Making and breaking of boron bridges in the pectic domain rhamnogalacturonan-II at apoplastic pH in vivo and in vitro.

Cross-linking of the cell-wall pectin domain rhamnogalacturonan-II (RG-II) via boron bridges between apiose residues is essential for normal plant growth and development, but little is known about its mechanism or reversibility. We characterized the making and breaking of boron bridges in vivo and in vitro at 'apoplastic' pH. RG-II (13-26 µm) was incubated in living Rosa cell cultures and cell-free media with and without 1.2 mm H3 BO3 and cationic chaperones (Ca2+ , Pb2+ , polyhistidine, or arabinogalactan-protein oligopeptides). The cross-linking status of RG-II was monitored electrophoretically. Dimeric RG-II was stable at pH 2.0-7.0 in vivo and in vitro. In-vitro dimerization required a 'catalytic' cation at all pHs tested (1.75-7.0); thus, merely neutralizing the negative charge of RG-II (at pH 1.75) does not enable boron bridging. Pb2+ (20-2500 µm) was highly effective at pH 1.75-4.0, but not 4.75-7.0. Cationic peptides were effective at approximately 1-30 µm; higher concentrations caused less dimerization, probably because two RG-IIs then rarely bonded to the same peptide molecule. Peptides were ineffective at pH 1.75, their pH optimum being 2.5-4.75. d-Apiose (>40 mm) blocked RG-II dimerization in vitro, but did not cleave existing boron bridges. Rosa cells did not take up d-[U-14 C]apiose; therefore, exogenous apiose would block only apoplastic RG-II dimerization in vivo. In conclusion, apoplastic pH neither broke boron bridges nor prevented their formation. Thus boron-starved cells cannot salvage boron from RG-II, and 'acid growth' is not achieved by pH-dependent monomerization of RG-II. Divalent metals and cationic peptides catalyse RG-II dimerization via co-ordinate and ionic bonding respectively (possible and impossible, respectively, at pH 1.75). Exogenous apiose may be useful to distinguish intra- and extra-protoplasmic dimerization.

CLosure of Abdominal MidlineS Survey (CLAMSS): A national survey investigating current practice in the closure of abdominal midline incisions in UK surgical practice.

AIM: Incisional herniation (IH) is a frequent complication following midline abdominal closure with significant associated morbidity. Randomized controlled trials have demonstrated that the small bites technique (SBT) and prophylactic mesh augmentation (PMA) may reduce IH compared to mass closure techniques, but data are lacking on their implementation in contemporary surgical practice. This survey aimed to evaluate the use of the SBT and PMA and to identify factors associated with their adoption. METHOD: Between 22 January 2023 and 16 March 2023, consultant surgeons across the UK were asked to complete a 25-question survey on closure of an elective primary midline incision. RESULTS: Responses were received from 267 of 675 eligible surgeons (39.6%) in 38 NHS Trusts. Respondents were evenly split between tertiary centres (47.6%) and district general hospitals (49.4%). SBT and PMA were used by 19.9% and 3.0% of respondents, respectively. Compared to other techniques, surgeons using the SBT were more likely to close the anterior aponeurotic layer only, use single suture filaments, 2-0 gauge sutures and sharp needle points and routinely dissect abdominal layers to aid closure (all p < 0.001). Attendance at lectures/conferences on SBT (p = 0.043) and basing practice on available evidence (p < 0.001) were independently associated with use of the SBT. The commonest barriers to adopting SBT were a perceived lack of evidence (23.8%) and belief that personal IH rates were low (16.8%). CONCLUSION: A minority of UK consultant surgeons have adopted the SBT or PMA. Practice change should be driven by more widespread dissemination of current evidence and procedural information.

SARS-CoV-2 infection among physicians over time in Ontario, Canada: a population-based retrospective cohort study.

AIM: To assess this risk of SARS-CoV-2 infection among Ontario physicians by specialty and in comparison with non-physician controls during the COVID-19 pandemic. METHODS: In this retrospective cohort study, the primary outcome was incident SARS-CoV-2 infection confirmed by polymerase chain reaction (PCR). Secondary outcomes were hospitalization, use of critical care, and mortality. RESULTS: From March 1, 2020 to December 31, 2022, 6172/30 617 (20%) active Ontario physicians tested positive for SARS-CoV-2. Infection was less likely if physicians were older (OR 0.78 [0.76-0.81] per 10 years), rural residents (OR 0.70 [0.59-0.83]), and lived in more marginalized neighborhoods (OR 0.74 [0.62-0.89]), but more likely if they were female (OR 1.14 [1.07-1.22]), worked in long-term care settings (OR 1.16 [1.02-1.32]), had higher patient volumes (OR 2.05 [1.82-2.30] for highest vs lowest), and were pediatricians (OR 1.25 [1.09-1.44]). Compared with community-matched controls (n=29 763), physicians had a higher risk of infection during the first two waves of the pandemic (OR 1.38 [1.20-1.59]) but by wave 3 the risk was no longer significantly different (OR 0.93 [0.83-1.05]). Physicians were less likely to be hospitalized within 14 days of their first positive PCR test than non-physicians (P<0.0001), but there was no difference in the use of critical care (P=0.48) or mortality (P=0.15). CONCLUSION: Physicians had higher rates of infection than community-matched controls during the first two waves of the pandemic in Ontario, but not from wave 3 onward. Physicians practicing in long-term care facilities and pediatricians were more likely to test positive for SARS-CoV-2 than other physicians.

Colorectal cancer incidence trends by tumour location among adults of screening-age in England: a population-based study.

AIM: Proximal and distal colorectal cancers (CRCs) exhibit different clinical, molecular and biological patterns. The aim of this study was to determine temporal trends in the age-standardized incidence rates (ASIRs) of proximal and distal CRC following the introduction of the English Bowel Cancer Screening Programme (BCSP) in 2006. METHOD: The National Cancer Registration and Analysis Service database was used to identify incident cases of CRC among adults of screening age (60-74 years) between 2001 and 2017. ASIRs were calculated using the European Standard Population 2013 and incidence trends analysed by anatomical subsite (proximal, caecum to descending colon; distal, sigmoid to rectum), sex and Index of Multiple Deprivation (IMD) quintile using Joinpoint regression software. RESULTS: Between 2001 and 2017, 541 515 incident cases of CRC were diagnosed [236 167 proximal (43.6%) and 305 348 distal (56.4%)]. A marginal reduction in the proximal ASIR was noted from 2008 [annual percentage change (APC) -1.4% (95% CI -2.0% to -0.9%)] compared with a greater reduction in distal ASIR from 2011 to 2014 [APC -6.6% (95% CI -11.5% to -1.5%)] which plateaued thereafter [APC -0.5% (95% CI -3.2% to 2.2%)]. Incidence rates decreased more rapidly in men than women. Adults in IMD quintiles 4-5 experienced the greatest reduction in distal tumours [APC -3.5% (95% CI -4.3% to -2.7%)]. CONCLUSION: Following the introduction of the English BCSP, the incidence of CRC has subsequently reduced among adults of screening age, with this trend being most pronounced in distal tumours and in men. There is also evidence of a reduction in the deprivation gap for distal tumour incidence. Strategies to improve the detection of proximal tumours are warranted.

Lesbian, gay, bisexual, transgender and or queer patient experiences in Canadian primary care and emergency departments: a literature review.

This literature review synthesises existing evidence and offers a thematic analysis of primary care and emergency department experiences of lesbian, gay, bisexual, transgender, queer and/or any other sexual or gender minority (LGBTQ+) individuals in Canada. Articles detailing first-person primary or emergency care experiences of LGBTQ + patients were included from EMBASE, MEDLINE, PsycINFO and CINHAL. Studies published before 2011, focused on the COVID-19 pandemic, unavailable in English, non-Canadian, specific to other healthcare settings, and/or only discussing healthcare provider experiences were excluded. Critical appraisal was performed following title/abstract screening and full-text review by three reviewers. Of sixteen articles, half were classified as general LGBTQ + experiences and half as trans-specific experiences. Three overarching themes were identified: discomfort/disclosure concerns, lack of positive space signalling, and lack of healthcare provider knowledge. Heteronormative assumptions were a key theme among general LGBTQ + experiences. Trans-specific themes included barriers to accessing care, the need for self-advocacy, care avoidance, and disrespectful communication. Only one study reported positive interactions. LGBTQ + patients continue to have negative experiences within Canadian primary and emergency care - at the provider level and due to system constraints. Increasing culturally competent care, healthcare provider knowledge, positive space signals, and decreasing barriers to care can improve LGBTQ + experiences.

Emergency department care experiences among members of equity-deserving groups: quantitative results from a cross-sectional mixed methods study.

BACKGROUND: Emergency departments (EDs) serve an integral role in healthcare, particularly for vulnerable populations. However, marginalized groups often report negative ED experiences, including stigmatizing attitudes and behaviours. We engaged with historically marginalized patients to better understand their ED care experiences. METHOD: Participants were invited to complete an anonymous mixed-methods survey about a previous ED experience. We analysed quantitative data including controls and equity-deserving groups (EDGs) - those who self-identified as: (a) Indigenous; (b) having a disability; (c) experiencing mental health issues; (d) a person who uses substances; (e) a sexual and gender minority; (f) a visible minority; (g) experiencing violence; and/or (h) facing homelessness - to identify differences in their perspectives. Differences between EDGs and controls were calculated with chi squared tests, geometric means with confidence ellipses, and the Kruskal-Wallis H test. RESULTS: We collected a total of 2114 surveys from 1973 unique participants, 949 controls and 994 who identified as equity-deserving. Members of EDGs were more likely to attribute negative feelings to their ED experience (p < 0.001), to indicate that their identity impacted the care received (p < 0.001), and that they felt disrespected and/or judged while in the ED (p < 0.001). Members of EDGs were also more likely to indicate that they had little control over healthcare decisions (p < 0.001) and that it was more important to be treated with kindness/respect than to receive the best possible care (p < 0.001). CONCLUSION: Members of EDGs were more likely to report negative ED care experiences. Equity-deserving individuals felt judged and disrespected by ED staff and felt disempowered to make decisions about their care. Next steps will include contextualizing findings using participants' qualitative data and identifying how to improve ED care experiences among EDGs to make it more inclusive and better able to meet their healthcare needs.

Managing surgical demand when needs outstrip resource: qualitative investigation of colorectal cancer surgery provision in the first wave of the COVID-19 pandemic.

BACKGROUND: At the onset of the COVID-19 pandemic, elective surgical provision was severely affected by the need for hospital reorganization to care for critically ill patients. In response, National Health Service (NHS) England issued national guidance proposing acceptable time intervals for postponing different types of surgical procedure. This study reports healthcare professionals' private accounts of the strategies adopted to manage the imbalance of demand and resource, using colorectal cancer surgery as a case study. METHODS: Twenty-seven semistructured interviews were conducted with healthcare professionals between June and November 2020. A key informant sampling approach was used, followed by snowballing to achieve maximum regional variation across the UK. Data were analysed thematically using the constant comparison approach. RESULTS: In the context of considerable resource constraint, surgical teams overcame challenges to continue elective cancer provision. They achieved this by pursuing a combination of strategies: relocating surgical services; prioritizing patients within and across surgical specialties; adapting patient treatment plans; and introducing changes to surgical team working practices. Despite national guidance, prioritization decisions were framed as complex, and the most challenging of the strategies to implement, both practically and emotionally. CONCLUSION: There is a need to better support surgeons tasked with prioritizing patients when capacity exceeds demand.

A combined spatial score of granzyme B and CD68 surpasses CD8 as an independent prognostic factor in TNM stage II colorectal cancer.

BACKGROUND: Previous assessments of peritumoral inflammatory infiltrate in colorectal cancer (CRC) have focused on the role of CD8+ T lymphocytes. We sought to compare the prognostic value of CD8 with downstream indicators of active immune cell function, specifically granzyme B (GZMB) and CD68 in the tumour microenvironment. METHODS: Immunohistochemical (IHC) staining was performed for CD8, GZMB, CD68 and CD163 on next-generation tissue microarrays (ngTMAs) in a primary cohort (n = 107) and a TNM stage II validation cohort (n = 151). Using digital image analysis, frequency of distinct immune cell types was calculated for tumour proximity (TP) zones with varying radii (10 µm-100 µm) around tumour cells. RESULTS: Associations notably of advanced TNM stage were observed for low density of CD8 (p = 0.002), GZMB (p < 0.001), CD68 (p = 0.034) and CD163 (p = 0.011) in the primary cohort. In the validation cohort only low GZMB (p = 0.036) was associated with pT4 stage. Survival analysis showed strongest prognostic effects in the TP25µm zone at the tumour centre for CD8, GZMB and CD68 (all p < 0.001) in the primary cohort and for CD8 (p = 0.072), GZMB (p = 0.035) and CD68 (p = 0.004) in the validation cohort with inferior prognostic effects observed at the tumour invasive margin. In a multivariate survival analysis, joint analysis of GZMB and CD68 was similarly prognostic to CD8 in the primary cohort (p = 0.007 vs. p = 0.002) and superior to CD8 in the validation cohort (p = 0.005 vs. p = 0.142). CONCLUSION: Combined high expression of GZMB and CD68 within 25 µm to tumour cells is an independent prognostic factor in CRC and of superior prognostic value to the well-established CD8 in TNM stage II cancers. Thus, assessment of antitumoral effect should consider the quality of immune activation in peritumoral inflammatory cells and their actual proximity to tumour cells.

Airway injury from the presence of endotracheal tubes and the association with subglottic secretion drainage: a prospective observational study.

PURPOSE: Laryngeal and tracheal injuries are known complications of endotracheal intubation. Endotracheal tubes (ETTs) with subglottic suction devices (SSDs) are commonly used in the critical care setting. There is concern that herniation of tissue into the suction port of these devices may lead to tracheal injury resulting in serious clinical consequences such as tracheal stenosis. We aimed to describe the type and location of tracheal injuries seen in intubated critically ill patients and assess injuries at the suction port as well as in-hospital complications associated with those injuries. METHODS: We conducted a prospective observational study of 57 critically ill patients admitted to a level 3 intensive care unit who were endotracheally intubated and underwent percutaneous tracheostomy. Investigators performed bronchoscopy and photographic evaluation of the airway during the percutaneous tracheostomy procedure to evaluate tracheal and laryngeal injury. RESULTS: Forty-one (72%) patients intubated with ETT with SSD and sixteen (28%) patients with standard ETT were included in the study. Forty-seven (83%) patients had a documented airway injury ranging from hyperemia to deep ulceration of the mucosa. A common tracheal injury was at the site of the tracheal cuff. Injury at the site of the subglottic suction device was seen in 5/41 (12%) patients. There were no in-hospital complications. CONCLUSIONS: Airway injury was common in critically ill patients following endotracheal intubation, and tracheal injury commonly occurred at the site of the endotracheal cuff. Injury occurred at the site of the subglottic suction port in some patients although the clinical consequences of these injuries remain unclear.

RéSUMé: OBJECTIF: Les lésions laryngées et trachéales sont des complications connues de l'intubation endotrachéale. Les sondes endotrachéales (SET) avec dispositifs d'aspiration sous-glottiques (DASG) sont couramment utilisées aux soins intensifs. On craint qu'une hernie tissulaire dans l'orifice d'aspiration de ces dispositifs n'entraîne des lésions trachéales, résultant en de graves conséquences cliniques telles qu'une sténose trachéale. Nous avons cherché à décrire le type et l'emplacement des lésions trachéales observées chez les patients gravement malades intubés et à évaluer les lésions au port d'aspiration ainsi que les complications hospitalières associées à ces lésions. MéTHODE: Nous avons mené une étude observationnelle prospective auprès de 57 patients gravement malades admis dans une unité de soins intensifs de niveau 3 qui ont été intubés par voie endotrachéale et ont subi une trachéostomie percutanée. Les chercheurs ont réalisé une bronchoscopie et une évaluation photographique des voies aériennes au cours de la trachéostomie percutanée afin d'évaluer les lésions trachéales et laryngées. RéSULTATS: Quarante et un (72 %) intubés par SET avec DASG et seize (28 %) patients avec SET standard ont été inclus dans l'étude. Quarante-sept (83 %) patients ont présenté une lésion documentée des voies aériennes allant de l'hyperémie à l'ulcération profonde de la muqueuse. Une lésion trachéale commune était localisée sur le site du ballonnet trachéal. Une lésion au site du dispositif d'aspiration sous-glottique a été observée chez 5/41 (12 %) patients. Il n'y a pas eu de complications à l'hôpital. CONCLUSION: Les lésions des voies aériennes étaient fréquentes chez les patients gravement malades après une intubation endotrachéale, et les lésions trachéales se produisaient généralement au site du ballonnet endotrachéal. Des lésions se sont produites au site de l'orifice d'aspiration sous-glottique chez certains patients, bien que les conséquences cliniques de ces lésions restent incertaines.

Outcomes following local excision of early anal squamous cell carcinomas of the anal canal and perianal margin.

AIM: There is a paucity of data on outcomes from local excision (LE) of early anal squamous cell carcinomas (ASCCs). This study aimed to assess survival outcomes according to tumour location, perianal (PAT) or anal canal (ACT), and to determine factors associated with R1 excision and outcomes according to T-category. METHODS: This was a retrospective cohort study of consecutive patients with early ASCC treated by LE from 2007 to 2019. Data were collected on baseline demographics, tumour location, staging, excision histology, adjuvant treatment, site and timing of recurrence. The main outcome measures were R1 resection, locoregional recurrence (LRR), disease-free survival and overall survival. RESULTS: Of 367 patients treated for ASCC, 39 (10.6%) patients with complete follow-up data underwent LE: 15 ACTs and 24 PATs. R1 resections were obtained in 27 patients (69.2%) and occurred more frequently in ACTs than PATs (93.3% vs. 54.2%, P = 0.006). Eighteen of 27 patients (66.7%) received adjuvant therapy (chemoradiotherapy [n = 11], radiotherapy alone [n = 7]) for R1 excision or re-excision, following which LRR developed in one of 10 (10.0%) patients in the ACT cohort and one of eight (12.5%) patients in the PAT cohort. There was no difference in 5-year LRR-free survival (82.0% vs. 70.1%, P = 0.252), disease-free survival (58.2% vs. 78.4%, P = 0.200) or overall survival (86.2% vs. 95.7%, P = 0.607) between the ACT and PAT cohorts. CONCLUSIONS: LE is a feasible treatment option for early ASCCs of the perianal margin but not the anal canal. Acceptable long-term outcomes can still be achieved with adjuvant therapy in the presence of a positive margin. Larger prospective studies to assess LE as a treatment strategy, such as the ACT3 trial, are warranted.

A multicentre investigation of organ and tissue donation education for critical care residents.

PURPOSE: To describe critical care medicine residents' training, expertise, and skills regarding organ and tissue donation processes and procedures. METHODS: We undertook a qualitative multicentre study and employed a purposive sample of program directors, physicians, nurses, residents, and organ donation leaders from all nine academic intensive care unit (ICU) training centres (five adult, four pediatric) in Ontario (n = 71). Interviews, conducted by telephone between December 2015 and March 2016, were audio-recorded and transcribed verbatim. Data collection and analysis were performed using an iterative process and continued until saturation was achieved. RESULTS: Five main themes were identified: 1) gaps in residents' knowledge for both neurologic determination of death (NDD) and circulatory determination of death (DCD) cases; 2) commitment to the provision of organ and tissue donation training; 3) limited experiential learning (NDD and DCD); 4) challenges related to the provision of training on organ donation and need for a standardized curriculum; and 5) communication with family members. Overall, this study showed system-level gaps in training resulting from the lack of a standardized provincial curriculum on organ donation. CONCLUSIONS: Qualitative data corroborated that residents need more exposure to clinical cases, especially regarding DCD donors. A standardized education curriculum would be beneficial for all residents within the ICU. Developing a better shared understanding of the donation process will improve team communication and performance, translate into a better end-of-life experience for families, and potentially result in increased donation rates.

HtrA3 stromal expression is correlated with tumor budding in stage II colorectal cancer.

Tumor budding is a well-established adverse prognostic factor in colorectal carcinoma (CRC). It may represent a form of epithelial-to-mesenchymal transition (EMT), although the underlying mechanisms remain unclear. High-temperature requirement A3 (HtrA3) is an inhibitor of the bone morphogenetic protein pathway, the suppression of which has been linked to EMT. Since HtrA3 is highly expressed in the desmoplastic stroma at the CRC invasive front, we sought to evaluate the relationship between tumor budding and HtrA3 expression in 172 stage II CRC resection specimens. All tumors were evaluated for tumor budding, with the highest budding slide selected for pan-keratin (CK) and HtrA3 immunohistochemistry. Representative areas of tumor core and invasive front, including budding and non-budding areas, were marked on CK stained slides, and then evaluated on HtrA3 stained slides. HtrA3 expression in tumor cells (tHtrA3) and peritumoral stroma (sHtrA3) was assessed for staining percentage and intensity (the product yielding a final score). Tumors with high-grade tumor budding (HGTB) showed increased expression of sHtrA3 in budding areas compared to non-budding areas at the invasive front (P<0.001). In addition, sHtrA3 expression at the invasive front was significantly higher in HGTB tumors compared to minimally budding tumors (P<0.05). tHtrA3 expression at the invasive front was significantly associated with high histological grade (P<0.05). Higher sHtrA3 expression in the tumor core (but not invasive front) was significantly associated with decreased 5-year overall survival on univariate analysis (P<0.05), but not multivariate analysis. HtrA3 expression in the peritumoral stroma of patients with stage II CRC is associated with HGTB and may be a novel marker of poor outcome.

Factors predicting outcome from enhanced recovery programmes in laparoscopic colorectal surgery: a systematic review.

OBJECTIVE: To perform a systematic review of published literature for the factors reported to predict outcomes of enhanced recovery after surgery (ERAS) programmes following laparoscopic colorectal surgery. BACKGROUND: ERAS programmes and the use of laparoscopy have been widely adopted in colorectal surgery bringing short-term patient benefit. However, there is a minority of patients that do not benefit from these strategies and their identification is not well characterised. The factors that underpin outcomes from ERAS programmes for laparoscopic patients are not understood. METHODS: A systematic search of the MEDLINE, Embase and Cochrane databases was conducted to identify suitable articles published between 2000 and 2015. The search strategy captured terms for ERAS, colorectal resection, prediction and outcome measures. RESULTS: Thirty-four studies containing 10,861 laparoscopic resections were included. Thirty-one (91 %) studies were confined to elective cases. Predictive analysis of outcome was most frequently based on length of stay (LOS), morbidity and readmission which were the main outcome measures of 29 (85 %), 26 (76 %) and 18 (53 %) of the included studies, respectively. Forty-seven percentage of included studies investigated the impact of ERAS programme compliance on these outcomes. Reduced protocol compliance was the most frequently identified modifiable predictive factor for adverse LOS, morbidity and readmission. CONCLUSION: Protocol compliance is the most frequently reported predictive factor for outcomes of ERAS programmes following laparoscopic colorectal resection. Reduced compliance increases LOS, morbidity and readmission to hospital. The impact of compliance with individual ERAS protocol elements is insufficiently studied, and the lack of a standardised framework for evaluating ERAS programmes makes it difficult to draw definite conclusions about which factors exert the greatest impact on outcome after laparoscopic colorectal resection.

A Systematic Review of Local Excision After Neoadjuvant Therapy for Rectal Cancer: Are ypT0 Tumors the Limit?

BACKGROUND: Neoadjuvant therapy reduces local recurrence after radical surgery for rectal cancer with complete pathological response in 15% to 25% of patients. Radical surgery is associated with significant morbidity that may be avoided by local excision in selected cases. OBJECTIVE: This systematic review aimed to determine the oncological outcomes and morbidity of local excision after neoadjuvant therapy. DATA SOURCES: Data sources included MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials databases. STUDY SELECTION: A systematic search of the databases using validated terms for rectal cancer, neoadjuvant therapy, and local excision was conducted. INTERVENTIONS: Neoadjuvant therapy and local excision were the included interventions. MAIN OUTCOME MEASURES: Pooled local recurrence, median survival, and pooled morbidity were measured. RESULTS: Twenty unique studies were included (14 cohort, 5 comparative cohort, and 1 randomized controlled trial), describing 1068 patients. Patient choice, prohibitive comorbidity, good clinical response, and early stage disease were the most frequent indications for local excision. Pretreatment T2 and T3 tumors accounted for 46.4% and 30.7% of cases. Long-course treatment was administered in all of the studies, except to a cohort of 64 patients who received short-course radiotherapy. Pooled complete clinical response was 45.8% (95% CI, 31.4%-60.5%), and pooled complete pathological response was 44.2% (95% CI, 36.4%-52.0%). Median follow-up was 54 months (range, 12-81 months). ypT0 tumors had a pooled local recurrence rate of 4.0% (95% CI, 1.9%-6.9%) and a median disease-free survival rate of 95.0% (95% CI, 87.4%-100%). Pooled local recurrence and median disease-free survival rates for ypT1 tumors or higher were 21.9% (95% CI, 15.9%-28.5%) and 68.0% (58.3%-69.0%). Pooled incidence of complications was 23.2% (95% CI, 15.7%-31.7%), with suture-line dehiscence reported in 9.9% (95% CI, 4.8%-16.7%). LIMITATIONS: Limitations included study quality, high risk of selection bias and detection bias in study designs, and limited sample sizes. CONCLUSIONS: Local excision after neoadjuvant therapy should only be considered a curative treatment if complete pathological response is obtained. Given the high rate of local recurrence among incomplete responders, future studies should focus on predicting patients who will achieve complete pathological response.

How we developed a comprehensive resuscitation-based simulation curriculum in emergency medicine.

Over the past decade, simulation-based education has emerged as a new and exciting adjunct to traditional bedside teaching and learning. Simulation-based education seems particularly relevant to emergency medicine training where residents have to master a very broad skill set, and may not have sufficient real clinical opportunities to achieve competence in each and every skill. In 2006, the Emergency Medicine program at Queen's University set out to enhance our core curriculum by developing and implementing a series of simulation-based teaching sessions with a focus on resuscitative care. The sessions were developed in such as way as to satisfy the four conditions associated with optimum learning and improvement of performance; appropriate difficulty of skill, repetitive practice, motivation, and immediate feedback. The content of the sessions was determined with consideration of the national training requirements set out by the Royal College of Physicians & Surgeons of Canada. Sessions were introduced in a stepwise fashion, starting with a cardiac resuscitation series based on the AHA ACLS guidelines, and leading up to a more advanced resuscitation series as staff became more adept at teaching with simulation, and as residents became more comfortable with this style of learning. The result is a longitudinal resuscitation curriculum that begins with fundamental skills of resuscitation and crisis resource management (CRM) in the first 2 years of residency and progresses through increasingly complex resuscitation cases where senior residents are expected to play a leadership role. This paper documents how we developed, implemented, and evaluated this resuscitation-based simulation curriculum for Emergency Medicine postgraduate trainees, with discussion of some of the challenges encountered.

Boron bridging of rhamnogalacturonan-II, monitored by gel electrophoresis, occurs during polysaccharide synthesis and secretion but not post-secretion.

The cell-wall pectic domain rhamnogalacturonan-II (RG-II) is cross-linked via borate diester bridges, which influence the expansion, thickness and porosity of the wall. Previously, little was known about the mechanism or subcellular site of this cross-linking. Using polyacrylamide gel electrophoresis (PAGE) to separate monomeric from dimeric (boron-bridged) RG-II, we confirmed that Pb(2+) promotes H3 BO3 -dependent dimerisation in vitro. H3 BO3 concentrations as high as 50 mm did not prevent cross-linking. For in-vivo experiments, we successfully cultured 'Paul's Scarlet' rose (Rosa sp.) cells in boron-free medium: their wall-bound pectin contained monomeric RG-II domains but no detectable dimers. Thus pectins containing RG-II domains can be held in the wall other than via boron bridges. Re-addition of H3 BO3 to 3.3 µm triggered a gradual appearance of RG-II dimer over 24 h but without detectable loss of existing monomers, suggesting that only newly synthesised RG-II was amenable to boron bridging. In agreement with this, Rosa cultures whose polysaccharide biosynthetic machinery had been compromised (by carbon starvation, respiratory inhibitors, anaerobiosis, freezing or boiling) lost the ability to generate RG-II dimers. We conclude that RG-II normally becomes boron-bridged during synthesis or secretion but not post-secretion. Supporting this conclusion, exogenous [(3) H]RG-II was neither dimerised in the medium nor cross-linked to existing wall-associated RG-II domains when added to Rosa cultures. In conclusion, in cultured Rosa cells RG-II domains have a brief window of opportunity for boron-bridging intraprotoplasmically or during secretion, but secretion into the apoplast is a point of no return beyond which additional boron-bridging does not readily occur.

Symptomatic diaphragmatic herniation following open and minimally invasive oesophagectomy: experience from a UK specialist unit.

BACKGROUND: The uptake of minimally invasive oesophagectomy (MIO) in the UK has increased dramatically in recent years. Post-oesophagectomy diaphragmatic hernias (PODHs) are rare, but may be influenced by the type of approach to resection. The aim of this study was to compare the incidence of symptomatic PODH following open and MIO in a UK specialist centre. METHODS: Consecutive patients undergoing oesophagectomy for malignant disease between 1996 and 2012 were included. A standardised, radical approach to the abdominal phase was employed, irrespective of the type of procedure undertaken. Patient demographics, details of surgery and post-operative complications were collected from patient records and a prospective database. RESULTS: A total of 273 oesophagectomies were performed (205 open; 68 MIO). There were 62 hybrid MIOs (laparoscopic abdomen and thoracotomy) and six total MIOs. Seven patients required conversion and were analysed as part of the open cohort. Nine patients (13.2 %) developed a PODH in the MIO cohort compared with two patients (1.0 %) in the open cohort, (p < 0.001). Five patients developed hernias in the early post-operative period (days 2-10): all following MIO. Both PODHs in the open cohort occurred following transhiatal oesophagectomy. All PODHs were symptomatic and required surgical repair. CT thorax confirmed the diagnosis in 10 patients. Seven hernias were repaired laparoscopically, including two cases in the early post-operative period. PODHs were repaired using the following techniques: suture (n = 6), mesh reinforcement (n = 4) and omentopexy to the anterior abdominal wall without hiatal closure (n = 1). There were two recurrences (18 %). CONCLUSIONS: The incidence of symptomatic PODH may be higher following MIO compared to open surgery. The reasons for this are unclear and may not be completely explained by the reduction in adhesion formation. Strategies such as fixation of the conduit to the diaphragm and omentopexy to the abdominal wall may reduce the incidence of herniation.

Subtotal colectomy in severe ulcerative and Crohn's colitis: what benefit does the laparoscopic approach confer?

BACKGROUND: Comparative outcome data for laparoscopic and open subtotal colectomy in IBD are lacking and often difficult to interpret owing to low case volumes, heterogeneity in case mix, and variation in laparoscopic technique. OBJECTIVE: This study aimed to determine the safety of laparoscopic subtotal colectomy in severe colitis and to determine whether the laparoscopic approach improved short-term outcomes in comparison with the open approach. DESIGN: This was a retrospective cohort study using data from a prospectively maintained clinical database. SETTING: This study was conducted at a single center, Mount Sinai Hospital, Toronto. PATIENTS: All patients undergoing subtotal colectomy for either ulcerative or Crohn's colitis between 2000 and 2011 were included. INTERVENTION: A standardized operative technique was used for both laparoscopic and open subtotal colectomies. Cases performed by non-laparoscopic surgeons were excluded. MAIN OUTCOME MEASURES: Perioperative outcome measures were operative duration, estimated blood loss, total morphine requirement, and length of postoperative stay. Postoperative outcome measures were the rates of minor and major complications. RESULTS: Laparoscopic subtotal colectomies were performed in 131 of 290 cases (45.2%). Nine patients required conversion to an open procedure (6.9%). The uptake of laparoscopic subtotal colectomy increased from 10.2% in 2000/2001 to 71.7% in 2010/2011. Regression analysis with propensity-score adjustment for operative approach revealed that the operative duration was 25.5 minutes longer in laparoscopic cases (95% CI 12.3-38.6; p < 0.001), but that patients experienced fewer minor complications (OR 0.47; 95% CI 0.23-0.96; p = 0.04) and required less morphine (adjusted difference, -72.8 mg; 95% CI 4.9-141; p = 0.04). LIMITATIONS: The inherent selection bias of this retrospective cohort study may not be accounted for by multivariate analysis with propensity-score adjustment. CONCLUSIONS: Laparoscopic subtotal colectomy is safe and may reduce the rate of minor postoperative complications. The increase in operative duration reflects the technical demands associated with this procedure (see Video, Supplemental Digital Content 1, http://links.lww.com/DCR/A160).

An adaptable in silico ensemble model of the arachidonic acid cascade.

Eicosanoids are a family of bioactive lipids, including derivatives of the ubiquitous fatty acid arachidonic acid (AA). The intimate involvement of eicosanoids in inflammation motivates the development of predictive in silico models for a systems-level exploration of disease mechanisms, drug development and replacement of animal models. Using an ensemble modelling strategy, we developed a computational model of the AA cascade. This approach allows the visualisation of plausible and thermodynamically feasible predictions, overcoming the limitations of fixed-parameter modelling. A quality scoring method was developed to quantify the accuracy of ensemble predictions relative to experimental data, measuring the overall uncertainty of the process. Monte Carlo ensemble modelling was used to quantify the prediction confidence levels. Model applicability was demonstrated using mass spectrometry mediator lipidomics to measure eicosanoids produced by HaCaT epidermal keratinocytes and 46BR.1N dermal fibroblasts, treated with stimuli (calcium ionophore A23187), (ultraviolet radiation, adenosine triphosphate) and a cyclooxygenase inhibitor (indomethacin). Experimentation and predictions were in good qualitative agreement, demonstrating the ability of the model to be adapted to cell types exhibiting differences in AA release and enzyme concentration profiles. The quantitative agreement between experimental and predicted outputs could be improved by expanding network topology to include additional reactions. Overall, our approach generated an adaptable, tuneable ensemble model of the AA cascade that can be tailored to represent different cell types and demonstrated that the integration of in silico and in vitro methods can facilitate a greater understanding of complex biological networks such as the AA cascade.

Do MRI reports contain adequate preoperative staging information for end users to make appropriate treatment decisions for rectal cancer?

PURPOSE: This study was designed to elicit end-user opinions regarding the importance and diagnostic accuracy of MRI for T-category, threatened or involved circumferential margin (CRMi), and lymph node involvement (LNi) for preoperative staging of rectal cancer and to determine completeness of MRI reports for these elements on a population based level. METHODS: The first part of this study was a mailed survey of surgeons, radiation oncologists, and medical oncologists to elicit their opinions regarding the importance and diagnostic accuracy of T-category, CRMi, and LNi on MRI. The second part of the study was an audit of MRI reports issued for pre-operative staging of rectal cancer to assess the completeness of these reports for T-category, CRMi, and LNi. RESULTS: Although T-category, CRMi, and LNi were considered essential by 97, 94, and 77 % of respondents, respectively, the MRI report audit showed that only 40 % of MRI reports captured all of these elements. The majority of end users reported moderate diagnostic accuracy on MRI for T-category and CRMi and low diagnostic accuracy for LNi (52.3, 43, and 48.5 % respectively). Multivariate analysis showed that specialty was the only independent predictor of correct reporting of the diagnostic accuracy for each of the MRI elements. CONCLUSIONS: While end users consider T-category, CRMi and LNi essential for preoperative staging of rectal cancer, less than 40 % of MRI reports captured all of these elements. Therefore, strategies to improve communication between radiologists and end users are critical to improve the overall quality of care for rectal cancer patients.