Elimination of Chlamydia muridarum from the female reproductive tract is IL-12p40 dependent, but independent of Th1 and Th2 cells.

Chlamydia vaccine approaches aspire to induce Th1 cells for optimal protection, despite the fact that there is no direct evidence demonstrating Th1-mediated Chlamydia clearance from the female reproductive tract (FRT). We recently reported that T-bet-deficient mice can resolve primary Chlamydia infection normally, undermining the potentially protective role of Th1 cells in Chlamydia immunity. Here, we show that T-bet-deficient mice develop robust Th17 responses and that mice deficient in Th17 cells exhibit delayed bacterial clearance, demonstrating that Chlamydia-specific Th17 cells represent an underappreciated protective population. Additionally, Th2-deficient mice competently clear cervicovaginal infection. Furthermore, we show that sensing of IFN-γ by non-hematopoietic cells is essential for Chlamydia immunity, yet bacterial clearance in the FRT does not require IFN-γ secretion by CD4 T cells. Despite the fact that Th1 cells are not necessary for Chlamydia clearance, protective immunity to Chlamydia is still dependent on MHC class-II-restricted CD4 T cells and IL-12p40. Together, these data point to IL-12p40-dependent CD4 effector maturation as essential for Chlamydia immunity, and Th17 cells to a lesser extent, yet neither Th1 nor Th2 cell development is critical. Future Chlamydia vaccination efforts will be more effective if they focus on induction of this protective CD4 T cell population.

Optimal generation of hepatic tissue-resident memory CD4 T cells requires IL-1 and IL-2.

Hepatic CD4 tissue-resident memory T cells (TRM) are required for robust protection against Salmonella infection; however, the generation of this T cell population is poorly understood. To interrogate the contribution of inflammation, we developed a simple Salmonella-specific T cell transfer system that allowed direct visualization of hepatic TRM formation. Salmonella-specific (SM1) T cell receptor (TCR) transgenic CD4 T cells were activated in vitro and adoptively transferred into C57BL/6 mice while hepatic inflammation was induced by acetaminophen overdose or L. monocytogenes infection. In both model systems, hepatic CD4 TRM formation was accentuated by local tissue responses. Liver inflammation also enhanced the suboptimal protection provided by a subunit Salmonella vaccine which typically induces circulating memory CD4 T cells. To further elucidate the mechanism of CD4 TRM formation in response to liver inflammation, various cytokines were examined by RNAseq, bone marrow chimeras, and in vivo neutralization. Surprisingly, IL-2 and IL-1 were found to enhance CD4 TRM formation. Thus, local inflammatory mediators enhance CD4 TRM populations and can boost the protective immunity provided by a suboptimal vaccine. This knowledge will be foundational for the development of a more effective vaccine against invasive nontyphoidal salmonellosis (iNTS).

Cutting Edge: Optimal Formation of Hepatic Tissue-Resident Memory CD4 T Cells Requires T-bet Regulation of CD18.

CD4 tissue-resident memory T cells (TRMs) allow robust protection of barrier surfaces against pathogens. We investigated the role of T-bet in the formation of liver CD4 TRMs using mouse models. T-bet-deficient CD4 T cells did not efficiently form liver TRMs when compared with wild-type (WT). In addition, ectopic expression of T-bet enhanced the formation of liver CD4 TRMs, but only when in competition with WT CD4 T cells. Liver TRMs also expressed higher levels of CD18, which was T-bet dependent. The WT competitive advantage was blocked by Ab neutralization of CD18. Taken together, our data show that activated CD4 T cells compete for entry to liver niches via T-bet-induced expression of CD18, allowing TRM precursors to access subsequent hepatic maturation signals. These findings uncover an essential role for T-bet in liver TRM CD4 formation and suggest targeted enhancement of this pathway could increase the efficacy of vaccines that require hepatic TRMs.

Th1 cells are dispensable for primary clearance of Chlamydia from the female reproductive tract of mice.

Protective immune responses to Chlamydia infection within the female reproductive tract (FRT) are incompletely understood. MHC class II-restricted CD4 Th1 responses are believed to be vital for bacterial clearance due to their capacity to secrete IFN-γ, but an essential requirement for T-bet-expressing Th1 cells has yet to be demonstrated in the mouse model of Chlamydia infection. Here, we investigated the role of T-bet and IFN-γ in primary clearance of Chlamydia after FRT infection. Surprisingly, IFN-γ producing CD4 T cells from the FRT expressed low levels of T-bet throughout infection, suggesting that classical T-bet-expressing Th1 cells are inefficiently generated and therefore unlikely to participate in bacteria clearance. Furthermore, mice deficient in T-bet expression or with a CD4-specific T-bet deficiency cleared FRT infection similarly to wild-type controls. T-bet-deficient mice displayed significant skewing of FRT CD4 T cells towards Th17 responses, demonstrating that compensatory effector pathways are generated in the absence of Th1 cells. In marked contrast, IFN-γ-, and IFN-γR-deficient mice were able to reduce FRT bacterial burdens, but suffered systemic bacterial dissemination and 100% mortality. Together, these data demonstrate that IFN-γ signaling is essential to protect mice from fatal systemic disease, but that classical T-bet-expressing Th1 cells are non-essential for primary clearance within the FRT. Exploring the protective contribution of Th1 cells versus other CD4 effector lineages could provide important information for the generation of new Chlamydia vaccines.

The Ets transcription factor Spi-B is essential for the differentiation of intestinal microfold cells.

Intestinal microfold cells (M cells) are an enigmatic lineage of intestinal epithelial cells that initiate mucosal immune responses through the uptake and transcytosis of luminal antigens. The mechanisms of M-cell differentiation are poorly understood, as the rarity of these cells has hampered analysis. Exogenous administration of the cytokine RANKL can synchronously activate M-cell differentiation in mice. Here we show the Ets transcription factor Spi-B was induced early during M-cell differentiation. Absence of Spi-B silenced the expression of various M-cell markers and prevented the differentiation of M cells in mice. The activation of T cells via an oral route was substantially impaired in the intestine of Spi-B-deficient (Spib(-/-)) mice. Our study demonstrates that commitment to the intestinal M-cell lineage requires Spi-B as a candidate master regulator.

Cachexia index for prognostication in surgical patients with locally advanced oesophageal or gastric cancer: multicentre cohort study.

BACKGROUND: Features of cancer cachexia adversely influence patient outcomes, yet few currently inform clinical decision-making. This study assessed the value of the cachexia index (CXI), a novel prognostic marker, in patients for whom neoadjuvant chemotherapy and surgery for oesophagogastric cancer is planned. METHODS: Consecutive patients newly diagnosed with locally advanced (T3-4 or at least N1) oesophagogastric cancer between 1 January 2010 and 31 December 2015 were identified through the West of Scotland and South-East Scotland Cancer Networks. CXI was calculated as (L3 skeletal muscle index) × (serum albumin)/(neutrophil lymphocyte ratio). Sex-stratified cut-off values were determined based on the area under the curve (AUC), and patients were divided into groups with low or normal CXI. Primary outcomes were disease progression during neoadjuvant chemotherapy and overall survival (at least 5 years of follow-up). RESULTS: Overall, 385 patients (72% men, median age 66 years) were treated with neoadjuvant chemotherapy for oesophageal (274) or gastric (111) cancer across the study interval. Although patients with a low CXI (men: CXI below 52 (AUC 0.707); women: CXI below 41 (AUC 0.759)) were older with more co-morbidity, disease characteristics were comparable to those in patients with a normal CXI. Rates of disease progression during neoadjuvant chemotherapy, leading to inoperability, were higher in patients with a low CXI (28 versus 12%; adjusted OR 3.07, 95% c.i. 1.67 to 5.64; P < 0.001). Low CXI was associated with worsened postoperative mortality (P = 0.019) and decreased overall survival (median 14.9 versus 56.9 months; adjusted HR 1.85, 1.42 to 2.42; P < 0.001). CONCLUSION: CXI is associated with disease progression, worse postoperative mortality, and overall survival, and could improve prognostication and decision-making in patients with locally advanced oesophagogastric cancer.

Salmonella Infection Drives Promiscuous B Cell Activation Followed by Extrafollicular Affinity Maturation.

The B cell response to Salmonella typhimurium (STm) occurs massively at extrafollicular sites, without notable germinal centers (GCs). Little is known in terms of its specificity. To expand the knowledge of antigen targets, we screened plasmablast (PB)-derived monoclonal antibodies (mAbs) for Salmonella specificity, using ELISA, flow cytometry, and antigen microarray. Only a small fraction (0.5%-2%) of the response appeared to be Salmonella-specific. Yet, infection of mice with limited B cell receptor (BCR) repertoires impaired the response, suggesting that BCR specificity was important. We showed, using laser microdissection, that somatic hypermutation (SHM) occurred efficiently at extrafollicular sites leading to affinity maturation that in turn led to detectable STm Ag-binding. These results suggest a revised vision of how clonal selection and affinity maturation operate in response to Salmonella. Clonal selection initially is promiscuous, activating cells with virtually undetectable affinity, yet SHM and selection occur during the extrafollicular response yielding higher affinity, detectable antibodies.

Robotic-assisted surgery for left-sided colon and rectal resections is associated with reduction in the postoperative surgical stress response and improved short-term outcomes: a cohort study.

INTRODUCTION: There is growing evidence that the use of robotic-assisted surgery (RAS) in colorectal cancer resections is associated with improved short-term outcomes when compared to laparoscopic surgery (LS) or open surgery (OS), possibly through a reduced systemic inflammatory response (SIR). Serum C-reactive protein (CRP) is a sensitive SIR biomarker and its utility in the early identification of post-operative complications has been validated in a variety of surgical procedures. There remains a paucity of studies characterising post-operative SIR in RAS. METHODS: Retrospective study of a prospectively collected database of consecutive patients undergoing OS, LS and RAS for left-sided and rectal cancer in a single high-volume unit. Patient and disease characteristics, post-operative CRP levels, and clinical outcomes were reviewed, and their relationships explored within binary logistic regression and propensity scores matched models. RESULTS: A total of 1031 patients were included (483 OS, 376 LS, and 172 RAS). RAS and LS were associated with lower CRP levels across the first 4 post-operative days (p < 0.001) as well as reduced complications and length of stay compared to OS in unadjusted analyses. In binary logistic regression models, RAS was independently associated with lower CRP levels at Day 3 post-operatively (OR 0.35, 95% CI 0.21-0.59, p < 0.001) and a reduction in the rate of all complications (OR 0.39, 95% CI 0.26-0.56, p < 0.001) and major complications (OR 0.5, 95% CI 0.26-0.95, p = 0.036). Within a propensity scores matched model comparing LS versus RAS specifically, RAS was associated with lower post-operative CRP levels in the first two post-operative days, a lower proportion of patients with a CRP ≥ 150 mg/L at Day 3 (20.9% versus 30.5%, p = 0.036) and a lower rate of all complications (34.7% versus 46.7%, p = 0.033). CONCLUSIONS: The present observational study shows that an RAS approach was associated with lower postoperative SIR, and a better postoperative complications profile.

Circulating immunity protects the female reproductive tract from Chlamydia infection.

Anatomical positioning of memory lymphocytes within barrier tissues accelerates secondary immune responses and is thought to be essential for protection at mucosal surfaces. However, it remains unclear whether resident memory in the female reproductive tract (FRT) is required for Chlamydial immunity. Here, we describe efficient generation of tissue-resident memory CD4 T cells and memory lymphocyte clusters within the FRT after vaginal infection with Chlamydia Despite robust establishment of localized memory lymphocytes within the FRT, naïve mice surgically joined to immune mice, or mice with only circulating immunity following intranasal immunization, were fully capable of resisting Chlamydia infection via the vaginal route. Blocking the rapid mobilization of circulating memory CD4 T cells to the FRT inhibited this protective response. These data demonstrate that secondary protection in the FRT can occur in the complete absence of tissue-resident immune cells. The ability to confer robust protection to barrier tissues via circulating immune memory provides an unexpected opportunity for vaccine development against infections of the FRT.

CD4+ T cell immunity to Salmonella is transient in the circulation.

While Salmonella enterica is seen as an archetypal facultative intracellular bacterial pathogen where protection is mediated by CD4+ T cells, identifying circulating protective cells has proved very difficult, inhibiting steps to identify key antigen specificities. Exploiting a mouse model of vaccination, we show that the spleens of C57BL/6 mice vaccinated with live-attenuated Salmonella serovar Typhimurium (S. Typhimurium) strains carried a pool of IFN-γ+ CD4+ T cells that could adoptively transfer protection, but only transiently. Circulating Salmonella-reactive CD4+ T cells expressed the liver-homing chemokine receptor CXCR6, accumulated over time in the liver and assumed phenotypic characteristics associated with tissue-associated T cells. Liver memory CD4+ T cells showed TCR selection bias and their accumulation in the liver could be inhibited by blocking CXCL16. These data showed that the circulation of CD4+ T cells mediating immunity to Salmonella is limited to a brief window after which Salmonella-specific CD4+ T cells migrate to peripheral tissues. Our observations highlight the importance of triggering tissue-specific immunity against systemic infections.

Toll-like receptor and inflammasome signals converge to amplify the innate bactericidal capacity of T helper 1 cells.

T cell effector functions can be elicited by noncognate stimuli, but the mechanism and contribution of this pathway to the resolution of intracellular macrophage infections have not been defined. Here, we show that CD4(+) T helper 1 (Th1) cells could be rapidly stimulated by microbe-associated molecular patterns during active infection with Salmonella or Chlamydia. Further, maximal stimulation of Th1 cells by lipopolysaccharide (LPS) did not require T-cell-intrinsic expression of toll-like receptor 4 (TLR4), interleukin-1 receptor (IL-1R), or interferon-γ receptor (IFN-γR) but instead required IL-18R, IL-33R, and adaptor protein MyD88. Innate stimulation of Th1 cells also required host expression of TLR4 and inflammasome components that together increased serum concentrations of IL-18. Finally, the elimination of noncognate Th1 cell stimulation hindered the resolution of primary Salmonella infection. Thus, the in vivo bactericidal capacity of Th1 cells is regulated by the response to noncognate stimuli elicited by multiple innate immune receptors.

Management of malignant T1 colorectal cancer polyps: results from a 10-year prospective observational study.

AIM: The recurrence risk associated with residual malignant cells (bowel wall/regional nodes) following T1 colorectal cancer (CRC) polypectomy must be weighed against operative morbidity. Our aim was to describe the management and outcomes of a large prospective cohort of T1 CRCs. METHOD: All T1 CRCs diagnosed between March 2007 and March 2017 at the Glasgow Royal Infirmary were included. Patients were grouped by polypectomy, rectal local excision and formal resection status. χ2 testing, multivariate binary logistic and Cox regression were performed. RESULTS: Of 236 patients, 90 (38.1%) underwent polypectomy only, six (2.6%) polypectomy and then rectal excision, 57 (24.2%) polypectomy and then resection, 14 (5.9%) rectal excision only and 69 (29.2%) primary resection. Polypectomy only correlated with male sex (P = 0.028), older age (P < 0.001), distal CRCs (P < 0.001) and pedunculated polyps (P < 0.001); primary resection with larger polyps (P < 0.001); polypectomy then resection with piecemeal excision (P = 0.002) and involved polypectomy margin (P < 0.001). Poor differentiation (OR 7.860, 95% CI 1.117-55.328; P = 0.038) independently predicted lymph node involvement. Submucosal venous invasion (hazard ratio [HR] 10.154, 95% CI 2.087-49.396; P = 0.004) and mucinous subtype (HR 7.779, 95% CI 1.566-38.625; P = 0.012) independently predicted recurrence. Submucosal venous invasion (HR 5.792, 95% CI 1.056-31.754; P = 0.043) predicted CRC-specific survival. Although 64.4% of polypectomy-only patients had margin involvement/other risk factors, none developed recurrence. Of 94 with polypectomy margin involvement, five (5.3%) had confirmed residual tumour. Overall, lymph node metastases (7.1%), recurrence (4.2%) and cancer-specific mortality (3.0%) were rare. Cancer-specific 5-year survival was high: polypectomy only (100%), polypectomy and then resection (98.2%), primary resection (100%). CONCLUSION: Surveillance may be safe for more T1 CRC polyp patients. Multidisciplinary team discussion and informed patient choice are critical.

Combining the quantitative faecal immunochemical test and full blood count reliably rules out colorectal cancer in a symptomatic patient referral pathway.

PURPOSE: Faecal Immunochemical Test (FIT) has proven utility for Colorectal Cancer (CRC) detection in symptomatic patients. Most studies have examined FIT in symptomatic patients subsequently referred from primary care. We investigated associations between CRC and FIT in both referred and non-referred symptomatic patients. METHODS: A retrospective, observational study of all patients with a FIT submitted Aug 2018 to Jan 2019 in NHS GG&C was performed. Referral to colorectal/gastroenterology and decision to perform colonoscopy were recorded. FIT results were grouped as f-Hb < 10/10-149/150-399/ ≥ 400 µg/g. The MCN cancer registry identified new cases of CRC. Covariables were compared using the χ2 test. Multivariate binary logistic regression identified independent predictors of CRC. RESULTS: A total of 4968 patients were included. Raised FIT correlated with decision to refer (p < 0.001) and scope (p < 0.001). With 23-month median follow-up, 61 patients were diagnosed with CRC. These patients were older (median 69 vs 59 years, cancer and no cancer respectively, p = 0.001), more likely to be male (55.7% vs 42.1%, p = 0.033), and to report rectal bleeding (51.7% vs 36.1%, p = 0.013). FIT (< 10 µg/g 8.2% vs 76.7% and ≥ 400 µg/g 55.7% vs 3.8%, p < 0.001) and anaemia (45.9% vs 19.7%, p < 0.001) were associated with CRC. On multivariate analysis, age (p = 0.023), male sex (p = 0.04), FIT (≥ 400 OR 54.256 (95% CI:20.683-142.325; p < 0.001)), and anaemia (OR 1.956 (1.071-3.574; p = 0.029)) independently predicted CRC. One patient (0.04%) with a negative FIT and normal haemoglobin had CRC. CONCLUSION: GP referral and secondary care investigation patterns were influenced by FIT. The combination of normal Hb and f-Hb excluded CRC in 99.96% of cases, providing excellent reassurance to those prioritising access to endoscopy services.

Prevalence of repeat faecal immunochemical testing in symptomatic patients attending primary care.

AIM: The faecal immunochemical test (FIT) for faecal haemoglobin (f-Hb) helps determine the risk of colorectal cancer (CRC) and has been integrated into symptomatic referral pathways. 'Safety netting' advice includes considering referral for persistent symptoms, but no published data exists on repeated FITs. We aimed to examine the prevalence of serial FITs in primary care and CRC risk in these patients. METHOD: A multicentre, retrospective, observational study was conducted of patients with two or more consecutive f-Hb results within a year from three Scottish Health Boards which utilize FIT in primary care. Cancer registry data ensured identification of CRC cases. RESULTS: Overall, 135 396 FIT results were reviewed, of which 12 359 were serial results reported within 12 months (9.1%), derived from 5761 patients. Of these, 42 (0.7%) were diagnosed with CRC. A total of 3487 (60.5%) patients had two f-Hb < 10 µg/g, 944 (16.4%) had f-Hb ≥ 10 µg/g followed by <10 µg/g, 704 (12.2%) f-Hb < 10 µg/g followed by ≥10 µg/g and 626 (10.9%) had two f-Hb ≥ 10 µg/g. The CRC rate in each group was 0.1%, 0.4%, 1.4% and 4.0%, respectively. Seven hundred and thirty four patients submitted more than two FITs within a year. The likelihood of one or more f-Hb ≥ 10 µg/g rose from 40.4% with two samples to 100% with six, while the CRC rate fell from 0.8% to 0%. CONCLUSION: Serial FITs within a year account for 9.1% of all results in our Boards. CRC prevalence amongst symptomatic patients with serial FIT is lower than in single-FIT cohorts. Performing two FITs within a year for patients with persistent symptoms effectively acts as a safety net, while performing more than two within this timeframe is unlikely to be beneficial.

NOD1 and NOD2 signalling links ER stress with inflammation.

Endoplasmic reticulum (ER) stress is a major contributor to inflammatory diseases, such as Crohn disease and type 2 diabetes. ER stress induces the unfolded protein response, which involves activation of three transmembrane receptors, ATF6, PERK and IRE1α. Once activated, IRE1α recruits TRAF2 to the ER membrane to initiate inflammatory responses via the NF-κB pathway. Inflammation is commonly triggered when pattern recognition receptors (PRRs), such as Toll-like receptors or nucleotide-binding oligomerization domain (NOD)-like receptors, detect tissue damage or microbial infection. However, it is not clear which PRRs have a major role in inducing inflammation during ER stress. Here we show that NOD1 and NOD2, two members of the NOD-like receptor family of PRRs, are important mediators of ER-stress-induced inflammation in mouse and human cells. The ER stress inducers thapsigargin and dithiothreitol trigger production of the pro-inflammatory cytokine IL-6 in a NOD1/2-dependent fashion. Inflammation and IL-6 production triggered by infection with Brucella abortus, which induces ER stress by injecting the type IV secretion system effector protein VceC into host cells, is TRAF2, NOD1/2 and RIP2-dependent and can be reduced by treatment with the ER stress inhibitor tauroursodeoxycholate or an IRE1α kinase inhibitor. The association of NOD1 and NOD2 with pro-inflammatory responses induced by the IRE1α/TRAF2 signalling pathway provides a novel link between innate immunity and ER-stress-induced inflammation.

Antibody, but not B-cell-dependent antigen presentation, plays an essential role in preventing Chlamydia systemic dissemination in mice.

The obligate intracellular bacterium Chlamydia trachomatis causes the most prevalent bacterial sexually transmitted infection worldwide. CD4 T cells play a central role in the protective immunity against Chlamydia female reproductive tract (FRT) infection, while B cells are thought to be dispensable for resolution of primary Chlamydia infection in mouse models. We recently reported an unexpected requirement of B cells in local Chlamydia-specific CD4 T-cell priming and bacterial containment within the FRT. Here, we sought to tackle the precise effector function of B cells during Chlamydia primary infection. Using mixed bone marrow chimeras that lack B-cell-dependent Ag presentation (MHCIIB-/- ) or devoid of circulating antibodies (AID-/- × µS-/- ), we show that Chlamydia-specific CD4 T-cell expansion does not rely on Ag presentation by B cells. Importantly, we demonstrate that antibody, but not B-cell-dependent Ag presentation, is required for preventing systemic bacterial dissemination following Chlamydia FRT infection.

Staging the Tumor and Staging the Host: Pretreatment Combined Neutrophil Lymphocyte Ratio and Modified Glasgow Prognostic Score Is Associated with Overall Survival in Patients with Esophagogastric Cancers Undergoing Treatment with Curative Intent.

BACKGROUND: This study examined whether an innate systemic inflammatory response (SIR) measured by combination neutrophil to lymphocyte ratio (NLR) and modified Glasgow Prognostic Score (mGPS) was associated with overall survival (OS) in patients with esophagogastric cancer (EC) undergoing neoadjuvant chemotherapy (NAC) followed by surgery. METHODS: Patients diagnosed with EC, managed with NAC prior to surgery at a regional referral center, between January 2010 and December 2015, were included. The mGPS and NLR were calculated within 12 weeks before NAC. Patients were grouped by combined NLR/mGPS score into three groups of increasing SIR: NLR ≤ 3 (n = 152), NLR > 3 + mGPS = 0 (n = 55), and NLR > 3 + mGPS > 0 (n = 32). Univariable and multivariable Cox regression was used to analyse OS. RESULTS: Overall, 337 NAC patients were included, with 301 (89%) proceeding to surgery and 215 (64%) having R0 resection. There were 203 deaths, with a median follow-up of those alive at censor of 69 months (range 44-114). Higher combined NLR/mGPS score (n = 239) was associated with poorer OS independent of clinical stage and performance status (hazard ratio 1.28, 95% confidence interval 1.02-1.61; p = 0.032), higher rate of progression on NAC (7% vs. 7% vs. 19%; p = 0.003), and lower proportion of eventual resection (80% vs. 84% vs. 53%; p = 0.003). CONCLUSIONS: The combined NLR/mGPS score was associated with OS and initial treatment outcomes in patients undergoing NAC prior to surgery for EC, stratifying survival in addition to clinical staging and performance status. The host SIR may be a useful adjunct to multidisciplinary decision making.

Postoperative C-reactive protein concentrations to predict infective complications following gastrectomy for cancer.

BACKGROUND AND OBJECTIVES: Gastrectomy for gastric cancer is associated with significant infective postoperative complications. C-reactive protein (CRP) is a useful biomarker in the early detection of infective complications following major abdominal surgery. This single-centre retrospective study aimed to determine the relationship between postoperative CRP levels and development of postoperative infective complications after gastrectomy. METHODS: Daily postoperative CRP levels were analyzed to determine a CRP threshold associated with infective complications. ROC curve analysis was used to determine which postoperative day (POD) gave the optimal cutoff. Multivariate analysis was performed to determine significant factors associated with complications. RESULTS: One hundred and forty-four patients were included. A total of 61 patients (42%) had at least one infective complication. A CRP level of 220 mg/L was associated with the highest AUC (0.765) with a sensitivity of 70% and specificity of 76% (positive predictive value, 67%; negative predictive value, 78%). More patients with a CRP > 220 mg/L on POD 3 developed infective complications (67% vs. 21%, p < 0.001). CONCLUSIONS: A CRP of more than 220 mg/L on POD 3 may be useful to alert clinicians to the increased risk of a postoperative infective complication or enable earlier safe discharge from critical care for those with a lower value.

Yield of colorectal cancer at colonoscopy according to faecal haemoglobin concentration in symptomatic patients referred from primary care.

AIM: Lower gastrointestinal (GI) symptoms are poor predictors of colorectal cancer (CRC). The aim of this study was to examine the diagnostic yield of colonoscopy by faecal haemoglobin (f-Hb) concentration in symptomatic patients assessed in primary care by faecal immunochemical testing (FIT). METHOD: In three Scottish NHS Boards, FIT kits (HM-JACKarc, Hitachi Chemical Diagnostics Systems Co., Ltd, Tokyo, Japan) were used by general practitioners to guide referrals for patients with lower GI symptoms (laboratory data studied for 12 months from December 2015 onwards in Tayside, 18 months from June 2018 onwards in Fife and 5 months from September 2018 onwards in Greater Glasgow and Clyde). Cases of CRC diagnosed at colonoscopy were ascertained from colonoscopy and pathology records. RESULTS: Four thousand eight hundred and forty one symptomatic patients who underwent colonoscopy after FIT submission were included. Of the 2166 patients (44.7%) with f-Hb <10 µg Hb/g faeces (µg/g), 14 (0.6%) were diagnosed with CRC, with a number needed to scope (NNS) of 155. Of the 2675 patients (55.3%) with f-Hb ≥10 µg/g, 252 were diagnosed with CRC (9.4%) with a NNS of 11. Of the 705 patients with f-Hb ≥400 µg/g, 158 (22.4%) were diagnosed with CRC with a NNS of 5. Over half of those diagnosed with CRC with f-Hb <10 µg/g had coexisting anaemia. CONCLUSION: Symptomatic patients with f-Hb ≥10 µg/g should undergo further investigation for CRC, while higher f-Hb concentrations could be used to triage for urgency during the COVID-19 recovery phase. Patients with f-Hb <10 µg/g and without anaemia are very unlikely to be diagnosed with CRC and the majority need no further investigation.