Exploring the Motivation to Lead in a Demanding Environment: The Role of Achievement Values, Grit, and Psychological Capital.

As leaders across organizational contexts continue to face volatile and often stressful environments, a greater understanding of the psychological underpinnings of the motivation to lead (MTL) in challenging circumstances is needed. Based on a sample of 242 cadets holding leadership positions in a military college, we utilized a distal and proximal conceptualization of MTL to test achievement values, grit, and psychological capital (PsyCap) as antecedents to the three factors of MTL. Controlling for gender, prior leadership positions, and leader tenure, regression modeling revealed grit and achievement values to be positively associated with affective/identity MTL, while PsyCap was positively associated with all three MTL factors. In addition, PsyCap mediated the relation between grit and all three MTL factors. Our findings suggest that PsyCap plays a critical proximal role in MTL in demanding environments, and further implications for research and practice are discussed.

Examining the impact of succession management practices on organizational performance: A national study of U.S. hospitals.

BACKGROUND: Spearheaded by the industry's transition from volume- to value-based care, the health care reform movement has spurred both unprecedented challenges and opportunities for developing more effective and sustainable health care delivery organizations. Whereas the formidable challenges of leading hospitals and health systems have been widely discussed, including reimbursement degradation, the rapidly aging workforce, and the imminent wave of executive retirements, the opportunity to leverage succession management and talent development capabilities to overcome these challenges has been largely overlooked. PURPOSE: To address this key research and practice need, this multiphase study develops and validates an assessment of succession management practices for health care organizations. METHODOLOGY: Utilizing data collected from two national samples of hospital organizations, the results provide a 32-item succession management assessment comprising seven distinct sets of succession management practices. RESULTS: The results indicate that succession management practices are strongly associated with multiple hospital performance metrics, including patient satisfaction and Medicare Spending per Beneficiary, leadership bench strength, and internal/external placement rate for executive level positions. PRACTICE IMPLICATIONS: The author concludes this article with a discussion of several practical implications for health care executives and boards, including employing the succession management assessment for diagnosing development opportunities, benchmarking succession planning and talent development practices against similar hospitals or health systems, and elevating the profile of succession management as a strategic priority in today's increasingly uncertain health care landscape.

Fluorescence imaging of bombesin and transferrin receptor expression is comparable to 18F-FDG PET in early detection of sorafenib-induced changes in tumor metabolism.

Physical measurement of tumor volume reduction is the most commonly used approach to assess tumor progression and treatment efficacy in mouse tumor models. However, it is relatively insensitive, and often requires long treatment courses to achieve gross physical tumor destruction. As alternatives, several non-invasive imaging methods such as bioluminescence imaging (BLI), fluorescence imaging (FLI) and positron emission tomography (PET) have been developed for more accurate measurement. As tumors have elevated glucose metabolism, 18F-fludeoxyglucose (18F-FDG) has become a sensitive PET imaging tracer for cancer detection, diagnosis, and efficacy assessment by measuring alterations in glucose metabolism. In particular, the ability of 18F-FDG imaging to detect drug-induced effects on tumor metabolism at a very early phase has dramatically improved the speed of decision-making regarding treatment efficacy. Here we demonstrated an approach with FLI that offers not only comparable performance to PET imaging, but also provides additional benefits, including ease of use, imaging throughput, probe stability, and the potential for multiplex imaging. In this report, we used sorafenib, a tyrosine kinase inhibitor clinically approved for cancer therapy, for treatment of a mouse tumor xenograft model. The drug is known to block several key signaling pathways involved in tumor metabolism. We first identified an appropriate sorafenib dose, 40 mg/kg (daily on days 0-4 and 7-10), that retained ultimate therapeutic efficacy yet provided a 2-3 day window post-treatment for imaging early, subtle metabolic changes prior to gross tumor regression. We then used 18F-FDG PET as the gold standard for assessing the effects of sorafenib treatment on tumor metabolism and compared this to results obtained by measurement of tumor size, tumor BLI, and tumor FLI changes. PET imaging showed ~55-60% inhibition of tumor uptake of 18F-FDG as early as days 2 and 3 post-treatment, without noticeable changes in tumor size. For comparison, two FLI probes, BombesinRSense™ 680 (BRS-680) and Transferrin-Vivo™ 750 (TfV-750), were assessed for their potential in metabolic imaging. Metabolically active cancer cells are known to have elevated bombesin and transferrin receptor levels on the surface. In excellent agreement with PET imaging, the BRS-680 imaging showed 40% and 79% inhibition on days 2 and 3, respectively, and the TfV-750 imaging showed 65% inhibition on day 3. In both cases, no significant reduction in tumor volume or BLI signal was observed during the first 3 days of treatment. These results suggest that metabolic FLI has potential preclinical application as an additional method for detecting drug-induced metabolic changes in tumors.

In vivo imaging and quantification of carbonic anhydrase IX expression as an endogenous biomarker of tumor hypoxia.

Carbonic anhydrase IX (CA IX) is a transmembrane protein that has been shown to be greatly upregulated under conditions of hypoxia in many tumor cell lines. Tumor hypoxia is associated with impaired efficacy of cancer therapies making CA IX a valuable target for preclinical and diagnostic imaging. We have developed a quantitative in vivo optical imaging method for detection of CA IX as a marker of tumor hypoxia based on a near-infrared (NIR) fluorescent derivative of the CA IX inhibitor acetazolamide (AZ). The agent (HS680) showed single digit nanomolar inhibition of CA IX as well as selectivity over other CA isoforms and demonstrated up to 25-fold upregulation of fluorescent CA IX signal in hypoxic versus normoxic cells, which could be blocked by 60%-70% with unlabeled AZ. CA IX negative cell lines (HCT-116 and MDA-MB-231), as well as a non-binding control agent on CA IX positive cells, showed low fluorescent signal under both conditions. In vivo FMT imaging showed tumor accumulation and excellent tumor definition from 6-24 hours. In vivo selectivity was confirmed by pretreatment of the mice with unlabeled AZ resulting in >65% signal inhibition. HS680 tumor signal was further upregulated >2X in tumors by maintaining tumor-bearing mice in a low oxygen (8%) atmosphere. Importantly, intravenously injected HS680 signal was co-localized specifically with both CA IX antibody and pimonidazole (Pimo), and was located away from non-hypoxic regions indicated by a Hoechst stain. Thus, we have established a spatial correlation of fluorescence signal obtained by non-invasive, tomographic imaging of HS680 with regions of hypoxia and CA IX expression. These results illustrate the potential of HS680 and combined with FMT imaging to non-invasively quantify CA IX expression as a hypoxia biomarker, crucial to the study of the underlying biology of hypoxic tumors and the development and monitoring of novel anti-cancer therapies.

Quantitative Longitudinal Imaging of Vascular Inflammation and Treatment by Ezetimibe in apoE Mice by FMT Using New Optical Imaging Biomarkers of Cathepsin Activity and α(v)ß(3) Integrin.

Inflammation as a core pathological event of atherosclerotic lesions is associated with the secretion of cathepsin proteases and the expression of α(v)ß(3) integrin. We employed fluorescence molecular tomographic (FMT) noninvasive imaging of these molecular activities using cathepsin sensing (ProSense, CatB FAST) and α(v)ß(3) integrin (IntegriSense) near-infrared fluorescence (NIRF) agents. A statistically significant increase in the ProSense and IntegriSense signal was observed within the chest region of apoE(-/-) mice (P < 0.05) versus C57BL/6 mice starting 25 and 22 weeks on high cholesterol diet, respectively. In a treatment study using ezetimibe (7 mg/kg), there was a statistically significant reduction in the ProSense and CatB FAST chest signal of treated (P < 0.05) versus untreated apoE(-/-) mice at 31 and 21 weeks on high cholesterol diet, respectively. The signal of ProSense and CatB FAST correlated with macrophage counts and was found associated with inflammatory cells by fluorescence microscopy and flow cytometry of cells dissociated from aortas. This report demonstrates that cathepsin and α(v)ß(3) integrin NIRF agents can be used as molecular imaging biomarkers for longitudinal detection of atherosclerosis, and cathepsin agents can monitor anti-inflammatory effects of ezetimibe with applications in preclinical testing of therapeutics and potentially for early diagnosis of atherosclerosis in patients.

Synthesis and evaluation of near-infrared fluorescent sulfonamide derivatives for imaging of hypoxia-induced carbonic anhydrase IX expression in tumors.

A series of human carbonic anhydrase (hCA) IX inhibitors conjugated to various near-infrared fluorescent dyes was synthesized with the aim of imaging hypoxia-induced hCA IX expression in tumor cells in vitro, ex vivo and in vivo. The resulting compounds were profiled for inhibition of transmembrane hCA IX showing a range of potencies from 7.5 to 116 nM and up to 50-fold selectivity over the cytosolic form hCA II. Some of the compounds also showed inhibition selectivity for other transmembrane forms hCA XII and XIV as well. Compounds incubated in vitro with HeLa cells cultured under normoxic and hypoxic conditions detected upregulation of hCA IX under hypoxia by fluorescence microscopy. A pilot in vivo study in HT-29 tumor bearing mice showed significant accumulation of a fluorescent acetazolamide derivative in tumor tissue with little accumulation in other tissues. Approximately 10% of injected dose was non-invasively quantified in tumors by fluorescence molecular tomography (FMT), demonstrating the promise of these new compounds for quantitative imaging of hCA IX upregulation in live animals.

Noninvasive in vivo quantification of neutrophil elastase activity in acute experimental mouse lung injury.

We developed a neutrophil elastase-specific near-infrared fluorescence imaging agent, which, combined with fluorescence molecular tomographic imaging, allowed us to detect and quantify neutrophil elastase activity in vivo, in real time, and noninvasively in an acute model of lung injury (ALI). Significantly higher fluorescent signal was quantified in mice with LPS/fMLP-induced ALI as compared to healthy controls, correlating with increases in the number of bronchoalveolar lavage cells, neutrophils, and elastase activity. The agent was significantly activated ex vivo in lung sections from ALI but not from control mice, and this activation was ablated by the specific inhibitor sivelestat. Treatment with the specific inhibitor sivelestat significantly reduced lung signal in mice with ALI. These results underscore the unique ability of fluorescence molecular imaging to quantify specific molecular processes in vivo, crucial for understanding the mechanisms underlying disease progression and for assessing and monitoring novel pharmacological interventions.

Talent management best practices: how exemplary health care organizations create value in a down economy.

BACKGROUND: : Difficult economic conditions and powerful workforce trends pose significant challenges to managing talent in health care organizations. Although robust research evidence supports the many benefits of maintaining a strong commitment to talent management practices despite these challenges, many organizations compound the problem by resorting to workforce reductions and limiting or eliminating investments in talent management. PURPOSE: : This study examines how nationwide health care systems address these challenges through best practice talent management systems. Addressing important gaps in talent management theory and practice, this study develops a best practice model of talent management that is grounded in the contextual challenges facing health care practitioners. METHODOLOGY: : Utilizing a qualitative case study that examined 15 nationwide health care systems, data were collected through semistructured interviews with 30 executives and document analysis of talent management program materials submitted by each organization. FINDINGS: : Exemplary health care organizations employ a multiphased talent management system composed of six sequential phases and associated success factors that drive effective implementation. Based on these findings, a model of talent management best practices in health care organizations is presented. PRACTICE IMPLICATIONS: : Health care practitioners may utilize the best practice model to assess and enhance their respective talent management systems by establishing the business case for talent management, defining, identifying, and developing high-potential leaders, carefully communicating high-potential designations, and evaluating talent management outcomes.

Compliance with outpatient stress testing in low-risk patients presenting to the emergency department with chest pain.

Recent evidence suggests that stress testing prior to emergency department (ED) release in low-risk chest pain patients identifies those who can be safely discharged home. When immediate stress testing is not feasible, rapid outpatient stress testing has been recommended. The objective of this study was to determine compliance rate and incidence of adverse cardiac events in patients presenting to the ED with low-risk chest pain referred for outpatient stress testing. Retrospective chart and social security death index review were conducted in 448 consecutive chest pain patients who presented to a university hospital and level I trauma center between April 30 and December 31, 2007. Patients were evaluated with an accelerated chest pain protocol defined as a 4-hour ED rule out and referral for outpatient stress testing within 72 hours of ED release. Only patients without known cardiac disease, a thrombolysis in myocardial infarction risk score ≤2, negative serial ECGs and cardiac biomarkers, and benign ED course were eligible for the protocol. Primary outcome measures included compliance with outpatient stress testing and documented 30-day incidence of adverse cardiac events following ED release. The social security death index was queried to determine 12-month incidence of all-cause mortality in enrolled patients. Logistic regression analysis of characteristics associated with outpatient stress test compliance was determined and incidence of adverse cardiac events in those who were and were not compliant with outpatient stress testing was compared. Significance was set at P < 0.05. A total of 188 patients (42%) completed outpatient stress testing, but only 27 (6%) completed testing within 72 hours of ED discharge. Compliance was correlated with insurance and race, but not patient age, gender, or thrombolysis in myocardial infarction risk score. No significant differences in adverse cardiac events were documented in patients who did and did not comply with outpatient stress testing. Compliance with outpatient stress testing is poor in low-risk chest pain patients following ED release. Despite poor compliance, the documented incidence of adverse cardiac events in this low-risk cohort was lower than that reported in patients with negative provocative testing prior to ED release.

Continuous localized monitoring of plasmin activity identifies differential and regional effects of the serine protease inhibitor aprotinin: relevance to antifibrinolytic therapy.

BACKGROUND: Antifibrinolytic therapy, such as the use of the serine protease inhibitor aprotinin, was a mainstay for hemostasis after cardiac surgery. However, aprotinin was empirically dosed, and although the pharmacological target was the inhibition of plasmin activity (PLact), this was never monitored, off-target effects occurred, and led to withdrawn from clinical use. The present study developed a validated fluorogenic microdialysis method to continuously measure PLact and tested the hypothesis that standardized clinical empirical aprotinin dosing would impart differential and regional effects on PLact. METHODS/RESULTS: Pigs (30 kg) were instrumented with microdialysis probes to continuously measure PLact in myocardial, kidney, and skeletal muscle compartments (deltoid) and then randomized to high-dose aprotinin administration (2 mKIU load/0.5 mKIU/hr infusion; n = 7), low-dose aprotinin administration (1 mKIU load/0.250 mKIU/hr infusion; n = 6). PLact was compared with time-matched vehicle (n = 4), and PLact was also measured in plasma by an in vitro fluorogenic method. Aprotinin suppressed PLact in the myocardium and kidney at both high and low doses, indicative that both doses exceeded a minimal concentration necessary for PLact inhibition. However, differential effects of aprotinin on PLact were observed in the skeletal muscle, indicative of different compartmentalization of aprotinin. CONCLUSIONS: Using a large animal model and a continuous method to monitor regional PLact, these unique results demonstrated that an empirical aprotinin dosing protocol causes maximal and rapid suppression in the myocardium and kidney and in turn would likely increase the probability of off-target effects and adverse events. Furthermore, this proof of principle study demonstrated that continuous monitoring of determinants of fibrinolysis might provide a novel approach for managing fibrinolytic therapy.

Hybrid in vivo FMT-CT imaging of protease activity in atherosclerosis with customized nanosensors.

OBJECTIVE: Proteases are emerging biomarkers of inflammatory diseases. In atherosclerosis, these enzymes are often secreted by inflammatory macrophages, digest the extracellular matrix of the fibrous cap, and destabilize atheromata. Protease function can be monitored with protease activatable imaging probes and quantitated in vivo by fluorescence molecular tomography (FMT). To address 2 major constraints currently associated with imaging of murine atherosclerosis (lack of highly sensitive probes and absence of anatomic information), we compared protease sensors (PS) of variable size and pharmacokinetics and coregistered FMT datasets with computed tomography (FMT-CT). METHODS AND RESULTS: Coregistration of FMT and CT was achieved with a multimodal imaging cartridge containing fiducial markers detectable by both modalities. A high-resolution CT angiography protocol accurately localized fluorescence to the aortic root of atherosclerotic apoE(-/-) mice. To identify suitable sensors, we first modeled signal kinetics in-silico and then compared 3 probes with oligo-L-lysine cleavage sequences: PS-5, 5 nm in diameter containing 2 fluorochromes, PS-25, a 25-nm version with an elongated lysine chain and PS-40, a polymeric nanoparticle. Serial FMT-CT showed fastest kinetics for PS-5 but, surprisingly, highest fluorescence in lesions of the aortic root for PS-40. PS-40 robustly reported therapeutic effects of atorvastatin, corroborated by ex vivo imaging and qPCR for the model protease cathepsin B. CONCLUSIONS: FMT-CT is a robust and observer-independent tool for noninvasive assessment of inflammatory murine atherosclerosis. Reporter-containing nanomaterials may have unique advantages over small molecule agents for in vivo imaging.

View from the top: CEO perspectives on executive development and succession planning practices in healthcare organizations.

Many healthcare professionals question whether the industry's hospitals and multi-site systems are implementing the necessary executive development and succession planning systems to ensure that high potential managers are prepared and aptly selected to assume key executive roles. Survey data, case studies, and cross-industry comparisons suggest that healthcare organizations may face a leadership crisis as the current generation of chief executive officers (CEOs) nears retirement while traditional means of developing the leadership pipeline, including middle-management positions and graduate programs requiring formal residencies, continue to dissipate. Given the daunting challenges that accompany the healthcare industry's quest to identify, develop, and retain leadership talent, this article provides best practice findings from a qualitative study of 13 healthcare organizations with a record of exemplary executive development and succession planning practices. CEOs from six single-site hospitals, six healthcare systems, and one medical group were interviewed to identify industry best practices so that healthcare practitioners and educators may utilize the findings to enhance the industry's leadership capacity.

Catalytic unfolding and proteolysis of cytochrome C induced by synthetic binding agents.

A class of polyanionic copper porphyrin dimers is shown to selectively increase the susceptibility of cytochrome c to proteolysis through binding-induced disruption of tertiary and secondary structure. The free energy of the protein conformation leading to proteolytic attack is stabilized by about 2.4 kcal/mol in the bound state. The proteolytic acceleration is catalytic in nature, requiring only a fraction of an equivalent of metalloporphyrin to effect complete, rapid digestion in the presence of a protease.

A forbidden rearrangement.

[reaction: see text] A barrelene derivative fragments to afford benzene and trappable 1,2,3-tricyanocyclopropene. The barrelene anion fragments more easily to liberate benzene and the 1,2,3-tricyanocyclopropenyl anion, which is not trappable or stable in solution. However, the major thermal product from the barrelene anion is a rearranged allyl anion that is formed by disrotatory cleavage of the cyclopropyl ring, a formally Woodward-Hoffmann-forbidden process. Several proposals are offered to rationalize this forbidden rearrangement.

Directed denaturation: room temperature and stoichiometric unfolding of cytochrome C by a metalloporphyrin dimer.

Using circular dichroism, UV-vis, and trypsin proteolysis, we have shown how a metalloporphyrin dimer induces the unfolding of a protein, cytochrome c, under physiologically relevant conditions and accelerates its rate of proteolytic degradation.

Antihydrophobic cosolvent effects for alkylation reactions in water solution, particularly oxygen versus carbon alkylations of phenoxide ions.

Antihydrophobic cosolvents such as ethanol increase the solubility of hydrophobic molecules in water, and they also affect the rates of reactions involving hydrophobic surfaces. In simple reactions of hydrocarbons, such as the Diels-Alder dimerization of 1,3-cyclopentadiene, the rate and solubility data directly reflect the geometry of the transition state, in which some hydrophobic surface becomes hidden. In reactions involving polar groups, such as alkylations of phenoxide ions or S(N)1 ionizations of alkyl halides, cosolvents in water can have other effects as well. However, solvation of hydrophobic surfaces is still important. By the use of structure-reactivity relationships, and comparing the effects of ethanol and DMSO as solvents, it has been possible to sort out these effects. The conclusions are reinforced by an ab initio computer model for hydrophobic solvation. The result is a sensible transition state for phenoxide ion as a nucleophile, using its oxygen n electrons to avoid loss of conjugation. The geometry of alkylation of aniline is very different, involving packing (stacking) of the aniline ring onto the phenyl ring of a benzyl group in the benzylation reaction. The alkylation of phenoxide ions by benzylic chlorides can occur both at the phenoxide oxygen and on ortho and para positions of the ring. Carbon alkylation occurs in water, but not in nonpolar organic solvents, and it is observed only when the phenoxide has at least one methyl substituent ortho, meta, or para. The effects of phenol substituents and of antihydrophobic cosolvents on the rates of the competing alkylation processes indicate that in water the carbon alkylation involves a transition state with hydrophobic packing of the benzyl group onto the phenol ring. The results also support our conclusion that oxygen alkylation uses the n electrons of the phenoxide oxygen as the nucleophile and does not have hydrophobic overlap in the transition state. The mechanisms and explanations for competing oxygen and carbon alkylations differ from previous proposals by others.