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Centralisation of rectal cancer surgery to designated centres was a key objective of the Irish national cancer control program. A national audit of rectal cancer surgery indicated centralisation was associated with improved early surgical outcomes. This study aimed to determine the impact of implementation of the national cancer strategy on survival from rectal cancer.Data were collected from the National Cancer Registry of Ireland to include all patients with Stage I-III rectal cancer undergoing rectal cancer surgery with curative intent between 2003 and 2012. Five-year overall survival and cancer-specific survival was compared between patients in the pre-centralisation (2003-2007) and post-centralisation period (2008-2012) and between patients receiving surgery in designated cancer centres and non-cancer centres.The proportion of rectal cancer surgery performed in a designated cancer centre increased from 42% during 2003-2007 to 58% during 2008-2012. Five-year overall survival increased from 66.1% in 2003-2007 to 73.5% in 2008-2012 (p 0.001). Five-year cancer-specific survival increased from 75.3% in 2003-2007 to 81.9% in 2008-2012 (p 0.001). Surgery in a cancer centre and surgery post-centralisation were significantly associated with overall and cancer specific survival using Cox proportional hazards regression.Survival following resection of rectal cancer was significantly improved following implementation of a national cancer strategy incorporating centralisation of rectal cancer surgery.

Mucinous rectal cancer is associated with a higher incidence of microsatellite instability, and a poorer response to neoadjuvant chemoradiotherapy compared to other subtypes of rectal adenocarcinoma. Immune checkpoint inhibitors are an emerging family of anti-cancer therapeutics associated with highly variable outcomes in colorectal cancer. Though the immune landscape of mucinous rectal cancer has not been fully explored, the presence of mucin is thought to act as a barrier preventing immune cell infiltration.The aim of this study was to determine the immune properties of mucinous rectal cancer and investigate the degree of lymphocyte infiltration in this cohort.This is a retrospective cohort study which involved, multiplexed immunofluorescence staining of tumor microarrays.Samples originated from a single university teaching hospital.Our cohort included 15 cases of mucinous and 43 cases of non-mucinous rectal cancer.Immune cells were classified and quantified. Immune cell counts were compared between mucinous and non-mucinous cohorts. Immune marker expression within tumor epithelial tissue was evaluated to determine degree of lymphocyte infiltration.Cytotoxic (p = 0.022), and regulatory T-cells (p = 0.010) were found to be overrepresented in the mucinous cohort compared to the non-mucinous group. PD-1 expression was also found to be significantly greater in the mucinous group (p = 0.001). CD3 (p = 0.001) and CD8 (p = 0.054) expression within tumor epithelium was also higher in the mucinous group, suggesting adequate immune infiltration despite the presence of mucin. Microsatellite instability status was not found to be a predictor of immune marker expression in our analysis.The relatively small size of the cohort.Mucinous rectal cancer is associated with an immune rich tumor microenvironment, which was not associated with microsatellite instability status. See Video Abstract at http://links.lww.com/DCR/C65.

Immune checkpoint inhibition has demonstrated success in overcoming tumor-mediated immune suppression in several types of cancer. However, its clinical use is limited to a small subset of colorectal cancer (CRC) patients, and response is highly variable between CRC subtypes. This study aimed to determine the profile of immune checkpoints and factors associated with immune checkpoint inhibitor response in mucinous CRC. Gene expression data from CRC was extracted from the TCGA PanCanAtlas data-freeze release. Gene expression data were reported as batch-corrected and normalized RNA expression derived from RNA-Seq quantification. Clinical, pathologic, and transcriptomic data were compared between mucinous and non-mucinous CRC cohorts. The 557 cases of CRC eligible for inclusion in this study comprised 486 cases of non-mucinous CRC (87.3 %) and 71 cases of mucinous CRC (12.7 %). High correlation was observed in the expression of the included immune checkpoints. Significantly higher expression of programmed cell death protein 1 ligand (PD-L1) and T cell immunoglobulin and mucin domain 3 (TIM-3) was observed in mucinous CRC than in non-mucinous CRC. In a multiple regression model, significant contributors to the prediction of TIM-3 gene expression were microsatellite instability (MSI) (unstandardized regression coefficient [B] = 1.223; p < 0.001), stage (American Joint Committee on Cancer [AJCC] 2; B = 0.423; p < 0.05), and mucinous status (B = 0.591; p < 0.01). Expression of TIM-3, an emerging immune checkpoint inhibition target, was significantly higher in mucinous CRC, and expression was predicted by mucinous status independently of MSI. These findings should prompt investigation of immune checkpoint signaling in the mucinous tumor microenvironment to clarify the potential for immune checkpoint inhibition in mucinous CRC.

Previous research has identified differences in mutation frequency in genes implicated in chemotherapy resistance between mucinous and non-mucinous colorectal cancers (CRC). We hypothesized that outcomes in mucinous and non-mucinous CRC may be influenced by expression of genes responsible for chemotherapy resistance. Gene expression data from primary tumor samples were extracted from The Cancer Genome Atlas PanCancer Atlas. The distribution of clinical, pathological, and gene expression variables was compared between 74 mucinous and 521 non-mucinous CRCs. Predictors of overall survival (OS) were assessed in a multivariate analysis. Kaplan–Meier curves were constructed to compare survival according to gene expression using the log rank test. The median expression of 5-FU-related genes TYMS, TYMP, and DYPD was significantly higher in mucinous CRC compared to non-mucinous CRC (p

Background Laparoscopic cholecystectomy is a safe ambulatory procedure in appropriately selected patients; however, day case rates remain low. The objective of this systematic review and meta-analysis was to identify interventions which are effective in reducing the length of stay (LOS) or improving the day case rate for elective laparoscopic cholecystectomy. Methods Comparative English-language studies describing perioperative interventions applicable to elective laparoscopic cholecystectomy in adult patients and their impact on LOS or day case rate were included. Results Quantitative data were available for meta-analysis from 80 studies of 10,615 patients. There were an additional 17 studies included for systematic review. The included studies evaluated 14 peri-operative interventions. Implementation of a formal day case care pathway was associated with a significantly shorter LOS (MD = 24.9 h, 95% CI, 18.7–31.2, p

ObjectivesTo evaluate the potential for long distance airborne transmission of SARS-CoV-2 in indoor community settings and to investigate factors that might influence transmission.DesignRapid systematic review and narrative synthesis.Data sourcesMedline, Embase, medRxiv, Arxiv, and WHO COVID-19 Research Database for studies published from 27 July 2020 to 19 January 2022; existing relevant rapid systematic review for studies published from 1 January 2020 to 27 July 2020; and citation analysis in Web of Science and Cocites.Eligibility criteria for study selectionObservational studies reporting on transmission events in indoor community (non-healthcare) settings in which long distance airborne transmission of SARS-CoV-2 was the most likely route. Studies such as those of household transmission where the main transmission route was likely to be close contact or fomite transmission were excluded.Data extraction and synthesisData extraction was done by one reviewer and independently checked by a second reviewer. Primary outcomes were SARS-CoV-2 infections through long distance airborne transmission (>2 m) and any modifying factors. Methodological quality of included studies was rated using the quality criteria checklist, and certainty of primary outcomes was determined using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework. Narrative synthesis was themed by setting.Results22 reports relating to 18 studies were identified (methodological quality was high in three, medium in five, and low in 10); all the studies were outbreak investigations. Long distance airborne transmission was likely to have occurred for some or all transmission events in 16 studies and was unclear in two studies (GRADE: very low certainty). In the 16 studies, one or more factors plausibly increased the likelihood of long distance airborne transmission, particularly insufficient air replacement (very low certainty), directional air flow (very low certainty), and activities associated with increased emission of aerosols, such as singing or speaking loudly (very low certainty). In 13 studies, the primary cases were reported as being asymptomatic, presymptomatic, or around symptom onset at the time of transmission. Although some of the included studies were well conducted outbreak investigations, they remain at risk of bias owing to study design and do not always provide the level of detail needed to fully assess transmission routes.ConclusionThis rapid systematic review found evidence suggesting that long distance airborne transmission of SARS-CoV-2 might occur in indoor settings such as restaurants, workplaces, and venues for choirs, and identified factors such as insufficient air replacement that probably contributed to transmission. These results strengthen the need for mitigation measures in indoor settings, particularly the use of adequate ventilation.Systematic review registrationPROSPERO CRD42021236762.

Background Response to neoadjuvant chemoradiotherapy (CRT) in locally advanced rectal cancer is variable. Identification of biomarkers to predict response is desirable in order to provide prognostic information and targeted therapy. Several studies have investigated microsatellite instability (MSI) as a predictor of response to CRT with contradictory results. This study aims to clarify the effect of MSI status on response to CRT in locally advanced rectal cancer through systematic review and meta-analysis. Methods A systematic search of PubMed, Embase and Cochrane databases was performed for all studies relating to MSI and response to CRT in rectal cancer using the search algorithm (Microsatellite Instability) AND (Chemoradiotherapy) AND (Rectal Cancer). From each included study the number of patients with MSI tumors and Microsatellite Stable (MSS) tumors and the numbers achieving pathological complete response (pCR) were recorded. Pooled outcome measures were determined using a random effects model and the odds ratio estimated with variance and 95% confidence interval. Results Nine published studies were identified reporting data on MSI and its effect on outcome after CRT for locally advanced rectal cancer. Five studies describing 5,877 patients included data on MSI and the number of patients achieving pCR. There was no significant association between MSI and pCR (MSI Vs MSS: 10.1% Vs 6.6%, OR 1.38, 95% CI: 0.7–2.72, p = 0.35). Conclusion This meta-analysis concludes that there appears to be no significant difference in pCR rate following CRT in patients with MSI versus MSS rectal tumors.

Aims: To investigate differences in expression of chemoresistance and cell death mediators between mucinous and non-mucinous CRC. Methods: Expression of chemotherapy resistance, cell death signalling and immune checkpoint genes was compared in mucinous and non-mucinous CRC in an open-access genetics database. A meta-analysis was performed measuring tumour response to neoadjuvant chemoradiotherapy according to expression of the fluorouracil target thymidylate synthase and the expression of thymidylate synthase was determined in an in-vitro model of mucinous rectal cancer. Cell death signalling proteins were analysed in mucinous versus non-mucinous cancer in an in-vitro model and in a tumour microarray. Results: Significant differences were observed in the expression of chemotherapy resistance genes between mucinous and non-mucinous CRC. SRPK1 was identified as a prognostic marker in rectal cancer. Significantly higher gene expression of immune checkpoints PD-L1 and TIM-3 was observed in mucinous CRC with mucinous status predicting expression of TIM-3. Low expression of the 5-FU target thymidylate synthase was associated with tumour response in a meta-analysis of neoadjuvant chemoradiotherapy for rectal cancer. Amplification of thymidylate synthase in response to fluorouracil was observed in a mucinous rectal cancer cell line. Significant differences in the expression of apoptotic and necroptotic proteins was observed between mucinous and non-mucinous cancer in a rectal cancer microarray and in a cell line model. Conclusion: Mucinous CRC is a distinct CRC subtype with molecular characteristics permitting chemotherapy resistance. These findings may inform investigation of targeted treatment in a therapeutically challenging cancer subtype.

Alternative splicing is implicated in each of the hallmarks of cancer, and is mechanised by various splicing factors. Serine-Arginine Protein Kinase 1 (SRPK1) is an enzyme which moderates the activity of splicing factors rich in serine/arginine domains. Here we review SRPK1’s relationship with various cancers by performing a systematic review of all relevant published data. Elevated SRPK1 expression correlates with advanced disease stage and poor survival in many epithelial derived cancers. Numerous pre-clinical studies investigating a host of different tumour types; have found increased SRPK1 expression to be associated with proliferation, invasion, migration and apoptosis in vitro as well as tumour growth, tumourigenicity and metastasis in vivo. Aberrant SRPK1 expression is implicated in various signalling pathways associated with oncogenesis, a number of which, such as the PI3K/AKT, NF-КB and TGF-Beta pathway, are implicated in multiple different cancers. SRPK1-targeting micro RNAs have been identified in a number of studies and shown to have an important role in regulating SRPK1 activity. SRPK1 expression is also closely related to the response of various tumours to platinum-based chemotherapeutic agents. Future clinical applications will likely focus on the role of SRPK1 as a biomarker of treatment resistance and the potential role of its inhibition.

Cancer cells’ ability to inhibit apoptosis is key to malignant transformation and limits response to therapy. Here, we performed multiplexed immunofluorescence analysis on tissue microarrays with 373 cores from 168 patients, segmentation of 2.4 million individual cells, and quantification of 18 cell lineage and apoptosis proteins. We identified an enrichment for BCL2 in immune, and BAK, SMAC, and XIAP in cancer cells. Ordinary differential equation-based modeling of apoptosis sensitivity at single-cell resolution was conducted and an atlas of inter- and intra-tumor heterogeneity in apoptosis susceptibility generated. Systems modeling at single-cell resolution identified an enhanced sensitivity of cancer cells to mitochondrial permeabilization and executioner caspase activation compared to immune and stromal cells, but showed significant inter- and intra-tumor heterogeneity.

Mucinous colorectal cancer is a unique histological subtype that is known to respond poorly to cytotoxic chemotherapy and radiotherapy. There are a number of genes known to be associated with resistance to 5-fluorouracil (5-FU), oxaliplatin, and irinotecan. The aim of this study was to compare the somatic mutation frequency and copy number variation (CNV) in these genes between mucinous and non-mucinous colorectal cancer. A systematic search of PubMed was performed to identify papers investigating drug resistance in colorectal cancer. From this review, a list of 26 drug-resistance-associated genes was compiled. Using patient data from The Cancer Genome Atlas (TCGA), the somatic mutation rate and CNV was compared between patients with mucinous and non-mucinous colorectal cancer. Statistical analysis was carried out using GraphPad PRISM® version 5.00. Data were available on 531 patients (464 non-mucinous, 67 mucinous). A statistically significant difference in the somatic mutation rate between the two cohorts was identified in the TYMP (p = 0.0179), ATP7B (p = 0.0465), SRPK1 (p = 0.0135), ABCB1 (p = 0.0423), and ABCG2 (p = 0.0102) genes. A statistically significant difference in CNV was identified between the two cohorts in the GSTP1 (p = 0.0405), CCS (p = 0.0063), and TOP1 (p = 0.0048) genes. Differences in somatic mutation rate and CNV in genes associated with resistance to 5-FU, oxaliplatin, and irinotecan may partly account for the pattern of resistance observed in mucinous colorectal cancers. These genetic alterations may prove useful when deciding on a personalized approach to chemotherapy and may also represent potential therapeutic targets going forward.

Background and objectives Mucinous adenocarcinoma is a distinct subtype of colorectal cancer (CRC) with a worse prognosis when compared with non-mucinous adenocarcinoma. The aim of this study was to compare somatic mutations and copy number alteration (CNA) between mucinous and non-mucinous CRC. Methods Data from The Cancer Genome Atlas-colon adenocarcinoma and rectum adenocarcinoma projects were utilized. Mucinous and non-mucinous CRC were compared with regard to microsatellite status, overall mutation rate, the most frequently mutated genes, mutations in genes coding for mismatch repair (MMR) proteins and genes coding for mucin glycoproteins. CNA analysis and pathway analysis was undertaken. Results Mucinous CRC was more likely to be microsatellite instability-high (MSI-H) and hypermutated. When corrected for microsatellite status the single-nucleotide variation and insertion-deletion rate was similar between the two cohorts. Mucinous adenocarcinoma was more likely to have mutations in genes coding for MMR proteins and mucin glycoproteins. Pathway analysis revealed further differences between the two histological subtypes in the cell cycle, RTK-RAS, transforming growth factor-β, and TP53 pathways. Conclusions Mucinous CRC has some distinct genomic aberrations when compared with non-mucinous adenocarcinoma, many of which are driven by the increased frequency of MSI-H tumors. These genomic aberrations may play an important part in the difference seen in response to treatment and prognosis in mucinous adenocarcinoma.

Mucinous adenocarcinoma of the rectum accounts for 10% of all rectal cancers and has an impaired response to neoadjuvant chemoradiotherapy and worse overall survival. To date, insufficient genomic research has been performed on this histological subtype.This study aims to define the mismatch repair deficiency rate and the driver mutations underpinning mucinous adenocarcinoma of the rectum and to compare it with rectal adenocarcinoma not otherwise specified.Immunohistochemistry and sequencing were performed on tumor samples from our tumor biobank.This study was conducted across 2 tertiary referral centers.Patients with mucinous adenocarcinoma and rectal adenocarcinoma not otherwise specified who underwent rectal resection between 2008 and 2018 were included.Mismatch repair status was performed by immunohistochemical staining. Mutations in the panel of oncogenes and tumor suppressor genes were determined by sequencing on the MiSeq V3 platform.The study included 33 patients with mucinous adenocarcinoma of the rectum and 100 patients with rectal adenocarcinoma not otherwise specified. Those with mucinous adenocarcinoma had a mismatch repair deficiency rate of 12.1% compared to 2.0% in the adenocarcinoma not otherwise specified cohort (p = 0.04). Mucinous adenocarcinoma and adenocarcinoma not otherwise specified rectal tumors had similar mutation frequencies in most oncogenes and tumor suppressor genes. No difference was found in the KRAS mutation rate (50.0% vs 37.1%, p = 0.29) or BRAF mutation rate (6.7% vs 3.1%, p = 0.34) between the cohorts. No difference was found between the cohorts regarding recurrence-free (p = 0.29) or overall survival (p = 0.14).The major limitations of this study were the use of formalin-fixed, paraffin-embedded tissue over fresh-frozen tissue and the small number of patients included, in particular, in the mucinous rectal cohort.Most mucinous rectal tumors develop and progress along the chromosomal instability pathway. Further research in the form of transcriptomics, proteomics, and analysis of the effects of the mucin barrier may yield valuable insights into the mechanisms of resistance to chemoradiotherapy in this cohort. See Video Abstract at http://links.lww.com/DCR/B464.ANTECEDENTES:El adenocarcinoma mucinoso del recto, representa el 10% de todos los cánceres rectales y tiene una respuesta deficiente a la quimioradioterapia neoadyuvante y una peor supervivencia en general. A la fecha, se han realizado muy pocas investigaciones genómicas sobre este subtipo histológico.OBJETIVO:Definir la tasa de deficiencia en la reparación de desajustes y mutaciones impulsoras, que sustentan el adenocarcinoma mucinoso del recto y compararlo con el adenocarcinoma rectal no especificado de otra manera.DISEÑO:Se realizaron inmunohistoquímica y secuenciación en muestras tumorales de nuestro biobanco de tumores.AJUSTE:El estudio se realizó en dos centros de referencia terciarios.PACIENTES:Se incluyeron pacientes con adenocarcinoma mucinoso y adenocarcinoma no especificado de otra manera, sometidos a resección rectal entre 2008 y 2018.PRINCIPALES MEDIDAS DE RESULTADO:El estado de reparación de desajustes se realizó mediante tinción inmunohistoquímica. Las mutaciones en el panel de oncogenes y genes supresores de tumores, se determinaron mediante secuenciación en la plataforma MiSeq V3.RESULTADOS:El estudio incluyó a 33 pacientes con adenocarcinoma mucinoso del recto y 100 pacientes con adenocarcinoma del recto no especificado de otra manera. Aquellos con adenocarcinoma mucinoso, tenían una tasa de deficiencia de reparación de desajustes del 12,1% en comparación con el 2,0% en la cohorte de adenocarcinoma no especificado de otra manera (p = 0,04). El adenocarcinoma mucinoso y el adenocarcinoma no especificado de otra manera, tuvieron frecuencias de mutación similares en la mayoría de los oncogenes y genes supresores de tumores. No se encontraron diferencias en la tasa de mutación de KRAS (50,0% frente a 37,1%, p = 0,29) o la tasa de mutación de BRAF (6,7% frente a 3,1%, p = 0,34) entre las cohortes. No se encontraron diferencias entre las cohortes con respecto a la supervivencia libre de recurrencia (p = 0,29) o la supervivencia global (p = 0,14).LIMITACIONES:Las mayores limitaciones de este estudio, fueron el uso de tejido embebido en parafina y fijado con formalina, sobre el tejido fresco congelado y el pequeño número de pacientes incluidos, particularmente en la cohorte mucinoso rectal.CONCLUSIONES:La mayoría de los tumores rectales mucinosos se desarrollan y progresan a lo largo de la vía de inestabilidad cromosómica. La investigación adicional en forma transcriptómica, proteómica y análisis de los efectos de la barrera de la mucina, puede proporcionar información valiosa sobre los mecanismos de resistencia a la quimioradioterapia, en esta cohorte. Consulte Video Resumen en http://links.lww.com/DCR/B464.

Introduction Mucinous adenocarcinoma (MA) of the rectum accounts for 5-15% of rectal cancers. This histological subtype has been shown to have a worse response to chemoradiotherapy and worse long term outcomes when compared to non-mucinous adenocarcinoma (NMA). The aim of this study was to compare the genomic landscape of rectal MA to rectal NMA. Method Using the BGISEQ PE100 platform, paired end whole genome sequencing was carried out on tumour and matched normal tissue from cases of MA. The Cancer Genome Atlas was interrogated to identify further cases of rectal MA and cases of rectal NMA with sequencing data that could be used as a control group. In-depth bioinformatic analysis was undertaken and the genomic landscapes of the two subtypes were compared. Result A total of 14 cases of MA were compared to 74 cases of NMA. The microsatellite instability-high rate in the MA group was 14.29% vs 4.05% in the NMA group. POLE mutations were found in 5.41% of the NMA group compared to 0.00% of the MA group. KRAS, BRAF and PIK3CA mutations were more frequent in the MA group whereas TP53 and APC mutations were more common in the NMA group. Significant differences between the groups were identified in the most frequently mutated genes. Copy number alteration, mutational signatures, structural variation and microbiome findings will also be described. Conclusion MA of the rectum is not just phenotypically distinct, it is a distinct genotype. This could have implications when considering neoadjuvant and adjuvant treatment strategies in the future. Take-home message Mucinous adenocarcinoma differs from a genomic perspective from non-mucinous adenocarcinoma and this may have implications for treatment strategies in the future

Simple Summary Mucinous colorectal cancer is characterised by abundant mucin glycoprotein production and is associated with resistance to chemotherapy-based treatments. This review outlines mechanisms for cell death resistance present in mucinous colorectal cancer including glycoprotein interactions with cell survival and cell apoptotic pathways. Further mechanisms are explored, including alterations in the expression of chemotherapy metabolism and resistance genes. This review identifies directions for future investigation of mucinous colorectal cancer and novel treatment strategies. Abstract Mucinous colorectal cancer (CRC) is estimated to occur in approximately 10–15% of CRC cases and is characterized by abundant extracellular mucin. Mucinous CRC is frequently associated with resistance to apoptosis. Inferior prognosis is observed in mucinous CRC, particularly in rectal cancer and metastatic cases. Mucins are heavily glycosylated secretory or transmembrane proteins that participate in protection of the colonic epithelium. MUC2 overexpression is a hallmark of mucinous CRCs. Mucinous CRC is associated with KRAS and BRAF mutation, microsatellite instability and the CpG island methylator phenotype. Mutations of the APC gene and p53 mutations which are characteristic non-mucinous colorectal adenocarcinoma are less common in mucinous CRC. Both physical and anti-apoptotic properties of mucin provide mechanisms for resistance to cell death. Mucin glycoproteins are associated with decreased expression of pro-apoptotic proteins, increased expression of anti-apoptotic proteins and increased cell survival signaling. The role for BCL-2 proteins, including BCL-XL, in preventing apoptosis in mucinous CRC has been explored to a limited extent. Additional mechanisms opposing cell death include altered death receptor expression and altered mutation rates in genes responsible for chemotherapy resistance. The roles of alternate cell death programs including necroptosis and pyroptosis are not well understood in mucinous CRC. While the presence of MUC2 is associated with an immunosuppressive environment, the tumor immune environment of mucinous CRC and the role of immune-mediated tumor cell death likewise require further investigation. Improved understanding of cell death mechanisms in mucinous CRC may allow modification of currently used regimens and facilitate targeted treatment.

Economic Evaluation The aim of the economic evaluation was to examine the cost effectiveness of the two screening models tested in the Chlamydia Screening in Ireland Pilot (CSIP) study: (a) Clinical Setting screening, and (b) ’Pee-in-a-pot’ periodic screening in third level institution/college settings. The methodological approach comprised of a dynamic transmission model paired with an economic model. In both analyses, screening was compared to a control strategy of no organised screening, that is existing care in Ireland. A public health system or provider perspective was adopted with respect to costs. The analysis considered the cost of screening to the health service, and the costs of infection and complications, not any additional costs reported by young people in accepting a chlamydia screening test. Health outcomes were assessed in terms of major outcomes (MOs) averted and quality adjusted life years (QALYs) gained. The costs of Clinical Setting screening were presented in terms of the cost per offer (€26 ), the cost per negative case (€66), the cost per positive case (€152), and the cost per partner notified and treated (€74). The costs of ’Pee-in-a-pot’ screening were presented in terms of the cost per negative case (€39), the cost per positive case (€125), and the cost per partner notified and treated (€74). In both analyses, screening was estimated to result in fewer major outcomes, fewer QALYs lost, and higher healthcare costs compared to the control strategy. The incremental cost effectiveness analyses indicated that screening in the Clinical Setting would result in an incremental cost per MO averted of €6,093 and an incremental cost per QALY gained of €94,717. ’Pee-in-a-pot’ screening was estimated to result in incremental cost effectiveness ratios of €2,294 per MO averted and €34,486 per QALY gained respectively. In Ireland, there is no fixed and generally agreed cost effectiveness threshold below which health care technologies would be considered by policy makers to be costeffective. Nonetheless, on the basis of other technologies that are currently funded, it is not likely that screening delivered in the Clinical Setting, given an incremental cost per QALY in the region of the €94,717 found in this study, would be considered cost effective. ’Pee-in-a-pot’ screening in third level institution/college settings may be considered cost effective if a cost effectiveness threshold in the region of €45,000 per QALY gained is used. This is open to question, however, given the current economic climate and its resulting impact in terms of imposing further constraints on future healthcare budgets. It is also important to note that this strategy would have minimal in impact in reducing overall chlamydia prevalence in the population, if not supported by general population screening and prevention strategy.

High ambient temperatures pose a significant risk to health. This study investigates the heatwave mortality in the summer of 2020 during the SARS-CoV-2 coronavirus (COVID-19) pandemic and related countermeasures. The heatwaves in 2020 caused more deaths than have been reported since the Heatwave Plan for England was introduced in 2004. The total and cause-specific mortality in 2020 was compared to previous heatwave events in England. The findings will help inform summer preparedness and planning in future years as society learns to live with COVID-19. Heatwave excess mortality in 2020 was similar to deaths occurring at home, in hospitals, and in care homes in the 65+ years group, and was comparable to the increases in previous years (2016–2018). The third heatwave in 2020 caused significant mortality in the younger age group (0–64) which has not been observed in previous years. Significant excess mortality was observed for cardiovascular disease, respiratory disease, and Alzheimer’s and Dementia across all three heatwaves in persons aged 65+ years. There was no evidence that the heatwaves affected the proportional increase of people dying at home and not seeking heat-related health care. The most significant spike in daily mortality in August 2020 was associated with a period of high night-time temperatures. The results provide additional evidence that contextual factors are important for managing heatwave risks, particularly the importance of overheating in dwellings. The findings also suggest more action is also needed to address the vulnerability in the community and in health care settings during the acute response phase of a heatwave.

Immune checkpoint inhibition has demonstrated success in overcoming tumor-mediated immune suppression in several types of cancer. However, its clinical use is limited to a small subset of colorectal cancer (CRC) patients, and response is highly variable between CRC subtypes. This study aimed to determine the profile of immune checkpoints and factors associated with immune checkpoint inhibitor response in mucinous CRC.Gene expression data from CRC was extracted from the TCGA PanCanAtlas data-freeze release. Gene expression data were reported as batch-corrected and normalized RNA expression derived from RNA-Seq quantification. Clinical, pathologic, and transcriptomic data were compared between mucinous and non-mucinous CRC cohorts.The 557 cases of CRC eligible for inclusion in this study comprised 486 cases of non-mucinous CRC (87.3 %) and 71 cases of mucinous CRC (12.7 %). High correlation was observed in the expression of the included immune checkpoints. Significantly higher expression of programmed cell death protein 1 ligand (PD-L1) and T cell immunoglobulin and mucin domain 3 (TIM-3) was observed in mucinous CRC than in non-mucinous CRC. In a multiple regression model, significant contributors to the prediction of TIM-3 gene expression were microsatellite instability (MSI) (unstandardized regression coefficient [B] = 1.223; p0.001), stage (American Joint Committee on Cancer [AJCC] 2; B = 0.423; p0.05), and mucinous status (B = 0.591; p0.01).Expression of TIM-3, an emerging immune checkpoint inhibition target, was significantly higher in mucinous CRC, and expression was predicted by mucinous status independently of MSI. These findings should prompt investigation of immune checkpoint signaling in the mucinous tumor microenvironment to clarify the potential for immune checkpoint inhibition in mucinous CRC.

Emergency general surgery (EGS) is a high-risk process and is associated with poor outcomes and high mortality. This study aimed to evaluate the service delivery factors in a tertiary referral centre which may influence patient outcomes in emergency general surgery.Data on consecutive patients undergoing emergency laparotomy in a tertiary referral centre were prospectively collected from July 2017-July 2018. An extensive review of patient charts and IT systems was performed to extract demographic, clinical and care pathway data. Transfers for surgery from within the institution or within the centralised hospital network were recorded.The unadjusted 30-day mortality rate in 163 patients undergoing emergency laparotomy was 13%. On multivariate analysis, 30-day mortality was significantly associated with p-POSSUM predicted mortality (p = 0.003), p-POSSUM predicted morbidity (p = 0.01), SORT mortality (p = 0.004), ICU admission (p = 0.02), ASA grade (p 0.001) and transfer from non-surgical services (p 0.001). 19.2% of patients were transferred from a referring hospital for emergency laparotomy. There was no association between inter-hospital transfer and 30-day mortality while increased mortality was observed in patients admitted to non-surgical services who required laparotomy (p 0.001).Inter-hospital transfer for emergency laparotomy was not associated with increased mortality. Increased mortality was observed in patients admitted to non-surgical services who subsequently required emergency laparotomy. Configuration of emergency general surgery services must accommodate safe and effective transfer of patients, both between and within hospitals.

Neoadjuvant chemoradiotherapy (CRT) is the standard of care for locally advanced rectal cancer. Morphologic changes such as fibrosis, inflammatory infiltrates, and the formation of extracellular mucin pools can be identified in the resection specimen after neoadjuvant CRT. The association of mucin pool formation with clinicopathologic variables and outcomes is unclear. The aim of this study was to meta-analyze all available evidence with regard to mucin pool formation and clinicopathologic outcomes following neoadjuvant CRT for rectal cancer. A comprehensive search for published studies analyzing outcomes between patients who formed mucin pools and patients who did not following neoadjuvant CRT for rectal cancer was performed. A random-effects model was used to combine the data. This study adhered to the recommendations of the MOOSE (Meta-analyses of Observational Studies in Epidemiology) guidelines. Data from 11 studies describing 1947 patients were included. Mucin pool formation was not associated with sex, T stage, N stage, tumor regression, pathologic complete response rate, lymphovascular invasion, perineural invasion, differentiation, margin status, local or distant recurrence, and disease-free or overall survival. Mucin pool formation is not associated with tumor response or downstaging; furthermore, on the basis of these data, it is not associated with local or systemic recurrence rate or survival.

Aim The diagnostic role for preoperative imaging of clinically benign rectal adenomas is unclear. The objective of this systematic review and meta-analysis was to examine the diagnostic accuracy of preoperative imaging in distinguishing benign adenomas from rectal cancer. Method A systematic search was performed for all studies published that correlated staging of clinically benign rectal adenomas with endorectal ultrasound (ERUS) or MRI and histology. Imaging was compared with postoperative histology and data on the numbers of true positives, false positives, true negatives and false negatives were extracted. Summary estimates of sensitivity and specificity with 95% CIs were calculated using a bivariate random effects model. The QUADAS2 tool was used to determine the methodological quality of included studies. Results Eleven studies describing 1511 patients were retrieved. A total of 1134 patients underwent local excision and 377 had a formal proctectomy. A benign rectal adenoma was diagnosed in 840 and 214 had a T1 rectal cancer. For confirming benign adenomas, the pooled sensitivity of ERUS was 0.81 (95% CI 0.69-0.89) and specificity was 0.85 (95% CI 0.68-0.93). For detecting occult T1 tumours, the pooled sensitivity of ERUS was 0.50 (95% CI 0.33-0.66) and specificity was 0.89 (95% CI 0.82-0.94). Quantitative analysis of MRI could not be performed due to insufficient studies. Conclusion This study demonstrates the limited accuracy of preoperative ERUS in distinguishing benign adenomas from T1 rectal cancer. Preoperative imaging must be interpreted with caution to prevent over-staging and unnecessary proctectomy. We propose that clinically benign lesions may undergo local excision, with subsequent management based on final histology.

Mucinous colorectal cancer is a unique histological subtype that is known to respond poorly to cytotoxic chemotherapy and radiotherapy. There are a number of genes known to be associated with resistance to 5-fluorouracil (5-FU), oxaliplatin, and irinotecan. The aim of this study was to compare the somatic mutation frequency and copy number variation (CNV) in these genes between mucinous and non-mucinous colorectal cancer. A systematic search of PubMed was performed to identify papers investigating drug resistance in colorectal cancer. From this review, a list of 26 drug-resistance-associated genes was compiled. Using patient data from The Cancer Genome Atlas (TCGA), the somatic mutation rate and CNV was compared between patients with mucinous and non-mucinous colorectal cancer. Statistical analysis was carried out using GraphPad PRISM® version 5.00. Data were available on 531 patients (464 non-mucinous, 67 mucinous). A statistically significant difference in the somatic mutation rate between the two cohorts was identified in the TYMP (p = 0.0179), ATP7B (p = 0.0465), SRPK1 (p = 0.0135), ABCB1 (p = 0.0423), and ABCG2 (p = 0.0102) genes. A statistically significant difference in CNV was identified between the two cohorts in the GSTP1 (p = 0.0405), CCS (p = 0.0063), and TOP1 (p = 0.0048) genes. Differences in somatic mutation rate and CNV in genes associated with resistance to 5-FU, oxaliplatin, and irinotecan may partly account for the pattern of resistance observed in mucinous colorectal cancers. These genetic alterations may prove useful when deciding on a personalized approach to chemotherapy and may also represent potential therapeutic targets going forward.

Unplanned readmission after surgery negatively impacts surgical recovery. Few studies have sought to define predictors of readmission in a rectal cancer cohort alone. Readmission following rectal cancer surgery may be reduced by the identification and modification of factors associated with readmission.This study seeks to characterize the predictors of 30-day readmission following proctectomy for rectal cancer.This study is a retrospective analysis of prospectively gathered cohort data. Outcomes were compared between readmitted and nonreadmitted patients. Multivariate analysis of factors association with readmission was performed by using binary logistic regression.This study was conducted at Beaumont Hospital, a nationally designated, publicly funded cancer center.Two hundred forty-six consecutive patients who underwent proctectomy for rectal cancer between January 2012 and December 2015 were selected.The primary outcomes measured were readmission within 30 days of discharge and the variables associated with readmission, categorized into patient factors, perioperative factors, and postoperative factors.Thirty-one (12.6%) patients were readmitted within 30 days of discharge following index rectal resection. The occurrence of anastomotic leaks, high-output stoma, and surgical site infections was significantly associated with readmission within 30 days (anastomotic leak OR 3.60, p = 0.02; high-output stoma OR 11.04, p = 0.003; surgical site infections OR 13.39, p = 0.01). Surgical site infections and high-output stoma maintained significant association on multivariate analysis (surgical site infections OR 10.02, p = 0.001; high-output stoma OR 9.40, p = 0.02). No significant difference was noted in the median length of stay or frequency of prolonged admissions (greater than 24 days) between readmitted and nonreadmitted patients.The institutional database omits a number of socioeconomic factors and comorbidities that may influence readmission, limiting our capacity to analyze the relative contribution of these factors to our findings.An early postoperative care bundle to detect postoperative complications could prevent some unnecessary inpatient admissions following proctectomy. Key constituents should include early identification and management of stoma-related complications and surgical site infection. See Video Abstract at http://links.lww.com/DCR/A912.

Background Over three-quarters of surgical trainees intend to undertake clinical fellowships to improve competence, confidence and the development of super specialised skills. At present there is no standardised national regulation for fellowships in the UK, leading to variability. The Association of Surgeons in Training (ASiT), an organisation representing surgical trainees in the UK and Ireland, sought to provide recommendations on the structure and quality assurance of fellowships in General Surgery. Methods A consensus session was held by ASiT at the Association of Surgeons of Great Britain and Ireland (ASGBI) 2017 Congress in Glasgow. A variety of perspectives on fellowships were presented by invited speakers, and thereafter a moderated discussion ensued in order to reach consensus. Live-polling using an electronic application facilitated consensus discussions. A writing group thereafter developed an initial consensus document which was then subject to electronic review by all authors and by ASiT council. Results Thirty-four delegates attended the consensus session. Views of the delegates and online discussants were that fellowships should be optional and not mandatory. There was (n = 16) no preference expressed between UK and international fellowships by half the group, while half expressed a preference for international fellowships. Regarding UK fellowships, the majority (n = 24) said that national registration of such fellowships should be established and (n = 23) agreed that a defined curriculum was required. However, national selection into fellowship training was not supported (n = 20). Perceived advantages of UK fellowships included ease of relocating within the same country (which was considered more family-friendly and cost-effective), and familiarity with the NHS system. Delegates considered the advantages of international fellowships to include: access to high-volume centres; diversity of case-mix; and structured, regulated fellowship programmes. Conclusion The consensus session found unanimous support for maintaining the option of both UK and international fellowships. While trainees support quality assurance of fellowships, they do not support a national selection process.

The first documented British outbreak of Shiga toxin-producing Escherichia coli (STEC) O55:H7 began in the county of Dorset, England, in July 2014. Since then, there have been a total of 31 cases of which 13 presented with haemolytic uraemic syndrome (HUS). The outbreak strain had Shiga toxin (Stx) subtype 2a associated with an elevated risk of HUS. This strain had not previously been isolated from humans or animals in England. The only epidemiological link was living in or having close links to two areas in Dorset. Extensive investigations included testing of animals and household pets. Control measures included extended screening, iterative interviewing and exclusion of cases and high risk contacts. Whole genome sequencing (WGS) confirmed that all the cases were infected with similar strains. A specific source could not be identified. The combination of epidemiological investigation and WGS indicated, however, that this outbreak was possibly caused by recurrent introductions from a local endemic zoonotic source, that a highly similar endemic reservoir appears to exist in the Republic of Ireland but has not been identified elsewhere, and that a subset of cases was associated with human-to-human transmission in a nursery.

SummaryWe investigated how young adults aged 18-29 years would like to be notified of chlamydia screening test results, and, when they test positive, their willingness and preferred mechanism for informing their partners. We conducted a cross-sectional survey of 6085 young adults and found that a call to their mobile phone was their preferred way of receiving positive test results (selected by 50%), followed by email. Text messages (short message service [SMS]) and calls to landline phones were unpopular options, selected by between 5 and 10%. Over 75% of respondents stated they would inform their current partner of a positive chlamydia diagnosis, and 50% would inform their previous partners. Most were willing to receive yearly reminders to go for a chlamydia test. Young adults preference for being informed of chlamydia test results by mobile phone call, rather than by email or SMS text, especially if they test positive, suggests they place high value on the security of the communication mechanism. Offering a range of mechanisms for receipt of test results may increase the acceptability and coverage of sexually transmitted infection (STI) control strategies.

Background This study measured the acceptability of urine-based chlamydia screening to young adults, where young adults wanted opportunistic chlamydia screening services to be located, and by whom they wanted to be offered screening. Methods A cross-sectional survey of 5685 university students and 400 young adult healthcares setting attendees (age: 1829 years). Results Ninety-six percent of males and 93 of females said that they would find it acceptable to be offered chlamydia screening. Seventy-six percent of males and 77 of females wanted to be offered screening by a doctor or nurse. Young women would prefer female staff. Most respondents preferred that screening be located in traditional healthcare settings such as General Practices, and offered by either doctors or nurses. More than 90 of respondents did not want screening services to be located in pharmacies and almost all rejected public non-health care screening settings. Conclusions Opportunistic chlamydia screening services should be located in traditional healthcare/medical settings, and screening should be offered by doctors and nurses.

Many women who might be at risk of having the sexually transmitted infection (STI) Chlamydia trachomatis either delay going, or do not go, for testing. We aimed to examine the factors that either prevent or discourage Irish young women from going for Chlamydia testing. We conducted in-depth interviews with 35 women in the Republic of Ireland who were between 18 and 29 years of age. Accounts were analysed using Goffman's stigma framework. Study respondents strongly associated Chlamydia and Chlamydia testing with stigma and felt that only irresponsible, promiscuous risk takers were at risk of contracting the infection. Respondents saw themselves as responsible, moral actors who avoided risk and took good care of their bodies; they were therefore not at risk of having Chlamydia. Going for Chlamydia testing was seen as a risky activity that could shift respondents identities into a negative ‘Other’ category. Respondents feared that if they found themselves in this ‘Other’ category they would open themselves t...

This study aimed to assess the care provided to patients with diabetes in general practices in the West of Ireland. A postal questionnaire was sent to all 103 general practices in County Galway. The questionnaire assessed diabetes prevalence and maintenance of a diabetes register, use of guidelines for the care of diabetes, appointments systems and the provision of specialised diabetes clinics in general practice, referrals to the hospital specialist team, and opportunities for developing diabetes care. The response rate was 76%. Mean estimated prevalence of diabetes was 2.7% (range 0.1–9.5%). A diabetes register was maintained by 33% of practices. Diabetes care guidelines were used by 56%. Thirty-five percent of practices had GP(s) and 33% had practice nurse(s) with a special interest in diabetes. Only 12% had a formal call/recall system with 41% having doctor or nurse initiated diabetes appointments. One in 10 practices reported running specific diabetes clinics. There is considerable scope for development of primary care diabetes services in the West of Ireland. Priority areas include the development and maintenance of diabetes registers, workforce enhancement through staff training in diabetes care and the adoption of best practice guidelines. All of this will require additional resources and incentives for GPs. Copyright © 2009 John Wiley & Sons.

Background The aim of the study was to explore the acceptability and uptake of on-campus screening using a youth friendly approach in two Third Level higher education institutions (HEIs). This study is part of wider research exploring the optimal setting for chlamydia screening in Ireland. Methods Male and female students were given the opportunity to take a free anonymous test for chlamydia during a one week programme of "pee-in-a-pot" days at two HEI campuses in the West of Ireland. The study was set up after extensive consultation with the two HEIs and advertised on the two campuses using a variety of media in the two weeks preceding the screening days. Screening involved the provision and distribution of testing packs at communal areas and in toilet facilities. In Ireland, chlamydia notifications are highest amongst 20-29 year olds and hence the screening criterion was aimed at 18-29 year olds. Urine samples were tested using a nucleic acid amplification test (NAAT). Following the screening days, qualitative in-depth interviews were conducted with participants about their experiences of the event. Results Out of 1,249 test kits distributed in two HEIs, 592 specimens were collected giving a return rate of 47.5%. Tests excluded (54) were due to labelling errors or ineligibility of participants' age. Two thirds of those tested were females and the mean age was 21 years. Overall,3.9% (21/538) of participants tested positive, 5% (17/336) among females and 2% (4/191) among males. Participant interviews identified factors which enhanced student participation such as anonymity, convenience, accessibility of testing, and the informal and non-medical approach to testing. Conclusions Screening for chlamydia using on-campus "pee-in-a-pot" days is an acceptable strategy in this population. This model can detect and treat asymptomatic cases of chlamydia and avoid many of the barriers associated with testing for sexually transmitted infections (STIs) in clinical settings.

Background An understanding of the factors that encourage young women to accept, and discourage them from accepting, STI (sexually transmitted infection) testing is needed to underpin opportunistic screening programs for the STI Chlamydia trachomatis (opportunistic screening involves healthcare professionals offering chlamydia tests to people while they are attending health services for reasons that are usually unrelated to their sexual health). We conducted a qualitative study to identify and explore: how young women would feel about being offered opportunistic tests for chlamydia?; how young women would like to be offered screening, and who they wanted to be offered screening by?; and what factors would influence young women's partner notification preferences for chlamydia (who they would notify in the event of a positive diagnosis of chlamydia, how they would want to do this). Methods Semi-structured interviews with 35 young women between eighteen and twenty nine years of age. The study was conducted in the Dublin and Galway regions of the Republic of Ireland. Young adults were recruited from General Practice (GP) practices, Third Level College health services, Family Planning clinics and specialist STI treatment services. Results Respondents were worried that their identities would become stigmatised if they accepted screening. Younger respondents and those from lower socio-economic backgrounds had the greatest stigma-related concerns. Most respondents indicated that they would accept screening if it was offered to them, however; accepting screening was seen as a correct, responsible action to engage in. Respondents wanted to be offered screening by younger female healthcare professionals. Respondents were willing to inform their current partners about positive chlamydia diagnoses, but were more ambivalent about informing their previous partners. Conclusions If an effort is not put into reducing young women's stigma-related concerns the population coverage of Chlamydia screening might be reduced.

Background There are no prevalence data on Chlamydia trachomatis relating to female students attending higher education available for the Republic of Ireland. This information is required to guide on the necessity for Chlamydia screening programmes in higher education settings. This research aimed to determine the prevalence of and predictive risk factors for Chlamydia trachomatis genital infection among female higher education students in Ireland. Methods All females presenting during one-day periods at Student Health Units in three higher education institutions in two cities in the Republic of Ireland were invited to participate. Participants completed a questionnaire on lifestyle and socio-demographic factors and provided a urine sample. Samples were tested for C. trachomatis DNA by a PCR based technique (Cobas Amplicor, Roche). To examine possible associations between a positive test and demographic and lifestyle risk factors, a univariate analysis was performed. All associations with a p value < 0.05 were included in a multivariate logistic regression analysis. Results Of the 460 sexually active participants 22 tested positive (prevalence 4.8%; 95% CI 3.0 to 7.1%). Variables associated with significantly increased risk were current suggestive symptoms, two or more one-night stands and three or more lifetime sexual partners. The students displayed high-risk sexual behaviour. Conclusion The prevalence of C. trachomatis infection and the lack of awareness of the significance of suggestive symptoms among sexually experienced female students demonstrate the need for a programme to test asymptomatic or non-presenting higher education students. The risk factors identified by multivariate analysis may be useful in identifying those who are most likely to benefit from screening. Alcohol abuse, condom use, sexual behaviour (at home and abroad) and, knowledge of sexually transmitted infections (STIs) (including asymptomatic nature or relevant symptoms) were identified as target areas for health promotion strategies. These strategies are needed in view of the high-risk sexual activity identified.

Objectives Chlamydia trachomatis is a sexually transmissible infection (STI) that affects significant numbers of men. Research on men’s perspectives on chlamydia screening (or testing) has been limited. We conducted a narrative review to examine: (1) what factors encourage or discourage men from attending health services for chlamydia screening, and/or from accepting screening once it has been offered to them, and (2) where men want chlamydia screening services to be located. Methods: A narrative review of the recent peer-reviewed literature (published between 1999 and 2009) on men’s attitudes towards chlamydia screening. To be included, articles had to explore men’s perspectives on screening (which could be ascertained through quantitative or qualitative studies, or from relevant discussion papers or reviews). Results: Forty-eight articles were included in all. Men’s attitudes towards chlamydia screening are influenced by their knowledge about the infection, their perceived vulnerability to the infection, the degree of embarrassment and shame that they associate with screening and the stigma that they associate with screening. Men prefer to be offered urine testing for chlamydia. Men want to be offered screening by non-judgemental professionals. Men’s attitudes towards screening for chlamydia in general practice, genito-urinary medicine clinics, home and outreach settings are also explored in this review. Conclusions: Several factors influence men’s attitudes towards screening. Two central themes underlie and influence many of these factors: men’s needs to make positive impressions on others, and men’s identification with particular ideals of masculinity. The review concludes with suggestions for future research on this topic.

Heatwaves are a serious threat to human life. Public health agencies that are responsible for delivering heat-health action plans need to assess and reduce the mortality impacts of heat. Statistical models developed in epidemiology have previously been used to attribute past observed deaths to high temperatures and project future heat-related deaths. Here, we investigate the novel use of summer temperature-mortality associations established by these models for monitoring heat-related deaths in regions in England in near real time. For four summers in the period 2011–2020, we find that coupling these associations with observed daily mean temperatures results in England-wide heatwave mortality estimates that are consistent with the excess deaths estimated by UK Health Security Agency. However, our results for 2013, 2018 and 2020 highlight that the lagged effects of heat and characteristics of individual summers contribute to disagreement between the two methods. We suggest that our method can be used for heatwave mortality monitoring in England because it has the advantages of including lagged effects and controlling for other risk factors. It could also be employed by health agencies elsewhere for reliably estimating the health burden of heat in near real time and near-term forecasts.