Using Deep Learning Artificial Intelligence Algorithms to Verify N-Nitroso-N-Methylurea and Urethane Positive Control Proliferative Changes in Tg-RasH2 Mouse Carcinogenicity Studies.

In Tg-rasH2 carcinogenicity mouse models, a positive control group is treated with a carcinogen such as urethane or N-nitroso-N-methylurea to test study validity based on the presence of the expected proliferative lesions in the transgenic mice. We hypothesized that artificial intelligence-based deep learning (DL) could provide decision support for the toxicologic pathologist by screening for the proliferative changes, verifying the expected pattern for the positive control groups. Whole slide images (WSIs) of the lungs, thymus, and stomach from positive control groups were used for supervised training of a convolutional neural network (CNN). A single pathologist annotated WSIs of normal and abnormal tissue regions for training the CNN-based supervised classifier using INHAND criteria. The algorithm was evaluated using a subset of tissue regions that were not used for training and then additional tissues were evaluated blindly by 2 independent pathologists. A binary output (proliferative classes present or not) from the pathologists was compared to that of the CNN classifier. The CNN model grouped proliferative lesion positive and negative animals at high concordance with the pathologists. This process simulated a workflow for review of these studies, whereby a DL algorithm could provide decision support for the pathologists in a nonclinical study.

Taking the sweetness out of the 'Share a Coke' marketing campaign: the influence of personalized labelling on elementary school children's bottled drink choices.

BACKGROUND: Drink personalization (featuring names on bottle labels) has been used by soft drink companies to make their drinks attractive to children, potentially increasing consumption. To date, no publically available research has evaluated the influence of personalization on children's drink choices. OBJECTIVES: To determine (i) whether personalizing bottled drinks influences children's drink choices; (ii) whether it is comparably effective in promoting healthy and unhealthy drinks and (iii) whether drink choices are affected by self-esteem, body mass index and parental factors. METHODS: Children aged 8-13 years (N = 404) were randomly assigned to one of three drink labeling conditions: Prime Healthy, Prime Unhealthy and Control. All participants selected one beverage from 12 options, comprising six healthy and unhealthy drinks. RESULTS: Personalizing healthy drinks increased choice of healthy drinks (OR, 2.21; 95% CI, 1.24-4.00), and personalizing unhealthy drinks reduced choice of healthy drinks (OR, 0.35; 95% CI, 0.15-.0.75). Higher self-esteem predicted choosing own-named drinks (OR = 1.08, 95% CI, 1.00-1.18; p = .049). CONCLUSIONS: Children's drink choices are influenced by personalizing drink bottles. Tighter regulation of this marketing strategy for soft drinks may reduce children choice of these drinks. Personalization may also be used to encourage children to choose healthy drinks.

Diagnosis and features of hospital-acquired pneumonia: a retrospective cohort study.

BACKGROUND: Hospital-acquired pneumonia (HAP) is defined as radiologically confirmed pneumonia occurring ≥48h after hospitalization, in non-intubated patients. Empirical treatment regimens use broad-spectrum antimicrobials. AIM: To evaluate the accuracy of the diagnosis of HAP and to describe the demographic and microbiological features of patients with HAP. METHODS: Medical and surgical inpatients receiving intravenous antimicrobials for a clinical diagnosis of HAP at a UK tertiary care hospital between April 2013 and 2014 were identified. Demographic and clinical details were recorded. FINDINGS: A total of 166 adult patients with a clinical diagnosis of HAP were identified. Broad-spectrum antimicrobials were prescribed, primarily piperacillin-tazobactam (57.2%) and co-amoxiclav (12.5%). Sputum from 24.7% of patients was obtained for culture. Sixty-five percent of patients had radiological evidence of new/progressive infiltrate at the time of HAP treatment, therefore meeting HAP diagnostic criteria (2005 American Thoracic Society/Infectious Diseases Society of America guidelines). Radiologically confirmed HAP was associated with higher levels of inflammatory markers and sputum culture positivity. Previous surgery and/or endotracheal intubation were associated with radiologically confirmed HAP. A bacterial pathogen was identified from 17/35 sputum samples from radiologically confirmed HAP patients. These were Gram-negative bacilli (N = 11) or Staphylococcus aureus (N = 6). Gram-negative bacteria tended to be resistant to co-amoxiclav, but susceptible to ciprofloxacin, piperacillin-tazobactam and meropenem. Five of the six S. aureus isolates were meticillin susceptible and all were susceptible to doxycycline. CONCLUSION: In ward-level hospital practice 'HAP' is an over-used diagnosis that may be inaccurate in 35% of cases when objective radiological criteria are applied. Radiologically confirmed HAP represents a distinct clinical and microbiological phenotype. Potential risk factors were identified that could represent targets for preventive interventions.

Ionizing radiation exposure as a result of diagnostic imaging in patients with lymphoma.

PURPOSE: Survival rates among patients with lymphoma continue to improve. Strategies aimed at reducing potential treatment-related toxicity are increasingly prioritized. While radiological procedures play an important role, ionizing radiation exposure has been linked to an increased risk of malignancy, particularly among individuals whose cumulative radiation exposure exceeds a specific threshold (75 millisieverts). METHODS: Within this retrospective study, the cumulative radiation exposure dose was quantified for 486 consecutive patients with lymphoma. RESULTS: The median estimated total cumulative effective dose (CED) of ionizing radiation per subject was 69 mSv (42-118). However, younger patients (under 40 years) had a median CED of 89 mSv (55-124). CONCLUSION: This study highlights the considerable radiation exposure occurring among patients with lymphoma as a result of diagnostic imaging. To limit the risk of secondary carcinogenesis, consideration should be given to monitoring cumulative radiation exposure in individual patients as well as considering imaging modalities, which do not impart an ionizing radiation dose.

Tissue specific regulation of glucocorticoids in severe obesity and the response to significant weight loss following bariatric surgery (BARICORT).

CONTEXT: Tissue cortisol exposure is under the control of the isozymes of 11ß-hydroxysteroid dehydrogenase (11ß-HSD). 11ß-HSD1 in vivo, acts as an oxoreductase converting inactive cortisone to active cortisol. We hypothesized that 11ß-HSD1 activity is dysregulated in obesity and alters following bariatric surgery induced weight loss in different tissues. METHODS: We recruited 21 patients prior to undergoing bariatric surgery and performed cortisol generation profiles (following oral cortisone administration), urinary corticosteroid metabolite analysis, adipose tissue microdialysis, and tissue gene expression before and after weight loss, following bariatric surgery. Archived tissue samples from 20 previous bariatric surgery patients were also used for tissue gene expression studies. RESULTS: Gene expression showed a positive correlation with 11ß-HSD1 and BMI in omental adipose tissue (OM) (r = +0.52, P = .0001) but not sc adipose tissue (r = +0.28, P = .17). 11ß-HSD1 expression in liver negatively correlated with body mass index (BMI) (r = -0.37, P = .04). 11ß-HSD1 expression in sc adipose tissue was significantly reduced after weight loss (0.41 ± 0.28 vs 0.17 ± 0.1 arbitrary units, P = .02). Following weight loss, serum cortisol generation increased during a cortisol generation profile (area under the curve 26 768 ± 16 880 vs 47 579 ± 16 086 nmol/L/minute, P ≤ .0001.) Urinary corticosteroid metabolites demonstrated a significant reduction in total cortisol metabolites after bariatric surgery (15 224 ± 6595 vs 8814 ± 4824 µg/24 h, P = .01). Microdialysis of sc adipose tissue showed a threefold reduction in cortisol/cortisone ratio after weight loss. CONCLUSIONS: This study highlights the differences in tissue specific regulation of cortisol metabolism in obesity and after weight loss. Following bariatric surgery hepatic 11ß-HSD1 activity increases, sc adipose tissue 11ß-HSD1 activity is reduced and total urinary cortisol metabolites are reduced indicating a possible reduction in hypothalamic pituitary adrenal axis drive. 11ß-HSD1 expression correlates positively with BMI in omental adipose tissue and negatively within hepatic tissue. 11ß-HSD1 expression is reduced in sc adipose tissue after weight loss.

Obesity-related chronic lymphoedema-like swelling and physical function.

BACKGROUND: People with severe obesity (body mass index [BMI] > 40 kg/m(2)) have an 85% higher mortality than people with a healthy BMI. Poor physical function may contribute to this excess mortality. Lymphoedema-like swelling can affect the legs of severely obese people with normal lymphoscintigraphy. AIM: We sought to determine the relationship between the presence of lymphoedema-like swelling and physical function in the severely obese. DESIGN AND METHODS: In people with severe obesity, we ascertained whether lower leg lymphoedema-like swelling was present and determined the circumference of the lower leg, time taken to ascend and descend a 17-cm step 50 times and time taken to walk 500 m. RESULTS: The 330 participants, 33% of whom were male, were aged 43.4 ± 12.7 years (mean ± standard deviation) and had a BMI of 51.7 ± 8.4 kg/m(2). Lymphoedema-like swelling was present in approximately one-third (n = 108) in whom a prior history of cellulitis and venous thromboembolism was more common (relative risks 6.16 and 3.86, respectively) than in those without lymphoedema-like swelling. Participants with lymphoedema-like swelling, compared with non-affected counterparts, had a higher lower leg circumference (35.0 ± 7.1 vs. 32.4 ± 4.8 cm), a slower step speed (0.40 ± 0.12 vs. 0.43 ± 0.10 steps/s) and a slower walking speed (0.97 ± 0.37 vs. 1.08 ± 0.30 m/s, P < 0.05 for all comparisons). CONCLUSIONS: In this cross-sectional study, 33% of our severely obese participants had lymphoedema-like swelling. Participants with lymphoedema-like swelling had worse physical function than those without. This association was independent of BMI. The presence of obesity-related chronic lymphoedema-like swelling should lead to interventions that improve physical function.

Incidental Phaeochromocytoma on Staging PET-CT in a Patient with a Sigmoid Tumour and Situs Inversalis Totalis.

An adrenal "incidentaloma" is defined as an unexpected finding on radiological imaging performed for unrelated indications. Improvements in radiological technology have seen a dramatic increase in this phenomenon. We report the unique case of a 60-year-old female presenting with a 6-month history of abdominal pain, altered bowel habit, and rectal bleeding. Her past medical history included situs inversus totalis and a patent ductus arteriosus. Colonoscopy revealed an ulcerated tumour in her sigmoid colon. Staging PET-CT confirmed a sigmoid tumour and also identified a large heterogenous enhancing FDG-avid right adrenal mass. Biochemical testing/MIBG imaging confirmed a right adrenal phaeochromocytoma. Hypertension was controlled and excision was performed via a transperitoneal laparoscopic adrenalectomy, in the left lateral decubitus position. Uniquely, liver retraction was not required due to its position in the left hypochondrium. Histology confirmed a benign 46 mm phaeochromocytoma. Subsequent uncomplicated sigmoid colectomy/right salpingo-oophorectomy for a locally advanced colonic tumour was performed with adjuvant chemotherapy. This case highlights the importance of accurately identifying functioning adrenal tumours before elective surgery as undiagnosed phaeochromocytomas carry significant intraoperative morbidity/mortality. Right adrenalectomy was made easier in this patient by the liver's unique position. Uncomplicated colorectal resection was made possible by combined preoperative functional/anatomical imaging.

Association between vitamin D status and physical function in the severely obese.

CONTEXT: Mortality is 85% higher in severely obese subjects (body mass index [BMI] > 40 kg/m(2)) than in subjects with a healthy BMI; poor physical function may be contributory. Hypovitaminosis D is common in obese subjects and is associated with physical dysfunction in the elderly. OBJECTIVE: We determined the relationship between vitamin D status and physical function in severely obese subjects. DESIGN, SETTING, AND PATIENTS: We conducted a clinic-based, cross-sectional study of severely obese subjects. Participants were stratified into three groups according to the Institute of Medicine (IOM) vitamin D status categorization. MAIN OUTCOME MEASURES: We compared levels of self-reported activity and times taken to walk 500 m and to ascend and descend a 17-cm step 50 times. RESULTS: We recruited 252 subjects (age, 43.7 ± 11.2 y; BMI, 50.7 ± 9.7 kg/m(2)); 25-hydroxyvitamin D (25OHD) concentrations were less than 30 nmol/L in 109 participants. Participants with a 25OHD > 50 nmol/L, compared to those with a 25OHD < 30 nmol/L, had the highest activity levels (3.1 ± 3.4 h/wk versus 1.5 ± 2.5 h/wk; P = .015) and the shortest 500-m walk times (6.2 ± 1.1 min versus 7.4 ± 1.5 min; P = .003). Serum 25OHD concentrations had a weakly positive association with activity level (r = 0.19; P = .008) and a moderately negative association with 500-m walk time (r = -0.343; P < .001). CONCLUSIONS: Vitamin D status had a significant relationship with physical activity and physical function in this cohort of severely obese subjects. Low activity levels are likely to perpetuate the problem of hypovitaminosis D due to less time spent outdoors. Studies exploring the effects of vitamin D supplementation in this population are warranted.

Glucagon-like peptide-1 analogue therapy for psoriasis patients with obesity and type 2 diabetes: a prospective cohort study.

BACKGROUND: Diabetes and obesity are more prevalent amongst psoriasis patients as is disturbance of the innate immune system. GLP-1 analogue therapy considerably improves weight and glycaemic control in people with type 2 diabetes and its receptor is present on innate immune cells. OBJECTIVE: We aimed to determine the effect of liraglutide, a GLP-1 analogue, on psoriasis severity. METHODS: Before and after 10 weeks of liraglutide therapy (1.2 mg subcutaneously daily) we determined the psoriasis area and severity index (PASI) and the dermatology life quality index (DLQI) in seven people with both psoriasis and diabetes (median age 48 years, median body mass index 48.2 kg/m(2) ). We also evaluated the immunomodulatory properties of liraglutide by measuring circulating lymphocyte subset numbers and monocyte cytokine production. RESULTS: Liraglutide therapy decreased the median PASI from 4.8 to 3.0 (P = 0.03) and the median DLQI from 6.0 to 2.0 (P = 0.03). Weight and glycaemic control improved significantly. Circulating invariant natural killer T (iNKT) cells increased from 0.13% of T lymphocytes to 0.40% (P = 0.03). Liraglutide therapy also effected a non-significant 54% decrease in the proportion of circulating monocytes that produced tumour necrosis factor alpha (P = 0.07). CONCLUSION: GLP-1 analogue therapy improves psoriasis severity, increases circulating iNKT cell number and modulates monocyte cytokine secretion. These effects may result from improvements in weight and glycaemic control as well as from direct immune effects of GLP-1 receptor activation. Prospective controlled trials of GLP-1 therapies are warranted, across all weight groups, in psoriasis patients with and without type 2 diabetes.

Glucagon like peptide-1 (GLP-1) dynamics following bariatric surgery: a Signpost to a new frontier.

Glucagon like peptide-1 (GLP-1) is one of the gastrointestinal peptides implicated in glycaemic homeostasis. In non-obese individuals with normal glucose tolerance GLP-1 is secreted in response to nutrient intake. However, this GLP- 1 response is generally accepted to be significantly diminished in those with diabetes, obesity or both. Given that GLP-1 is secreted from enteroendocrine L cells in the intestine, it is not surprising that manipulation of the gastro- intestinal tract has been shown to alter GLP-1 secretion; particularly when this intestinal manipulation is designed to aid weight reduction. GLP-1 dynamics are altered by bariatric surgery, with an improved secretory response to nutrient intake. However, there remains debate on the mechanisms responsible for the alterations in GLP-1 dynamics. Here we review the evidence for GLP-1 dynamics after Roux-en-Y gastric bpyass (RYGB), adjustable gastric banding (AGB), biliopancreatic diversion (BPD) and sleeve gastrectomy (SG), and make comparisons between modalities. In addition, we review the potential mechanisms underlying these dynamics, other molecules that may add to the "incretin effect" and other possible roles for GLP-1 following bariatric surgery. Finally, we will offer our critique of the evidence base.

Preadipocyte factor-1 is associated with metabolic profile in severe obesity.

CONTEXT: Dysfunctional adipose tissue has been proposed as a key pathological process linking obesity and metabolic disease. Preadipocyte factor-1 (Pref-1) has been shown to inhibit differentiation in adipocyte precursor cells and could thereby play a role in determining adipocyte size, adipose tissue functioning, and metabolic profile in obese individuals. OBJECTIVE: We hypothesized that adipose tissue from metabolically healthy obese (MHO) and matched metabolically unhealthy obese individuals would demonstrate distinct differences in relation to Pref-1 expression, adipocyte size, and inflammatory markers. DESIGN, SETTING, AND PATIENTS: This was a cross-sectional study, investigating obese patients undergoing bariatric surgery at a tertiary referral centre. Patients included 12 MHO and 17 age- and body mass index-matched metabolically unhealthy obese individuals. MAIN OUTCOME MEASURES: Pref-1, monocyte chemotactic protein-1, TNF-α, granulocyte colony-stimulating factor, IL-6, and adiponectin levels, macrophage numbers, and adipocyte size were measured in omental and subcutaneous adipose tissue. RESULTS: The MHO group had a lower level of Pref-1 (per 1000 adipocytes) in both subcutaneous [160 (136-177) versus 194 (153-355); P < 0.05] and omental adipose tissue [102 (32-175) versus 194 (100-350); P < 0.005]. This was associated with lower numbers of macrophages, lower levels of TNF-α, monocyte chemotactic protein-1, and granulocyte colony-stimulating factor, and higher levels of adiponectin. Omental Pref-1 showed strong correlations with adipocyte size (r = 0.67, P < 0.0005) and metabolic and adipokine parameters, including percent fatty liver (r = 0.62, P < 0.005), fasting glucose (r = 0.68, P < 0.0005), triglyceride (r = 0.60, P < 0.005), high-density lipoprotein cholesterol (r = -0.46, P < 0.05), and adiponectin (r = -0.71, P < 0.05). CONCLUSION: Adipose tissue in MHO individuals had lower levels of Pref-1, a known inhibitor of preadipocyte differentiation, and a more favorable inflammatory profile. These factors may be key to protecting this subgroup of obese individuals from the adverse metabolic profile associated with excess adiposity.

Laparoscopic bariatric surgery for morbid obesity: the first hundred cases in an Irish centre.

INTRODUCTION: This study evaluated outcomes for the first 100 bariatric surgical procedures in a single, publicly funded Irish centre. METHODS: This was a retrospective, chart-based study. Demographics and comorbidities of patients, peri- and post-operative outcomes and health benefits obtained by surgery were assessed. RESULTS: In total, 87 patients underwent Roux-en-Y gastric bypass procedures, 11 underwent sleeve gastrectomies and 2 underwent duodenal switch. The first 13 operations were done as open procedures. Of the remaining 87 cases, 85 were started laparoscopically. Postoperatively, 2 laparotomies were performed for bleeding and 2 patients developed incarcerated incisional hernias that required repair. The 30-day readmission rate was 6% of which 2 patients required emergency surgery. There was one postoperative mortality from cardio-respiratory failure. CONCLUSIONS: This series audits the introduction of a publicly funded bariatric service in Ireland and reports a high percentage of procedures completed laparoscopically with an acceptable morbidity and mortality.

Vascular-targeted photodynamic therapy with BF2-chelated Tetraaryl-Azadipyrromethene agents: a multi-modality molecular imaging approach to therapeutic assessment.

BACKGROUND: Photodynamic therapy (PDT) is a treatment modality for a range of diseases including cancer. The BF(2)-chelated tetraaryl-azadipyrromethenes (ADPMs) are an emerging class of non-porphyrin PDT agent, which have previously shown excellent photochemical and photophysical properties for therapeutic application. Herein, in vivo efficacy and mechanism of action studies have been completed for the lead agent, ADMP06. METHODS: A multi-modality imaging approach was employed to assess efficacy of treatment, as well as probe the mechanism of action of ADPM06-mediated PDT. RESULTS: Tumour ablation in 71% of animals bearing mammary tumours was achieved after delivery of 2 mg kg(-1) of ADPM06 followed immediately by light irradiation with 150 J cm(-2). The inherent fluorescence of ADPM06 was utilised to monitor organ biodistribution patterns, with fluorescence reaching baseline levels in all organs within 24 h. Mechanism of action studies were carried out using dynamic positron emission tomography and magnetic resonance imaging techniques, which, when taken together, indicated a decrease in tumour vascular perfusion and concomitant reduction in tumour metabolism over time after treatment. CONCLUSION: The encouraging treatment responses in vivo and vascular-targeting mechanism of action continue to indicate therapeutic benefit for this new class of photosensitiser.

Array-based DNA methylation profiling in follicular lymphoma.

Quantitative methylation profiling was performed using the Illumina GoldenGate Assay in untreated follicular lymphoma (FL) (164), paired pre- and post-transformation FL (20), benign haematopoietic (24) samples and purified B and T cells from two FL cases. Methylation values allowed separation of untreated FL samples from controls with one exception, based primarily on tumour-specific gains of methylation typically occurring within CpG islands. Genes that are targets for epigenetic repression in stem cells by Polycomb Repressor Complex 2 were significantly over-represented among hypermethylated genes. Methylation profiles were conserved in sequential FL and t-FL biopsies, suggesting that widespread methylation represents an early event in lymphomagenesis and may not contribute substantially to transformation. A significant (P<0.05) correlation between FL methylation values and reduced gene expression was shown for up to 28% of loci. Methylation changes occurred predominantly in B cells with variability in the amount of non-malignant tissue between samples preventing conclusive correlation with survival. This represents an important caveat in attributing prognostic relevance to methylation and future studies in cancer will optimally require purified tumour populations to address the impact of methylation on clinical outcome.

Recommended evaluation of adrenal incidentalomas is costly, has high false-positive rates and confers a risk of fatal cancer that is similar to the risk of the adrenal lesion becoming malignant; time for a rethink?

OBJECTIVE: To assess the performance of current clinical recommendations for the evaluation of an adrenal incidentaloma. DESIGN AND METHODS LITERATURE REVIEW: Electronic databases (Pubmed, Ovid and citation searches from key articles) from 1980 to 2008 were searched. Eligible studies were those deemed most applicable to the clinical scenario of a patient referred to an endocrinologist for assessment of an incidentally detected adrenal mass. Surgical series, histopathological series and oncological series were reviewed and most were excluded. RESULTS: The prevalence of functional and malignant lesions presenting as adrenal incidentaloma was similar to that quoted in most reviews, other than a lower incidence of adrenal carcinoma (1.9 vs 4.7%) and metastases (0.7 vs 2.3%). The development of functionality or malignancy during follow-up was rare (<1% becoming functional and 0.2% becoming malignant). During follow-up, false-positive rates of the recommended investigations are typically 50 times greater than true positive rates. The average recommended computed tomography (CT) scan follow-up exposes each patient to 23 mSv of ionising radiation, equating to a 1 in 430 to 2170 chance of causing fatal cancer. This is similar to the chance of developing adrenal malignancy during 3-year follow-up of adrenal incidentaloma. CONCLUSION: Current recommendations for evaluation of adrenal incidentaloma are likely to result in significant costs, both financial and emotional, due to high false-positive rates. The dose of radiation involved in currently recommended CT scan follow-up confers a risk of fatal cancer that is similar to the risk of the adrenal becoming malignant. This argues for a review of current guidelines.

An examination of the prevalence of IDF- and ATPIII-defined metabolic syndrome in an Irish screening population.

OBJECTIVES: To investigate the prevalence of ATPIII- and IDF-defined metabolic syndrome (MetS) in an Irish screening population and to determine the calculated cardiovascular risk for each group. DESIGN: A total of 1,716 subjects were enrolled over a 12-month period. MAIN OUTCOMES: The ATPIII-defined prevalence of MetS in this population was 13.2%. Using IDF criteria, 21.4% of subjects were identified as having the MetS. Correlation between the two definitions was high; however, IDF criteria identified an additional 9.5% (n = 164) of the population as having MetS, which ATPIII criteria failed to recognise. CONCLUSION: We noted a higher prevalence of MetS in the studied population when defined by IDF criteria. However, those identified by IDF and not by ATPIII definition did not have a higher cardiovascular risk score by either Framingham or European Score than those without MetS. Thus, application of the ATPIII definition of MetS, may be the more practical.