512 research outputs found
Protecting Human and Animal Health: The Road from Animal Models to New Approach Methods
Animals and animal models have been invaluable for our current understanding of human and animal biology, including physiology, pharmacology, biochemistry, and disease pathology. However, there are increasing concerns with continued use of animals in basic biomedical, pharmacological, and regulatory research to provide safety assessments for drugs and chemicals. There are concerns that animals do not provide sufficient information on toxicity and/or efficacy to protect the target population, so scientists are utilizing the principles of replacement, reduction, and refinement (the 3Rs) and increasing the development and application of new approach methods (NAMs). NAMs are any technology, methodology, approach, or assay used to understand the effects and mechanisms of drugs or chemicals, with specific focus on applying the 3Rs. Although progress has been made in several areas with NAMs, complete replacement of animal models with NAMs is not yet attainable. The road to NAMs requires additional development, increased use, and, for regulatory decision making, usually formal validation. Moreover, it is likely that replacement of animal models with NAMs will require multiple assays to ensure sufficient biologic coverage. The purpose of this manuscript is to provide a balanced view of the current state of the use of animal models and NAMs as approaches to development, safety, efficacy, and toxicity testing of drugs and chemicals. Animals do not provide all needed information nor do NAMs, but each can elucidate key pieces of the puzzle of human and animal biology and contribute to the goal of protecting human and animal health. SIGNIFICANCE STATEMENT: Data from traditional animal studies have predominantly been used to inform human health safety and efficacy. Although it is unlikely that all animal studies will be able to be replaced, with the continued advancement in new approach methods (NAMs), it is possible that sometime in the future, NAMs will likely be an important component by which the discovery, efficacy, and toxicity testing of drugs and chemicals is conducted and regulatory decisions are made
An XMM-Newton observation of the galaxy group MKW 4
We present an X-ray study of the galaxy group or poor cluster MKW 4. Working
with XMM data we examine the distribution and properties of the hot gas which
makes up the group halo. The inner halo shows some signs of structure, with
circular or elliptical beta models providing a poor fit to the surface
brightness profile. This may be evidence of large scale motion in the inner
halo, but we do not find evidence of sharp fronts or edges in the emission. The
temperature of the halo declines in the core, with deprojected spectral fits
showing a central temperature of ~1.3 keV compared to ~3 keV at 100 kpc. In the
central ~30 kpc of the group multi-temperature spectral models are required to
fit the data, but they indicate a lack of gas at low temperatures. Steady state
cooling flow models provide poor fits to the inner regions of the group and the
estimated cooling time of the gas is long except within the central dominant
galaxy, NGC 4073. Abundance profiles show a sharp increase in the core of the
group, with mean abundance rising by a factor of two in the centre of NGC 4073.
Fitting individual elements shows the same trend, with high values of Fe, Si
and S in the core. We estimate that ~50% of the Fe in the central 40 kpc was
injected by SNIa, in agreement with previous ASCA studies. Using our best
fitting surface brightness and temperature models, we calculate the mass, gas
fraction, entropy and mass-to-light ratio of the group. At 100 kpc (~0.1 virial
radii) the total mass and gas entropy of the system (~2x10^13 Msol and ~300 keV
cm^2) are quite comparable to those of other systems of similar temperature,
but the gas fraction is rather low (~1%). We conclude that MKW 4 is a fairly
relaxed group, which has developed a strong central temperature gradient but
not a large-scale cooling flow.Comment: 17 pages, 9 postscript figures, accepted for publication in MNRA
Objective and subjective assessment of sleep in chronic low back pain patients compared with healthy age and gender matched controls: a pilot study
<p>Abstract</p> <p>Background</p> <p>While approximately 70% of chronic low back pain (CLBP) sufferers complain of sleep disturbance, current literature is based on self report measures which can be prone to bias and no objective data of sleep quality, based exclusively on CLBP are available. In accordance with the recommendations of The American Sleep Academy, when measuring sleep, both subjective and objective assessments should be considered as the two are only modestly correlated, suggesting that each modality assesses different aspects of an individual's sleep experience. Therefore, the purpose of this study was to expand previous research into sleep disturbance in CLBP by comparing objective and subjective sleep quality in participants with CLBP and healthy age and gender matched controls, to identify correlates of poor sleep and to test logistics and gather information prior to a larger study.</p> <p>Methods</p> <p>15 CLBP participants (mean age = 43.8 years (SD = 11.5), 53% female) and 15 healthy controls (mean age = 41.5 years (SD = 10.6), 53% female) consented. All participants completed the Pittsburgh Sleep Quality Index, Insomnia Severity Index, Pittsburgh Sleep Diary and the SF36v2. CLBP participants also completed the Oswestry Disability Index. Sleep patterns were assessed over three consecutive nights using actigraphy. Total sleep time (TST), sleep efficiency (SE), sleep latency onset (SL) and number of awakenings after sleep onset (WASO) were derived. Statistical analysis was conducted using unrelated t-tests and Pearson's product moment correlation co-efficients.</p> <p>Results</p> <p>CLBP participants demonstrated significantly poorer overall sleep both objectively and subjectively. They demonstrated lower actigraphic SE (p = .002) and increased WASO (p = .027) but no significant differences were found in TST (p = .43) or SL (p = .97). Subjectively, they reported increased insomnia (p =< .001), lower SE (p =< .001) and increased SL (p =< .001) but no difference between TST (p = .827) and WASO (p = .055). Statistically significant associations were found between low back pain (p = .021, r = -.589), physical health (p = .003, r = -.713), disability levels (p = .025, r = .576), and subjective sleep quality in the CLBP participants but not with actigraphy.</p> <p>Conclusion</p> <p>CLBP participants demonstrated poorer overall sleep, increased insomnia symptoms and less efficient sleep. Further investigation using a larger sample size and a longer period of sleep monitoring is ongoing.</p
Health-related quality of life in patients with locally recurrent or metastatic breast cancer treated with etirinotecan pegol versus treatment of physician’s choice: Results from the randomised phase III BEACON trial
Background: Health-related quality of life (HRQoL) enhances understanding of treatment effects that impact clinical decision-making. Although the primary end-point was not achieved, the BEACON (BrEAst Cancer Outcomes with NKTR-102) trial established etirinotecan pegol, a long-acting topoisomerase-1 (TOP1) inhibitor, as a promising therapeutic for patients with advanced/metastatic breast cancer (MBC) achieving clinically meaningful benefits in median overall survival (OS) for patients with stable brain metastases, with liver metastases or ≥ 2 sites of metastatic disease compared to treatment of physician’s choice (TPC). Reported herein are the findings from the preplanned secondary end-point of HRQoL. Patients and methods: HRQoL, assessed by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) (version 3.0) supplemented by the breast cancer-specific Quality of Life Questionnaire (QLQ-BR23), was evaluated post randomisation in 733 of 852 patients with either anthracycline-, taxane- and capecitabine-pretreated locally recurrent or MBC randomised to etirinotecan pegol (n = 378; 145 mg/m2 every 3 weeks (q3wk)) or single-agent TPC (n = 355). Patients completed assessments at screening, every 8 weeks (q8wk) during treatment, and end-of-treatment. Changes from baseline were analysed, and the proportions of patients achieving differences (≥5 points) in HRQoL scores were compared. Results: Differences were seen favouring etirinotecan pegol up to 32 weeks for global health status (GHS) and physical functioning scales (P < 0.02); numerical improvement was reported in other functional scales. The findings from HRQoL symptom scales were consistent with adverse event profiles; etirinotecan pegol was associated with worsening gastrointestinal symptoms whereas TPC was associated with worsened dyspnoea and other systemic side-effects. Analysis of GHS and physical functioning at disease progression showed a decline in HRQoL in both treatment arms, with a mean change from baseline of −9.4 and −10.8 points, respectively. Conclusion: There was evidence of benefit associated with etirinotecan pegol compared with current standard of care agents in multiple HRQoL measurements, including global health status and physical functioning, despite worse gastrointestinal symptoms (e.g. diarrhoea). Patients in both arms had a decline in HRQoL at disease progression. Study number: NCT01492101
Increasing crop rotational diversity can enhance cereal yields
Diversifying agriculture by rotating a greater number of crop species in sequence is a promising practice to reduce negative impacts of crop production on the environment and maintain yields. However, it is unclear to what extent cereal yields change with crop rotation diversity and external nitrogen fertilization level over time, and which functional groups of crops provide the most yield benefit. Here, using grain yield data of small grain cereals and maize from 32 long-term (10–63 years) experiments across Europe and North America, we show that crop rotational diversity, measured as crop species diversity and functional richness, enhanced grain yields. This yield benefit increased over time. Only the yields of winter-sown small grain cereals showed a decline at the highest level of species diversity. Diversification was beneficial to all cereals with a low external nitrogen input, particularly maize, enabling a lower dependence on nitrogen fertilisers and ultimately reducing greenhouse gas emissions and nitrogen pollution. The results suggest that increasing crop functional richness rather than species diversity can be a strategy for supporting grain yields across many environments
Increasing crop rotational diversity can enhance cereal yields
9 Pág.Diversifying agriculture by rotating a greater number of crop species in sequence is a promising practice to reduce negative impacts of crop production on the environment and maintain yields. However, it is unclear to what extent cereal yields change with crop rotation diversity and external nitrogen fertilization level over time, and which functional groups of crops provide the most yield benefit. Here, using grain yield data of small grain cereals and maize from 32 long-term (10–63 years) experiments across Europe and North America, we show that crop rotational diversity, measured as crop species diversity and functional richness, enhanced grain yields. This yield benefit increased over time. Only the yields of winter-sown small grain cereals showed a decline at the highest level of species diversity. Diversification was beneficial to all cereals with a low external nitrogen input, particularly maize, enabling a lower dependence on nitrogen fertilisers and ultimately reducing greenhouse gas emissions and nitrogen pollution. The results suggest that increasing crop functional richness rather than species diversity can be a strategy for supporting grain yields across many environments.G.V., R.B. and S.H. acknowledge FORMAS grants 2018-02872 and 2018-02321. TMB acknowledges USDA AFRI grant 2017-67013-26254. LTEs managed by SRUC were supported by the Scottish Government RESAS Strategic Research Programme under project D3-, Healthy Soils for a Green Recovery. Swedish LTEs were funded by the Swedish University of Agricultural Sciences (SLU). We thank the Lawes Agricultural Trust and Rothamsted Research for data from the e-RA database. The Rothamsted Long-term Experiments National Capability (LTE-NC) was supported by the UK BBSRC (Biotechnology and Biological Sciences Research Council, BBS/E/C/000J0300) and the Lawes Agricultural Trust. The Woodslee site was supported by the Agro-Ecosystem Resilience Program (Agriculture & Agri-Food Canada) and field management provided by field crews over 6 decades is appreciated. La Canaleja LTE (Spain) was supported by RTA2017-00006-C03-01 project (Ministry of Science and Innovation. El Encín LTEs were supported by Spanish Ministry of Economy and Competitiveness funds (projects AGL2002-04186-C03-01.03, AGL2007-65698-C03-01.03, AGL2012-39929-C03-01 of which L. Navarrete was the P.I). R.A., A.G.D. and E.H.P. are also grateful to all members of the Weed Science Group from El Encín Experimental Station for their technical assistance in managing the experiments. The Brody/Poznan University of Life Sciences long-term experiments were funded by the Polish Ministry of Education and Science. We acknowledge the E-Obs dataset from the EU-FP6 project UERRA (http://www.uerra.eu) and the Copernicus Climate Change Service, and the data providers in the ECA&D project (https://www.ecad.eu/).Peer reviewe
Long-acting injectable Cabotegravir + Rilpivirine for HIV maintenance therapy: Week 48 pooled analysis of phase 3 ATLAS and FLAIR trials
BACKGROUND: Long-acting (LA) injectable regimens are a potential therapeutic option in people living with HIV-1. SETTING: ATLAS (NCT02951052) and FLAIR (NCT02938520) were 2 randomized, open-label, multicenter, multinational phase 3 studies. METHODS: Adult participants with virologic suppression (plasma HIV-1 RNA <50 copies/mL) were randomized (1:1) to continue with their current antiretroviral regimen (CAR) or switch to the long-acting (LA) regimen of cabotegravir (CAB) and rilpivirine (RPV). In the LA arm, participants initially received oral CAB + RPV once-daily for 4 weeks to assess individual safety and tolerability, before starting monthly injectable therapy. The primary endpoint of this combined analysis was antiviral efficacy at week 48 (FDA Snapshot algorithm: noninferiority margin of 4% for HIV-1 RNA ≥50 copies/mL). Safety, tolerability, and confirmed virologic failure (2 consecutive plasma HIV-1 RNA ≥200 copies/mL) were secondary endpoints. RESULTS: The pooled intention-to-treat exposed population included 591 participants in each arm [28% women (sex at birth), 19% aged ≥50 years]. Noninferiority criteria at week 48 were met for the primary (HIV-1 RNA ≥50 copies/mL) and key secondary (HIV-1 RNA <50 copies/mL) efficacy endpoints. Seven individuals in each arm (1.2%) developed confirmed virologic failure; 6/7 (LA) and 3/7 (CAR) had resistance-associated mutations. Most LA recipients (83%) experienced injection site reactions, which decreased in incidence over time. Injection site reactions led to the withdrawal of 6 (1%) participants. The serious adverse event rate was 4% in each arm. CONCLUSION: This combined analysis demonstrates monthly injections of CAB + RPV LA were noninferior to daily oral CAR for maintaining HIV-1 suppression
Enhancer viruses and a transgenic platform for combinatorial cell subclass-specific labeling
The rapid pace of cell type identification by new single-cell analysis methods has not been met with efficient experimental access to the newly discovered types. To enable flexible and efficient access to specific neural populations in the mouse cortex, we collected chromatin accessibility data from individual cells and clustered the single-cell data to identify enhancers specific for cell classes and subclasses. When cloned into adeno-associated viruses (AAVs) and delivered to the brain by retro-orbital injections, these enhancers drive transgene expression in specific cell subclasses in the cortex. We characterize several enhancer viruses in detail to show that they result in labeling of different projection neuron subclasses in mouse cortex, and that one of them can be used to label the homologous projection neuron subclass in human cortical slices. To enable the combinatorial labeling of more than one cell type by enhancer viruses, we developed a three-color Cre-, Flp- and Nigri- recombinase dependent reporter mouse line, Ai213. The delivery of three enhancer viruses driving these recombinases via a single retroorbital injection into a single Ai213 transgenic mouse results in labeling of three different neuronal classes/subclasses in the same brain tissue. This approach combines unprecedented flexibility with specificity for investigation of cell types in the mouse brain and beyond
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