Resources medical students use to derive a differential diagnosis.

BACKGROUND: Deriving an appropriate differential diagnosis is a key clinical competency, but there is little data available on how medical students learn this skill. Software resources designed to complement clinical reasoning might be asset in helping them in this task. AIMS: The goals of this study were to identify the resources third year medical students use to solve a challenging diagnostic case, and specifically to evaluate the usefulness of Isabel, a second-generation electronic diagnosis support system. METHODS: Third year medical students (n = 117) were presented a challenging case and asked to identify and prioritize their top 3 diagnoses, report the time devoted to the exercise, and list the resources they used and their relative usefulness. Students were randomized to receive (or not) free access, instruction, and encouragement to use to a web-based decision support system (Isabel). RESULTS: Students who identified the correct diagnosis as their first choice spent significantly more time on the case than did the other students (3.75 +/- 0.28 hours vs 2.88 +/- 0.15 hours, p < 0.05). Students used electronic resources extensively, in particular Google. Students who self-reported use of Isabel had greater success identifying the correct diagnosis (24/33 = 73% for users vs 45/84 = 53% for non-users) a difference of borderline statistical significance. CONCLUSIONS: These findings indicate that medical trainees use a wide range of electronic decision support products to solve challenging cases. Medical education needs to adapt to this reality, and address the need to teach future clinicians how to use these tools to advantage.

Primer on medical genomics. Part XIV: Introduction to systems biology--a new approach to understanding disease and treatment.

The advent of the "-omics revolution" has forced us to reevaluate our ability to acquire, measure, and handle large data sets. Omic platforms such as expression arrays and mass spectrometry, with their exquisite selectivity, sensitivity, and specificity, are unrivaled technologies for detection, quantitation, and identification of DNA, messenger RNA, proteins, and metabolites derived from complex body tissue and fluids. More recently, attempts have been made to capture the utility of these platform technologies and combine them under the umbrella of systems biology, also referred to as pathway, network, or integrative biology. Applied systems biology is the integrated analysis of genetic, genomic, protein, metabolite, cellular, and pathway events that are in flux and interdependent. It necessitates the use of a variety of analytic platforms as well as biostatistics, bioinformatics, data integration, computational biology, modeling, and knowledge assembly protocols. Such sophisticated analyses may provide new insight into the understanding of disease processes and mechanisms of action of pharmaceutical agents. Ultimately, this requires a perspective on how complex systems behave and are modulated. In this regard, systems biology, more appropriately considered as a process containing a series of modules, aims to provide tools and capabilities to carry out such tasks. We describe the essentials required to carry out systems biology experiments, the method in which integrated data in the form of a systems biology correlation network affords new insight into understanding disease, and the vista of developing more efficient biomarkers and therapeutic agents.

Success and predictors of blood pressure control in diverse North American settings: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT).

CONTEXT: Blood pressure control (<140/90 mm Hg) rates for hypertension fall far short of the US national goal of 50% or more. Achievable control rates in varied practice settings and geographic regions and factors that predict improved blood pressure control are not well identified. OBJECTIVE: To determine the success and predictors of blood pressure control in a large hypertension trial involving a multiethnic population in diverse practice settings. DESIGN: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial is a randomized, double-blind, active-controlled clinical trial with a mean follow-up of 4.9 years. Participant enrollment began in February 1994 and follow-up was completed in March 2002. SETTING: A total of 623 centers in the United States, Canada, and the Caribbean. PARTICIPANTS: A total of 33,357 participants (aged > or =55 years) with hypertension and at least one other coronary heart disease risk factor. INTERVENTIONS: Participants were randomly assigned to receive (double-blind) chlorthalidone, 12.5-25 mg/d (n=15,255), amlodipine 2.5-10 mg/d (n=9048), or lisinopril 10-40 mg/d (n=9054) after other medication was discontinued. Doses were increased within these ranges and additional drugs from other classes were added as needed to achieve blood pressure control (<140/90 mm Hg). MAIN OUTCOME MEASURES: The outcome measures for this report are systolic and diastolic blood pressure, the proportion of participants achieving blood pressure control (<140/90 mm Hg), and the number of drugs required to achieve control in all three groups combined. RESULTS: Mean age was 67 years, 47% were women, 35% black, 36% diabetic; 90% were on antihypertensive drug treatment at entry. At the first of two pre-randomization visits, blood pressure was <140/90 mm Hg in only 27.4% of participants. After 5 years of follow-up, the percent controlled improved to 66%. Systolic blood pressure was <140 mm Hg in 67% of participants, diastolic blood pressure was <90 mm Hg in 92%, the mean number of drugs prescribed was 2.0+/-1.0, and the percent on > or =2 drugs was 63%. Blood pressure control varied by geographic regions, practice settings, and demographic and clinical characteristics of participants. CONCLUSIONS: These data demonstrate that blood pressure may be controlled in two thirds of a multiethnic hypertensive population in diverse practice settings. Systolic blood pressure is more difficult to control than diastolic blood pressure, and at least two antihypertensive medications are required for most patients to achieve blood pressure control. It is likely that the majority of people with hypertension could achieve a blood pressure <140/90 mm Hg with the antihypertensive medications available today.

First Desymmetrization of a Centrosymmetric Molecule in Natural Product Synthesis: Preparation of a Key Fragment in the Synthesis of Hemibrevetoxin B.

Exploitation of molecular symmetry can greatly improve the efficiency of syntheses. The symmetry embedded in the centrosymmetric AB dioxepane fragment of hemibrevetoxin B was exploited for the first time in the preparation of an established intermediate in its total synthesis. Desymmetrization of the centrosymmetric diepoxide 1 by enantioselective epoxide hydrolysis followed by acetonization gave the known synthetic intermediate 2.

Desymmetrization of a centrosymmetric diepoxide: efficient synthesis of a key intermediate in a total synthesis of hemibrevetoxin B.

The preparation of an established intermediate in a total synthesis of hemibrevetoxin B is described. The acid-catalyzed cyclization of trans-4,5-epoxyoctane-2,7-dione exhibited a valuable mixture of kinetic and thermodynamic control: stereospecific epoxide opening was followed by equilibration of the products to provide the required trans-fused octahydropyrano[3,2-b]pyran ring system. Two-directional elaboration, by acetal substitution, ozonolysis, and sulfur ylide-mediated epoxidation, provided a centrosymmetric diepoxide. The key step of the synthesis was the first desymmetrization of a centrosymmetric molecule in natural product synthesis: Jacobsen asymmetric epoxide hydrolysis and acetonization provided the known synthetic intermediate in 97% yield and >95% ee over two steps. The exploitation of the center of symmetry of the AB ring system of the natural product contributed greatly to the efficiency (eight steps, 34% overall yield) of the synthesis.

Exploiting predisposition in the stereoselective synthesis of mono-, bi- and tetracyclic oxygen heterocycles: equilibration between, and trapping of, alternative di- and tetraacetals.

The desymmetrisation of 1,4-difuran-2-ylbutane-1,4-diol by Sharpless asymmetric oxidation gave the corresponding desymmetrised product in > 96% ee. However, the product existed as a mixture of two interconverting isomers, both of which were mixtures of anomers. The product could be trapped in high yield with a range of reagents to give stable adducts with embedded pyran-3-one, 1,6-dioxaspiro[4.5]decane or pyrano[3,2-b]pyran ring systems. The strategy was also applied in the interconversion between alternative tetracycles and, under acidic conditions, this process was thermodynamically controlled. The selectivity of the process was rationalised by molecular modelling using the HF/6-31G* parameter set.