Biopsychosocial rehabilitation in the working population with chronic low back pain:a concept analysis

OBJECTIVE: To identify the essential attributes of biopsychosocial rehabilitation for chronic low back pain in the working population.DESIGN: A concept analysis was conducted according to the 8-step method of Walker and Avant. This framework provides a clear concept and theoretical and operational definitions.METHODS: Five databases were searched, followed by a systematic screening. Subsequently, attributes, illustrative cases, antecedents, consequences and empirical referents were formulated.RESULTS: Of the 3793 studies identified, 42 unique references were included. Eleven attributes were identified: therapeutic exercise, psychological support, education, personalization, self-management, participation, follow-up, practice standard, goal-setting, social support, and dietary advice. Subsequently, illustrative cases were described. Antecedents, such as motivation, preparedness and a multidisciplinary team, were found, together with consequences such as decreased pain, less sick-leave and increased function and work status. Finally, examples of empirical referents were given.CONCLUSION: This study identified the attributes that are necessary to develop biopsychosocial rehabilitation intervention programmes for chronic low back pain. The defined concept of biopsychosocial rehabilitation for chronic low back pain may serve as a solid base to further develop and apply interventions. Future research should focus on the objectification of biopsychosocial rehabilitation and conceptualization regarding how personalization is done.</p

Impact of allosteric modulation: exploring the binding kinetics of glutamate and other orthosteric ligands of the metabotropic glutamate receptor 2

While many orthosteric ligands have been developed for the mGlu2 receptor, little is known about their target binding kinetics and how these relate to those of the endogenous agonist glutamate. Here, the kinetic rate constants, i.e. kon and koff, of glutamate were determined for the first time followed by those of the synthetic agonist LY354740 and antagonist LY341495. To increase the understanding of the binding mechanism and impact of allosteric modulation thereon, kinetic experiments were repeated in the presence of allosteric modulators. Functional assays were performed to further study the interplay between the orthosteric and allosteric binding sites, including an impedance-based morphology assay. We found that dissociation rate constants of orthosteric mGlu2 ligands were all within a small 6-fold range, whereas association rate constants were ranging over more than three orders of magnitude and correlated to both affinity and potency. The latter showed that target engagement of orthosteric mGlu2 ligands is kon-driven in vitro. Moreover, only the off-rates of the two agonists were decreased by a positive allosteric modulator (PAM), thereby increasing their affinity. Interestingly, a PAM increased the duration of a glutamate-induced cellular response. A negative allosteric modulator (NAM) increased both on- and off-rate of glutamate without changing its affinity, while it did not affect these parameters for LY354740, indicating probe-dependency. In conclusion, we found that affinity- or potency-based orthosteric ligand optimization primarily results in ligands with high kon values. Moreover, positive allosteric modulators alter the binding kinetics of orthosteric agonists mainly by decreasing koff, which we were able to correlate to a lengthened cellular response. Together, this study shows the importance of studying binding kinetics in early drug discovery, as this may provide important insights towards improved efficacy in vivo.Medicinal Chemistr

Discovery and Kinetic Profiling of 7-Aryl-1,2,4-triazolo[4,3-a]pyridines: Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 2

We report the synthesis and biological evaluation of a series of 7-aryl-1,2,4-triazolo[4,3-c]pyridines with mGlu(2) positive allosteric modulator (PAM) activity and affinity. Besides traditional in vitro parameters of potency and affinity, kinetic parameters k(on), k(off) and residence time (RT) were determined. The PAMs showed various kinetic profiles; k(on) values ranged over 2 orders of magnitude, whereas RT values were within a 10-fold range. Association rate constant k(on) was linearly correlated to affinity. Evaluation of a short, medium, and long RT compound in a label-free assay indicated a correlation between RT and functional effect. The effects of long RT compound 9 on sleep-wake states indicated long RT was translated into sustained inhibition of rapid eye movement (REM) in vivo. These results show that affinity-only driven selection would have resulted in mGlu(2) PAMs with high values for k(on) but not necessarily optimized RT, which is key to predicting optimal efficacy in vivo

Exploring the reasons behind nurses' intentions to leave their hospital or profession: A cross-sectional survey

Background Multiple factors can fuel nurses’ intention to leave their employing hospital or their profession. Job dissatisfaction and burnout are contributors to this decision. Sociodemographic and work context factors can also play a role in explaining nurses’ intention to leave. Objective To investigate the role of sociodemographic and work context factors, including job resources, job demands, job dissatisfaction, depersonalization, and emotional exhaustion, on nurses’ intention to leave their hospital or their profession. Design Multicentre cross-sectional study. Setting(s) Eight European hospitals, two per each country, including Belgium, the Netherlands, Italy, and Poland. Participants From May 16 to September 30, 2022, we collected 1,350 complete responses from nurses working at the selected hospitals (13 % response rate). Methods The intention to leave was assessed through two 5-Likert scale outcomes, agreeing with the intention to leave the profession and the intention to leave the hospital. Logistic regression models were used for statistical analysis. Results At the multivariable analysis, a higher intention to leave the hospital was observed for: younger age, having served on the frontline against COVID-19, lack of quipment, living in the Netherlands, emotional exhaustion, dissatisfaction with work prospects, and dissatisfaction with the use of professional abilities. There was a higher intention to leave the profession for: younger age, living in the Netherlands, having work-related health problems, depersonalization, emotional exhaustion, low possibilities of professional development, dissatisfaction with work prospects, lack of use of professional abilities, overall ob issatisfaction, and dissatisfaction with salary. Nurses living in Italy expressed the lowest intention to leave. Conclusion While confirming the role of job dissatisfaction and burnout, we found higher intention to leave for young nurses, nurses with work-related health problems, and caregivers during the COVID-19 pandemic. Dissatisfaction with work prospects, professional development, and salary also increased the intention to leave. We call for educators, managers, and policymakers to address these factors to retain at-risk nursing categories, implementing strategies to mitigate intentions to leave

Constitutive activity of the metabotropic glutamate receptor 2 explored with a whole-cell label-free biosensor

 Label-free cellular assays using a biosensor provide new opportunities for studying G protein-coupled receptor (GPCR) signaling. As opposed to conventional in vitro assays, integrated receptor-mediated cellular responses are determined in real-time rather than a single downstream signaling pathway. In this study, we examined the potential of a label-free whole cell impedance-based biosensor system (i.e. xCELLigence) to study the pharmacology of one GPCR in particular, the mGlu2 receptor. This receptor is a target for the treatment of several psychiatric diseases such as schizophrenia and depression. After optimization of assay conditions to prevent interference of endogenous glutamate in the culture medium, detailed pharmacological assessments were performed. Concentration-response curves showed a concentration-dependent increase in impedance for agonists and positive allosteric modulators, whereas receptor inhibition by an antagonist or negative allosteric modulator resulted in a concentration-dependent decrease in cellular impedance. Interestingly, constitutive receptor activity was observed that was decreased by LY341495, which therefore behaved as an inverse agonist here, a property that was heretofore unappreciated. This was confirmed by concentration-dependent modulation of LY341495 potency and efficacy by a allosteric modulators. In summary, the use of the xCELLigence system to study mGlu2 receptor pharmacology was validated. This is the first class C GPCR to be characterized extensively by such method, opening new avenues to study receptor pharmacology including inverse agonism and demonstrating its value for future drug discovery efforts of mGlu receptors as well as other GPCRs.Medicinal Chemistr

Intention to leave, depersonalisation and job satisfaction in physicians and nurses: a cross-sectional study in Europe

The European healthcare sector faces a significant shortage of healthcare workers. Assessing the prevalence of this issue and understanding its direct and indirect determinants are essential for formulating effective recruitment programs and enhancing job retention strategies for physicians and nurses. A multicentric cross-sectional study was conducted, involving 381 physicians and 1351 nurses recruited from eight European hospitals in Belgium, the Netherlands, Italy, and Poland. The study focused on assessing turnover intentions among healthcare workers based on the Job Demands-Resources model, using an online questionnaire. Structural equation models were employed to test the data collection questionnaires' construct validity and internal consistency. The turnover intention was assessed by agreement with the intention to leave either the hospital or the profession. Among physicians, 17% expressed an intention to leave the hospital, while 9% intended to leave the profession. For nurses, the figures were 8.9% and 13.6%, respectively. The internal consistency of the questionnaires exceeded 0.90 for both categories of health workers. Depersonalization and job dissatisfaction were identified as direct determinants of turnover intention, with work engagement being particularly relevant for nurses. We found a higher intention to leave the hospital among physicians, while nurses were more prone to leave their profession. To mitigate turnover intentions, it is recommended to focus on improving job satisfaction, work engagement and fostering a positive working climate, thereby addressing depersonalisation and promoting job retention