CD4 induced antibody, 17b. Results In all models, the inhibitory activity of DS003 was increased with longer periods of exposure and by combination with a fusion inhibitor. Pre-exposure to sCD4 impeded DS003 binding to viral envelope (Env). In contrast, DS003 did not impact subsequent binding of sCD4. Furthermore, sCD4-induced epitope exposure as assessed by 17b binding was significantly reduced in the presence of DS003. Conclusion DS003 inhibits HIV-1 infection by binding to or near the CD4 binding site of gp120, preventing CD4-induced conformational change essential for viral fusion. These data highlight the potential of DS003 for development as a pre-exposure prophylaxis candidate.

Background Inflammatory bowel disease [IBD] is a risk factor for colorectal cancer [CRC]. The aim of this study is to determine whether stage at diagnosis and survival differ between sporadic, ulcerative colitis [UC]- and Crohn’s disease [CD]-related CRC. Methods The English National Cancer Registry [NCIN], Hospital Episode Statistics [HES] and Office for National Statistics [ONS] datasets between 2000 and 2010 were linked, providing data on comorbidities, stage and date of death. A logistic regression model determined whether IBD was associated with an early [I/II] or late [III/IV] cancer. Cox regression analysis was used to examine survival differences between sporadic, UC- and CD-related cancers. Results A total of 234 009 patients with CRC were included, of whom 985 [0.4%] and 1922 [0.8%] had CD and UC, respectively. UC, but not CD, was associated with an earlier stage compared with sporadic cancers (odds ratio [OR] 0.88, 95% confidence interval [CI] 0.79 to 0.98, p = 0.02). CD had a significantly worse survival compared with sporadic patients for stage II [HR = 1.71, CI 1.26 to 2.31 p Conclusions Patients with IBD are diagnosed at an earlier stage but tend to have a worse survival compared with sporadic cases of CRC, in particular for nodal disease [stage III].Specifically, patients with CD-related CRC appear to fare worst in terms of survival compared with both the sporadic and UC groups.

Non-human primates (NHP) are widely used for the pre-clinical assessment of antiretrovirals (ARVs) for HIV treatment and prevention. However, the utility of these models is questionable given the differences in ARV pharmacology between humans and macaques. Here, we report a model based on

Background Obesity is among the fastest growing global health threats. Among the management options for patients with obesity, bariatric surgery is a rapidly evolving field that has been shown to result in reliable weight loss. The association between obesity and atrial fibrillation has been well established; but the long-term impact of bariatric surgery on atrial fibrillation has not yet been explored. This study aims to assess the long-term incidence and resolution rates of atrial fibrillation in patients who undergo bariatric surgery in the United Kingdom. Methods The primary and secondary electronic healthcare records included in the Clinical Practice Research Datalink (CPRD) database were used to conduct a nation-wide cohort study. The 3,077 patients in the CPRD with no previous history of atrial fibrillation who had undergone bariatric surgery, were matched to 3,077 age, gender and BMI matched controls, also with no past history of atrial fibrillation. The primary endpoint was the incidence of any type of atrial fibrillation by clinical coded diagnosis. The secondary endpoint was a coded resolution of atrial fibrillation among the patients who received a diagnosis during follow-up. Results Patients were followed up for a median of 12.3 years; the median age was 50 years and median BMI was 43 kg/m2. Patients who had undergone bariatric surgery did not have a significantly lower occurrence of the primary outcome of incident AF (adjusted HR 0.720; 95% CI 0.492–1.054; p=0.091). However, secondary analysis among patients with AF identified higher rates of resolution among patients who had undergone bariatric surgery (p=0.049). Conclusion The results of this nationwide cohort study identify an association between bariatric surgery and higher rates of AF resolution; and describe a non-significant but biologically plausible trend towards lower rates of incident AF in patients who underwent bariatric surgery.

Objective The aim of this study is to evaluate the effect of bariatric surgery on long-term risk of VTEs in a large cohort of patients with obesity. Background Obesity is a well-established risk factor for VTEs, such as pulmonary embolism and deep vein thrombosis. The rising prevalence of obesity and its associated co-morbidities, including VTE, represent a growing public health issue. Methods A nested, retrospective matched cohort study was designed and conducted on prospectively collected national electronic healthcare records data from the Clinical Practice Research Datalink. Eight thousand, one hundred twelve patients were included in the study: the 4056 patients on the database who had undergone bariatric surgery, and equal numbers of age, sex, and body mass index matched controls. The primary endpoint was the occurrence of VTEs; secondary endpoints were the occurrence of deep vein thrombosis alone, pulmonary embolism alone. Results Patients were followed up for a median of 10.7 years. The bariatric surgery cohort had a significantly lower occurrence of the primary outcome [hazard ratio (HR) 0.601; 95% confidence interval (CI) 0.430-0.841, P = 0.003]; mainly driven by a reduction in deep vein thrombosis (HR 0.523; 95% CI 0.349-0.783, P = 0·002) and not in pulmonary embolism (HR 0.882; 95% CI 0.511-1.521, P = 0.651). Conclusions The results of this nation-wide study set out to characterize the impact of bariatric surgery on long-term risk of thromboembolic events outline a significant reduction in thromboembolic events, driven by a reduction in deep vein thrombosis.

Non-human primates (NHP) are widely used for the pre-clinical assessment of antiretrovirals (ARVs) for HIV treatment and prevention. However, the utility of these models is questionable given the differences in ARV pharmacology between humans and macaques. Here, we report a model based on ex vivo ARV exposure and the challenge of mucosal tissue explants to define pharmacological differences between NHPs and humans. For colorectal and cervicovaginal explants in both species, high concentrations of tenofovir (TFV) and maraviroc were predictive of anti-viral efficacy. However, their combinations resulted in increased inhibitory potency in NHP when compared to human explants. In NHPs, higher TFV concentrations were measured in colorectal versus cervicovaginal explants (p = 0.042). In humans, this relationship was inverted with lower levels in colorectal tissue (p = 0.027). TFV-resistance caused greater loss of viral fitness for HIV-1 than SIV. This, tissue explants provide an important bridge to refine and appropriately interpret NHP studies. This work was supported by an NIH R21 award AI094515 and by the European Commission’s seventh Framework "Combined Highly Active Retroviral Microbicides" (CHAARM) (242135). This work was partially supported by project PI19CIII/00004 and the Spanish AIDS Research Network (RIS) funded by Instituto de Salud Carlos III and co-funded by European Development Fund (ERDF) "A way to build Europe" (project RD16CIII/0002/0001). Sí

Author(s): Crakes, Katti R; Herrera, Carolina; Morgan, Jessica L; Olstad, Katie; Hessell, Ann J; Ziprin, Paul; LiWang, Patricia J; Dandekar, Satya | Abstract: IntroductionThe majority of new HIV infections occur through mucosal transmission. The availability of readily applicable and accessible platforms for anti-retroviral (ARV) delivery is critical for the prevention of HIV acquisition through sexual transmission in both women and men. There is a compelling need for developing new topical delivery systems that have advantages over the pills, gels and rings, which currently fail to guarantee protection against mucosal viral transmission in vulnerable populations due to lack of user compliance. The silk fibroin (SF) platform offers another option that may be better suited to individual circumstances and preferences to increase efficacy through user compliance. The objective of this study was to test safety and efficacy of SF for anti-HIV drug delivery to mucosal sites and for viral prevention.MethodsWe formulated a potent HIV inhibitor Griffithsin (Grft) in a mucoadhesive silk fibroin (SF) drug delivery platform and tested the application in a non-human primate model in vivo and a pre-clinical human cervical and colorectal tissue explant model. Both vaginal and rectal compartments were assessed in rhesus macaques (Mucaca mulatta) that received SF (nn=n4), no SF (nn=n7) and SF-Grft (nn=n11). In this study, we evaluated the composition of local microbiota, inflammatory cytokine production, histopathological changes in the vaginal and rectal compartments and mucosal protection after ex vivo SHIV challenge.ResultsEffective Grft release and retention in mucosal tissues from the SF-Grft platform resulted in protection against HIV in human cervical and colorectal tissue as well as against SHIV challenge in both rhesus macaque vaginal and rectal tissues. Mucoadhesion of SF-Grft inserts did not cause any inflammatory responses or changes in local microbiota.ConclusionsWe demonstrated that in vivo delivery of SF-Grft in rhesus macaques fully protects against SHIV challenge ex vivo after two hours of application and is safe to use in both the vaginal and rectal compartments. Our study provides support for the development of silk fibroin as a highly promising, user-friendly HIV prevention modality to address the global disparity in HIV infection.

Patient selection for critical care admission must balance patient safety with optimal resource allocation. This study aimed to determine the relationship between critical care admission, and postoperative mortality after abdominal surgery.This prespecified secondary analysis of a multicentre, prospective, observational study included consecutive patients enrolled in the DISCOVER study from UK and Republic of Ireland undergoing major gastrointestinal and liver surgery between October and December 2014. The primary outcome was 30-day mortality. Multivariate logistic regression was used to explore associations between critical care admission (planned and unplanned) and mortality, and inter-centre variation in critical care admission after emergency laparotomy.Of 4529 patients included, 37.8% (n=1713) underwent planned critical care admissions from theatre. Some 3.1% (n=86/2816) admitted to ward-level care subsequently underwent unplanned critical care admission. Overall 30-day mortality was 2.9% (n=133/4519), and the risk-adjusted association between 30-day mortality and critical care admission was higher in unplanned [odds ratio (OR): 8.65, 95% confidence interval (CI): 3.51-19.97) than planned admissions (OR: 2.32, 95% CI: 1.43-3.85). Some 26.7% of patients (n=1210/4529) underwent emergency laparotomies. After adjustment, 49.3% (95% CI: 46.8-51.9%, P0.001) were predicted to have planned critical care admissions, with 7% (n=10/145) of centres outside the 95% CI.After risk adjustment, no 30-day survival benefit was identified for either planned or unplanned postoperative admissions to critical care within this cohort. This likely represents appropriate admission of the highest-risk patients. Planned admissions in selected, intermediate-risk patients may present a strategy to mitigate the risk of unplanned admission. Substantial inter-centre variation exists in planned critical care admissions after emergency laparotomies.

Purpose Idiopathic intracranial hypertension (IIH) is a syndrome that is characterized by persistently high intracranial pressure and associated with high rates of morbidity and visual loss. Its exact etiology and clinical picture is poorly understood, but it is known to be associated with obesity. The aim of this study was to investigate the prevalence and clinical manifestations of IIH using a large nationwide database of British subjects. Materials and methods The anonymized healthcare records of patients with a BMI of ≥ 30 kg/m2 were extracted from the Clinical Practice Research Datalink (CPRD), and analyzed. Results The patients with IIH were older and more likely to have peripheral vascular disease, ischemic heart disease, and anemia; to have had a previous myocardial infarction; and have used non-steroidal anti-inflammatory drugs (NSAIDs) and steroids. Multivariate analysis with adjustment for confounders showed that anemia (p = 0.033) and the use of NSAIDs (p = 0.011) were the only factors independently associated with IIH. Increases in BMI beyond the threshold of obesity did not independently increase risk of IIH. Conclusions IIH is a multifactorial disease; the risk of which is increased in patients with a background of anemia, and those who use NSAIDs. Across BMI categories beyond the threshold for obesity (BMI ≥ 30 kg/m2), there is no continuation of the previously described “dose-response” relationship between BMI and IIH. Ethical approval Scientific approval for the study was granted from the Regulatory Agency’s Independent Scientific Advisory Committee and ethical approval by the Health Research Authority IRAS Project ID: 203143. ISAC approval registration number 16_140R2.

Summary Background The aim was to determine whether a simulation-based care pathway approach (CPA) curriculum could improve compliance for enhanced recovery programs (ERP), and residents’ participation in laparoscopic colorectal surgery (LCS). Indeed, trainee surgeons have limited access to LCS as primary operator, and ERP have improved patients’ outcomes in colorectal surgery (CS). Methods All residents of our department were trained in a simulation-based CPA: perioperative training consisted in virtual patients built according to guidelines in both ERP and CS, whilst intraoperative training involved a virtual reality simulator curriculum. Twenty consecutive patients undergoing CS were prospectively included before (n = 10) and after (n = 10) the training. All demographic and perioperative data were prospectively collected, including compliance for ERP. Residents’ participation as primary operator in LCS was measured. Results Five residents (PGY 4–7) were enrolled. None had performed LCS as primary operator. Overall satisfaction and usefulness were both rated 4.5/5, usefulness of pre-, post- and intraoperative training was rated 5/5, 4.5/5 and 4/5, respectively. Residents’ participation in LCS significantly improved after the training (0% (0–100) vs. 82.5% (10–100); P = 0.006). Pre- and intraoperative data were comparable between groups. Postoperative morbidity was also comparable. Compliance for ERP improved at Day 2 in post-training patients (3 (30%) vs. 8 (80%); P = 0.035). Length of stay was not modified. Conclusions A simulated CPA curriculum to training in LCS and ERP was correctly implemented. It seemed to improve compliance for ERP, and promoted residents participation as primary operator without adversely altering patients’ outcomes.

Resume Objectif Determiner si une formation en parcours de soin simule (FPSS) ameliore le respect des objectifs rehabilitation amelioree (ORA) et la participation des internes au bloc operatoire en chirurgie colorectale laparoscopique (CCL). Methodes Tous les internes du service ont recu cette FPSS : les entrainements pre- et postoperatoires etaient constitues de patients virtuels scenarises selon les recommandations de rehabilitation amelioree et de chirurgie colorectale (CC) ; l’entrainement peroperatoire etait un programme valide en CCL sur simulateur. Vingt patients admis consecutivement pour CC ont ete inclus prospectivement avant (n = 10) et apres (n = 10) FPSS. Les donnees demographiques, perioperatoires, et le respect des ORA ont ete collectes. La participation des internes en CCL a ete mesuree comme % de temps en tant qu’operateur. Resultats Cinq internes (4e–7e annee) ont ete formes. Aucun n’avait realise de CCL comme operateur. La satisfaction et l’utilite globale de la FPSS etaient de 4,5/5, l’utilite des formations pre-, per- et postoperatoires de 5/5, 4,5/5 et 4/5. La participation des internes en CCL a augmente apres formation (0 % [0–100] vs. 82,5 % [10–100] ; p = 0,006). Les donnees preoperatoires des patients etaient comparables entre les groupes. La morbidite postoperatoire, dont la morbidite majeure (4 [40 %] vs. 1 [10 %] ; p = 0,15) etait egalement inchangee. Le respect des ORA etait meilleur a j2 dans le groupe post-FPSS (3 [30 %] vs. 8 [80 %] ; p = 0,035). La duree d’hospitalisation etait inchangee (p = 0,74). Conclusion La FPSS a permis d’ameliorer le respect des ORA. Elle a aussi augmente la participation des internes comme operateur sans alterer les suites operatoires des patients.

Objective: Colorectal cancer is the fourth most common cancer worldwide, with a lifetime risk of around 20%. Current solutions do not allow clinicians to objectively assess tissue abnormality during endoscopy and perioperatively. A solution capable of objectively assessing samples in real time could greatly improve the treatment process. A solution that can be integrated in minimally invasive diagnostics and management strategies to provide real-time point-of-care information would be greatly transformative. Electrical impedance spectroscopy (EIS) may provide such a solution. In this paper, we present a feasibility study on using EIS in assessing colorectal tissue. Approach: We performed tetrapolar EIS using ZedScan on excised human colorectal tumour tissue and the matched normal colonic mucosa in 22 freshly resected specimens following elective surgery for colorectal cancer. Histopathological examination was used to confirm the final diagnosis. Statistical significance was assessed with Wilcoxon signed rank test. Main results: Tetrapolar EIS could discriminate cancer with statistically significant results when applying frequencies between 305 Hz – 625 kHz (p < 0.05). 300 Ω was set as the transfer impedance threshold to detect cancer. Thus, the area under the corresponding receiver operating characteristic curve for this threshold was 0.7105. Significance: This feasibility study demonstrates that impedance spectra changes in colorectal cancer tissue are detectable and may be statistically significant, suggesting that EIS has the potential to be the core technology in a novel non-invasive point of care test for detecting colorectal cancer. These results warrant further development and increasing the size of the study with a device specificity designed for colorectal cancer.

Based on the structure of an HIV-1 entry inhibitor peptide two stapled- and a retro-enantio peptides have been designed to provide novel prevention interventions against HIV transmission. The three peptides show greater inhibitory potencies in cellular and mucosal tissue pre-clinical models than the parent sequence and the retro-enantio shows a strengthened proteolytic stability. Since HIV-1 fusion inhibitor peptides need to be embedded in the membrane to properly interact with their viral target, the structural features were determined by NMR spectroscopy in micelles and solved by using restrained molecular dynamics calculations. Both parent and retro-enantio peptides demonstrate a topology compatible with a shared helix–turn–helix conformation and assemble similarly in the membrane maintaining the active conformation needed for its interaction with the viral target site. This study represents a straightforward approach to design new targeted peptides as HIV-1 fusion inhibitors and lead us to define a retro-enantio peptide as a good candidate for pre-exposure prophylaxis against HIV-1., Financial support from the Spanish Ministry of Economy, Industry and Competitiveness (MINECO) and the European Regional Development Fund (Grant RTI2018-094120-B-I00 to I.H.) is gratefully acknowledged. A.M. is supported by a grant SAF2016-75505-R (AEI/MINECO/FEDER, UE) and through the “María de Maeztu” Programme for Units of Excellence in R&D (MDM-2014-0370). The 500-MHz spectrometer was purchased in part through a Research Infraestructure MINECO-FEDER fund (Grant CSIC13-4E-2076). Partial financial support from the Spanish National Research Council (CSIC) is also gratefully acknowledged.

Background Obesity is a cardinal risk factor for the development of atherosclerotic cardiovascular disease. Bariatric surgery is an effective method of achieving weight reduction and improving control of cardiovascular risk factors in patients with obesity. However, the effect of bariatric surgery on long-term cardiovascular outcomes has yet to be defined. Purpose The aim of this study is to evaluate the effect of bariatric surgery on long-term risk of major adverse cardiovascular events in a large population of patients with obesity. Methods A nested cohort study was carried out; including the 3,701 patients of the Clinical Practice Research Datalink database who had undergone bariatric surgery, and 3,701 age, gender and BMI matched controls. The primary endpoint was the composite of fatal or non-fatal myocardial infarction; and fatal or non-fatal acute ischaemic stroke. Secondary endpoints included all-cause mortality, new diagnosis of heart failure, fatal or non-fatal myocardial infarction, and fatal or non-fatal acute ischaemic stroke. Data was analysed using a Cox proportional hazards model to account for multiple covariates. Results Patients were followed up for a median of 11.2 years; 20.3% of the population were female, the median age was 36 years and median BMI was 40.4 kg/m2. Patients who had undergone bariatric surgery had a significantly lower occurrence of the primary composite outcome (HR 0.450; 95% CI 0.312–0.671, p Table 1. Primary and secondary endpoints during follow-up Events No Bariatric Surgery Bariatric Surgery HR 95% CI p (n=3,701) (n=3,701) Primary endpoint 93 37 0.458 0.312–0.671 Adjusted primary endpoint rates Conclusion The results of this large, nation-wide nested cohort study support the role of bariatric surgery in reducing the risk of major cardiovascular events, all-cause mortality and new onset of heart failure in patients with obesity.

BACKGROUND The United Kingdom has lower survival figures for all types of cancers compared to many European countries despite similar national expenditures on health. This discrepancy may be linked to long diagnostic and treatment delays. OBJECTIVE The aim of this study was to determine whether delays experienced by patients with colorectal cancer (CRC) affect their survival. METHODS This observational study utilized the Somerset Cancer Register to identify patients with CRC who were diagnosed on the basis of positive histology findings. The effects of diagnostic and treatment delays and their subdivisions on outcomes were investigated using Cox proportional hazards regression. Kaplan-Meier plots were used to illustrate group differences. RESULTS A total of 648 patients (375 males, 57.9% males) were included in this study. We found that neither diagnostic delay nor treatment delay had an effect on the overall survival in patients with CRC (χ23=1.5, P=.68; χ23=0.6, P=.90, respectively). Similarly, treatment delays did not affect the outcomes in patients with CRC (χ23=5.5, P=.14). The initial Cox regression analysis showed that patients with CRC who had short diagnostic delays were less likely to die than those experiencing long delays (hazard ratio 0.165, 95% CI 0.044-0.616; P=.007). However, this result was nonsignificant following sensitivity analysis. CONCLUSIONS Diagnostic and treatment delays had no effect on the survival of this cohort of patients with CRC. The utility of the 2-week wait referral system is therefore questioned. Timely screening with subsequent early referral and access to diagnostics may have a more beneficial effect.

BackgroundDelays in referral for patients with colorectal cancer may occur if the presenting symptom is falsely attributed to a benign condition.AimTo investigate whether delays in referral from primary care are associated with a later stage of cancer at diagnosis and worse prognosis.Design and settingA national retrospective cohort study in England including adult patients with colorectal cancer identified from the cancer registry with linkage to Clinical Practice Research Datalink, who had been referred following presentation to their GP with a ‘red flag’ or ‘non-specific’ symptom.MethodThe hazard ratios (HR) of death were calculated for delays in referral of between 2 weeks and 3 months, and >3 months, compared with referrals within 2 weeks.ResultsA total of 4527 (63.5%) patients with colon cancer and 2603 (36.5%) patients with rectal cancer were included in the study. The percentage of patients presenting with red-flag symptoms who experienced a delay of >3 months before referral was 16.9% of those with colon cancer and 13.5% of those with rectal cancer, compared with 35.7% of patients with colon cancer and 42.9% of patients with rectal cancer who presented with non-specific symptoms. Patients referred after 3 months with red-flag symptoms demonstrated a significantly worse prognosis than patients who were referred within 2 weeks (colon cancer: HR 1.53; 95% confidence interval [CI] = 1.29 to 1.81; rectal cancer: HR 1.30; 95% CI = 1.06 to 1.60). This association was not seen for patients presenting with non-specific symptoms. Delays in referral were associated with a significantly higher proportion of late-stage cancers.ConclusionThe first presentation to the GP provides a referral opportunity to identify the underlying cancer, which, if missed, is associated with a later stage in diagnosis and worse survival.

OBJECTIVE: This study aimed to analyze the Clinical Practice Research Datalink to identify the prognostic factors of all-cause mortality in the severely obese. BACKGROUND: Patients who are severely obese [body mass index (BMI) ≥35 kg/m] are at increased risk of all-cause mortality as a result of metabolic sequelae including hyperlipidemia, hypertension, and diabetes. Bariatric surgery has been shown to reduce the severity of the metabolic complications of obesity. METHOD: A case-controlled analysis was carried out of patients with a BMI of 35 kg/m or more from the Clinical Practice Research Datalink, a UK database of primary care clinics. Clinicopathological characteristics at baseline diagnosis were extracted. Cases of all-cause mortality were identified as a clinical endpoint. A Cox proportional hazard model was used to calculate hazard ratios (HRs) for different patient factors. A P value less than 0.050 was defined as significant. RESULTS: A total of 187,061 records were identified for analysis. Median follow-up time was 98.0 months (range: 3.0-1095.0). A total of 8655(4.6%) were identified as having died during the study period. The median time from baseline obesity diagnosis until death was 137.0 months (range: 3.0-628.7). Multivariate analysis found bariatric surgery to be associated with reduced risk of all-cause mortality (HR: 0.487; P < 0.001). The following were associated with increased risk of death: male sex (HR: 1.805; P < 0.001), BMI of 60 or greater (HR: 2.541; P < 0.001), hypertension (HR: 2.108; P < 0.001), diabetes (HR: 2.766; P < 0.001), and hyperlipidemia (HR: 1.641; P < 0.001). CONCLUSIONS: Factors such as high BMI, diabetes, hyperlipidemia, and hypertension at first diagnosis of severe obesity were each independently associated with an increased risk of death. Bariatric surgery was shown to be associated with reduced risk of all-cause mortality. Improving access to bariatric surgery and public health campaigns can improve the prognosis of severely obese patients.

BackgroundOptimal surgical intervention for low-grade haemorrhoids is unknown. Rubber band ligation (RBL) is probably the most common intervention. Haemorrhoidal artery ligation (HAL) is a novel alternative that may be more efficacious.ObjectiveThe comparison of HAL with RBL for the treatment of grade II/III haemorrhoids.DesignA multicentre, parallel-group randomised controlled trial.PerspectiveUK NHS and Personal Social Services.Setting17 NHS Trusts.ParticipantsPatients aged ≥ 18 years presenting with grade II/III (second- and third-degree) haemorrhoids, including those who have undergone previous RBL.InterventionsHAL with Doppler probe compared with RBL.OutcomesPrimary outcome – recurrence at 1 year post procedure; secondary outcomes – recurrence at 6 weeks; haemorrhoid severity score; European Quality of Life-5 Dimensions, 5-level version (EQ-5D-5L); Vaizey incontinence score; pain assessment; complications; and cost-effectiveness.ResultsA total of 370 participants entered the trial. At 1 year post procedure, 30% of the HAL group had evidence of recurrence compared with 49% after RBL [adjusted odds ratio (OR) = 2.23, 95% confidence interval (CI) 1.42 to 3.51;p = 0.0005]. The main reason for the difference was the number of extra procedures required to achieve improvement/cure. If a single HAL is compared with multiple RBLs then only 37.5% recurred in the RBL arm (adjusted OR 1.35, 95% CI 0.85 to 2.15;p = 0.20). Persistence of significant symptoms at 6 weeks was lower in both arms than at 1 year (9% HAL and 29% RBL), suggesting significant deterioration in both groups over the year. Symptom score, EQ-5D-5L and Vaizey score improved in both groups compared with baseline, but there was no difference between interventions. Pain was less severe and of shorter duration in the RBL group; most of the HAL group who had pain had mild to moderate pain, resolving by 3 weeks. Complications were low frequency and not significantly different between groups. It appeared that HAL was not cost-effective compared with RBL. In the base-case analysis, the difference in mean total costs was £1027 higher for HAL. Quality-adjusted life-years (QALYs) were higher for HAL; however, the difference was very small (0.01) resulting in an incremental cost-effectiveness ratio of £104,427 per additional QALY.ConclusionsAt 1 year, although HAL resulted in fewer recurrences, recurrence was similar to repeat RBL. Symptom scores, complications, EQ-5D-5L and continence score were no different, and patients had more pain in the early postoperative period after HAL. HAL is more expensive and unlikely to be cost-effective in terms of incremental cost per QALY.LimitationsBlinding of participants and site staff was not possible.Future workThe incidence of recurrence may continue to increase with time. Further follow-up would add to the evidence regarding long-term clinical effectiveness and cost-effectiveness. The polysymptomatic nature of haemorrhoidal disease requires a validated scoring system, and the data from this trial will allow further assessment of validity of such a system. These data add to the literature regarding treatment of grade II/III haemorrhoids. The results dovetail with results from the eTHoS study [Watson AJM, Hudson J, Wood J, Kilonzo M, Brown SR, McDonald A,et al.Comparison of stapled haemorrhoidopexy with traditional excisional surgery for haemorrhoidal disease (eTHoS): a pragmatic, multicentre, randomised controlled trial.Lancet2016, in press.] comparing stapled haemorrhoidectomy with excisional haemorrhoidectomy. Combined results will allow expansion of analysis, allowing surgeons to tailor their treatment options to individual patients.Trial registrationCurrent Controlled Trials ISRCTN41394716.FundingThis project was funded by the NIHR Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 20, No. 88. See the NIHR Journals Library website for further project information.

With obesity levels increasing, it is important to consider the mental health risks associated with this condition to optimize patient care. Links between depression and obesity have been explored, but few studies focus on the risk profiles of patients across stratified body mass index (BMI) classes above 30 kg/m2 . This study aims to determine the impact of BMI on depression risk in patients with obesity and to investigate trends of depression in a large cohort of British patients with BMI > 30 kg/m2 . A nationwide primary care database, the Clinical Practice Research Datalink (CPRD), was analysed for diagnoses of obesity (BMI > 30 kg/m2 ). Obese patients were then sub-classified into seven BMI categories. Primary health care-based records of patients entered in the CPRD were analysed. A total of 363 037 patients had a BMI ≥ 30 kg/m2 ; of these patients 97 392 (26.8%) also had a diagnosis of depression. Absolute event rates over time and hazard risk of depression were analysed by BMI category. On Cox regression analysis of time to development of depression, the cumulative hazard increased significantly and linearly across BMI groups (P < 0.001). Compared to those with BMI 30 to 35 kg/m2 , patients with BMI 35 to 40 kg/m2 had a 20% higher risk of depression (hazard ratio [HR] 1.206, confidence interval [CI] 1.170-1.424), and those with BMI > 60 kg/m2 had a 98% higher risk (HR 1.988, CI 1.513-2.612). This study identified the prevalence and time course of depression in a cohort of obese patients in the United Kingdom. Findings suggest the risk of depression is directly proportional to BMI above 30 kg/m2 . Therefore, clinicians should note higher BMI levels confer increased risk of depression.

This case report describes the development of a rash in a patient admitted with large bowel obstruction secondary to carcinoma of the sigmoid colon. The patient underwent a Hartmann’s procedure and right hemicolectomy for a metastatic deposit at the terminal ileum. On postoperative day 3, the patient developed a bullous haemorrhagic rash on the thighs, flanks and abdomen, associated with a sharp drop in platelet count. Suspicion of heparin-induced skin necrosis was raised, and prophylactic enoxaparin was switched to fondaparinux. Skin biopsy results later confirmed the diagnosis. Clinical suspicion of heparin-induced skin necrosis is essential and should prompt a switch between prophylactic agents, in order to prevent potentiation of this life-threatening side effect.

OBJECTIVE: BACKGROUND:: Breath VOCs have the potential to noninvasively diagnose cancer. METHODS: Exhaled breath samples were collected using 2-L double-layered Nalophan bags, and were analyzed using selected-ion-flow-tube mass-spectrometry. Gold-standard test for comparison was endoscopy for luminal inspection and computed tomography (CT) to confirm cancer recurrence. Three studies were conducted: RESULTS:: CONCLUSION:: This study suggests the association of a single breath biomarker with the primary presence and recurrence of CRCa. Further multicenter validation studies are required to validate these findings.

Background The objective of this study was to assess the face and content validity of the sheep head model in endoscopic rhinology training. Methods This study was a prospective evaluation study. Experienced otolaryngologists and trainees were recruited to complete 7 endoscopic rhinology tasks on pre-prepared sheep heads. All participants completed a validated 20­item questionnaire using a 5-point Likert scale to assess the model across 4 domains: face validity (FV), global content (GC), task-specific content (TSC), and curriculum applicability (CTR). Results Participants, including 25 experienced otolaryngologists and 45 trainees, completed all tasks. There were no statistically significant differences between the 2 groups’ ratings for FV, GC, or CTR (p = 0.50.7, 0.278, and 0.157, respectively). The model achieved median face validity of 4 (interquartile range [IQR]: 4 to 5) with the agreement of experienced surgeons and trainees alike (95% and 90%, respectively). The median global content was 4 (IQR: 4 to 5 and agreement of 88% and 87%. There was some variation in the rating of task-specific content. A total of 6 tasks achieved validity with the agreement of experienced otolaryngologists. The highest-rated tasks were “examination under anesthesia” and “foreign body retrieval.” Participants agreed on curriculum incorporation, transferability, and recommendation to trainees (median: 5; IQR: 4 to 5 and 95% to 97% agreement). Conclusion The sheep head model achieved face and content validity for endoscopic rhinology training. It is safe, affordable, and can aid early-years trainees in acquiring a range of basic endoscopic rhinology skills.

Background Postoperative pain is an important adverse event following inguinal hernia repair. The aim of this trial was to compare postoperative pain within the first 3 months and 1 year after surgery in patients undergoing open mesh inguinal hernia repair using either a self-gripping lightweight polyester mesh or a polypropylene lightweight mesh fixed with sutures. Methods Adult men undergoing Lichtenstein repair for primary inguinal hernia were randomized to ProGrip™ self-gripping mesh or standard sutured lightweight polypropylene mesh. Results In total 557 men were included in the final analysis (self-gripping mesh 270, sutured mesh 287). Early postoperative pain scores were lower with self-gripping mesh than with sutured lightweight mesh: mean visual analogue pain score relative to baseline +1·3 and +8·6 respectively at discharge (P = 0·033), and mean surgical pain scale score relative to baseline +4·2 and +9·7 respectively on day 7 (P = 0·027). There was no significant difference in mid-term (1 month) and long-term (3 months and 1 year) pain scores between the groups. Surgery was significantly quicker with self-gripping mesh (mean difference 7·6 min; P < 0·001). There were no significant differences in reported mesh handling, analgesic consumption, other wound complications, patient satisfaction or hernia recurrence between the groups. Conclusion Self-gripping mesh for open inguinal hernia repair was well tolerated and reduced early postoperative pain (within the first week), without increasing the risk of early recurrence. It did not reduce chronic pain. Registration number: NCT00827944 (http://www.clinicaltrials.gov).

Aim Up to a quarter of patients with rectal cancer have synchronous liver metastases at the time of diagnosis. This is a predictor of poor outcome. There are no standardized guidelines for treatment. We reviewed the outcomes of our patients with synchronous rectal liver metastases treated with a curative intent by neoadjuvant chemotherapy with or without chemoradiotherapy followed by resection of the primary tumour and then liver metastases. Method Between 2004 and 2012, patients who presented with rectal cancer and synchronous liver metastasis were treated with curative intent with peri-operative systemic chemotherapy as the first line of treatment. Responders to chemotherapy underwent resection of the primary tumour with or without preoperative chemoradiotherapy followed by hepatic resection. Results Fifty-three rectal cancer patients with 152 synchronous liver lesions were identified. After a median follow-up of 29.6 months, the median survival was 41.4 months. Overall survival was 59.0% at 3 years and 39.0% at 5 years. Conclusion Rectal resection before hepatic resection combined with neoadjuvant chemotherapy is associated with promising clinical outcome. It allows downstaging of liver lesions and removal of the primary tumour before the progression of further micrometastases. Furthermore, patients who do not respond to chemotherapy can be identified and may avoid major surgical intervention.

Shortened postgraduate surgical training reforms, known as Calman, have altered delivery of surgical training in the UK with reduced working hours and training time aiming to produce a more subspecialised workforce. This study aims to compare rectal cancer surgical outcomes of Calman-trained consultants in a single institution to published data. Additionally, the study compared colorectal cancer surgical outcome between Calman-trained consultants (CTCs) and non-Calman consultants (NCTCs) in a national dataset. Local dataset Clinicopathological outcome of rectal cancer resection undertaken by CTCs in a single institution (2006–2010) were compared against NCTC counterparts. National dataset All elective colorectal cancer resections between 2004 and 2008 in English NHS hospitals were included. CTCs (present from 2004 onwards) were compared to NCTCs (present prior to 2004). Outcome measures included 30-day in-hospital mortality, reoperation and readmission rates. Local dataset One hundred thirteen patients were operated under five CTC. The 30-day in-hospital mortality for CTCs (1 %) was favourable compared to published rates (3–5 %). Local recurrence rate (4.4 %) was comparable to NCTC (3.6 %). National dataset Between 2004 and 2008, 44,106 patients underwent elective colorectal resection. Multiple regression demonstrated CTC patients had a reduced length of stay and reduced reoperation rate. No difference in mortality and unplanned readmission rates were seen. CTCs have similar safety outcome to NCTCs for colorectal cancer resection procedures. Further work is needed to assess the impact of further training reductions on clinical outcome.

Topical microbicides have the potential to provide effective protection against sexual transmission of HIV. Challenges in developing microbicides include their application in resource-poor settings with high temperatures and a lack of refrigeration, and low user adherence to a rigorous daily regimen. Several protein-based HIV inhibitors show great promise as microbicides, being highly specific and not expected to lead to resistance that would affect the efficacy of current antiretroviral treatments. We show that four potent protein HIV inhibitors, 5P12-RANTES, 5P12-RANTES-L-C37, Grft, and Grft-L-C37 can be formulated into silk fibroin (SF) disks and remain functional for 14 months at 25, 37, and 50 °C. These HIV inhibitor-encapsulated SF disks show excellent inhibition properties in PBMC and in human colorectal and cervical tissue explants, and do not induce inflammatory cytokine secretion. Further, the SF provides a mechanically robust matrix with versatile material formats for this type of application. Finally, a formulation was developed to allow sustained release of functional Grft for 4 weeks at levels sufficient to inhibit HIV transmission. This work establishes the suitability of HIV inhibitor-encapsulated SF disks as topical HIV microbicides that can be further developed to allow easy insertion for extended protection.

Definition of the key parameters mediating effective antibody blocking of HIV-1 acquisition within mucosal tissue may prove critical to effective vaccine development and the prophylactic use of monoclonal antibodies. Although direct antibody-mediated neutralization is highly effective against cell-free virus, antibodies targeting different sites of envelope vulnerability may display differential activity against mucosal infection. Nonneutralizing antibodies (nnAbs) may also impact mucosal transmission events through Fc-gamma receptor (FcγR)-mediated inhibition. In this study, a panel of broadly neutralizing antibodies (bnAbs) and nnAbs, including those associated with protection in the RV144 vaccine trial, were screened for the ability to block HIV-1 acquisition and replication across a range of cellular and mucosal tissue models. Neutralization potency, as determined by the TZM-bl infection assay, did not fully predict activity in mucosal tissue. CD4-binding site (CD4bs)-specific bnAbs, in particular VRC01, were consistent in blocking HIV-1 infection across all cellular and tissue models. Membrane-proximal external region (MPER) (2F5) and outer domain glycan (2G12) bnAbs were also efficient in preventing infection of mucosal tissues, while the protective efficacy of bnAbs targeting V1-V2 glycans (PG9 and PG16) was more variable. In contrast, nnAbs alone and in combinations, while active in a range of cellular assays, were poorly protective against HIV-1 infection of mucosal tissues. These data suggest that tissue resident effector cell numbers and low FcγR expression may limit the potential of nnAbs to prevent establishment of the initial foci of infection. The solid protection provided by specific bnAbs clearly demonstrates their superior potential over that of nonneutralizing antibodies for preventing HIV-1 infection at the mucosal portals of infection. IMPORTANCE Key parameters mediating effective antibody blocking of HIV-1 acquisition within mucosal tissue have not been defined. While bnAbs are highly effective against cell-free virus, they are not induced by current vaccine candidates. However, nnAbs, readily induced by vaccines, can trigger antibody-dependent cellular effector functions, through engagement of their Fc-gamma receptors. Fc-mediated antiviral activity has been implicated as a secondary correlate of decreased HIV-1 risk in the RV144 vaccine efficacy trial, suggesting that protection might be mediated in the absence of classical neutralization. To aid vaccine design and selection of antibodies for use in passive protection strategies, we assessed a range of bnAbs and nnAbs for their potential to block ex vivo challenge of mucosal tissues. Our data clearly indicate the superior efficacy of neutralizing antibodies in preventing mucosal acquisition of infection. These results underscore the importance of maintaining the central focus of HIV-1 vaccine research on the induction of potently neutralizing antibodies.

Colorectal cancer (CRC) is a major cause of morbidity and mortality in developed countries. Despite operative advances and the widespread adoption of combined-modality treatment, the 5-year survival rarely exceeds 60%. Improving our understanding of the biological processes involved in CRC development and progression will help generate new diagnostic and prognostic approaches. Previous studies have identified altered metabolism as a common feature in carcinogenesis, and quantitative measurement of this altered activity (metabonomics/metabolomics) has the potential to generate novel metabolite-based biomarkers for CRC diagnosis, staging and prognostication. In the present study we applied high-resolution magic angle spinning nuclear magnetic resonance (HR-MAS NMR) spectroscopy to analyze metabolites in intact tumor samples (n = 83) and samples of adjacent mucosa (n = 87) obtained from 26 patients undergoing surgical resection for CRC. Orthogonal partial least-squares discriminant analysis (OPLS-DA) of metabolic profiles identified marked biochemical differences between cancer tissue and adjacent mucosa (R(2) = 0.72; Q(2) = 0.45; AUC = 0.91). Taurine, isoglutamine, choline, lactate, phenylalanine, tyrosine (increased concentrations in tumor tissue) together with lipids and triglycerides (decreased concentrations in tumor tissue) were the most discriminant metabolites between the two groups in the model. In addition, tumor tissue metabolic profiles were able to distinguish between tumors of different T- and N-stages according to TNM classification. Moreover, we found that tumor-adjacent mucosa (10 cm from the tumor margin) harbors unique metabolic field changes that distinguish tumors according to T- and N-stage with higher predictive capability than tumor tissue itself and are accurately predictive of 5-year survival (AUC = 0.88), offering a highly novel means of tumor classification and prognostication in CRC.

Laparoscopic cholecystectomy is commonly performed, and several factors increase the risk of open conversion, prolonging operating time and hospital stay. Preoperative stratification would improve consent, scheduling and identify appropriate training cases. The aim of this study was to develop a validated risk score for conversion for use in clinical practice.Preoperative patient and disease-related variables were identified from a prospective cholecystectomy database (CholeS) of 8820 patients, divided into main and validation sets. Preoperative predictors of conversion were identified by multivariable binary logistic regression. A risk score was developed and validated using a forward stepwise approach.Some 297 procedures (3.4%) were converted. The risk score was derived from six significant predictors: age (p = 0.005), sex (p 0.001), indication for surgery (p 0.001), ASA (p 0.001), thick-walled gallbladder (p = 0.040) and CBD diameter (p = 0.004). Testing the score on the validation set yielded an AUROC = 0.766 (p 0.001), and a score6 identified patients at high risk of conversion (7.1% vs. 1.2%).This validated risk score allows preoperative identification of patients at six-fold increased risk of conversion to open cholecystectomy.

The majority of new Human Immunodeficiency Virus (HIV)-1 infections are acquired via sexual transmission at mucosal surfaces. Partial efficacy (31.2%) of the Thai RV144 HIV-1 vaccine trial has been correlated with Antibody-dependent Cellular Cytotoxicity (ADCC) mediated by non-neutralizing antibodies targeting the V1V2 region of the HIV-1 envelope. This has led to speculation that ADCC and other antibody-dependent cellular effector functions might provide an important defense against mucosal acquisition of HIV-1 infection. However, the ability of antibody-dependent cellular effector mechanisms to impact on early mucosal transmission events will depend on a variety of parameters including effector cell type, frequency, the class of Fc-Receptor (FcR) expressed, the number of FcR per cell and the glycoslyation pattern of the induced antibodies. In this study, we characterize and compare the frequency and phenotype of IgG (CD16 [FcγRIII], CD32 [FcγRII] and CD64 [FcγRI]) and IgA (CD89 [FcαR]) receptor expression on effector cells within male and female genital mucosal tissue, colorectal tissue and red blood cell-lysed whole blood. The frequency of FcR expression on CD14+ monocytic cells, myeloid dendritic cells and natural killer cells were similar across the three mucosal tissue compartments, but significantly lower when compared to the FcR expression profile of effector cells isolated from whole blood, with many cells negative for all FcRs. Of the three tissues tested, penile tissue had the highest percentage of FcR positive effector cells. Immunofluorescent staining was used to determine the location of CD14+, CD11c+ and CD56+ cells within the three mucosal tissues. We show that the majority of effector cells across the different mucosal locations reside within the subepithelial lamina propria. The potential implication of the observed FcR expression patterns on the effectiveness of FcR-dependent cellular effector functions to impact on the initial events in mucosal transmission and dissemination warrants further mechanistic studies.

OBJECTIVE Receptive anal intercourse in both men and women is associated with the highest probability for sexual acquisition of HIV infection. As part of a program to develop an effective prevention strategy, we performed an ex-vivo preclinical evaluation to determine the efficacy of multiple double combinations of maraviroc (MVC) and reverse transcriptase inhibitors (RTIs). DESIGN The entry inhibitor, MVC, a nucleotide RTI, tenofovir and two non-nucleoside RTIs, UC781 and TMC120 (dapivirine, DPV), were used in double, combinations against a panel of CCR5-using clade B and clade C HIV-1 isolates and against MVC-escape variants. A gel-formulated version of MVC-DPV combination was also tested. METHODS Indicator cells, cocultures of immature dendritic cells with CD4T cells, and colorectal tissue explants were used to assess antiviral activity of drug combinations. RESULTS All dual MVC-RTI combinations tested inhibited MVC-sensitive and resistant isolates in cellular and colorectal explants models. All the combinations were positive with no reduction in the activity of MVC. In tissue explants, the combinations against all viral isolates tested produced an increase in the activity of MVC. An initial gel-formulation of MVC-DPV combination showed greater and prolonged antiviral activity of MVC in mucosal tissue explants. CONCLUSION This study demonstrates that combinations based on antiretroviral drugs inhibiting HIV transmission at viral entry and reverse transcription have potential as prevention strategies against colorectal transmission of HIV-1 including MVC-resistant isolates. Preclinical evaluation with colorectal tissue explants indicates that a gel-formulation of MVC-DPV is an effective candidate colorectal microbicide.

Elderly patients are often regarded as high-risk patients for major abdominal surgery because of a lack of functional reserve and associated medical comorbidities. The aim of this systematic review and pooled analysis was to review the current data published regarding the differences in operative outcomes of laparoscopic and open surgery in the elderly population.A systematic literature search of Medline, Embase, Web of Science, and Cochrane databases was performed. Studies that compared outcome following laparoscopic and open colorectal resections in the elderly (≥70) population were included. Primary outcomes were operative death, anastomotic leak, pneumonia, length of hospital stay, and return to bowel function. Secondary outcomes were operative time, intraoperative blood loss, postoperative cardiac morbidity, ileus, and postoperative wound infection.The results of this systematic review and pooled analysis demonstrate the safety and potential benefits of laparoscopic colorectal resection in the elderly population. The latter include reduction in length of hospital stay, intraoperative blood loss, incidence of postoperative pneumonia, time to return of normal bowel function, incidence of postoperative cardiac complications, and wound infections.The results of this pooled analysis demonstrate the potential short-term advantages of laparoscopic colorectal resection in the elderly population. Further studies are required to examine the long-term survival following laparoscopic and open colorectal resections in the elderly population.

A 72-year-old female presented with a six-month history of increased frequency of defecation, rectal bleeding, and severe rectal pain. Digital rectal examination and endoscopy revealed a low rectal lesion lying anteriorly. This was confirmed histologically as adenocarcinoma. Radiological staging was consistent with a T3N2rectal tumour. Following long-course chemoradiotherapy repeat staging did not identify any metastatic disease. She underwent a laparoscopic cylindrical abdominoperineal excision withen blocresection of the coccyx and posterior wall of the vagina with a negative circumferential resection margin. The perineal defect was reconstructed with Permacol (biological implant, Covidien) mesh. She had no clinical evidence of a perineal hernia at serial followup. Dynamic MRI images of the pelvic floor obtained during valsalva at 10 months revealed an intact pelvic floor. A control case that had undergone a conventional abdominoperineal excision with primary perineal closure without clinical evidence of herniation was also imaged. This confirmed subclinical perineal herniation with significant downward migration of the bowel and bladder below the pubococcygeal line. We eagerly await further evidence supporting a role for dynamic MR imaging in assessing the integrity of a reconstructed pelvic floor following cylindrical abdominoperineal excision.

Background The aim of this study was to provide pooled analysis of individually small trials comparing robotic Roux-en-Y gastric bypass (RRYGB) with standard laparoscopic RYGB (LRYGB). Methods A systematic literature search of Medline, Embase and Cochrane Library databases was performed. Primary outcome measures were the incidence of anastomotic leak and stricture. Secondary outcome measures were post-operative complications, operative time and length of hospital stay. Results Seven relevant studies of 1686 patients were included in this analysis. There was a significantly reduced incidence of anastomotic stricture in the robotic group (POR = 0.43; 95% CI = 0.19 to 0.98; p = 0.04). There was no significant difference between robotic and laparoscopic groups for anastomotic leak, post-operative complications, operative time and length of hospital stay. Conclusion The incidence of anastomotic stricture was reduced with RRYGB compared with LRYGB over a minimum follow-up period of 6 months, thus demonstrating the potential benefit of RRYGB. Copyright © 2011 John Wiley & Sons, Ltd.

Routinely collected data sets are increasingly used for research, financial reimbursement and health service planning. High quality data are necessary for reliable analysis. This study aims to assess the published accuracy of routinely collected data sets in Great Britain.Systematic searches of the EMBASE, PUBMED, OVID and Cochrane databases were performed from 1989 to present using defined search terms. Included studies were those that compared routinely collected data sets with case or operative note review and those that compared routinely collected data with clinical registries.Thirty-two studies were included. Twenty-five studies compared routinely collected data with case or operation notes. Seven studies compared routinely collected data with clinical registries. The overall median accuracy (routinely collected data sets versus case notes) was 83.2% (IQR: 67.3-92.1%). The median diagnostic accuracy was 80.3% (IQR: 63.3-94.1%) with a median procedure accuracy of 84.2% (IQR: 68.7-88.7%). There was considerable variation in accuracy rates between studies (50.5-97.8%). Since the 2002 introduction of Payment by Results, accuracy has improved in some respects, for example primary diagnoses accuracy has improved from 73.8% (IQR: 59.3-92.1%) to 96.0% (IQR: 89.3-96.3), P= 0.020.Accuracy rates are improving. Current levels of reported accuracy suggest that routinely collected data are sufficiently robust to support their use for research and managerial decision-making.

We report the case of a 65-year-old Caucasian woman who experienced two separate episodes of acute renal failure within an 18-month period, both requiring emergency admission and complicated treatment. Each episode was precipitated by hypovolaemia from intestinal fluid losses, but from two rare and independent pathologies. Her first admission was attributed to community-acquired Clostridium difficile-associated diarrhoea (CDAD) and was treated in the intensive therapy unit. She returned 18 months later with volume depletion and electrolyte disturbances, but on this occasion a giant hypersecretory villous adenoma of the rectum (McKittrick-Wheelock syndrome) was diagnosed following initial abnormal findings on digital rectal examination by a junior physician. Unlike hospital-acquired C. difficile, community-acquired infection is not common, although increasing numbers are being reported. Whilst community-acquired CDAD can be severe, it rarely causes acute renal failure. This case report highlights the pathological mechanisms whereby C. difficile toxin and hypersecretory villous adenoma of the rectum can predispose to acute renal failure, as well as the values of thorough clinical examination in the emergency room, and early communication with intensivist colleagues in dire situations.

Background Peritoneal metastasis occurs in up to 30% of patients with gastric cancer. The aim of this experimental study is to develop and validate a novel ex vivo model of the human peritoneum to better identify factors involved in the development of peritoneal metastasis in order to improve its management and prognosis. Methods Peritoneal discs harvested from hernia sacs obtained at inguinal hernia surgery were suspended in media using Teflon rings. Viability of the tissue was investigated using MTS assay, light and scanning electron microscopy (LM and SEM) over 72 h. To assess validity of the model, phenotypic changes in tumor cells were investigated. Changes in matrix metalloproteinases (MMP)-2 and -9 activities in HGC and AGS gastric adenocarcinoma cells after co-culture were investigated using zymography. Modulation of tumor cell adhesion to peritoneum after exposure to heparin was assessed using a fluorometric adhesion assay. Analysis was performed using Kruskal-Wallis for multiple comparisons and Mann-Witney U for comparisons between each group. Results MTS assay showed reduced viability after 72 h ( P = 0.047, compared with 24 h). Mesothelial cell loss at 48 h was demonstrated by LM and SEM, confirming peritoneal viability for at least 24 h after tissue harvesting. Zymography confirmed increased MMP2 and -9 activities in tumor cells and peritoneal tissue during co-culture compared with controls, and heparin significantly reduced tumor cell adherence ( P = 0.04), as observed in published in vivo models. Conclusion A validated complete model of peritoneum was developed that has shown potential to determine realistic mechanisms of peritoneal metastasis.

Proctalgia fugax (PF) is a benign anorectal condition which has been described in the literature since the nineteenth century commonly presenting to general surgeons. There is little high level evidence on the subject and its therapeutic modalities. We aimed through this systematic literature review to outline the definition and diagnostic criteria of this condition, the aetiology and differential diagnoses and describe the different treatment modalities that have been attempted and their success. A literature search of Google Scholar™ and Medline using Pubmed as the search engine was used to identify all studies directly related to the definition, aetiology and treatment options for this condition (latest at 12 August 2008) was performed. The search produced 61 references with three others obtained from the references of these papers. The prevalence of PF in the general population ranges from 4% to 18%. The diagnosis is based on the presence of characteristic symptoms as defined by Rome III guidelines and physical examination. The mainstay of treatment is reassurance and careful counselling with evidence in the literature for warm baths, topical treatment with glyceryl trinitrate or diltiazem and salbutamol inhalation. In persistent cases, local anaesthetic blocks, clonidine or Botox injections can be considered after clarification of risk and benefit. Based on this we suggest that diagnosis should be made through exclusion of common organic causes such as haemorrhoids, anal fissure or anorectal carcinoma and on the fulfilment of Rome III criteria. The main treatment for this benign condition remains reassurance and topical treatment.

Background: The role of adjuvant chemotherapy after resection of colorectal cancers (CRCs) is well understood for patients with stage-I or stage-III disease. Its efficacy for those with stage-II disease remains much less clear. Many investigators have sought to identify prognostic markers that might clarify which patients have the highest risk of recurrence and would, therefore, be most likely to benefit from chemotherapy. This systematic review examines evidence for the use of peripherally sampled, circulating tumour cells (CTCs) as such a prognostic marker. Methods: A comprehensive literature search was used to identify studies reporting on the significance of CTCs in the postoperative blood of CRC patients. Results: Fourteen studies satisfied the inclusion criteria. Six of the nine studies that took blood samples 24 h or more postoperatively found detection of postoperative CTCs to be an independent predictor of cancer recurrence. Conclusion: The presence of CTCs in peripheral blood at least 24 h after resection of CRCs is an independent prognostic marker of recurrence. Further studies are needed to clarify the optimal time point for blood sampling and determine the benefit of chemotherapy in CTC-positive patients with stage-II disease.

Background Training within a proficiency-based virtual reality (VR) curriculum may reduce errors during real surgical procedures. This study used a scientific methodology for development of a VR training curriculum for laparoscopic cholecystectomy. Methods Inexperienced (had performed fewer than ten laparoscopic cholecystectomies), intermediate (20–50) and experienced (more than 100) surgeons were recruited. Construct validity was defined as the ability to differentiate between the three levels of experience, based on simulator-derived metrics for nine basic skills, four procedural tasks and full laparoscopic cholecystectomy on a high-fidelity VR simulator. Inexperienced subjects performed ten repetitions for learning curve analysis. Proficiency measures were based on the performance of experienced surgeons. Results Thirty inexperienced, 11 intermediate and 16 experienced operators were recruited. Eight of nine basic skills and three of four procedural tasks were found to be construct valid. The full procedure revealed significant intergroup differences for time (1541, 673 and 816 s; P = 0·002), movements (1021, 595 and 638; P = 0·006) and path length (2038, 1235 and 1303 cm; P = 0·033). Learning curves plateaued between the second and ninth sessions. Conclusion This study shows that it is possible to define and develop a whole-procedure VR training curriculum for laparoscopic cholecystectomy using structured scientific methodology.

Introduction The aim of the study was to evaluate the diagnostic precision of serum carcinoembryonic antigen (CEA) in the detection of local or distant recurrence following resectional surgery for colon and rectal cancer. Methods Quantitative meta-analysis was performed on 20 studies, comparing serum CEA with radiological imaging and/or pathology in detecting colorectal cancer (CRC) recurrence in 4285 patients. The cut-off for a ‘positive’ CEA ranged from 3 to 15 ng/ml between the various studies. Sensitivity, specificity and diagnostic odds ratio (DOR) were calculated for each study. Summary receiver operating characteristic curves (SROC) and sub-group analysis were undertaken. Results The overall sensitivity and specificity of CEA for detecting CRC recurrence was 0.64 (95% CI: 0.61–0.67) and 0.90 (95% CI: 0.89–0.91), respectively. The area under the SROC curve was 0.75 (SE = 0.04) and the diagnostic odds ratio was 18.44 (95% CI: 11.94–28.49). A CEA cut-off of 5 ng/ml yielded a higher diagnostic odds ratio than a cut-off of 3 ng/ml (15.5 vs. 11.1). Using meta-regression analysis the optimum CEA cut-off point for the best combination of sensitivity and specificity was 2.2 ng/ml. On sub-group analysis high quality studies, and those involving ≥100 patients yielded a marginal improvement in the sensitivity and specificity with minimal change to the SROC. Conclusion Serum CEA is a test with high specificity but insufficient sensitivity for detecting CRC recurrence in isolation. A cut-off of 2.2 ng/ml may provide an ideal balance of sensitivity and specificity. It may be useful as a first-line surveillance investigation in patients during surgical follow-up based on serial CEA measurements using temporal trends in conjunction with clinical, radiological and/or histological confirmation.

Rectal squamous cell carcinoma is a rare tumour accounting for only 0.25% of all rectal carcinomas, yet it carries a significant mortality and morbidity. Radical surgery has been advocated as the primary treatment modality with or without adjunctive therapies despite the proven benefits of primary chemoradiotherapy for squamous cell carcinoma (SCC) of the anus. This report describes 7 cases of rectal squamous cell carcinoma from a single institution over a four-year period, treated with primary chemoradiotherapy. All patients demonstrated significant tumour regression, and surgery to the primary tumour was avoided in all but one of these cases. Primary chemoradiotherapy can achieve excellent local control for rectal squamous cell carcinoma with surgery employed only for unresponsive or recurrent tumours.

In this study, the authors review their initial results with the laparoscopic approach for parastomal hernia repair. Between 2006 and 2007, 4 patients were treated laparoscopically at our institution. The hernia sac was not excised. A piece of Gore-Tex DualMesh with a central keyhole and a radial incision was cut so that it could provide at least 3 to 5 cm of overlap of the fascial defect. The mesh was secured to the margins of the hernia with circumferential metal tacking and trans-fascial sutures. No complications occurred in the postoperative period. After a median follow-up of 9 months, recurrence occurred in 1 patient. This was our first patient in whom mesh fixation was performed only with circumferential metal tacking. The laparoscopic repair of parastomal hernias seems to be a safe, feasible and promising technique offering the advantages of minimally-invasive surgery. The success of this approach depends on longer follow-up reports and standardization of the technical elements.

Background The aim of this study is to describe a single institution’s experience in the use of transanal endoscopic microsurgery for rectal tumors. Methods Between 1996 and 2005, transanal endoscopic microsurgery was performed in 76 patients. The histologic diagnosis was adenoma in 48 and adenocarcinoma in 28 patients. Results Clear resection margins were achieved in 71 of 74 patients (95.9%). Overall morbidity was 18.9% because 14 patients developed minor (10 patients) or major complications (4 patients). During the follow-up, benign tumor recurrence was detected in 3 patients (6.3%). The recurrence rates among patients with T1, T2, and T3 malignant tumors were 7.1%, 42.8%, and 66.6%, respectively. Comments Transanal endoscopic microsurgery is a safe and feasible technique with low incomplete excision rates and may be the preferred method in patients with benign rectal tumors. Its role in the management of malignant tumors should be limited to selected patients with T1 lesions.

Recent evidence has suggested improved outcomes following incorporation of intraperitoneal chemotherapy administration with intravenous systemic chemotherapy as first-line treatment of small volume residual epithelial ovarian cancer. This review focuses on the mechanism of actions of the chemotherapeutic drugs and reviews the possible reasons for the superior outcomes of intraperitoneal chemotherapy.