Embeddedness and perceived oneness: Examining the effects of job embeddedness and its trajectory on employee proactivity via an identification perspective.

Although job embeddedness has consistently been shown to be associated with positive workplace behaviors, our theoretical understanding of such associations remains far behind our empirical knowledge. In particular, it is unclear how job embeddedness goes beyond its common conceptualization as "stuckness" to motivate employees' discretionary, change-oriented behaviors at work. To this end, we trace the original theoretical foundation of job embeddedness theory in field theory and establish its theoretical connection to social identity theory. We propose that increased organizational identification is an intrinsic psychological mechanism through which job embeddedness motivates proactive behaviors from employees. Further informed by field theory, we also examine the implications of job embeddedness change over time. We propose that a more positive trajectory of embeddedness over time contributes to enhanced organizational identification and employee proactivity, above and beyond the absolute level of embeddedness. We report a longitudinal study that surveyed 264 employees at three points in time over the course of 1 year and provide substantial support for the hypotheses. Implications of our work are discussed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

The nonlinear relationship between atypical applicant experience and hiring: The red flags perspective.

Hiring managers regularly encounter job applicants with atypical levels of experience across several common domains-For example, occupational experience, general work experience, educational experience, and life experience. Surprisingly, few large-scale studies have investigated how hiring managers respond to applicants with atypical experience for the job, leaving a substantial lacuna in our knowledge. The primary goal of the present study is to examine the association between relative under- and over-experience in the aforementioned domains and the likelihood of applicants being subsequently interviewed and eventually hired. We draw on insights from attribution theory to introduce the concept of red flags in the judgment of applicant experience. In doing so, we propose that hiring managers may avoid interviewing and hiring applicants with atypical experience relative to the applicant pool (i.e., relative over- or underexperience). Overall, our red flags perspective posits that job applicants with typical amounts of experience will be favored by hiring managers, which may be a useful lens for explaining why highly experienced applicants are not always considered. We test these predictions on a unique dataset parsed from 53,194 résumés and the corresponding application forms from 42 different organizations. Our results are broadly consistent with the red flags perspective, notably uncovering some intricate nonlinear effects. Implications for theory and practice are discussed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

The CNS-Penetrant Soluble Guanylate Cyclase Stimulator CY6463 Reveals its Therapeutic Potential in Neurodegenerative Diseases.

Effective treatments for neurodegenerative diseases remain elusive and are critically needed since the burden of these diseases increases across an aging global population. Nitric oxide (NO) is a gasotransmitter that binds to soluble guanylate cyclase (sGC) to produce cyclic guanosine monophosphate (cGMP). Impairment of this pathway has been demonstrated in neurodegenerative diseases. Normalizing deficient NO-cGMP signaling could address multiple pathophysiological features of neurodegenerative diseases. sGC stimulators are small molecules that synergize with NO, activate sGC, and increase cGMP production. Many systemic sGC stimulators have been characterized and advanced into clinical development for a variety of non-central nervous system (CNS) pathologies. Here, we disclose the discovery of CY6463, the first brain-penetrant sGC stimulator in clinical development for the treatment of neurodegenerative diseases, and demonstrate its ability to improve neuronal activity, mediate neuroprotection, and increase cognitive performance in preclinical models. In several cellular assays, CY6463 was demonstrated to be a potent stimulator of sGC. In agreement with the known effects of sGC stimulation in the vasculature, CY6463 elicits decreases in blood pressure in both rats and mice. Relative to a non-CNS penetrant sGC stimulator, rodents treated with CY6463 had higher cGMP levels in cerebrospinal fluid (CSF), functional-magnetic-resonance-imaging-blood-oxygen-level-dependent (fMRI-BOLD) signals, and cortical electroencephalographic (EEG) gamma-band oscillatory power. Additionally, CY6463 improved cognitive performance in a model of cognitive disruption induced by the administration of a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. In models of neurodegeneration, CY6463 treatment increased long-term potentiation (LTP) in hippocampal slices from a Huntington's disease mouse model and decreased the loss of dendritic spines in aged and Alzheimer's disease mouse models. In a model of diet-induced obesity, CY6463 reduced markers of inflammation in the plasma. Furthermore, CY6463 elicited an additive increase in cortical gamma-band oscillatory power when co-administered with donepezil: the standard of care in Alzheimer's disease. Together, these data support the clinical development of CY6463 as a novel treatment for neurodegenerative disorders.

Discovery of CYR715: A novel carboxylic acid-containing soluble guanylate cyclase stimulator.

Soluble guanylate cyclase (sGC) is a clinically validated therapeutic target in the treatment of pulmonary hypertension. Modulators of sGC have the potential to treat diseases that are affected by dysregulation of the NO-sGC-cGMP signal transduction pathway. This letter describes the SAR efforts that led to the discovery of CYR715, a novel carboxylic acid-containing sGC stimulator, with an improved metabolic profile relative to our previously described stimulator, IWP-051. CYR715 addressed potential idiosyncratic drug toxicity (IDT) liabilities associated with the formation of reactive, migrating acyl glucuronides (AG) found in related carboxylic acid-containing analogs and demonstrated high oral bioavailability in rat and dose-dependent hemodynamic pharmacology in normotensive Sprague-Dawley rats.

Thermodynamic and kinetic evaluation of the impact of polymer excipients on storage stability of amorphous itraconazole.

Two pharmaceutical polymers with high glass transition temperatures (Tg > 100 °C), polyvinylpyrrolidone-vinyl acetate copolymer (PVPVA) and hydroxypropyl methylcellulose acetate succinate (HPMCAS), have been assessed for their impact on the storage stability of itraconazole (ITZ) amorphous solid dispersions (ASDs). The results showed that the inhibitory effect of PVPVA on the recrystallization of amorphous ITZ was highly sensitive to surrounding relative humidity (RH), especially at RH above 60%. In contrast, amorphous ITZ in HPMCAS matrix exhibited much stronger resistance to recrystallization even under high RH conditions, reflecting the superior crystallization-inhibitory effect of HPMCAS. While the ITZ loads in the two polymers far exceeded the respective thermodynamic solubility limits, both ASD systems remained physically stable over an extended storage period at RH ≤ 60%. Kinetics rather than thermodynamics dictate the physical stability of ITZ ASDs. Crystallization of ITZ in ASDs appears to involve a complex interplay of multiple factors, including polymer type, glass transition temperatures (Tgs) of drug and polymer, crystallization tendency of amorphous drug, and storage conditions. Specifically, with respect to the impact of polymer type, HPMCAS is particularly effective for maintaining the storage stability of ITZ ASDs, which can be attributed to its higher Tg and lower hydrophilicity.

Effect of Alkylation on the Cellular Uptake of Polyethylene Glycol-Coated Gold Nanoparticles.

Alkyl groups (CnH2n+1) are prevalent in engineered bionanomaterials used for many intracellular applications, yet how alkyl groups dictate the interactions between nanoparticles and mammalian cells remains incomprehensively investigated. In this work, we report the effect of alkylation on the cellular uptake of densely polyethylene glycol-coated nanoparticles, which are characterized by their limited entry into mammalian cells. Specifically, we prepare densely PEGylated gold nanoparticles that bear alkyl chains of varying carbon chain lengths (n) and loading densities (termed "alkyl-PEG-AuNPs"), followed by investigating their uptake by Kera-308 keratinocytes. Strikingly, provided a modest alkyl mass percentage of 0.2% (2 orders of magnitude lower than that of conventional lipid-based NPs) in their PEG shells, dodecyl-PEG-AuNPs (n = 12) and octadecyl-PEG-AuNPs (n = 18) can enter Kera-308 cells 30-fold more than methoxy-PEG-AuNPs (no alkyl groups) and hexyl-PEG-AuNPs (n = 6) after 24 h of incubation. Such strong dependence on n is valid for all serum concentrations considered (even under serum-free conditions), although enhanced serum levels can trigger the agglomeration of alkyl-PEG-AuNPs (without permanent aggregation of the AuNP cores) and can attenuate their cellular uptake. Additionally, alkyl-PEG-AuNPs can rapidly enter Kera-308 cells via the filipodia-mediated pathway, engaging the tips of membrane protrusions and accumulating within interdigital folds. Most alkyl-PEG-AuNPs adopt the "endo-lysosomal" route of trafficking, but ∼15% of them accumulate in the cytosol. Regardless of intracellular location, alkyl-PEG-AuNPs predominantly appear as individual entities after 24 h of incubation. Our work offers insights into the incorporation of alkyl groups for designing bionanomaterials for cellular uptake and cytosolic accumulation with intracellular stability.

One hundred years of employee turnover theory and research.

We review seminal publications on employee turnover during the 100-year existence of the Journal of Applied Psychology. Along with classic articles from this journal, we expand our review to include other publications that yielded key theoretical and methodological contributions to the turnover literature. We first describe how the earliest papers examined practical methods for turnover reduction or control and then explain how theory development and testing began in the mid-20th century and dominated the academic literature until the turn of the century. We then track 21st century interest in the psychology of staying (rather than leaving) and attitudinal trajectories in predicting turnover. Finally, we discuss the rising scholarship on collective turnover given the centrality of human capital flight to practitioners and to the field of human resource management strategy. (PsycINFO Database Record

The effects of proximal withdrawal states on job attitudes, job searching, intent to leave, and employee turnover.

We present the first major test of proximal withdrawal states theory (PWST; Hom, Mitchell, Lee, & Griffeth, 2012). In addition, we develop and test new ideas to demonstrate how PWST improves our understanding and prediction of employee turnover. Across 2 studies, we corroborate that reluctant stayers (those who want to leave but have to stay) are similar to enthusiastic leavers (those who want to leave and can leave) in affective commitment, job satisfaction, and job embeddedness, and that reluctant leavers (those who want to stay but have to leave) are similar to enthusiastic stayers (those who want to stay and can stay) on these dimensions. We find that job satisfaction and job embeddedness more strongly influence the intent to leave and job search behavior for enthusiastic stayers and leavers than for reluctant stayers and leavers. More important, we show that for those experiencing low control over their preference for leaving or staying (i.e., reluctant stayers and leavers), traditional variables such as job satisfaction, job embeddedness, and intent to leave are poor predictors of their turnover behavior. We further demonstrate that focusing on enthusiastic stayers and leavers can significantly enhance the accuracy of job satisfaction, job embeddedness, and intent to leave for predicting actual employee turnover. (PsycINFO Database Record

Discovery of IWP-051, a Novel Orally Bioavailable sGC Stimulator with Once-Daily Dosing Potential in Humans.

In recent years, soluble guanylate cyclase (sGC, EC 4.6.1.2) has emerged as an attractive therapeutic target for treating cardiovascular diseases and diseases associated with fibrosis and end-organ failure. Herein, we describe our design and synthesis of a series of 4-hydroxypyrimidine sGC stimulators starting with an internally discovered lead. Our efforts have led to the discovery of IWP-051, a molecule that achieves good alignment of potency, stability, selectivity, and pharmacodynamic effects while maintaining favorable pharmacokinetic properties with once-daily dosing potential in humans.

Micellar delivery of dasatinib for the inhibition of pathologic cellular processes of the retinal pigment epithelium.

The objective of this study was to fabricate dasatinib-loaded nanoparticles and evaluate their efficacy in inhibiting cellular processes of the retinal pigment epithelium (RPE) related to proliferative vitreoretinopathy (PVR), for which there are no approved pharmacological approaches. We successfully encapsulated dasatinib, a poorly soluble multi-targeted tyrosine kinase inhibitor which has great potential for the treatment of PVR, into nanoparticles prepared from micellation of PEG-b-PCL. The size of the nanomicelles was approximately 55nm with a narrow distribution. They increased the solubility of dasatinib by 475× and provided a sustained drug release. ARPE-19, an immortal RPE cell line, was used to assess the in vitro efficacy of micellar dasatinib because the RPE is believed to play a key role in the pathogenesis of PVR. Three cell-based assays, namely, proliferation, adhesion and migration, which represent three important PVR-related cellular changes of the RPE, were conducted and the cytotoxicity of micelles was also evaluated. Both blank and dasatinib-loaded micelles were non-cytotoxic towards ARPE-19 cells. Micellar dasatinib significantly inhibited cell proliferation, adhesion and migration compared to the free drug; this might be attributable to enhanced solubility. PEG-b-PCL micelles were taken up into the ARPE-19 cells by an energy-dependent clatharin and caveolae-mediated endocytosis. Our results indicated that cellular uptake and the anti-proliferation effect of drugloaded micelles were linearly correlated. Drug loading appears to be a critical parameter for cellular uptake which in turn impacts the in vitro bioactivities of polymeric micelles. Our results clearly demonstrated that dasatinib-encapsulated micelles offer considerable promise in the management of PVR.

Delivery of poorly soluble compounds by amorphous solid dispersions.

Solid state manipulation by amorphous solid dispersion has been the subject of intensive research for decades due to their excellent potential for dissolution and bioavailability enhancement. The present review aims to highlight the latest advancement in this area, with focus on the fundamentals, characterization, formulation development and manufacturing of amorphous solid dispersions as well as the new generation amorphization technologies. Additionally, specific applications of amorphous solid dispersion in the formulation of herbal drugs or bioactive natural products are reviewed to reflect the growing interest in this relatively neglected area.

Reviewing employee turnover: focusing on proximal withdrawal states and an expanded criterion.

We reconceptualize employee turnover to promote researchers' understanding and prediction of why employees quit or stay in employing institutions. A literature review identifies shortcomings with prevailing turnover dimensions. In response, we expand the conceptual domain of the turnover criterion to include multiple types of turnover (notably, involuntary quits) and multiple types of staying. Guided by the premise that "everyone eventually leaves; no one stays with an organization forever," we also suggest considering where leavers end up-or post-exit destinations, such as another job, full-time parenting, or educational pursuits. We propose "proximal withdrawal states" that motivate members to participate or withdraw from organizations as an expanded criterion. These motivational states precede turnover and are derived from 2 overarching dimensions: desired employment status (whether employees want to stay or leave) and perceived volitional control (whether quit or stay decisions are completely up to them or at least partially under external regulation). Crossing these dimensions yields 4 prime states: enthusiastic leavers and stayers and reluctant leavers and stayers. We further subdivide these mind-sets into subtypes by differentiating employer from other forms of external control (e.g., family). Focusing on more common subtypes, we explain how they arise from particular motivational forces and profile how they differ by attitudes, behaviors, and turnover speed and destinations. We further discuss ways to measure this expanded criterion and proximal states (and subtypes) and investigate the latter's profiled differences. Finally, we discuss scientific and practical implications and future research directions.

Further clarification on the Hom, Mitchell, Lee, and Griffeth (2012) model: Reply to Bergman, Payne, and Boswell (2012) and Maertz (2012).

In this article, we reply to Bergman, Payne, and Boswell (2012) and Maertz (2012), who commented on our reconceptualization of the employee turnover criterion and proximal withdrawal states (Hom, Mitchell, Lee, & Griffeth, 2012). We agree with some points (e.g., anticipated destinations) but take issue with others (e.g., turnover intentions as the criterion). Nonetheless, our aim is to clarify our integrative formulation about mindsets for organizational participation and withdrawal. In our view, the current process of "article-commentaries-reply" advances our collective understanding of staying and leaving, which is of longstanding interest to scholars in industrial and organizational psychology, organizational behavior, and human resource management.

When and how is job embeddedness predictive of turnover? a meta-analytic investigation.

The present meta-analytic study introduces an overall model of the relationships between job embeddedness and turnover outcomes. Drawing on 65 independent samples (N = 42,907), we found that on-the-job and off-the-job embeddedness negatively related to turnover intentions and actual turnover, after controlling for job satisfaction, affective commitment, and job alternatives. In addition, the negative relationships between on-the-job embeddedness (off-the-job embeddedness) and turnover criteria were stronger in female-dominated samples and public organizations (collectivistic countries). Finally, turnover intentions, job search behavior, and job performance fully (partially) mediated the effect of on-the-job embeddedness (off-the-job embeddedness) on actual turnover. The research and practical implications of our findings are noted, in light of study limitations and future research needs.

Iron replacement therapy in inflammatory bowel disease patients with iron deficiency anemia: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Iron deficiency anemia (IDA) is a common problem in patients with Inflammatory Bowel Disease (IBD) and has a significant negative impact on quality of life. The aim was to compare the clinical efficacy of intravenous (IV) versus oral (PO) iron replacement in adult IBD with iron deficiency anemia (IDA). METHODS: A systematic search for randomized controlled trials comparing the efficacy of IV versus PO iron therapy in the treatment of IDA in adult IBD patients. The primary outcome was the mean change in the hemoglobin at the end of study and secondary outcomes include mean change in ferritin, clinical disease activity index, quality of life score and the adverse reaction rate. RESULTS: The search strategy identified 757 articles while only three industry-funded articles met the inclusion criteria for systematic review and meta-analysis. The total sample size was 333 patients with 203 patients receiving IV therapy. IV route was associated with a 6.8 g/L higher mean hemoglobin increment and 110 µg/L higher mean ferritin increment. The IBD activity index and Quality of Life scores were comparable between the two treatment groups. More adverse events were reported in the oral treatment group with the odds for discontinuation being 6.2 (CI 2.2, 17.1). CONCLUSIONS: Intravenous iron treatment is better tolerated and more effective than oral iron treatment in improving ferritin. The higher hemoglobin gain with the IV route was small and of uncertain clinical significance. The combined sample size of the included studies was small and further clinical trials are required.

The effects of autonomy and empowerment on employee turnover: test of a multilevel model in teams.

Extending research on voluntary turnover in the team setting, this study adopts a multilevel self-determination theoretical approach to examine the unique roles of individual and social-contextual motivational precursors, autonomy orientation and autonomy support, in reducing team member voluntary turnover. Analysis of multilevel time-lagged data collected from 817 employees on 115 teams indicates that psychological empowerment mediates the main effect of autonomy orientation and the interactive effect of autonomy support and its differentiation on a team member's voluntary turnover. The findings have meaningful implications for the turnover and self-determination literatures as well as for managers who endeavor to prevent voluntary turnover in teams.

Tumor necrosis factor-α monoclonal antibodies in the treatment of inflammatory bowel disease: clinical practice pharmacology.

In the last 10 years, anti-tumor necrosis factor (TNF)-α therapy has become a cornerstone in the management of autoimmune diseases. Clinical trial data have consistently found that infliximab, adalimumab, and recently certolizumab pegol offer therapeutic benefits to patients with inflammatory bowel diseases (Crohn's disease and ulcerative colitis). Recent understanding on how these monoclonal antibodies evoke changes at the physiological and molecular levels have provided insights into disease pathogenesis and helped to identify new targets for future drug therapy. With increased experience in the use of these anti-TNF-α antibodies the long-term safety data, use in pregnancy have become available. This article provides an overview of the current knowledge regarding anti-TNF-α therapies for clinicians caring for patients with Crohn's disease and ulcerative colitis.

Explaining employment relationships with social exchange and job embeddedness.

The research reported in this article clarifies how employee-organization relationships (EORs) work. Specifically, the authors tested whether social exchange and job embeddedness mediate how mutual-investment (whereby employers offer high inducements to employees for their high contributions) and over-investment (high inducements without corresponding high expected contributions) EOR approaches, which are based on Tsui, Pearce, Porter, and Tripoli's (1997) framework, affect quit propensity and organizational commitment. Two studies evaluated these intervening mechanisms. Study 1 surveyed 953 Chinese managers attending part-time master of business administration (MBA) programs in China, whereas Study 2 collected cross-sectional and longitudinal data from 526 Chinese middle managers in 41 firms. Standard and multilevel causal modeling techniques affirmed that social exchange and job embeddedness translate EOR influence. A second multilevel test using lagged outcome measures further established that job embeddedness mediates long-term EOR effects over 18 months. These findings corroborate prevailing views that social exchange explains how mutual- and over-investment EORs motivate greater workforce commitment and loyalty. This study enriches EOR perspectives by identifying job embeddedness as another mediator that is more enduring than social exchange.

Thiopurines, a previously unrecognised cause for fatigue in patients with inflammatory bowel disease.

BACKGROUND: Active inflammatory bowel disease, anaemia, iron deficiency and depression, alone or in combination, are known contributing factors of fatigue in inflammatory bowel disease. However, in some patients, fatigue cannot be attributed to known causes. Thiopurines are not a recognized cause. AIM: To describe the clinical scenario of a series of patients where thiopurines were the likely cause of fatigue. METHOD: The clinical scenario of 5 patients was examined with specific reference to the temporal association of thiopurine therapy with fatigue, the effect of its withdrawal and rechallenge, and drug specificity. RESULTS: The onset of severe fatigue was related to the introduction of azathioprine or 6-mercaptopurine, rapid relief was experienced on its withdrawal in all patients, and fatigue rapidly occurred on rechallenge. The speed of onset was rapid in two patients and in the context of gradual withdrawal of moderate steroid dose, but recurred rapidly on rechallenge when not on steroids. CONCLUSIONS: Marked fatigue is a previously unrecognized adverse effect of thiopurines. It does not appear to be drug-specific. Its onset might be masked by concurrent steroid therapy.