Implementing Individually Tailored Prescription of Physical Activity in Routine Clinical Care:A Process Evaluation of the Physicians Implement Exercise = Medicine Project

BACKGROUND: Although the prescription of physical activity in clinical care has been advocated worldwide, in the Netherlands, "Exercise is Medicine" (E = M) is not yet routinely implemented in clinical care.METHODS: A set of implementation strategies was pilot implemented to test its feasibility for use in routine care by clinicians in 2 departments of a university medical center. An extensive learning process evaluation was performed, using structured mixed methods methodology, in accordance with the Reach, Effect, Adoption, Implementation, and Maintenance framework.RESULTS: From 5 implementation strategies employed (education, E = M tool embedded in the electronic medical records, lifestyle coach situated within the department, overviews of referral options, and project support), the presence of adequate project support was a strong facilitator of the implementation of E = M. Also, the presence of the lifestyle coach within the department seemed essential for referral rate. Although clinicians appreciated the E = M tool, barriers hampered its use in practice.CONCLUSIONS: Specific implementation strategies, tailored to the setting, are effective in facilitating the implementation of E = M with specific regard to education for clinicians on E = M, deployment of a lifestyle coach within a department, and project coordination. Care providers do see a future for lifestyle coaches who are structurally embedded in the hospital, to whom they can easily refer.</p

Comorbidity and sex differences in functional disorders and internalizing disorders

OBJECTIVE: In the current exploratory study we estimate comorbidity rates between FDs [fibromyalgia (FM), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and irritable bowel syndrome (IBS)]-and IDs-[major depressive disorder (MDD) and generalized anxiety disorder (GAD)] by using self-reported diagnostic criteria.METHOD: We analyzed data from 107,849 participants (mean age = 49.3 (SD = 13.0), 58.6% women) of the Lifelines Cohort Study. Lifelines is a prospective population-based cohort study in the northeast of the Netherlands. Current IDs were assessed using the Mini-International Neuropsychiatric Interview. Current FM, ME/CFS, and IBS were assessed according to the 2010 American College of Rheumatology criteria, the 1994 Centers for Disease Control and Prevention criteria and the ROME IV criteria, respectively. We estimated tetrachoric correlations between diagnoses and tested for sex differences. Additionally, we estimated the ratio of observed-to-expected frequency for combinations of diagnoses.RESULTS: FDs and IDs are highly comorbid (odds ratios: 3.2-12.6) with associations stronger among men. Participants with at least three disorders/diagnoses were more prevalent than expected by chance.CONCLUSION: Studies that aim to explain sex differences and the comorbidity of specific combinations of IDs and FDs will be an important contribution to understanding the etiology of these conditions.</p

Dissipativity Analysis for Economic Nonlinear MPC of District Heating Networks

The inherently nonlinear, large-scale, and time-varying nature of district heating systems pose significant challenges from a control perspective. In this paper, we address these challenges by applying an economic MPC. Economic MPC is a dynamic real-time optimization method, enabling both optimal planning and stability of the closed-loop system. Our strategy constitutes several steps. First, we introduce a discrete-time modular framework for the district heating system, establishing its strict dissipativity with respect to a desired, potentially time-varying, equilibrium. We identify a set of meaningful objective functions for the district heating systems, preserving this property. Second, we show how strict dissipativity implies the turnpike property, which, in turn, guarantees approximate optimality, practical stability, and recursive feasibility for the EMPC closed-loop. Finally, we provide numerical simulations to demonstrate the effectiveness of our work

Multi-mem behavior at reduced voltages in La_1/2Sr_1/2Mn_1/2Co_1/2 O_3-x perovskite modified with Sm:Ce O₂

The use of machine learning algorithms is exponentially growing and concerns are being raised about their sustainability. Neuromorphic computing aims to mimic the architecture and the information processing mechanisms of the mammalian brain, appearing as the only avenue that offers significant energy savings compared to the standard digital computers. Memcapacitive devices, which can change their capacitance between different nonvolatile states upon the application of electrical stimulation, can significantly reduce the energy consumption of bio-inspired circuitry. In the present work, we study the multi-mem (memristive and memcapacitive) behavior of devices based on thin films of the topotactic redox La1/2Sr1/2Mn1/2Co1/2O3-x (LSMCO) perovskite modified with Sm:CeO2 (SCO), grown on Nb:SrTiO3 with (001) and (110) out-of-plane orientations. Either the self-assembling at the nanoscale of both LSMCO and SCO phases or the doping with Ce(Sm) of the LSMCO perovskite were observed for different fabrication conditions and out-of-plane orientations. The impact of these changes on the device electrical behavior was determined. The optimum devices resulted those with (110) orientation and Ce(Sm) doping the perovskite. These devices displayed a multi-mem behavior with robust memcapacitance and significantly lower operation voltages (especially the reset voltage) in comparison with devices based on pristine LSMCO. In addition, they were able to endure electrical cycling - and the concomitant perovskite topotactic redox transition between oxidized and reduced phases - without suffering nanostructural changes nor cationic segregation. We link these properties to an enhanced perovskite reducibility upon Ce(Sm) doping. Our work contributes to increasing the reliability of LSMCO-based multi-mem systems and to reducing their operating voltages closer to the 1 V threshold, which are key issues for the development of nanodevices for neuromorphic or in-memory computing.</p

Semisynthetic guanidino lipoglycopeptides with potent in vitro and in vivo antibacterial activity

Gram-positive bacterial infections present a major clinical challenge, with methicillin- and vancomycin-resistant strains continuing to be a cause for concern. In recent years, semisynthetic vancomycin derivatives have been developed to overcome this problem as exemplified by the clinically used telavancin, which exhibits increased antibacterial potency but has also raised toxicity concerns. Thus, glycopeptide antibiotics with enhanced antibacterial activities and improved safety profiles are still necessary. We describe the development of a class of highly potent semisynthetic glycopeptide antibiotics, the guanidino lipoglycopeptides, which contain a positively charged guanidino moiety bearing a variable lipid group. These glycopeptides exhibited enhanced in vitro activity against a panel of Gram-positive bacteria including clinically relevant methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant strains, showed minimal toxicity toward eukaryotic cells, and had a low propensity for resistance selection. Mechanistically, guanidino lipoglycopeptides engaged with bacterial cell wall precursor lipid II with a higher binding affinity than vancomycin. Binding to both wild-type d-Ala-d-Ala lipid II and the vancomycin-resistant d-Ala-d-Lac variant was confirmed, providing insight into the enhanced activity of guanidino lipoglycopeptides against vancomycin-resistant isolates. The in vivo efficacy of guanidino lipoglycopeptide EVG7 was evaluated in a S. aureus murine thigh infection model and a 7-day sepsis survival study, both of which demonstrated superiority to vancomycin. Moreover, the minimal to mild kidney effects at supratherapeutic doses of EVG7 indicate an improved therapeutic safety profile compared with vancomycin. These findings position guanidino lipoglycopeptides as candidates for further development as antibacterial agents for the treatment of clinically relevant multidrug-resistant Gram-positive infections. </p

Relativistic and quantum electrodynamics effects on NMR shielding tensors of TlX (X = H, F, Cl, Br, I, At) molecules

The results of relativistic calculations of nuclear magnetic resonance shielding tensors (σ) for the thallium monocation (Tl+), thallium hydride (TlH), and thallium halides (TlF, TlCl, TlBr, TlI, and TlAt) are presented as obtained within a four-component polarization propagator formalism and a two-component linear response approach within the zeroth-order regular approximation. In addition to a detailed analysis of relativistic effects performed in this work, some quantum electrodynamical (QED) effects on those nuclear magnetic resonance shieldings and other small contributions are estimated. A strong dependence of σ(Tl) on the bonding partner is found, together with a very weak dependence of QED effects with them. In order to explain the trends observed, the excitation patterns associated with relativistic ee (or paramagnetic-like) and pp (or diamagnetic-like) contributions to σ are analyzed. For this purpose, the electronic spin-free and spin-dependent contributions are separated within the two-component zeroth-order regular approximation, and the influence of spin-orbit coupling on involved molecular orbitals is studied, which allows for a thorough understanding of the underlying mechanisms.</p

On the pivotal role of drug discovery in sustainable EU pharma reform

The proposed EU pharma reform adds the ERA as a mandatory fourth approval criterion.A global evaluation of drug sustainability throughout the full life cycle is needed.The early discovery phase is pivotal for the environmental impact of a medicine.The evaluation of drug sustainability should involve all relevant stakeholders

How to Get Rid of Vetoes in EU Foreign and Security Policy?

This is a statement by Members of the Sounding Board of the EU ‘Group of Friends of Qualified Majority Voting (QMV)’. The Group of Friends of QMV was established in 2023 by several EU Member States to prepare proposals to overcome the requirement of unanimity in the EU’s Common Foreign and Security Policy. Discussions take place at various levels, including that of the so-called European Correspondents at the various Ministries of Foreign Affairs. The Sounding Board consists of academics and was installed to provide advice on the various proposals. The present Statement aims to draw attention to options that are currently on the table

Substituent effects on first generation photochemical molecular motors probed by femtosecond stimulated Raman

Unidirectional photochemical molecular motors can act as a power source for molecular machines. The motors operate by successive excited state isomerization and ground state helix inversion reactions, attaining unidirectionality from an interplay of steric strain and stereochemistry. Optimizing the yield of the excited state isomerization reaction is an important goal that requires detailed knowledge of excited state dynamics. Here, we investigate the effect of electron withdrawing and donating substituents on excited state structure and ultrafast dynamics in a series of newly synthesized first generation photochemical molecular motors. All substituents red-shift the absorption spectra, while some modify the Stokes shift and render the fluorescence quantum yield solvent polarity dependent. Raman spectra and density functional theory calculations reveal that the stretching mode of the C=C "axle" in the electronic ground state shows a small red-shift when conjugated with electron withdrawing substituents. Ultrafast fluorescence measurements reveal substituent and solvent polarity effects, with the excited state decay being accelerated by both polar solvent environment and electron withdrawing substituents. Excited state structural dynamics are investigated by fluorescence coherence spectroscopy and femtosecond stimulated Raman spectroscopy. The time resolved Raman measurements are shown to provide structural data specifically on the Franck-Condon excited state. The C=C localized modes have a different substituent dependence compared to the ground state, with the unsubstituted motor having the most red-shifted mode. Such measurements provide valuable new insights into pathways to optimize photochemical molecular motor performance, especially if they can be coupled with high-quality quantum molecular dynamics calculations.</p