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Purpose Future organizations must focus on their ability to change to be sustainable, and this calls more attention to sustainability as an organizational issue. However, change initiatives often fail because of a lack of employee commitment. The purpose of this study is to examine how organizational culture and individual readiness for change (IRFC) relate to types of commitment to change. Design/methodology/approach Survey data from a sample of 259 employees in a Norwegian public organization undergoing major strategic changes were used to test the hypothesized relations. Findings The results show that flexible and stable organizational cultures did not relate differently to types of change commitment. This may indicate that the strength, rather than the type, of organizational culture is vital for change commitment. Nevertheless, a flexible organizational culture had a clearer relation to positive change commitment; in part through its positive relation with both change self-efficacy and negative personal valence. These are important dimensions of IRFC. Originality/value The study contributes to a nuanced understanding of the role of contextual and individual factors in explaining various types of commitment to organizational change, in particular, by examining the distinction between flexible and stable organizational culture, as well as separate dimensions of IRFC. A flexible culture together with both of the included dimensions of IRFC is shown to be of importance in fostering affective commitment to change – the gold standard of change commitment. Recognizing sustainability as an organizational issue underscores the need for creating a culture conducive to change.

Purpose The purpose of this paper was to test a model that differentiated between two types of job demands in relation to basic psychological need satisfaction, work motivation, and, in turn, employee well-being. In particular, job challenges and job hindrances were hypothesized to relate to this motivational process in different ways. Design/methodology/approach Survey data from a sample of 160 entrepreneurs were used in path analyses to test the hypothesized relations. Findings The results showed that job challenges related positively to autonomy- and competence need satisfaction as well as to autonomous work motivation, while job hindrances related negatively to satisfaction of the needs for autonomy, competence and relatedness. Further, satisfaction of the need for autonomy, competence and relatedness related positively to autonomous work motivation. Finally, all of the three basic psychological needs as well as autonomous work motivation related directly and positively to vitality. Originality/value These results support a view on job challenges and job hindrances as distinct within the job demands-resources model by showing how they are differently related to basic psychological needs, autonomous work motivation and, subsequently, worker well-being.

Although both employee wellbeing and performance are valued by organizations, achieving them conjointly is not simple in practice. Prior studies have highlighted the role of daily experiences of recovery from work stress for employee wellbeing and performance. In a work-life characterized by pressures to intensify the pace of work, employees may increasingly use proactive efforts to shape their daily off-job time to effectively recover from stress and maintain their wellbeing and performance. Based on the integrative needs model of crafting, effort-recovery model, and conservation of resources theory as guiding frameworks, we examine whether employees’ daily proactive recovery strategies predict daily off-job and work stress, affect, and subjective work performance through enhanced recovery experiences. Daily diary measurements were collected among a sample of 377 Norwegian employees across a period of two weeks in early 2022 (from Monday to Thursday, i.e., eight measurement days in total). Results of Bayesian multilevel models showed that crafting for detachment, for relaxation, and for autonomy during off-job time negatively predicted off-job stress and negative affect through matching recovery experiences, whereas crafting for mastery positively predicted positive affect through mastery experiences. Crafting for relaxation and for autonomy were directly negatively related to next-day work stress, but these effects were not mediated by matching recovery experiences. Crafting for autonomy positively predicted next-day self-rated work performance through control experiences. Our study contributes to the literature on recovery from work by highlighting proactive recovery strategies as important initiators of daily recovery processes.

Since previous in vitro experiments revealed that nicotine can impair endothelial intercellular communication via the downregulation of connexin43 (Cx43), we wanted to find out which nicotinic acetylcholine receptors are involved in the molecular mechanism of communication failure. Cultured human endothelial cells were exposed to 1 μM nicotine for 5 days. Intercellular communication was measured using dye transfer study with/without subtype-specific nicotinic acetylcholine receptor (nAChR) inhibitors. Reverse transcriptase (RT)-PCR was used to further investigate the regulation of nAChR subtypes. Electron microscopy together with MAP LC3-II western blot was used to investigate possible autophagy processes. In cultured human endothelial cells, nicotine decreased the Cx43 protein amount as shown by western blot and immunohistochemistry; however, together with an unaltered mRNA expression as shown by RT-PCR. The nicotine-induced Cx43 downregulation functionally impaired intercellular dye transfer, which could be prevented by mecamylamine, κ-bungarotoxin, lobeline, and dihydro-β-erythroidine but not α-bungarotoxin, indicating that the nAChR subtypes α4β2 and α3β2 but not α7 are involved in signal cascade. RT-PCR analysis revealed that nicotine exposure resulted in the upregulation of α3 and β4 and the downregulation of α4-nAChR, while α7- and β2-nAChR-mRNA expressions remained unaltered. Furthermore, nicotine increased total protein ubiquinylation and proteasome activity as was shown by immunohistochemistry and peptide degradation analysis. Evidence of enhanced autophagic processes was assured by the occurrence of autophagic vacuoles in transmission electron microscopy and enhanced formation of MAP LC3-II in western blot. Reduced intercellular endothelial communication together with programmed cell death helps to explain the toxic effect of nicotine leading to endothelial dysfunction. The nAChR involved in the impairment of intercellular communication seem to be α4β2 and α3β2 but not α7.

To identify persons with a high risk for cardiovascular diseases (CVD) special tools (scores, charts, graphics or computer programs) for CVD-risk assessment based on levels of the certain risk factors have been constructed. The applicability of these instruments depends on the derivation cohorts, considered risk factors and endpoints, applied statistical methods as well as used formats. The review addresses the risk-estimation tools for primary prevention of CVD potentially relevant for European populations. The risk-estimation tools were identified using two previously published systematic reviews as well as conducting a literature search in MEDLINE and a manual search. Only instruments were considered which were derived from cohorts of at least 1,000 participants of one gender without pre-existing CVD, enable risk assessment for a period of at least 5 years, were designed for an age-range of at least 25 years and published after the year 2000. A number of risk-estimation tools for CVD derived from single European, several European and from non-European cohorts were identified. From a clinical perspective, seem to be preferable instruments for risk of CVD contemporary developed for the population of interest, which use easily accessible measures and show a high discriminating ability. Instruments, restricting risk-estimation to certain cardiovascular events, recalibrated high-accuracy tools or tools derived from European populations with similar risk factors distribution and CVD-incidence are the second choice. In younger people, calculating the relative risk or cardiovascular age equivalence measures may be of more benefit.

Background Allopurinol, an xanthine oxidase (XO) inhibitor, is a promising intervention that may provide neuroprotection for neonates with hypoxic-ischemic encephalopathy (HIE). Currently, a double-blind, placebo-controlled study (ALBINO, NCT03162653) is investigating the neuroprotective effect of allopurinol in HIE neonates. Objective The aim of the current study was to establish the pharmacokinetics (PK) of allopurinol and oxypurinol, and the pharmacodynamics (PD) of both compounds on hypoxanthine, xanthine, and uric acid in HIE neonates. The dosage used and the effect of allopurinol in this population, either or not undergoing therapeutic hypothermia (TH), were evaluated. Methods Forty-six neonates from the ALBINO study and two historical clinical studies were included. All doses were administered on the first day of life. In the ALBINO study ( n  = 20), neonates received a first dose of allopurinol 20 mg/kg, and, in the case of TH ( n  = 13), a second dose of allopurinol 10 mg/kg. In the historical cohorts ( n  = 26), neonates (all without TH) received two doses of allopurinol 20 mg/kg in total. Allopurinol and oxypurinol population PK, and their effects on inhibiting conversions of hypoxanthine and xanthine to uric acid, were assessed using nonlinear mixed-effects modelling. Results Allopurinol and oxypurinol PK were described by two sequential one-compartment models with an autoinhibition effect on allopurinol metabolism by oxypurinol. For allopurinol, clearance (CL) was 0.83 L/h (95% confidence interval [CI] 0.62–1.09) and volume of distribution ( V d ) was 2.43 L (95% CI 2.25–2.63). For metabolite oxypurinol, CL and V d relative to a formation fraction ( f m ) were 0.26 L/h (95% CI 0.23–0.3) and 11 L (95% CI 9.9–12.2), respectively. No difference in allopurinol and oxypurinol CL was found between TH and non-TH patients. The effect of allopurinol and oxypurinol on XO inhibition was described by a turnover model of hypoxanthine with sequential metabolites xanthine and uric acid. The combined allopurinol and oxypurinol concentration at the half-maximal XO inhibition was 0.36 mg/L (95% CI 0.31–0.42). Conclusion The PK and PD of allopurinol, oxypurinol, hypoxanthine, xanthine, and uric acid in neonates with HIE were described. The dosing regimen applied in the ALBINO trial leads to the targeted XO inhibition in neonates treated with or without TH.

Background and Objective Previously, we developed a pharmacokinetic-pharmacodynamic model of allopurinol, oxypurinol, and biomarkers, hypoxanthine, xanthine, and uric acid, in neonates with hypoxic-ischemic encephalopathy, in which high initial biomarker levels were observed suggesting an impact of hypoxia. However, the full pharmacodynamics could not be elucidated in our previous study. The current study included additional data from the ALBINO study (NCT03162653) placebo group, aiming to characterize the dynamics of hypoxanthine, xanthine, and uric acid in neonates with hypoxic-ischemic encephalopathy. Methods Neonates from the ALBINO study who received allopurinol or placebo mannitol were included. An extended population pharmacokinetic-pharmacodynamic model was developed based on the mechanism of purine metabolism, where synthesis, salvage, and degradation via xanthine oxidoreductase pathways were described. The initial level of the biomarkers was a combination of endogenous turnover and high disease-related amounts. Model development was accomplished by nonlinear mixed-effects modeling (NONMEM ® , version 7.5). Results In total, 20 neonates treated with allopurinol and 17 neonates treated with mannitol were included in this analysis. Endogenous synthesis of the biomarkers reduced with 0.43% per hour because of precursor exhaustion. Hypoxanthine was readily salvaged or degraded to xanthine with rate constants of 0.5 1/h (95% confidence interval 0.33–0.77) and 0.2 1/h (95% confidence interval 0.09–0.31), respectively. A greater salvage was found in the allopurinol treatment group consistent with its mechanism of action. High hypoxia-induced initial levels of biomarkers were quantified, and were 1.2-fold to 2.9-fold higher in neonates with moderate-to-severe hypoxic-ischemic encephalopathy compared with those with mild hypoxic-ischemic encephalopathy. Half-maximal xanthine oxidoreductase inhibition was achieved with a combined allopurinol and oxypurinol concentration of 0.68 mg/L (95% confidence interval 0.48–0.92), suggesting full xanthine oxidoreductase inhibition during the period studied. Conclusions This extended pharmacokinetic-pharmacodynamic model provided an adequate description of the complex hypoxanthine, xanthine, and uric acid metabolism in neonates with hypoxic-ischemic encephalopathy, suggesting a positive allopurinol effect on these biomarkers. The impact of hypoxia on their dynamics was characterized, underlining higher hypoxia-related initial exposure with a more severe hypoxic-ischemic encephalopathy status.

Background Therapeutic hypothermia (TH) is an established intervention to improve the outcome of neonates with moderate-to-severe hypoxic-ischemic encephalopathy resulting from perinatal asphyxia. Despite this beneficial effect, TH may further affect drug elimination pathways such as the glomerular filtration rate. Objectives The objective of this study was to quantify the effect of TH in addition to asphyxia on mannitol clearance as a surrogate for the glomerular filtration rate. Methods The effect of asphyxia and TH (mild vs moderate/severe) on mannitol clearance was assessed using a population approach, based on mannitol observations collected in the ALBINO ( AL lopurinol in addition to TH for hypoxic-ischemic B rain I njury on N eurocognitive O utcome) trial, as some were exposed to a second dose of 10 mg/kg intravenous mannitol as placebo to ensure blinding. Pharmacokinetic analysis and model development were conducted using NONMEM version 7.4. Results Based on 77 observations from 17 neonates (TH = 13), a one-compartment model with first-order linear elimination best described the observed data. To account for prenatal glomerular filtration rate maturation, both birthweight and gestational age were implemented as clearance covariates using an earlier published three-quarters power function and a sigmoid hyperbolic function. Our final model predicted a mannitol clearance of 0.15 L/h for a typical asphyxia neonate (39.5 weeks, birthweight 3.25 kg, no TH), lower than the reported value of 0.33 L/h for a healthy neonate of similar age and weight. By introducing TH as a binary covariate on clearance, the additional impact of TH on mannitol clearance was quantified (60% decrease). Conclusions Mannitol clearance was decreased by approximately 60% in neonates undergoing TH, although this is likely confounded with asphyxia severity. Trial Registration ClinicalTrials.gov identifier NCT03162653.

The therapy of coronary heart disease (CHD) leads to an enormous economic burden on health-care systems. Coronary artery bypass grafting (CABG) and percutaneous revascularizations with implantation of drug-eluting stents (DES) are important treatment methods in CHD. The presented evaluation addresses cost efficacy of the use of DES versus CABG in CHD patients. A health-economic model considering linear resource use was performed from a restricted societal perspective for time periods of 1 and 3 years. Because of the short time horizon discounting was not applied. The clinical assumptions for event rates at 1 and 3 years were derived from the ARTS-I study for CABG, and from the ARTS-II study for DES (sirolimus-eluting stents). Cost assumptions for the resources used were based on the German Diagnosis Related Groups 2007 (G-DRG-2007). The base case value was assumed to be 2,800 Euros, the average DES price 1,200 Euros, and the average DES use per patient 3.7. The average per-patient daily clopidogrel costs were assumed to be 2.57 Euros, and the duration of the clopidogrel therapy 12 months. Within the scope of sensitivity analyses, different model parameters were varied and the evaluation was tested for its robustness. The average costs for percutaneous coronary intervention (PCI) without DES were found to be 4,420 Euros, for CABG 12,840 Euros, and for DES intervention 8,860 Euros (Table 4). 1-year clopidogrel intake resulted in 938 Euros, the treatment of patients with myocardial infarction during follow-up in 3,989 Euros. The 1-year per-patient total costs after CABG were calculated to be 13,373 Euros and after DES 10,443 Euros, leading to a difference of 2,930 Euros in favor of DES implantation (Table 6). The 3-year per-patient total costs after CABG were estimated to be 13,630 Euros and after DES 10,905 Euros, showing a Rehabilitationsmasscost difference of 2,725 Euros in favor of DES implantation (Table 6). Changes in cost-weights of G-DRG-2007 for CABG and PCI, DES price and DES use per patient as well as in the duration of the clopidogrel therapy influenced the cost differences considerably; however, they did not reach a break-even point (Figures 2 and 3). Changes in the clinical follow-up assumptions showed a lower effect on the difference in total costs (Figures 2 and 3). The presented data, indicating a possible economic middle-term advantage of DES versus CABG, should be proven with clinical assumptions derived from randomized clinical trials.

Zusammenfassung Hintergrund und Fragestellung: Wichtige Behandlungsmethoden bei koronarer Herzkrankheit (KHK) sind Bypassoperationen (CABG) und perkutane Revaskularisationen mit Implantation eines Medikamente freisetzenden Stent (DES). Es stellt sich die Frage nach der Kostenwirksamkeit beim Einsatz von DES versus CABG bei KHK-Patienten. Methodik: Eine gesundheitsökonomische Modellierung wurde aus einer eingeschränkten gesellschaftlichen Perspektive mit einem Zeithorizont von 1 bzw. 3 Jahren durchgeführt. Klinische Wahrscheinlichkeitsannahmen wurden für CABG der ARTS-I- und für DES der ARTS-II-Studie entnommen. Für die Kostenannahmen wurden die Bewertungsrelationen aus den deutschen Fallpauschalen (G-DRG-2007) herangezogen. Als Basisfallwert wurden 2 800 Euro angenommen. Der Preis für einen DES wurde mit 1 200 Euro, die Anzahl der angewendeten Stents pro Patient mit 3,7 und die Tagestherapiekosten für Clopidogrel mit 2,57 Euro pro Patient angesetzt, die angenommene Therapiedauer mit Clopidogrel betrug 12 Monate. Ergebnisse: Die Gesamtkosten pro Patient 1 Jahr bzw. 3 Jahre nach CABG betrugen 13 373 bzw. 13 630 Euro und nach DES 10 443 bzw. 10 905 Euro, d.h., es ergab sich ein Kostenunterschied von 2 930 bzw. 2 725 Euro zugunsten der DES-Implantation. Bei den durchgeführten Sensitivitätsanalysen kam es zu keiner Umkehr des Kostenunterschieds. Schlussfolgerung: Der vorliegende Hinweis auf einen möglichen ökonomischen Vorteil von DES-Implantationen im Vergleich zu CABG sollte im langfristigen Follow-up und in randomisiert-kontrollierten Studien überprüft werden.