The influence of age and body mass index on the metabolic syndrome and its components.

OBJECTIVE: The aim of this study was to evaluate the influence of ageing and body mass index (BMI) on the revised National Cholesterol Education Program (NCEP)-defined metabolic syndrome, its components, diabetes and coronary heart disease prevalence using the Third National Health and Nutrition Examination Survey. METHODS: Data from adults aged 20 and older who received morning physical examinations after a fast of at least 9 h (n = 7959), representing 196.8 million Americans were used in this analysis. The population was stratified by age deciles and BMI categories using standard definitions of overweight and obesity. Due to small sample size, those few individuals with BMI <18.5 were excluded. RESULTS: Fasting glucose, diabetes and systolic blood pressure (SBP) seem to have a linear relationship with age and BMI, that is, increasing BMI seems to linearly reduce the age decile when the mean exceeds the NCEP cutpoint. Regardless of BMI, the prevalence of diabetes and hypertension increases with age. Triglyceride levels and prevalence of metabolic syndrome follow a pattern that is less linear. Fasting insulin and C-reactive protein (CRP) levels correlate better with BMI than age. Diastolic BP and HDL cholesterol for men and women (analysed separately) did not correlate with either age or BMI. CONCLUSION: For each component of the metabolic syndrome and associated factors, there is a complex interaction between ageing and obesity. Some components are associated with obesity but not ageing (e.g. CRP), while others are associated with both obesity and ageing (e.g. glucose). Even when the association exists, the specific relationship can appear to be more (e.g. SBP) or less (e.g. triglycerides) linear.

Adverse events after discontinuing medications in elderly outpatients.

BACKGROUND: Discontinuation of drug therapy is an important intervention in elderly outpatients receiving multiple medications, but it may be associated with adverse drug withdrawal events (ADWEs). OBJECTIVE: To determine the frequency, types, timing, severity, and factors associated with ADWEs after discontinuing medications in elderly outpatients. PATIENTS: One hundred twenty-four ambulatory elderly participants in 1-year health service intervention trial at the Durham Veterans Affairs General Medicine Clinic in Durham, NC, who stopped taking medications. METHODS: A geriatrician retrospectively reviewed computerized medication records and clinical charts to determine medications no longer being taken and adverse events in the subsequent 4-month period. Possible ADWEs, determined by using the Naranjo causality algorithm, were categorized by therapeutic class, organ system, and severity. RESULTS: Of 238 drugs stopped, 62 (26%) resulted in 72 ADWEs among 38 patients. Cardiovascular (42%) and central nervous system (18%) drug classes were most frequently associated with ADWEs. The ADWEs most commonly involved the circulatory (51%) and central nervous (13%) systems, and 88% were attributed to exacerbations of underlying disease. Twenty-six ADWEs (36%) resulted in hospitalization or an emergency department or urgent care clinic visit. Only the number of medications stopped was associated with ADWE occurrence (adjusted odds ratio, 1.89; 95% confidence interval, 1.33-2.67). CONCLUSIONS: Most medications can be stopped in elderly outpatients without an ADWE occurrence. However, when ADWEs occur they resulted in substantial health care utilization. Practitioners should strive to discontinue drug therapy in the elderly but be vigilant for disease recurrence.

A telephone-delivered intervention for patients with NIDDM. Effect on coronary risk factors.

OBJECTIVE: To examine whether a telephone-delivered intervention (TDI), designed to improve glycemic control in patients with non-insulin-dependent diabetes mellitus (NIDDM), improved coronary risk factors in high-risk patients. RESEARCH DESIGN AND METHODS: This randomized controlled trial involved 275 veterans with NIDDM followed in a general medical clinic. Intervention (TDI) patients were telephoned at least monthly by a nurse. Calls emphasized compliance with the medical regimen (diet, medications, and exercise), encouraged behavioral changes, and facilitated referrals to a dietitian or smoking cessation clinic. Control patients received no such calls. Baseline and 12-month follow-up measurements included fasting lipid profiles, weight, smoking status (self-reported; cessation verified by measurement of exhaled CO), adherence to diet and exercise (self-reported), appointments, and medications (hospital computerized data base). RESULTS: After 12 months, equal numbers of obese patients in the two groups reported adhering to a diabetic diet and exercising, although more obese TDI patients had seen a dietitian (30 vs. 7%, P = 0.003). Weight loss was not seen in either group (-0.9 +/- 5.3 vs. -0.1 +/- 3.6 kg, P = 0.202). Hyperlipidemic TDI patients were more likely to see a dietitian (31 vs. 6%, P = 0.003) and receive lipid-lowering medications (22 vs. 9%, P = 0.096), but serum cholesterol reduction was similar between groups (-11.7 +/- 33.4 vs. -4.3 +/- 32.7 mg/dl, P = 0.270); comparable results were seen for high-density lipoprotein, low-density lipoprotein, and triglyceride levels. More TDI group smokers reported quitting (26 vs. 0%, P = 0.033), but the difference was not significant for CO-verified abstention (10 vs. 0%, P = 0.231). CONCLUSIONS: The TDI improved self-reported adherence to regimens that might reduce coronary risk, but had little effect on objective measures of risk.

Patients with prior fractures have an increased risk of future fractures: a summary of the literature and statistical synthesis.

Numerous studies have reported increased risks of hip, spine, and other fractures among people who had previous clinically diagnosed fractures, or who have radiographic evidence of vertebral fractures. However, there is some variability in the magnitudes of associations among studies. We summarized the literature and performed a statistical synthesis of the risk of future fracture, given a history of prior fracture. The strongest associations were observed between prior and subsequent vertebral fractures; women with preexisting vertebral fractures (identified at baseline by vertebral morphometry) had approximately 4 times greater risk of subsequent vertebral fractures than those without prior fractures. This risk increases with the number of prior vertebral fractures. Most studies reported relative risks of approximately 2 for other combinations of prior and future fracture sites (hip, spine, wrist, or any site). The confidence profile method was used to derive a single pooled estimate from the studies that provided sufficient data for other combinations of prior and subsequent fracture sites. Studies of peri- and postmenopausal women with prior fractures had 2.0 (95 % CI = 1.8, 2.1) times the risk of subsequent fracture compared with women without prior fractures. For other studies (including men and women of all ages), the risk was increased by 2.2 (1.9, 2.6) times. We conclude that history of prior fracture at any site is an important risk factor for future fractures. Patients with a history of prior fracture, therefore, should receive further evaluation for osteoporosis and fracture risk.

A randomized, controlled trial of a clinical pharmacist intervention to improve inappropriate prescribing in elderly outpatients with polypharmacy.

PURPOSE: To evaluate the effect of sustained clinical pharmacist interventions involving elderly outpatients with polypharmacy and their primary physicians. PATIENTS AND METHODS: Randomized, controlled trial of 208 patients aged 65 years or older with polypharmacy (> or = 5 chronic medications) from a general medicine clinic of a Veterans Affairs Medical Center. A clinical pharmacist met with intervention group patients during all scheduled visits to evaluate their drug regimens and make recommendations to them and their physicians. Outcome measures were prescribing appropriateness, health-related quality of life, adverse drug events, medication compliance and knowledge, number of medications, patient satisfaction, and physician receptivity. RESULTS: Inappropriate prescribing scores declined significantly more in the intervention group than in the control group by 3 months (decrease 24% versus 6%, respectively; P = 0.0006) and was sustained at 12 months (decrease 28% versus 5%, respectively; P = 0.0002). There was no difference between groups at closeout in health-related quality of life (P = 0.99). Fewer intervention than control patients (30.2%) versus 40.0%; P = 0.19) experienced adverse drug events. Measures for most other outcomes remained unchanged in both groups. Physicians were receptive to the intervention and enacted changes recommended by the clinical pharmacist more frequently than they enacted changes independently for control patients (55.1% versus 19.8%; P <0.001). CONCLUSIONS: This study demonstrates that a clinical pharmacist providing pharmaceutical care for elderly primary care patients can reduce inappropriate prescribing and possibly adverse drug effects without adversely affecting health-related quality of life.

Diabetes mellitus, impaired fasting glucose, atherosclerotic risk factors, and prevalence of coronary heart disease.

Patients with diabetes mellitus (DM), both diagnosed (history of) and undiagnosed (by fasting glucose [FG] only), as well as impaired FG have an increased risk of coronary heart disease (CHD), compared with those with normal FG. Elevations in FG levels, even in normoglycemic subjects (<110 mg/dl), may be significantly related to CHD morbidity and mortality. Improving lipid profiles and blood pressure can decrease both CHD morbidity and mortality in these patients. We evaluated the relation of glucose status to lipid levels, other risk factors, and prevalence of CHD using the 1997 American Diabetes Association diagnostic criteria in a representative sample of United States adults studied in the Third National Health and Nutrition Examination Survey from 1988 to 1994. Impaired FG, diagnosed DM, and undiagnosed DM were more prevalent in older age groups; those > or =65 years had increased prevalence compared with those <50 years old (rate ratios for IFG, DM-FG, and history of DM were 3.5, 4.8, and 10.8, respectively). Glycosylated hemoglobin levels were increased by glucose status. The frequency of known CHD risk factors also increased with worsening glucose status. Age-adjusted CHD prevalence was increased with impaired FG (rate ratio 1.47), DM-FG (rate ratio 1.56), and history of DM (rate ratio 1.72), compared with normal FG. Adjusting for age and other CHD risk factors, hyperglycemia was no longer significantly associated with CHD prevalence. Lipid values, especially high-density lipoprotein cholesterol, hypertension, and other CHD risk factors were more strongly associated with CHD than glucose status. Thus, patients with impaired FG, DM-FG, and history of DM should be considered at higher risk for CHD morbidity and mortality. However, hyperglycemia, per se, does not explain the excess risk. In addition to glucose, lipid profiles and blood pressure should be periodically monitored and appropriate treatment provided to reduce morbidity and mortality from CHD.

Are health-related quality-of-life measures affected by the mode of administration?

While measures of health-related quality of life (HRQOL) are increasingly being used as outcomes in clinical trials, it is unknown whether HRQOL assessments are influenced by the method of administration. We compared telephone, face-to-face, and self-administration of a commonly-used HRQOL measure, the SF-36. Veterans (N = 172) receiving care in the General Medicine Clinic were randomized into groups differing only in order of administration. All patients were asked to complete the SF-36 three times over a 4-week period. The SF-36 demonstrated high internal consistency, regardless of mode of administration, but showed large variation over short intervals. This variation may: (1) increase dramatically sample size requirements to detect between-group differences in randomized trials and (2) reduce the SF-36's usefulness for clinicians wishing to follow individual patients over time.

A summated score for the medication appropriateness index: development and assessment of clinimetric properties including content validity.

Inappropriate medication prescribing is an important problem in the elderly, but is difficult to measure. As part of a randomized controlled trial to evaluate the effectiveness of a pharmacist intervention among elderly veterans using many medications, we developed the Medication Appropriateness Index (MAI), which uses implicit criteria to measure elements of appropriate prescribing. This paper describes the development and validation of a weighting scheme used to produce a single summated MAI score per medication. Using this weighting scheme, two clinical pharmacists rated 105 medications prescribed to 10 elderly veterans from a general medicine clinic. The summated score demonstrated acceptable reliability (intraclass correlation co-efficient = 0.74). In addition, the summated MAI adequately reflected the putative heterogeneity in prescribing appropriateness among 1644 medications prescribed to 208 elderly veterans in the same general medicine clinic. These data support the content validity of the summated MAI. The MAI appears to be a relatively reliable, valid measure of prescribing appropriateness and may be useful for research studies, quality improvement programs, and patient care.

Adverse drug events in high risk older outpatients.

OBJECTIVE: To describe the prevalence, types, and consequences of adverse drug events (ADEs) in older outpatients with polypharmacy. DESIGN: A cohort study. SETTING: General Medicine Clinic at the Durham Veterans Affairs Medical Center. PATIENTS: A total of 167 high risk (taking > or = 5 scheduled medications) ambulatory older veterans who participated in a year long health service intervention trial. MEASUREMENTS: Potential ADEs were identified by asking patients during closeout interviews whether, in the past year, they had experienced any side effects, unwanted reactions, or other problems from any medication. All reported medications and corresponding adverse experiences were assessed for plausibility by a research clinical pharmacist using two standard pharmacological textbooks and categorized by predictability, therapeutic class, and organ system. RESULTS: Eighty self-reported ADEs involving 72 medications taken by 58 (35%) of 167 patients were textbook confirmed. Seventy-six of 80 (95%) ADEs were classified as Type A (predictable) reactions. Cardiovascular (33.3%) and central nervous system (27.8%) medication classes were most commonly implicated. Gastrointestinal (30%) and central nervous system (28.8%) ADE symptoms were common. Sixty-three percent of patients with ADEs required physician contacts, 10% emergency room visits, and 11% hospitalization. Twenty percent of medications implicated with ADEs required dosage adjustments, and 48% of ADE-related medications were discontinued. No significant differences (P > .05) were observed when ADE reporters (n = 58) and nonreporters (n = 109) were compared. CONCLUSION: Predictable ADEs are common in high risk older outpatients, resulting in considerable medication modification and substantial healthcare utilization.

Appropriateness of medication prescribing in ambulatory elderly patients.

OBJECTIVE: To assess the quality of medication prescribing in ambulatory elderly patients on multiple medications using the Medication Appropriateness Index (MAI). DESIGN: Cross-sectional study. SETTING: General Medical Clinic of the Durham VA Medical Center. PATIENTS: 208 elderly outpatients on five or more regularly scheduled medications. MEASUREMENTS: Medication prescribing appropriateness was measured with the MAI, a reliable method that employs 10 implicit criteria. A weighted MAI score (range 0-18 per drug) served as a summary measure of appropriateness. RESULTS: There were 1644 medications evaluated; 26% received no inappropriate ratings, 37% had one, 19% had two, and 18% had three or more. Of 16,440 ratings, 2295 (14%) were evaluated as inappropriate. The percentage of inappropriate ratings varied across prescribing dimensions: drug-drug interactions, 0%; drug-disease interactions, 1.4%; medication effectiveness, 4.7%; therapeutic duplication, 5.7%; indication, 11.5%; duration of treatment, 16.5%; dosage, 17.3%; practical directions, 20.3%; cost, 29.7%; and correct directions, 32.4%. The mean MAI score for all medications was 2.2 +/- 2.1 (range 0-10) and varied by therapeutic class. MAI scores were significantly lower for medications with a high potential for adverse effects compared with those with a low potential (MAI score of 1.8 vs 2.9, P < 0.001). Regression analysis revealed that no patient characteristics were associated with a higher likelihood of inappropriate prescribing. CONCLUSIONS: Medication prescribing for elderly outpatients taking multiple medications was substantially appropriate. Prescribing dimensions with the most room for improvement were more exact directions, less expensive drugs, and practical directions. Drugs at high risk for adverse effects were prescribed more appropriately than those at low risk.

Assessing health-related quality of life in elderly outpatients: telephone versus face-to-face administration.

OBJECTIVE: While health-related quality of life (HRQOL) is increasingly being used as an outcome in clinical trials, it is unknown whether HRQOL assessments are influenced by the method of administration. Within the context of a randomized, controlled trial evaluating a pharmacist intervention for elderly outpatients prescribed at least five medications, we compared telephone and face-to-face administration of the SF-36, a widely used HRQOL measure. DESIGN: Survey. SETTING: General Medicine Clinic, Veterans Affairs Medical Center. PATIENTS: At entry, participants in the randomized trial received continuous care from a general medicine clinic physician, were > or = 65 years of age, and were prescribed > or = 5 regularly scheduled medications. Patients were excluded if they were cognitively impaired and had no caregiver available to participate in the study as a proxy or if they resided in a nursing home. MEASUREMENTS: Subjects completed the SF-36 by telephone at closeout and face-to-face at clinic visits within 1 month (mean = 16.7 days). MAIN RESULTS: Telephone administration required significantly less time than face-to-face interviews (10.2 vs 14.0 minutes, P < 0.001). Although systematic differences between modes of administration were generally small, there were substantial nonsystematic discrepancies for all eight SF-36 scales (mean absolute difference scores ranged from 10.8 to 30.1). Discrepancies were greatest for emotional role functioning, physical role functioning, social functioning, and bodily pain; these four scales also demonstrated low to moderate correlations (.33 to .58). CONCLUSIONS: The two modes of administration may not produce interchangeable results. Researchers should be cautious when mixing modes of administration to elderly patients.

The cost-effectiveness of a clinical pharmacist intervention among elderly outpatients.

We estimated the cost and cost-effectiveness of a clinical pharmacist intervention known to improve the appropriateness of drug prescribing. Elderly veteran outpatients prescribed at least five drugs were randomized to an intervention (105 patients) or control (103) group and followed for 1 year. The intervention pharmacist provided advice to patients and their physicians during all general medicine visits. Mean fixed and variable costs/intervention patient were $36 and $84, respectively Health services use and costs were comparable between groups. Intervention costs ranged from $7.50-30/patient/unit change in drug appropriateness. The cost to improve the appropriateness of drug prescribing is thus relatively low.

Influence of projected complication rates on estimated appropriate use rates for carotid endarterectomy. Appropriateness Project Investigators. Academic Medical Center Consortium.

OBJECTIVE: To examine specifically the influence of estimated perioperative mortality and stroke rate on the assessment of appropriateness of carotid endarterectomy. DATA SOURCES/STUDY SETTING: An expert panel convened to rate the appropriateness of a variety of potential indications for carotid endarterectomy based on various rates of perioperative complications. We then applied these ratings to the charts of 1,160 randomly selected patients who had carotid endarterectomy in one of the 12 participating academic medical centers. STUDY DESIGN: An expert panel evaluated indications for carotid endarterectomy using the modified Delphi approach. Charts of patients who received surgery were abstracted, and clinical indications for the procedure as well as perioperative complications were recorded. To examine the impact of surgical risk assessment on the rates of appropriateness, three different definitions of risk strata for combined perioperative death or stroke were used: Definition A, low risk < 3 percent; Definition B, low risk < 5 percent; and Definition C, low risk < 7 percent. PRINCIPAL FINDINGS: Overall hospital-specific mortality ranged from 0 percent to 4.0 percent and major complications, defined as death, stroke, intracranial hemorrhage, or myocardial infarction, varied from 2.0 percent to 11.1 percent. Most patients (72 percent) had surgery for transient ischemic attack or stroke; 24 percent of patients were asymptomatic. Most patients (82 percent) had surgery on the side of a high-grade stenosis (70-99 percent). When the thresholds for operative risk were placed at the values defined by the expert panel (Definition A), only 33.5 percent of 1,160 procedures were classified as "appropriate." When the definition of low risk was shifted upward, the proportion of cases categorized as appropriate increased to 58 percent and 81.5 percent for Definitions B and C, respectively. CONCLUSIONS: Despite the high proportion of procedures performed for symptomatic patients with a high degree of ipsilateral extracranial carotid artery stenosis and generally low rates of surgical complications at the participating institutions, the overall rate of "appropriateness" using a perioperative complication rate of < 3 percent was low. However, the rate of "appropriateness" was extremely sensitive to judgments about a single clinical feature, surgical risk. These data show that before applying such "appropriateness" ratings, it is crucial to perform sensitivity analyses in order to assess the stability of the results. Results that are robust to moderate in variation in surgical risk provide a much sounder basis for policy making than those that are not.

Inpatient hospital utilization among veterans with traumatic spinal cord injury.

OBJECTIVE: To describe the pattern of inpatient hospital utilization, up to 15 years after injury, among a cohort of veterans with service-connected traumatic spinal cord injury (SCI). PATIENTS: A cohort of 1,250 male veterans, with traumatic SCI occurring between 1970 and 1986, who visited the VA within 1 year of injury, was assembled from VA administrative files; diagnosis was verified by examining hospital discharge summaries. DESIGN: Computerized record linkage among Department of Veterans Affairs (VA) administrative files was used to determine patterns of inpatient hospital utilization. MAIN OUTCOME MEASURE: Pattern of inpatient admissions and length of stay (LOS). RESULTS: Patients were typically white males injured in their mid-twenties. The initial VA hospitalization began approximately 6 weeks after injury and lasted 4 to 7 months, depending on injury level and completeness. Subsequent hospitalizations usually lasted approximately 10 days, but 22% of stays exceeded 1 months. Most hospitalizations took place in specialized SCI Centers. Comparing the 1980s with the 1970s, patients in the 1980s entered VA facilities sooner after injury, were more likely to visit SCI Centers, and had shorter initial stays. Rates for the incidence of rehospitalization decreased rapidly in years 2-5 after injury and declined less rapidly thereafter. Occupancy rates and proportion rehospitalized followed similar patterns. The incidence rate for persons with complete quadriplegia was approximately twice that of patients with incomplete paraplegia. Between 1970 and 1991, both the rehospitalization incidence rate and LOS decreased by approximately 20%. Only 10% of patients accounted for 46% of the total LOS. LOS during the first five years was predictive of later LOS. CONCLUSIONS: The pattern of rehospitalization in VA facilities was generally consistent with that of the Model Systems. Efforts toward preventing rehospitalization should target persons with previous high utilization.

Race, treatment, and survival among colorectal carcinoma patients in an equal-access medical system.

BACKGROUND: The aim of this study was to assess the influence of race on the treatment and survival of patients with colorectal carcinoma. METHODS: This retrospective cohort study included all white or black male veterans given a new diagnosis of colorectal carcinoma in 1989 at Veterans Affairs Medical Centers nationwide. After adjusting for patient demographics, comorbidity, distant metastases, and tumor location, the authors determined the likelihood of surgical resection, chemotherapy, radiation therapy, and death in each case. RESULTS: Of the 3176 veterans identified, 569 (17.9%) were black. Bivariate analyses and logistic regression revealed no significant differences in the proportions of patients undergoing surgical resection (70% vs. 73%, odds ratio 0.92, 95% confidence interval 0.74-1.15), chemotherapy (23% vs. 23%, odds ratio 0.99, 95% confidence interval 0.78-1.24), or radiation therapy (17% vs. 16%, odds ratio 1.10, 95% confidence interval 0.85-1.43) for black versus white patients. Five-year relative survival rates were similar for black and white patients (42% vs. 39%, respectively; P=0.16), though the adjusted mortality risk ratio was modestly increased (risk ratio 1.13, 95% confidence interval 1.01-1.28). CONCLUSIONS: Overall, race was not associated with the use of surgery, chemotherapy, or radiation therapy in the treatment of colorectal carcinoma among veterans seeking health care at Veterans Affairs Medical Centers. Although mortality from all causes was higher among black veterans with colorectal carcinoma, this finding may be attributed to underlying racial differences associated with survival. This study suggests that when there is equal access to care, there are no differences with regard to race.

Enhanced access to primary care for patients with congestive heart failure. Veterans Affairs Cooperative Study Group on Primary Care and Hospital Readmission.

OBJECTIVE: To determine whether enhanced access to primary care affects the diagnostic evaluation, pharmacologic management, or health outcomes of patients hospitalized with congestive heart failure (CHF). DESIGN: Multisite randomized, controlled trial. SETTING: Nine Veterans Affairs medical centers. PATIENTS: 443 patients who were hospitalized with a diagnosis of CHF. INTERVENTION: Enhanced access to primary care, including assignment of a primary care nurse and physician, increased telephone contact, additional outpatient visits, and patient education. MAIN OUTCOME MEASURES: Diagnostic evaluation, pharmacologic management, health-related quality of life, and hospital readmission rates. RESULTS: About 80% of patients who had enhanced access to care and patients receiving usual care underwent recommended evaluation of left ventricular ejection fraction. Among the subset of patients for whom an angiotensin-converting enzyme (ACE) inhibitor was recommended (i.e., ejection fraction < 40%), three quarters of the patients in both the enhanced access and usual care groups received the drug (75% vs. 73%; P > 0.2). Enhanced access to primary care did not improve quality of life and increased hospital readmissions, with an average of 1.5 +/- SD 2.0 readmissions per 6 months of follow-up for patients who had enhanced access compared with 1.1 +/- SD 1.8 for those who received usual care (P = 0.02). CONCLUSIONS: Compliance with recommended CHF testing and treatment guidelines was equally high in both study groups. Enhanced access to primary care did not improve patients' self-reported health status and was associated with more frequent hospitalizations.

Distributions of intramolecular distances in the reduced and denatured states of bovine pancreatic ribonuclease A. Folding initiation structures in the C-terminal portions of the reduced protein.

The purpose of this investigation is to characterize the reduced state of RNase A (r-RNase A) in terms of (i) intramolecular distances, (ii) the sequence of formation of stable loops in the initial stages of folding, and (iii) the unfolding transitions induced by GdnHCl. This is accomplished by identifying specific subdomain structures and local and long-range interactions that direct the folding process of this protein and lead to the native fold and formation of the disulfide bonds. Eleven pairs of dispersed sites in the RNase A molecule were labeled with fluorescent donor and acceptor probes, and the distributions of intramolecular distances (IDDs) were determined by means of time-resolved dynamic nonradiative excitation energy transfer (TR-FRET) measurements. The mutants were designed to search for (a) a possible nonrandom fold of the backbone in the collapsed state and (b) possible loops stabilized by long-range interactions. It was found that, under folding conditions, (i) the labeled mutants of r-RNase A in refolding buffer (the R(N) state) exhibit features of specific (nonrandom) compact but very dispersed subdomain structures (indicated by short mean distances, broad IDDs, and a weak dependence of the mean distances on segment length), (ii) the backbone fold in the C-terminal beta-like portion of the molecule appears to adopt a native-like overall fold, (iii) the N-terminal alpha-like portion of the chain is separated from the C-terminal core by very large intramolecular distances, larger than those in the crystal structure, and (iv) perturbations by addition of GdnHCl reveal several conformational transitions in different sections of the chain. Addition of GdnHCl to the native disulfide-intact protein provided a reference state for the extent of expansion of intramolecular distances under denaturing conditions. In conclusion, r-RNase A under folding conditions (the R(N) state) is poised for the final folding step(s) with a native-like trace of the chain fold but a large separation between the two subdomains which is then decreased upon introduction of three of the four native disulfide cross-links.

Inappropriate prescribing and health outcomes in elderly veteran outpatients.

OBJECTIVE: To determine the relationship of inappropriate prescribing in the elderly to health outcomes. SETTING: General Medical Clinic of the Durham Veterans Affairs Medical Center. PATIENTS: A total of 208 veterans more than 65 years old who were each taking five or more drugs and participated in a pharmacist intervention trial. MEASUREMENTS: Prescribing appropriateness was assessed by a clinical pharmacist using the medication appropriateness index (MAI). A summed MAI score was calculated, with higher scores indicating less appropriate prescribing. The health outcomes were hospitalization, unscheduled ambulatory or emergency care visits, and blood pressure control. RESULTS: Bivariate analyses revealed that mean MAI scores at baseline were higher for those with hospital admissions (18.9 vs. 16.9, p = 0.07) and unscheduled ambulatory or emergency care visits (18.8 vs. 16.3, p = 0.05) over the subsequent 12 months than for those without admissions and emergency care visits. MAI scores for antihypertensive medications were higher for patients with inadequate blood pressure control (> 160/90 mm Hg) than for those whose blood pressure was controlled (4.7 vs. 3.1, p = 0.02). CONCLUSIONS: Inappropriate prescribing appeared to be associated with adverse health outcomes. This findings needs to be confirmed in future studies that have larger samples and control for potential confounders.