"Not" in the brain and behavior.

Negation is key for cognition but has no physical basis, raising questions about its neural origins. A new study in PLOS Biology on the negation of scalar adjectives shows that negation acts in part by altering the response to the adjective it negates.

Experimental and Machine-Learning-Assisted Design of Pharmaceutically Acceptable Deep Eutectic Solvents for the Solubility Improvement of Non-Selective COX Inhibitors Ibuprofen and Ketoprofen.

Deep eutectic solvents (DESs) are commonly used in pharmaceutical applications as excellent solubilizers of active substances. This study investigated the tuning of ibuprofen and ketoprofen solubility utilizing DESs containing choline chloride or betaine as hydrogen bond acceptors and various polyols (ethylene glycol, diethylene glycol, triethylene glycol, glycerol, 1,2-propanediol, 1,3-butanediol) as hydrogen bond donors. Experimental solubility data were collected for all DES systems. A machine learning model was developed using COSMO-RS molecular descriptors to predict solubility. All studied DESs exhibited a cosolvency effect, increasing drug solubility at modest concentrations of water. The model accurately predicted solubility for ibuprofen, ketoprofen, and related analogs (flurbiprofen, felbinac, phenylacetic acid, diphenylacetic acid). A machine learning approach utilizing COSMO-RS descriptors enables the rational design and solubility prediction of DES formulations for improved pharmaceutical applications.

Long-range sequential dependencies precede complex syntactic production in language acquisition.

To convey meaning, human language relies on hierarchically organized, long-range relationships spanning words, phrases, sentences and discourse. As the distances between elements (e.g. phonemes, characters, words) in human language sequences increase, the strength of the long-range relationships between those elements decays following a power law. This power-law relationship has been attributed variously to long-range sequential organization present in human language syntax, semantics and discourse structure. However, non-linguistic behaviours in numerous phylogenetically distant species, ranging from humpback whale song to fruit fly motility, also demonstrate similar long-range statistical dependencies. Therefore, we hypothesized that long-range statistical dependencies in human speech may occur independently of linguistic structure. To test this hypothesis, we measured long-range dependencies in several speech corpora from children (aged 6 months-12 years). We find that adult-like power-law statistical dependencies are present in human vocalizations at the earliest detectable ages, prior to the production of complex linguistic structure. These linguistic structures cannot, therefore, be the sole cause of long-range statistical dependencies in language.

[Positive experiences of specialist assistants and physicians with respect to the delegation research project StaerkeR : Evaluation of the training and experiences within the framework of this project]. / Positive Erfahrungen von Fachassistent:innen und Ärzt:innen hinsichtlich des Delegations-Forschungsprojekts StärkeR : Evaluation der Schulung und Erfahrungen im Rahmen dieses Projekts.

INTRODUCTION: The delegation of medical services to rheumatology assistants (RFA) has proven to be safe and effective in the evaluation of the research project "StaerkeR". Afterwards, the experiences of the participating RFAs and rheumatologists with delegation were surveyed and discussed within the framework of an opinion research project. METHODS: At the end of the project, the participating RFAs and rheumatologists were surveyed via an online questionnaire (quantitative analysis) (21 questions for physicians and 44 questions for RFAs). In addition, focus group meetings were held for the RFAs, which were led by a moderator and a secretary. The results of the focus group sessions (qualitative analyses) were analyzed according to the structured method of Kuckartz. RESULTS: All 31 RFAs and 25 rheumatologists involved in the project participated in the online surveys and 9 RFAs took part in the 2 focus groups. In the online surveys, both the RFAs and the rheumatologists gave predominantly good to very good ratings with respect to RFA training, the implementation of delegation in the practices and outpatient clinics, the role of the RFAs and the overall evaluation of the delegation concept. In the focus group discussions, many possible limitations regarding acceptance and implementation of the delegation concept were mentioned. CONCLUSION: The delegation of medical tasks to RFAs is a concept that is positively assessed and highly accepted by both sides, the rheumatologists and the RFAs. In a comparison between the individual practices and hospital outpatient departments, there is still a clear heterogeneity with respect to the willingness and logistical possibilities in the implementation of the delegation concept.

Endothelial cell-specific reactive oxygen species production increases susceptibility to aortic dissection.

BACKGROUND: Increased production of reactive oxygen species (ROS) throughout the vascular wall is a feature of cardiovascular disease states, but therapeutic strategies remain limited by our incomplete understanding of the role and contribution of specific vascular cell ROS to disease pathogenesis. To investigate the specific role of endothelial cell (EC) ROS in the development of structural vascular disease, we generated a mouse model of endothelium-specific Nox2 overexpression and tested the susceptibility to aortic dissection after angiotensin II (Ang II) infusion. METHODS AND RESULTS: A specific increase in endothelial ROS production in Nox2 transgenic mice was sufficient to cause Ang II-mediated aortic dissection, which was never observed in wild-type mice. Nox2 transgenic aortas had increased endothelial ROS production, endothelial vascular cell adhesion molecule-1 expression, matrix metalloproteinase activity, and CD45(+) inflammatory cell infiltration. Conditioned media from Nox2 transgenic ECs induced greater Erk1/2 phosphorylation in vascular smooth muscle cells compared with wild-type controls through secreted cyclophilin A (CypA). Nox2 transgenic ECs (but not vascular smooth muscle cells) and aortas had greater secretion of CypA both at baseline and in response to Ang II stimulation. Knockdown of CypA in ECs abolished the increase in vascular smooth muscle cell Erk1/2 phosphorylation conferred by EC conditioned media, and preincubation with CypA augmented Ang II-induced vascular smooth muscle cell ROS production. CONCLUSIONS: These findings demonstrate a pivotal role for EC-derived ROS in the determination of the susceptibility of the aortic wall to Ang II-mediated aortic dissection. ROS-dependent CypA secretion by ECs is an important signaling mechanism through which EC ROS regulate susceptibility of structural components of the aortic wall to aortic dissection.

Feasibility assessment of a novel selective peptide derivatization strategy for sensitivity enhancement for the liquid chromatography/tandem mass spectrometry bioanalysis of protein therapeutics in serum.

RATIONALE: Sensitivity is one major challenge limiting the application of liquid chromatography/tandem mass spectrometry (LC/MS/MS) methods for bioanalysis of proteins. A novel selective peptide derivatization (SPD) strategy was proposed to improve assay sensitivity. The main concept of the SPD strategy is to selectively derivatize surrogate peptides of the target protein in the digests, while not derivatizing the abundant background peptides, thereby improving the separation of target peptides during sample extraction and chromatography, and increasing the sensitivity. Additional benefits may help improve sensitivity include (1) increased ionization efficiency; (2) improved fragmentation pattern; and (3) increased sample extraction recovery of target peptides. METHODS: Feasibility assessment of the SPD strategy was conducted using BMS-986012, a monoclonal antibody, as the model protein, and with malondialdehyde (MDA) to selectively derivatize the arginine-containing surrogate peptide SLIY in tryptic-digested monkey serum samples. RESULTS: The decreased polarity and basicity of the MDA-derivatized peptide SLIY (MDA-SLIY) helped improve its separation from the background peptides during solid-phase extraction (SPE) and chromatography. The recovery of MDA-SLIY was 36.1-44.2%, which was ~3-fold higher than the recovery of peptide SLIY (11.9-16.1%). There was no significant ion suppression for MDA-SLIY. Overall, SPD improved the sensitivity ~5-fold. SPD methodology was then successfully applied to the development of a sensitive LC/MS/MS assay for BMS-986012 in monkey serum. CONCLUSIONS: This work demonstrates the feasibility of the SPD strategy for sensitivity enhancement. SPD can provide a simple, cost-efficient, and antibody-free sample preparation approach to improve sensitivity.

Diurnal profiles of pedometer-determined physical activity in chronically ill and mobility-limited older adults: a cross-sectional study.

BACKGROUND: The aim of this study was to analyze diurnal profiles of physical activity for community-dwelling adults aged 70 years and over, and to explore the moderating effect of sex, age, morbidity, mobility limitation, and season on physical activity throughout the day. METHODS: A sample of 149 primary health care patients (mean age 79.5 ± 5.2 years, 74.5% females) was included in the analyses. Participants' physical activity was measured on up to six consecutive days via Omron Walking Style Pro HJ-720IT-E2 pedometer. Step count per day and per hour, and pedometer wear time were descriptively analyzed. A repeated measures ANOVA with physical activity per hour as dependent variable was performed to analyze the moderating effect of sex, age, morbidity, mobility limitation, and season on diurnal profiles of physical activity. The diurnal profile for the total sample and adjusted diurnal profiles for subgroups are presented. RESULTS: Participants' daily step count averaged 3280 ± 1873 steps/day. They wore the pedometer for 14.2 ± 1.7 hours per day and walked on average 234 ± 139 steps per hour. With respect to diurnal profiles, there were two peaks at 10-11 AM (mean [95%-confidence interval]: 382 [329-435] steps) and at 3-4 pm (313 [261-365] steps) interrupted by a period of lower activity with a low point at 1-2 pm (229 [190-268] steps). A mobility limitation, defined by use of a cane or a rollator, had a significant moderating effect (p = 0.0237) on diurnal physical activity. CONCLUSIONS: This is the first study to explore pedometer-determined diurnal profiles of physical activity in chronically ill and mobility-limited older adults. Prolonging periods of elevated physical activity in the afternoon while respecting individual daily routine and commitments could be one option for facilitating the integration of physical activity and for making it a habit in older adults' daily lives. The use of a walking aid seems to be an indicator for a quite low activity plateau during the second half of the day. People who use walking aids should be motivated to increase their physical activity during afternoon; this might help to increase the overall low physical activity level of this vulnerable subgroup of older adults.

Acoustic and language-specific sources for phonemic abstraction from speech.

Spoken language comprehension requires abstraction of linguistic information from speech, but the interaction between auditory and linguistic processing of speech remains poorly understood. Here, we investigate the nature of this abstraction using neural responses recorded intracranially while participants listened to conversational English speech. Capitalizing on multiple, language-specific patterns where phonological and acoustic information diverge, we demonstrate the causal efficacy of the phoneme as a unit of analysis and dissociate the unique contributions of phonemic and spectrographic information to neural responses. Quantitive higher-order response models also reveal that unique contributions of phonological information are carried in the covariance structure of the stimulus-response relationship. This suggests that linguistic abstraction is shaped by neurobiological mechanisms that involve integration across multiple spectro-temporal features and prior phonological information. These results link speech acoustics to phonology and morphosyntax, substantiating predictions about abstractness in linguistic theory and providing evidence for the acoustic features that support that abstraction.

The Efficacy of Short-Term Bridging Strategies With High- and Low-Dose Prednisolone on Radiographic and Clinical Outcomes in Active Early Rheumatoid Arthritis: A Double-Blind, Randomized, Placebo-Controlled Trial.

OBJECTIVE: In active early rheumatoid arthritis (RA), glucocorticoids are often used for bridging, due to the delayed action of methotrexate. This study was undertaken to compare the effect of 3 bridging strategies, including high-dose and low-dose prednisolone, on radiographic and clinical outcomes. METHODS: Adult RA patients from 1 rheumatology hospital and 23 rheumatology practices who presented with moderate/high disease activity were randomized (1:1:1) to receive 60 mg prednisolone (high-dose prednisolone [HDP]) or 10 mg prednisolone (low-dose prednisolone [LDP]) daily (tapered to 0 mg within 12 weeks) or placebo. The 12-week intervention period was followed by 40 weeks of therapy at the physicians' discretion. The primary outcome measure was radiographic change at 1 year measured using the total modified Sharp/van der Heijde score (SHS). Disease activity was assessed with the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR). RESULTS: Of 395 randomized patients (HDP, n = 132; LDP, n = 131; placebo, n = 132), 375 (95%) remained in the modified intention-to-treat analysis. Mean ± SD changes in SHS scores in the 3 groups after 1 year were comparable: mean ± SD 1.0 ± 2.0 units in the HDP group, 1.1 ± 2.2 units in the LDP group, and 1.1 ± 1.5 units in the placebo group. The primary analysis showed no superiority of HDP compared to placebo (estimated difference of the mean change -0.04 [95% confidence interval (95% CI) -0.5, 0.4]). At week 12, the mean DAS28-ESR differed: -0.6 (95% CI -1.0, -0.2) for HDP versus placebo; -0.8 (95% CI -1.2, -0.5) for LDP versus placebo. At week 52, there was no significant difference in DAS28-ESR between the 3 groups (range 2.6-2.8). Serious adverse events occurred similarly often. CONCLUSION: Short-term glucocorticoid bridging therapy at a high dose showed no benefit with regard to progression of radiographic damage at 1 year.

The Structured Delegation of Medical Care Services for Patients With Inflammatory Rheumatic Diseases.

BACKGROUND: In some areas of Germany, there is a shortage of specialist physicians for patients with inflammatory rheumatic diseases. Delegating certain medical care services to qualified, specialized rheumatological assistants (SRAs) might be an effective way to supplement the available capacity for specialized medical care. METHODS: Patients under stable treatment for rheumatoid arthritis (RA) or psoriatic arthritis (PsA) were included in this trial, which was designed to demonstrate, in a first step, the non-inferiority of a form of care involving delegation of physicians' tasks to SRAs (team-based care), in comparison to standard care, with respect to changes in disease activity at one year. "Non-inferiority," in this context, means either superiority or else an irrelevant extent of inferiority. In a second step, in case non-inferiority could be shown, the superiority of team-based care with respect to changes in patients' health-related quality of life would be tested as well. Disease activity was measured with the Disease Activity Score 28, and health-related quality of life with the EQ-5D-5L. This was a randomized, multicenter, rater-blinded trial with two treatment arms (team-based care and standard care). The statistical analysis was performed with mixed linear models (DRKS00015526). RESULTS: From September 2018 to June 2019, 601 patients from 14 rheumatological practices and 3 outpatient rheumatological clinics in the German states of North Rhine-Westphalia and Lower Saxony were randomized to either team-based or standard care. Team-based care was found to be non-inferior to standard care with respect to changes in disease activity (adjusted difference = -0.19; 95% confidence interval [-0.36; -0.02]; p <0.001 for non-inferiority). Superiority with respect to health-related quality of life was not demonstrated (adjusted difference = 0.02 [-0.02; 0.05], p = 0.285). CONCLUSION: Team-based care, with greater integration of SRAs, is just as good as standard care in important respects. Trained SRAs can effectively support rheumatologists in the care of stable patients with RA or PsA.

Nurse-led care versus physician-led care in the management of rheumatoid arthritis and psoriatic arthritis (StaerkeR): study protocol for a multi-center randomized controlled trial.

BACKGROUND: In Germany, the care of patients with inflammatory arthritis could be improved. Although specialized rheumatology nurses could take over substantial aspects of patient care, this hardly occurs in Germany. Thus, the aim of the study is to examine structured nursing consultation in rheumatology practices. METHODS/DESIGN: In total, 800 patients with a stable course of rheumatoid arthritis or psoriatic arthritis in 20 centers in North Rhine-Westphalia and Lower Saxony will be randomized to either nurse-led care or standard care. Participating nurses will study for a special qualification in rheumatology and trial-specific issues. It is hypothesized that nurse-led care is non-inferior to standard care provided by rheumatologists with regard to a reduction of disease activity (DAS28) while it is hypothesized to be superior regarding changes in health-related quality of life (EQ-5D-5L) after 1 year. Secondary outcomes include functional capacity, patient satisfaction with treatment, and resource consumption. DISCUSSION: Since there is insufficient care of rheumatology patients in Germany, the study may be able to suggest improvements. Nurse-led care has the potential to provide more efficient and effective patient care. This includes a more stringent implementation of the treat-to-target concept, which may lead to a higher percentage of patients reaching their treatment targets, thereby improving patient-related outcomes, such as quality of life, functional capacity, and participation. Additionally, nurse-led care may be highly cost-effective. Finally, this project may form the basis for a sustainable implementation of nurse-led care in standard rheumatology care in Germany. TRIAL REGISTRATION: German Clinical Trials Register, DRKS00015526. Registered on 11 January 2019.

N-{3-[Bis(2-hydroxy-ethyl)amino-meth-yl]-5-nitro-phen-yl}benzamide.

The title compound, C(18)H(21)N(3)O(5), was prepared by the reaction of 3-benzamido-5-nitro-benzyl methane-sulfonate with diethano-lamine and is an inter-mediate in the synthesis of DNA minor-groove-binding polybenzamide agents capable of being conjugated to additional biologically active species. The asymmetric unit contains two independent mol-ecules, which differ only in the orientations of the hydroxy-ethyl groups. In the crystal structure, inter-molecular N-H⋯O and O-H⋯O hydrogen bonds link mol-ecules into one-dimensional chains.

Home-Based Exercise Supported by General Practitioner Practices: Ineffective in a Sample of Chronically Ill, Mobility-Limited Older Adults (the HOMEfit Randomized Controlled Trial).

OBJECTIVES: To evaluate the effects a home-based exercise program delivered to ill and mobility-limited elderly individuals on physical function, physical activity, quality of life, fall-related self-efficacy, and exercise self-efficacy. DESIGN: Randomized controlled trial (ISRCTN Registry, Reg.-No. ISRCTN17727272). SETTING: Fifteen general practitioner (GP) practices and participants' homes. PARTICIPANTS: Chronically ill and mobility-limited individuals aged 70 and older (N = 209). INTERVENTIONS: An exercise therapist delivered the experimental intervention-a 12-week multidimensional home-based exercise program integrating behavioral strategies-in individual counseling sessions at the GPs' practices and over the telephone. The control intervention focused on promoting light-intensity activities of daily living. Interventions took place between February 2012 and March 2013. MEASUREMENTS: The primary outcome was functional lower body strength (chair-rise test). Secondary outcomes were physical function (battery of motor tests), physical activity (step count), health-related quality of life (Medical Outcomes Study 8-item Short-Form Survey), fall-related (Falls Efficacy Scale-International Version), and exercise self-efficacy (Selbstwirksamkeit zur sportlichen Aktivitaet (SSA) scale). Postintervention differences between the groups were tested using analysis of covariance (intention to treat; adjusted for baseline value and GP practice; significance level P ≤ .05). RESULTS: Participants had a mean age ± standard deviation of 80 ± 5, 74% were female, 87% had three or more chronic diseases, and 54% used a walking aid. The difference (intention to treat; experimental minus control) between adjusted postintervention chair-rise times was -0.1 (95% confidence interval = -1.8-1.7). Differences for all secondary outcomes were also nonsignificant. CONCLUSION: The program was ineffective in the target population. Possibilities for improving the concept will have to be evaluated.

Crucial roles of Nox2-derived oxidative stress in deteriorating the function of insulin receptors and endothelium in dietary obesity of middle-aged mice.

BACKGROUND AND PURPOSE: Systemic oxidative stress associated with dietary calorie overload plays an important role in the deterioration of vascular function in middle-aged patients suffering from obesity and insulin resistance. However, effective therapy is still lacking. EXPERIMENTAL APPROACH: In this study, we used a mouse model of middle-aged obesity to investigate the therapeutic potential of pharmaceutical inhibition (apocynin, 5 mM supplied in the drinking water) or knockout of Nox2, an enzyme generating reactive oxygen species (ROS), in high-fat diet (HFD)-induced obesity, oxidative stress, insulin resistance and endothelial dysfunction. Littermates of C57BL/6J wild-type (WT) and Nox2 knockout (KO) mice (7 months old) were fed with a HFD (45% kcal fat) or normal chow diet (NCD, 12% kcal fat) for 16 weeks and used at 11 months of age. KEY RESULTS: Compared to NCD WT mice, HFD WT mice developed obesity, insulin resistance, dyslipidaemia and hypertension. Aortic vessels from these mice showed significantly increased Nox2 expression and ROS production, accompanied by significantly increased ERK1/2 activation, reduced insulin receptor expression, decreased Akt and eNOS phosphorylation and impaired endothelium-dependent vessel relaxation to acetylcholine. All these HFD-induced abnormalities (except the hyperinsulinaemia) were absent in apocynin-treated WT or Nox2 KO mice given the same HFD. CONCLUSIONS AND IMPLICATIONS: In conclusion, Nox2-derived ROS played a key role in damaging insulin receptor and endothelial function in dietary obesity after middle-age. Targeting Nox2 could represent a valuable therapeutic strategy in the metabolic syndrome.