Studies of anorectal function using high resolution anorectal manometry in health and faecal incontinence

PhDFaecal incontinence (FI) is a prevalent complaint in Western populations and causes significant disability. Impaired motor function of the anal canal is a common pathophysiological feature and assessment of sphincteric function with manometry is a routine part of symptom assessment. High-resolution anorectal manometry (HRAM) may provide a more detailed understanding of anorectal function, however its clinical utility has not been established. Aims The principal aims of this thesis were to: (1) Explore existing practices of anorectal manometry (2) Examine current evidence supporting the use of HRAM (3) Develop and validate a protocol for the performance of HRAM (4) Define normal values for traditional measures of sphincteric function using HRAM (5) Develop and validate novel measures of sphincteric function, and explore whether they improve diagnostic accuracy in patients with FI (6) Examine anorectal function over a prolonged period with HRAM to evaluate the phenomenon of anal sampling (referred to in this thesis as transient anal sphincter relaxations [TASRs]) Methods The following methods were used: (1) A worldwide survey of current practices of anorectal manometry (2) A systemic review of the literature (3) Prospective studies (both standard and prolonged) of anal function in healthy volunteers and patients with FI Results The practice of anorectal manometry is markedly variable internationally with no two centres surveyed employing the same methods. Within the 62 centres surveyed, there were 16 combinations of ways in which squeeze data were reported. A review of the literature demonstrated a growing evidence base for the use of HRAM however there is a paucity of data that confirm added benefits of HRAM over conventional manometry. A standardized protocol for HRAM was developed to allow the reporting of traditional measures of anorectal function. Novel measures derived from HRAM were developed which demonstrate increased sensitivity for the detection of impaired sphincteric control in patients with FI (sensitivity of traditional measure [conventional squeeze increment] 36% vs. 59% for the novel HRAM measure [5-second squeeze profile]). Transient anal sphincter relaxations (TASRs) were characterized using HRAM. In health, TASRs are often perceived by the individual as the urge to pass wind (39% of events) and their frequency increases following meal consumption. Conversely in FI, TASRs are a rare occurrence and are generally not perceived (only one patient (1/10 [10%]) with FI reported GI sensations associated with TASR events). Conclusions Anorectal manometry is in need of standardization. Novel measures derived from HRAM may improve diagnostic utility and further exploration of TASR characteristics might give insight into the pathophysiology of FI.Stefan Galeski fellowship Royal College of Surgeons of Englan

The London Classification: Improving Characterization and Classification of Anorectal Function with Anorectal Manometry.

PURPOSE OF REVIEW: Objective measurement of anorectal sensorimotor function is a requisite component in the clinical evaluation of patients with intractable symptoms of anorectal dysfunction. Regrettably, the utility of the most established and widely employed investigations for such measurement (anorectal manometry (ARM), rectal sensory testing and the balloon expulsion test) has been limited by wide variations in clinical practice. RECENT FINDINGS: This article summarizes the recently published International Anorectal Physiology Working Group (IAPWG) consensus and London Classification of anorectal disorders, together with relevant allied literature, to provide guidance on the indications for, equipment, protocol, measurement definitions and results interpretation for ARM, rectal sensory testing and the balloon expulsion test. The London Classification is a standardized method and nomenclature for description of alterations in anorectal motor and sensory function using office-based investigations, adoption of which should bring much needed harmonization of practice

Guideline for the diagnosis and treatment of Faecal Incontinence-A UEG/ESCP/ESNM/ESPCG collaboration

INTRODUCTION The goal of this project was to create an up-to-date joint European clinical practice guideline for the diagnosis and treatment of faecal incontinence (FI), using the best available evidence. These guidelines are intended to help guide all medical professionals treating adult patients with FI (e.g., general practitioners, surgeons, gastroenterologists, other healthcare workers) and any patients who are interested in information regarding the diagnosis and management of FI. METHODS These guidelines have been created in cooperation with members from the United European Gastroenterology (UEG), European Society of Coloproctology (ESCP), European Society of Neurogastroenterology and Motility (ESNM) and the European Society for Primary Care Gastroenterology (ESPCG). These members made up the guideline development group (GDG). Additionally, a patient advisory board (PAB) was created to reflect and comment on the draft guidelines from a patient perspective. Relevant review questions were established by the GDG along with a set of outcomes most important for decision making. A systematic literature search was performed using these review questions and outcomes as a framework. For each predefined review question, the study or studies with the highest level of study design were included. If evidence of a higher-level study design was available, no lower level of evidence was sought or included. Data from the studies were extracted by two reviewers for each predefined important outcome within each review question. Where possible, forest plots were created. After summarising the results for each review question, a systematic quality assessment using the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) approach was performed. For each review question, we assessed the quality of evidence for every predetermined important outcome. After evidence review and quality assessment were completed, recommendations could be formulated. The wording used for each recommendation was dependent on the level of quality of evidence. Lower levels of evidence resulted in weaker recommendations and higher levels of evidence resulted in stronger recommendations. Recommendations were discussed within the GDG to reach consensus. RESULTS These guidelines contain 45 recommendations on the classification, diagnosis and management of FI in adult patients. CONCLUSION These multidisciplinary European guidelines provide an up-to-date comprehensive evidence-based framework with recommendations on the diagnosis and management of adult patients who suffer from FI

Contrasting prefrontal cortex contributions to episodic memory dysfunction in behavioural variant frontotemporal dementia and alzheimer's disease

Recent evidence has questioned the integrity of episodic memory in behavioural variant frontotemporal dementia (bvFTD), where recall performance is impaired to the same extent as in Alzheimer's disease (AD). While these deficits appear to be mediated by divergent patterns of brain atrophy, there is evidence to suggest that certain prefrontal regions are implicated across both patient groups. In this study we sought to further elucidate the dorsolateral (DLPFC) and ventromedial (VMPFC) prefrontal contributions to episodic memory impairment in bvFTD and AD. Performance on episodic memory tasks and neuropsychological measures typically tapping into either DLPFC or VMPFC functions was assessed in 22 bvFTD, 32 AD patients and 35 age- and education-matched controls. Behaviourally, patient groups did not differ on measures of episodic memory recall or DLPFC-mediated executive functions. BvFTD patients were significantly more impaired on measures of VMPFC-mediated executive functions. Composite measures of the recall, DLPFC and VMPFC task scores were covaried against the T1 MRI scans of all participants to identify regions of atrophy correlating with performance on these tasks. Imaging analysis showed that impaired recall performance is associated with divergent patterns of PFC atrophy in bvFTD and AD. Whereas in bvFTD, PFC atrophy covariates for recall encompassed both DLPFC and VMPFC regions, only the DLPFC was implicated in AD. Our results suggest that episodic memory deficits in bvFTD and AD are underpinned by divergent prefrontal mechanisms. Moreover, we argue that these differences are not adequately captured by existing neuropsychological measures

The first T cell response to transmitted/founder virus contributes to the control of acute viremia in HIV-1 infection

Identification of the transmitted/founder virus makes possible, for the first time, a genome-wide analysis of host immune responses against the infecting HIV-1 proteome. A complete dissection was made of the primary HIV-1–specific T cell response induced in three acutely infected patients. Cellular assays, together with new algorithms which identify sites of positive selection in the virus genome, showed that primary HIV-1–specific T cells rapidly select escape mutations concurrent with falling virus load in acute infection. Kinetic analysis and mathematical modeling of virus immune escape showed that the contribution of CD8 T cell–mediated killing of productively infected cells was earlier and much greater than previously recognized and that it contributed to the initial decline of plasma virus in acute infection. After virus escape, these first T cell responses often rapidly waned, leaving or being succeeded by T cell responses to epitopes which escaped more slowly or were invariant. These latter responses are likely to be important in maintaining the already established virus set point. In addition to mutations selected by T cells, there were other selected regions that accrued mutations more gradually but were not associated with a T cell response. These included clusters of mutations in envelope that were targeted by NAbs, a few isolated sites that reverted to the consensus sequence, and bystander mutations in linkage with T cell–driven escape

Case report: Acute appendicitis in appendix duplication

Introduction Duplication of the appendix is a very rare presentation. According to the Cave–Wallbridge classification, there are three types of duplicate appendix. Presentation of case A 43 year old female presented with classical symptoms of acute appendicitis, with unremarkable inflammatory markers. The diagnosis was confirmed on pre-operative computer tomography (CT). During laparoscopy two tubular structures were identified: one arising from the tenia libera of the caecum adjacent to the terminal ileum and one retrocaecally at the confluence of the teniae. Both structures were excised using a laparoscopic linear stapler. Histopathological analysis demonstrated the accessory structure to be a microscopically unremarkable blind-ended tubular structure. The other specimen demonstrated acute gangrenous inflammation of the appendix. The patient had an uneventful recovery and was discharged home the following day. Discussion Appendix duplication is rare; however, failure to recognise it in a patient with acute appendicitis could result in a retained source of sepsis, requiring subsequent re-exploration of the abdomen. The case presented here represents a Type B2 according to the Cave-Wallbridge classification and is the most susceptible to inadvertent error due to having appendixes in both typical and atypical anatomical locations. This case also highlights the probability of this diagnosis being missed on pre-operative CT. Conclusion This case report presents a unique opportunity for surgical trainees to review intra-operative laparoscopic images of a duplicate appendix, both to allow them to recognise this pathology if encountered in the future, and to embed the importance of ruling it out with thorough intra-operative examination