A method for exposing rodents to resuspended particles using whole-body plethysmography

BACKGROUND: Epidemiological studies have reported increased risks of cardiopulmonary-related hospitalization and death in association with exposure to elevated levels of particulate matter (PM) across a wide range of urban areas. In response to these findings, researchers have conducted animal inhalation exposures aimed at reproducing the observed toxicologic effects. However, it is technically difficult to quantitate the actual amount of PM delivered to the lung in such studies, and dose is frequently estimated using default respiration parameters. Consequently, the interpretation of PM-induced effects in rodents exposed via whole-body inhalation is often compromised by the inability to determine deposited dose. To address this problem, we have developed an exposure system that merges the generation of dry, aerosolized particles with whole-body plethysmography (WBP), thus permitting inhalation exposures in the unrestrained rat while simultaneously obtaining data on pulmonary function. RESULTS: This system was validated using an oil combustion-derived particle (HP12) at three nominal concentrations (3, 12, and 13 mg/m(3)) for four consecutive exposure days (6 hr/day); a single 6-hour exposure to 13 mg/m(3 )of HP12 was also conducted. These results demonstrated that the system was both reliable and consistent over these exposure protocols, achieving average concentrations that were within 10% of the targeted concentration. In-line filters located on the exhaust outlets of individual WBP chambers showed relative agreement in HP12 mass for each day and were not statistically different when compared to one another (p = 0.16). Temperatures and relative humidities were also similar between chambers during PM and air exposures. Finally, detailed composition analyses of both HP12 filter and bulk samples showed that grinding and aerosolization did not change particle chemistry. CONCLUSION: The results of this study demonstrate that it is possible to expose rodents to resuspended, dry PM via whole-body inhalation while these animals are maintained in WBP chambers. This new methodology should significantly improve the ability to assess dosimetry under minimally stressful exposure conditions

Effect of trimetazidine dihydrochloride therapy on exercise capacity in patients with nonobstructive hypertrophic cardiomyopathy: A randomized clinical trial

Importance: Hypertrophic cardiomyopathy causes limiting symptoms in patients, mediated partly through inefficient myocardial energy use. There is conflicting evidence for therapy with inhibitors of myocardial fatty acid metabolism in patients with nonobstructive hypertrophic cardiomyopathy. Objective: To determine the effect of oral therapy with trimetazidine, a direct inhibitor of fatty acid β-oxidation, on exercise capacity in patients with symptomatic nonobstructive hypertrophic cardiomyopathy. Design, Setting, and Participants: This randomized, placebo-controlled, double-blind clinical trial at The Heart Hospital, University College London Hospitals, London, United Kingdom was performed between May 31, 2012, and September 8, 2014. The trial included 51 drug-refractory symptomatic (New York Heart Association class ≥2) patients aged 24 to 74 years with a maximum left ventricular outflow tract gradient 50 mm Hg or lower and a peak oxygen consumption during exercise of 80% or less predicted value for age and sex. Statistical analysis was performed from March 1, 2016 through July 4, 2018. Interventions: Participants were randomly assigned to trimetazidine, 20 mg, 3 times daily (n = 27) or placebo (n = 24) for 3 months. Main Outcomes and Measures: The primary end point was peak oxygen consumption during upright bicycle ergometry. Secondary end points were 6-minute walk distance, quality of life (Minnesota Living with Heart Failure questionnaire), frequency of ventricular ectopic beats, diastolic function, serum N-terminal pro-brain natriuretic peptide level, and troponin T level. Results: Of 49 participants who received trimetazidine (n = 26) or placebo (n = 23) and completed the study, 34 (70%) were male; the mean (SD) age was 50 (13) years. Trimetazidine therapy did not improve exercise capacity, with patients in the trimetazidine group walking 38.4 m (95% CI, 5.13 to 71.70 m) less than patients in the placebo group at 3 months after adjustment for their baseline walking distance measurements. After adjustment for baseline values, peak oxygen consumption was 1.35 mL/kg per minute lower (95% CI, -2.58 to -0.11 mL/kg per minute; P = .03) in the intervention group after 3 months. Conclusions and Relevance: In symptomatic patients with nonobstructive hypertrophic cardiomyopathy, trimetazidine therapy does not improve exercise capacity. Pharmacologic therapy for this disease remains limited. Trial Registration: ClinicalTrials.gov identifier: NCT01696370

SelfPub 2.0

The self-publishing revolution has created a drastic increase in the number or works being published in the social sciences and humanities. This windfall of content has created an abundance that can be overwhelming, but it ultimately presents an opportunity for libraries to develop deeper and more unique collections. The preconference at the 2013 Charleston Conference focused on several interrelated topics in the self-publishing world: navigating the abundance of self-published material, libraries’ adoption of the role of publisher, vendor perspectives on self-published content and plans for the future, issues in humanities and social science acquisitions of self-published works, and an agent’s perspective on how self-publishing fits into the traditional publishing world. Speakers include librarians, publishers, vendors, and academics involved with a number of projects and efforts to pioneer this emerging field

Regional models of the influence of human disturbance and habitat quality on the distribution of breeding territories of common ringed plover Charadrius hiaticula and Eurasian oystercatcher Haematopus ostralegus

We estimated the influence of human disturbance and environmental factors on territory establishment in common ringed plovers Charadrius hiaticula and Eurasian oystercatchers Haematopus ostralegus, to inform the conservation of these species. We examined a 212 km stretch of coastline in the United Kingdom in 2003, mapping all breeding pairs of both study species, as well as the environmental characteristics of beaches and locations of visitors on the beach, the latter measured by filming from a light aircraft. Of the 1,003 200 m sections of beach surveyed, 183 contained ringed plover territories (267 breeding pairs) and 117 contained oystercatcher territories (226 breeding pairs). 38,634 human visitors to the beach were mapped from three flights. Population densities of both ringed plovers and oystercatchers were lower in locations with high visitor numbers, even when accounting for the influence of the environmental characteristics of the beach. The two bird species showed similar rates of territory establishment at very low visitor rates, but oystercatchers showed a stronger negative response when visitor rates reached higher levels. Binary logistic regression models were used to identify areas where the birds would benefit most from reductions in the number of visitors and we illustrate how this information could be used to inform management around sites otherwise favourable for territory establishment

Is the High-resolution Coronal Imager Resolving Coronal Strands? Results from AR 12712

Following the success of the first mission, the High-Resolution Coronal Imager (Hi-C) was launched for a third time (Hi-C 2.1) on 2018 May 29 from the White Sands Missile Range, NM, USA. On this occasion, 329 s of 17.2 nm data of target active region AR 12712 were captured with a cadence of ≈4 s, and a plate scale of 0farcs129 pixel−1. Using data captured by Hi-C 2.1 and co-aligned observations from SDO/AIA 17.1 nm, we investigate the widths of 49 coronal strands. We search for evidence of substructure within the strands that is not detected by AIA, and further consider whether these strands are fully resolved by Hi-C 2.1. With the aid of multi-scale Gaussian normalization, strands from a region of low emission that can only be visualized against the contrast of the darker, underlying moss are studied. A comparison is made between these low-emission strands and those from regions of higher emission within the target active region. It is found that Hi-C 2.1 can resolve individual strands as small as ≈202 km, though the more typical strand widths seen are ≈513 km. For coronal strands within the region of low emission, the most likely width is significantly narrower than the high-emission strands at ≈388 km. This places the low-emission coronal strands beneath the resolving capabilities of SDO/AIA, highlighting the need for a permanent solar observatory with the resolving power of Hi-C

The First Flight of the Marshall Grazing Incidence X-ray Spectrometer (MaGIXS)

The Marshall Grazing Incidence X-ray Spectrometer (MaGIXS) sounding rocket experiment launched on July 30, 2021 from the White Sands Missile Range in New Mexico. MaGIXS is a unique solar observing telescope developed to capture X-ray spectral images, in the 6 - 24 Angstrom wavelength range, of coronal active regions. Its novel design takes advantage of recent technological advances related to fabricating and optimizing X-ray optical systems as well as breakthroughs in inversion methodologies necessary to create spectrally pure maps from overlapping spectral images. MaGIXS is the first instrument of its kind to provide spatially resolved soft X-ray spectra across a wide field of view. The plasma diagnostics available in this spectral regime make this instrument a powerful tool for probing solar coronal heating. This paper presents details from the first MaGIXS flight, the captured observations, the data processing and inversion techniques, and the first science results.Comment: 20 pages, 18 figure

The First Flight of the Marshall Grazing Incidence X-Ray Spectrometer (MaGIXS)

The Marshall Grazing Incidence X-ray Spectrometer (MaGIXS) sounding rocket experiment launched on 2021 July 30 from the White Sands Missile Range in New Mexico. MaGIXS is a unique solar observing telescope developed to capture X-ray spectral images of coronal active regions in the 6–24 Å wavelength range. Its novel design takes advantage of recent technological advances related to fabricating and optimizing X-ray optical systems, as well as breakthroughs in inversion methodologies necessary to create spectrally pure maps from overlapping spectral images. MaGIXS is the first instrument of its kind to provide spatially resolved soft X-ray spectra across a wide field of view. The plasma diagnostics available in this spectral regime make this instrument a powerful tool for probing solar coronal heating. This paper presents details from the first MaGIXS flight, the captured observations, the data processing and inversion techniques, and the first science results

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society