Effects of acute and chronic interval sprint exercise performed on a manually propelled treadmill on upper limb vascular mechanics in healthy young men

© 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society. Interval sprint exercise performed on a manually propelled treadmill, where the hands grip the handle bars, engages lower and upper limb skeletal muscle, but little is known regarding the effects of this exercise modality on the upper limb vasculature. We tested the hypotheses that an acute bout of sprint exercise and 6 weeks of training induces brachial artery (BA) and forearm vascular remodeling, favoring a more compliant system. Before and following a single bout of exercise as well as 6 weeks of training three types of vascular properties/methodologies were examined in healthy men: (1) stiffness of the entire upper limb vascular system (pulse wave velocity (PWV); (2) local stiffness of the BA; and (3) properties of the entire forearm vascular bed (determined by a modified lumped parameter Windkessel model). Following sprint exercise, PWV declined (P \u3c 0.01), indices of BA stiffness did not change (P ≥ 0.10), and forearm vascular bed compliance increased and inertance and viscoelasticity decreased (P ≤ 0.03). Following manually propelled treadmill training, PWV remained unchanged (P = 0.31), indices of BA stiffness increased (P ≤ 0.05) and forearm vascular bed viscoelasticity declined (P = 0.02), but resistance, compliance, and inertance remained unchanged (P ≥ 0.10) compared with pretraining values. Sprint exercise induced a more compliant forearm vascular bed, without altering indices of BA stiffness. These effects were transient, as following training the forearm vascular bed was not more compliant and indices of BA stiffness increased. On the basis of these data, we conclude that adaptations to acute and chronic sprint exercise on a manually propelled treadmill are not uniform along the arterial tree in upper limb

Metabolic Imaging Detects Low Levels of Glycolytic Activity That Vary with Levels of c-Myc Expression in Patient-Derived Xenograft Models of Glioblastoma.

13C MRI of hyperpolarized [1-13C]pyruvate metabolism has been used in oncology to detect disease, investigate disease progression, and monitor response to treatment with a view to guiding treatment in individual patients. This technique has translated to the clinic with initial studies in prostate cancer. Here, we use the technique to investigate its potential uses in patients with glioblastoma (GB). We assessed the metabolism of hyperpolarized [1-13C]pyruvate in an orthotopically implanted cell line model (U87) of GB and in patient-derived tumors, where these were produced by orthotopic implantation of cells derived from different patients. Lactate labeling was higher in the U87 tumor when compared with patient-derived tumors, which displayed intertumoral heterogeneity, reflecting the intra- and intertumoral heterogeneity in the patients' tumors from which they were derived. Labeling in some patient-derived tumors could be observed before their appearance in morphologic images, whereas in other tumors it was not significantly greater than the surrounding brain. Increased lactate labeling in tumors correlated with c-Myc-driven expression of hexokinase 2, lactate dehydrogenase A, and the monocarboxylate transporters and was accompanied by increased radioresistance. Because c-Myc expression correlates with glioma grade, this study demonstrates that imaging with hyperpolarized [1-13C]pyruvate could be used clinically with patients with GB to determine disease prognosis, to detect early responses to drugs that modulate c-Myc expression, and to select tumors, and regions of tumors for increased radiotherapy dose.Significance: Metabolic imaging with hyperpolarized [1-13C]pyruvate detects low levels of c-Myc-driven glycolysis in patient-derived glioblastoma models, which, when translated to the clinic, could be used to detect occult disease, determine disease prognosis, and target radiotherapy. Cancer Res; 78(18); 5408-18. ©2018 AACR.The work was supported by a Cancer Research UK Programme grant (17242) and by the CRUK-EPSRC Imaging Centre in Cambridge and Manchester (16465) awarded to K. M. Brindle. F. Kreis was supported by a Marie Curie ITN studentship (EUROPOL) and R. Mair by Addenbrooke's Charitable Trust and a CRUK Cambridge Centre Fellowship

Personalised Prescription of Scalable High Intensity Interval Training to Inactive Female Adults of Different Ages

Stepping is a convenient form of scalable high-intensity interval training (HIIT) that may lead to health benefits. However, the accurate personalised prescription of stepping is hampered by a lack of evidence on optimal stepping cadences and step heights for various populations. This study examined the acute physiological responses to stepping exercise at various heights and cadences in young (n = 14) and middle-aged (n = 14) females in order to develop an equation that facilitates prescription of stepping at targeted intensities. Participants completed a step test protocol consisting of randomised three-minute bouts at different step cadences (80, 90, 100, 110 steps·min-1) and step heights (17, 25, 30, 34 cm). Aerobic demand and heart rate values were measured throughout. Resting metabolic rate was measured in order to develop female specific metabolic equivalents (METs) for stepping. Results revealed significant differences between age groups for METs and heart rate reserve, and within-group differences for METs, heart rate, and metabolic cost, at different step heights and cadences. At a given step height and cadence, middle-aged females were required to work at an intensity on average 1.9 ± 0.26 METs greater than the younger females. A prescriptive equation was developed to assess energy cost in METs using multilevel regression analysis with factors of step height, step cadence and age. Considering recent evidence supporting accumulated bouts of HIIT exercise for health benefits, this equation, which allows HIIT to be personally prescribed to inactive and sedentary women, has potential impact as a public health exercise prescription tool

Molecular genetics and comparative genomics reveal RNAi is not functional in malaria parasites

Techniques for targeted genetic disruption in Plasmodium, the causative agent of malaria, are currently intractable for those genes that are essential for blood stage development. The ability to use RNA interference (RNAi) to silence gene expression would provide a powerful means to gain valuable insight into the pathogenic blood stages but its functionality in Plasmodium remains controversial. Here we have used various RNA-based gene silencing approaches to test the utility of RNAi in malaria parasites and have undertaken an extensive comparative genomics search using profile hidden Markov models to clarify whether RNAi machinery exists in malaria. These investigative approaches revealed that Plasmodium lacks the enzymology required for RNAi-based ablation of gene expression and indeed no experimental evidence for RNAi was observed. In its absence, the most likely explanations for previously reported RNAi-mediated knockdown are either the general toxicity of introduced RNA (with global down-regulation of gene expression) or a specific antisense effect mechanistically distinct from RNAi, which will need systematic analysis if it is to be of use as a molecular genetic tool for malaria parasites

Knowledge Management for Policy: Stocktaking of one year of JRC activities

Improving knowledge management and collaborative working is a priority for overcoming silos mentalities and connecting synergies between portfolios, as envisaged in the Commission Communication C(2016)6626. In its 2030 Strategy, the JRC took up this challenge by 1) introducing a horizontal ‘knowledge management’ layer in the organigram, to mobilise scientific competences from different Directorates around the Commission’s policy goals 2) championing the implementation of new collaboration practices and platforms as well as the development of a knowledge management professionalisation programme; 3) starting to transform itself from a traditional research-producing organisation into a world-leading manager of knowledge for EU policy-making. One year after the reorganisation carried out on the 1st of July 2016 to align the JRC organigram with the new strategy, this report reviews the progress made and describes the main achievements.JRC.H-Knowledge Management (Ispra

Improved Calibration Functions of Three Capacitance Probes for the Measurement of Soil Moisture in Tropical Soils

Single capacitance sensors are sensitive to soil property variability. The objectives of this study were to: (i) establish site-specific laboratory calibration equations of three single capacitance sensors (EC-20, EC-10, and ML2x) for tropical soils, and (ii) evaluate the accuracy and precision of these sensors. Intact soil cores and bulk samples, collected from the top 20 and 80 cm soil depths at five locations across the Upper Mākaha Valley watershed, were analyzed to determine their soil bulk density (ρb), total porosity (θt), particle size distribution, and electrical conductivity (EC). Laboratory calibration equations were established using soil packed columns at six water content levels (0–0.5 cm3 cm−3). Soil bulk density and θt significantly varied with sampling depths; whereas, soil clay content (CC) and EC varied with sampling locations. Variations of ρb and θt at the two depths significantly affected the EC-20 and ML2x laboratory calibration functions; however, there was no effect of these properties on calibration equation functions of EC-10. There was no significant effect of sampling locations on the laboratory calibration functions suggesting watershed-specific equations for EC-20 and ML2x for the two depths; a single watershed-specific equation was needed for EC-10 for both sampling depths. The laboratory calibration equations for all sensors were more accurate than the corresponding default equations. ML2x exhibited better precision than EC-10, followed by EC-20. We conclude that the laboratory calibration equations can mitigate the effects of varying soil properties and improve the sensors’ accuracy for water content measurements

A Century of Drought in Hawaiʻi: Geospatial Analysis and Synthesis across Hydrological, Ecological, and Socioeconomic Scales

Drought is a prominent feature of Hawaiʻi’s climate. However, it has been over 30 years since the last comprehensive meteorological drought analysis, and recent drying trends have emphasized the need to better understand drought dynamics and multi-sector effects in Hawaiʻi. Here, we provide a comprehensive synthesis of past drought effects in Hawaiʻi that we integrate with geospatial analysis of drought characteristics using a newly developed 100-year (1920–2019) gridded Standardized Precipitation Index (SPI) dataset. The synthesis examines past droughts classified into five categories: Meteorological, agricultural, hydrological, ecological, and socioeconomic drought. Results show that drought duration and magnitude have increased significantly, consistent with trends found in other Pacific Islands. We found that most droughts were associated with El Niño events, and the two worst droughts of the past century were multi-year events occurring in 1998–2002 and 2007–2014. The former event was most severe on the islands of O’ahu and Kaua’i while the latter event was most severe on Hawaiʻi Island. Within islands, we found different spatial patterns depending on leeward versus windward contrasts. Droughts have resulted in over $80 million in agricultural relief since 1996 and have increased wildfire risk, especially during El Niño years. In addition to providing the historical context needed to better understand future drought projections and to develop effective policies and management strategies to protect natural, cultural, hydrological, and agricultural resources, this work provides a framework for conducting drought analyses in other tropical island systems, especially those with a complex topography and strong climatic gradients

Management of antipsychotics in primary care: Insights from healthcare professionals and policy makers in the United Kingdom

Introduction Antipsychotic medication is increasingly prescribed to patients with serious mental illness. Patients with serious mental illness often have cardiovascular and metabolic comorbidities, and antipsychotics independently increase the risk of cardiometabolic disease. Despite this, many patients prescribed antipsychotics are discharged to primary care without planned psychiatric review. We explore perceptions of healthcare professionals and managers/directors of policy regarding reasons for increasing prevalence and management of antipsychotics in primary care. Methods Qualitative study using semi-structured interviews with 11 general practitioners (GPs), 8 psychiatrists, and 11 managers/directors of policy in the United Kingdom. Data was analysed using thematic analysis. Results Respondents reported competency gaps that impaired ability to manage patients prescribed antipsychotic medications, arising from inadequate postgraduate training and professional development. GPs lacked confidence to manage antipsychotic medications alone; psychiatrists lacked skills to address cardiometabolic risks and did not perceive this as their role. Communication barriers, lack of integrated care records, limited psychology provision, lowered expectation towards patients with serious mental illness by professionals, and pressure to discharge from hospital resulted in patients in primary care becoming ‘trapped’ on antipsychotics, inhibiting opportunities to deprescribe. Organisational and contractual barriers between services exacerbate this risk, with socioeconomic deprivation and lack of access to non-pharmacological interventions driving overprescribing. Professionals voiced fears of censure if a catastrophic event occurred after stopping an antipsychotic. Facilitators to overcome these barriers were suggested. Conclusions People prescribed antipsychotics experience a fragmented health system and suboptimal care. Several interventions could be taken to improve care for this population, but inadequate availability of non-pharmacological interventions and socioeconomic factors increasing mental distress need policy change to improve outcomes. The role of professionals’ fear of medicolegal or regulatory censure inhibiting antipsychotic deprescribing was a new finding in this study

Prehospital transdermal glyceryl trinitrate in patients with ultra-acute presumed stroke (RIGHT-2): an ambulance-based, randomised, sham-controlled, blinded, phase 3 trial

Background: High blood pressure is common in acute stroke and is a predictor of poor outcome; however, large trials of lowering blood pressure have given variable results, and the management of high blood pressure in ultra-acute stroke remains unclear. We investigated whether transdermal glyceryl trinitrate (GTN; also known as nitroglycerin), a nitric oxide donor, might improve outcome when administered very early after stroke onset. Methods: We did a multicentre, paramedic-delivered, ambulance-based, prospective, randomised, sham-controlled, blinded-endpoint, phase 3 trial in adults with presumed stroke within 4 h of onset, face-arm-speech-time score of 2 or 3, and systolic blood pressure 120 mm Hg or higher. Participants were randomly assigned (1:1) to receive transdermal GTN (5 mg once daily for 4 days; the GTN group) or a similar sham dressing (the sham group) in UK-based ambulances by paramedics, with treatment continued in hospital. Paramedics were unmasked to treatment, whereas participants were masked. The primary outcome was the 7-level modified Rankin Scale (mRS; a measure of functional outcome) at 90 days, assessed by central telephone follow-up with masking to treatment. Analysis was hierarchical, first in participants with a confirmed stroke or transient ischaemic attack (cohort 1), and then in all participants who were randomly assigned (intention to treat, cohort 2) according to the statistical analysis plan. This trial is registered with ISRCTN, number ISRCTN26986053. Findings: Between Oct 22, 2015, and May 23, 2018, 516 paramedics from eight UK ambulance services recruited 1149 participants (n=568 in the GTN group, n=581 in the sham group). The median time to randomisation was 71 min (IQR 45–116). 597 (52%) patients had ischaemic stroke, 145 (13%) had intracerebral haemorrhage, 109 (9%) had transient ischaemic attack, and 297 (26%) had a non-stroke mimic at the final diagnosis of the index event. In the GTN group, participants' systolic blood pressure was lowered by 5·8 mm Hg compared with the sham group (p<0·0001), and diastolic blood pressure was lowered by 2·6 mm Hg (p=0·0026) at hospital admission. We found no difference in mRS between the groups in participants with a final diagnosis of stroke or transient ischaemic stroke (cohort 1): 3 (IQR 2–5; n=420) in the GTN group versus 3 (2–5; n=408) in the sham group, adjusted common odds ratio for poor outcome 1·25 (95% CI 0·97–1·60; p=0·083); we also found no difference in mRS between all patients (cohort 2: 3 [2–5]; n=544, in the GTN group vs 3 [2–5]; n=558, in the sham group; 1·04 [0·84–1·29]; p=0·69). We found no difference in secondary outcomes, death (treatment-related deaths: 36 in the GTN group vs 23 in the sham group [p=0·091]), or serious adverse events (188 in the GTN group vs 170 in the sham group [p=0·16]) between treatment groups. Interpretation: Prehospital treatment with transdermal GTN does not seem to improve functional outcome in patients with presumed stroke. It is feasible for UK paramedics to obtain consent and treat patients with stroke in the ultra-acute prehospital setting