Analgesic effect of local anaesthetic in haemorrhoid banding: systematic review and meta-analysis.

PURPOSE: Rubber band ligation of haemorrhoids can be,painful and there is no consensus regarding the optimal analgesic strategy. This study aims to determine whether there is a difference in post-procedural pain in adults undergoing haemorrhoid banding who have received local anaesthetic, a pudendal nerve block or no regional or local analgesia. METHODS: MEDLINE, Embase, Google Scholar and clinical trial registries were searched for randomised trials of local anaesthetic or pudendal nerve block use in banding. Primary outcomes were patient-reported pain scores. The quality of the evidence was assessed using the GRADE approach. RESULTS: Seven studies were included in the final review. No articles were identified that studied pudendal nerve blocks. The difference in numerical pain scores between treatment groups favoured the local anaesthetic group at all timepoints. The mean difference in scores on a 10-point scale was at 1 h,-1.43 (95% CI-2.30 to-0.56, p < 0.01, n = 342 (175 in treatment group)); 6 h,-0.52 (95% CI-1.04 to 0.01, p = 0.05, n = 250 (130 in treatment group)); and 24 h,-0.31 (95% CI-0.82 to 0.19, p = 0.86, n = 247 (127 in treatment group)). Of reported safety outcomes, vasovagal symptoms proceeded to meta-analysis, with a risk ratio of 1.01 (95% CI 0.64-1.60). The quality of the evidence was rated down to 'low' due to inconsistency and imprecision. CONCLUSION: This review supports the use of LA for reducing early post-procedural pain following haemorrhoid banding. The evidence was limited by small sample sizes and substantial heterogeneity across studies. REGISTRATION: PROSPERO (ID CRD42022322234).

Does complete pathological response increase perioperative morbidity risk in rectal cancer?

AIM: The optimal management of patients with clinical complete response after neoadjuvant treatment for rectal cancer is controversial. The aim of this study is to compare the morbidity between patients with locally advanced rectal cancer who have had a pathological complete response (pCR) or not after neoadjuvant chemoradiotherapy (NCRT) and total mesorectal excision (TME). The study hypothesis was that pCR may impact the surgical complication rate. METHOD: A retrospective cohort study was conducted of a prospectively maintained database in Australia and New Zealand, the Binational Colorectal Cancer Audit, that identified patients with locally advanced rectal cancer (<15 cm from anal verge) from 1 January 2007 to 31 December 2019. Patients were included if they had locally advanced rectal cancer and had undergone NCRT and proceeded to surgical resection. RESULTS: There were 4584 patients who satisfied the inclusion criteria, 65% being male. The mean age was 63 years and 11% had a pCR (ypT0N0). TME with anastomosis was performed in 67.8% of patients, and the majority of the cohort received long-course radiotherapy (81.7%). Both major and minor complications were higher in the TME without anastomosis group (17.3% vs. 14.7% and 30.6% vs. 20.8%, respectively), and the 30-day mortality was 1.31%. In the TME with anastomosis group, pCR did not contribute to higher rates of surgical complications, but male gender (p < 0.0012), age (p < 0.0001), preoperative N stage (p = 0.0092) and American Society of Anesthesologists (ASA) score ≥3 (p < 0.0002) did. In addition, pCR had no significant effect (p = 0.44) but male gender (p = 0.0047) and interval to surgery (p = 0.015) contributed to higher rates of anastomotic leak. In the TME without anastomosis cohort, the only variable that contributed to higher rates of complications was ASA score ≥3 (p = 0.033). CONCLUSION: Patients undergoing TME dissection for rectal cancer following NCRT showed no difference in complications whether they had achieved pCR or not.

Use of pudendal nerve blocks in rubber band ligation of haemorrhoids: an Australia-wide cross-sectional analysis.

BACKGROUND: Surgeons vary in their approach to preventing pain post rubber band ligation (RBL) of haemorrhoids, with pudendal nerve blocks (PNB) being one analgesic strategy. No data exists on how commonly PNBs are used in RBL in Australia, and whether use varies by year and patient and hospital characteristics. METHODS: Aggregate data from the National Hospital Morbidity Database was obtained for all admissions for RBL in Australia from 2012 to 2021, with and without a PNB, overall and in relation to sex, age group, hospital remoteness, hospital sector, and year of procedure. Adjusted relative risks (adj. RR) of PNB were estimated using Poisson regression, mutually adjusting for all variables. RESULTS: Of the 346 542 admissions for RBL, 14013 (4.04%) involved a PNB. The proportion of patients receiving a PNB increased between 2012-2013 and 2020-2021, from 1.62% to 6.63% (adj. RR 3.99, CI 3.64-4.36). Patients most likely to receive a PNB were female (adj. RR 1.10; CI 1.07-1.14) aged 25-34 years (adj. RR 1.13; CI 1.01-1.26); in major-city (adj. RR 1.25 CI 1.20-1.30) and private hospitals (adj. RR 3.28 CI 3.13-3.45). CONCLUSION: This is the first published analysis of the use of PNB in RBL. Pudendal nerve block use has increased over time, with substantial variation in practice. Blocks were more than three times as likely to be used in private compared to public hospitals. If evidence supporting PNB use is established, equitable access to the procedure should be pursued.

Challenges in evaluating pelvic floor physiotherapy based strategies in low anterior resection syndrome: a systematic review and qualitative analysis.

AIM: Physiotherapy is an established treatment strategy for low anterior resection syndrome (LARS). However, data on its efficacy are limited. This is in part due to the inherent challenges in study design in this context. This systematic review aims to analyse the methodology of studies using pelvic floor physiotherapy for treatment of LARS to elucidate the challenges and limitations faced, which may inform the design of future prospective trials. METHODOLOGY: A systematic review of the literature was undertaken through MEDLINE, Embase and Cochrane Library, yielding 345 unique records for screening. Five studies were identified for review. Content thematic analysis of study limitations was carried out using the Braun and Clarke method. Line-by-line coding was used to organize implicit and explicit challenges and limitations under broad organizing categories. RESULTS: Key challenges fell into five overarching categories: patient-related issues, cancer-related issues, adequate symptomatic control, intervention-related issues and measurement of outcomes. Adherence, attrition and randomization contributed to potential bias within these studies, with imbalance in the baseline patient characteristics, particularly gender and baseline pelvic floor function scores. Outcome measurements consisted of patient-reported measures and quality of life measures, where significant improvements in bowel function according to patient-reported outcome measures were not reflected in the quality of life scores. CONCLUSION: Upcoming trial design in the area of pelvic floor physiotherapy for faecal incontinence related to rectal cancer surgery can be cognisant of and design around the challenges identified in this systematic review, including the reduction of bias, exclusion of the placebo effect and the potential cultural differences in attitude towards a sensitive intervention.

Evaluating the Educational Value of Cancer Registries - a Systematic Review and Thematic Analysis.

Cancer registries encompass a broad array of functions that underpin cancer control efforts. Despite education being fundamental to improving patient outcomes, little is known regarding the educational value of cancer registries. This review will evaluate the educational value of cancer registries for key stakeholders as reported within published literature and identify opportunities for enhancing their educational value. Four databases (Ovid Medline, Embase, CINAHL and Web of Science) were searched using a predefined search strategy in keeping with the PRISMA statement. Data was extracted and synthesised in narrative format. Themes and frequency of discussion of educational content were explored using thematic content analysis. From 952 titles, ten eligible studies were identified, highlighting six stakeholder groups. Educational outcomes were identified relating to clinicians (6/10), researchers (5/10), patients (4/10), public health organisations (3/10), medical students (1/10) and the public (1/10). Cancer registries were found to educationally benefit key stakeholders despite educational value not being a key focus of any study. Deliberate efforts to harness the educational value of cancer registries should be considered to enable data-driven quality improvement, with the vast amount of data promising ample educational benefit.

Exploring the educational value of the general surgical outpatient clinic: a systematic review.

Purpose: Optimising opportunities for exposure and learning in the clinical environment is a priority for surgical education. The surgical outpatient clinic provides a setting for engaging with the patient journey while gaining essential surgical knowledge and skills. This systematic review seeks to determine the role of the outpatient clinic in current surgical education for multiple levels of learners and identify strategies to improve educational utility. Methods: A systematic search strategy was conducted across Medline (OVID), Embase, PubMed, and Web of Science databases according to PRISMA guidelines. A comprehensive grey literature search for evaluation of international postgraduate surgical curricula was also performed. Publications were included if they discussed or utilised the general surgical outpatient clinic in an educational context. Results: Nine publications were included in this review. Educational interventions in a surgical outpatient clinic setting were discussed in three publications and two publications presented observational data relating to educational opportunities in the surgical outpatient clinic. Four postgraduate surgical curricula outlined the current approaches to surgical education in the outpatient clinic setting. Assessment of included studies by Kirkpatrick level of evidence highlighted that included studies did not investigate high-order educational outcomes. Thematic analysis of curricula was utilised to build a common set of learning outcomes. Conclusions: Educational interventions were found to improve learning outcomes, particularly those that facilitated active student participation. Postgraduate surgical curricula utilise the surgical outpatient clinic and recognise its importance in surgical training through the implementation of outpatient-based learning objectives which serve as fundamental components of training. Common learning objectives can be used to direct further research into the efficacy of this educational context. Supplementary Information: The online version contains supplementary material available at 10.1007/s44186-023-00106-8.

Actin cytoskeleton remodeling disrupts physical barriers to infection and presents entry receptors to respiratory syncytial virus.

RSV is the leading cause of infant hospitalizations and a significant cause of paediatric and geriatric morbidity worldwide. Recently, we reported that insulin-like growth factor 1 receptor (IGF1R) was a receptor for respiratory syncytial virus (RSV) in airway epithelial cells and that activation of IGF1R recruited the coreceptor, nucleolin (NCL), to the cell surface. Cilia and mucus that line the airways pose a significant barrier to viral and bacterial infection. The cortical actin cytoskeleton has been shown by others to mediate RSV entry, so we studied the roles of the RSV receptors and actin remodelling during virus entry. We found that IGF1R expression and phosphorylation were associated with the ability of RSV to infect cells. Confocal immunofluorescence imaging showed that actin projections, a hallmark of macropinocytosis, formed around viral particles 30 min after infection. Consistent with prior reports we also found that virus particles were internalized into early endosome antigen-1 positive endosomes within 90 min. Inhibiting actin polymerization significantly reduced viral titre by approximately ten-fold. Inhibiting PI3 kinase and PKCζ in stratified air-liquid interface (ALI) models of the airway epithelium had similar effects on reducing the actin remodelling observed during infection and attenuating viral entry. Actin projections were associated with NCL interacting with RSV particles resting on apical cilia of the ALIs. We conclude that macropinocytosis-like actin projections protrude through normally protective cilia and mucus layers of stratified airway epithelium that helps present the IGF1R receptor and the NCL coreceptor to RSV particles waiting at the surface.

Cancer incidence and outcomes registries in an Australian context: a systematic review.

BACKGROUND: Multiple cancer registries in Australia are used to track the incidence of cancer and the outcomes of their treatment. These registries can be broadly classed into a few types with an increasing number of registries comes a greater potential for collaboration and linkage. This article aims to critically review cancer registry types in Australia and evaluate the Australian Cancer registry landscape to identify these areas. METHODS: A systematic review was performed through MEDLINE, EMBASE and Cochrane Library, updated to September 2022 using a predefined search strategy. Inclusion criteria were those that only analysed Australian and/or New Zealand based cancer registries, appraised the utility of cancer outcomes and/or incidence registries, and explored the utility of linked databases using cancer outcomes and/or incidence registries. The grey literature was searched for all operating cancer registries in Australia. Details of registry infrastructure was extracted for analysis and comparison. RESULTS: Three thousand two hundred and sixteen articles identified from the three databases. Twelve met the inclusion criteria. Twenty-eight registries were identified using the grey literature. Strengths and weaknesses of Cancer Outcome Registries(COR) and Cancer Incidence Registries(CIR) were compared. Data linkage between registries or with other healthcare databases show great benefits in improving evidence for cancer research but are challenging to implement. Both registry types utilize differing modes of administration, influencing their accuracy and completeness. CONCLUSION: Outcome registries provide detailed data but their weakness lies in incomplete data coverage. Incidence registries record a large dataset which contain inaccuracies. Improving coverage of quality outcome registries, and quality assurance of data in incidence registries is required to ensure collection of accurate, meaningful data. Areas for collaboration identified included establishment of defined definitions and outcomes, data linkage between registry types or with healthcare databases, and collaboration in logistical planning to improve clinical utility of cancer registries.

Weight a minute: Exploring the effect on weight and body composition after the initiation of elexacaftor/tezacaftor/ivacaftor in adults with CF.

BACKGROUND: Life expectancy for people with CF (PwCF) continues to increase. However, a trend of overweight and obesity is emerging along with concern of developing comorbitities. Body composition (BC) is associated with several health indices. However, body mass index (BMI) does not provide information on BC. METHODS: BMI, fat mass (FM), fat free mass (FFM), using bioelectrical impedance, lung function and sweat chloride (SwCl) were assessed in adult PwCF in routine clinic before and after commencement of the CFTR modulator Elexacaftor/Tezacaftor/Ivacaftor. RESULTS: 109 PwCF (76 male) underwent assessments at both time points. In all PwCF a significant upward trend in BMI was observed (p < 0.001). Males significantly gained more FFM compared to females (p0.03), whilst prevalence of normal weight obesity increased primarily in females (25-38%). CONCLUSION: Routine BC assessment identifies individuals with elevated FM or depleted FFM enabling individualised care with the focus of optimising BC.

DECIDE: Delphi Expert Consensus Statement on Inflammatory Bowel Disease Dysplasia Shared Management Decision-Making.

BACKGROUND AND AIMS: Inflammatory bowel disease colitis-associated dysplasia is managed with either enhanced surveillance and endoscopic resection or prophylactic surgery. The rate of progression to cancer after a dysplasia diagnosis remains uncertain in many cases and patients have high thresholds for accepting proctocolectomy. Individualised discussion of management options is encouraged to take place between patients and their multidisciplinary teams for best outcomes. We aimed to develop a toolkit to support a structured, multidisciplinary and shared decision-making approach to discussions about dysplasia management options between clinicians and their patients. METHODS: Evidence from systematic literature reviews, mixed-methods studies conducted with key stakeholders, and decision-making expert recommendations were consolidated to draft consensus statements by the DECIDE steering group. These were then subjected to an international, multidisciplinary modified electronic Delphi process until an a priori threshold of 80% agreement was achieved to establish consensus for each statement. RESULTS: In all, 31 members [15 gastroenterologists, 14 colorectal surgeons and two nurse specialists] from nine countries formed the Delphi panel. We present the 18 consensus statements generated after two iterative rounds of anonymous voting. CONCLUSIONS: By consolidating evidence for best practice using literature review and key stakeholder and decision-making expert consultation, we have developed international consensus recommendations to support health care professionals counselling patients on the management of high cancer risk colitis-associated dysplasia. The final toolkit includes clinician and patient decision aids to facilitate shared decision-making.

Local anaesthetic infiltration in rubber band ligation of rectal haemorrhoids: study protocol for a three-arm, double-blind randomised controlled trial (PLATIPUS trial).

INTRODUCTION: Rubber band ligation ('banding') is a common approach for the management of symptomatic haemorrhoids. However, up to 90% of patients experience postprocedural pain, and there is no consensus regarding the optimal analgesic strategy. In practice, patients may receive submucosal local anaesthetic, pudendal nerve block or routine periprocedural analgesia. The aim of this study is to compare the efficacy of submucosal local anaesthetic, pudendal nerve block and routine analgesia for postprocedural pain in patients undergoing haemorrhoid banding. METHODS AND ANALYSIS: This is a multicentre, prospective, three-arm, double-blind randomised controlled trial of adults booked for haemorrhoid banding. Participants will be randomised to one of three groups in a 1:1:1 ratio: (1)submucosal bupivacaine injection; (2) pudendal nerve ropivacaine injection and (3) no local anaesthetic. The primary outcome is patient reported postprocedural pain (scored 0-10) from 30 min to 2 weeks. Secondary outcomes include postprocedural analgesia use, time to discharge, patient satisfaction, time to return to work and complications. A sample size of 120 patients is required to achieve statistical significance. ETHICS AND DISSEMINATION: This study received Human Research Ethics Approval from the Austin Health Human Research Ethics Committee (March 2022). Trial results will be submitted to a peer-reviewed journal, and presented at academic meetings. A summary of the trial results will be made available to study participants on request. TRIAL REGISTRATION NUMBER: ACTRN12622000006741p.

Reactive Oxygen Species as Mediators of Disease Progression and Therapeutic Response in Colorectal Cancer.

Significance: Reactive oxygen species (ROS) are critical to normal cellular function with redox homeostasis achieved by balancing ROS production with removal through detoxification mechanisms. Many of the conventional chemotherapies used to treat colorectal cancer (CRC) derive a proportion of their cytotoxicity from ROS generation, and resistance to chemotherapy is associated with elevated detoxification mechanisms. Furthermore, cancer stem cells demonstrate elevated detoxification mechanisms making definitive treatment with existing chemotherapy challenging. In this article, we review the roles of ROS in normal and malignant colonic cell biology and how existing and emerging therapies might harness ROS for therapeutic benefit. Recent Advances: Recent publications have elucidated the contribution of ROS to the cytotoxicity of conventional chemotherapy alongside the emerging approaches of photodynamic therapy (PDT), sonodynamic therapy (SDT), and radiodynamic therapy (RDT), in which ROS are generated in response to excitatory light, sound, or X-ray stimuli to promote cancer cell apoptosis. Critical Issues: The majority of patients with metastatic CRC have a very poor prognosis with a 5-year survival of ∼13% making the need for new or more effective treatments an imperative. Future Directions: Modulation of ROS through a combination of new and emerging therapies may improve the efficacy of current chemotherapy providing novel approaches to treat the otherwise resistant disease. Antioxid. Redox Signal. 39, 186-205.

Respiratory Viral and Bacterial Exacerbations of COPD-The Role of the Airway Epithelium.

COPD is a leading cause of death worldwide, with acute exacerbations being a major contributor to disease morbidity and mortality. Indeed, exacerbations are associated with loss of lung function, and exacerbation frequency predicts poor prognosis. Respiratory infections are important triggers of acute exacerbations of COPD. This review examines the role of bacterial and viral infections, along with co-infections, in the pathogenesis of COPD exacerbations. Because the airway epithelium is the initial site of exposure both to cigarette smoke (or other pollutants) and to inhaled pathogens, we will focus on the role of airway epithelial cell responses in regulating the pathophysiology of exacerbations of COPD. This will include an examination of the interactions of cigarette smoke alone, and in combination with viral and bacterial exposures in modulating epithelial function and inflammatory and host defense pathways in the airways during COPD. Finally, we will briefly examine current and potential medication approaches to treat acute exacerbations of COPD triggered by respiratory infections.

PGC-1α mediates a metabolic host defense response in human airway epithelium during rhinovirus infections.

Human rhinoviruses (HRV) are common cold viruses associated with exacerbations of lower airways diseases. Although viral induced epithelial damage mediates inflammation, the molecular mechanisms responsible for airway epithelial damage and dysfunction remain undefined. Using experimental HRV infection studies in highly differentiated human bronchial epithelial cells grown at air-liquid interface (ALI), we examine the links between viral host defense, cellular metabolism, and epithelial barrier function. We observe that early HRV-C15 infection induces a transitory barrier-protective metabolic state characterized by glycolysis that ultimately becomes exhausted as the infection progresses and leads to cellular damage. Pharmacological promotion of glycolysis induces ROS-dependent upregulation of the mitochondrial metabolic regulator, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), thereby restoring epithelial barrier function, improving viral defense, and attenuating disease pathology. Therefore, PGC-1α regulates a metabolic pathway essential to host defense that can be therapeutically targeted to rescue airway epithelial barrier dysfunction and potentially prevent severe respiratory complications or secondary bacterial infections.

A toolbox for studying respiratory viral infections using air-liquid interface cultures of human airway epithelial cells.

Submerged cultures of primary human airway epithelial cells or human airway epithelial cell lines have been a mainstay of airway epithelial biology research for decades due to their robust in vitro proliferative capacity, relatively low maintenance culture conditions, and clinically translatable results to nasal or bronchial brushings. With the development and improvement of air-liquid interface (ALI) cultures of human airway epithelial cells, such cultures have been considered superior to immortalized cell lines and primary cell monolayers, as such cultures effectively recapitulate in vivo epithelial architecture and cell types. Although ALI culture growth protocols are well-established and widely available, many researchers have avoided their use, as ALI cultures not only take longer to grow but also present technical challenges and limitations that make in vitro intracellular and structural assays taxing. Challenges arise relating to their complex structure, requirements for air exposure, the constraints of transwell growth apparatus, and interference in assays caused by mucus secretion. Although few publications briefly describe technical adaptations for some assays, there is still considerable trial and error required for researchers to establish consistent and reliable assay adaptations, often becoming a deterrent for pursuing mechanistic investigation. We have created a user-friendly toolbox detailing comprehensive protocols for numerous techniques and assay adaptations, particularly focusing on respiratory virus infections. By expanding the repertoire of ALI culture-adapted in vitro assays, we hope to facilitate the widespread adoption of this valuable culture system for mechanistic investigations of respiratory viral infections or other epithelial-pathogen models.