Yap regulates skeletal muscle fatty acid oxidation and adiposity in metabolic disease.

Obesity is a major risk factor underlying the development of metabolic disease and a growing public health concern globally. Strategies to promote skeletal muscle metabolism can be effective to limit the progression of metabolic disease. Here, we demonstrate that the levels of the Hippo pathway transcriptional co-activator YAP are decreased in muscle biopsies from obese, insulin-resistant humans and mice. Targeted disruption of Yap in adult skeletal muscle resulted in incomplete oxidation of fatty acids and lipotoxicity. Integrated 'omics analysis from isolated adult muscle nuclei revealed that Yap regulates a transcriptional profile associated with metabolic substrate utilisation. In line with these findings, increasing Yap abundance in the striated muscle of obese (db/db) mice enhanced energy expenditure and attenuated adiposity. Our results demonstrate a vital role for Yap as a mediator of skeletal muscle metabolism. Strategies to enhance Yap activity in skeletal muscle warrant consideration as part of comprehensive approaches to treat metabolic disease.

Senescence in immunity against helminth parasites predicts adult mortality in a wild mammal.

Our understanding of the deterioration in immune function in old age-immunosenescence-derives principally from studies of modern human populations and laboratory animals. The generality and significance of this process for systems experiencing complex, natural infections and environmental challenges are unknown. Here, we show that late-life declines in an important immune marker of resistance to helminth parasites in wild Soay sheep predict overwinter mortality. We found senescence in circulating antibody levels against a highly prevalent nematode worm, which was associated with reduced adult survival probability, independent of changes in body weight. These findings establish a role for immunosenescence in the ecology and evolution of natural populations.

The latest FAD - Faecal antibody detection in cattle. Protocol and results from three UK beef farms naturally infected with gastrointestinal nematodes.

Antibodies at gastrointestinal mucosal membranes play a vital role in immunological protection against a range of pathogens, including helminths. Gastrointestinal health is central to efficient livestock production, and such infections cause significant losses. Fecal samples were taken from 114 cattle, across three beef farms, with matched blood samples taken from 22 of those animals. To achieve fecal antibody detection, a novel fecal supernatant was extracted. Fecal supernatant and serum samples were then analysed, using adapted enzyme-linked immunosorbent assay protocols, for levels of total immunoglobulin (Ig)A, IgG, IgM, and Teladorsagia circumcincta-specific IgA, IgG, IgM and IgE (in the absence of reagents for cattle-specific nematode species). Fecal nematode egg counts were conducted on all fecal samples. Assays performed successfully and showed that IgA was the predominant antibody in fecal samples, whereas IgG was predominant in serum. Total IgA in feces and serum correlated within individuals (0.581, P = 0.005), but other Ig types did not. Results support the hypothesis that the tested protocols are an effective method for the non-invasive assessment of cattle immunology. The method could be used as part of animal health assessments, although further work is required to interpret the relationship between results and levels of infection and immunity.

Liver Transplantation Trends and Outcomes for Hereditary Hemorrhagic Telangiectasia in the United States.

BACKGROUND: Liver arteriovenous malformations (AVM) in hereditary hemorrhagic telangiectasia (HHT) can necessitate liver transplantation. There is limited data on HHT patients undergoing liver transplantation (LT) in the United States. METHODS: Two sources of data were used: (1) Scientific Registry of Transplant Recipients (SRTR) database (1998-2016) (2) Single center liver transplant database (Mayo Clinic Rochester, MN). The aims of this study were (1) to determine trends in LT for HHT-related liver involvement in the United States using the SRTR database; (2) to identify clinical characteristics, indications, and outcomes for LT in HHT. RESULTS: Thirty-nine HHT patients were listed for LT in the SRTR database from 1998-2016 to 1998-2001 (n = 1); 2002-2005 (n = 4); 2006-2010 (n = 10), and 2011-2016 (n = 24). Twenty-four underwent LT at a median age of 47.5 years (interquartile range, 37.0-58.5 years). Median calculated MELD score at time of LT was 8.0 (interquartile range, 7.0-9.5), and 75% received an exception MELD score. Two status-1 patients died during transplant surgery. Nineteen (86%) patients were alive after a median post-LT follow-up of 48 months, whereas 2 patients were lost to follow-up. Five of the aforementioned HHT patients underwent LT at Mayo Clinic, 4 with high output cardiac failure, and 1 with biliary ischemia. All 5 were alive at the time of last follow-up with good graft function and resolution of heart failure. CONCLUSIONS: Outcomes after LT for HHT patients are excellent with 86% survival after a median follow-up of 48 months and resolution of heart failure. LT listing for HHT has increased in substantially in more recent eras.

Feasibility and outcomes of percutaneous thermal ablation of hepatocellular carcinoma in a transplanted allograft.

PURPOSE: To examine the safety, feasibility, and oncologic control following percutaneous image-guided thermal ablation of hepatocellular carcinoma (HCC) in a transplanted allograft. MATERIALS AND METHODS: Retrospective review was performed to identify patients who underwent liver transplantation for HCC and subsequently underwent percutaneous hepatic thermal ablation for recurrent HCC within the allograft between January 1st, 2000-September 1st, 2016. Eleven patients with hepatic allograft HCC underwent twelve percutaneous thermal ablation procedures to treat 16 lesions. Patient, procedural characteristics, and local oncologic efficacy were reviewed. Complications were characterized via the Common Terminology for Clinically Adverse Events nomenclature [CTCAE] v4.03). RESULTS: Eleven transplant recipients underwent treatment of 16 HCC tumors in their allografts during 12 ablation sessions. Mean follow-up time was 25 months (range 2-96 months). Local oncologic control was achieved in 10 of 11 tumors (91%) with imaging follow-up. One patient (8%) with Roux-en-Y biliary reconstruction developed a major complication with hepatic abscess. CONCLUSION: Thermal ablation of recurrent HCC in transplanted allografts can be accomplished safely with acceptable rates of local control for patients with duct-to-duct biliary reconstruction. Due to the high number of patients deemed surgically unresectable, the morbidity of surgical resection, the side effects of targeted therapies, and significant mortality associated with recurrences in the transplanted allograft, patients may benefit from percutaneous thermal ablative treatments. Further study is needed to assess the role of thermal ablation in allograft HCC recurrences as primary therapy or in a multimodality approach with emerging systemic therapies.

Systematic review with meta-analysis: the association between hepatitis E seroprevalence and haemodialysis.

BACKGROUND: Hepatitis E virus (HEV) infection appears to be more common than previously thought. HEV seroprevalence in patients on maintenance haemodialysis (HD) is unclear with a range from 0% to 44%. In addition, risk factors of transmission of HEV in patients on haemodialysis are unknown. AIM: To perform a systematic review and meta-analysis of HEV seroprevalence in HD patients compared with controls. METHODS: A systematic search of several databases identified all observational studies with comparative arms. Two reviewers extracted data and assessed the methodological quality. A random-effects model was used for pooled odds ratio (OR) and 95% confidence interval (CI) of positive anti-HEV IgG in both groups. Heterogeneity and publication bias were assessed with appropriate tests. RESULTS: We identified 31 studies from 17 countries between 1994 and 2016. Sixteen studies were judged to have adequate quality and 15 to have moderate limitations. HEV infection was more prevalent in patients on haemodialysis compared with controls (OR 2.47, 95% CI 1.79-3.40, I2 = 75.2%, P < .01). We conducted several subgroup analyses without difference in results. Egger regression test did not suggest publication bias (P = .83). Specific risk factors of HEV transmission in patients on haemodialysis were not clearly identified. CONCLUSIONS: Hepatitis E virus infection is more prevalent in patients on haemodialysis compared with non-haemodialysis control groups. Further studies are needed to determine risk factors of acquisition, impact on health, and risk for chronic HEV especially among those patients going to receive organ transplantation.

Robust extraction of quantitative structural information from high-variance histological images of livers from necropsied Soay sheep.

Quantitative information is essential to the empirical analysis of biological systems. In many such systems, spatial relations between anatomical structures is of interest, making imaging a valuable data acquisition tool. However, image data can be difficult to analyse quantitatively. Many image processing algorithms are highly sensitive to variations in the image, limiting their current application to fields where sample and image quality may be very high. Here, we develop robust image processing algorithms for extracting structural information from a dataset of high-variance histological images of inflamed liver tissue obtained during necropsies of wild Soay sheep. We demonstrate that features of the data can be measured in a fully automated manner, providing quantitative information which can be readily used in statistical analysis. We show that these methods provide measures that correlate well with a manual, expert operator-led analysis of the same images, that they provide advantages in terms of sampling a wider range of information and that information can be extracted far more quickly than in manual analysis.

Hot tea and tiny tots don't mix: A cross-sectional survey on hot beverage scalds.

OBJECTIVE: Hot beverage scalds are a leading cause of burns in young children. The aim of this study was to look at the circumstances surrounding these injuries in terms of setting, mechanism, supervision and first aid to inform a prevention campaign. METHODS: A cross-sectional study was delivered via iPad to parents and caregivers presenting with a child aged 0-36 months with a hot beverage scald at a major paediatric burns centre. RESULTS: Of the 101 children aged 0-36 months that presented with a hot beverage scald over a 12-month period, 54 participants were included. The scald aetiology was as expected with the peak prevalence in children aged 6-24 months, pulling a cup of hot liquid down over themselves. The majority of injuries occurred in the child's home and were witnessed by the caregiver or parent. The supervising adult was often in close proximity when the scald occurred. Less than a third (28%) of participants received recommended first aid treatment at the scene, with an additional 18% receiving this treatment with three hours of the injury-usually at an emergency department. CONCLUSIONS: While the aetiology of these scalds were as expected, the low use of recommended burn first aid was of concern. Although supervision was present in almost all cases, with the parent/caregiver close-by, this proximity still permitted injury. Attentiveness and continuity of supervision, which can be difficult with competing parental demands, appear to play a more important role role; as do considerations of other safety mechanisms such as hazard reduction through keeping hot drinks out of reach and engineering factors such as improved cup design. By incorporating the findings from this study and other research into a hot beverage scald prevention campaign, we hope to see a change in knowledge and behaviour in parents and caregivers of young children, and ultimately a reduction in the incidence of hot beverage scalds.

Review article: maximising quality of life while aspiring for quantity of life in end-stage liver disease.

BACKGROUND: With recent advances in the management of chronic liver disease and its complications, the long-term survival in cirrhosis has improved. Therefore, the number of individuals who will spend a significant proportion of their life with end-stage liver disease (ESLD) may continue to rise. Thus, more attention to quality of life (QOL) and its integration with traditional clinical endpoints is needed. AIMS: Recently, there have been many studies looking at treatment outcomes and their impact on the QOL in patients with ESLD. The aim of this review was to summarise and compare the insights gained from these intervention studies and to make concise recommendations to further promote and improve QOL in this patient population. METHODS: A literature search was conducted using PubMed and Web of Science. Search terms "Quality of life" "Cirrhosis" and "end-stage liver disease" were used as MeSH terms or searched in the title of the article. RESULTS: These studies uniformly show significant improvement in health-related QOL (HRQOL) with management of malnutrition, hepatic encephalopathy and ascites. Thus, early recognition and management of these complications are keys to better serve our patients. Early involvement of palliative care also leads to improved quality of end-of-life care. CONCLUSIONS: Complications of cirrhosis including malnutrition, encephalopathy, ascites and variceal bleeding lead to a decrease in HRQOL. Assessment of HRQOL has an important implication for the patient. The findings of this review illuminate the importance of using consistent tools to accurately assess QOL in patients with ESLD.

Cool Runnings - an app-based intervention for reducing hot drink scalds: study protocol for a randomised controlled trial.

BACKGROUND: Globally, burns are the fifth leading cause of non-fatal children's injuries, and the leading cause of childhood burns is hot beverage scalds. Although there have been a number of programmes aimed at preventing scalds in children, very few have specifically addressed hot beverage scalds, and fewer have reported a reduction in injury rates. In Australia, hot beverage scalds account for 18 % of all childhood burns - a figure that has remained constant for the past decade. Innovative new technologies, such as Smartphone applications (apps), present a novel way for delivering individual-level injury prevention messages. The low cost, scalability and broad reach make this technology an ideal channel for health interventions. One of the latest methods being used in health-related apps aimed at behaviour change is gamification. Gamification uses the gaming principles of rewards, competition and personalisation to engage participants and motivate them towards preferred behaviours. This intervention will use a Smartphone app-based platform that combines gamification and behaviour-change strategies to increase knowledge and awareness of hot beverage scald risks and burn first aid among mothers of young children. METHODS/DESIGN: This is a two-group, parallel, single-blinded randomised control trial (RCT) to evaluate the efficacy of a Smartphone app-based injury prevention intervention. The primary outcome measure is change in knowledge. Change in knowledge is measured in three components: knowledge of correct burns first aid; knowledge of the main cause of burns/scalds in children aged 0-15yrs; knowledge of the main age group at risk for burns/scalds. The secondary outcome measures relate to the gamification methods, measuring participants frequency of engagement with the Cool Runnings app. Queensland-based mothers aged 18+ years who own a Smartphone and have at least one child aged 5-12 months are eligible to participate. DISCUSSION: To our knowledge, this is the first study to evaluate an app-based delivery of injury prevention messages, and the first study to test the efficacy of gamification techniques in an injury prevention intervention. If this intervention is found to be effective, this RCT will provide a platform for targeting other childhood injury prevention campaigns. TRIAL REGISTRATION: This trial was registered on 14 January 2016 with the Australian New Zealand Clinical Trials Registry ( ACTRN12616000019404 ).

Reorientation of health services: enablers and barriers faced by organisations when increasing health promotion capacity.

Issue addressed Primary healthcare settings are important providers of health promotion approaches. However, organisational challenges can affect their capacity to deliver these approaches. This review identified the common enablers and barriers health organisations faced and it aimed to explore the experiences health organisations, in particular Aboriginal organisations, had when increasing their health promotion capacity. Methods A systematic search of peer-reviewed literature was conducted. Articles published between 1990-2014 that focused on a health care-settings approach and discussed factors that facilitated or hindered an organisation's ability to increase health promotion capacity were included. Results Twenty-five articles met the inclusion criteria. Qualitative (n=18) and quantitative (n=7) study designs were included. Only one article described the experiences of an Aboriginal health organisation. Enablers included: management support, skilled staff, provision of external support to the organisation, committed staffing and financial resources, leadership and the availability of external partners to work with. Barriers included: lack of management support, lack of dedicated health promotion staff, staff lacking skills or confidence, competing priorities and a lack of time and resources allocated to health promotion activities. Conclusions While the literature highlighted the importance of health promotion work, barriers can limit the delivery of health promotion approaches within primary healthcare organisations. A gap in the literature exists about how Aboriginal health organisations face these challenges. So what? Primary healthcare organisations wanting to increase their health promotion capacity can pre-empt the common barriers and strengthen identified enablers through the shared learnings outlined in this review.

Exposure to viral and bacterial pathogens among Soay sheep (Ovis aries) of the St Kilda archipelago.

We assessed evidence of exposure to viruses and bacteria in an unmanaged and long-isolated population of Soay sheep (Ovis aries) inhabiting Hirta, in the St Kilda archipelago, 65 km west of Benbecula in the Outer Hebrides of Scotland. The sheep harbour many metazoan and protozoan parasites but their exposure to viral and bacterial pathogens is unknown. We tested for herpes viral DNA in leucocytes and found that 21 of 42 tested sheep were infected with ovine herpesvirus 2 (OHV-2). We also tested 750 plasma samples collected between 1997 and 2010 for evidence of exposure to seven other viral and bacterial agents common in domestic Scottish sheep. We found evidence of exposure to Leptospira spp., with overall seroprevalence of 6·5%. However, serological evidence indicated that the population had not been exposed to border disease, parainfluenza, maedi-visna, or orf viruses, nor to Chlamydia abortus. Some sheep tested positive for antibodies against Mycobacterium avium subsp. paratuberculosis (MAP) but, in the absence of retrospective faecal samples, the presence of this infection could not be confirmed. The roles of importation, the pathogen-host interaction, nematode co-infection and local transmission warrant future investigation, to elucidate the transmission ecology and fitness effects of the few viral and bacterial pathogens on Hirta.

Uptake of selenium and mercury by captive mink: Results of a controlled feeding experiment.

Captive, juvenile, ranch-bred, male mink (Neovison vison) were fed diets containing various concentrations of methyl-mercury (MeHg) and selenium (Se) for a period of 13 weeks and then sacrificed to determine total Hg levels in fur, blood, brain, liver and kidneys and total Se concentrations in brain tissue. As MeHg concentrations in the diet increased, concentrations of total Hg in the tissues also increased with the highest level occurring in the fur > liver = kidney > brain > blood. Concentrations of Hg in the fur were correlated (r(2) > 0.97) with liver, kidney, blood and brain concentrations. The addition of Se to the mink diet did not appear to affect most tissue concentrations of total Hg nor did it affect the partitioning of Hg between the liver:blood, kidney:blood and brain:blood; however, partitioning of Hg between fur and blood was apparently affected.

Comparing Cardiopulmonary Exercise Testing in End-Stage Liver Disease Patients.

UNLABELLED: Poor cardiopulmonary fitness has been associated with worse outcomes in liver transplant candidates. PURPOSE: To determine if a modified 3-minute step test (potentially office based) is feasible and equivalent to standard cardiopulmonary exercise testing (CPET) in liver transplant candidates with severe decompensation. METHODS: Five patients with Childs-Pugh C end-stage liver disease and severe debility awaiting liver transplantation performed both standard CPET and the modified 3-minute step test (Shape medical systems). RESULTS: All 5 patients were able to complete both tests. Mean age was 59.8 ± 9 years, mean MELD score was 20 (range 13-26), and mean BMI was 27.6 kg/m(2) (range 16.4-37.2). Peak Vo2 was similar with a mean of 901 mL/min (step test) compared to 856 mL/min (cycle test), P = .64. Vo2 at a respiratory exchange ratio (RER) of 1.0 was similar with both tests (681 mL/min (step) vs 646 mL/min (cycle), P = .69. Ve/Vco2 slope (ventilatory efficiency) was similar (40 vs 39, P = .94). The ventilatory compensation point (i.e. anaerobic threshold) was also similar (∼80% of peak Vo2) for both studies. CONCLUSION: The modified 3-minute step test provides a simplified, potentially office-based assessment of cardiopulmonary exercise capacity and gas exchange measures as standard testing in patients with decompensated end-stage liver disease, with similar tolerability.

Internal hernia and small bowel obstruction following open ileoanal pouch formation: A case report.

INTRODUCTION: Internal herniae, although rare, can give rise to potentially serious morbidity and mortality. The protrusion and entrapment of the small bowel through an embryological or iatrogenic mesenteric aperture within the confines of the peritoneal cavity can be difficult to diagnose, and delay treatment (operative). Timely intervention must be achieved to minimize small bowel ischemia and infarction. CASE PRESENTATION: In this case, a young lady who had a previous laparoscopic total colectomy and ileostomy developed an unusual internal hernia. Small bowel was passing behind the lesser curvature of the stomach causing the stomach to be rotated to form of a tight "band" trapping bowel. The herniated small bowel was reduced, hence, avoiding resection; the defect closed by interupted 4-0 PDS. "Prompt" surgery avoided small bowel length resection and sacrifice of the ileoanal pouch reconstruction. DISCUSSION: It is theorized that a laparoscopic approach results in a more advanced mobilization of the mesentery right up to the small bowel origin, and with less adhesion formation may in fact promote unusual internal hernia and volvulus. CONCLUSION: The case presented highlights the difficulty in making the diagnosis, and the pictures clearly indicate an unusual hernia passing directly behind the stomach and involving a large section of the small bowel. The lead up history of several admissions with sub acute small bowel obstruction suggested the underlying problem was adhesional but quite clearly there was a well defined internal hernia. Without timely surgery she would have been at high risk of losing her pouch.

The Hippo pathway effector YAP is a critical regulator of skeletal muscle fibre size.

The Yes-associated protein (YAP) is a core effector of the Hippo pathway, which regulates proliferation and apoptosis in organ development. YAP function has been extensively characterized in epithelial cells and tissues, but its function in adult skeletal muscle remains poorly defined. Here we show that YAP positively regulates basal skeletal muscle mass and protein synthesis. Mechanistically, we show that YAP regulates muscle mass via interaction with TEAD transcription factors. Furthermore, YAP abundance and activity in muscles is increased following injury or degeneration of motor nerves, as a process to mitigate neurogenic muscle atrophy. Our findings highlight an essential role for YAP as a positive regulator of skeletal muscle size. Further investigation of interventions that promote YAP activity in skeletal muscle might aid the development of therapeutics to combat muscle wasting and neuromuscular disorders.

CIP4 promotes lung adenocarcinoma metastasis and is associated with poor prognosis.

Aberrant epidermal growth factor receptor (EGFR) signaling in non-small cell lung cancer (NSCLC) is linked to tumor progression, metastasis and poor survival rates. Here we report the role of Cdc42-interacting protein 4 (CIP4) in the regulation of NSCLC cell invasiveness and tumor metastasis. CIP4 was highly expressed in a panel of NSCLC cell lines and normal lung epithelial cell lines. Stable knockdown (KD) of CIP4 in lung adenocarcinoma H1299 cells, expressing wild-type EGFR, led to increased EGFR levels on the cell surface and defects in sustained activation of Erk kinase in H1299 cells treated with EGF. CIP4 localized to leading edge projections in NSCLC cells, and CIP4 KD cells displayed defects in EGF-induced cell motility and invasion through extracellular matrix. This correlated with reduced expression and activity of matrix metalloproteinase-2 (MMP-2) in CIP4 KD cells compared with control. In xenograft assays, CIP4 silencing had no effect on tumor growth but resulted in significant defects in spontaneous metastases to the lungs from these subcutaneous tumors. This correlated with reduced expression of the Erk target gene Zeb1 and the Zeb1 target gene MMP-2 in CIP4 KD tumors compared with control. CIP4 also enhanced rates of metastasis to the liver and lungs in an intrasplenic experimental metastasis model. In human NSCLC tumor sections, CIP4 expression was elevated greater than or equal to twofold in 43% of adenocarcinomas and 32% of squamous carcinomas compared with adjacent normal lung tissues. Analysis of microarray data for NSCLC patients also revealed that high CIP4 transcript levels correlated with reduced overall survival. Together, these results identify CIP4 as a positive regulator of NSCLC metastasis and a potential poor prognostic biomarker in lung adenocarcinoma.

Use of opportunistic clinical data and a population pharmacokinetic model to support dosing of clindamycin for premature infants to adolescents.

Clindamycin is commonly prescribed to treat children with skin and skin-structure infections (including those caused by community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA)), yet little is known about its pharmacokinetics (PK) across pediatric age groups. A population PK analysis was performed in NONMEM using samples collected in an opportunistic study from children receiving i.v. clindamycin per standard of care. The final model was used to optimize pediatric dosing to match adult exposure proven effective against CA-MRSA. A total of 194 plasma PK samples collected from 125 children were included in the analysis. A one-compartment model described the data well. The final model included body weight and a sigmoidal maturation relationship between postmenstrual age (PMA) and clearance (CL): CL (l/h) = 13.7 × (weight/70)(0.75) × (PMA(3.1)/(43.6(3.1) + PMA(3.1))); V (l) = 61.8 × (weight/70). Maturation reached 50% of adult CL values at ~44 weeks PMA. Our findings support age-based dosing.

Recurrence of hepatocellular carcinoma: importance of mRECIST response to chemoembolization and tumor size.

Determining risk for recurrence of hepatocellular carcinoma (HCC) following liver transplantation (LT) is an important clinical need. We assessed consecutive patients who underwent LT for HCC following sequential transarterial chemoembolization (TACE). Treatment response was assessed using modified response evaluation criteria in solid tumors (mRECIST) categories: complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). Cox proportional hazard models were used to predict HCC recurrence. One hundred seventy-three patients underwent TACE and imaging to assess response prior to LT. TACE responses were: CR = 23.7%, PR = 24.3%, SD = 27.7% and PD = 24.3%. Five-year HCC recurrence rate was 5.3% in patients responding to TACE (CR/PR), versus 17.6%, among patients who did not respond (SD/PD, p = 0.014). In multivariate analysis, independent pre-LT predictors of recurrence were response to TACE and largest radiologic size of tumor (>3 cm vs. ≤3 cm). HCC recurrence rate for patients with tumor size >3 cm and no response to TACE was 35.8%, compared with 1.9% for patients with tumor size ≤3 cm and response to TACE (p = 0.0007). We conclude that mRECIST criteria and tumor size differentiate patients with high or low likelihood of HCC recurrence after LT. These findings raise the possibility of incorporating response to TACE and largest tumor size to identify patients at highest risk for HCC recurrence.