Enhancing metabolite coverage in MALDI-MSI using laser post-ionisation (MALDI-2).

Matrix-assisted laser desorption/ionisation mass spectrometry imaging (MALDI-MSI) of metabolites can reveal how metabolism is altered throughout heterogeneous tissues. Here negative ion mode MALDI-MSI has been coupled with laser post-ionisation (MALDI-2) and applied to the MSI of low molecular weight (LMW) metabolites (

Parent perceptions of cycle training for children with special education needs and disabilities: What drives intention to cycle?

Background: Young people with Special Educational Needs and Disabilities (SEND) are especially vulnerable to physical inactivity. Research has demonstrated the effectiveness of tailored cycle training for children with SEND, however, it is unclear whether this then results in a greater uptake of cycling. Aims: To determine parent based perceptions of a SEND cycle training programme, factors which predict intention to cycle more and ongoing barriers to cycling. Methods: A tailored questionnaire was distributed to parents of children who took part in the cycle training. Results: Parents reported increased confidence in their child's ability to cycle independently with many also highlighting improvements in confidence and resilience. The outcome of the cycle training (level of enjoyment and change in cycling ability) had a positive influence on intention to cycle more while cycling frequency prior to training had a negative influence. Continuing barriers to cycling were identified which included difficulties accessing specialised equipment and a need for additional on-road cycle training. Conclusions and implications: This study demonstrates the success of a specialised cycle training programme for children with SEND in terms of improvement to cycling and influences on the intention to cycle more.

Bacterial contamination of surgical loupes and headlights.

BACKGROUND: Medical equipment can transmit pathogenic bacteria to patients. This single-institution point prevalence study aimed to characterise the types and relative amount of bacteria found on surgical loupes, headlights and their battery packs. METHOD: Surgical loupes, headlights and battery packs of 16 otolaryngology staff and residents were sampled, cultured and quantified. Plate scores were summed for each equipment type, and the total was divided by the number of users to generate mean bacterial burden scores. Residents completed a questionnaire regarding their equipment cleaning practices. RESULTS: The contamination rates of loupes, headlights and battery packs were 68.75 per cent, 100 per cent and 75 per cent, respectively. Battery packs cultured more bacteria (1.58 per swab ± 1.00) than loupes (0.75 per swab ± 0.66; p = 0.024). Headlights had non-significantly greater growth (1.50 per swab ± 0.71) than loupes (p = 0.052). Bacterial growth was significantly higher from inner surfaces of loupes (p = 0.035) and headlights (p = 0.037). Potentially pathogenic bacteria were cultured from the equipment of five participants, including: Pantoea agglomerans, Acinetobacter radioresistens, Staphylococcus aureus, Acinetobacter calcoaceticus baumannii complex and Moraxella osloensis. CONCLUSION: This study demonstrates that surgical loupes and headlights used in otolaryngology harbour non-pathogenic skin flora and potentially pathogenic bacteria.

Increasing stomatal conductance in response to rising atmospheric CO2.

Background and Aims: Studies have indicated that plant stomatal conductance (gs) decreases in response to elevated atmospheric CO2, a phenomenon of significance for the global hydrological cycle. However, gs increases across certain CO2 ranges have been predicted by optimization models. The aim of this work was to demonstrate that under certain environmental conditions, gs can increase in response to elevated CO2. Methods: Using (1) an extensive, up-to-date synthesis of gs responses in free air CO2 enrichment (FACE)experiments, (2) in situ measurements across four biomes showing dynamic gs responses to a CO2 rise of ~50 ppm (characterizing the change in this greenhouse gas over the past three decades) and (3) a photosynthesis-stomatal conductance model, it is demonstrated that gs can in some cases increase in response to increasing atmospheric CO2. Key Results: Field observations are corroborated by an extensive synthesis of gs responses in FACE experiments showing that 11.8 % of gs responses under experimentally elevated CO2 are positive. They are further supported by a strong data-model fit (r2 = 0.607) using a stomatal optimization model applied to the field gs dataset. A parameter space identified in the Farquhar-Ball-Berry photosynthesis-stomatal conductance model confirms field observations of increasing gs under elevated CO2 in hot dry conditions. Contrary to the general assumption, positive gs responses to elevated CO2, although relatively rare, are a feature of woody taxa adapted to warm, low-humidity conditions, and this response is also demonstrated in global simulations using the Community Land Model (CLM4). Conclusions: The results contradict the over-simplistic notion that global vegetation always responds with decreasing gs to elevated CO2, a finding that has important implications for predicting future vegetation feedbacks on the hydrological cycle at the regional level.

Safety profile of a replication-deficient human adenovirus-vectored foot-and-mouth disease virus serotype A24 subunit vaccine in cattle.

The safety of a replication-deficient, human adenovirus-vectored foot-and-mouth disease virus (FMDV) serotype A24 Cruzeiro capsid-based subunit vaccine (AdtA24) was evaluated in five independent safety studies. The target animal safety studies were designed in compliance with United States (U.S.) regulatory requirements (Title 9, U.S. Code of Federal Regulation [9CFR]) and international standard guidelines (VICH Topic GL-44) for veterinary live vaccines. The first three studies were conducted in a total of 22 vaccinees and demonstrated that the AdtA24 master seed virus (MSV) was safe, did not revert to virulence and was not shed or spread from vaccinees to susceptible cattle or pigs. The fourth safety study conducted in 10 lactating cows using an AdtA24 vaccine serial showed that the vaccine was completely absent from milk. The fifth safety study was conducted under typical U.S. production field conditions in 500 healthy beef and dairy cattle using two AdtA24 vaccine serials. These results demonstrated that the vaccine was safe when used per the product label recommendations. Additional data collected during these five studies confirmed that AdtA24 vaccinees developed FMDV A24 and the HAd5 vaccine vector serum neutralization antibodies that test negative in a FMDV non-structural protein antibody test, confirming AdtA24 vaccine's capability to differentiate infected from vaccinated animals (DIVA). In conclusion, results from this comprehensive set of cattle studies demonstrated the safety of the replication-deficient AdtA24 vaccine and fulfilled safety-related requirements for U.S. regulatory requirements.

Women's experiences of more than one termination of pregnancy within two years: a mixed-methods study.

OBJECTIVE: To examine the experiences of women seeking more than one termination of pregnancy (TOP) within 2 years. DESIGN: Mixed methods study. SETTING: Six TOP services across Scotland. SAMPLE: Women presenting for TOP between July and December 2015. METHODS: Descriptive and inferential analysis of quantitative survey data, thematic analysis of qualitative interview data and integrative analysis. In quantitative analysis, multinomial logistic regression was used to compare three groups: previous TOP within 2 years, previous TOP beyond 2 years and no previous TOP. MAIN OUTCOME MEASURES: Characteristics and experiences of women seeking TOP. RESULTS: Of 1662 questionnaire respondents, 14.6% (n = 242) and 19.8% (n = 329) reported previous TOP within and beyond 2 years, respectively. The previous TOP within 2 years group was significantly less likely to own their accommodation than the no previous TOP group (adjusted odds ratio [aOR] 0.34, 95% CI: 0.18-0.62) and previous TOP beyond 2 years group (aOR: 0.44, 95% CI: 0.23-0.85); and more likely to report inconsistent (aOR: 1.63, 95% CI: 1.04-2.57; aOR: 1.95, 95% CI: 1.16-3.28) and consistent (aOR: 2.13, 95% CI: 1.39-3.26; aOR: 1.71, 95% CI: 1.07-2.76) contraceptive use than the no previous TOP and previous TOP within 2 years groups, respectively. Twenty-three women from the previous TOP within 2 years group were interviewed. Qualitative and integrative analyses highlight issues relating to contraceptive challenges, intimate partner violence, life aspirations and socio-economic disadvantage. CONCLUSIONS: Women undergoing more than one TOP within 2 years may experience particular challenges and vulnerabilities. Service provision should recognise this and move away from stigmatising discourses of 'repeat abortion'. FUNDING: Scottish Government. TWEETABLE ABSTRACT: Women having two or more terminations of pregnancy in 2 years may face key challenges/vulnerabilities including intimate partner violence and socio-economic disadvantage.

Appropriateness of different pedagogical approaches to road safety education for children with Developmental Coordination Disorder (DCD).

BACKGROUND: In 2016, 29% of pedestrians killed or seriously injured on the roads in Great Britain were under 15 years of age. Children with Developmental Coordination Disorder (DCD), a chronic disorder affecting the acquisition and execution of motor skills, may be more vulnerable at the roadside than typically developing (TD) children. Current methods used to teach road safety are typically knowledge-based and do not necessarily improve behaviour in real traffic situations. Virtual reality road crossing tasks may be a viable alternative. AIMS/METHODS: The present study aimed to test the road crossing accuracy of children with and without DCD in virtual reality tasks that varied the viewpoint to simulate the teaching methods currently used in road safety educational programmes. Twenty-one children with DCD and twenty-one age and gender matched TD peers were required to locate the safest road crossing sites in two conditions: allocentric (aerial viewpoint) and egocentric (first-person viewpoint). PROCEDURES/OUTCOMES: All children completed both conditions and were required to navigate either themselves or an avatar across the road using the safest crossing route. The primary outcome was accuracy defined as the number of trials, out of 10, on which the child successfully identified and used the safest crossing route. RESULTS/CONCLUSIONS: Children with DCD performed equally poorly in both conditions, while TD children were significantly more accurate in the egocentric condition. This difference cannot be explained by self-reported prior road crossing education, practice or confidence. IMPLICATIONS: While TD children may benefit from the development of an egocentric virtual reality road crossing task, multimodal methods may be needed to effectively teach road safety to children with DCD.

Self-management of first trimester medical termination of pregnancy: a qualitative study of women's experiences.

OBJECTIVE: To explore the experiences of women in Scotland who return home to complete medical termination of pregnancy (TOP) ≤63 days of gestation, after being administered with mifepristone and misoprostol at an NHS TOP clinic. DESIGN: Qualitative interview study. SETTING: One National Health Service health board (administrative) area in Scotland. POPULATION OR SAMPLE: Women in Scotland who had undergone medical TOP ≤63 days, and self-managed passing the pregnancy at home; recruited from three clinics in one NHS health board area between January and July 2014. METHODS: In-depth, semi-structured interviews with 44 women in Scotland who had recently undergone TOP ≤63 days of gestation, and who returned home to pass the pregnancy. Data were analysed thematically using an approach informed by the Framework method. MAIN OUTCOME MEASURES: Women's experiences of self-management of TOP ≤63 days of gestation. RESULTS: Key themes emerging from the analysis related to self-administration of misoprostol in clinic; reasons for choosing home self-management; facilitation of self-management and expectation-setting; experiences of getting home; self-managing and monitoring treatment progress; support for self-management (in person and remotely); and pregnancy self-testing to confirm completion. CONCLUSIONS: Participants primarily found self-administration of misoprostol and home self-management to be acceptable and/or preferable, particularly where this was experienced as a decision made jointly with health professionals. The way in which home self-management is presented to women at clinic requires ongoing attention. Women could benefit from the option of home administration of misoprostol. TWEETABLE ABSTRACT: Women undergoing medical TOP 63 days found home self-management to be acceptable and/or preferable.

Barriers to accessing termination of pregnancy in a remote and rural setting: a qualitative study.

OBJECTIVE: To explore the experiences of women from a remote and rural setting who had a termination of pregnancy (TOP), in relation to any barriers they may have experienced trying to access TOP. DESIGN: Qualitative interview study. SETTING: Scottish Highlands and Western Isles. POPULATION: Women who had undergone TOP in the Scottish Highlands National Health Service between October 2014 and May 2015. METHODS: Sixteen semi-structured, audio-recorded telephone interviews were conducted by a researcher with women who had consented to be interviewed at their initial assessment. Six stages of thematic analysis were followed to explore themes in and across participant accounts. MAIN OUTCOME MEASURES: Themes derived from interview transcripts. RESULTS: Four themes emerged relating to barriers to access and experience: (1) the impact of travel for TOP, (2) temporal factors unique to this population and how they affected women, (3) the attitude of health professionals, notably general practitioners, as a result of local culture, and (4) stigma surrounding TOP and the expectation that abortion will be traumatising. CONCLUSION: Women in remote and rural areas experience barriers to accessing TOP. Prompt referrals, more providers of TOP and tackling stigma associated with TOP could make delivery of this service more equitable and improve women's journey through TOP. TWEETABLE ABSTRACT: Women in remote and rural areas of Scotland face multiple barriers to accessing termination of pregnancy.

A phase I trial of bortezomib in combination with epirubicin, carboplatin and capecitabine (ECarboX) in advanced oesophagogastric adenocarcinoma.

PURPOSE: The protease inhibitor bortezomib attenuates the action of NF-κB and has shown preclinical activity alone and in combination with chemotherapy. DESIGN: A Phase I dose-escalation study was performed administering bortezomib (0.7, 1.0, 1.3 and 1.6 mg m(-2) on days 1 and 8 from cycle 2 onwards) in combination with Epirubicin 50 mg m(-2) intravenously on day 1, Carboplatin AUC 5 day 1 and Capecitabine 625 mg m(-2) BD days 1-21 every 21 days (VECarboX regimen), in patients with advanced oesophagogastric adenocarcinoma. The primary objective was to define the maximum tolerated dose (MTD) of Bortezomib when combined with ECarboX. RESULTS: 18 patients received bortezomib 0.7 (n = 6), 1.0 (n = 3), 1.3 (n = 6) and 1.6 mg m(-2) (n = 3) and a protocol amendment reducing the capecitabine dose to 500 mg m(-2) BD was enacted due to myelotoxicity. Common treatment-related non-haematological adverse events of any grade were fatigue (83.3 %), anorexia (55.6 %), constipation (55.6 %) and nausea (55.6 %). Common Grade 3/4 haematological toxicities were neutropenia (77.8 %) and thrombocytopenia (44.4 %). Objective responses were achieved in 6 patients (33.3 %) and a further 5 patients (27.8 %) had stable disease for >8 weeks. CONCLUSIONS: The addition of Bortezomib to ECarboX is well tolerated and response rates are comparable with standard chemotherapy.

Human adenovirus-vectored foot-and-mouth disease vaccines: establishment of a vaccine product profile through in vitro testing.

Next generation, foot-and-mouth disease (FMD) molecular vaccines based on replication deficient human adenovirus serotype 5 viral vectored delivery of FMD capsid genes (AdFMD) are being developed by the United States Dept. of Homeland Security and industry partners. The strategic goal of this program is to develop AdFMD licensed vaccines for the USA National Veterinary Stockpile for use, if needed, as emergency response tools during an FMD outbreak. This vaccine platform provides a unique opportunity to develop a set of in vitro analytical parameters to generate an AdFMD vaccine product profile to replace the current lot release test for traditional, inactivated FMD vaccines that requires FMDV challenge in livestock. The possibility of an indirect FMD vaccine potency test based on a serological alternative was initially investigated for a lead vaccine candidate, Adt.A24. Results show that serum virus neutralization (SVN) based serology testing for Adt.A24 vaccine lot release is not feasible, at least not in the context of vaccine potency assessment at one week post-vaccination. Thus, an in vitro infectious titer assay (tissue culture infectious dose 50, TCID50) which measures FMD infectious (protein expression) titer was established. Pre-validation results show acceptable assay variability and linearity and these data support further studies to validate the TCID50 assay as a potential potency release test. In addition, a quantitative physiochemical assay (HPLC) and three immunochemical assays (Fluorescent Focus-Forming Unit (FFU); tissue culture expression dose 50 (TCED50); Western blot) were developed for potential use as in vitro assays to monitor AdFMD vaccine lot-to-lot consistency and other potential applications. These results demonstrate the feasibility of using a traditional modified-live vaccine virus infectivity assay in combination with a set of physiochemical and immunochemical tests to build a vaccine product profile that will ensure the each AdFMD vaccine lot released is similar to a reference vaccine of proven clinical safety and efficacy.

The expression and prognostic impact of CXC-chemokines in stage II and III colorectal cancer epithelial and stromal tissue.

BACKGROUND: The CXC-chemokine expression is linked with colorectal cancer (CRC) progression but their significance in resected CRC is unclear. We explored the prognostic impact of such expression in stage II and III CRC. METHODS: Tissue microarrays were constructed from stage II and III CRC biopsies (n=254), and the expression of CXCL1 and CXCL8, and their receptors CXCR1 and CXCR2, in malignant and adjacent normal tissue was graded by immunohistochemistry and was correlated with prognostic factors. RESULTS: Expression of CXCL1, CXCR1 and CXCR2 was elevated in tumour epithelium relative to normal adjacent tissue (P<0.001). CXCL8 expression was detectable in the peritumoural inflammatory infiltrate. There was no overall association between CXCL1, CXCR1 or CXCR2 expression and prognostic endpoints; however, univariate subgroup survival analysis demonstrated an inverse association between CXCL1 and recurrence-free survival (RFS) in stage III patients (P=0.041). The CXCL8 positivity in the tumour infiltrate, however, correlated with earlier disease stage (P<0.001) and improved relapse-free survival across the cohort (P<0.001). Disease stage (P<0.001) and tumour infiltrate CXCL8 positivity (P=0.007) were associated with enhanced RFS in multivariate Cox regression analysis. CONCLUSION: Autocrine CXC-chemokine signalling may have adverse prognostic effects in early CRC. Conversely, CXCL8 positivity within the immune infiltrate may have good prognostic significance.

Isolation and characterization of 10 polymorphic microsatellite markers from striped marlin, Tetrapturus audax.

We present the isolation and characterization of 10 microsatellite loci for striped marlin, Tetrapturus audax. Thirty individuals from each of four locations revealed that all loci were polymorphic with two to 31 alleles per locus. Observed levels of heterozygosity ranged from 0.3000 to 0.9667. Significant deviations from Hardy-Weinberg equilibrium were detected in two loci, TA105 in Hawaii and New Zealand and TA155 in Hawaii, and null alleles may be present in loci TA105 and TA155 in those locations, and in locus TA193 in Mexico. No significant linkage disequilibrium was detected in any pairwise-locus comparison.

The human force:velocity relationship; activity in the knee flexor and extensor muscles before and after eccentric practice.

The human voluntary force:velocity relationship frequently fails to demonstrate the expected high eccentric forces. Possible explanations include unique activation strategies which might be affected by neural learning mechanisms. We investigated the effect of practicing eccentric contractions on (1) the force:velocity relationship of the human knee extensor muscles and (2) the extent of agonist and antagonist muscle activity. Eight healthy adults [seven women, group mean age 31 (SEM 5) years +/-] practiced twice a week for 4 weeks using their non-dominant legs. Each session comprised three isokinetic concentric and eccentric maximal voluntary contractions (MVC) at randomised angular velocities of 100, 200 and 300 degrees.s-1. Before and after, the force:velocity relationship was determined bilaterally (angular velocities 0-300 degrees.s-1). There were no significant differences in the forces generated or relative electromyogram (EMG) activity after practice, although there was a trend for dynamic forces to increase. Beforehand, the bilateral eccentric MVC forces were lower than isometric (P < 0.0025); afterwards they were broadly similar. The agonist EMG was similar during isometric and eccentric contractions, but lower during concentric (P < 0.03). Antagonist EMG activity showed considerable individual variation, was similar during all contraction types and tended to be greater during dynamic contractions. These data indicate that neither central learning mechanisms nor total muscle activation strategies underlie the human failure to produce the expected high eccentric voluntary forces in humans.

Action of mannitol in ciguatoxin-intoxicated rats.

This study reports the effects of mannitol on nerve conduction when used as a therapeutic agent in mammals following the administration of ciguatoxin. Electrophysiological studies were performed in vivo on the rat ventral coccygeal nerve. The absolute and relative refractory periods, conduction velocity and the supernormal response were measured in rats treated with i.p. ciguatoxin, both prior to, and following, the infusion of i.v. mannitol. Ciguatoxin induced significant prolongation of the absolute refractory period as well as significant slowing of the compound nerve conduction velocity. The magnitude of the supernormal response was significantly increased and the duration of the supernormal period extended in ciguatoxin-treated animals. Recordings collected following the infusion of mannitol in these ciguatoxin-treated animals showed that mannitol did not reverse the effects of ciguatoxin on nerve conduction in any of the parameters measured.

Intraductal proliferations of the breast: a review of histologic criteria for atypical intraductal hyperplasia and ductal carcinoma in situ, including apocrine and papillary lesions.

The proliferation of intraductal mammary epithelium forms a continuum that begins with intraductal hyperplasia and ends with ductal carcinoma in situ. Atypical intraductal hyperplasia is the midpoint between the benign and malignant poles of this proliferative continuum. By defining the histological criteria for atypical intraductal hyperplasia, distinction from ordinary intraductal hyperplasia and the noncomedo forms of ductal carcinoma in situ becomes easier. Histopathologic criteria for atypical intraductal hyperplasia, ductal carcinoma in situ, and intraductal hyperplasia and their relative risks for the development of invasive breast carcinoma are reviewed. Related topics of intraductal apocrine and papillary proliferative lesions also are discussed.

Vascular tissue adaptations in end-to-end autologous arterial grafts in rats: a morphometric analysis.

Autologous vein grafts are employed extensively to bypass stenoses in the arterial circulation. More recently arterial segments have been used for such bypass surgery. In this study the adaptation of regenerating vascular tissues in experimental autologous artery grafts (4 mm long and 1 mm in diameter) in 20 adult male Wistar rats was analysed. At 1, 2, 4, 8 and 16 wk after insertion, 4 grafts per time interval were removed, processed for high resolution light microscopy and the thicknesses of the media and neointima, as well as the area fractions of smooth muscle cells, were analysed morphometrically. All grafts were reendothelialised by 2 wk. Neointimal hyperplasia (a subendothelial layer of smooth muscle cells) developed in all grafts and reached its maximal thickness (40.4 +/- 4.7 microns) at 2 wk. The area fraction of smooth muscle cells in the neointima of the artery grafts did not change significantly at any time from 2 to 16 wk. The media underlying the neointima of the artery grafts remained relatively constant throughout the 16 wk duration of the experiment. Whilst the total wall thickness of the grafts reduced significantly between 2 and 4 wk after insertion, at all times the grafts were thicker than the host artery.