Outcomes following emergency colorectal cancer presentation in the elderly.

AIM: Colorectal cancer is predominantly a disease of the elderly and up to 30% of these patients will present as an emergency. We compared the outcomes of 'elderly' patients presenting to our unit with a colorectal cancer emergency over a 10-year period with those of a 'younger' cohort. METHODS: A single centre retrospective review of colorectal cancer emergencies between 1 April 2007 and 1 April 2017 was performed. Patients were separated into two cohorts: 'young' (< 75 years) and 'elderly' (≥ 75 years). Data collected included demographics, disease status, treatment and outcomes. RESULTS: A total of 341 patients (< 75 years: n = 154; ≥ 75 years: n = 187) presented as a colorectal cancer emergency. Significantly fewer 'elderly' patients underwent curative surgical procedures (72% vs 49%, P < 0.0001) or received adjuvant chemotherapy (56% vs 21%, P < 0.0001). 'Elderly' patients had significantly more postoperative cardio-respiratory complications (7% vs 36%, P < 0.0001), but despite this there was no significant difference in 30-day mortality (7% vs 12%) and survival rates at 1 year (75% vs 74%) or 3 years (56% vs 49%). Elderly patients treated with best supportive care had a median overall survival of just 62 (range 1-955) days. CONCLUSION: Patients ≥ 75 years presenting as a colorectal cancer emergency were significantly less likely to undergo emergency curative surgery or receive adjuvant chemotherapy than those < 75 years. However, the 30-day mortality, 1- and 3-year survival rates for patients undergoing curative surgery were comparable.

The stability of imaging biomarkers in radiomics: a framework for evaluation.

This paper studies the sensitivity of a range of image texture parameters used in radiomics to: (i) the number of intensity levels, (ii) the method of quantisation to select the intensity levels and (iii) the use of an intensity threshold. 43 commonly used texture features were studied for the gross target volume outlined on the CT component of PET/CT scans of 50 patients with non-small cell lung carcinoma (NSCLC). All cases were quantised for all values between 4 and 128 intensity levels using four commonly used quantisation methods. All results were analysed with and without a threshold range of -200 HU to 300 HU. Cases were ranked for each texture feature and for all quantisation methods with the Spearman's rank correlation coefficient determined to evaluate stability. Results showed large fluctuations in ranking, particularly for low numbers of levels, differences between quantisation methods and with the use of a threshold, with values Spearman's Rank Correlation for many parameters below 0.2. Our results demonstrated the sensitivity of radiomics features to the parameters used during analysis and highlight the risk of low reproducibility comparing studies with slightly different parameters. In terms of the lung cancer CT datasets, this study supports the use of 128 intensity levels, the same uniform quantiser applied to all scans and thresholding of the data. It also supports several of the features recommended in the literature for such studies such as skewness and kurtosis. A recommended framework is presented for curation of the data analysis process to ensure stability of results.

Piezo1 channels are mechanosensors in human fetoplacental endothelial cells.

STUDY QUESTION: Does the shear stress sensing ion channel subunit Piezo1 have an important mechanotransduction role in human fetoplacental endothelium? SUMMARY ANSWER: Piezo1 is present and functionally active in human fetoplacental endothelial cells, and disruption of Piezo1 prevents the normal response to shear stress. WHAT IS KNOWN ALREADY: Shear stress is an important stimulus for maturation and function of placental vasculature but the molecular mechanisms by which the force is detected and transduced are unclear. Piezo1 channels are Ca2+-permeable non-selective cationic channels which are critical for shear stress sensing and maturation of murine embryonic vasculature. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: We investigated the relevance of Piezo1 to placental vasculature by studying human fetoplacental endothelial cells (FpECs) from healthy pregnancies. Endothelial cells were isolated from placental cotyledons and cultured, for the study of tube formation and cell alignment to shear stress. In addition, human placental arterial endothelial cells were isolated and studied immediately by patch-clamp electrophysiology. MAIN RESULTS AND THE ROLE OF CHANCE: The synthetic Piezo1 channel agonist Yoda1 caused strong elevation of the intracellular Ca2+ concentration with a 50% effect occurring at about 5.4 µM. Knockdown of Piezo1 by RNA interference suppressed the Yoda1 response, consistent with it being mediated by Piezo1 channels. Alignment of cells to the direction of shear stress was also suppressed by Piezo1 knockdown without loss of cell viability. Patch-clamp recordings from freshly isolated endothelium showed shear stress-activated single channels which were characteristic of Piezo1. LIMITATIONS, REASONS FOR CAUTION: The in vitro nature of fetoplacental endothelial cell isolation and subsequent culture may affect FpEC characteristics and PIEZO1 expression. In addition to Piezo1, alternative shear stress sensing mechanisms have been suggested in other systems and might also contribute in the placenta. WIDER IMPLICATIONS OF THE FINDINGS: These data suggest that Piezo1 is an important molecular determinant of blood flow sensitivity in the placenta. Establishing and manipulating the molecular mechanisms regulating shear stress sensing could lead to novel therapeutic strategies to improve blood flow in the placenta. LARGE-SCALE DATA: Not applicable. STUDY FUNDING/COMPETING INTEREST(S): LCM was funded by a Clinical Research Training Fellowship from the Medical Research Council and by the Royal College of Obstetricians and Gynaecologists, and has received support from a Wellcome Trust Institutional Strategic Support Fund. JS was supported by the Wellcome Trust and a BHF Intermediate Research Fellowship. HJG, CW, AJH and PJW were supported by PhD Studentships from BHF, BBSRC and the Leeds Teaching Hospitals Charitable Foundation respectively. All authors declare no conflict of interest.

Repeated inoculations with the lung and heartworm nematode Angiostrongylus vasorum result in increasing larval excretion and worm burden in the red fox (Vulpes vulpes).

The French heartworm Angiostongylus vasorum is found in European red fox (Vulpes vulpes) and dog populations, where it appears to be spreading geographically. Once introduced into new areas, it establishes in local fox populations, typically to over 50% prevalence in a few years. High susceptibility and constant excretion of first stage larvae (L1) by the definitive hosts are prerequisites for sustaining high parasite biomass in a particular habitat. The present study explores the hypothesis that repeated ingestion of gastropods in nature will result in accumulation of adult worms and elevated excretion of L1 in feces. Experimentally infected foxes were subsequently inoculated via stomach tube once (9 weeks post initial inoculation) or twice (9 and 13 weeks post inoculation (wpi)) with 100 third stage A. vasorum larvae (L3) previously isolated from aquatic snails infected with L1 from a naturally infected dog. Despite large variation in fecal larval excretion for the individual animals within the groups, excretion of L1 was significantly higher in foxes twice inoculated as compared to foxes inoculated only once. With an outlier in the once inoculated group removed, excretion became significantly higher in the three times inoculated group. Establishment of adult worms varied and only a trend to higher worm burdens was found in the group of foxes inoculated three times. However, this became significant with the same single outlier removed. Overall, it appears that protective immunity to A. vasorum does not appear to occur in V. vulpes with animals exhibiting high infection intensities without obvious clinical signs. The increasing larval excretion in foxes being repeatedly exposed to A. vasorum L3 support the hypothesis that foxes under natural conditions may repeatedly ingest infected gastropods and remain a source of environmental contamination for several months, potentially contributing to the establishment of endemic foci through increasing L1 excretion.

Exploratory examination of the utility of demoralization as a diagnostic specifier for adjustment disorder and major depression.

OBJECTIVE: Demoralization, a state of lowered morale and poor coping, has a prevalence of 13-18% among patients with advanced cancer. We surveyed clinicians' perspectives of the utility of "with demoralization" as a diagnostic specifier for adjustment and depressive disorders. METHOD: Using comparative clinical vignettes in a field survey, clinicians from a range of disciplines were asked their perception of the utility of diagnosis and treatment options. Response frequencies were compared using Cochran's Q and McNemar's tests, with sensitivity and specificity rated against expert rankings of diagnosis. Analysis of variance and paired t-tests examined significant differences in ratings of utility. RESULTS: Vignettes were assessed by 280 clinicians; 77% supported utility of the category 'adjustment disorder with demoralization' compared to 33% supporting 'adjustment disorder with anxiety' (McNemar test, p<0.001), while 83% supported the utility of 'with demoralization' for major depressive episode, matching 83% perceiving utility for 'with melancholia.' Sensitivity and specificity ratings were 77% and 94% for adjustment disorder with demoralization and 83% and 91% for major depression with demoralization. CONCLUSION: Clinicians perceived the specifier 'with demoralization' to deepen diagnostic understanding, treatment choice, and ability to communicate with clinicians and patients, particularly for the category of adjustment disorder with demoralization.

Small bowel obstruction in pregnancy is a complex surgical problem with a high risk of fetal loss.

INTRODUCTION: Small bowel obstruction (SBO) in pregnancy is rare and is most commonly caused by adhesions from previous abdominal surgery. Previous literature reviews have emphasised the need for prompt laparotomy in all cases of SBO because of the significant risks of fetal loss and maternal mortality. We undertook a review of the contemporary literature to determine the optimum management strategy for SBO in pregnancy. METHODS: The MEDLINE® and PubMed databases were searched for cases of SBO in pregnancy between 1992 and 2014. Two cases from our own institution were also reviewed. RESULTS: Forty-six cases of SBO in pregnancy were identified, with adhesions being the most common aetiology (50%). The overall risk of fetal loss was 17% and the maternal mortality rate was 2%. In cases of adhesional SBO, 91% of cases were managed surgically, with 14% fetal loss. Two cases (9%) were managed conservatively with no complications. Magnetic resonance imaging (MRI) was used to diagnose SBO in 11% of cases. CONCLUSIONS: Based on our experience and the contemporary literature, we recommend that urgent MRI of the abdomen should be undertaken to diagnose the aetiology of SBO in pregnancy. In cases of adhesional SBO, conservative treatment may be safely commenced, with a low threshold for laparotomy. In other causes, such as volvulus or internal hernia, laparotomy remains the treatment of choice.

Oxytocin is unequally distributed in a bag of normal saline--true or false?

Oxytocin infusion used in labour can sometimes be left hung on the stand for many hours. There has been no study to determine if oxytocin is equally distributed throughout the infusion bag and if the distribution stays the same with time. We postulated that there may be settling of the molecules such that oxytocin concentrates at the bottom of the infusion bag. Eight infusion bags were prepared by mixing 10 IU of oxytocin in 1 litre of normal saline. The infusion bags were hung on infusion stands for 8 hours after which 10 samples of 100 mls of the solution from each bag were taken in different containers and the concentration of oxytocin calculated using oxytocin specific Enzyme Immunoassay (EIA) in the different samples. No statistically significant correlation between the oxytocin concentration and the sample number was observed (p-value = 0.738). There was no obvious relationship between oxytocin concentration and the sample number in each bag. There was no evidence to suggest that a linear oxytocin concentration gradient develops in a bag of normal saline over an 8-hour period. In fact the distribution appears to be random and unequal.

Automatic laser welding and milling with in situ inline coherent imaging.

Although new affordable high-power laser technologies enable many processing applications in science and industry, depth control remains a serious technical challenge. In this Letter we show that inline coherent imaging (ICI), with line rates up to 312 kHz and microsecond-duration capture times, is capable of directly measuring laser penetration depth, in a process as violent as kW-class keyhole welding. We exploit ICI's high speed, high dynamic range, and robustness to interference from other optical sources to achieve automatic, adaptive control of laser welding, as well as ablation, achieving 3D micron-scale sculpting in vastly different heterogeneous biological materials.

Tacrolimus is an effective treatment for lupus nephritis in pregnancy.

Lupus nephritis during pregnancy increases morbidity and mortality for mother and baby. Flares are difficult to treat as many therapeutic options are teratogenic or fetotoxic. Steroids alone may be unable to control disease activity and are associated with higher rates of preterm delivery, sepsis and gestational diabetes. Reports of using tacrolimus to treat lupus nephritis in pregnancy are limited. We describe the pregnancies of nine women in whom tacrolimus was successfully used to treat lupus nephritis flare (six patients) or maintain stable disease (three patients). Introduction or dose escalation of oral steroids was avoided in five of the patients who developed active disease and steroid dose was rapidly reduced in the sixth patient. All women with disease flare attained partial or complete remission after starting tacrolimus. None of the women on maintenance treatment developed active disease. We propose tacrolimus as an effective adjuvant or alternative therapy to steroids for treating lupus nephritis flare or maintaining stable disease during pregnancy.

Evaluation of a nonthermal plasma needle to eliminate ex vivo biofilms in root canals of extracted human teeth.

AIM: To evaluate the efficacy of a nonthermal plasma (NTP) at atmospheric pressure on ex vivo biofilm in root canals of extracted teeth. METHODOLOGY: Intracanal contents from three teeth with root canal infections were collected, pooled and grown in thirty-five microCT-mapped root canals of extracted and instrumented human teeth. One group of teeth was treated with NTP, another with 6% NaOCl and one set was left untreated. The intracanal contents from twenty-seven teeth (nine teeth in each group) were plated on agar and colony forming units were determined. Parametric test of one-way analysis of variance (anova) was used to analyse statistical significance. The remaining teeth were cut open, stained with LIVE/DEAD(®) and examined with confocal laser scanning microscopy. RESULTS: The untreated root canals were covered with biofilm of varying thickness. Treatment with nonthermal plasma decreased the number of viable bacteria in biofilms by one order of magnitude, whilst the NaOCl control achieved a reduction of more than four magnitudes. Both the NTP and the NaOCl treatment results were significantly different from the negative control (P < 0.05). CONCLUSION: The nonthermal plasma displayed antimicrobial activity against endodontic biofilms in root canals, but was not as effective as the use of 6% NaOCl.

Phenotypic characterization of the foldase homologue PrsA in Streptococcus mutans.

Streptococcus mutans is generally considered to be the principal etiological agent for dental caries. Many of the proteins necessary for its colonization of the oral cavity and pathogenesis are exported to the cell surface or the extracellular matrix, a process that requires the assistance of the export machineries. Bioinformatic analysis revealed that the S. mutans genome contains a prsA gene, whose counterparts in other gram-positive bacteria, including Bacillus and Lactococcus, encode functions involved in protein post-export. In this study, we constructed a PrsA-deficient derivative of S. mutans and demonstrated that the prsA mutant displayed an altered cell wall/membrane protein profile as well as cell-surface-related phenotypes, including auto-aggregation, increased surface hydrophobicity and abnormal biofilm formation. Further analysis revealed that the disruption of the prsA gene resulted in reduced insoluble glucan production by cell surface localized glucosyltransferases, and mutacin as well as cell surface-display of a heterologous expressed GFP fusion to the cell surface protein SpaP. Our study suggested that PrsA in S. mutans encodes functions similar to those identified in Bacillus, and so is likely to be involved in protein post-export.

What influences the decision to undergo institutional delivery by skilled birth attendants? A cohort study in rural Andhra Pradesh, India.

INTRODUCTION: Despite continuing efforts to promote skilled institutional delivery, eight women die every hour in India due to causes related to pregnancy and child birth. The objectives of this study were to assess the prevalence and the determinants of institutional delivery by skilled birth attendants in a rural population in Andhra Pradesh, India. METHODS: This cross-sectional study used data from 'Young Lives', a longitudinal study on childhood poverty, and the study population was a cohort of 1419 rural, economically deprived women (from the Young Lives study) in Andhra Pradesh, India. The data are from round-1 of Young Lives younger cohort recruited in 2002 and followed until 2015. The participation rate of households was 99.5%. RESULTS: Prevalence of skilled institutional delivery was 36.8%. Women's education (odds ratio [OR] for secondary education 2.06; 95% confidence interval [95%CI] 1.33-3.19), desire to be pregnant (OR 1.89; 95% CI 1.12-3.22) and adequate prenatal care (OR 1.69; 95% CI 1.30-2.21) were found to be the positive determinants of skilled institutional delivery. High birth order (OR for second birth 0.44; 95% CI 0.32-0.60, OR for third birth 0.47; 95% CI 0.30-0.72 and OR for ≥fourth 0.47; 95% CI 0.27-0.81), schedule caste/schedule tribe social background (OR 0.70; 95% CI 0.53-0.93) and poor economic status of the household (OR for the poorest households 0.67; 95% CI 0.46-0.99) were negatively associated with skilled institutional delivery. CONCLUSIONS: Despite existence of supporting schemes, the utilisation of skilled institutional delivery services was low in the study population. Educated women and women with adequate prenatal care who have a desired pregnancy were more likely to utilise health institutions and skilled delivery care. There is a need for integrated approaches through maternal health, family planning and education programs, and a focus on uneducated, poor women belonging to disadvantaged social groups.

Small bowel perforation secondary to accidental dental plate ingestion.

The majority of ingested foreign bodies will pass through the gastrointestinal tract without incident, with less than 1% of cases resulting in complications. Herein we present a case of small bowel perforation secondary to the accidental ingestion of a dental plate. A diagnosis of perforation was made by CT imaging, but the exact cause could only be determined after resection of the affected bowel and histo-pathological examination. We re-iterate the importance of accurate and thorough history taking in patients with possible foreign body ingestion.

An ELISA for sensitive and specific detection of circulating antigen of Angiostrongylus vasorum in serum samples of naturally and experimentally infected dogs.

Canine angiostrongylosis is an emerging cardiopulmonary disease in Europe which can be fatal if left untreated. We developed a sandwich-ELISA based on a monoclonal antibody (mAb Av 56/1/2) and on polyclonal rabbit antibodies directed against Angiostrongylus vasorum adult excretory/secretory - antigen for the detection of circulating serum antigen of A. vasorum. The sensitivity of the test was 95.7% (78.1-99.9, 95% CI) as determined with sera of 23 dogs naturally infected with A. vasorum. The specificity was 94.0% (83.5-98.7, 95% CI) using 50 dog sera (control group) submitted for reasons other than parasitic infections. Potential cross-reactions were investigated with sera of a group of totally 61 dogs with proven infections with Dirofilaria immitis (n=23), Crenosoma vulpis (n=14), Ancylostoma caninum (n=4) or Toxocara canis (n=20). No significant difference was observed concerning the proportion of positive reactions between the control group and the group with proven helminth infections other than A. vasorum. In experimentally inoculated dogs with proven worm burdens of A. vasorum, the proportion of seropositive dogs increased over the first 3 months of infection, starting from 35 days post inoculation (dpi) which was before the onset of larval excretion. Ten weeks post inoculation, 98.6% of the dogs were seropositive, and circulating antigen persisted in two dogs with long-term follow-up over 286 and 356 days, respectively. In contrast, in dogs with a single treatment with imidacloprid/moxidectin at four or 32 dpi, no circulating antigen was observed, while in dogs treated at 88-92 dpi, OD values decreased within 13-34 days. The specific detection of circulating A. vasorum antigen by ELISA represents a valid alternative for reliable diagnosis and for follow-up investigations after anthelmintic treatment. Moreover, the test can be used for mass screening in large epidemiological investigations.

Glucocorticoid-stimulated, transcription-independent release of annexin A1 by cochlear Hensen cells.

BACKGROUND AND PURPOSE: The current clinical strategy to protect the auditory organ against inflammatory damage by migrating leukocytes is the local delivery of glucocorticoids. However, the mechanism by which glucocorticoids confer this protection remains unknown. Therefore, we investigated the cellular and molecular targets of glucocorticoids in the cochlea that could be involved in preventing leukocyte migration. EXPERIMENTAL APPROACH: We used microscopy as well as immunocytochemical and microfluidic techniques to elucidate the effect of dexamethasone, hydrocortisone and prednisolone on the cellular and intracellular distribution of annexin A1 (ANXA1) - a glucocorticoid target known to inhibit leukocyte migration by receptor-mediated signalling - in the cochlea and isolated cochlear cells of guinea pigs. KEY RESULTS: All the cells lining the scala media - the cochlear compartment containing the auditory organ - express ANXA1 and the ANXA1 receptor FPR2/ALX is present in the scala media, as well as in other cochlear ducts. The majority of ANXA1 in the scala media is stored inside lipid droplets within cochlear Hensen cells. Glucocorticoids activate a myosin IIC-mediated mechanism that drives ANXA1 from the lipid droplets to the apical region of the Hensen cells, where ANXA1 is released to the external milieu by a process involving ABC transporters. CONCLUSIONS AND IMPLICATIONS: These findings suggest that ANXA1 could be a major mediator of the anti-inflammatory effects of glucocorticoids in the cochlea and identify new molecular targets for prevention of sudden sensorineural hearing loss.

Larvicidal effect of imidacloprid/moxidectin spot-on solution in dogs experimentally inoculated with Angiostrongylus vasorum.

A controlled, randomized, blinded dose confirmation study was conducted to evaluate the larvicidal efficacy and safety of imidacloprid 10 mg/kg/moxidectin 2.5 mg/kg body weight spot-on solution in dogs experimentally inoculated with 200 infective third stage larvae (L3) of Angiostrongylus vasorum. Twenty-four adult dogs were randomly allocated to three study groups of 8 dogs each. Animals in group 1 were treated 4 days post-inoculation (dpi), those in group 2 at 32 dpi, and the dogs in group 3 were left untreated. All dogs were euthanized and necropsied 56-59 dpi. In order to determine the worm burdens in the arterial lung vessels a method of reverse lung perfusion with phosphate buffered solution after inhibition of coagulation with heparin was applied. In the control group, excretion of first stage larvae (L1) of A. vasorum started 47-55 dpi and all dogs excreted L1 at least on one sample day before euthanasia (0.1-32.5 larvae per gram of faeces). A mean of 99 (SD 42.8) adult parasites were recovered in the post-mortem examinations in these eight control dogs. In contrast, no L1 at all were found in the faeces of dogs of groups 1 and 2, nor were any adult parasites detected at necropsy. Respiratory symptoms were observed in dogs of groups 2 and 3. Pathological findings in the lungs correlated with the treatment groups: in the animals of group 1, no or minimal lesions were found, while in all those of group 2 dispersed patterns of pale pink, slightly raised and consolidated foci were present in all lung lobes. In contrast, the lungs of the dogs from group 3 were severely affected: large confluent areas were hardened, raised and discoloured, with frequent haemorrhagic patches. Pneumonia, thrombi and parasites were histologically confirmed. The lung lymph nodes were regularly enlarged. Hence, imidacloprid/moxidectin spot-on effectively eliminated fourth stage larvae (L4) and immature adult A. vasorum in experimentally infected dogs and prevented patent infections. The earlier an infected dog was treated, the less severe were the pathological lesions observed in the lungs.

Imaging of endodontic biofilms by combined microscopy (FISH/cLSM - SEM).

Scanning electron microscopy is a useful imaging approach for the visualization of bacterial biofilms in their natural environments including their medical and dental habitats, because it allows for the exploration of large surfaces with excellent resolution of topographic features. Most biofilms in nature, however, are embedded in a thick layer of extracellular matrix that prevents a clear identification of individual bacteria by scanning electron microscopy. The use of confocal laser scanning microscopy on the other hand in combination with fluorescence in situ hybridization enables the visualization of matrix embedded bacteria in multi-layered biofilms. In our study, fluorescence in situ hybridization/confocal laser scanning microscopy and scanning electron microscopy were applied to visualize bacterial biofilm in endodontic root canals. The resulting fluorescence in situ hybridization /confocal laser scanning microscopy and scanning electron microscopy and pictures were subsequently combined into one single image to provide high-resolution information on the location of hidden bacteria. The combined use of scanning electron microscopy and fluorescence in situ hybridization / confocal laser scanning microscopy has the potential to overcome the limits of each single technique.

The burden of smoking-related ill health in the UK.

BACKGROUND: Smoking is one of the biggest avoidable causes of morbidity and mortality in the United Kingdom. This paper quantifies the current health and economic burden of smoking in the UK. It provides comparisons with previous studies of the burden of smoking in the UK and with the costs for other chronic disease risk factors. METHODS: A systematic literature review to identify previous estimates of National Health Service costs attributable to smoking was undertaken. Information from the World Health Organization's Global Burden of Disease Project and routinely collected mortality data were used to calculate mortality due to smoking in the UK. Population-attributable fractions for smoking-related diseases from the Global Burden of Disease Project were applied to NHS cost data to estimate direct financial costs. RESULTS: Previous studies estimated that smoking costs the NHS about 1.4 billion to 1.7 billion pound in 1991 and has been responsible for about 100,000 deaths per annum over the past 10 years. This paper estimates that the number of deaths attributable to smoking in 2005 was 109,164 (19% of all deaths, 27% deaths in men and 11% of deaths in women). Smoking was directly responsible for 12% of disability adjusted life years lost in 2002 (15.4% in men; 8.5% in women) and the direct cost to the NHS was 5.2 billion pound in 2005-6. CONCLUSION: Smoking is still a considerable public health burden in the UK. Accurately establishing the burden in terms of death, disability and financial costs is important for informing national public health policy.