Prodrug-Based Targeting Approach for Inflammatory Bowel Diseases Therapy: Mechanistic Study of Phospholipid-Linker-Cyclosporine PLA2-Mediated Activation.

Therapeutics with activity specifically at the inflamed sites throughout the gastrointestinal tract (GIT) would be a major advance in our therapeutic approach to inflammatory bowel disease (IBD). We aimed to develop the prodrug approach that can allow such site-specific drug delivery. Currently, using cyclosporine as a drug of choice in IBD is limited to the most severe cases due to substantial systemic toxicities and narrow therapeutic index of this drug. Previously, we synthesized a series of a phospholipid-linker-cyclosporine (PLC) prodrugs designed to exploit the overexpression of phospholipase A2 (PLA2) in the inflamed intestinal tissues, as the prodrug-activating enzyme. Nevertheless, the extent and rate of prodrug activation differed significantly. In this study we applied in-vitro and modern in-silico tools based on molecular dynamics (MD) simulation, to gain insight into the dynamics and mechanisms of the PLC prodrug activation. We aimed to elucidate the reason for the significant activation change between different linker lengths in our prodrug design. Our work reveals that the PLC conjugate with the 12-carbon linker length yields the optimal prodrug activation by PLA2 in comparison to shorter linker length (6-carbons). This optimized length efficiently allows cyclosporine to be released from the prodrug to the active pocket of PLA2. This newly developed mechanistic approach, presented in this study, can be applied for future prodrug optimization to accomplish optimal prodrug activation and drug targeting in various conditions that include overexpression of PLA2.

PLA2-Triggered Activation of Cyclosporine-Phospholipid Prodrug as a Drug Targeting Approach in Inflammatory Bowel Disease Therapy.

Oral medication with activity specifically at the inflamed sites throughout the gastrointestinal tract and limited systemic exposure would be a major advance in our therapeutic approach to inflammatory bowel disease (IBD). For this purpose, we have designed a prodrug by linking active drug moiety to phospholipid (PL), the substrate of phospholipase A2 (PLA2). PLA2 expression and activity is significantly elevated in the inflamed intestinal tissues of IBD patients. Since PLA2 enzyme specifically hydrolyses the sn-2 bond within PLs, in our PL-based prodrug approach, the sn-2 positioned FA is replaced with cyclosporine, so that PLA2 may be exploited as the prodrug-activating enzyme, releasing the free drug from the PL-complex. Owing to the enzyme overexpression, this may effectively target free cyclosporine to the sites of inflammation. Four PL-cyclosporine prodrugs were synthesized, differing by their linker length between the PL and the drug moiety. To study the prodrug activation, a novel enzymatically enriched model was developed, the colonic brush border membrane vesicles (cBBMVs); in this model, tissue vesicles were produced from colitis-induced (vs. healthy) rat colons. PLA2 overexpression (3.4-fold) was demonstrated in diseased vs. healthy cBBMVs. Indeed, while healthy cBBMVs induced only marginal activation, substantial prodrug activation was evident by colitis-derived cBBMVs. Together with the PLA2 overexpression, these data validate our drug targeting strategy. In the diseased cBBMVs, quick and complete activation of the entire dose was obtained for the 12-carbon linker prodrug, while slow and marginal activation was obtained for the 6/8-carbon linkers. The potential to target the actual sites of inflammation and treat any localizations throughout the GIT, together with the extended therapeutic index, makes this orally delivered prodrug approach an exciting new therapeutic strategy for IBD treatment.

Lactococcus lactis Delivery of Surface Layer Protein A Protects Mice from Colitis by Re-Setting Host Immune Repertoire.

Inflammatory bowel disease (IBD) is characterized by gastrointestinal inflammation comprised of Crohn's disease and ulcerative colitis. Centers for Disease Control and Prevention report that 1.3% of the population of the United States (approximately 3 million people) were affected by the disease in 2015, and the number keeps increasing over time. IBD has a multifactorial etiology, from genetic to environmental factors. Most of the IBD treatments revolve around disease management, by reducing the inflammatory signals. We previously identified the surface layer protein A (SlpA) of Lactobacillus acidophilus that possesses anti-inflammatory properties to mitigate murine colitis. Herein, we expressed SlpA in a clinically relevant, food-grade Lactococcus lactis to further investigate and characterize the protective mechanisms of the actions of SlpA. Oral administration of SlpA-expressing L. lactis (R110) mitigated the symptoms of murine colitis. Oral delivery of R110 resulted in a higher expression of IL-27 by myeloid cells, with a synchronous increase in IL-10 and cMAF in T cells. Consistent with murine studies, human dendritic cells exposed to R110 showed exquisite differential gene regulation, including IL-27 transcription, suggesting a shared mechanism between the two species, hence positioning R110 as potentially effective at treating colitis in humans.

Phospholipid Cyclosporine Prodrugs Targeted at Inflammatory Bowel Disease (IBD) Treatment: Design, Synthesis, and in Vitro Validation.

Novel phospholipid (PL)-cyclosporine conjugates were prepared and studied as potential prodrugs for inflammatory bowel disease (IBD). Our approach relies on phospholipase A2 (PLA2 ), which is overexpressed in the inflamed intestinal tissues, as the prodrug activator to potentially release cyclosporine at the site of inflammation. PL-cyclosporine prodrug conjugates with methylene linkers of various lengths between the sn-2 position of the PL and cyclosporine were synthesized and evaluated for in vitro activation. Surprisingly, despite previous work indicating that conjugates with six methylene linkers between the lipid and drug would suffer rapid enzymatic hydrolysis, with cyclosporine this was not observed. However, compounds with longer linkers (n=10, 12 methylene units) display complete release of the drug by PLA2 -catalyzed hydrolysis, thus demonstrating the importance and profound impact of structural fine-tuning. This study represents a proof-of-concept for our hypothesis and a first step towards a truly targeted IBD treatment with cyclosporine that could be administered throughout the GI tract.

College Students with Inflammatory Bowel Disease: A Qualitative Study of Challenges Associated with College Transition and Self-Care.

Introduction: The social impact of inflammatory bowel disease (IBD) on student transition to college is significant, yet poorly understood. Methods: Two 90-min focus groups (FGs) were conducted with eight student-patients with IBD. Reflective journals were used to corroborate, elaborate, or challenge emergent FG findings. Results: Six themes emerged: (1) transitioning to college, (2) interacting with physicians, (3) affecting social life, (4) managing the disease by yourself and through support, (5) coping strategies, and (6) facing disease challenges. These themes remained relevant in the reflective writings. Analysis of serial journal entries showed that students' social life and engagement in coursework was affected 66% and 54% of the time, respectively. Conclusion: Our findings offer guidance for improving students' college success, quality of care, and enhancing physician-patient interactions. Students with IBD have a disability that may not be obvious or visible. They require specific support to help them transition and succeed in college.

Lipids and Lipid-Processing Pathways in Drug Delivery and Therapeutics.

The aim of this work is to analyze relevant endogenous lipid processing pathways, in the context of the impact that lipids have on drug absorption, their therapeutic use, and utilization in drug delivery. Lipids may serve as biomarkers of some diseases, but they can also provide endogenous therapeutic effects for certain pathological conditions. Current uses and possible clinical benefits of various lipids (fatty acids, steroids, triglycerides, and phospholipids) in cancer, infectious, inflammatory, and neurodegenerative diseases are presented. Lipids can also be conjugated to a drug molecule, accomplishing numerous potential benefits, one being the improved treatment effect, due to joined influence of the lipid carrier and the drug moiety. In addition, such conjugates have increased lipophilicity relative to the parent drug. This leads to improved drug pharmacokinetics and bioavailability, the ability to join endogenous lipid pathways and achieve drug targeting to the lymphatics, inflamed tissues in certain autoimmune diseases, or enable overcoming different barriers in the body. Altogether, novel mechanisms of the lipid role in diseases are constantly discovered, and new ways to exploit these mechanisms for the optimal drug design that would advance different drug delivery/therapy aspects are continuously emerging.

Characteristics of Faculty at Risk of Leaving Their Medical Schools: An Analysis of the StandPoint™ Faculty Engagement Survey.

PURPOSE: This study seeks to identify the characteristics and attitudes of faculty in US medical colleges who are at risk of leaving their institution. METHODS: This research leverages data from the AAMC StandPoint Faculty Engagement Survey administered to 37,779 faculty representing 36 institutions participating during 2013-2016. Univariate and multivariable robust logistic regression models were used to assess predictors of the intent to leave based on the question: "Do you plan to leave this medical school in the next 1-2 years?". RESULTS: Thirty percent (n=5559/18,475) of faculty responded that they were considering leaving their institution. Thirty-one percent of female faculty vs 29% of male faculty expressed an intent to leave. At-risk faculty were likely to be at junior faculty rank and at their institutions for 6-15 years vs other time periods (OR=1.16; p≤0.001). Having an administrative title (OR=0.72; p≤0.001) and receiving formal mentorship (OR=0.65; p≤0.001) were protective. Finally, faculty answering "disagree" or "strongly disagree" to any one of these StandPoint Survey questions were at > 6 fold risk of expressing an intent to leave: 1) I am satisfied with my opportunities for professional development, 2) I feel appreciated by my supervisor, 3) My day-to-day activities give me a sense of accomplishment. CONCLUSION: Faculty expressing an intent to leave their institution have an identifiable profile. Top concerns of at-risk faculty relate to supervisory relationships and growth opportunities rather than compensation or governance. Institutional leaders should consider these factors in the development of a proactive strategy to retain talented faculty.

The prospects of lipidic prodrugs: an old approach with an emerging future.

Nowadays, prodrugs are no longer used as a last resort, rather, they are intentionally designed at the early stages of drug development. Lipidic prodrug strategy, where a drug moiety is covalently bound to a lipid carrier, was initially proposed half a century ago, yet, this approach still remains to be explored. Lipidic prodrugs can join physiological lipid metabolic pathways, and hence provide drug targeting via lymphatic transport or site-specific drug release, improve drugs' pharmacokinetic profile, overcome obstacles originating from biological barriers and bypass hepatic first-pass metabolism. Physiological pathways of lipid processing, uses of different lipidic prodrugs and their clinical benefits are overviewed. Overall, lipidic prodrugs present a promising approach for overcoming different obstacles and fulfilling various unmet needs in drug delivery/targeting.

Small bowel stricture is associated with abnormal motility on the cine MRI sequence in patients with Crohn's disease.

PURPOSE: A multiphasic cine sequence performed during magnetic resonance enterography (MRE) has been shown to increase diagnostic accuracy of MRE demonstrating limited movement in inflamed intestine in patients with Crohn's disease (CD). Our aim was to confirm in our study population that intestinal inflammation was associated with decreased motility and determine if factors suggestive of complicated disease such as the presence of a stricture or fistula were associated with decreased motility on the MRE cine sequence. METHODS: This was a retrospective study of 59 patients (mean age 40.8 ±â€¯16.1) with Crohn's disease who had a small bowel lesion on MRE. Two gastrointestinal radiologists independently scored MRE findings using a qualitative, subjective scoring system. Univariate and multivariable ordered logistic regression models were used to evaluate the associations between cine sequence score, radiologic image findings, and clinical data. RESULTS: On univariate analysis, radiologic findings reflecting active inflammation, the presence of a stricture, and penetrating disease were associated with decreased motility. On multivariable analysis, hyper-enhancement, the presence of a comb sign, and global evidence of active inflammation remained associated with decreased motility. Of the factors suggesting complicated disease, the presence of stricture (Odds Ratio 0.40, 95% Confidence Interval 0.17-0.95, p-value 0.038) was associated with decreased motility. CONCLUSIONS: As previously shown, well-established radiologic findings of bowel inflammation were associated with decreased small bowel motility. In this study, we have added that the radiologic finding of a fixed stricture is also associated with decreased motility.

Molecular Modeling-Guided Design of Phospholipid-Based Prodrugs.

The lipidic prodrug approach is an emerging field for improving a number of biopharmaceutical and drug delivery aspects. Owing to their structure and nature, phospholipid (PL)-based prodrugs may join endogenous lipid processing pathways, and hence significantly improve the pharmacokinetics and/or bioavailability of the drug. Additional advantages of this approach include drug targeting by enzyme-triggered drug release, blood-brain barrier permeability, lymphatic targeting, overcoming drug resistance, or enabling appropriate formulation. The PL-prodrug design includes various structural modalities-different conjugation strategies and/or the use of linkers between the PL and the drug moiety, which considerably influence the prodrug characteristics and the consequent effects. In this article, we describe how molecular modeling can guide the structural design of PL-based prodrugs. Computational simulations can predict the extent of phospholipase A2 (PLA2)-mediated activation, and facilitate prodrug development. Several computational methods have been used to facilitate the design of the pro-drugs, which will be reviewed here, including molecular docking, the free energy perturbation method, molecular dynamics simulations, and free density functional theory. Altogether, the studies described in this article indicate that computational simulation-guided PL-based prodrug molecular design correlates well with the experimental results, allowing for more mechanistic and less empirical development. In the future, the use of molecular modeling techniques to predict the activity of PL-prodrugs should be used earlier in the development process.

Pre-operative total parenteral nutrition improves post-operative outcomes in a subset of Crohn's disease patients undergoing major abdominal surgery.

BACKGROUND: Despite major advances in the medical management of Crohn's disease (CD), a significant proportion of patients will require surgery within 5 years of diagnosis. Malnutrition is an independent risk factor for adverse post-operative outcomes following gastrointestinal surgery. Data on the value of pre-operative total parenteral nutrition (TPN) in CD patients are mixed and there is a paucity of data in the biologic era. We aimed to define the role of pre-operative TPN in this population. METHODS: This was a retrospective cohort study conducted at a tertiary referral center. CD patients who underwent major abdominal surgery were identified. Patients receiving pre-operative TPN were compared to controls. We compared the incidence of 30-day infectious and non-infectious post-operative complications between the two groups. RESULTS: A total of 144 CD patients who underwent major abdominal surgery between March 2007 and March 2017 were included. Fifty-five patients who received pre-operative TPN were compared to 89 controls. Twenty-one (14.6%) patients developed infectious complications (18.2% in TPN group vs 12.3% in non-TPN group, P = 0.34) and 23 (15.9%) developed non-infectious complications (14.5% in TPN group vs 16.9% in non-TPN group, P = 0.71). In a multivariate analysis, controlling for differences in baseline disease severity and malnutrition between groups, patients receiving pre-operative TPN for ≥60 days had significantly lower odds of developing non-infectious complications (odds ratio 0.07, 95% confidence interval: 0.01-0.80, P = 0.03). Weight loss of >10% in the past 6 months was a significant predictor of post-operative complications. CONCLUSIONS: In a subset of malnourished CD patients, TPN is safe and allows comparable operative outcomes to controls. Pre-operative TPN for ≥60 days reduced post-operative non-infectious complications without associated increase in infectious complications.

Phospholipid-Based Prodrugs for Colon-Targeted Drug Delivery: Experimental Study and In-Silico Simulations.

In ulcerative colitis (UC), the inflammation is localized in the colon, and one of the successful strategies for colon-targeting drug delivery is the prodrug approach. In this work, we present a novel phospholipid (PL)-based prodrug approach, as a tool for colonic drug targeting in UC. We aim to use the phospholipase A2 (PLA2), an enzyme that is overexpressed in the inflamed colonic tissues of UC patients, as the PL-prodrug activating enzyme, to accomplish the liberation of the parent drug from the prodrug complex at the specific diseased tissue(s). Different linker lengths between the PL and the drug moiety can dictate the rate of activation by PLA2, and subsequently determine the amount of free drugs at the site of action. The feasibility of this approach was studied with newly synthesized PL-Fmoc (fluorenylmethyloxycarbonyl) conjugates, using Fmoc as a model compound for testing our hypothesis. In vitro incubation with bee venom PLA2 demonstrated that a 7-carbon linker between the PL and Fmoc has higher activation rate than a 5-carbon linker. 4-fold higher colonic expression of PLA2 was demonstrated in colonic mucosa of colitis-induced rats when compared to healthy animals, validating our hypothesis of a colitis-targeting prodrug approach. Next, a novel molecular dynamics (MD) simulation was developed for PL-based prodrugs containing clinically relevant drugs. PL-methotrexate conjugate with 6-carbon linker showed the highest extent of PLA2-mediated activation, whereas shorter linkers were activated to a lower extent. In conclusion, this work demonstrates that for carefully designed PL-drug conjugates, PLA2 overexpression in inflamed colonic tissues can be used as prodrug-activating enzyme and drug targeting strategy, including insights into the activation mechanisms in a PLA2 binding site.

Real-world Pattern of Biologic Use in Patients With Inflammatory Bowel Disease: Treatment Persistence, Switching, and Importance of Concurrent Immunosuppressive Therapy.

BACKGROUND AND AIMS: Medication persistence, defined as the time from drug initiation to discontinuation of therapy, has been suggested as a proxy for real-world therapeutic benefit and safety. This study seeks to compare the persistence of biologic drugs among patients with inflammatory bowel disease (IBD). METHODS: Patients with newly diagnosed IBD were included in a retrospective study using Truven MarketScan database. Treatment persistence and switching was compared among biologic medications including infliximab, adalimumab, certolizumab, golimumab, and vedolizumab. Predictors for discontinuation and switching were evaluated using time-dependent proportional hazard regression. RESULTS: In total, 5612 patients with Crohn's disease (CD) and 3533 patients with ulcerative colitis (UC) were included in this analysis. Less than half of the patients continued using their initial biologic treatment after 1 year (48.48% in CD cohort; 44.78% in UC cohort). In the first year, adalimumab had the highest persistence and lowest switching rates for both CD (median survival time: 1.04 years) and UC (median survival time: 0.84 years). In subsequent years, infliximab users were more likely to persist in the use of biologic. Combination therapy with immunomodulators significantly decreased the risk of discontinuation, especially when immunomodulator therapy was started more than 30 days before the biologic (hazard ratio [HR], 0.22; CI, 0.16, 0.32). The major predictors for noncompliance included infection and hospitalization. CONCLUSION: Overall, the persistence profiles of biologics suggest a high rate of dissatisfaction or adverse disease outcomes resulting in discontinuation and switching to a different agent. Early initiation of immunomodulators will substantially increase the persistence of biologic treatment.

Lipidic prodrug approach for improved oral drug delivery and therapy.

In the past, a prodrug design was used as a last option to improve bioavailability through controlling transport, distribution, metabolism, or other mechanisms. Prodrugs are currently used even in early stages of drug development, and a significant percentage of all drugs in the market are prodrugs. The focus of this article is lipidic prodrugs, a strategy whereby a lipid carrier is covalently bound to the drug moiety. The increased lipophilicity of the lipid-drug conjugate can improve the pharmacokinetic profile and provide meaningful advantages: increased absorption across biological barriers, prolonged circulation half-life, selective distribution profile (eg brain penetration), reduced hepatic first-pass metabolism, and overall enhanced bioavailability of the parent drug. Moreover, lipidic prodrugs may join the endogenous lipid trafficking pathways, thereby facilitate drug targeting, either by selective absorption pathway (eg lymphatic transport) or drug release at specific target site(s). The different lipid-drug conjugates (triglyceride-, fatty acids, phospholipid-, and steroid-based prodrugs), the physiological barriers that challenge the absorption of these conjugates, followed by their current utilization and potential clinical benefits are described and analyzed, and future opportunities this approach could provide are discussed. Altogether, lipidic prodrugs represent an exciting approach for improving different aspects of oral drug delivery/therapy and may provide solutions for various unmet needs; the use of this strategy is expected to grow.

Prospects and Challenges of Phospholipid-Based Prodrugs.

Nowadays, the prodrug approach is used already at the early stages of drug development. Lipidic prodrug approach is a growing field for improving a number of drug properties/delivery/therapy aspects, and can offer solutions for various unmet needs. This approach includes drug moiety bound to the lipid carrier, which can be triglyceride, fatty acids, steroid, or phospholipid (PL). The focus of this article is PL-based prodrugs, which includes a PL carrier covalently bound to the active drug moiety. An overview of relevant physiological lipid processing pathways and absorption barriers is provided, followed by drug delivery/therapeutic application of PL-drug conjugates, as well as computational modeling techniques, and a modern bioinformatics tool that can aid in the optimization of PL conjugates. PL-based prodrugs have increased lipophilicity comparing to the parent drug, and can therefore significantly improve the pharmacokinetic profile and overall bioavailability of the parent drug, join the endogenous lipid processing pathways and therefore accomplish drug targeting, e.g., by lymphatic transport, drug release at specific target site(s), or passing the blood-brain barrier. Moreover, an exciting gateway for treating inflammatory diseases and cancer is presented, by utilizing the PL sn-2 position in the prodrug design, aiming for PLA2-mediated activation. Overall, a PL-based prodrug approach shows great potential in improving different drug delivery/therapy aspects, and is expected to grow.

Effects of Preoperative Use of Biologic Agents on Operative Outcomes in Crohn's Disease Patients.

Although the effects of biologic agents on postoperative outcomes in Crohn's disease patients have been extensively studied, the effects on intraoperative outcomes, including blood loss, operative time, and length of small bowel resection, remain to be determined. This was a retrospective cohort study at a single tertiary referral center. Crohn's disease (CD) patients who underwent major abdominal surgery were identified. Patients receiving preoperative biologic agents were compared with controls. We compare operative outcomes between groups. A total of 144 patients who underwent major abdominal surgery at the University of Florida between March 2007 and March 2017 were included. One hundred and ten patients (76%) who received preoperative biologic therapy were compared with 34 controls. On univariate analysis, preoperative biologic use was associated with a significantly shorter length of small bowel resection (21.2 cm in biologic group vs 34.5 cm, P = 0.01). There were no significant differences in intraoperative blood loss (100 vs 87.5 mL, P = 0.40) or total operative time (142 vs 154 minutes, P = 0.39) between groups. On multivariate analysis controlling for variables reflecting severity of disease and malnutrition, biologic use remained significantly associated with shorter length of bowel resection (incident rate ratio 0.58, P = 0.04). Preoperative biologic use is associated with a significantly shorter length of bowel resection in CD patients undergoing major abdominal surgery. No negative effects were noted on operative blood loss or total operative time. Our findings allow improved preoperative planning for surgeons and informed decision-making for CD patients undergoing major abdominal surgery.

Perioperative Care of Patients with Inflammatory Bowel Disease: Focus on Nutritional Support.

Patients with inflammatory bowel disease (IBD) commonly require surgery despite the availability of an increasingly large repertoire of powerful immunosuppressive medications for the treatment of IBD. Optimizing patients' care preoperatively is crucial to obtaining good surgical outcomes. This review discusses preoperative assessment and management principles including assessing disease location and activity with cross-sectional or endoscopic imaging, addressing modifiable risk factors (i.e., stopping smoking, weaning steroids, and correcting anemia), and properly managing medications. The major focus of our literature review is the evaluation for malnutrition, a common finding that affects up to 70% of patients with IBD and a well-known, independent risk factor for adverse postoperative outcomes. Our review confirms that whenever feasible, oral or enteral nutrition (EN) is the preferred method of nutritional support; parenteral nutrition (PN) should be reserved for nutritionally deficient IBD patients unable to tolerate EN. In selected patients, recent data demonstrated that the use of preoperative PN resulted in improved nutritional status, fewer postoperative complications, and reduced disease severity. Our review highlights the need for well-designed, prospective trials investigating perioperative nutritional support in patients with IBD. Future studies should perform modern nutritional assessment, standardize for diet, and include patients with UC since this subset of patients is underrepresented in existing studies. In addition, relevant outcome of interest specific to Crohn's disease (CD) patients such as length of small bowel resected, number of anastomoses, and need for an ostomy should be included as these patients may require repeated small bowel resections.

What a medical school chair wants from the dean.

Economic pressure has led the evolution of the role of the medical school dean from a clinician educator to a health care system executive. In addition, other dynamic requirements also have likely led to changes in their leadership characteristics. The most important relationship a dean has is with the chairs, yet in the context of the dean's changing role, little attention has been paid to this relationship. To frame this discussion, we asked medical school chairs what characteristics of a dean's leadership were most beneficial. We distributed a 26-question survey to 885 clinical and basic science chairs at 41 medical schools. These chairs were confidentially surveyed on their views of six leadership areas: evaluation, barriers to productivity, communication, accountability, crisis management, and organizational values. Of the 491 chairs who responded (response rate =55%), 88% thought that their dean was effective at leading the organization, and 89% enjoyed working with their dean. Chairs indicated that the most important area of expertise of a dean is to define a strategic vision, and the most important value for a dean is integrity between words and deeds. Explaining the reasons behind decisions, providing good feedback, admitting errors, open discussion of complex or awkward topics, and skill in improving relations with the teaching hospital were judged as desirable attributes of a dean. Interestingly, only 23% of chairs want to be a dean in the future. Financial acumen was the least important skill a chair thought a dean should hold, which is in contrast to the skill set for which many deans are hired and evaluated. After reviewing the literature and analyzing these responses, we assert that medical school chairs want their dean to maintain more traditional leadership than that needed by a health care system executive, such as articulating a vision for the future and keeping their promises. Thus, there appears to be a mismatch between what medical school chairs perceive they need from their dean and how the success of a dean is evaluated.