Characteristics, management and outcome of a large necrotising otitis externa case series: need for standardised case definition.

BACKGROUND: Necrotising otitis externa is a severe ear infection for which there are no established diagnostic or treatment guidelines. METHOD: This study described clinical characteristics, management and outcomes for patients managed as necrotising otitis externa cases at a UK tertiary referral centre. RESULTS: A total of 58 (63 per cent) patients were classified as definite necrotising otitis externa cases, 31 (34 per cent) as probable cases and 3 (3 per cent) as possible cases. Median duration of intravenous and oral antimicrobial therapy was 6.0 weeks (0.49-44.9 weeks). Six per cent of patients relapsed a median of 16.4 weeks (interquartile range, 23-121) after stopping antimicrobials. Twenty-eight per cent of cases had complex disease. These patients were older (p = 0.042), had a longer duration of symptoms prior to imaging (p < 0.0001) and higher C-reactive protein at diagnosis (p = 0.005). Despite longer courses of intravenous antimicrobials (23 vs 14 days; p = 0.032), complex cases were more likely to relapse (p = 0.016). CONCLUSION: A standardised case-definition of necrotising otitis externa is needed to optimise diagnosis, management and research.

Development and internal validation of clinical prediction models for outcomes of complicated intra-abdominal infection.

BACKGROUND: Complicated intra-abdominal infections (cIAIs) are associated with significant morbidity and mortality. The aim of this study was to describe the clinical characteristics of patients with cIAI in a multicentre study and to develop clinical prediction models (CPMs) to help identify patients at risk of mortality or relapse. METHODS: A multicentre observational study was conducted from August 2016 to February 2017 in the UK. Adult patients diagnosed with cIAI were included. Multivariable logistic regression was performed to develop CPMs for mortality and cIAI relapse. The c-statistic was used to test model discrimination. Model calibration was tested using calibration slopes and calibration in the large (CITL). The CPMs were then presented as point scoring systems and validated further. RESULTS: Overall, 417 patients from 31 surgical centres were included in the analysis. At 90 days after diagnosis, 17.3 per cent had a cIAI relapse and the mortality rate was 11.3 per cent. Predictors in the mortality model were age, cIAI aetiology, presence of a perforated viscus and source control procedure. Predictors of cIAI relapse included the presence of collections, outcome of initial management, and duration of antibiotic treatment. The c-statistic adjusted for model optimism was 0.79 (95 per cent c.i. 0.75 to 0.87) and 0.74 (0.73 to 0.85) for mortality and cIAI relapse CPMs. Adjusted calibration slopes were 0.88 (95 per cent c.i. 0.76 to 0.90) for the mortality model and 0.91 (0.88 to 0.94) for the relapse model; CITL was -0.19 (95 per cent c.i. -0.39 to -0.12) and - 0.01 (- 0.17 to -0.03) respectively. CONCLUSION: Relapse of infection and death after complicated intra-abdominal infections are common. Clinical prediction models were developed to identify patients at increased risk of relapse or death after treatment, these now require external validation.

The governance of overseas surgical collaborations - BFIRST/BSSH.

Clinical governance is the structured approach to maintaining and improving the quality of patient care and is a vital part of global surgery. BFIRST and BSSH closely collaborate with local doctors on a number of overseas projects, seeking to strengthen and develop local knowledge and skills, aiming for an independent local practice in reconstructive and upper limb surgery. Thoughts on essential requirements, improvements and pitfalls in the ethical approach to global collaboratives are presented.

Effects of tracheal intubation and tracheal tube position on regional lung ventilation: an observational study.

Anaesthesia and positive pressure ventilation cause ventral redistribution of regional ventilation, potentially caused by the tracheal tube. We used electrical impedance tomography to map regional ventilation during anaesthesia in 10 patients with and without a tracheal tube. We recorded impedance data in subjects who were awake, during bag-mask ventilation, with the tracheal tube positioned normally, rotated 90° to each side and advanced until in an endobronchial position. We recorded the following measurements: ventilation of the right lung (proportion, %); centre of ventilation (100% = entirely ventral); global inhomogeneity (0% = homogenous); and regional ventilation delay, an index of temporal heterogeneity. We compared the results using Student's t-tests. Relative to subjects who were awake, anaesthesia with bag-mask ventilation reduced right-sided ventilation by 5.6% (p = 0.002), reduced regional ventilation delay by 1.6% (p = 0.025), and moved the centre of ventilation ventrally from 51.4% to 58.2% (p = 0.0001). Tracheal tube ventilation caused a further centre of ventilation increase of 1.3% (p = 0.009). With the tube near the carina, right-sided ventilation increased by 3.2% (p = 0.031) and regional ventilation delay by 2.8% (p = 0.049). Tube rotation caused a 1.6% increase in right-sided ventilation compared with normal position (p = 0.043 left and p = 0.031 right). Global inhomogeneity remained mostly unchanged. Ventral ventilation with positive pressure ventilation occurred with bag-mask ventilation, but was exacerbated by a tracheal tube. Tube position influenced ventilation of the right and left lungs, while ventilation overall remained homogenous. Tube rotation in either direction resulted in ventilation patterns being closer to when awake than either bag-mask ventilation or a normally positioned tube. These results suggest that even ideal tube positioning cannot avoid the ventral shift in ventilation.

A case of co-existing paraganglioma and thymoma.

BACKGROUND: Head and neck paragangliomas are rare tumours and can arise as a part of inherited syndromes. Their association with thymic tumour is not well known. CASE DESCRIPTION: This report describes a female patient who presented with right sided neck paragangliomas. The histology of the tumour was consistent with paraganlioma. Few years later her MRI scan of the chest revealed presence of an anterior mediastinal mass that corresponded to the location of the thymus. Review of her previous scans showed that the mass was present all along and had gradually increased in size. Patient developed symptoms including fatigue, dyspnoea, migratory polyarthritis, Raynaud's phenomenon and erythema nodosum. She had sternotomy and excision of mediastinal mass. The histology was consistent with cortical thymoma (WHO type B2) and she had radiotherapy. After treatment her constitutional symptoms improved. Her paraganglioma susceptibility genes are negative. DISCUSSION AND EVALUATION: To our knowledge this is only the second case report in the literature of coexistence of carotid body tumour and thymoma. The first case reported was bilateral carotid body tumour, thyroid gland adenoma and thymoma. This case also highlights the importance of long term surveillance, multidisciplinary management and being aware of associated pathologies in patients with isolated paraganglioma.

International scale implementation of the CNOSSOS-EU road traffic noise prediction model for epidemiological studies.

The EU-FP7-funded BioSHaRE project is using individual-level data pooled from several national cohort studies in Europe to investigate the relationship of road traffic noise and health. The detailed input data (land cover and traffic characteristics) required for noise exposure modelling are not always available over whole countries while data that are comparable in spatial resolution between different countries is needed for harmonised exposure assessment. Here, we assess the feasibility using the CNOSSOS-EU road traffic noise prediction model with coarser input data in terms of model performance. Starting with a model using the highest resolution datasets, we progressively introduced lower resolution data over five further model runs and compared noise level estimates to measurements. We conclude that a low resolution noise model should provide adequate performance for exposure ranking (Spearman's rank = 0.75; p < 0.001), but with relatively large errors in predicted noise levels (RMSE = 4.46 dB(A)).

Expression and DNA methylation of TNF, IFNG and FOXP3 in colorectal cancer and their prognostic significance.

BACKGROUND: Colorectal cancer (CRC) progression is associated with suppression of host cell-mediated immunity and local immune escape mechanisms. Our aim was to assess the immune function in terms of expression of TNF, IFNG and FOXP3 in CRC. METHODS: Sixty patients with CRC and 15 matched controls were recruited. TaqMan quantitative PCR and methylation-specific PCR was performed for expression and DNA methylation analysis of TNF, IFNG and FOXP3. Survival analysis was performed over a median follow-up of 48 months. RESULTS: TNF was suppressed in tumour and IFNG was suppressed in peripheral blood mononuclear cells (PBMCs) of patients with CRC. Tumours showed enhanced expression of FOXP3 and was significantly higher when tumour size was >38 mm (median tumour size; P=0.006, Mann-Whitney U-test). Peripheral blood mononuclear cell IFNG was suppressed in recurrent CRC (P=0.01). Methylated TNFpromoter (P=0.003) and TNFexon1 (P=0.001) were associated with significant suppression of TNF in tumours. Methylated FOXP3cpg was associated with significant suppression of FOXP3 in both PBMC (P=0.018) and tumours (P=0.010). Reduced PBMC FOXP3 expression was associated with significantly worse overall survival (HR=8.319, P=0.019). CONCLUSIONS: We have detected changes in the expression of immunomodulatory genes that could act as biomarkers for prognosis and future immunotherapeutic strategies.

Performance of the fullPIERS model in predicting adverse maternal outcomes in pre-eclampsia using patient data from the PIERS (Pre-eclampsia Integrated Estimate of RiSk) cohort, collected on admission.

The fullPIERS (Pre-eclampsia Integrated Estimate of RiSk) model is a promising tool for the prediction of adverse outcomes in pre-eclampsia, developed using the worst values for predictor variables measured within 48 hours of admission. We reassessed the performance of fullPIERS using predictor variables obtained within 6 and 24 hours of admission, and found that the stratification capacity, calibration ability, and classification accuracy of the model remained high. The fullPIERS model is accurate as a rule-in test for adverse maternal outcome, with a likelihood ratio of 14.8 (95% CI 9.1-24.1) or 17.5 (95% CI 11.7-26.3) based on 6- and 24-hour data, respectively, for the women identified to be at highest risk (predicted probability ≥ 30%).

A study of genomic instability in early preneoplastic colonic lesions.

It is difficult to explain the differential rates of progression of premalignant colonic lesions and differences in behaviour of morphologically similar lesions. Heterogeneity for microsatellite instability (MSI) and promoter methylation in driving these phenomena forward may explain this; however, no previous analysis has examined this in detail at the gland level, the smallest unit of colorectal premalignant lesions. We aimed to carry out an analysis of gland level genomic instability for MSI and promoter methylation. MSI occurred significantly more frequently (20%) in colonic glands than has previously been observed in whole colorectal polyps. Significant promoter methylation was seen in MLH1, PMS2, MLH3 and MSH3 as well as significant heterogeneity for both MSI and promoter methylation. Methylation and MSI may have a significant role in driving forward colorectal carcinogenesis, although in the case of MSI, this association is less clear as it occurs significantly more frequently than previously thought, and may simply be a passenger in the adenoma-carcinoma sequence. Promoter methylation in MLH1, MLH3, MSH3 and PMS2 was also found to be significantly associated with MSI and should be investigated further. A total of 273 colorectal glands (126 hyperplastic, 147 adenomatous) were isolated via laser capture microdissection (targeted at regions of MLH1 loss) from 93 colonic polyps and tested for MSI, and promoter methylation of the DNA mismatch repair genes MLH1, MSH2, MLH3, MSH6, PMS2, MGMT and MLH3 via methylation specific multiplex ligation-dependent probe amplification. Logistic regression modelling was then used to identify significant associations between promoter methylation and gland histological type and MSI status.

A complex endocrine conundrum.

We describe a case of recurrent primary hyperparathyroidism, manifested as 3 metachronous parathyroid adenomata, in a 50 year-old woman who also had Hashimoto hypothyroidism, gastric gastrointestinal stromal tumour (GIST), cysts in liver and kidneys, 5 intestinal polyps (one of these a villous adenoma), diverticulitis and telangiectasia of lips. She did not have medullary thyroid carcinoma (MTC). Genetic analysis of the CDC73 gene [for Hyperparathyroidism-jaw tumor (HPT-JT)], MEN1 for Multiple Endocrine Neoplasia Type1, CDKN1B for MEN4, SDHB and SDHD for Paraganglioma/Pheochromocytoma susceptibility, VHL for von Hippel-Lindau Syndrome, BMPR1A and SMAD4 for Juvenile Polyposis Syndrome (JPS) (sequencing and MLPA), karyotype and array CGH (44 K) were all normal. She was found to be homozygous for a synonomous germline variant in exon 14 (p. Ser836Ser) of the RET oncogene. This RET variant is of unclear clinical significance, and has been previously reported both in normal individuals and in individuals with MTC. It is unlikely that homozygosity for the RET variant has been casual in the multiple pathologies that our patient has developed.

Is colorectal surveillance indicated in patients with PTEN mutations?

AIM: Patients with germline phosphatase and tensin homologue (PTEN) mutations develop hamartomatous lesions in several organs and are at increased risk of various malignancies. We assessed the lifetime risk of benign and malignant gastrointestinal lesions in patients with a proven PTEN mutation. METHOD: Data on gender, mutation, dates of birth, last contact, and diagnosis, location and type of gastrointestinal lesions were collected from nine countries. The lifetime risk of gastrointestinal lesions was calculated by Kaplan-Meier methods. RESULTS: A total of 156 patients (67 men, 43%) from 101 families with a PTEN mutation were included. Patients were born between 1928 and 2008. Benign gastrointestinal polyps were reported in 49 (31%) patients at a mean age of 38 years (range 18-62 years) and were most often hamartomas. Twenty-two (44%) patients had upper as well as lower gastrointestinal lesions, 14 (29%) had only colonic lesions and 13 (27%) had gastrointestinal lesions at unknown sites. The cumulative risk of developing benign gastrointestinal polyps was 70% at age 60. Four patients (two men) developed colorectal carcinoma at 53, 57, 59 and 62 years, respectively. The cumulative risk of developing colorectal carcinoma was 18% at age 60. Except for one carcinoid in the small intestine, no upper gastrointestinal cancers were observed. CONCLUSION: Benign gastrointestinal lesions are common in PTEN mutation carriers, and a three- to four-fold increased lifetime risk of colorectal cancer compared with the general population may exist. Colorectal screening of patients with germline PTEN mutations is recommended, starting at age 40 years.

TERC polymorphisms are associated both with susceptibility to colorectal cancer and with longer telomeres.

BACKGROUND AND AIMS: Shorter telomeres have been associated with increased risk of malignancy, including colorectal cancer (CRC). Telomere length is heritable and may be an intermediate phenotype linked to genetic susceptibility to CRC. METHODS: In a large sample, the study investigated whether candidate single nucleotide polymorphisms (SNP) in 'telomere biology' genes were associated with telomere length in leucocytes. SNP associated with an increased risk of CRC were searched for separately. RESULTS: Carriers of the common allele at SNP rs10936599, near the telomerase RNA component (TERC) locus, had significantly longer telomeres. It was independently found that the same rs10936599 allele was associated with increased risk of both CRC and colorectal adenomas. Neither telomere length nor CRC risk was associated with variation near telomerase reverse transcriptase or other telomere biology genes. In silico analysis showed that SNP rs2293607 was strongly correlated with rs10936599, mapped within TERC transcripts, had a predicted effect on messenger RNA folding and lay at a reported transcription factor binding site. TERC mRNA were expressed, differing only at the alleles of rs2293607, in CRC cell line HCT116. The long-telomere/CRC-risk allele was associated with higher levels of TERC mRNA and the formation of longer telomeres. CONCLUSIONS: Common genetic variation at TERC is associated with both longer telomeres and an increased risk of CRC, a potential mechanism being reduced levels of cell senescence or death. This finding is somewhat paradoxical, given retrospective studies reporting that CRC cases have shorter telomeres than controls. One possibility is that that association actually results from poorer survival in patients with longer telomeres.

Pharmacological characterization of GSK1004723, a novel, long-acting antagonist at histamine H(1) and H(3) receptors.

BACKGROUND AND PURPOSE: Preclinical pharmacological characterization of GSK1004723, a novel, dual histamine H(1) and H(3) receptor antagonist. EXPERIMENTAL APPROACH: GSK1004723 was characterized in vitro and in vivo using methods that included radioligand binding, intracellular calcium mobilization, cAMP production, GTPγS binding, superfused human bronchus and guinea pig whole body plethysmography. KEY RESULTS: In cell membranes over-expressing human recombinant H(1) and H(3) receptors, GSK1004723 displayed high affinity, competitive binding (H(1) pKi = 10.2; H(3) pKi = 10.6). In addition, GSK1004723 demonstrated slow dissociation from both receptors with a t(1/2) of 1.2 and 1.5 h for H(1) and H(3) respectively. GSK1004723 specifically antagonized H(1) receptor mediated increases in intracellular calcium and H(3) receptor mediated increases in GTPγS binding. The antagonism exerted was retained after cell washing, consistent with slow dissociation from H(1) and H(3) receptors. Duration of action was further evaluated using superfused human bronchus preparations. GSK1004723 (100 nmol·L(-1) ) reversed an established contractile response to histamine. When GSK1004723 was removed from the perfusate, only 20% recovery of the histamine response was observed over 10 h. Moreover, 21 h post-exposure to GSK1004723 there remained almost complete antagonism of responses to histamine. In vivo pharmacology was studied in conscious guinea pigs in which nasal congestion induced by intranasal histamine was measured indirectly (plethysmography). GSK1004723 (0.1 and 1 mg·mL(-1) intranasal) antagonized the histamine-induced response with a duration of up to 72 h. CONCLUSIONS AND IMPLICATIONS: GSK1004723 is a potent and selective histamine H(1) and H(3) receptor antagonist with a long duration of action and represents a potential novel therapy for allergic rhinitis.

Targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2 detects aggressive prostate cancer: preliminary analysis of the results of the IMPACT study.

OBJECTIVE: To evaluate the role of targeted prostate cancer screening in men with BRCA1 or BRCA2 mutations, an international study, IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls), was established. This is the first multicentre screening study targeted at men with a known genetic predisposition to prostate cancer. A preliminary analysis of the data is reported. PATIENTS AND METHODS: Men aged 40-69 years from families with BRCA1 or BRCA2 mutations were offered annual prostate specific antigen (PSA) testing, and those with PSA > 3 ng/mL, were offered a prostate biopsy. Controls were men age-matched (± 5 years) who were negative for the familial mutation. RESULTS: In total, 300 men were recruited (205 mutation carriers; 89 BRCA1, 116 BRCA2 and 95 controls) over 33 months. At the baseline screen (year 1), 7.0% (21/300) underwent a prostate biopsy. Prostate cancer was diagnosed in ten individuals, a prevalence of 3.3%. The positive predictive value of PSA screening in this cohort was 47·6% (10/21). One prostate cancer was diagnosed at year 2. Of the 11 prostate cancers diagnosed, nine were in mutation carriers, two in controls, and eight were clinically significant. CONCLUSIONS: The present study shows that the positive predictive value of PSA screening in BRCA mutation carriers is high and that screening detects clinically significant prostate cancer. These results support the rationale for continued screening in such men.

Peutz-Jeghers syndrome: a systematic review and recommendations for management.

Peutz-Jeghers syndrome (PJS, MIM175200) is an autosomal dominant condition defined by the development of characteristic polyps throughout the gastrointestinal tract and mucocutaneous pigmentation. The majority of patients that meet the clinical diagnostic criteria have a causative mutation in the STK11 gene, which is located at 19p13.3. The cancer risks in this condition are substantial, particularly for breast and gastrointestinal cancer, although ascertainment and publication bias may have led to overestimates in some publications. Current surveillance protocols are controversial and not evidence-based, due to the relative rarity of the condition. Initially, endoscopies are more likely to be done to detect polyps that may be a risk for future intussusception or obstruction rather than cancers, but surveillance for the various cancers for which these patients are susceptible is an important part of their later management. This review assesses the current literature on the clinical features and management of the condition, genotype-phenotype studies, and suggested guidelines for surveillance and management of individuals with PJS. The proposed guidelines contained in this article have been produced as a consensus statement on behalf of a group of European experts who met in Mallorca in 2007 and who have produced guidelines on the clinical management of Lynch syndrome and familial adenomatous polyposis.

Recommendations to improve identification of hereditary and familial colorectal cancer in Europe.

Familial colorectal cancer (CRC) accounts for 10-15% of all CRCs. In about 5% of all cases, CRC is associated with a highly penetrant dominant inherited syndrome. The most common inherited form of non-polyposis CRC is the Lynch syndrome which is responsible for about 2-4% of all cases. Surveillance of individuals at high risk for CRC prevents the development of advanced CRC. About 1 million individuals in Western Europe are at risk for Lynch syndrome. We performed a survey to evaluate the strategies currently used to identify individuals at high risk for CRC in 14 Western European countries. Questionnaires were distributed amongst members of a European collaborative group of experts that aims to improve the prognosis of families with hereditary CRC. The survey showed that in all countries obtaining a family history followed by referral to clinical genetics centres of suspected cases was the main strategy to identify familial and hereditary CRC. In five out of seven countries with a (regional or national) CRC population screening program, attention was paid in the program to the detection of familial CRC. In only one country were special campaigns organized to increase the awareness of familial CRC among the general population. In almost all countries, the family history is assessed when a patient visits a general practitioner or hospital. However, the quality of family history taking was felt to be rather poor. Microsatellite instability testing (MSI) or immunohistochemical analysis (IHC) of CRC are usually recommended as tools to select high-risk patients for genetic testing and are performed in most countries in patients suspected of Lynch syndrome. In one country, IHC was recommended in all new cases of CRC. In most countries there are no specific programs on cancer genetics in the teaching curriculum for medical doctors. In conclusion, the outcome of this survey and the discussions within an European expert group may be used to improve the strategies to identify individuals at high risk of CRC. More attention should be given to increasing the awareness of the general population of hereditary CRC. Immunohistochemical analysis or MSI-analysis of all CRCs may be an effective tool for identifying all Lynch syndrome families. The cost-effectiveness of this approach should be further evaluated. All countries with a CRC population screening program should obtain a full family history as part of patient assessment.

Morphine-induced stereotyped thigmotaxis could appear as enhanced fear and anxiety in some behavioural tests.

This study questions whether the classical interpretation for unconditional fear/anxiety tests is valid when animals are under the influence of some drugs of abuse. We used a modified version of the trimethylthiazoline (TMT)-avoidance task, a measure of unconditional fear. Halfway into a corridor maze we placed a 3-cm-high barrier. This provided a wall in the middle of the corridor, one that the mice can easily climb over. Saline- and morphine-treated mice were randomly placed in the 'safe' or 'unsafe' (TMT) side and observed for 10 min. As expected, saline-injected mice spent only about 25% of the time in the TMT side, regardless of the side they were initially placed into. In contrast, morphine-treated mice did not cross the barrier even once, regardless of their initial placement. Specifically, morphine-treated mice initially placed in the TMT side appeared to exhibit the expected reduction in unconditional fear, that is, spending the entire time in the TMT side, a significant increase over the controls. Yet, morphine-treated mice placed in the safe side never even entered the TMT side; thus, these mice appeared to exhibit a behavioural response that is classically interpreted as increased fear, that is, spending significantly less time in the TMT side versus the controls. In summary, this study demonstrates that the classical interpretation of some unconditioned fear or anxiety tests could be misleading when animals are under the influence of drugs that might induce other competing behaviours.