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Abstract Background Measurement-Based Care (MBC) is the routine administration of measures, clinicians’ review of the feedback and discussion of the feedback with their clients, and collaborative evaluation of the treatment plan. Although MBC is a promising way to improve outcomes in clinical practice, the implementation of MBC faces many barriers, and its uptake by clinicians is low. The purpose of this study was to investigate whether implementation strategies that were developed with clinicians and aimed at clinicians had an effect on (a) clinicians’ uptake of MBC and (b) clients’ outcomes of MBC. Methods We used an effectiveness-implementation hybrid design based on Grol and Wensing’s implementation framework to assess the impact of clinician-focused implementation strategies on both clinicians’ uptake of MBC and outcomes obtained with MBC for clients in general mental health care. We hereby focused on the first and second parts of MBC, i.e., the administration of measures and use of feedback. Primary outcome measures were questionnaire completion rate and discussion of the feedback with clients. Secondary outcomes were treatment outcome, treatment length, and satisfaction with treatment. Results There was a significant effect of the MBC implementation strategies on questionnaire completion rate (one part of clinicians’ uptake), but no significant effect on the amount of discussion of the feedback (the other part of clinicians’ uptake). Neither was there a significant effect on clients’ outcomes (treatment outcome, treatment length, and satisfaction with treatment). Due to various study limitations, the results should be viewed as exploratory. Conclusions Establishing and sustaining MBC in real-world general mental health care is complex. This study helps to disentangle the effects of MBC implementation strategies on differential clinician uptake, but the effects of MBC implementation strategies on client outcomes need further examination.

Infrared spectroscopy is widely used for detailed insights into the three-dimensional molecular structure of biomolecules, however, the accurate description of experimental data by theoretical approaches remains challenging due to the dynamic processes that occur in biomolecules. Here, the authors report the accurate interpretation and reproduction of experimental infrared spectra of a model peptide in the gas phase using a combination of replica-exchange molecular dynamics simulations, machine learning and ab initio calculations based on representative structural conformers.

A series of new granular carbonaceous adsorbents was prepared via single-stage physical and chemical activation of walnut shells. Their suitability for removing various types of organic pollutants (represented by dyes, surfactants and water-soluble polymers) from the liquid phase was assessed. The activation of the precursor was carried out with CO2 and H3PO4 using conventional heating. Activated biocarbons were characterized in terms of chemical composition, acidic–basic nature of the surface, textural and electrokinetic properties as well as thermal stability. Depending on the type of activating agent used during the activation procedure, the obtained biocarbons differed in terms of specific surface area (from 401 to 1361 m2/g) and the type of porous structure produced (microporosity contribution in the range of 45–75%). Adsorption tests proved that the effectiveness of removing organic pollutants from the liquid phase depended to a large extent on the type of prepared adsorbent as well as the chemical nature and the molecular size of the adsorbate used. The chemically activated sample showed greater removal efficiency in relation to all tested pollutants. Its maximum adsorption capacity for methylene blue, poly(acrylic acid), poly(ethylene glycol) and Triton X-100 reached the levels of 247.1, 680.9, 38.5 and 61.8 mg/g, respectively.

Background: Premature atrial contractions (PACs) are potential markers for imminent onset of both atrial fibrillation (AF) and brain ischemia (BI; transient ischemic attack [TIA] or ischemic stroke). We investigated the association of PACs with incident AF and BI events separately, and of incident AF with BI events in people with type 2 diabetes (T2D) without pre-existing AF or cerebrovascular disease. Methods: A prospective longitudinal study of 12,242 people with T2D without known AF or cerebrovascular disease from the Hoorn Diabetes Care System cohort. Annual measurements (1998–2018) included cardiovascular risk factors, over 85,000 ECGs, and self-reported cardiovascular events. We assessed the association of PACs with incident AF and BI events and of incident AF with BI events using time-dependent Cox-regression models, adjusted for time-varying cardiovascular risk factors and medication use (Hazard Ratios with 95%CIs). Results: The baseline mean age was 62.2 ± 11.9 years. During a median follow-up of 7.0 (IQR 3.4–11.0) years, 1031 (8.4 %) participants had PACs, and 566 (4.6 %) had incident AF at any of the median 6 (IQR 3–10) annual ECG recordings. BI events occurred in 517 (4.2 %) people (304 TIAs, 213 ischemic strokes). After adjustment, PACs were associated with incident AF (Hazard Ratio, 1.96 (95%CI, 1.53–2.50)), but not with overall BI events (1.09 (0.76–1.56)), or with TIA (0.91 (0.57–1.46)) or ischemic stroke (1.50 (0.88–2.54)) separately. AF was not associated with BI events (0.95 (0.55–1.63)). Conclusions: In people with T2D without a history of AF or BI events, PACs are associated with a two-fold increased risk of incident AF.

Age-associated sarcopenia, characterized by a progressive loss in muscle mass and strength, is the largest cause of frailty and disability in the elderly worldwide. Current treatments involve nonpharmacological guidelines that few subjects can abide by, highlighting the need for effective drugs. Preclinical models were employed to test the benefits of RJx-01, a combination drug composed of metformin and galantamine, on sarcopenia. In worms, RJx-01 treatment improved lifespan, locomotion, pharyngeal pumping, and muscle fiber organization. The synergistic effects of RJx-01 were recapitulated in a transgenic mouse model that displays an exacerbated aging phenotype (Opa1–/–). In these mice, RJx-01 ameliorated physical performance, muscle mass and force, neuromuscular junction stability, and systemic inflammation. RJx-01 also improved physical performance and muscle strength in 22-month-old WT mice and also improved skeletal muscle ultrastructure, mitochondrial morphology, autophagy, lysosomal function, and satellite cell content. Denervation and myofiber damage were decreased in RJx-01–treated animals compared with controls. RJx-01 improved muscle quality rather than quantity, indicating that the improvement in quality underlies the beneficial effects of the combination drug. The studies herein indicate synergistic beneficial effects of RJx-01 in the treatment of sarcopenia and support the pursuit of RJx-01 in a human clinical trial as a therapeutic intervention for sarcopenia.

Abstract The development of rapid, selective, and sensitive fluorescent sensors is essential for visualizing and quantifying biological molecules and processes in vitro, ex vitro, and in vivo, which is important for not only fundamental biological studies but the accurate diagnosis of diseases. The emerging field of activity‐based sensing (ABS), a sensing method that utilizes molecular reactivity for analyte detection possesses many advantages including high specificity, sensitivity and accuracy. The aggregation caused quenching phenomenon which occurs in most conventional fluorophores results in reduced labeling efficiency of the target analytes and low photobleaching resistance, therefore limiting the applications of the ABS strategy. In contrast, aggregation induced emission (AIE) active luminogens (AIEgens) provide exceptional molecular frameworks for ABS. Of the many reaction classes utilized in the AIEgen ABS approach, click chemistry has become increasing popular. In this review, the sensing concepts of the ABS approach with AIEgens and the principles of click chemistry are discussed, followed by a systematic summary of the application of specific click chemistry reactions in AIEgen ABS protocols for the detection of an array of target analytes. Furthermore, the utility of click chemistry in the construction of AIEgens for bioimaging will also be showcased throughout the review.

A genome-wide association study on classic bladder exstrophy reveals eight genome-wide significant loci, most of which contained genes expressed in embryonic developmental bladder stages.

Perception is driven not only by current stimulation but also by previous sensory experience, which may serve as a perceptual prior for stimulus processing. A possible mechanism underlying this phenomenon is formalized in the internal reference model, which assumes that humans rely on an internal reference that updates continuously by integrating past and present stimulus representations. As a direct consequence of this process, discrimination sensitivity is higher when a constant standard precedes rather than follows a variable comparison in two-alternative forced-choice tasks. The present study exploited this Type B effect in order to examine whether an internal reference can be formed across stimuli varying within and across modalities. In a series of four experiments, task-irrelevant and/or task-relevant features either remained constant or varied from trial to trial. In duration discrimination, the Type B effect as a proxy of perceptual prior formation was not affected by variation of pitch or modality. However, in intensity discrimination, it was considerably reduced when stimulus modality and thus also the task-relevant feature (i.e., brightness and loudness) alternated rather than remained constant. These results indicate that temporal information can be isolated from stimulus-specific features and integrated across subsequent trials into a perceptual prior for stimulus judgment, whereas intensity information from different modalities seems to hamper this process. In general, our findings contribute to a growing body of research aimed at understanding the formation and content of perceptual priors.

In a recent clinical trial for oral administration of cipargamin in individuals with malaria, there was an emergence of recrudescent parasites with a G358S mutation in PfATP4. In this work, the authors investigate the effect of this mutation on the function of the ATPase, on parasite growth and susceptibility to antimalarial drugs.

Apicomplexans are widespread parasites of humans and other animals, and include the causative agents of malaria (Plasmodium species) and toxoplasmosis (Toxoplasma gondii). Existing anti-apicomplexan therapies are beset with issues around drug resistance and toxicity, and new treatment options are needed. The mitochondrial electron transport chain (ETC) is one of the few processes that has been validated as a drug target in apicomplexans. To identify new inhibitors of the apicomplexan ETC, we developed a Seahorse XFe96 flux analyzer approach to screen the 400 compounds contained within the Medicines for Malaria Venture 'Pathogen Box' for ETC inhibition. We identified six chemically diverse, on-target inhibitors of the ETC in T. gondii, at least four of which also target the ETC of Plasmodium falciparum. Two of the identified compounds (MMV024937 and MMV688853) represent novel ETC inhibitor chemotypes. MMV688853 belongs to a compound class, the aminopyrazole carboxamides, that were shown previously to target a kinase with a key role in parasite invasion of host cells. Our data therefore reveal that MMV688853 has dual targets in apicomplexans. We further developed our approach to pinpoint the molecular targets of these inhibitors, demonstrating that all target Complex III of the ETC, with MMV688853 targeting the ubiquinone reduction (Qi) site of the complex. Most of the compounds we identified remain effective inhibitors of parasites that are resistant to Complex III inhibitors that are in clinical use or development, indicating that they could be used in treating drug resistant parasites. In sum, we have developed a versatile, scalable approach to screen for compounds that target the ETC in apicomplexan parasites, and used this to identify and characterize novel inhibitors.

The mitochondrial electron transport chain (ETC) of apicomplexan parasites differs considerably from the ETC of the animals that these parasites infect, and is the target of numerous anti-parasitic drugs. The cytochrome c oxidase complex (Complex IV) of the apicomplexan Toxoplasma gondii ETC is more than twice the mass and contains subunits not found in human Complex IV, including a 13 kDa protein termed TgApiCox13. TgApiCox13 is homologous to a human iron-sulfur (Fe-S) cluster-containing protein called the mitochondrial inner NEET protein (HsMiNT) which is not a component of Complex IV in humans. Here, we establish that TgApiCox13 is a critical component of Complex IV in T. gondii, required for complex activity and stability. Furthermore, we demonstrate that TgApiCox13, like its human homolog, binds two Fe-S clusters. We show that the Fe-S clusters of TgApiCox13 are critical for ETC function, having an essential role in mediating Complex IV integrity. Our study provides the first functional characterisation of an Fe-S protein in Complex IV.

Unlike mammals, adult zebrafish are able to fully regenerate axons and functionally recover from neuronal damage in the mature central nervous system (CNS). Decades of research have tried to identify the mechanisms behind their spontaneous regenerative capacity, but the exact underlying pathways and molecular drivers remain to be fully elucidated. By studying optic nerve injury-induced axonal regrowth of adult zebrafish retinal ganglion cells (RGCs), we previously reported transient dendritic shrinkage and changes in the distribution and morphology of mitochondria in the different neuronal compartments throughout the regenerative process. These data suggest that dendrite remodeling and temporary changes in mitochondrial dynamics contribute to effective axonal and dendritic repair upon optic nerve injury. To further elucidate these interactions, we here present a novel adult zebrafish microfluidic model in which we can demonstrate compartment-specific alterations in resource allocation in real-time at single neuron level. First, we developed a pioneering method that enables to isolate and culture adult zebrafish retinal neurons in a microfluidic setup. Notably, with this protocol, we report on a long-term adult primary neuronal culture with a high number of surviving and spontaneously outgrowing mature neurons, which was thus far only very limitedly described in literature. By performing time-lapse live cell imaging and kymographic analyses in this setup, we can explore changes in dendritic remodeling and mitochondrial motility during spontaneous axonal regeneration. This innovative model system will enable to discover how redirecting intraneuronal energy resources supports successful regeneration in the adult zebrafish CNS, and might facilitate the discovery of new therapeutic targets to promote neuronal repair in humans.

We report experimental values for the CH stretch frequencies of the protonated fullerenes C _60 H ^+ and C _70 H ^+ . Anharmonic frequency calculations at the B3LYP/6-31G level of theory, which are independent of empirical scaling factors, reproduce the experimental values to within approximately 5 cm ^−1 . Scaling theoretical harmonic frequencies by applying factors derived for polycyclic aromatic hydrocarbons deviate significantly from the experimentally measured frequency. We attribute this deviation to the unusual hydrocarbon structure that affects the degree of anharmonicity of the CH stretch. This result allows us to propose an original, specific scaling factor of 0.9524 to correct harmonic frequencies of CH stretches of protonated fullerenes calculated at the B3LYP/6-311 + G(d,p) level of theory. The special spectral position of the protonated fullerene CH stretch bands makes it a diagnostic marker that may aid in their detection in the interstellar medium.

In this paper, we present a meta-analysis of the motivational and performance effects of experimentally induced achievement goals and the moderating effects of "goal standard" and "goal framing"; comprising 90 studies which provided 235 effect sizes (11,247 participants). The findings show that, relative to performance-approach and performance-avoidance goals and no-goals, induced mastery-approach goals enhanced performance, but not motivation. With regards to the goal standard used in the inducement, mastery-approach goals related to better performance than performance-approach goals, when mastery-approach goals were based on task-referenced standards or when social comparison was used as a standard for inducing performance-approach goals. With regards to the goal framing used in the inducement, mastery-approach goals were more beneficial when achievement goals were induced by means of goal content. We therefore conclude that goal framing and goal standard should be taken into consideration in achievement goal research and practice.