A Solid-Solution Approach for Redox Active Metal-Organic Frameworks with Tunable Redox Conductivity.

Systematically tuning the conductivity of metal-organic frameworks (MOFs) is key to synergizing their attractive synthetic control and porosity with electrochemical attributes useful in energy and sensing technologies. A priori control of charge transfer is possible by exploiting the solid-solution properties of MOFs together with electronic self-exchange enabled by redox pendants. Here we introduce a new strategy for preparing redox-active MOF thin-film electrodes with finely tuned redox pendant content. Varying the ratios of alkyl-ferrocene containing redox-active and inactive links during MOF synthesis enabled the fabrication of electrodes with tunable redox conductivity. The prepared MOF electrodes display maximum electron conductivity of 1.10 mS m-1, with crystallographic and electrochemical stability upon thousands of redox cycles. Electroanalytical studies demonstrated that the conductivity follows solution-like diffusion-controlled behavior with nonlinear electron diffusion coefficients consistent with charge hopping and percolation models of spatially fixed redox centers. Our studies create new prospects in the design and synthesis of redox-active MOFs with targeted properties for the design of advanced electrochemical devices.

Modular Design of Fluorescent Dibenzo- and Naphtho-Fluoranthenes: Structural Rearrangements and Electronic Properties.

A library of 12 dibenzo- and naphtho-fluoranthene polycyclic aromatic hydrocarbons (PAHs) with MW = 302 (C24H14) was synthesized via a Pd-catalyzed fluoranthene ring-closing reaction. By understanding the various modes by which the palladium migrates during the transformation, structural rearrangements were bypassed, obtaining pure PAHs in high yields. Spectroscopic and electrochemical characterization demonstrated the profound diversity in the electronic structures between isomers. Highlighting the significant differences in emission of visible light, this library of PAHs will enable their standardization for toxicological assessment and potential use as optoelectronic materials.

Evaluation of Cardiac Toxicity Biomarkers in Rats from Different Laboratories.

There is a great need for improved diagnostic and prognostic accuracy of potential cardiac toxicity in drug development. This study reports the evaluation of several commercially available biomarker kits by 3 institutions (SRI, Eli Lilly, and Pfizer) for the discrimination between myocardial degeneration/necrosis and cardiac hypertrophy as well as the assessment of the interlaboratory and interplatform variation in results. Serum concentrations of natriuretic peptides (N-terminal pro-atrial natriuretic peptide [NT-proANP] and N-terminal pro-brain natriuretic peptide [NT-proBNP]), cardiac and skeletal troponins (cTnI, cTnT, and sTnI), myosin light chain 3 (Myl3), and fatty acid binding protein 3 (FABP3) were assessed in rats treated with minoxidil (MNX) and isoproterenol (ISO). MNX caused increased heart-to-body weight ratios and prominent elevations in NT-proANP and NT-proBNP concentrations detected at 24-hr postdose without elevation in troponins, Myl3, or FABP3 and with no abnormal histopathological findings. ISO caused ventricular leukocyte infiltration, myocyte fibrosis, and necrosis with increased concentrations of the natriuretic peptides, cardiac troponins, and Myl3. These results reinforce the advantages of a multimarker strategy in elucidating the underlying cause of cardiac insult and detecting myocardial tissue damage at 24-hr posttreatment. The interlaboratory and interplatform comparison analyses also showed that the data obtained from different laboratories and platforms are highly correlated and reproducible, making these biomarkers widely applicable in preclinical studies.

Women Accessing Care at a National Network of Retail Health Clinics.

Background: Retail health clinics offer easy access and lower costs in seeking nonemergent and usually focused care. The objective of this observational study was to describe the use of retail clinic services by women at MinuteClinic at CVS, the largest network of retail clinics in the United States. Methods: The retail clinic's large database included complete national data for every in-person encounter as recorded on the same electronic health record. Virtual care and pharmacist-delivered services like COVID-19 testing were excluded from the analysis. The primary reason for the visit and the patient's age group (<15, 15-44, 45-64, ≥65 years) and self-reported sex were recorded at each encounter from the most recent 5 years (January 1, 2018, to December 31, 2022). Results: There were 17,969,483 encounters by women seeking care, and women ≥15 years old were more likely than men to attend the clinics. Half of all encounters (50.6%) were for non-gynecologic acute care, whereas one-third (33.6%) dealt with either an infection or the need for a vaccination. Gynecologic reasons involved 5.6% of all encounters in women ≥15 years of age. No obstetrical care was provided except for pregnancy testing with referral, acute non-obstetric needs, or guideline-recommended vaccinations. Conclusion: Women, especially of reproductive age, are more inclined than men to seek care at retail clinics. Acute care is the most common need, although requests for immunizations, infection screening and treatment, and reproductive health issues occurred often.

A multifaceted approach to education, observation, and feedback in a successful hand hygiene campaign.

BACKGROUND: Prevention of health care-associated infections starts with scrupulous hand hygiene (HH). Improving HH compliance is a major target for the World Health Organization Patient Safety Challenge and is one of The Joint Commission's National Patient Safety Goals. Yet, adherence to HH protocols is generally poor for health care professionals, despite interventions designed to improve compliance. At Tufts Medical Center (Boston), HH compliance rates were consistently low despite the presence of a traditional HH campaign that used communication and education. METHODS: A comprehensive program incorporated strong commitment by hospital leadership-who were actively involved in responsibilities previously only performed by infection preventionists and quality and patient safety staff-dedication of financial resources, including securing a grant; collaborating with a private advertising firm in a marketing campaign; and employing a multifaceted approach to education, observation, and feedback. RESULTS: This campaign resulted in a rapid and sustained improvement in HH compliance: Compared with the mean HH compliance rate for the six months before the campaign (72%), postcampaign HH compliance (mean = 94%) was significantly greater (p < .0001). Factors contributing to the success of the campaign included the development of the marketing campaign to fit this academic medical center's particular culture, strong support from the medical center leadership, a multifaceted educational approach, and monthly feedback on HH compliance. CONCLUSIONS: A comprehensive campaign resulted in rapid and sustained improvement in HH compliance at an academic medical center after traditional communication and education strategies failed to improve HH performance.

J-dimer emission in interwoven metal-organic frameworks.

J-dimer emission is an emergent property that occurs when pairs of ground state fluorophores associate, typically in a dilute solution medium. The resulting fluorescence is shifted with respect to the monomer. J-dimer emission, however, has never been observed in concentrated dispersions or in the solid state. We posited that multivariate (MTV) MOFs with double interwoven structures would help to isolate these dimers within their crystalline matrix. Using this strategy, J-aggregate density was controlled during crystallization by following a substitutional solid solution approach. Here, we identified the presence of J-dimers over the entire composition range for interwoven PIZOF-2/NNU-28 structures with variable amounts of a diethynyl-anthracene aggregate-forming link. We produced bulk crystals that systematically shifted their fluorescence from green to red with lifetimes (up to 13 ns) and quantum yields (up to 76%) characteristic of π-π stacked aggregates. Photophysical studies also revealed an equilibrium constant of dimerization, K D = 1.5 ± 0.3 M-1, enabling the first thermodynamic quantification of link-link interactions that occur during MOF assembly. Our findings elucidate the role that supramolecular effects play during crystallization of MTV MOFs, opening pathways for the preparation of solid-state materials with solution-like properties by design.

Impact of computerized decision support on blood pressure management and control: a randomized controlled trial.

BACKGROUND: We conducted a cluster randomized controlled trial to examine the effectiveness of computerized decision support (CDS) designed to improve hypertension care and outcomes in a racially diverse sample of primary care patients. METHODS: We randomized 2,027 adult patients receiving hypertension care in 14 primary care practices to either 18 months of their physicians receiving CDS for each hypertensive patient or to usual care without computerized support for the control group. We assessed prescribing of guideline-recommended drug therapy and levels of blood pressure control for patients in each group and examined if the effects of the intervention differed by patients' race/ethnicity using interaction terms. MEASUREMENTS AND MAIN RESULTS: Rates of blood pressure control were 42% at baseline and 46% at the outcome visit with no significant differences between groups. After adjustment for patients' demographic and clinical characteristics, number of prior visits, and levels of baseline blood pressure control, there were no differences between intervention groups in the odds of outcome blood pressure control. The use of CDS to providers significantly improved Joint National Committee (JNC) guideline adherent medication prescribing compared to usual care (7% versus 5%, P < 0.001); the effects of the intervention remained after multivariable adjustment (odds ratio [OR] 1.39 [CI, 1.13-1.72]) and the effects of the intervention did not differ by patients' race and ethnicity. CONCLUSIONS: CDS improved appropriate medication prescribing with no improvement in disparities in care and overall blood pressure control. Future work focusing on improvement of these interventions and the study of other practical interventions to reduce disparities in hypertension-related outcomes is needed.

Harderian Gland Tumorigenesis: Low-Dose and LET Response.

Increased cancer risk remains a primary concern for travel into deep space and may preclude manned missions to Mars due to large uncertainties that currently exist in estimating cancer risk from the spectrum of radiations found in space with the very limited available human epidemiological radiation-induced cancer data. Existing data on human risk of cancer from X-ray and gamma-ray exposure must be scaled to the many types and fluences of radiations found in space using radiation quality factors and dose-rate modification factors, and assuming linearity of response since the shapes of the dose responses at low doses below 100 mSv are unknown. The goal of this work was to reduce uncertainties in the relative biological effect (RBE) and linear energy transfer (LET) relationship for space-relevant doses of charged-particle radiation-induced carcinogenesis. The historical data from the studies of Fry et al. and Alpen et al. for Harderian gland (HG) tumors in the female CB6F1 strain of mouse represent the most complete set of experimental observations, including dose dependence, available on a specific radiation-induced tumor in an experimental animal using heavy ion beams that are found in the cosmic radiation spectrum. However, these data lack complete information on low-dose responses below 0.1 Gy, and for chronic low-dose-rate exposures, and there are gaps in the LET region between 25 and 190 keV/µm. In this study, we used the historical HG tumorigenesis data as reference, and obtained HG tumor data for 260 MeV/u silicon (LET ∼70 keV/µm) and 1,000 MeV/u titanium (LET ∼100 keV/µm) to fill existing gaps of data in this LET range to improve our understanding of the dose-response curve at low doses, to test for deviations from linearity and to provide RBE estimates. Animals were also exposed to five daily fractions of 0.026 or 0.052 Gy of 1,000 MeV/u titanium ions to simulate chronic exposure, and HG tumorigenesis from this fractionated study were compared to the results from single 0.13 or 0.26 Gy acute titanium exposures. Theoretical modeling of the data show that a nontargeted effect model provides a better fit than the targeted effect model, providing important information at space-relevant doses of heavy ions.

A randomized trial of electronic clinical reminders to improve quality of care for diabetes and coronary artery disease.

OBJECTIVE: The aim of this study was to evaluate the impact of an integrated patient-specific electronic clinical reminder system on diabetes and coronary artery disease (CAD) care and to assess physician attitudes toward this reminder system. DESIGN: We enrolled 194 primary care physicians caring for 4549 patients with diabetes and 2199 patients with CAD at 20 ambulatory clinics. Clinics were randomized so that physicians received either evidence-based electronic reminders within their patients' electronic medical record or usual care. There were five reminders for diabetes care and four reminders for CAD care. MEASUREMENTS: The primary outcome was receipt of recommended care for diabetes and CAD. We created a summary outcome to assess the odds of increased compliance with overall diabetes care (based on five measures) and overall CAD care (based on four measures). We surveyed physicians to assess attitudes toward the reminder system. RESULTS: Baseline adherence rates to all quality measures were low. While electronic reminders increased the odds of recommended diabetes care (odds ratio [OR] 1.30, 95% confidence interval [CI] 1.01-1.67) and CAD (OR 1.25, 95% CI 1.01-1.55), the impact of individual reminders was variable. A total of three of nine reminders effectively increased rates of recommended care for diabetes or CAD. The majority of physicians (76%) thought that reminders improved quality of care. CONCLUSION: An integrated electronic reminder system resulted in variable improvement in care for diabetes and CAD. These improvements were often limited and quality gaps persist.

Evaluation of mutant frequencies of chemically induced tumors and normal tissues in lambda/cII transgenic mice.

Genomic instability has been implicated as an important component in tumor progression. Evaluation of mutant frequencies (MFs) in tumors of transgenic mice containing nontranscribed marker genes should be useful for quantitating mutation rates in tumors as the physiologically inactive transgene provides neither a positive nor a negative selective pressure on the tumor. We have conducted long-term carcinogenicity studies in lambda/cII transgenic B6C3F1 mice using a variety of genotoxic and nongenotoxic test agents and have evaluated the mutant frequencies in both tumors and normal tissues from these animals. Mice were administered diethylnitrosamine (DEN) as three intraperitoneal injections of 15 mg/kg; phenobarbital (PB) or oxazepam (OXP) provided ad libitum at 0.1% or 0.25% in the diet, respectively; DEN initiation plus PB in the diet; or urethane (UTH) provided ad libitum at 0.2% in the drinking water. Normal tissues and tumors were isolated at various times over a 2-year period and half of each tissue/tumor was evaluated histopathologically and the other half was evaluated for MF in the cII transgene. Approximately 20 mutants from each of 166 individual tissues (tumor and nontumor) were sequenced to determine whether increases in MF represented unique mutations or were due to clonal expansion. UTH produced significant increases in MF in normal liver and lung. DEN either with or without PB promotion produced significant increases in MF in liver and correction of MF for clonality produced little change in the overall MF in these groups. PB produced a twofold increase in liver MF over controls after 27 weeks of treatment, but a similar increase was not observed with longer dosing times; at later time points, the MF in the PB groups was lower than that of the control group, suggesting that PB is not producing direct DNA damage in the liver. OXP failed to produce an increase in MF over controls, even after 78 weeks of treatment. Selected cases of genomic instability were observed in tumors from all treatments except OXP, with individual liver tumors showing very high MF values even after clonal correction. One rare and interesting finding was noted in a single mouse treated with UTH, where a mammary metastasis had an MF approximately 10-fold greater than the parent tumor, with 75% of the mutations independent, providing strong evidence of genomic instability. There was no clear correlation between tumor phenotype and MF except that pulmonary adenomas generally had higher MFs than normal lung in both genotoxic and nongenotoxic treatment groups. Likewise, there was no correlation between tumor size and MF after correction for clonality. The results presented here demonstrate that individual tumors can show significant genomic instability, with very significant increases in MF that are not attributed to clonal expansion of a single mutant cell.

Improving completion of advance directives in the primary care setting: a randomized controlled trial.

BACKGROUND: Since 1991, hospitals have asked patients whether they have advance directives, but few patients complete these documents. We assessed two simple interventions to improve completion of advance directives among elderly or chronically ill outpatients. METHODS: We conducted a cluster randomized controlled trial involving 1079 patients from five general medicine clinics that were affiliated with an academic medical center. Patients were either > or =70 years of age or > or =50 years old with a chronic illness. The study comprised three arms: physician reminders recommending documentation of advance directives, physician reminders plus mailing advance directives to patients together with educational literature, or neither intervention (control). The main outcome measure was completion of an advance directive. RESULTS: After 28 weeks, 1.5% (5/332) of patients in the physician reminder group, 14% (38/277) in the physician reminder plus patient mailing group, and 1.8% (5/286) in the control group had completed advance directives. In multivariate analyses, patients in the physician reminder plus patient mailing group were much more likely than controls to have completed advance directives (odds ratio [OR] = 5.9; 95% confidence interval [CI]: 1.5 to 22), whereas patients in the physician reminder-only group were no more likely than controls to have completed advance directives (OR = 0.88; 95% CI: 0.21 to 3.7). CONCLUSION: Mailing health care proxy and living will forms and literature to patients before an appointment at which their physicians received a reminder about advance directives yielded a small but significant improvement in completion of these documents. A physician reminder alone did not have an effect.

A cost-benefit analysis of electronic medical records in primary care.

Electronic medical record systems improve the quality of patient care and decrease medical errors, but their financial effects have not been as well documented. The purpose of this study was to estimate the net financial benefit or cost of implementing electronic medical record systems in primary care. We performed a cost-benefit study to analyze the financial effects of electronic medical record systems in ambulatory primary care settings from the perspective of the health care organization. Data were obtained from studies at our institution and from the published literature. The reference strategy for comparisons was the traditional paper-based medical record. The primary outcome measure was the net financial benefit or cost per primary care physician for a 5-year period. The estimated net benefit from using an electronic medical record for a 5-year period was 86,400 US dollars per provider. Benefits accrue primarily from savings in drug expenditures, improved utilization of radiology tests, better capture of charges, and decreased billing errors. In one-way sensitivity analyses, the model was most sensitive to the proportion of patients whose care was capitated; the net benefit varied from a low of 8400 US dollars to a high of 140,100 US dollars . A five-way sensitivity analysis with the most pessimistic and optimistic assumptions showed results ranging from a 2300 US dollars net cost to a 330,900 US dollars net benefit. Implementation of an electronic medical record system in primary care can result in a positive financial return on investment to the health care organization. The magnitude of the return is sensitive to several key factors.

Genotoxicity and toxicity of the potential cancer-preventive agent polyphenon E.

The potential health benefits of green tea continue to attract public and scientific interests and are attributed in part to polyphenolic catechin constituents. Polyphenon E (Poly E) is a decaffeinated green tea catechin mixture containing about 50% epigallocatechin gallate and 30% other catechins. We evaluated the toxicity and genotoxicity of Poly E by using two in vitro assays: bacterial mutagenesis in a Salmonella typhimurium-E. coli assay and the L5178Y mouse lymphoma cell thymidine kinase (Tk) gene mutation assay. In addition, we used two in vivo genotoxicity assays: the mouse micronucleus assay and the Big Blue cII transgenic mouse mutation assay. Repeat-dose toxicity evaluations were performed in mice in parallel with the Big Blue transgenic mutation assays. No significant increases in the revertant colonies were found in the bacterial mutagenesis assay, but a significant increase in the mutant frequency (MF) at the Tk locus was observed in the mouse lymphoma test system. We observed toxicity in mice when Poly E was administered at doses of 2,000 mg/kg/day. Lower doses produced no significant increases in micronucleated erythrocytes in the bone marrow of Swiss-Webster mice and no significant increases in cII transgene MF in the liver, lung, or spleen compared with controls. These results indicate that Poly E, although toxic at high doses (2,000 mg/kg/day), poses minimal genotoxic concern. In addition, these studies highlight the importance of using both in vitro and in vivo systems in genetic toxicity screening of pharmaceuticals before they are administered to humans.

Physician leadership: enhancing the career development of academic physician administrators and leaders.

As the health care environment grows more complex, there is greater opportunity for physician administrative and management leadership. Although physicians in general, and academic physicians in particular, view management as outside their purview, the increased importance of physician administrative leadership represents an opportunity for academic physicians interested in working at the interface of clinical medicine, health care, finance, and management. These physicians are called academic physician administrators and leaders (APALs). APALs are clinician-administrators whose academic contributions include both scholarly work related to their administrative duties and administrative leadership of academically important programs. However, existing academic career development infrastructure, such as academic promotions, is oriented toward traditional clinician-educator and clinician-researcher faculty. The APAL career path differs from traditional academic pathways because APALs require unique skills, different mentors, and a more expansive definition of academic productivity. This article describes how academic medical institutions could enhance the career development of academic physicians in administrative and leadership positions.

Association of region of residence and immigrant status with hypertension, renal failure, cardiovascular disease, and stroke, among African-American participants in the third National Health and Nutrition Examination Survey (NHANES III).

OBJECTIVE: To determine whether current region of residence and immigrant status (born in the United States [US] vs abroad), are associated with the prevalence of hypertension (HTN), uncontrolled HTN, and HTN-related target-organ damage, among African Americans. METHODS: We studied the survey and physical examination data from a nationally representative cohort of 3,369 self-designated Black participants, aged 30-79 years, in the third National Health and Nutrition Examination Survey (NHANES III), which took place during 1988-1994. We calculated the age-adjusted prevalence rates of HTN, uncontrolled HTN, and history of HTN-related target-organ damage in US-born northern African Americans, US-born southern African Americans, and foreign-born African Americans. RESULTS: Hypertension (HTN) was more common among southern African-American men and women, compared to northern African-American men and women (42.2% vs 34.1%, P<.002 for men; 42.7% vs 37.2%, P=.02 for women). Uncontrolled HTN was also more common among hypertensive southern African-American women compared to hypertensive northern African-American women (79.8% vs 70.4%, P=.05). Among women, hypertensive Black immigrants had lower rates of HTN-related target-organ damage than either hypertensive US-born southern and northern African Americans (3.3% vs 16.3% and 15.8%, respectively, P=.05). CONCLUSIONS: In this nationally representative cohort, immigrant status and geographic region of residence were associated with HTN prevalence, rates of blood pressure control, and HTN-related target-organ damage. Further examination of environmental exposures, cultural issues, and access to care, factors that can differ between groups, may yield important information about modifiable risk factors associated with HTN and target organ damage.

Patient satisfaction profiling of individual physicians: impact of panel status.

RATIONALE, AIMS AND OBJECTIVES: Evaluation of physician performance is increasingly based on patient satisfaction. However, few data are available regarding the extent to which individual physician profiles might be influenced by factors such as whether a physician's practice is open or closed. We evaluated whether panel status (whether or not a physician is accepting new patients) is associated with patient satisfaction with their primary care physician (PCP). METHODS: Cross-sectional analysis of patient satisfaction surveys. Surveys were available for 1,750 patients cared for by 69 PCPs. Patient satisfaction with their PCP was determined based on a composite of six questions derived from the Medical Outcomes Study. We used Generalized Estimating Equations to adjust for physician level variation. RESULTS: Patients of closed-panel physicians were more likely to rate their satisfaction with the provider as 'Excellent' or 'Very Good' compared to patients of open-panel physicians (78% vs. 69%, P <0.0001). After adjusting for satisfaction with the practice site, provider years in practice, managed care coverage, provider productivity, and patient race, the association between a closed panel and satisfaction remained significant (odds ratio 1.60, 95% confidence interval 1.10-2.31). CONCLUSIONS: Individual physicians' patient satisfaction data are confounded by factors not likely to be adjusted for in available profiles. After adjusting for other variables, physicians with closed panels still had better patient satisfaction compared to physicians with open panels. Further research is necessary to determine if panel status might also confound patient satisfaction.

Impact of cardiac telemetry on patient safety and cost.

BACKGROUND: With the impetus for healthcare reform and the imperative for healthcare organizations to improve efficiency and reduce waste, it is valuable to examine high-volume procedures and practices in order to identify potential overuse. At the same time, organizations must ensure that improved efficiency does not inadvertently reduce patient safety. METHODS: We undertook a multicenter analysis of the use of adult cardiac telemetry outside of the intensive care unit or step-down units at 4 teaching hospitals to determine the percentage of monitoring days that were not justified by an accepted indication and the monetary costs associated with these nonindicated days. We also assessed the safety of eliminating monitoring on days when it was not justified by looking at the incidence of arrhythmias. RESULTS: We found that in 35% of telemetry days, telemetry use was not supported by an accepted set of clinical indications. The incidence of arrhythmias on nonindicated days was low (3.1 per 100 days of monitoring per nonindicated day),and the arrhythmias detected were clinically insignificant. Eliminating monitoring on nonindicated days could save a minimum of $53 per patient per day. The average 400-bed hospital with a conservative estimate of 5000 nonindicated patientdays per year could save $250,000 per year. CONCLUSION: Reducing the use of telemetry on nonindicated days may provide an opportunity for institutions to safely reduce cost as well as staff time and effort, while maintaining and potentially increasing patient safety.

Monitoring universal protocol compliance through real-time clandestine observation by medical students results in performance improvement.

OBJECTIVE: To measure universal protocol compliance through real-time, clandestine observation by medical students compared with chart audit reviews, and to enable medical students the opportunity to become conscious of the importance of medical errors and safety initiatives. DESIGN: With endorsement from Tufts Medical Center's (TMC's) Chief Medical Officer and Surgeon-in-Chief, 8 medical students performed clandestine observation audits of 98 cases from April to August 2009. A compliance checklist was based on TMC's presurgical checklist. Our initial results led to interventions to improve our universal protocol procedures, including modifications to the operating room white board and presurgical checklist, and specific feedback to surgical departments. One year later, 6 medical students performed observations of 100 cases from June to August 2010. SETTING: Tufts Medical Center, Boston, Massachusetts, which is an academic medical center and the principal teaching hospital for Tufts University School of Medicine. PARTICIPANTS: An operating room coordinator placed the medical students into 1 of our 25 operating rooms with students entering under the premise of observing the anesthesiologist for clinical education. The observations were performed Monday to Friday between 7 am and 4 pm. Although observations were not randomized, no single service or type of surgery was targeted for observation. RESULTS: A broad range of departments was observed. In 8.2% of cases, the surgical site was unmarked. A Time Out occurred in 89.7% of cases. The entire surgical team was attentive during the time out in 82% of cases. The presurgical checklist was incomplete before incision in 13 cases. Images were displayed in 82% of cases. The operating room "white board" was filled out completely in 49% of cases. Team introductions occurred in 13 cases. One year later, compliance increased in all Universal Protocol dimensions. CONCLUSIONS: Direct, real-time observation by medical students provides an accurate and granular assessment of compliance with specific components of the universal protocol and engages medical students in the quality improvement process, raises their awareness of the gravity of medical errors, and ensures appreciation of the importance of quality and safety initiatives.

Toxicogenomics and metabolomics of pentamethylchromanol (PMCol)-induced hepatotoxicity.

Pentamethyl-6-chromanol (PMCol), a chromanol-type compound related to vitamin E, was proposed as an anticancer agent with activity against androgen-dependent cancers. In repeat dose-toxicity studies in rats and dogs, PMCol caused hepatotoxicity, nephrotoxicity, and hematological effects. The objectives of this study were to determine the mechanisms of the observed toxicity and identify sensitive early markers of target organ injury by integrating classical toxicology, toxicogenomics, and metabolomic approaches. PMCol was administered orally to male Sprague-Dawley rats at 200 and 2000 mg/kg daily for 7 or 28 days. Changes in clinical chemistry included elevated alanine aminotransferase, total bilirubin, cholesterol and triglycerides-indicative of liver toxicity that was confirmed by microscopic findings (periportal hepatocellular hydropic degeneration and cytomegaly) in treated rats. Metabolomic evaluations of liver revealed time- and dose-dependent changes, including depletion of total glutathione and glutathione conjugates, decreased methionine, and increased S-adenosylhomocysteine, cysteine, and cystine. PMCol treatment also decreased cofactor levels, namely, FAD and increased NAD(P)+. Microarray analysis of liver found that differentially expressed genes were enriched in the glutathione and cytochrome P450 pathways by PMCol treatment. Reverse transcription-polymerase chain reaction of six upregulated genes and one downregulated gene confirmed the microarray results. In conclusion, the use of metabolomics and toxicogenomics demonstrates that chronic exposure to high doses of PMCol induces liver damage and dysfunction, probably due to both direct inhibition of glutathione synthesis and modification of drug metabolism pathways. Depletion of glutathione due to PMCol exposure ultimately results in a maladaptive response, increasing the consumption of hepatic dietary antioxidants and resulting in elevated reactive oxygen species levels associated with hepatocellular damage and deficits in liver function.