Gender-Related Differences of Tachykinin NK2 Receptor Expression and Activity in Human Colonic Smooth Muscle.

The tachykinin NK2 receptor plays a key role in gastrointestinal motor function. Enteric neurons release neurokinin A (NKA), which activates NK2 receptors on gastrointestinal smooth muscle, leading to contraction and increased motility. In patients with diarrhea-predominant irritable bowel syndrome, the NK2 receptor antagonist ibodutant had a greater therapeutic effect in females than males. The present study aimed to determine whether gender influences the expression and activity of NK2 receptors in human colonic smooth muscle. In vitro functional studies were performed to examine the contractile responses of colonic muscle strips to NKA and the selective NK2 receptor agonist [Lys5,MeLeu9,Nle10]NKA(4-10). Contractions were also measured in the presence of ibodutant to determine its antagonistic potency. The signal transduction pathways coupled to NK2 receptor activation were investigated using second messenger inhibitors. Western blot and fluorescent immunohistochemistry were conducted to determine the protein expression and localization of NK2 receptors. NK2 receptor-mediated contractility was greater in females compared with males. When against NKA, ibodutant was more potent in females. NK2 receptor expression increased with age in females, but not in males. Phospholipase C-mediated signaling was less prominent in females compared with males, whereas Ca2+ sensitization via Rho kinase and protein kinase C appeared to be the dominant pathway in both genders. The distribution of NK2 receptors in the human colon did not differ between the genders. Overall, gender differences exist in the expression and activity of NK2 receptors in colonic smooth muscle. These gender distinctions should be considered in the therapeutic development of NK2 receptor agents. SIGNIFICANCE STATEMENT: The tachykinin NK2 receptor has been identified as a therapeutic target for the treatment of bowel and bladder dysfunctions. The present study has revealed gender-related variations in NK2 receptor activity, signaling transduction pathways, antagonist potency, and changes in expression with age. These factors may underlie the gender differences in the treatment of diarrhea-predominant irritable bowel syndrome with NK2 receptor antagonists. Our findings highlight that gender differences should be considered in the therapeutic development of NK2 receptor agents.

Process evaluation of a behaviour change approach to improving clinical practice for detecting hereditary cancer.

BACKGROUND: This retrospective process evaluation reports on the application of a 1-year implementation program to increase identification and management of patients at high risk of a hereditary cancer syndrome. The project used the Theoretical Domains Framework Implementation (TDFI) approach, a promising implementation methodology, used successfully in the United Kingdom to address patient safety issues. This Australian project run at two large public hospitals aimed to increase referrals of patients flagged as being at risk of Lynch syndrome on the basis of a screening test to genetic services. At the end of the project, the pathologists' processes had changed, but the referral rate remained inconsistent and low. METHODS: Semi-structured interviews explored participants' perceptions of the TDFI approach and Health services researchers wrote structured reflections. Interview transcripts and reflections were coded initially against implementation outcomes for the various TDFI approach activities: acceptability, appropriateness, feasibility, value for time cost, and adoption. On a second pass, themes were coded around challenges to the approach. RESULTS: Interviews were held with nine key project participants including pathologists, oncologists, surgeons, genetic counsellors and an administrative officer. Two health services researchers wrote structured reflections. The first of two major themes was 'Theory-related challenges', with subthemes of accessibility of theory underpinning the TDFI, commitment to that theory-based approach, and the problem of complexity. The second theme was 'Practical challenges' with subthemes of stakeholder management, navigating the system, and perceptions of the problem. Health services researchers reflected on the benefits of bridging professional divides and facilitating collective learning and problem solving, but noted frustrations around clinicians' time constraints that led to sparse interactions with the team, and lack of authority to effect change themselves. CONCLUSIONS: Mixed success of adoption as an outcome was attributed to the complexity and highly nuanced nature of the setting. This made identifying the target behaviour, a key step in the TDFI approach, challenging. Introduced changes in the screening process led to new, unexpected issues yet to be addressed. Strategies to address challenges are presented, including using an internal facilitator with a focus on applying a theory-based implementation approach.

Using behaviour change and implementation science to address low referral rates in oncology.

BACKGROUND: Patients undergoing surgery for bowel cancer now have a routine screening test to assess their genetic predisposition to this and other cancers (Lynch syndrome). A result indicating a high risk should trigger referral to a genetic clinic for diagnostic testing, information, and management. Appropriate management of Lynch syndrome lowers morbidity and mortality from cancer for patients and their family, but referral rates are low. The aim of this project was to increase referral rates for patients at high risk of Lynch syndrome at two Australian hospitals, using the Theoretical Domains Framework (TDF) Implementation approach. METHODS: Multidisciplinary teams at each hospital mapped the referral process and discussed barriers to referral. A 12-month retrospective audit measured baseline referral rates. The validated Influences on Patient Safety Behaviours Questionnaire was administered to evaluate barriers using the TDF. Results were discussed in focus groups and interviews, and interventions co-designed, guided by theory. Continuous monitoring audits assessed change in referral rates. RESULTS: Teams (n = 8, 11) at each hospital mapped referral processes. Baseline referral rates were 80% (4/5) from 71 screened patients and 8% (1/14) from 113 patients respectively. The questionnaire response rate was 51% (36/71). Most significant barrier domains were: 'environmental context;' 'memory and decision making;' 'skills;' and 'beliefs about capabilities.' Focus groups and interviews with 19 healthcare professionals confirmed these domains as significant. Fifteen interventions were proposed considering both emerging and theory-based results. Interventions included: clarification of pathology reports, education, introduction of e-referrals, and inclusion of genetic status in documentation. Audits continued to December 2016 showing a change in pathology processes which increased the accuracy of screening. The referral rate remained low: 46% at Hospital A and 9% Hospital B. Results suggest patients who have their referral deferred for some reason are not referred later. CONCLUSION: Lynch syndrome is typical of low incidence problems likely to overwhelm the system as genomic testing becomes mainstream. It is crucial for health researchers to test methods and define generalizable solutions to address this problem. Whilst our approach did not improve referrals, we have deepened our understanding of barriers to referral and approaches to low frequency conditions.

How to do it: delayed sphincteroplasty for obstetric anal sphincter injury.

Obstetric anal sphincter injuries are a common cause of faecal incontinence in women. Symptoms can arise immediately after delivery or have an onset many years postpartum. The anterior sphincter defect may be occult and unrecognised at the time of delivery or result from a breakdown of a primary repair. A delayed sphincteroplasty is a management option for those with persistent symptoms after a non-operative approach. Our patient is a 35-year-old female who presented with faecal urgency and incontinence to liquid stool and flatus. She was 8 months post-partum (G4P2) following a singleton vaginal delivery. She suffered a sphincter injury following a precipitous labour, described as a grade 3c perineal tear, which was repaired at the time in the operating theatre. Endoanal ultrasound revealed a persistent 40% defect in the anterior internal and external anal sphincters. Our approach to a delayed sphincteroplasty is described in detail. We employed a method that involved the identification, careful dissection, and separate repair of both anal sphincter muscles.

Single stage repair of a giant inguinoscrotal hernia by a combined laparotomy and inguinal approach.

Giant inguinoscrotal hernias are an uncommon but challenging surgical entity. We report on how to repair a giant inguinoscrotal hernia using a single-stage approach suitable for emergency surgery. This involves a combined laparotomy and inguinal approach, with posterior component separation and transversus abdominis release.

Robotic resection of a multicystic tailgut cyst.

A 29-year-old woman with recurrent pelvic pain that progressed post partum was diagnosed with a multicystic pararectal lesion on ultrasound and CT scan. Physiology was conducted to establish a preoperative function and pudendal nerve integrity. The lesion was resected using a Da Vinci Xi robotic system. She recovered uneventfully with complete resolution of her symptoms. Hindgut cysts most often arise in the presacral space as the result of incomplete embryogenesis. Patients may present with various non-specific symptoms. Although the majority are benign, resection is recommended, as there is a 30%-43% risk of malignancy.

Patient compliance with surveillance colonoscopy: patient factors and the use of a graded recall system.

BACKGROUND: Surveillance colonoscopy allows for the early detection and improved treatment outcomes in colorectal neoplasms but compliance rates and factors require further investigation. METHODS: This is a retrospective cohort study examining 816 patients recalled for surveillance colonoscopy at an Australian colorectal practice over a 6-month period. Primary outcome was compliance with colonoscopy within 12 months of recall. The secondary outcome of this study was to identify factors affecting compliance including patient factors and the practices' graded recall system. RESULTS: A total of 715 patients (87.6%) were compliant with recall requests for repeat colonoscopy. Significantly higher compliance rates were noted with a personal history of adenomatous polyps (90.9% versus 85.6%, P = 0.025). Those with private insurance or Department of Veterans Affairs were more likely to be compliant than those publicly funded (89.0% versus 93.3% versus 79.0%, P = 0.007). No statistically significant difference in compliance was shown with a personal history of colorectal cancer, diverticular disease, perianal disease, National Health and Medical Research Council risk category, gender, time associated with the practice or the clinician. There was a significant positive correlation between the number of letters sent and compliance with recall, with 61.8% being compliant after a single letter, and a final cumulative compliance after five letters of 87.6% (R = 0.882, P = 0.048). CONCLUSION: A graded recall system can achieve compliance rates as high as 87.6% compared to a single letter only achieving 61.8% compliance. A history of adenomatous polyps and insurance status were the only factors shown to result in higher recall compliance.

Imaging of the thyroid gland.

Incidental and symptomatic pathology of the thyroid gland is common in the community. Although technological advances have led to the development and improvement of imaging modalities, ultrasound remains the primary diagnostic tool. In this article, the authors examine the role of imaging and its recent advances in the management of thyroid cancer.