Parity and housing effects on the behavioural and hypothalamic-pituitary-adrenal axis responses of pregnant ewes.

It is common in many countries for sheep to be housed during winter from mid-gestation until lambing to protect ewes and lambs from adverse conditions and improve late gestation nutritional management. Keeping ewes indoors, however, has its own challenges as the animals may be mixed with unfamiliar conspecifics, have limited floor and feeding space, experience changes to their diet and increased handling by humans. Therefore, the objective of this study was to investigate the effect of variation in housing management (space allowance and social stability) on the behaviour and hypothalamic-pituitary-adrenal (HPA) axis responses of pregnant ewes from mid-to-late gestation (weeks 11-18 of pregnancy). Seventy-seven ewes (41 primiparous, 36 multiparous) were divided into two groups: 'Control' and 'Restricted space and mixed' (RS-Mix), where RS-Mix ewes were allocated half the amount of space (1.27 vs 2.5 m2 for RS-Mix and Control, respectively) and feedface (concentrate feeder space) allowance (36 vs 71 cm per ewe) given to the Control group and were also subjected to two social mixing events. Aggressive behaviour at the feedface and time spent standing, lying, walking, feeding and ruminating were recorded and faecal samples were collected for assessment of faecal glucocorticoid metabolite (FGM) concentrations. Higher aggression was observed in RS-Mix ewes during the first week of observation (P = 0.044), which gradually declined to the same level as Control ewes by the end of the study (P = 0.045). RS-Mix ewes were significantly less likely to be able to freely join the feedface compared to Controls (P = 0.022). No other significant treatment effects on aggressive behaviour or FGM during gestation were found. RS-Mix ewes displayed significantly higher ruminating behaviour at week 18 of gestation compared to Control ewes (P < 0.001), but no other effects were seen on general pen behaviour. However, the effect of indoor housing had a significant impact on primiparous ewes, who had lower weight gain (P = 0.015) and higher FGM concentrations (P = 0.014) compared to multiparous ewes regardless of treatment group. The data suggest that, although no sustained effects on behaviour or HPA axis responses were seen with the differences in space and feeder allowance or social stability at the levels used in this study, inexperienced (primiparous) ewes may find indoor housing more stressful; and are less able to adapt compared to multiparous ewes. These effects may influence the behaviour of the ewe at lambing time, and her offspring.

Non-invasive Detection of Persistent Cortical Hypoxia in Multiple Sclerosis Using Frequency Domain Near-Infrared Spectroscopy (fdNIRS).

There may be a relationship between hypoxia and inflammation, which is important in the outcomes of a wide array of human diseases. Multiple sclerosis (MS) is one such disease. There is evidence that hypoxia may influence inflammation in MS. We showed previously that about 40% of participants with MS had hypoxia in the cortical grey matter using frequency-domain near-infrared spectroscopy (fdNIRS). In this study, we aimed to determine if hypoxia in MS persists chronically (for a year or more) by measuring at baseline and ≥12 months later. We found that hypoxia persists for at least a year in 80% of participants with MS. As more individuals remained hypoxic than returned to normoxia, the development of hypoxia may relate to disease progression.

Atmospheric pollution, soil nutrients and climate effects on Mucoromycota arbuscular mycorrhizal fungi.

Fine root endophyte mycorrhizal fungi in the Endogonales (Mucoromycota arbuscular mycorrhizal fungi, M-AMF) are now recognized as at least as important globally as Glomeromycota AMF (G-AMF), yet little is known about the environmental factors which influence M-AMF diversity and colonization, partly because they typically only co-colonize plants with G-AMF. Wild populations of Lycopodiella inundata predominantly form mycorrhizas with M-AMF and therefore allow focussed study of M-AMF environmental drivers. Using microscopic examination and DNA sequencing we measured M-AMF colonization and diversity over three consecutive seasons and modelled interactions between these response variables and environmental data. Significant relationships were found between M-AMF colonization and soil S, P, C:N ratio, electrical conductivity, and the previously overlooked micronutrient Mn. Estimated N deposition was negatively related to M-AMF colonization. Thirty-nine Endogonales Operational Taxonomic Units (OTUs) were identified in L. inundata roots, a greater diversity than previously recognized in this plant. Endogonales OTU richness correlated negatively with soil C:N while community composition was mostly influenced by soil P. This study provides first evidence that M-AMF have distinct ecological preferences in response to edaphic variables also related to air pollution. Future studies require site-level atmospheric pollution monitoring to guide critical load policy for mycorrhizal fungi in heathlands and grasslands.

Designing a survey to monitor multi-scale impacts of agri-environment schemes on mobile taxa.

Agri-environment schemes (AES) are key mechanisms to deliver conservation policy, and include management to provide resources for target taxa. Mobile species may move to areas where resources are increased, without this necessarily having an effect across the wider countryside or on populations over time. Most assessments of AES efficacy have been at small spatial scales, over short timescales, and shown varying results. We developed a survey design based on orthogonal gradients of AES management at local and landscape scales, which will enable the response of several taxa to be monitored. An evidence review of management effects on butterflies, birds and pollinating insects provided data to score AES options. Predicted gradients were calculated using AES uptake, weighted by the evidence scores. Predicted AES gradients for each taxon correlated strongly, and with the average gradient across taxa, supporting the co-location of surveys across different taxa. Nine 1 × 1 km survey squares were selected in each of four regional blocks with broadly homogenous background habitat characteristics. Squares in each block covered orthogonal contrasts across the range of AES gradients at local and landscape scales. This allows the effects of AES on species at each scale, and the interaction between scales, to be tested. AES options and broad habitats were mapped in field surveys, to verify predicted gradients which were based on AES option uptake data. The verified AES gradient had a strong positive relationship with the predicted gradient. AES gradients were broadly independent of background habitat within each block, likely allowing AES effects to be distinguished from potential effects of other habitat variables. Surveys of several mobile taxa are ongoing. This design will allow mobile taxa responses to AES to be tested in the surrounding countryside, as well as on land under AES management, and potentially in terms of population change over time. The design developed here provides a novel, pseudo-experimental approach for assessing the response of mobile species to gradients of management at two spatial scales. A similar design process could be applied in other regions that require a standardized approach to monitoring the impacts of management interventions on target taxa at landscape scales, if equivalent spatial data are available.

High fat diet causes distinct aberrations in the testicular proteome.

Diet has important effects on normal physiology and the potential deleterious effects of high fat diets and obesity on male reproductive health are being increasingly described. We conducted a histological review of the effects of chronic high fat (HF) diet (using a mouse model fed a 45% fat diet for 21 weeks) with a discovery proteomic study to assess for changes in the abundance of proteins in the testis. Mice on a HF diet became obese and developed glucose intolerance. Using mass spectrometry, we identify 102 proteins affected in the testis of obese mice. These included structural proteins important for the blood testis barrier (filamin A, FLNA), proteins involved in oxidative stress responses (spermatogenesis associated 20, SPATA-20) and lipid homoeostasis (sterol regulatory element-binding protein 2, SREBP2 and apolipoprotein A1, APOA1). In addition, an important regulator protein paraspeckle component 1, PSPC-1, which interacts with the androgen receptor was significantly downregulated. Proteomic data was validated using both Western blotting and immunostaining which confirmed and localised protein expression in both mouse and human testis using biopsy specimens. This study focused mainly on the abnormalities that occurred at the protein level and as a result, we have identified several candidate proteins and conducted pathway analysis around the effects of HF diet on the testis providing novel insights not previously described. Some of the identified targets could be targeted therapeutically and future work is directed in this area.

Pregnancy outcomes in women with primary biliary cholangitis and primary sclerosing cholangitis: a retrospective cohort study.

OBJECTIVE: To determine maternal, obstetric and neonatal outcomes in a cohort of women with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). DESIGN: Retrospective cohort study. SETTING: Ten specialist centres managing pregnant women with liver disease. POPULATION: Women with a diagnosis of PBC and PSC and a pregnancy of ≥20 completed weeks of gestation. METHODS: Retrospective case notes review. MAIN OUTCOME MEASURES: Adverse outcomes were defined as: maternal - development of ascites, variceal bleeding, encephalopathy and jaundice; obstetric events - gestational hypertension, pre-eclampsia and postpartum haemorrhage; and neonatal - stillbirth, preterm delivery and admission to neonatal unit. The relationship of alanine transferase (ALT) and bile acid levels with gestation at delivery was studied. RESULTS: The first recorded pregnancies of 34 women with PSC and 27 women with PBC were analysed. There were 60 live births and one intrapartum stillbirth that did not occur in the context of maternal cholestasis. The overall median gestation of delivery was 38 weeks but the rate of preterm birth was 28% (17/61 deliveries), 76% (13/17) of which were spontaneous. Gestation at birth negatively correlated with maternal serum ALT concentration at booking (P = 0.017) and serum bile acid concentration during pregnancy (P = 0.016). There were no other significant correlations and maternal and neonatal outcomes were good. CONCLUSIONS: Pregnancy in PBC and PSC is well tolerated, but women should be counselled regarding the increased risk of preterm birth. Measurement of maternal ALT and bile acids may help identify women at risk of preterm delivery. TWEETABLE ABSTRACT: Pregnancy in women with PBC and PSC is well tolerated; however, rates of preterm birth are high and are related to maternal bile acid levels.

The effect of orthopaedic surgeons' and interventional radiologists' availability on the priority treatment sequence for hemodynamically unstable pelvic fractures: a survey of US Level I trauma centers.

BACKGROUND: Most guidelines recommend both pelvic packing (PP) and angioembolization for hemodynamically unstable pelvic fractures, however their sequence varies. Some argue to use PP first because orthopaedic surgeons are more available than interventional radiologists; however, there is no data confirming this. METHODS: This cross-sectional survey of 158 trauma medical directors at US Level I trauma centers collected the availability of orthopaedic surgeons and interventional radiologists, the number of orthopaedic trauma surgeons trained to manage pelvic fractures, and priority treatment sequence for hemodynamically unstable pelvic fractures. The study objective was to compare the availability of orthopaedic surgeons to interventional radiologists and describe how the availability of orthopaedic surgeons and interventional radiologists affects the treatment sequence for hemodynamically unstable pelvic fractures. Fisher's exact, chi-squared, and Kruskal-Wallis tests were used, alpha = 0.05. RESULTS: The response rate was 25% (40/158). Orthopaedic surgeons (86%) were on-site more often than interventional radiologists (54%), p = 0.003. Orthopaedic surgeons were faster to arrive 39% of the time, and interventional radiologists were faster to arrive 6% of the time. There was a higher proportion of participants who prioritized PP before angioembolization at centers with above the average number (> 3) of orthopaedic trauma surgeons trained to manage pelvic fractures, as among centers with equal to or below average, p = 0.02. Arrival times for orthopaedic surgeons did not significantly predict prioritization of angioembolization or PP. CONCLUSIONS: Our results provide evidence that orthopaedic surgeons typically are more available than interventional radiologists but contrary to anecdotal evidence most participants used angioembolization first. Familiarity with the availability of orthopaedic surgeons and interventional radiologists may contribute to individual trauma center's treatment sequence.

Willingness to pay for policies to reduce future deaths from climate change: evidence from a British survey.

OBJECTIVES: Without urgent action, climate change will put the health of future populations at risk. Policies to reduce these risks require support from today's populations; however, there are few studies assessing public support for such policies. Willingness to pay (WtP), a measure of the maximum a person is prepared to pay for a defined benefit, is widely used to assess public support for policies. We used WtP to investigate whether there is public support to reduce future health risks from climate change and if individual and contextual factors affect WtP, including perceptions of the seriousness of the impacts of climate change. STUDY DESIGN: A cross-sectional British survey. METHODS: Questions about people's WtP for policies to reduce future climate change-related deaths and their perceptions of the seriousness of climate change impacts were included in a British survey of adults aged 16 years and over (n=1859). We used contingent valuation, a survey-based method for eliciting WtP for outcomes like health which do not have a direct market value. RESULTS: The majority (61%) were willing to pay to reduce future increases in climate change-related deaths in Britain. Those regarding climate change impacts as not at all serious were less willing to pay than those regarding the impacts as extremely serious (OR 0.04, 95% CI 0.02-0.09). Income was also related to WtP; the highest-income group were twice as likely to be willing to pay as the lowest-income group (OR 2.14, 95% CI 1.40-3.29). CONCLUSIONS: There was public support for policies to address future health impacts of climate change; the level of support varied with people's perceptions of the seriousness of these impacts and their financial circumstances. Our study adds to evidence that health, including the health of future populations, is an outcome that people value and suggests that framing climate change around such values may help to accelerate action.

Determination of the median effective dose of propofol in combination with different doses of ketamine during gastro-duodenoscopy in children: a randomised controlled trial.

BACKGROUND: Propofol is used to induce deep sedation or general anaesthesia for procedures in children. Adjuvants, such as ketamine, are routinely added to reduce the dose of propofol required and propofol-related adverse events. We conducted a randomised controlled trial to determine the effective bolus dose of propofol in combination with ketamine that induces adequate depth of anaesthesia in 50% of children (ED50) undergoing gastro-duodenoscopy. METHODS: Children were randomised to one of four doses of ketamine: 0 (control), 0.25, 0.5, and 1 mg kg-1, followed by a dose of propofol according to Dixon's up-and-down methodology. Excessive movement, coughing, gagging, or airway obstruction that prevented endoscope insertion was considered a failure. RESULTS: The ED50 of propofol (median, 95% CI) was greater in the ketamine 0, 0.25, and 0.5 mg kg-1 groups compared with the ketamine 1 mg kg-1 group (6.1, 4.1-8.1; 4.5, 2.9-6; 4.7, 3.1-6.2 mg kg-1vs 1.1, 0.5-1.8 mg kg-1, respectively, P<0.008). Total dose of propofol administered during the procedure was reduced with ketamine 1 mg kg-1. The mean arterial pressure was lower in the ketamine 0 mg kg-1 group compared with the 1 mg kg-1 group during and immediately after the procedure. The ketamine 1 mg kg-1 group experienced a higher incidence of nausea and visual disturbances. CONCLUSIONS: Ketamine at 0.5-1 mg kg-1 reduces the dose of propofol required to provide general anaesthesia for gastro-duodenoscopy in children and may reduce the incidence of propofol-related changes in haemodynamics. CLINICAL TRIAL REGISTRATION: NCT 02295553.

Patient perceptions of clear/almost clear skin in moderate-to-severe plaque psoriasis: results of the Clear About Psoriasis worldwide survey.

BACKGROUND: Therapeutic advances have made the achievement of clear/almost clear skin possible for many patients with moderate-to-severe plaque psoriasis. OBJECTIVE: To determine patient perceptions of the impact of psoriasis and of attaining clear/almost clear skin. METHODS: Global survey of patients with moderate-to-severe psoriasis. RESULTS: A total of 8338 patients from 31 countries participated. The majority (57%) had not achieved self-assessed clear/almost clear skin with their current therapy, and 56% of those who had not met this goal believed it would be impossible to do so. Among the patients who had clear/almost clear skin, 73% had not initiated their current treatment until >1 year after psoriasis diagnosis, and 28% had to wait >5 years. Eighty-four percent of all respondents experienced discrimination and/or humiliation due to psoriasis, and many reported negative effects on work, intimate relationships, sleep and mental health. Patients without clear/almost clear skin reported that such achievement would open new possibilities, such as swimming (58%), a wider choice of clothing (40%), and meeting new people (26%). A limitation of this study, as with any survey-based research, is that selection and recall bias may have been present. Additionally, respondent definitions of clear/almost clear skin were subjective and may have varied. CONCLUSION: Despite the importance of clear/almost clear skin to psoriasis patients, most are still not achieving it, and many are unaware it is possible.

Exploring knowledge, attitudes and experience of genitourinary symptoms in women with early breast cancer on adjuvant endocrine therapy.

Clinical trials of adjuvant endocrine therapy in women with early breast cancer have consistently reported that genitourinary symptoms are common. However, little is known about women's experiences of genitourinary symptoms, their views about the symptoms and how they impact on their lives. The aim of this study was to explore knowledge, attitudes and experiences of genitourinary symptoms among women receiving adjuvant endocrine therapy for early breast cancer. Thirty-two semi-structured interviews were conducted and subjected to a rigorous qualitative analysis. Genitourinary symptoms were commonly reported to negatively impact on personal, social and physical activities, were often attributed to anxiety and stress and were a source of embarrassment. Women also commented on the limited information available or provided regarding the potential genitourinary adverse effects of adjuvant endocrine therapy. There was a general lack of awareness that their symptoms could be associated with or exacerbated by adjuvant endocrine therapy. Women indicated a preference to receive information and advice about potential management options from either their general practitioner or specialist. These findings underscore the importance of improving communication and increasing awareness among both clinicians and patients about the potential impact of adjuvant endocrine therapy on genitourinary symptoms.

Maintaining social care provision in the context of financial austerity.

There is significant national interest in tackling issues surrounding the needs of vulnerable children and adults. At the same time, UK cities are under significant financial strain, as local government financial settlements (the distribution of central government resources) decrease in real terms and yet urban populations, which draw on local government services, continue to grow. This study focusses on the city of Birmingham, the UK's largest and most populous city outside of London. In a data-led study, using data derived from personal social care records, we analyse the management and delivery of social care services by Birmingham City Council, which itself is the largest local authority in Europe. This research employs state-of-the-art data analytic techniques to analyse six years of Birmingham City Council social care data, to identify: (i) Service cost profiles over time; (ii) Geographic dimensions to service demand and delivery; (iii) Patterns in the provision of services, which may assist with future service planning and provision and (iv) The extent to which data value and data protection interact. In response to recent fiscal challenges, Birmingham City Council is expected to make savings of £815 million over the 9-year period 2011/12 to 2019/20. Delivering savings of this scale, whilst protecting and safeguarding the most vulnerable citizens within a growing urban population, is one of the biggest challenges facing the UK's second largest city.

Comparison of the National Early Warning Score in non-elective medical and surgical patients.

BACKGROUND: The National Early Warning Score (NEWS) is used to identify deteriorating patients in hospital. NEWS is a better discriminator of outcomes than other early warning scores in acute medical admissions, but it has not been evaluated in a surgical population. The study aims were to evaluate the ability of NEWS to discriminate cardiac arrest, death and unanticipated ICU admission in patients admitted to surgical specialties, and to compare the performance of NEWS in admissions to medical and surgical specialties. METHODS: Hospitalwide data over 31 months, from adult inpatients who stayed at least one night or died on the day of admission, were analysed. The data were categorized as elective or non-elective surgical or medical admissions. The ability of NEWS to discriminate the outcomes above in these different groups was assessed using the area under the receiver operating characteristic curve (AUROC). RESULTS: There were too few outcomes to permit meaningful comparison of elective admissions, so the analysis was constrained to comparison of non-elective admissions. NEWS performed equally well, or better, for surgical as for medical patients. For death within 24 h the AUROC for surgical admissions was 0·914 (95 per cent c.i. 0·907 to 0·922), compared with 0·902 (0·898 to 0·905) for medical admissions. For the combined outcome of any of death, cardiac arrest or unanticipated ICU admission, the AUROC was 0·874 (0·868 to 0·880) for surgical admissions and 0·874 (0·871 to 0·877) for medical admissions. CONCLUSION: NEWS discriminated deterioration in non-elective surgical patients at least as well as in non-elective medical patients.

Single cell active force generation under dynamic loading - Part I: AFM experiments.

A novel series of experiments are performed on single cells using a bespoke AFM system where the response of cells to dynamic loading at physiologically relevant frequencies is uncovered. Measured forces for the untreated cells are dramatically different to cytochalasin-D (cyto-D) treated cells, indicating that the contractile actin cytoskeleton plays a critical role in the response of cells to dynamic loading. Following a change in applied strain magnitude, while maintaining a constant applied strain rate, the compression force for contractile cells recovers to 88.9±7.8% of the steady state force. In contrast, cyto-D cell compression forces recover to only 38.0±6.7% of the steady state force. Additionally, untreated cells exhibit strongly negative (pulling) forces during unloading half-cycles when the probe is retracted. In comparison, negligible pulling forces are measured for cyto-D cells during probe retraction. The current study demonstrates that active contractile forces, generated by actin-myosin cross-bridge cycling, dominate the response of single cells to dynamic loading. Such active force generation is shown to be independent of applied strain magnitude. Passive forces generated by the applied deformation are shown to be of secondary importance, exhibiting a high dependence on applied strain magnitude, in contrast to the active forces in untreated cells. STATEMENT OF SIGNIFICANCE: A novel series of experiments are performed on single cells using a bespoke AFM system where the response of cells to dynamic loading at physiologically relevant frequencies is uncovered. Contractile cells, which contain the active force generation machinery of the actin cytoskeleton, are shown to be insensitive to applied strain magnitude, exhibiting high resistance to dynamic compression and stretching. Such trends are not observed for cells in which the actin cytoskeleton has been chemically disrupted. These biomechanical insights have not been previously reported. This detailed characterisation of single cell active and passive stress during dynamic loading has important implications for tissue engineering strategies, where applied deformation has been reported to significantly affect cell mechanotransduction and matrix synthesis.

Measuring the mechanical properties of molecular conformers.

Scanning probe-actuated single molecule manipulation has proven to be an exceptionally powerful tool for the systematic atomic-scale interrogation of molecular adsorbates. To date, however, the extent to which molecular conformation affects the force required to push or pull a single molecule has not been explored. Here we probe the mechanochemical response of two tetra(4-bromophenyl)porphyrin conformers using non-contact atomic force microscopy where we find a large difference between the lateral forces required for manipulation. Remarkably, despite sharing very similar adsorption characteristics, variations in the potential energy surface are capable of prohibiting probe-induced positioning of one conformer, while simultaneously permitting manipulation of the alternative conformational form. Our results are interpreted in the context of dispersion-corrected density functional theory calculations which reveal significant differences in the diffusion barriers for each conformer. These results demonstrate that conformational variation significantly modifies the mechanical response of even simple porpyhrins, potentially affecting many other flexible molecules.

Changes in gait which occur before and during the adolescent growth spurt in children treated by selective dorsal rhizotomy.

This paper presents long term follow up results from 17 children (6 girls, 11 boys, GMFCS levels II-IV), treated by means of selective dorsal rhizotomy (SDR). The particular focus is on the effect of the adolescent growth spurt on patients who had previously undergone SDR. The children were all assessed using 3D gait analysis, in combination with clinical examination at three time points-before SDR surgery (PRE), after SDR surgery when pre-adolescent (POST1) and post-adolescence (POST2). The total follow up period to POST2 was 8 years 6 months for girls and 9 years 5 months for boys. All children maintained or improved their GMFCS level. Positive changes in ranges of motion and gait were observed at POST1 and these were generally maintained over adolescence to POST2. The mean Gait Profile Score (GPS) had improved by 3.2 points (14.7-11.5) at POST1, with a non-significant deterioration of 0.3 over the adolescent growth spurt. These positive results reflect the total package of care for the children, involving careful pre-operative selection by a multidisciplinary team and post-operative management including intensive physiotherapy and maintenance in tuned ankle foot orthoses. Fifty-nine per cent of children had some additional orthopaedic surgery, mostly bony procedures. The overall benefits arising from their management need to be considered in the light of the likely deterioration experienced by this patient group. The results of this study support the use of SDR as part of a management strategy for carefully selected children with cerebral palsy with the aim of optimizing gait at skeletal maturity.

Simulated structure and imaging of NTCDI on Si(1 1 1)-7 × 7 : a combined STM, NC-AFM and DFT study.

The adsorption of naphthalene tetracarboxylic diimide (NTCDI) on Si(1 1 1)-7 × 7 is investigated through a combination of scanning tunnelling microscopy (STM), noncontact atomic force microscopy (NC-AFM) and density functional theory (DFT) calculations. We show that NTCDI adopts multiple planar adsorption geometries on the Si(1 1 1)-7 × 7 surface which can be imaged with intramolecular bond resolution using NC-AFM. DFT calculations reveal adsorption is dominated by covalent bond formation between the molecular oxygen atoms and the surface silicon adatoms. The chemisorption of the molecule is found to induce subtle distortions to the molecular structure, which are observed in NC-AFM images.