Interferon lambda restricts herpes simplex virus skin disease by suppressing neutrophil-mediated pathology.

Type III interferons (IFN-λ) are antiviral and immunomodulatory cytokines that have been best characterized in respiratory and gastrointestinal infections, but the effects of IFN-λ against skin infections have not been extensively investigated. We sought to define the skin-specific effects of IFN-λ against the highly prevalent human pathogen, herpes simplex virus (HSV). We infected mice lacking the IFN-λ receptor (Ifnlr1-/-), both the IFN-λ and the IFN-α/ß receptors (Ifnar1-/-Ifnlr1-/-), or IFN-λ cytokines (Ifnl2/3-/-) and found that IFN-λ restricts the severity of HSV-1 and HSV-2 skin lesions without affecting viral loads. We used RNAseq to define IFN-λ- and IFN-ß-induced transcriptional responses in primary mouse keratinocytes. Using conditional knockout mice, we found that IFN-λ signaling in both keratinocytes and neutrophils was necessary to control HSV-1 skin lesion severity and that IFN-λ signaling in keratinocytes suppressed CXCL9-mediated neutrophil recruitment to the skin. Furthermore, depleting neutrophils or blocking CXCL9 protected against severe HSV-1 skin lesions in Ifnlr1-/- mice. Altogether, our results suggest that IFN-λ plays an immunomodulatory role in the skin that restricts neutrophil-mediated pathology during HSV infection and suggests potential applications for IFN-λ in treating viral skin infections.IMPORTANCEType III interferons (IFN-λ) have been shown to have antiviral and immunomodulatory effects at epithelial barriers such as the respiratory and gastrointestinal tracts, but their effects on the skin have not been extensively investigated. We used mice lacking IFN-λ signaling to investigate the skin-specific effects of IFN-λ against the herpes simplex virus (HSV), which targets epithelial tissues to cause cold sores and genital herpes. We found that IFN-λ limited the severity of HSV skin lesions without affecting viral load and that this protective effect required IFN-λ signaling in both keratinocytes and neutrophils. We found that IFN-λ signaling in keratinocytes suppressed neutrophil recruitment to the skin and that depleting neutrophils protected against severe HSV skin lesions in the absence of IFN-λ. Altogether, our results suggest that IFN-λ plays an immunomodulatory role in the skin that restricts neutrophil-mediated pathology during HSV infection and suggests potential applications for IFN-λ in treating viral skin infections.

A fur plucking model to study herpes simplex virus reactivation and recurrent disease.

Herpes simplex viruses (HSV-1 and HSV-2) most commonly cause ulcerative epithelial lesions (cold sores, genital herpes). Importantly, HSV establishes life-long persistent (latent) infection in sensory neurons. Reactivation from latency produces recurrent epithelial lesions, which constitute the greatest burden of HSV disease in people. The mechanisms that regulate latency and reactivation remain poorly understood, in part due to limitations in the animal models available for studying HSV reactivation. We have developed a simple and tractable model to induce HSV-1 and HSV-2 reactivation from latently infected sensory ganglia. We infected C57BL/6 mice with 1 × 106 FFU of HSV-1 (strain NS) or 500 FFU of HSV-2 (strain 333) on flank skin depilated by manual plucking. 35 days post-infection (dpi) we re-plucked the fur from the infected flank and observed recurrent lesions in the same dermatome as the primary infection. We detected HSV DNA in dermatome skin through 4 days post-re-plucking. We found that shaving the ipsilateral flank or plucking the contralateral flank did not induce recurrent skin lesions, suggesting that fur plucking is a specific stimulus that induces HSV reactivation. Further, we were able to induce multiple rounds of plucking induced recurrent disease, providing a model to investigate the lifelong nature of HSV infection. This new model provides a tractable system for studying pathogenic mechanisms of and therapeutic interventions against HSV reactivation and recurrent disease.

Interferon lambda restricts herpes simplex virus skin disease by suppressing neutrophil-mediated pathology.

Type III interferons (IFN-λ) are antiviral and immunomodulatory cytokines that have been best characterized in respiratory and gastrointestinal infections, but the effects of IFN-λ against skin infections have not been extensively investigated. We sought to define the skin-specific effects of IFN-λ against the highly prevalent human pathogen herpes simplex virus (HSV). We infected mice lacking the IFN-λ receptor (Ifnlr1-/-), both the IFN-λ and the IFN-αß receptor (Ifnar1-/- Ifnlr1-/-), or IFN-λ cytokines (Ifnl2/3-/-) and found that IFN-λ restricts the severity of HSV-1 and HSV-2 skin lesions, independent of a direct effect on viral load. Using conditional knockout mice, we found that IFN-λ signaling in both keratinocytes and neutrophils was necessary to control HSV-1 skin lesion severity, and that IFN-λ signaling in keratinocytes suppressed CXCL9-mediated neutrophil recruitment to the skin. Furthermore, depleting neutrophils or blocking CXCL9 protected against severe HSV-1 skin lesions in Ifnlr1-/- mice. Altogether, our results suggest that IFN-λ plays an immunomodulatory role in the skin that restricts neutrophil-mediated pathology during HSV infection, and suggest potential applications for IFN-λ in treating viral skin infections.

Considering equity in priority setting using transmission models: Recommendations and data needs.

OBJECTIVES: Disease transmission models are used in impact assessment and economic evaluations of infectious disease prevention and treatment strategies, prominently so in the COVID-19 response. These models rarely consider dimensions of equity relating to the differential health burden between individuals and groups. We describe concepts and approaches which are useful when considering equity in the priority setting process, and outline the technical choices concerning model structure, outputs, and data requirements needed to use transmission models in analyses of health equity. METHODS: We reviewed the literature on equity concepts and approaches to their application in economic evaluation and undertook a technical consultation on how equity can be incorporated in priority setting for infectious disease control. The technical consultation brought together health economists with an interest in equity-informative economic evaluation, ethicists specialising in public health, mathematical modellers from various disease backgrounds, and representatives of global health funding and technical assistance organisations, to formulate key areas of consensus and recommendations. RESULTS: We provide a series of recommendations for applying the Reference Case for Economic Evaluation in Global Health to infectious disease interventions, comprising guidance on 1) the specification of equity concepts; 2) choice of evaluation framework; 3) model structure; and 4) data needs. We present available conceptual and analytical choices, for example how correlation between different equity- and disease-relevant strata should be considered dependent on available data, and outline how assumptions and data limitations can be reported transparently by noting key factors for consideration. CONCLUSIONS: Current developments in economic evaluations in global health provide a wide range of methodologies to incorporate equity into economic evaluations. Those employing infectious disease models need to use these frameworks more in priority setting to accurately represent health inequities. We provide guidance on the technical approaches to support this goal and ultimately, to achieve more equitable health policies.

Interferon Lambda Signals in Maternal Tissues to Exert Protective and Pathogenic Effects in a Gestational Stage-Dependent Manner.

Interferon lambda (IFN-λ) (type III IFN) is constitutively secreted from human placental cells in culture and reduces Zika virus (ZIKV) transplacental transmission in mice. However, the roles of IFN-λ during healthy pregnancy and in restricting congenital infection remain unclear. Here, we used mice lacking the IFN-λ receptor (Ifnlr1-/-) to generate pregnancies lacking either maternal or fetal IFN-λ responsiveness and found that the antiviral effect of IFN-λ resulted from signaling exclusively in maternal tissues. This protective effect depended on gestational stage, as infection earlier in pregnancy (E7 rather than E9) resulted in enhanced transplacental transmission of ZIKV. In Ifnar1-/- dams, which sustain robust ZIKV infection, maternal IFN-λ signaling caused fetal resorption and intrauterine growth restriction. Pregnancy pathology elicited by poly(I·C) treatment also was mediated by maternal IFN-λ signaling, specifically in maternal leukocytes, and also occurred in a gestational stage-dependent manner. These findings identify an unexpected effect of IFN-λ signaling, specifically in maternal (rather than placental or fetal) tissues, which is distinct from the pathogenic effects of IFN-αß (type I IFN) during pregnancy. These results highlight the complexity of immune signaling at the maternal-fetal interface, where disparate outcomes can result from signaling at different gestational stages. IMPORTANCE Pregnancy is an immunologically complex situation, which must balance protecting the fetus from maternal pathogens with preventing maternal immune rejection of non-self fetal and placental tissue. Cytokines, such as interferon lambda (IFN-λ), contribute to antiviral immunity at the maternal-fetal interface. We found in a mouse model of congenital Zika virus infection that IFN-λ can have either a protective antiviral effect or cause immune-mediated pathology, depending on the stage of gestation when IFN-λ signaling occurs. Remarkably, both the protective and pathogenic effects of IFN-λ occurred through signaling exclusively in maternal immune cells rather than in fetal or placental tissues or in other maternal cell types, identifying a new role for IFN-λ at the maternal-fetal interface.

Repeatability of burst swimming performance in medaka (Oryzias latipes).

Burst swimming performance (Uburst) is a putative indicator of "success" in wild fish. In this study, thirty-five lab-reared medaka (Oryzias latipes) were tested for Uburst using a French press exercise system. Fish were tested once a week for four consecutive weeks and repeatability was estimated in several ways to allow comparisons between studies. Following the initial swimming tests, 50% of fish were either thermally stressed, or not, for 180 s prior to testing Uburst once a week for four consecutive weeks. Burst swimming performance was found to be 24.0 ± 6.7 (s.d.) cm s-1 and repeatability prior to the thermal stress experiment was estimated to be 0.28 (intraclass correlation coefficient) with an upper and lower limit of 0.48 and 0.12, respectively. The measured Uburst and repeatability estimate in the thermal stressor experiment did not significantly differ from the first four trials. Swimming velocities observed match what is known about medaka swimming capabilities and, interestingly, are similar to maximum current velocities observed in their native habitat. Furthermore, our repeatability estimates confirm that burst swimming performance in medaka is a repeatable trait and validate the apparatus and swimming test used.

National prospective cohort study of the burden of acute small bowel obstruction.

Background: Small bowel obstruction is a common surgical emergency, and is associated with high levels of morbidity and mortality across the world. The literature provides little information on the conservatively managed group. The aim of this study was to describe the burden of small bowel obstruction in the UK. Methods: This prospective cohort study was conducted in 131 acute hospitals in the UK between January and April 2017, delivered by trainee research collaboratives. Adult patients with a diagnosis of mechanical small bowel obstruction were included. The primary outcome was in-hospital mortality. Secondary outcomes included complications, unplanned intensive care admission and readmission within 30 days of discharge. Practice measures, including use of radiological investigations, water soluble contrast, operative and nutritional interventions, were collected. Results: Of 2341 patients identified, 693 (29·6 per cent) underwent immediate surgery (within 24 h of admission), 500 (21·4 per cent) had delayed surgery after initial conservative management, and 1148 (49·0 per cent) were managed non-operatively. The mortality rate was 6·6 per cent (6·4 per cent for non-operative management, 6·8 per cent for immediate surgery, 6·8 per cent for delayed surgery; P = 0·911). The major complication rate was 14·4 per cent overall, affecting 19·0 per cent in the immediate surgery, 23·6 per cent in the delayed surgery and 7·7 per cent in the non-operative management groups (P < 0·001). Cox regression found hernia or malignant aetiology and malnutrition to be associated with higher rates of death. Malignant aetiology, operative intervention, acute kidney injury and malnutrition were associated with increased risk of major complication. Conclusion: Small bowel obstruction represents a significant healthcare burden. Patient-level factors such as timing of surgery, acute kidney injury and nutritional status are factors that might be modified to improve outcomes.

Systematic review of the use of big data to improve surgery in low- and middle-income countries.

BACKGROUND: Technological advances have led to the generation of large amounts of data, both in surgical research and practice. Despite this, it is unclear how much originates in low- and middle-income countries (LMICs) and what barriers exist to the use of such data in improving surgical care. The aim of this review was to capture the extent and impact of programmes that use large volumes of patient data on surgical care in LMICs. METHODS: A PRISMA-compliant systematic literature review of PubMed, Embase and Google Scholar was performed in August 2018. Prospective studies collecting large volumes of patient-level data within LMIC settings were included and evaluated qualitatively. RESULTS: A total of 68 studies were included from 71 LMICs, involving 708 032 patients. The number of patients in included studies varied widely (from 335 to 428 346), with 25 reporting data on 3000 or more LMIC patients. Patient inclusion in large-data studies in LMICs has increased dramatically since 2015. Studies predominantly involved Brazil, China, India and Thailand, with low patient numbers from Africa and Latin America. Outcomes after surgery were commonly the focus (33 studies); very few large studies looked at access to surgical care or patient expenditure. The use of large data sets specifically to improve surgical outcomes in LMICs is currently limited. CONCLUSION: Large volumes of data are becoming more common and provide a strong foundation for continuing investigation. Future studies should address questions more specific to surgery.

The diagnostic yield of computed tomography in the management of acute flank pain and the emergency intervention rate for a proven acute ureteric stone.

INTRODUCTION: The diagnostic and management pathways for patients presenting with acute flank pain are complex. Although computed tomography (CT) of the kidneys, ureters and bladder (KUB) is the gold standard investigation for urolithiasis, the multitude of differential diagnoses must also be considered in the context of long-term risk from ionising radiation. This study investigated the integrated role and diagnostic yield of non-contrast CT in cases of acute flank pain. METHODS: A retrospective cohort study was undertaken of 1,442 consecutive patients investigated with CT KUB between March 2013 and February 2015. The primary outcome was diagnostic yield of CT with secondary outcomes being predictors of need for urological intervention. RESULTS: A cause for acute flank pain was identified in 717 patients (50%), there was an incidental finding in 389 patients (27%) and normal imaging was reported in 336 patients (23%). A diagnosis was more commonly made in male than in female patients (70% vs 40%) and with increasing age (46% in patients aged <30 years, 56% in those aged 30-49 years and 63% in those aged ≥50 years). The overall rate for an ipsilateral urinary tract stone was 41%. Factors strongly associated with emergency intervention included stone size >10mm (odds ratio [OR]: 11.7, 95% confidence interval [CI]: 3.3-42.7), stones located at the pelviureteric junction (OR: 7.8, 95% CI: 2.6-22.9), C-reactive protein >50mg/l and ≤100mg/l (OR: 15.2, 95% CI: 5.1-45.3), and estimated glomerular filtration rate ≤30ml/min (OR: 5.8, 95% CI: 1.5-21.8). CONCLUSIONS: This contemporary study identifies age and sex as independent variables affecting the diagnostic yield of CT KUB in cases of acute flank pain, and highlights factors associated with a need for emergency intervention in proven ureteric stones.

Factors Predicting a Good Symptomatic Outcome After Prostate Artery Embolisation (PAE).

INTRODUCTION: As prostate artery embolisation (PAE) becomes an established treatment for benign prostatic obstruction, factors predicting good symptomatic outcome remain unclear. Pre-embolisation prostate size as a predictor is controversial with a handful of papers coming to conflicting conclusions. We aimed to investigate if an association existed in our patient cohort between prostate size and clinical benefit, in addition to evaluating percentage volume reduction as a predictor of symptomatic outcome following PAE. MATERIALS OR METHODS: Prospective follow-up of 86 PAE patients at a single institution between June 2012 and January 2016 was conducted (mean age 64.9 years, range 54-80 years). Multiple linear regression analysis was performed to assess strength of association between clinical improvement (change in IPSS) and other variables, of any statistical correlation, through Pearson's bivariate analysis. RESULTS: No major procedural complications were identified and clinical success was achieved in 72.1% (n = 62) at 12 months. Initial prostate size and percentage reduction were found to have a significant association with clinical improvement. Multiple linear regression analysis (r2 = 0.48) demonstrated that percentage volume reduction at 3 months (r = 0.68, p < 0.001) had the strongest correlation with good symptomatic improvement at 12 months after adjusting for confounding factors. CONCLUSION: Both the initial prostate size and percentage volume reduction at 3 months predict good symptomatic outcome at 12 months. These findings therefore aid patient selection and counselling to achieve optimal outcomes for men undergoing prostate artery embolisation.

A systematic review of the incidence of and risk factors for postoperative atrial fibrillation following general surgery.

Atrial fibrillation is a common cardiac arrhythmia and can occur de novo following a surgical procedure. It is associated with increased inpatient and long-term mortality. There is limited evidence concerning new-onset atrial fibrillation following abdominal surgery. This study aimed to identify the prevalence of and risk factors for postoperative atrial fibrillation in the general surgical population. A systematic search of the Embase, MEDLINE and Cochrane (CENTRAL) databases was conducted. Studies were included in the review if they reported cases of new-onset atrial fibrillation within 30 days of the index operation. Results were evaluated qualitatively due to substantial clinical heterogeneity. Incidence rates were pooled using a weighted random-effects meta-analysis model. A total of 835 records were initially identified, from which 32 full texts were retrieved. Following review, 13 studies were included that involved 52,959 patients, of whom 10.94% (95%CI 7.22-15.33) developed atrial fibrillation. Five studies of patients undergoing oesophagectomy (n = 376/1923) had a weighted average rate of 17.66% (95%CI 12.16-21.47), compared with 7.63% (95%CI 4.39-11.98) from eight studies of non-oesophageal surgery (n = 2927/51,036). Identified risk factors included: increasing age; history of cardiac disease; postoperative complications, particularly, sepsis, pneumonia and pleural effusions. New-onset postoperative atrial fibrillation is common, and is more frequent after surgery involving the thorax. Future work should focus on stratifying risk to allow targeted prophylaxis of atrial fibrillation and other peri-operative complications.

The major targets of acute norovirus infection are immune cells in the gut-associated lymphoid tissue.

Noroviruses are the leading cause of food-borne gastroenteritis outbreaks and childhood diarrhoea globally, estimated to be responsible for 200,000 deaths in children each year 1-4 . Thus, reducing norovirus-associated disease is a critical priority. Development of vaccines and therapeutics has been hindered by the limited understanding of basic norovirus pathogenesis and cell tropism. While macrophages, dendritic cells, B cells and stem-cell-derived enteroids can all support infection of certain noroviruses in vitro 5-7 , efforts to define in vivo norovirus cell tropism have generated conflicting results. Some studies detected infected intestinal immune cells 8-12 , other studies detected epithelial cells 13 , and still others detected immune and epithelial cells 14-16 . Major limitations of these studies are that they were performed on tissue sections from immunocompromised or germ-free hosts, chronically infected hosts where the timing of infection was unknown, or following non-biologically relevant inoculation routes. Here, we report that the dominant cellular targets of a murine norovirus inoculated orally into immunocompetent mice are macrophages, dendritic cells, B cells and T cells in the gut-associated lymphoid tissue. Importantly, we also demonstrate that a norovirus can infect T cells, a previously unrecognized target, in vitro. These findings represent the most extensive analyses to date of in vivo norovirus cell tropism in orally inoculated, immunocompetent hosts at the peak of acute infection and thus they significantly advance our basic understanding of norovirus pathogenesis.

Resource variation in colorectal surgery: a national centre level analysis.

AIM: Delivery of quality colorectal surgery requires adequate resources. We set out to assess the relationship between resources and outcomes in English colorectal units. METHOD: Data were extracted from the Association of Coloproctology of Great Britain and Ireland resource questionnaire to profile resources. This was correlated with Hospital Episode Statistics outcome data including 90-day mortality and readmissions. Patient satisfaction measures were extracted from the Cancer Experience Patient Survey and compared at unit level. Centres were divided by workload into low, middle and top tertile. RESULTS: Completed questionnaires were received from 75 centres in England. Service resources were similar between low and top tertiles in access to Confidential Enquiry into Patient Outcome and Death (CEPOD) theatre, level two or three beds per 250 000 population or the likelihood of having a dedicated colorectal ward. There was no difference in staffing levels per 250 000 unit of population. Each 10% increase in the proportion of cases attempted laparoscopically was associated with reduced 90-day unplanned readmission (relative risk 0.94, 95% CI 0.91-0.97, P < 0.001). The presence of a dedicated colorectal ward (relative risk 0.85, 95% CI 0.73-0.99, P = 0.040) was also associated with a significant reduction in unplanned readmissions. There was no association between staffing or service factors and patient satisfaction. CONCLUSION: Resource levels do not vary based on unit of population. There is benefit associated with increased use of laparoscopy and a dedicated surgical ward. Alternative measures to assess the relationship between resources and outcome, such as failure to rescue, should be explored in UK practice.

Longitudinal analysis of reporting and quality of systematic reviews in high-impact surgical journals.

BACKGROUND: The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) Statement aims to optimize the reporting of systematic reviews. The performance of the PRISMA Statement in improving the reporting and quality of surgical systematic reviews remains unclear. METHODS: Systematic reviews published in five high-impact surgical journals between 2007 and 2015 were identified from online archives. Manuscripts blinded to journal, publication year and authorship were assessed according to 27 reporting criteria described by the PRISMA Statement and scored using a validated quality appraisal tool (AMSTAR, Assessing the Methodological Quality of Systematic Reviews). Comparisons were made between studies published before (2007-2009) and after (2011-2015) its introduction. The relationship between reporting and study quality was measured using Spearman's rank test. RESULTS: Of 281 eligible manuscripts, 80 were published before the PRISMA Statement and 201 afterwards. Most manuscripts (208) included a meta-analysis, with the remainder comprising a systematic review only. There was no meaningful change in median compliance with the PRISMA Statement (19 (i.q.r. 16-21) of 27 items before versus 19 (17-22) of 27 after introduction of PRISMA) despite achieving statistical significance (P = 0·042). Better reporting compliance was associated with higher methodological quality (rs = 0·70, P < 0·001). CONCLUSION: The PRISMA Statement has had minimal impact on the reporting of surgical systematic reviews. Better compliance was associated with higher-quality methodology.

Pharmacological management to prevent ileus in major abdominal surgery: a systematic review and meta-analysis.

BACKGROUND: Prolonged ileus is a common complication following gastrointestinal surgery, with an incidence of up to 40 %. Investigations examining pharmacological treatment of ileus have proved largely disappointing; however, recently, several compounds have been shown to have benefited when used as prophylaxis to prevent ileus. OBJECTIVE: This review aimed to evaluate the safety and efficacy of compounds which have been recently developed or repurposed to reduce bowel recovery time, thereby preventing ileus. DATA SOURCES: Data were taken from a systematic review of the MEDLINE, EMBASE and Cochrane Library Databases, in addition to manual searching of reference lists up to April 2015. No limits were applied. STUDY SELECTION: Only randomized trials were eligible for inclusion. INTERVENTIONS: Opioid receptor antagonists, ghrelin receptor agonists and serotonin receptor agonists used for the prevention of postoperative ileus in gastrointestinal surgery. MAIN OUTCOME MEASURES: Outcomes of time to first defecation, first flatus and composite bowel recovery endpoints (GI2 and GI3) were used to determine efficacy. Pooled treatment effects were presented as the standard mean difference or as hazard ratios alongside the corresponding 95 % confidence intervals. Risk of bias was assessed using the Cochrane risk of bias framework. RESULTS: A total of 17 studies were included in the final analysis. The µ-opioid receptor antagonist alvimopan and serotonin receptor agonists appeared to significantly shorten the duration of ileus. The use of Ghrelin receptor agonists did not appear to have any effect in five trials. No publication bias was detected. LIMITATIONS: Most of the trials were poorly reported and of mixed quality. Future studies must focus on the development of a set of core outcomes. CONCLUSIONS: There is evidence to make a strong recommendation for the use of alvimopan in major gastrointestinal surgery to reduce postoperative ileus. Further randomized trials are required to establish whether serotonin receptor agonists are of use. Identifying a low-cost compound to promote bowel recovery following surgery could reduce complications and shorten duration of hospital admissions.

A Randomised Assessment of Trainee Doctors' Understanding and Interpretation of Diagnostic Test Results.

INTRODUCTION: Doctors are unfamiliar with diagnostic accuracy parameters despite routine clinical use of diagnostic tests to estimate disease probability. METHODS: Trainee doctors completed a questionnaire exploring their understanding of diagnostic accuracy parameters; ability to calculate post-test probability of a common surgical condition (appendicitis) and their perceptions on training in this area. To determine whether the method of information provision altered interpretation, trainees were randomised to receive diagnostic test information in three ways: positive test only; positive test with specificity and sensitivity; positive test with positive likelihood ratio in layman terms. RESULTS: 326 candidates were recruited across 30 training sessions. Trainees scored a median of three out of seven in questions concerning knowledge of diagnostic accuracy parameters. This was affected neither by training level (P = 0.737) nor by experience in acute general surgery (P = 0.738). 30 (11.8%) candidates correctly estimated post-test probability; with 86.6% overestimating this value. Neither level of training (P = 0.180) nor experience (P = 0.242) influenced the accuracy of the estimate. Provision of the ultrasound scan results in different ways was not associated with likelihood of a correct response (P = 0.857). CONCLUSION: This study highlights the deficiencies in trainee doctors' understanding and application of diagnostic tests results. Most trainees over-estimated disease probability, increasing the risk of unnecessary intervention and treatment.

Factors associated with failure to achieve a glycated haemoglobin target of <8.0% in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.

The aim of this study was to identify the clinical features of participants in the standard therapy arm of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) glycaemia trial who failed to reach the glycated haemoglobin (HbA1c) target. We analysed 4685 participants in the standard therapy arm, comparing participants who reached the HbA1c target of <8.0% with those whose HbA1c level was ≥8.0% 12 months after randomization. Baseline and 12-month clinical characteristics were compared. At 12 months after randomization, 3194 participants had HbA1c <8.0% and 1491 had HbA1c ≥8.0%. Black race [odds ratio (OR) 0.74, 95% confidence interval (CI) 0.61-0.89; p = 0.002], severe hypoglycaemia (OR 0.57, CI 0.37-0.89; p = 0.014) and insulin use (OR 0.51, CI 0.40-0.65; p < 0.001) were associated with failure to reach HbA1c goal at 12 months in the adjusted model. Even with free medications, free visits with clinicians and aggressive titration of medications, >30% of participants in the standard arm of the ACCORD trial had an HbA1c ≥8.0% at 1 year. Participants who were black, had severe hypoglycaemia and were on insulin were more likely to have an above-target HbA1c concentration after 12 months on the standard protocol.

Targeting the endoplasmic reticulum mediates radiation sensitivity in colorectal cancer.

BACKGROUND: Radiotherapy is an established treatment modality for early and locally advanced rectal cancer as part of short course radiotherapy and long course chemoradiotherapy. The unfolded protein response (UPR) is a cellular stress response pathway often activated in human solid tumours which has been implicated in resistance to both chemotherapy and radiotherapy. This research has investigated whether the UPR pathway is upregulated in ex-vivo samples of human colorectal cancer and characterised the interaction between radiotherapy and UPR activation in two human colorectal cancer cell lines in vitro. METHODS: In vitro UPR expression was determined in response to clinical doses of radiotherapy in both the human colorectal adenocarcinoma (HT-29) cell line and a radio-resistant clone (HT-29R) using western blotting and quantitative polymerase chain reaction. The UPR was induced using a glucose deprivation culture technique before irradiation and radiosensitivity assessed using a clonogenic assay. Ex-vivo human colorectal cancer tissue was immuno-histochemically analysed for expression of the UPR marker glucose regulated protein 78 (GRP-78). RESULTS: The UPR was strongly up regulated in ex-vivo human colorectal tumours with 36 of 50 (72.0%) specimens demonstrating moderate to strong staining for the classic UPR marker GRP-78. In vitro, therapeutic doses of radiotherapy did not induce UPR activation in either radiosensitive or radioresistant cell lines. UPR induction caused significant radiosensitisation of the radioresistant cell line (HT-29R SF2Gy=0.90 S.E.M. +/-0.08; HT-29RLG SF2Gy=0.69 S.E.M. +/-0.050). CONCLUSION: This suggests that UPR induction agents may be potentially useful response modifying agents in patients undergoing therapy for colorectal cancer.

Serum total hCGß level is an independent prognostic factor in transitional cell carcinoma of the urothelial tract.

BACKGROUND: Serum total human chorionic gonadotrophin ß subunit (hCGß) level might have prognostic value in urothelial transitional cell carcinoma (TCC) but has not been investigated for independence from other prognostic variables. METHODS: We utilised a clinical database of patients receiving chemotherapy between 2005 and 2011 for urothelial TCC and an independent cohort of radical cystectomy patients for validation purposes. Prognostic variables were tested by univariate Kaplan-Meier analyses and log-rank tests. Statistically significant variables were then assessed by multivariate Cox regression. Total hCGß level was dichotomised at < vs ≥2 IU l(-1). RESULTS: A total of 235 chemotherapy patients were eligible. For neoadjuvant chemotherapy, established prognostic factors including low ECOG performance status, normal haemoglobin, lower T stage and suitability for cisplatin-based chemotherapy were associated with favourable survival in univariate analyses. In addition, low hCGß level was favourable when assessed either before (median survival not reached vs 1.86 years, P=0.001) or on completion of chemotherapy (4.27 vs 0.42 years, P=0.000002). This was confirmed in multivariate analyses and in patients receiving first- and second-line palliative chemotherapy, and in a radical cystectomy validation set. CONCLUSIONS: Serum total hCGß level is an independent prognostic factor in patients receiving chemotherapy for urothelial TCC in both curative and palliative settings.