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Fixed-dose combinations of a long-acting beta agonist and an inhaled corticosteroid are more effective than the individual components in COPD. The primary study objective was to demonstrate that the combination indacaterol acetate/mometasone furoate (IND/MF [QMF149]) was non-inferior to the twice-daily combination salmeterol xinafoate/fluticasone propionate (Sal/Flu) in terms of trough FEV at week 12 (day 85). Secondary objectives were to compare the efficacy of IND/MF (QMF149) vs Sal/Flu with respect to other lung function parameters, COPD exacerbations, symptoms and dyspnea, health status/health-related quality of life, and rescue medication use. This was a 12-week multicenter, randomized, double-blind, double-dummy, parallel-group, Phase II study in patients with moderate-to-very-severe COPD, who were randomized (1:1) to IND/MF (QMF149) (150/160 µg once daily; n=316) or Sal/Flu (50/500 µg twice daily; n=313). Over 90% of patients completed the study: 94.6% in the IND/MF (QMF149) group and 92.0% in the Sal/Flu group. The primary objective of non-inferiority of IND/MF (QMF149) to Sal/Flu for trough FEV at week 12 (day 85) was met: the lower limit of the CI (95% CI: 27.7, 83.3 mL) was greater than -60 mL. The analysis for superiority of IND/MF (QMF149) to Sal/Flu demonstrated superiority of IND/MF (QMF149), with a difference of 56 mL ( <0.001). In addition, IND/MF (QMF149) treatment significantly improved COPD exacerbation-related parameters during the 12-week period. Other significant improvements with IND/MF (QMF 149) vs Sal/Flu were noted for dyspnea at week 12 and other COPD symptoms and COPD rescue medication use over the 12 weeks. The safety and tolerability profiles of both the treatments were similar. IND/MF (QMF149) (150/160 µg once daily) offered superior lung function and symptom efficacy and a favorable safety profile compared with Sal/Flu (50/500 µg twice daily) in patients with moderate-to-very severe COPD.

Hybrid quantum optomechanical systems 1 interface a macroscopic mechanical degree of freedom with a single two-level system such as a single spin 2 – 4 , a superconducting qubit 5 – 7 or a single optical emitter 8 – 12 . Recently, hybrid systems operating in the microwave domain have witnessed impressive progress 13 , 14 . Concurrently, only a few experimental approaches have successfully addressed hybrid systems in the optical domain, demonstrating that macroscopic motion can modulate the two-level system transition energy 9 , 10 , 15 . However, the reciprocal effect, corresponding to the backaction of a single quantum system on a macroscopic mechanical resonator, has remained elusive. In contrast to an optical cavity, a two-level system operates with no more than a single energy quantum. Hence, it requires a much stronger hybrid coupling rate compared to cavity optomechanical systems 1 , 16 . Here, we build on the large strain coupling between an oscillating microwire and a single embedded quantum dot 9 . We resonantly drive the quantum dot’s exciton using a laser modulated at the mechanical frequency. State-dependent strain then results in a time-dependent mechanical force that actuates microwire motion. This force is almost three orders of magnitude larger than the radiation pressure produced by the photon flux interacting with the quantum dot. In principle, the state-dependent force could constitute a strategy to coherently encode the quantum dot quantum state onto a mechanical degree of freedom 1 . Hybrid quantum optomechanical systems interface a single two-level system with a macroscopic mechanical degree of freedom. In a microwire with a single embedded semiconductor quantum dot, not only can the wire vibration modulate the excitonic transition energy, but the optical drive of the quantum dot can also induce motion in the wire.

With the progress of nano-technology, thermodynamics also has to be scaled down, calling for specific protocols to extract and measure work. Usually, such protocols involve the action of an external, classical field (the battery) of infinite energy, that controls the energy levels of a small quantum system (the calorific fluid). Here we suggest a realistic device to reversibly extract work in a battery of finite energy : a hybrid optomechanical system. Such devices consist of an optically active two-level quantum system interacting strongly with a nano-mechanical oscillator that provides and stores mechanical work, playing the role of the battery. We identify protocols where the battery exchanges large, measurable amounts of work with the quantum emitter without getting entangled with it. When the quantum emitter is coupled to a thermal bath, we show that thermodynamic reversibility is attainable with state-of-the-art devices, paving the road towards the realization of a full cycle of information-to-energy conversion at the single bit level.

Rationale An increasing number of investigators utilize the marble-burying assay despite the paucity of information available regarding what underlies the behavior. Objectives We tested the possibility that a genetic component underlies marble burying in mice and if there is a genetic correlation with other anxiety-like traits. Since findings reported in the literature indicate that marble-burying behavior reflects an anxiety-like response, we explored the assumption that the novel nature of a marble induces this anxiety. Finally, we investigated how the natural response of a mouse to dig relates to the marble-burying phenomenon. Methods We examined ten different inbred mouse strains to determine if marble-burying behavior is genetically regulated and correlated with anxiety-like traits in two other assays. We employed multiple variants of the “traditional” marble-burying assay to address how issues such as the novelty of marbles and digging behavior contribute to marble burying. Results Marble-burying behavior varied across strain and did not correlate with anxiety measures in other assays. Multiple tests conducted to reduce the novelty of marbles failed to alter burying behavior. Additionally, digging behavior correlated with marble burying, and the presence of marbles did not significantly impact the digging response. Conclusions Our results indicate that mouse marble burying is genetically regulated, not correlated with other anxiety-like traits, not stimulated by novelty, and is a repetitive behavior that persists/perseveres with little change across multiple exposures. Marble burying is related to digging behavior and may in fact be more appropriately considered as an indicative measure of repetitive digging.

Nations struggled to decide when and how to end COVID-19 inspired lockdowns, with sharply divergent views between those arguing for a resumption of economic activity and those arguing for continuing the lockdown in some form. We examine the choice between continuing or ending a full lockdown within a simple optimal control model that encompasses both health and economic outcomes, and pays particular attention to when need for care exceeds hospital capacity. The model shows that very different strategies can perform similarly well and even both be optimal for the same relative valuation on work and life because of the presence of a so-called Skiba threshold. Qualitatively the alternate strategies correspond to trying essentially to eradicate the virus or merely to flatten the curve so fewer people urgently need healthcare when hospitals are already filled to capacity.

Rationale Studies in the Fmr1 knockout (KO) mouse, a model of fragile X syndrome (FXS), suggest that excessive signaling through group I metabotropic glutamate receptors (mGluRs), comprised of subtypes mGluR1 and mGluR5, may play a role in the pathogenesis of FXS. Currently, no studies have assessed the effect of mGluR1 modulation on Fmr1 KO behavior, and there has not been an extensive behavioral analysis of mGluR5 manipulation in Fmr1 KO mice. Objectives The goals for this study were to determine if pharmacologic blockade of mGluR1 may affect Fmr1 KO behavior as well as to expand on the current literature regarding pharmacologic blockade of mGluR5 on Fmr1 KO behavior. Methods Reduction of mGluR1 or mGluR5 activity was evaluated on a variety of behavioral assays in wild-type (WT) and Fmr1 KO mice through the use of antagonists: JNJ16259685 (JNJ, mGluR1 antagonist) and MPEP (mGluR5 antagonist). Results JNJ and MPEP decreased marble burying in both WT and Fmr1 KO mice without reductions in activity. Neither JNJ nor MPEP affected the prepulse inhibition in either WT or Fmr1 KO mice. JNJ did not affect Fmr1 KO motor coordination but did impair WT performance. MPEP improved a measure of motor learning in Fmr1 KO but not WT mice. While both JNJ and MPEP decreased the audiogenic seizures in the Fmr1 KO, MPEP completely abolished the manifestation of seizures. Conclusion These data illustrate that, while the manipulation of either mGluR1 or mGluR5 can affect select behaviors in the Fmr1 KO, we observe greater effects upon mGluR5 reduction.

Coastal countries have traditionally relied on the existing marine resources (e.g., fishing, food, transport, recreation, and tourism) as well as tried to support new economic endeavors (ocean energy, desalination for water supply, and seabed mining). Modern societies and lifestyle resulted in an increased demand for dietary diversity, better health and well-being, new biomedicines, natural cosmeceuticals, environmental conservation, and sustainable energy sources. These societal needs stimulated the interest of researchers on the diverse and underexplored marine environments as promising and sustainable sources of biomolecules and biomass, and they are addressed by the emerging field of marine (blue) biotechnology. Blue biotechnology provides opportunities for a wide range of initiatives of commercial interest for the pharmaceutical, biomedical, cosmetic, nutraceutical, food, feed, agricultural, and related industries. This article synthesizes the essence, opportunities, responsibilities, and challenges encountered in marine biotechnology and outlines the attainment and valorization of directly derived or bio-inspired products from marine organisms. First, the concept of bioeconomy is introduced. Then, the diversity of marine bioresources including an overview of the most prominent marine organisms and their potential for biotechnological uses are described. This is followed by introducing methodologies for exploration of these resources and the main use case scenarios in energy, food and feed, agronomy, bioremediation and climate change, cosmeceuticals, bio-inspired materials, healthcare, and well-being sectors. The key aspects in the fields of legislation and funding are provided, with the emphasis on the importance of communication and stakeholder engagement at all levels of biotechnology development. Finally, vital overarching concepts, such as the quadruple helix and Responsible Research and Innovation principle are highlighted as important to follow within the marine biotechnology field. The authors of this review are collaborating under the European Commission-funded Cooperation in Science and Technology (COST) Action Ocean4Biotech – European transdisciplinary networking platform for marine biotechnology and focus the study on the European state of affairs.

Protected areas are a principal conservation tool for addressing biodiversity loss. Such protection is especially needed in freshwaters, given their greater biodiversity losses compared to terrestrial and marine ecosystems. However, broad-scale evaluations of protected area effectiveness for freshwater biodiversity are lacking. Here, we provide a continental-scale analysis of the relationship between protected areas and freshwater biodiversity using 1,754 river invertebrate community time series sampled between 1986 and 2022 across ten European countries. Protected areas primarily benefited poor-quality communities (indicative of higher human impacts) that were protected, or that gained protection, across a substantial proportion of their upstream catchment. Protection had little to no influence on moderate- and high-quality communities, although high-quality communities potentially provide less scope for effect. Our results reveal the overall limited effectiveness of current protected areas for freshwater biodiversity, likely because they are typically designed and managed to achieve terrestrial conservation goals. Broadly improving effectiveness for freshwater biodiversity requires catchment-scale management approaches involving larger and more continuous upstream protection, and efforts to address remaining stressors. These approaches would also benefit connected terrestrial and coastal ecosystems, thus generally helping bend the curve of global biodiversity loss.

Background To improve understanding of influenza and rurality, we investigated differences in influenza testing and anti-viral treatment rates between micropolitan (muSAs) and metropolitan statistical areas (MSAs) using national medical claims data over multiple influenza seasons. Methods Using billing data from the Centers for Medicare and Medicaid Services for those aged 65 years and older, we estimated weekly rates of ordered rapid influenza diagnostic tests (RIDT) and antivirals (AV) among Medicare enrollees by core-based statistical areas (CBSAs) during 2010–2016. We used Negative Binomial generalized mixed models to estimate adjusted rate ratios (aRR) between MSAs and muSAs, adjusting for clustering by CBSA plus explanatory variables. We ran models for all weeks and only high influenza activity weeks. Results For all weeks, the unadjusted rate of RIDTs was 1.97 per 10,000 people in MSAs compared with 2.69 in muSAs (Rate ratio (RR) = 0.73, 95% Confidence Interval (CI): 0.73–0.74) and of AVs was 1.85 in MSAs compared with 1.40 in muSAs (RR = 1.32, CI: 1.31–1.32). From the multivariate model, aRR for RIDTs was 0.82 (0.73–0.94) and for AVs was 1.12 (1.04–1.22) in MSAs versus muSAs. For high influenza activity weeks, aRR for RIDTs was 0.82 (0.73–0.92) and for AVs was 1.15 (1.06–1.24). All models found influenza testing rates higher in muSAs and treatment rates higher in MSAs. Conclusions Our study found lower testing and higher treatment in U.S. metropolitan versus micropolitan areas from 2010 to 2016 for those aged 65 years and older in our population. Identifying differences in influenza rates by rurality may improve public health response. Further research into the relationship of rurality and health disparities is needed.

Granule cells (GCs) are the most abundant inhibitory neuronal type in the olfactory bulb and play a critical role in olfactory processing. GCs regulate the activity of principal neurons, the mitral cells, through dendrodendritic synapses, shaping the olfactory bulb output to other brain regions. GC excitability is regulated precisely by intrinsic and extrinsic inputs, and this regulation is fundamental for odor discrimination. Here, we used channelrhodopsin to stimulate GABAergic axons from the basal forebrain selectively and show that this stimulation generates reliable inhibitory responses in GCs. Furthermore, selective in vivo inhibition of GABAergic neurons in the basal forebrain by targeted expression of designer receptors exclusively activated by designer drugs produced a reversible impairment in the discrimination of structurally similar odors, indicating an important role of these inhibitory afferents in olfactory processing.