The range of potential applications of compact laser-plasma ion sources motivates the development of new acceleration schemes to increase achievable ion energies and conversion efficiencies. Whilst ...the evolving nature of laser-plasma interactions can limit the effectiveness of individual acceleration mechanisms, it can also enable the development of hybrid schemes, allowing additional degrees of control on the properties of the resulting ion beam. Here we report on an experimental demonstration of efficient proton acceleration to energies exceeding 94 MeV via a hybrid scheme of radiation pressure-sheath acceleration in an ultrathin foil irradiated by a linearly polarised laser pulse. This occurs via a double-peaked electrostatic field structure, which, at an optimum foil thickness, is significantly enhanced by relativistic transparency and an associated jet of super-thermal electrons. The range of parameters over which this hybrid scenario occurs is discussed and implications for ion acceleration driven by next-generation, multi-petawatt laser facilities are explored.
Magnetic resonance imaging (MRI) is a widely used method for non-invasive study of the structure and function of the human brain. Increasing magnetic field strengths enable higher resolution imaging; ...however, long scan times and high motion sensitivity mean that image quality is often limited by the involuntary motion of the subject. Prospective motion correction is a technique that addresses this problem by tracking head motion and continuously updating the imaging pulse sequence, locking the imaging volume position and orientation relative to the moving brain. The accuracy and precision of current MR-compatible tracking systems and navigator methods allows the quantification and correction of large-scale motion, but not the correction of very small involuntary movements in six degrees of freedom. In this work, we present an MR-compatible tracking system comprising a single camera and a single 15 mm marker that provides tracking precision in the order of 10 m and 0.01 degrees. We show preliminary results, which indicate that when used for prospective motion correction, the system enables improvement in image quality at both 3 T and 7 T, even in experienced and cooperative subjects trained to remain motionless during imaging. We also report direct observation and quantification of the mechanical ballistocardiogram (BCG) during simultaneous MR imaging. This is particularly apparent in the head-feet direction, with a peak-to-peak displacement of 140 m.
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Photometric surveys such as Kepler have the precision to identify exoplanet and eclipsing binary candidates from only a single transit. K2, with its 75 d campaign duration, is ideally suited to ...detect significant numbers of single-eclipsing objects. Here we develop a Bayesian transit-fitting tool (‘Namaste: An Mcmc Analysis of Single Transit Exoplanets’) to extract orbital information from single transit events. We achieve favourable results testing this technique on known Kepler planets, and apply the technique to seven candidates identified from a targeted search of K2 campaigns 1, 2 and 3. We find EPIC203311200 to host an excellent exoplanet candidate with a period, assuming zero eccentricity, of
$540 ^{+410}_{-230}$
d and a radius of 0.51 ± 0.05R
Jup. We also find six further transit candidates for which more follow-up is required to determine a planetary origin. Such a technique could be used in the future with TESS, PLATO and ground-based photometric surveys such as NGTS, potentially allowing the detection of planets in reach of confirmation by Gaia.
The t(10;11)(p12;q23) translocation and the t(10;11)(p12;q14) translocation, which encode the MLL (mixed lineage leukemia)-AF10 and CALM (clathrin assembly lymphoid myeloid leukemia)-AF10 fusion ...oncoproteins, respectively, are two recurrent chromosomal rearrangements observed in patients with acute myeloid leukemia and acute lymphoblastic leukemia. Here, we demonstrate that MLL-AF10 and CALM-AF10-mediated transformation is dependent on the H3K79 methyltransferase Dot1l using genetic and pharmacological approaches in mouse models. Targeted disruption of Dot1l using a conditional knockout mouse model abolished in vitro transformation of murine bone marrow cells and in vivo initiation and maintenance of MLL-AF10 or CALM-AF10 leukemia. The treatment of MLL-AF10 and CALM-AF10 transformed cells with EPZ004777, a specific small-molecule inhibitor of Dot1l, suppressed expression of leukemogenic genes such as Hoxa cluster genes and Meis1, and selectively impaired proliferation of MLL-AF10 and CALM-AF10 transformed cells. Pretreatment with EPZ004777 profoundly decreased the in vivo spleen-colony-forming ability of MLL-AF10 or CALM-AF10 transformed bone marrow cells. These results show that patients with leukemia-bearing chromosomal translocations that involve the AF10 gene may benefit from small-molecule therapeutics that inhibit H3K79 methylation.
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The aim of this study was to develop a measure of the impact of pulmonary hypertension (PH) on health-related quality of life (HRQoL) as there is a need for a short, validated instrument that can be ...used in routine clinical practice. Interviews were conducted with 30 PH patients to derive 32 statements, which were presented as a semantic differential six-point scale (0-5), with contrasting adjectives at each end. This item list was completed by patients attending PH clinics across the UK and Ireland. Rasch analysis was applied to identify items fitting a uni-dimensional model. 226 patients (mean age 55.6±14 years; 70% female) with PH (82% had pulmonary arterial hypertension) completed the study questionnaires. 10 of the 32 items demonstrated fit to the Rasch model (Chi-squared 16; p>0.05) and generated the emPHasis-10 questionnaire. Test-retest (intraclass correlation coefficient 0.95, n=33) and internal consistency (Chronbach's α=0.9) were strong. emPHasis-10 scores correlated consistently with other relevant measures and discriminated subgroups of patients stratified by World Health Organization functional class (ANOVA F=1.73; p<0.001). The emPHasis-10 is a short questionnaire for assessing HRQoL in pulmonary arterial hypertension. It has excellent measurement properties and is sensitive to differences in relevant clinical parameters. It is freely available for clinical and academic use.
PURPOSETo investigate the effects of an exhaustive run on trunk and lower extremity strength and mechanics in patients with and without patellofemoral pain (PFP), we hypothesized that strength would ...decrease and mechanics would change after the exhaustive run.
METHODSNineteen subjects with PFP and 19 controls participated (10 men and 9 women per group). Lower extremity and trunk mechanics during running, body mass–normalized strength, and pain assessments before and after an exhaustive run were quantified. A repeated-measures ANOVA was used to assess group differences and exhaustion-related changes (P < 0.05), with t-test post hoc analyses performed when significant interactions were identified (P < 0.0125).
RESULTSPain significantly increased with the exhaustive run in the PFP group (P = 0.021). Hip strength was reduced after the exhaustive run, more so in those with PFP (abductionbefore = 0.384 ± 0.08, after = 0.314 ± 0.08, P < 0.001; external rotationbefore = 0.113 ± 0.02, after = 0.090 ± 0.02, P < 0.001). Persons with PFP also demonstrated increased knee flexion (before = 41.6° ± 5.5°, after = 46.9° ± 7.5°, P < 0.001), hip flexion (before = 30.4° ± 6.8°, after = 42.5° ± 9.7°, P < 0.001), and anterior pelvic tilt (before = 7.2° ± 5.1°, after = 13.3° ± 6.7°, P = 0.001) after the exhaustive run compared to controls. Trunk flexion increased in both PFP (before = 13.09° ± 6.2°, after = 16.31° ± 5.3°, P < 0.001) and control (before = 1393° ± 4.7°, after = 15.99° ± 5.9°, P < 0.001) groups. Hip extension (before = −2.09 ± 0.49 N·m·kg, after = −2.49 ± 0.54 N·m·kg, P = 0.002) moments increased only in subjects with PFP.
CONCLUSIONSExhaustive running results in reduced hip strength in subjects with PFP; however, this did not result in changes to hip internal rotation or adduction kinematics. Kinematic and kinetic changes after the exhaustive run are more indicative of compensatory changes to reduce pain. Increasing trunk flexion during running might provide pain relief during running; however, reducing anterior pelvic tilt may also warrant attention during treatment.
Aim
There is a requirement of an expansive and up to date review of surgical management of inflammatory bowel disease (IBD) that can dovetail with the medical guidelines produced by the British ...Society of Gastroenterology.
Methods
Surgeons who are members of the ACPGBI with a recognised interest in IBD were invited to contribute various sections of the guidelines. They were directed to produce a procedure based document using literature searches that were systematic, comprehensible, transparent and reproducible. Levels of evidence were graded. An editorial board was convened to ensure consistency of style, presentation and quality. Each author was asked to provide a set of recommendations which were evidence based and unambiguous. These recommendations were submitted to the whole guideline group and scored. They were then refined and submitted to a second vote. Only those that achieved >80% consensus at level 5 (strongly agree) or level 4 (agree) after 2 votes were included in the guidelines.
Results
All aspects of surgical care for IBD have been included along with 157 recommendations for management.
Conclusion
These guidelines provide an up to date and evidence based summary of the current surgical knowledge in the management of IBD and will serve as a useful practical text for clinicians performing this type of surgery.
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Background Currently available selective estrogen receptor modulators reduce the risk of breast cancer, but they are not widely used. In the Postmenopausal Evaluation and Risk-Reduction with ...Lasofoxifene (PEARL) trial, lasofoxifene was shown to reduce the risk of estrogen receptor–positive (ER+) breast cancer, nonvertebral and vertebral fractures, coronary artery disease, and stroke, but the effects on total breast cancer (invasive and ductal carcinoma in situ, ER+ and estrogen receptor–negative ER−) and ER+ invasive breast cancer are unknown. Methods Postmenopausal women (n = 8556) aged 59–80 years with low bone density and normal mammograms were randomly assigned to two doses of lasofoxifene (0.25 and 0.5 mg) or placebo. The primary endpoints of the PEARL trial were incidence of ER+ breast cancer and nonvertebral fractures at 5 years. A nested case–control study of 49 incident breast cancer case patients and 156 unaffected control subjects from the PEARL trial was performed to evaluate treatment effects on risk of total and ER+ invasive breast cancer by baseline serum estradiol and sex hormone–binding globulin levels using logistic regression models. Cox proportional hazards models were used to evaluate risk of total breast cancer and ER+ invasive breast cancer using intention-to-treat analysis. All statistical tests were two-sided. Results Breast cancer was confirmed in 49 women. Compared with placebo, 0.5 mg of lasofoxifene statistically significantly reduced the risk of total breast cancer by 79% (hazard ratio = 0.21; 95% confidence interval CI = 0.08 to 0.55) and ER+ invasive breast cancer by 83% (hazard ratio = 0.17; 95% CI = 0.05 to 0.57). The effects of 0.5 mg of lasofoxifene on total breast cancer were similar regardless of Gail score, whereas the effects were markedly stronger for women with baseline estradiol levels greater than the median (odds ratio = 0.11; 95% CI = 0.02 to 0.51) vs those with levels less than the median (odds ratio = 0.78; 95% CI = 0.16 to 3.79; Pinteraction = .04). Conclusion A 0.5-mg dose of lasofoxifene appears to reduce the risks of both total and ER+ invasive breast cancer in postmenopausal women with osteoporosis.
The aim of this study was the development and evaluation of a real-time guidance support using optical Moiré Phase Tracking (MPT) for magnetic resonance (MR) guided percutaneous interventions. A ...gradient echo sequence, capable of real-time position updates by the MPT system, was modified to enable needle guidance based on four rigidly attached MPT markers at the back of a needle. Two perpendicular imaging planes were automatically aligned along the calibrated needle and centered at its tip. For user guidance, additional information about the needle trajectory and the tip to target distance were added as image overlay. Both, images and guiding information were displayed on the in-room monitor to facilitate MR guided interventions. The guidance support was evaluated by four experienced interventional radiologists and four novices targeting rubber O-rings embedded in a custom-made phantom on a 3T wide-bore MRI system (80 punctures). The skin to target time, user error, system error and total error were analyzed. The mean skin to target time was 146s±68s with no statistically significant difference between experts and novices. A low mean user error (0.91mm±0.43mm), system error (0.53mm±0.27mm) and total error (0.99mm±0.47mm) was reached in all directions. No statistically significant difference in user error, system error and total error could be found between experts and novices. The presented tracking and image guidance system combined with the user interface offers continuous and interactive control of the imaging plane while puncturing in the magnet enabling accurate real-time feedback for both, experienced and non-experienced users.
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The Concise Guide to PHARMACOLOGY 2023/24: Transporters Alexander, Stephen P. H.; Fabbro, Doriano; Kelly, Eamonn ...
British journal of pharmacology,
October 2023, 2023-10-00, 20231001, Volume:
180, Issue:
S2
Journal Article
Peer reviewed
Open access
The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of ...approximately 1800 drug targets, and over 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org/), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.16182. Transporters are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, ion channels, nuclear hormone receptors, catalytic receptors and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
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