Kevin B. Weiss

Acellular Normal and Fibrotic Human Lung Matrices as a Culture System for In Vitro Investigation

RATIONALE Extracellular matrix (ECM) is a dynamic tissue that contributes to organ integrity and function, and its regulation of cell phenotype is a major aspect of cell biology. However, standard in vitro culture approaches are of unclear physiologic relevance because they do not mimic the compositional, architectural, or distensible nature of a living organ. In the lung, fibroblasts exist in ECM-rich interstitial spaces and are key effectors of lung fibrogenesis. OBJECTIVES To better address how ECM influences fibroblast phenotype in a disease-specific manner, we developed a culture system using acellular human normal and fibrotic lungs. METHODS Decellularization was achieved using treatment with detergents, salts, and DNase. The resultant matrices can be sectioned as uniform slices within which cells were cultured. MEASUREMENTS AND MAIN RESULTS We report that the decellularization process effectively removes cellular and nuclear material while retaining native dimensionality and stiffness of lung tissue. We demonstrate that lung fibroblasts reseeded into acellular lung matrices can be subsequently assayed using conventional protocols; in this manner we show that fibrotic matrices clearly promote transforming growth factor-β-independent myofibroblast differentiation compared with normal matrices. Furthermore, comprehensive analysis of acellular matrix ECM details significant compositional differences between normal and fibrotic lungs, paving the way for further study of novel hypotheses. CONCLUSIONS This methodology is expected to allow investigation of important ECM-based hypotheses in human tissues and permits future scientific exploration in an organ- and disease-specific manner.

Transitions of Care Consensus Policy Statement: American College of Physicians, Society of General Internal Medicine, Society of Hospital Medicine, American Geriatrics Society, American College of Emergency Physicians, and Society for Academic Emergency Medicine

The American College of Physicians, Society of Hospital Medicine, and Society of General Internal Medicine convened a multi-stakeholder consensus conference in July 2007 to address the quality gaps in the transitions between inpatient and outpatient settings and to develop consensus standards for these transitions. Over 30 organizations sent representatives to the Transitions of Care Consensus Conference. Participating organizations included medical specialty societies from internal medicine as well as family medicine and pediatrics, governmental agencies such as the Agency for Healthcare Research and Quality and the Centers for Medicare and Medicaid Services, performance measure developers such as the National Committee for Quality Assurance and the American Medical Association Physician Consortium on Performance Improvement, nurse associations such as the Visiting Nurse Associations of America and Home Care and Hospice, pharmacist groups, and patient groups such as the Institute for Family-Centered Care. The Transitions of Care Consensus Conference made recommendations for standards concerning the transitions between inpatient and outpatient settings for future implementation. The American College of Physicians, Society of Hospital Medicine, Society of General Internal Medicine, American Geriatric Society, American College of Emergency Physicians, and Society for Academic Emergency Medicine all endorsed this document.

Lipid Control in the Management of Type 2 Diabetes Mellitus: A Clinical Practice Guideline from the American College of Physicians

Diabetes mellitus is a leading cause of morbidity and mortality in the United States. Type 2 diabetes mellitus is most common (90% to 95% of persons with diabetes) and affects older adults, particularly those older than 50 years of age. An estimated 16 million Americans have type 2 diabetes, and up to 800000 new diagnoses are made each year (1, 2). Most adverse diabetes outcomes are a result of vascular complications, which are generally classified as microvascular (such as retinopathy, nephropathy, and neuropathy, although the latter may not be entirely a microvascular disease) or macrovascular (such as coronary artery disease, cerebrovascular disease, and peripheral vascular disease). To prevent or diminish the progression of microvascular and macrovascular complications, recommended diabetes management necessarily encompasses both metabolic control and control of cardiovascular risk factors (3-5). The need for good glycemic control is supported by the Diabetes Control and Complications Trial (6) in type 1 diabetes and, more recently, the United Kingdom Prospective Diabetes Study in type 2 diabetes (7). In these studies, tight blood sugar control reduced microvascular complications such as nephropathy and retinopathy but had little effect on macrovascular outcomes. Up to 80% of patients with type 2 diabetes will develop or die of macrovascular disease, underscoring the importance of preventing macrovascular complications. In an effort to provide internists and other primary care physicians with effective management strategies for diabetes care, the American College of Physicians (ACP) decided to develop guidelines on the management of dyslipidemia, particularly hypercholesterolemia, in people with type 2 diabetes. A previous College guideline addressed the critical role of tight blood pressure control in type 2 diabetes mellitus (8, 9). The target audience for this guideline is all clinicians who care for patients with type 2 diabetes. The target patient population is all persons with type 2 diabetes, including those who already have some form of microvascular complication and, of particular importance, premenopausal women. In this guideline we address the following questions. 1. What are the benefits of tight lipid control for both primary and secondary prevention in type 2 diabetes? 2. What is the evidence for treating to certain target levels of low-density lipoprotein (LDL) cholesterol for patients with type 2 diabetes? 3. Are certain lipid-lowering agents more effective or beneficial in patients with type 2 diabetes? This guideline is based on the systematic review of the evidence presented in the background paper by Vijan and colleagues in this issue (10). When Vijan and colleagues analyzed benefit or effectiveness, only studies that measured clinical end points were included. The major clinical end points in trials used to support the evidence for these guidelines were all-cause mortality, cardiovascular mortality, and cardiovascular events (that is, myocardial infarction, stroke, and cardiovascular mortality). No studies of lipid-lowering therapy have been conducted solely in patients with diabetes. Moreover, many trials excluded patients with diabetes. The sample sizes of participants with diabetes were often small, and many studies reported results only for the combined groups. Thus, the reports included in this review are of the subgroup analyses for studies that included patients with diabetes. The review was stratified into 2 categories. The first category evaluated the effects of lipid management in primary prevention (that is, in patients without known coronary disease). The second category evaluated the effects in secondary prevention (that is, in patients with established coronary disease). A total of 12 lipid-lowering studies presented diabetes-specific data and reported clinical outcomes. A discussion of this evidence follows (for a more detailed description of methodology, refer to the background paper by Vijan and colleagues [10]). Primary Prevention Six studies of primary prevention in patients with diabetes were identified. The Air Force Coronary Atherosclerosis Prevention Study/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) randomly assigned patients with average cholesterol levels and lower than average high-density lipoprotein (HDL) cholesterol levels to lovastatin, 20 to 40 mg/d, or placebo (in addition to a low-fat and low-cholesterol diet) for an average follow-up of 5.2 years (11). Based on data from the Third National Health and Nutrition Examination Survey, mean total cholesterol level was 5.72 mmol/L (221 mg/dL), mean LDL cholesterol level was 3.88 mmol/L (150 mg/dL), and mean HDL cholesterol level was 0.93 mmol/L (36 mg/dL) for men and 1.03 mmol/L (40 mg/dL) for women. One hundred fifty-five patients had diabetes. Lovastatin therapy led to a relative risk of 0.56 (95% CI, 0.17 to 1.92) for any atherosclerotic cardiovascular event (first fatal or nonfatal myocardial infarction, unstable angina, or sudden cardiac death) and an absolute risk reduction of 0.04 (CI, 0.04 to 0.12), neither of which was statistically significant. The mean LDL cholesterol level at the end of the study was 2.97 mmol/L (115 mg/dL), and the mean HDL cholesterol level was 1.00 mmol/L (39 mg/dL). The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial-Lipid-Lowering Trial (ALLHAT-LLT) randomly assigned patients 55 years of age and older who had hypertension and at least one other coronary heart disease (CHD) risk factor to pravastatin, 40 mg/d, or placebo (12). In the subgroup analysis of 3638 patients with type 2 diabetes, the relative risk for CHD events was 0.89 (CI, 0.71 to 1.10); the absolute risk reduction was not reported. This study has been criticized because of the smaller difference between LDL cholesterol levels in the control and intervention groups, which is probably due in part to contamination of the control group by publication of several other lipid-lowering trials during the study. The Helsinki Heart Study (13) randomly assigned men age 40 to 55 years with elevated non-HDL cholesterol levels to gemfibrozil, 600 mg 2 times per day, or placebo. The mean total cholesterol level was 7.5 mmol/L (290 mg/dL), and mean HDL cholesterol level was 1.23 mmol/L (47.6 mg/dL). In the 135 patients with diabetes, the incidence of CHD at 5 years was 3.4% in the gemfibrozil group and 10.5% in the placebo group. The relative risk was 0.32 (CI, 0.07 to 1.46), and the absolute risk reduction was 0.07 (CI, 0.01 to 0.15). None of these differences were statistically significant (14). The Heart Protection Study (HPS) included data on both primary and secondary prevention in patients with diabetes who were at high risk for cardiovascular disease (15). The objective of this study was to examine the effects of therapy to lower LDL cholesterol level across a broad range of lipid levels and risk factors. The HPS enrolled patients 40 to 80 years of age with nonfasting total cholesterol levels of at least 3.49 mmol/L ( 135 mg/dL). In the primary prevention group, 3982 patients had diabetes. Treatment with simvastatin, 40 mg, led to reduced risks for CHD events (relative risk, 0.74 [CI, 0.64 to 0.85]; absolute risk reduction, 0.05 [CI, 0.03 to 0.07]). The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) randomly assigned men and women 70 to 82 years of age with a history of cerebral or peripheral vascular disease or risk factors for such disease (such as smoking, hypertension, and diabetes) to pravastatin, 40 mg/d, or placebo (16). In the primary prevention group, 396 patients had diabetes. In these patients, treatment with pravastatin led to a trend toward harm (relative risk, 1.23 [CI, 0.77 to 1.95]; absolute risk reduction, 0.03 [CI, 0.10 to 0.04]). The interaction between diabetes and the treatment group was statistically significant, suggesting that patients with diabetes did substantially worse than those without diabetes. The Anglo-Scandinavian Cardiac Outcome Trial-Lipid Lowering Arm (ASCOT-LLA) randomly assigned patients age 40 to 79 years without CHD but with hypertension and at least 3 other cardiovascular risk factors (left ventricular hypertrophy, other electrocardiographic abnormalities, type 2 diabetes, peripheral arterial disease, previous stroke or transient ischemic attack, male sex, age 55 years, microalbuminuria, proteinuria, smoking, ratio of plasma total to HDL cholesterol of 6 or higher, or family history of premature CHD) to atorvastatin, 10 mg/d, or placebo (17). The diabetes subgroup, 2532 patients who had hypertension and at least 2 other risk factors, had low event rates of 3.6% in the control group and 3.0% in the intervention group. Thus, lipid-lowering treatment, with a relative risk of 0.84 (CI, 0.55 to 1.29) and an absolute risk reduction of 0.006 (CI, 0.008 to 0.019), did not lead to statistically significant improvements in the diabetes group. Secondary Prevention Eight trials reported on secondary prevention in patients with diabetes. The first, the Scandinavian Simvastatin Survival Study (4S), randomly assigned patients with coronary disease to simvastatin, 20 mg, or placebo (18). In a secondary analysis of the 202 patients with diabetes, simvastatin led to large benefits (relative risk for cardiovascular events, 0.50 [CI, 0.33 to 0.76]; absolute risk reduction, 0.23 [CI, 0.10 to 0.35]). Of note is the relatively high event rate in the control group (45%) compared with those seen in other trials. The Cholesterol and Recurrent Events (CARE) trial randomly assigned patients with previous myocardial infarction to pravastatin, 40 mg/d, or placebo (19). Pravastatin improved CHD outcomes in the 586 patients with diabetes (relative risk for cardiovascular events, 0.78 [CI, 0.62 to 0.99]; absolute risk reduction, 0.08 [CI, 0.01 to 0.16]). Results were reported as stratified by baseline LDL cholesterol levels and showed that for th

Management of Newly Detected Atrial Fibrillation: A Clinical Practice Guideline from the American Academy of Family Physicians and the American College of Physicians

Atrial fibrillation is the most common type of arrhythmia in adults. It is more common as patients age; the prevalence is 1% among those younger than age 60 years and increases to more than 8% in those older than age 80 years. When data are adjusted for age, men are affected more often than women. Cardiac conditions associated with the development of atrial fibrillation are hypertension, rheumatic mitral valve disease, coronary artery disease, and congestive heart failure. Noncardiac causes include hyperthyroidism, hypoxic pulmonary conditions, surgery, and alcohol intoxication. Patients with atrial fibrillation may have symptoms of hemodynamic compromise, such as irregular palpitations and lightheadedness, or more vague symptoms, such as malaise, but may be asymptomatic. Patients with atrial fibrillation are at increased risk for thromboembolic disease. The purpose of this guideline is to make recommendations on the pharmacologic management of newly detected atrial fibrillation in primary care. The target patient population is adult patients with first-detected atrial fibrillation, defined as the presence of symptoms or electrocardiographic evidence of atrial fibrillation. The American College of Cardiology/American Heart Association has recommended using first-detected atrial fibrillation regardless of whether it is symptomatic or self-limited, recognizing that there can be uncertainty about the duration of the episode and about previous undetected episodes (1). This guideline does not apply to patients with postoperative or postmyocardial infarction atrial fibrillation, patients with class IV heart failure, patients already taking antiarrhythmic drugs, or patients with valvular disease. The target physician audience is internists and family physicians dedicated to primary care. This guideline is based on the accompanying background paper by McNamara and colleagues (2) and on the evidence report Management of New-Onset Atrial Fibrillation (3), which was produced by the Johns Hopkins Evidence-based Practice Center under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, Maryland. The American Academy of Family Physicians (AAFP) and the American College of Physicians (ACP) created this guideline in collaboration. The Joint AAFP/ACP Panel reviewed the evidence and developed and graded the recommendations (Table 1). The guideline was then approved by both organizations. The guideline makes recommendations in the following areas: rate control versus rhythm control, stroke prevention and anticoagulation, electrical cardioversion versus pharmacologic cardioversion, the role of transesophageal echocardiography in guiding therapy, and maintenance therapy. Table 1. The Guyatt Approach to Grading Recommendations* Section 1: Rate Control versus Rhythm Control One of the fundamental questions in the management of atrial fibrillation is whether to attempt cardioversion. The answer to this question depends on whether rate control or rhythm control provides more effective protection from thromboembolic events, improved mortality, better relief of symptoms, or improved quality of life. Another significant clinical question is whether certain populations, such as women, patients with hypertension or congestive heart failure, or young people with structurally healthy hearts, have better outcomes with one or the other strategy. Four studies have compared rate control with rhythm control. The study samples have generally involved older patients (>65 years of age), and women and younger patients with healthy hearts and paroxysmal atrial fibrillation have not been well represented (5). The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial compared rhythm control versus rate control, and use of anticoagulation was recommended in both arms (6). More than 4000 patients who were at least 65 years of age or who had at least 1 risk factor for stroke or death, such as hypertension, diabetes, previous stroke, or poor ventricular function, were followed for a mean of 3.5 years. Slightly more than one third of the patients were enrolled after their first episode of atrial fibrillation, and more than 90% had had their qualifying episode within the previous 6 weeks. In more than two thirds of patients, the qualifying episode lasted at least 2 days. The average patient age was 70 years. Sixty-one percent of patients were men, and 89% were white. Seventy-one percent of patients had hypertension, 38% had coronary heart disease, 18% had previously had failure of antiarrhythmic therapy, and 12% had no apparent heart disease (lone atrial fibrillation). Patients were randomly assigned to rate or rhythm control, and their physicians chose the specific therapies (pharmacologic first, then nonpharmacologic if needed). Anticoagulation was continued indefinitely in the rate-control group and was encouraged in the rhythm-control group but could be stopped at the physicians discretion if sinus rhythm had been maintained for at least 4, and preferably 12, consecutive weeks with antiarrhythmic therapy. The prevalence of sinus rhythm in the rhythm-control group was 82%, 73%, and 63% at 1, 3, and 5 years, respectively. The prevalence of sinus rhythm in the rate-control group was 34.6% at 5 years. The primary end point in the AFFIRM trial, overall mortality, was not statistically significantly different between the groups. However, the rhythm-control strategy was associated with a higher risk for death than the rate-control strategy among older patients, those without congestive heart failure, and those with coronary disease. Rates of stroke also did not differ between groups; 70% of all strokes occurred in patients who had stopped receiving anticoagulation or who had subtherapeutic international normalized ratios (<2.0). More hospitalizations were reported in the rhythm-control group (P < 0.001). Another recent study, the RAte Control versus Electrical cardioversion for persistent atrial fibrillation (RACE) study, randomly assigned patients to receive aggressive rhythm control or rate control (7). This was a smaller study, involving 522 patients (mean age, 68 years). Sixty-four percent of patients were men, 49% had hypertension, and 27% had coronary artery disease. All patients had persistent atrial fibrillation lasting less than 1 year and had had at least 1 previous electrical cardioversion (a maximum of 2 previous cardioversions was permitted for study inclusion). The primary end point was a composite of cardiovascular mortality, heart failure, thromboembolic complications, bleeding, pacemaker implantation, and severe side effects of antiarrhythmic drugs. Again, no difference was seen between groups in the primary composite end point. As in the AFFIRM study, most of the strokes occurred in patients whose anticoagulation had been halted or patients whose international normalized ratio was subtherapeutic (<2.0). In post hoc analysis, a benefit for rate control over rhythm control was seen in patients with hypertension and in women. Since this was a post hoc analysis, these results will need to be confirmed by further studies. Of note, despite an aggressive treatment protocol, at the end of follow-up only 39% of the patients in the rhythm-control group were in sinus rhythm. The Pharmacological Intervention in Atrial Fibrillation (PIAF) trial randomly assigned 252 patients 18 to 75 years of age with new-onset or permanent symptomatic atrial fibrillation (mean duration of atrial fibrillation, approximately 4 months) to rate control with diltiazem or aggressive conversion (many times if necessary) and maintenance therapy with amiodarone (8). The primary end point of the study was improvement in symptoms related to atrial fibrillation. After 1 year of follow-up, relief of symptoms was similar in both groups, as were quality-of-life measures. Walking distance was improved in the rhythm-control group, but hospital admissions were more frequent in this group. Although final results are not yet available, preliminary reports of the Strategies of Treatment of Atrial Fibrillation (STAF) trial have been presented (9). Patients were randomly assigned to receive anticoagulation for 3 weeks before conversion and for 4 weeks after attempted conversion, with antiarrhythmic therapy to maintain sinus rhythm, or to long-term anticoagulation and rate control. (Patients included in this study had at least 1 previous conversion attempt.) After more than 1.5 years of follow-up, no difference was seen between the groups in rates of the primary end points of death, stroke, transient ischemic attacks, cardiopulmonary resuscitation, or thromboembolism. Of interest, only 40% of patients in the rhythm-control group were still in sinus rhythm at 1 year, and all primary end points occurred in patients in atrial fibrillation, even in the rhythm-control group. This result has created speculation about whether fewer events would have occurred if anticoagulation had been continued indefinitely in the conversion group. It also suggests that despite aggressive rhythm management, a substantial number of patients cannot maintain sinus rhythm. In general, the trial samples were older and male and had risk factors for stroke, such as hypertension, congestive heart failure, and coronary disease. Certain subgroups of patients with atrial fibrillation, such as younger patients with healthy hearts or paroxysmal atrial fibrillation, were not well represented in the trials. Therefore, it is not certain whether these subgroups of patients may benefit from more aggressive rhythm control or rate control. Recommendation 1: Rate control with chronic anticoagulation is the recommended strategy for the majority of patients with atrial fibrillation. Rhythm control has not been shown to be superior to rate control (with chronic anticoagulation) in reducing morbidity and mortality and may be inferior in some patient subgroups to rate control. Rhythm control

Transitions of Care Consensus Policy Statement American College of Physicians-Society of General Internal Medicine-Society of Hospital Medicine-American Geriatrics Society-American College of Emergency Physicians-Society of Academic Emergency Medicine

The American College of Physicians (ACP), Society of Hospital Medicine (SHM), Society of General Internal Medicine (SGIM), American Geriatric Society (AGS), American College of Emergency Physicians (ACEP) and the Society for Academic Emergency Medicine (SAEM) developed consensus standards to address the quality gaps in the transitions between inpatient and outpatient settings. The following summarized principles were established: 1.) Accountability; 2) Communication; 3.) Timely interchange of information; 4.) Involvement of the patient and family member; 5.) Respect the hub of coordination of care; 6.) All patients and their family/caregivers should have a medical home or coordinating clinician; 7.) At every point of transitions the patient and/or their family/caregivers need to know who is responsible for their care at that point; 9.) National standards; and 10.) Standardized metrics related to these standards in order to lead to quality improvement and accountability. Based on these principles, standards describing necessary components for implementation were developed: coordinating clinicians, care plans/transition record, communication infrastructure, standard communication formats, transition responsibility, timeliness, community standards, and measurement.

The Evidence Base for Tight Blood Pressure Control in the Management of Type 2 Diabetes Mellitus

Diabetes mellitus is a leading cause of morbidity and death in the United States. Type 2 diabetes mellitus accounts for the majority of affected persons (90% to 95%) and affects older adults, particularly those older than 50 years of age. It affects an estimated 16 million Americans, 11 million of whom have both diabetes and hypertension (1). Most adverse diabetes outcomes are a result of vascular complications. These complications are generally classified as microvascular, such as retinopathy, nephropathy, and neuropathy (although neuropathy may not be entirely a microvascular disease), or macrovascular, such as coronary artery disease, cerebrovascular disease, and peripheral vascular disease. In order to prevent, or diminish the progression of, microvascular and macrovascular complications, recommended diabetes management necessarily encompasses both metabolic control and cardiovascular risk factor control (2-4). The need for good glycemic control is supported by the Diabetes Control and Complications Trial (5) in type 1 diabetes mellitus and, more recently, the United Kingdom Prospective Diabetes Study (UKPDS) in type 2 diabetes mellitus (6). In these studies, tight blood sugar control reduced microvascular complications, such as nephropathy and retinopathy, but had little effect on macrovascular outcomes. Up to 80% of patients with type 2 diabetes mellitus will develop or die of macrovascular disease, underscoring the importance of preventing macrovascular complications. In an effort to provide internists and other primary care physicians with effective management strategies for diabetes care, the American College of Physicians decided to develop guidelines on the management of hypertension in people with type 2 diabetes mellitus. The target audience for this guideline is all clinicians who provide care to patients with type 2 diabetes. The target patient population is all persons with type 2 diabetes who have hypertension, defined as systolic blood pressure of at least 140 mm Hg or diastolic blood pressure of at least 90 mm Hg. This target patient population includes those who already have some form of microvascular complication and, of particular importance, premenopausal women with diabetes. We will attempt to answer the following questions: 1) What are the benefits of tight blood pressure control in type 2 diabetes? 2) What should the target levels of systolic blood pressure and diastolic blood pressure be for patients with type 2 diabetes? and 3) Are certain antihypertensive agents more effective or beneficial in patients with diabetes? When analyzing benefit or effectiveness for this review, we included only studies that measured clinical end points. The four major classes of clinical end points were all-cause mortality, cardiovascular mortality, cardiovascular events (myocardial infarction, stroke, or congestive heart failure), and microvascular complications (photocoagulation, nephropathy, neuropathy, or amputation). The review was divided into two categories. The first included studies that evaluated the effects of blood pressure control if the comparison examined an antihypertensive drug versus placebo or the effects of different target blood pressure levels. The second category evaluated the effect of different classes of drugs. A discussion of this evidence follows. Blood Pressure Control Benefits Three studies have compared focused treatment of hypertension in subgroups of people with diabetes versus placebo or usual care. They are the Systolic Hypertension in the Elderly Program (SHEP), the Hypertension Detection and Follow-up Program (HDFP), and the Systolic Hypertension in Europe (Syst-Eur) study (7-9). In SHEP, patients were randomly assigned to intensive treatment versus placebo and usual care by primary providers. The intensive group achieved reductions of 9.8 mm Hg in systolic blood pressure and 2.2 mm Hg in diastolic blood pressure, as well as a significant decline in total cardiovascular events (relative risk [RR], 0.66 [95% CI, 0.46 to 0.94]). The HDFP randomly assigned patients to stepped care (intensive) versus referred care (usual care). The primary data from this trial were analyzed by the Cochrane Database of Systematic Reviews (10), which found an odds ratio for cardiovascular mortality and morbidity of 0.62 (CI, 0.44 to 0.87) in the intensive group. The Syst-Eur study randomly assigned patients to nitrendipine or placebo. The mean decrease in systolic blood pressure and diastolic blood pressure for diabetic patients in the intervention group was 8.6 and 3.9 mm Hg, respectively, resulting in a 70% reduction in cardiovascular mortality, a 62% reduction in all cardiovascular events, and a 69% reduction in stroke. After adjustment for confounders, there was a 55% reduction in overall mortality. Target Blood Pressure Levels Three recent studies, the Hypertension Optimal Treatment (HOT) study, the UKPDS, and the Appropriate Blood Pressure Control in Diabetes (ABCD) trial, specifically compared the effects of randomly assigning participants to different blood pressure targets on cardiovascular outcomes. In the HOT study, patients were randomly assigned to target diastolic blood pressures of 90, 85, and 80 mm Hg (11). Achieved diastolic blood pressures in each group were 85.2, 83.2, and 81.1 mm Hg, respectively. The group randomly assigned to a target of 80 mm Hg had a significantly lower relative risk for cardiovascular death and major cardiovascular events compared with the group randomly assigned to a target of 90 mm Hg. The UKPDS (12) randomly assigned patients to a tight blood pressure control group with a target of less than 150/85 mm Hg or a less tight control group with a target of less than 180/105 mm Hg. The achieved blood pressures were 144/82 mm Hg and 154/87 mm Hg, respectively. (It is important to note that these targets, described as tight and less tight control, do not conform with current standards from the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, in which a blood pressure above 140/90 mm Hg is considered uncontrolled.) In the tight control group, there were substantial reductions in risk for any diabetes end point, deaths related to diabetes, and stroke. In addition, there was also a significant reduction in risk for microvascular disease, with actual improvements in visual acuity. The ABCD study (13) randomly assigned patients to intensive treatment (target diastolic blood pressure, 75 mm Hg) or moderate control (target diastolic blood pressure, 80 to 89 mm Hg). Achieved blood pressure was 132/78 mm Hg in the intensive group and 138/86 mm Hg in the moderate group. After 5 years of follow-up, there were no differences between the groups in progression of nephropathy, retinopathy, or neuropathy. Total mortality rate was 5.5% in the intensive group and 10.7% in the moderate group, but there were no differences in cardiovascular mortality to explain this. In summary, in the HOT study, a four-point difference in diastolic blood pressure, from 85 to 81 mm Hg, resulted in a 50% decrease in risk for cardiovascular events in patients with diabetes. If this study is used as the lowest mean value achieved in the trials, a diastolic blood pressure of 80 mm Hg should be the goal for patients with diabetes. It is not clear whether diastolic blood pressure lower than 80 mm Hg is beneficial. Systolic target goals have not been tested in randomized trials, but the UKPDS showed that a 10-point reduction in systolic blood pressure, from 154 mm Hg to 144 mm Hg, led to a substantial decrease in diabetes-related mortality and end points. Thus, while the optimal level of control for systolic blood pressure has not been clearly established, it may be reasonable to target a systolic blood pressure of 130 to 135 mm Hg based on the levels attained in the ABCD trial. The studies of hypertension control in diabetes show a clear and consistent effect: Improved control of blood pressure leads to substantially reduced risks for cardiovascular events and death. The Table highlights the numbers needed to treat for benefit for tight blood pressure control in the UKPDS (14). Table. Number Needed To Treat for Benefit for Tight Hypertension Control in the United Kingdom Prospective Diabetes Study Effectiveness of Different Classes of Antihypertensive Medications Three trials have compared calcium-channel blockers and angiotensin-converting enzyme (ACE) inhibitors: the ABCD trial, the Fosinopril versus Amlodipine Cardiovascular Events Trial (FACET), and the Swedish Trial in Old Patients with Hypertension-2 (STOP-2). In a substudy of the ABCD trial (15), patients were randomly assigned to treatment with nisoldipine or enalapril. The achieved blood pressure was the same in each group, but by the end of the study nearly half of the patients were not taking their initially assigned drug. In intention-to-treat analyses, the rate of myocardial infarction was substantially higher (RR, 5.5 [CI, 2.1 to 14.6]) in the nisoldipine group compared with the enalapril group. These effects persisted after adjustment for confounders and for the length of time that the patients were actually exposed to the drugs. The relatively higher mortality rate in the calcium-channel blocker group was not due to a detrimental or adverse effect of nisoldipine but was most likely a result of the greater efficacy of the ACE inhibitor. In FACET (16), patients were randomly assigned to fosinopril or amlodipine. Systolic blood pressure control was better in the amlodipine group than in the fosinopril group, while diastolic blood pressure was similar. Despite higher systolic blood pressure, patients randomly assigned to fosinopril had significantly fewer combined cardiovascular events (RR, 0.49 [CI, 0.26 to 0.95]). Individual events were not significantly different between groups, nor was mortality, although all trends favored fosinopril. In STOP-2, three drug groups were compared:

Screening for Hereditary Hemochromatosis: A Clinical Practice Guideline from the American College of Physicians

Recommendations Recommendation 1: There is insufficient evidence to recommend for or against screening for hereditary hemochromatosis in the general population. There is currently insufficient evidence to determine whether the benefits of screening the general population outweigh the risks. The C282Y mutation is prevalent in certain populations, particularly white men, and treatment is not costly nor is it associated with any significant harm. Although patients homozygous for C282Y are more likely to have elevated serum ferritin level and transferrin saturation percentage, there currently is no way of predicting which patients will progress to overt disease. For clinicians who choose to screen, 1-time phenotypic screening of asymptomatic non-Hispanic white men with serum ferritin level and transferrin saturation would have the highest yield (1). Recommendation 2: In case-finding for hereditary hemochromatosis, serum ferritin and transferrin saturation tests should be performed. There is no information available on risk-stratifying in patients with an associated condition or conditions such as type 2 diabetes, cardiac arrhythmias and cardiomyopathies, liver failure, hepatomegaly, cirrhosis, elevated liver enzyme levels, hepatocellular carcinoma, arthritis, hypogonadism, or changes in skin pigmentation. The initial symptoms associated with iron overload might be nonspecific, and the decision to perform tests should be based on clinical judgment regarding what may cause such protean manifestations. If testing is performed for these patients, the cutoff values for serum ferritin level of more than 200 g/L in women or more than 300 g/L in men and transferrin saturation greater than 55% may be used as criteria for case-finding; however, there is no general agreement about diagnostic criteria. Case-finding may also be considered if there is a family history of hereditary hemochromatosis for an individual, as the risk for developing the disease may be higher than that of the general population. Recommendation 3: Physicians should discuss the risks, benefits, and limitations of genetic testing in patients with a positive family history of hereditary hemochromatosis or those with elevated serum ferritin level or transferrin saturation. Before genetic testing, individuals should be made aware of the benefits and risks of genetic testing. This should include discussing available treatment and its efficacy; costs involved (2); and social issues, such as impact of disease labeling, insurability and psychological well-being, and the possibility of as-yet-unknown genotypes associated with hereditary hemochromatosis. Recommendation 4: Further research is needed to establish better diagnostic, therapeutic, and prognostic criteria for hereditary hemochromatosis. The lack of information on the natural history of the disease makes it difficult to manage patients with hereditary hemochromatosis. There are no clearly defined criteria to risk-stratify patients into groups more or less likely to develop overt disease. Future developments in technology and genetic screening might help in the diagnosis and management of hereditary hemochromatosis. In addition, there is a need for more uniform diagnostic criteria. Introduction Hereditary hemochromatosis is a genetic disorder of iron metabolism and is characterized by tissue injury resulting from an abnormal accumulation of iron in various organs. This disease is usually a consequence of an increased absorption of iron from the gastrointestinal tract, which results in increased iron deposition in tissue, particularly in the liver, heart, and pancreas. If left untreated, it can lead to organ damage, such as cirrhosis, as well as hepatocellular cancer. However, early diagnosis of hereditary hemochromatosis is difficult because of variability in the case definition and diagnostic standard used. Diagnosis of hereditary hemochromatosis is usually based on a combination of various genetic or phenotypic criteria. Genetically, it can be based on direct DNA testing for the 2 HFE gene mutations (C282Y and H63D) associated with hereditary hemochromatosis. The mutation of C282Y in the HFE gene on chromosome 6 is present in almost 90% of those affected. Most patients are homozygous, and mutation transmission is autosomal recessive. The H63D mutation may be associated with hereditary hemochromatosis, but the actual clinical effects of this mutation are uncertain (3). Although in a small proportion, compound heterozygotes (C282Y/H63D) can develop iron overload. Phenotypic markers of hereditary hemochromatosis may be used to identify the disease. Percentage of transferrin saturation and serum ferritin level have been used to confirm the diagnosis of hereditary hemochromatosis. Transferrin saturation determines how much iron is bound to the protein that carries iron in the blood. Serum ferritin level is elevated in patients with hereditary hemochromatosis and correlates with liver iron and development of cirrhosis. Liver biopsy to measure hepatic iron concentration by staining is considered the gold standard to test for hereditary hemochromatosis. However, with the advent of genetic testing, liver biopsy is not widely used to confirm the diagnosis. There is a consensus on the various diagnostic tests that could be used to diagnose hereditary hemochromatosis. However, the threshold levels that should be used to define the disease remain controversial. On the basis of the review of the background paper by Schmitt and colleagues (4), also in this issue, and considering that lower cutoffs are more sensitive and less specific, serum ferritin level greater than 200 g/mL and transferrin saturation greater than 55% suggest an increased risk for hereditary hemochromatosis and the need for further investigation (5). Hereditary hemochromatosis is the most common recessive genetic trait in white persons. However, estimating the prevalence of this disease is difficult. Genetic testing of populations originating in northern Europe showed that approximately 0.5% are homozygous for the C282Y mutation (6). The Hemochromatosis and Iron Overload Screening (HEIRS) Study showed that the prevalence of C282Y homozygotes was highest among non-Hispanic white persons (0.44% [95% CI, 0.42% to 0.47%]) (1). Phenotypic screening of the population in the United States demonstrated that 1% to 6% have elevated transferrin saturation and 11% to 22% of this group have an increased serum ferritin level (7). Hereditary hemochromatosis has been estimated to be present in 3 to 5 people per 1000 in the general population (8). Decisions regarding screening are difficult because of the variable penetrance of mutations of the HFE gene and the absence of any definitive trials addressing the benefits and risks of therapeutic phlebotomy in asymptomatic patients or those with only laboratory abnormalities. The purpose of this guideline is to increase physician awareness of hereditary hemochromatosis, particularly the variable penetrance of genetic mutations; aid in case finding; and explain the role of genetic testing. The target audience for this guideline is internists and other primary care physicians. The target patient population is all persons who have a probability or susceptibility of developing hereditary hemochromatosis, including the relatives of individuals who already have the disease. This guideline is based on the systematic review of the evidence in the background paper (4). This guideline attempts to answer the following questions: 1) What is the prevalence of hereditary hemochromatosis in the primary care setting? 2) In asymptomatic patients with hereditary hemochromatosis, what is the risk for end-organ damage or death? 3) How diagnostically useful are transferrin saturation and serum ferritin in identifying patients with hereditary hemochromatosis in the primary care setting? 4) Is phlebotomy efficacious in reducing morbidity or fatal complications in asymptomatic patients with hereditary hemochromatosis? 5) Do the benefits of screening primary care patients for hereditary hemochromatosis outweigh the risks? Prevalence Estimates of the prevalence of hereditary hemochromatosis in the general population vary widely because no set criteria define what constitutes hereditary hemochromatosis (5, 9, 10). Some argue that genotyping should be used as the gold standard and that the sensitivity and specificity of phenotyping should be calculated and compared with those of genotyping. Others support the use of persistently elevated serum ferritin level and percentage of transferrin saturation as the case definition of hereditary hemochromatosis. Studies of differing populations, using strict criteria recommended in the HEIRS Study (11), have estimated that the prevalence of hereditary hemochromatosis ranges from 1 in 357 persons to 1 in 625 persons in the general population to rates almost as high as 1 in 135 persons among Norwegian men (4). The Table lists various studies showing the prevalence of hereditary hemochromatosis in primary care settings. Table. Prevalence of Hereditary Hemochromatosis in Primary Care Settings Risk for Complications in Asymptomatic Patients Asymptomatic individuals are patients in the latent phase of hereditary hemochromatosis who were incidentally identified. These persons have not yet shown any signs or symptoms related to the disease. Although clinical manifestations associated with hereditary hemochromatosis are influenced by age, sex, diet, and other unknown factors, it is imperative to know the path of disease progression for treatment of the disease. Clinical outcomes that can be associated with hereditary hemochromatosis are cirrhosis, hepatocellular carcinoma, type 2 diabetes, congestive heart failure, arthritis, hypogonadism in males, and even death. However, most persons with the mutated gene remain asymptomatic. The literature that discusses the relationship between biochemical primary iron overload (

Changing Impact of Gastroesophageal Reflux in Medical and Otolaryngology Practice

Objectives/Hypothesis: A major trend in gastroesophageal reflux disease (GERD) is an observed increased prevalence of the problem, with an associated burden on health care resources. There are relatively few objective reports of increasing prevalence of this disease, and there are no epidemiologic reports that discuss changing practice strategies in managing the disease. The clinical problem is of critical importance to practicing otolaryngologists, who manage the impact of GERD on diseases affecting the ear, nose, and throat. The hypothesis of this thesis is that 1) GERD is an increasing problem affecting outpatient office visits over time, and 2) the disease is increasingly managed with prescription pharmacotherapy.

The Clinical Learning Environment: The Foundation of Graduate Medical Education

MORE THAN A DECADE AFTER THE INSTITUTE OF Medicine reported problems with the quality and safety of US health care, formal training of the health care workforce in quality and patient safety is still inadequate. A recently released survey of hospital leaders from the American Hospital Association (AHA) highlighted the need to educate US physicians and trainees regarding quality improvement. The AHA report identified deficiencies in newly trained physicians in systems-based practice, communication skills, and the ability to work within teams. The Accreditation Council for Graduate Medical Education (ACGME) recognizes the public’s need for a physician workforce capable of meeting the requirements of the rapidly evolving health care environment. This effort dates to the late 1990s, when the ACGME, collaborating with the American Board of Medical Specialties, established 6 core competencies creating a framework for attaining the skills needed for the modern practice of medicine. This framework drives both curriculum design and evaluation of educational outcomes for resident physicians. The next step in the evolution of resident physician training is the Next Accreditation System (NAS), which is now being implemented by the ACGME. The NAS emphasizes outcomes instead of processes for resident learning. These outcomes are assessed by achievement of performance measures, including milestones as residents progress toward independent practice. Examples of these outcomes include clinical experience as evidenced by case logs, milestones progression, scholarly activity, and specialty certification pass rates. The Clinical Learning Environment Review (CLER) program is the first component of the NAS to be operationalized nationally. The CLER program identifies US teaching hospitals’ efforts to engage residents in 6 focus areas: patient safety; health care quality, including reduction in health care disparities; transitions in care; supervision; duty hours and fatigue management and mitigation; and professionalism. CLER site visits have started at all ACGME-accredited sponsoring institutions having more than 1 training program. The CLER site visits are being conducted by a team including ACGME staff and volunteer site visitors from other sponsoring institutions and involve discussions and observations with hospital executive leadership (including the chief executive officer), resident physicians, faculty, graduate medical education leadership, nursing, and other hospital staff. These visits are designed to stimulate improvement in residents’ engagement in the 6 focus areas and, as such, are intentionally not directly linked to accreditation. Site visitors gain knowledge about residents’ engagement in the 6 focus areas through group meetings and visits in clinical service areas. Group meetings involve structured interviews with residents, faculty, and program directors. Walking rounds entail unplanned visits to various clinical sites at random times of the day and evening to meet with physicians, nursing, and other staff and discuss resident engagement. From these 2 sources of information, the site visit team assesses how the institution is performing in each of the 6 focus areas. At the end of the visit, the site visit team provides the institution with feedback and a written report soon thereafter. The ACGME is currently planning on repeating the CLER visits every 18 months to assess institutional progress in improving resident involvement in the 6 focus areas. A newly established evaluation committee is developing a set of performance expectations for teaching hospitals and medical centers. Institutional performance will be evaluated in light of these expectations. With time, the aggregated experience regarding institutional performance in these areas will shape future ACGME accreditation requirements. Early experience with CLER visits revealed numerous interesting improvement projects and some efforts in the education and training of residents and fellows in the 6 focus areas. Site visitors have also encountered hospitals and medical centers where the role of the residents in organizational efforts to improve health care quality and patient safety was, at best, uncertain. These visits revealed significant opportunities to enhance graduate medical education as well as institutional performance to better meet the needs of pa-

Improving Clinical Learning Environments for Tomorrow's Physicians

On the basis of site visits that it has conducted for its Clinical Learning Environment Review program, the Accreditation Council for Graduate Medical Education reports finding a generalized lack of resident engagement in systems-based practice.