Effect of Prolonged Methylprednisolone Therapy in Unresolving Acute Respiratory Distress Syndrome: A Randomized Controlled Trial

Context.— No pharmacological therapeutic protocol has been found effective in modifying the clinical course of acute respiratory distress syndrome (ARDS) and mortality remains greater than 50%. Objective.— To determine the effects of prolonged methylprednisolone therapy on lung function and mortality in patients with unresolving ARDS. Design.— Randomized, double-blind, placebo-controlled trial. Setting.— Medical intensive care units of 4 medical centers. Participants.— Twenty-four patients with severe ARDS who had failed to improve lung injury score (LIS) by the seventh day of respiratory failure. Interventions.— Sixteen patients received methylprednisolone and 8 received placebo. Methylprednisolone dose was initially 2 mg/kg per day and the duration of treatment was 32 days. Four patients whose LIS failed to improve by at least 1 point after 10 days of treatment were blindly crossed over to the alternative treatment. Main Outcome Measures.— Primary outcome measures were improvement in lung function and mortality. Secondary outcome measures were improvement in multiple organ dysfunction syndrome (MODS) and development of nosocomial infections. Results.— Physiological characteristics at the onset of ARDS were similar in both groups. At study entry (day 9 [SD, 3] of ARDS), the 2 groups had similar LIS, ratios of PaO₂ to fraction of inspired oxygen (FIO₂), and MODS scores. Changes observed by study day 10 for methylprednisolone vs placebo were as follows: reduced LIS (mean [SEM], 1.7 [0.1] vs 3.0 [0.2]; P<.001); improved ratio of PaO₂ to FIO₂ (mean [SEM], 262 [19] vs 148 [35]; P<.001); decreased MODS score (mean [SEM], 0.7 [0.2] vs 1.8 [0.3]; P<.001); and successful extubation (7 vs 0; P=.05). For the treatment group vs the placebo group, mortality associated with the intensive care unit was 0 (0%) of 16 vs 5 (62%) of 8 (P=.002) and hospital-associated mortality was 2 (12%) of 16 vs 5 (62%) of 8 (P=.03). The rate of infections per day of treatment was similar in both groups, and pneumonia was frequently detected in the absence of fever. Conclusions.— In this study, prolonged administration of methylprednisolone in patients with unresolving ARDS was associated with improvement in lung injury and MODS scores and reduced mortality.      

Early Inpatient Rehabilitation After Elective Hip and Knee Arthroplasty

Context.— Inpatient rehabilitation after elective hip and knee arthroplasty is often necessary for patients who cannot function at home soon after surgery, but how soon after surgery inpatient rehabilitation can be initiated has not been studied. Objective.— To test the hypothesis that high-risk patients undergoing elective hip and knee arthroplasty would incur less total cost and experience more rapid functional improvement if inpatient rehabilitation began on postoperative day 3 rather than day 7, without adverse consequences to the patients. Design.— Randomized controlled trial conducted from 1994 to 1996. Setting.— Tertiary care center. Participants.— A total of 86 patients undergoing elective hip or knee arthroplasty and who met the following criteria for being high risk: 70 years of age or older and living alone, 70 years of age or older with 2 or more comorbid conditions, or any age with 3 or more comorbid conditions. Of the 86 patients, 71 completed the study. Interventions.— Random assignment to begin inpatient rehabilitation on postoperative day 3 vs postoperative day 7. Main Outcome Measures.— Total length of stay and cost from orthopedic and rehabilitation hospital admissions, functional performance in hospitals using a subset of the functional independence measure, and 4-month follow-up assessment using the RAND 36-item health survey I and the functional status index. Results.— Patients who completed the study and began inpatient rehabilitation on postoperative day 3 exhibited shorter mean (±SD) total length of stay (11.7±2.3 days vs 14.5±1.9, P<.001), lower mean (±SD) total cost ($25891±$3648 vs $27762±$3626, P<.03), more rapid attainment of short-term functional milestones between days 6 and 10 (36.2±14.4 m ambulated vs 21.4±13.3 m, P<.001; 4.8±0.8 mean transfer functional independence measure score vs 4.3±0.7, P<.01), and equivalent functional outcome at 4-month follow-up. Conclusion.— These data showed that high-risk individuals were able to tolerate early intensive rehabilitation, and this intervention yielded faster attainment of short-term functional milestones in fewer days using less total cost.      

Effects of Raloxifene on Serum Lipids and Coagulation Factors in Healthy Postmenopausal Women

Context.— Raloxifene is a selective estrogen receptor modulator that has estrogen-agonistic effects on bone and estrogen-antagonistic effects on breast and uterus. Objective.— To identify the effects of raloxifene on markers of cardiovascular risk in postmenopausal women, and to compare them with those induced by hormone replacement therapy (HRT). Design.— Double-blind, randomized, parallel trial. Setting.— Eight sites in the United States. Participants.— 390 healthy postmenopausal women recruited by advertisement. Intervention.— Participants were randomized to receive 1 of 4 treatments: raloxifene, 60 mg/d; raloxifene, 120 mg/d; HRT (conjugated equine estrogen, 0.625 mg/d, and medroxyprogesterone acetate, 2.5 mg/d); or placebo. Main Outcome Measures.— Change and percent change from baseline of lipid levels and coagulation parameters after 3 months and 6 months of treatment. Results.— At the last visit completed, compared with placebo, both dosages of raloxifene significantly lowered low-density lipoprotein cholesterol (LDL-C) by 12% (P<.001), similar to the 14% reduction with HRT (P<.001). Both dosages of raloxifene significantly lowered lipoprotein(a) by 7% to 8% (P<.001), less than the 19% decrease with HRT (P<.001). Raloxifene increased high-density lipoprotein-2 cholesterol (HDL₂-C) by 15% to 17% (P<.05), less than the 33% increase with HRT (P<.001). Raloxifene did not significantly change high-density lipoprotein cholesterol (HDL-C), triglycerides, or plasminogen activator inhibitor-1 (PAI-1); whereas HRT increased HDL-C by 11% and triglycerides by 20%, and decreased PAI-1 by 29% (for all, P< .001). Raloxifene significantly lowered fibrinogen by 12% to 14% (P<.001), unlike HRT, which had no effect. Neither treatment changed fibrinopeptide A or prothrombin fragment 1 and 2. Conclusions.— Raloxifene favorably alters biochemical markers of cardiovascular risk by decreasing LDL-C, fibrinogen, and lipoprotein(a), and by increasing HDL₂-C without raising triglycerides. In contrast to HRT, raloxifene had no effect on HDL-C and PAI-1, and a lesser effect on HDL₂-C and lipoprotein(a). Further clinical trials are necessary to determine whether these favorable biochemical effects are associated with protection against cardiovascular disease.      

Effect of the Statistical Significance of Results on the Time to Completion and Publication of Randomized Efficacy Trials

Context.— Medical evidence may be biased over time if completion and publication of randomized efficacy trials are delayed when results are not statistically significant. Objective.— To evaluate whether the time to completion and the time to publication of randomized phase 2 and phase 3 trials are affected by the statistical significance of results and to describe the natural history of such trials. Design.— Prospective cohort of randomized efficacy trials conducted by 2 trialist groups from 1986 to 1996. Setting.— Multicenter trial groups in human immunodeficiency virus infection sponsored by the National Institutes of Health. Patients.— A total of 109 efficacy trials (total enrollment, 43708 patients). Main Outcome Measures.— Time from start of enrollment to completion of follow-up and time from completion of follow-up to peer-reviewed publication assessed with survival analysis. Results.— The median time from start of enrollment to publication was 5.5 years and was substantially longer for negative trials than for results favoring an experimental arm (6.5 vs 4.3 years, respectively; P<.001; hazard ratio for time to publication for positive vs negative trials, 3.7; 95% confidence interval [CI], 1.8-7.7). This difference was mostly attributable to differences in the time from completion to publication (median, 3.0 vs 1.7 years for negative vs positive trials; P<.001). On average, trials with significant results favoring any arm completed follow-up slightly earlier than trials with nonsignificant results (median, 2.3 vs 2.5 years; P=.045), but long-protracted trials often had low event rates and failed to reach statistical significance, while trials that were terminated early had significant results. Positive trials were submitted for publication significantly more rapidly after completion than were negative trials (median, 1.0 vs 1.6 years; P=.001) and were published more rapidly after submission (median, 0.8 vs 1.1 years; P=.04). Conclusion.— Among randomized efficacy trials, there is a time lag in the publication of negative findings that occurs mostly after the completion of the trial follow-up.      

Publication Bias and Research on Passive Smoking: Comparison of Published and Unpublished Studies

Context.— The results of reviews may be biased by delays in publication and failure to publish nonsignificant results. Objective.— To determine the extent of unpublished results on the health effects of passive smoking and whether passive smoking studies with statistically nonsignificant results would have longer time to publication than those with statistically significant results. Design.— Semistructured telephone interviews of principal investigators of published or unpublished studies funded between 1981 and 1995, identified by information obtained from 76 (85%) of 89 organizations contacted that potentially funded research on passive smoking. Participants.— Seventy-eight investigators were eligible and could be located; 65 (83%) responded. They had conducted 61 studies of the health effects of passive smoke in humans or animals between 1981 and 1995 that met the criteria for the analysis of time to publication. Main Outcome Measure.— Time to publication for published studies and statistical significance of results of published and unpublished studies. Results.— Fourteen of the 61 studies were unpublished. Median time to publication was 5 years (95% confidence interval [CI], 4-7 years) for statistically nonsignificant studies and 3 years (95% CI, 3-5 years) for statistically significant studies (P=.004). Statistically significant results (P=.004), experimental study design (P=.01), study size less than or equal to 500 (P=.01), and animals as subjects (P=.03) were predictive of time to publication. When the studies with human participants were analyzed separately, only statistically significant data were predictive of publication (P=.007). Multivariate analysis of all studies indicated that statistical significance (P=.001) and study design (P=.01) were the only independent predictors of time to publication, while for the human studies only statistical significance was predictive of publication (P=.007). Conclusion.— There is a publication delay for passive smoking studies with nonsignificant results compared with those with significant results.      

Reorganizing an Academic Medical Service: Impact on Cost, Quality, Patient Satisfaction, and Education

Robert M. Wachter, MD; Patricia Katz, PhD; Jonathan Showstack, PhD, MPH; Andrew B. Bindman, MD; Lee Goldman, MD, MPH

JAMA. 1998;279:1560-1565.

Context.— Academic medical centers are under enormous pressure to improve quality and cut costs while preserving education.

Objective.— To determine whether a reorganized academic medical service, led by faculty members who attended more often and became involved earlier and more intensively in care, would lower costs without compromising quality and education.

Design.— Alternate-day controlled trial.

Setting.— Inpatient academic general medical service.

Patients.— The 1623 patients discharged from the Moffitt-Long medical service between July 1, 1995, and June 30, 1996.

Interventions.— We divided our 4-team inpatient general medical service into 2 managed care service (MCS) teams and 2 traditional service (TS) teams. The MCS faculty served as attending physicians more often and were required to provide early input into clinical decisions. Patients were assigned to teams based on alternate days of admission.

Main Outcome Measures.— Outcome measures included resource use and outcomes for MCS vs TS patients, and for MCS patients vs patients seen the previous year, adjusted for demographic characteristics and case mix. Satisfaction of patients, house staff, and faculty was also assessed, as was educational emphasis.

Results.— A total of 806 patients were admitted to the MCS and 817 to the TS. Demographic characteristics and case mix were similar. Clinical outcomes, including mortality and readmission rates, were also similar, as was patient satisfaction. Resident and faculty satisfaction were high on both services. The average adjusted length of stay of patients on the MCS was 4.3 days vs 4.9 days on the TS and 5 days in 1994-1995 (adjusted P=.01 for MCS vs TS; MCS vs 1994-1995, P<.001). Average adjusted hospital costs were $7007 on the MCS vs $7777 on the TS and $8078 in 1994-1995 (adjusted P=.05 for MCS vs TS; MCS vs 1994-1995, P=.002).

Conclusions.— A reorganized academic medical service, led by faculty members who attended more often and became involved earlier and more intensively, resulted in significant resource savings with no changes in clinical outcomes or patient, faculty, and house staff satisfaction.

     

Physicians' Experiences and Beliefs Regarding Informal Consultation

Context.— Efforts to control medical expenses by emphasizing primary care and limiting specialty care may influence how physicians use informal or "curbside" consultation. Objective.— To understand physicians' use of and beliefs about informal consultation. Design.— Survey mailed in July 1997. Participants.— Of a random sample of Massachusetts general internists, pediatricians, cardiologists, orthopedic surgeons (n=300 each), and infectious disease specialists (n=200) surveyed, 1225 were eligible and 705 (58%) responded. Main Outcome Measures.— Self-reported use of and beliefs about informal consultation. Results.— Generalist physicians requested more informal consultations than specialists (median, 3 vs 1 per week; P <.001) and were asked to provide fewer (2 vs 5 per week; P <.001). In multivariate analyses, physicians in a health maintenance organization, multispecialty group, or single-specialty group requested more informal consultations than those in solo practice (82%, 40%, and 28% more, respectively; all P<.001) and were more often asked to provide them (43%, 63%, and 14% more, respectively; all P<.05). Physicians with at least 30% of their income from capitation requested 38% more and were asked to provide 46% more informal consultations than those with little or no income from capitation (both P<.001). Generalists' overall approval of informal consultation was greater than specialists' (mean 5.9 vs 5.1 on a 7-point Likert scale; P<.001), and approval was strongly associated with beliefs about how informal consultation affects quality of care (P<.001). Conclusions.— Use of informal consultation is common, varies by specialty, practice setting, and capitation, and therefore may increase with current trends toward group practice and managed care. Because overall approval of informal consultation is strongly associated with beliefs about how it affects quality of care, this issue should be carefully considered by physicians who participate in informal consultation.      

A Prospective Trial of Risk Factors for Sulfonylurea-Induced Hypoglycemia in Type 2 Diabetes Mellitus

Context.— Retrospective studies have identified oral sulfonylureas, age, and fasting as major risk factors for hypoglycemia in patients with type 2 diabetes. Sulfonylureas may be withheld from elderly patients out of concern for hypoglycemia. Objective.— To evaluate the hypoglycemic effects of maximum doses of once-daily second-generation sulfonylureas administered to fasting elderly patients. Design.— A prospective, randomized, double-blind clinical trial. Setting.— The University of New Mexico General Clinical Research Center. Patients.— Fifty-two sulfonylurea-treated subjects with type 2 diabetes with a mean (SD) age of 65.1 (5.7) years. Interventions.— Subjects were randomly assigned to glyburide or glipizide gastrointestinal therapeutic system (GITS). Each subject participated in three 23-hour fasting studies after the sequential administration of 1 week of placebo and 1 week of 10 mg and 1 week of 20 mg of the assigned sulfonylurea. Main Outcome Measures.— Occurrence of hypoglycemia (defined as plasma glucose level <3.33 mmol/L [60 mg/dL]) and hormonal parameters during the final 9 hours of the 23-hour fast in patients who had taken sulfonylureas vs placebo. Results.— No hypoglycemia was observed during 156 fasting studies. Plasma glucose level was decreased (nadir, 4.9 mmol/L [88 mg/dL] for a 20-mg dose of glyburide vs 8.3 mmol/L [150 mg/dL] for placebo; nadir, 5.8 mmol/L [105 mg/dL] for a 20-mg dose of glipizide GITS vs 8.7 mmol/L [157 mg/dL] for placebo), and serum insulin was increased in the sulfonylurea studies compared with placebo (P<.001). Plasma glucose parameters did not differ between the 2 sulfonylureas, but C peptide concentrations were increased in the glyburide group compared with glipizide GITS in the 20-mg study (P=.05). Concentrations of epinephrine were increased in the sulfonylurea studies compared with placebo (P<.001). Epinephrine secretion increased when glucose concentration fell below the mean (SD) level of 9.10 (2.66) mmol/L (164 [48] mg/dL) in the 10-mg study and 8.77 (2.83) mmol/L (158 [51] mg/dL) in the 20-mg study. Conclusions.— Fasting was well tolerated among these elderly patients with type 2 diabetes treated with sulfonylureas. Older age should not be considered a contraindication to sulfonylurea treatment for diabetes. Stimulation of epinephrine secretion at normal or elevated plasma glucose levels appears to be the primary mechanism of protection against hypoglycemia in this study.      

Low-Dose Hydrocortisone for Treatment of Chronic Fatigue Syndrome: A Randomized Controlled Trial

Context.— Chronic fatigue syndrome (CFS) is associated with a dysregulated hypothalamic–pituitary adrenal axis and hypocortisolemia. Objective.— To evaluate the efficacy and safety of low-dose oral hydrocortisone as a treatment for CFS. Design.— A randomized, placebo-controlled, double-blind therapeutic trial, conducted between 1992 and 1996. Setting.— A single-center study in a tertiary care research institution. Patients.— A total of 56 women and 14 men aged 18 to 55 years who met the 1988 Centers for Disease Control and Prevention case criteria for CFS and who withheld concomitant treatment with other medications. Intervention.— Oral hydrocortisone, 13 mg/m² of body surface area every morning and 3 mg/m² every afternoon, or placebo, for approximately 12 weeks. Main Outcome Measures.— A global Wellness scale and other self-rating instruments were completed repeatedly before and during treatment. Resting and cosyntropin-stimulated cortisol levels were obtained before and at the end of treatment. Patients recorded adverse effects on a checklist. Results.— The number of patients showing improvement on the Wellness scale was 19 (54.3%) of 35 placebo recipients vs 20 (66.7%) of 30 hydrocortisone recipients (P=.31). Hydrocortisone recipients had a greater improvement in mean Wellness score (6.3 vs 1.7 points; P=.06), a greater percentage (53% vs 29%; P=.04) recording an improvement of 5 or more points in Wellness score, and a higher average improvement in Wellness score on more days than did placebo recipients (P<.001). Statistical evidence of improvement was not seen with other self-rating scales. Although adverse symptoms reported by patients taking hydrocortisone were mild, suppression of adrenal glucocorticoid responsiveness was documented in 12 patients who received it vs none in the placebo group (P<.001). Conclusions.— Although hydrocortisone treatment was associated with some improvement in symptoms of CFS, the degree of adrenal suppression precludes its practical use for CFS.      

Effect of a Garlic Oil Preparation on Serum Lipoproteins and Cholesterol Metabolism: A Randomized Controlled Trial

Context.— Garlic-containing drugs have been used in the treatment of hypercholesterolemia even though their efficacy is not generally established. Little is known about the mechanisms of action of the possible effects on cholesterol in humans. Objective.— To estimate the hypocholesterolemic effect of garlic oil and to investigate the possible mechanism of action. Design.— Double-blind, randomized, placebo-controlled trial. Setting.— Outpatient lipid clinic. Patients.— We investigated 25 patients (mean age, 58 years) with moderate hypercholesterolemia. Intervention.— Steam-distilled garlic oil preparation (5 mg twice a day) vs placebo each for 12 weeks with wash-out periods of 4 weeks. Main Outcome Measures.— Serum lipoprotein concentrations, cholesterol absorption, and cholesterol synthesis. Results.— Baseline lipoprotein profiles were (mean [SD]): total cholesterol, 7.53 (0.75) mmol/L (291 [29] mg/dL); low-density lipoprotein cholesterol (LDL-C), 5.35 (0.78) mmol/L (207 [30] mg/dL); high-density lipoprotein cholesterol (HDL-C), 1.50 (0.41) mmol/L (58 [16] mg/dL); and triglycerides, 1.45 (0.73) mmol/L (127 [64] mg/dL). Lipoprotein levels were virtually unchanged at the end of both treatment periods (mean difference [95% confidence interval]): total cholesterol, 0.085 (-0.201 to 0.372) mmol/L (3.3 [-7.8 to 14.4] mg/dL), P=.54; LDL-C, 0.001 (-0.242 to 0.245) mmol/L (0.04 [-9.4 to 9.5] mg/dL), P=.99; HDL-C, 0.050 (-0.028 to 0.128) mmol/L (1.9 [-1.1 to 4.9] mg/dL), P=.20; triclycerides, 0.047 (-0.229 to 0.135) mmol/L (4.2 [-20.3 to 12.0]) mg/dL, P=.60. Cholesterol absorption (37.5% [10.5%] vs 38.3% [10.7%], P=.58), cholesterol synthesis (12.7 [6.5] vs 13.4 [6.6] mg/kg of body weight per day, P=.64), mevalonic acid excretion (192 [66] vs 187 [66] µg/d, P=.78), and changes in the ratio of lathosterol to cholesterol in serum (4.4% [24.3%] vs 10.6% [21.1%], P=.62) were not different in garlic and placebo treatment. Conclusions.— The commercial garlic oil preparation investigated had no influence on serum lipoproteins, cholesterol absorption, or cholesterol synthesis. Garlic therapy for treatment of hypercholesterolemia cannot be recommended on the basis of this study.      

Tolterodine and tamsulosin for treatment of men with lower urinary tract symptoms and overactive bladder: a randomized controlled trial

Context  Men with overactive bladder and other lower urinary tract symptoms may not respond to monotherapy with antimuscarinic agents or -receptor antagonists. Objective  To evaluate the efficacy and safety of tolterodine extended release (ER), tamsulosin, or both in men who met research criteria for both overactive bladder and benign prostatic hyperplasia. Design, Setting, and Participants  Randomized, double-blind, placebo-controlled trial conducted at 95 urology clinics in the United States involving men 40 years or older who had a total International Prostate Symptom Score of 12 or higher and, an International Prostate Symptom Score quality-of-life (QOL) item score of 3 or higher, a self-rated bladder condition of at least moderate bother, and a bladder diary documenting micturition frequency (8 micturitions per 24 hours) and urgency (3 episodes per 24 hours), with or without urgency urinary incontinence. Patients were recruited between November 2004 and February 2006, and the study was completed May 2006. Interventions  Patients were randomly assigned to receive placebo (n = 222), 4 mg of tolterodine ER (n = 217), 0.4 mg of tamsulosin (n = 215), or both tolterodine ER plus tamsulosin (n = 225) for 12 weeks. Main Outcome Measures  Patient perception of treatment benefit, bladder diary variables, International Prostate Symptom Scores, and safety and tolerability were assessed. Results  A total of 172 men (80%) receiving tolterodine ER plus tamsulosin reported treatment benefit by week 12 compared with 132 patients (62%) receiving placebo (P<.001), 146 (71%) receiving tamsulosin (P=.06 vs placebo), or 135 (65%) receiving tolterodine ER (P=.48 vs placebo). Patients receiving tolterodine ER plus tamsulosin compared with placebo experienced significant reductions in urgency urinary incontinence (–0.88 vs –0.31, P=.005), urgency episodes without incontinence (–3.33 vs –2.54, P=.03), micturitions per 24 hours (–2.54 vs –1.41, P<.001), and micturitions per night (–0.59 vs –0.39, P.02). Patients receiving tolterodine ER plus tamsulosin demonstrated significant improvements on the total International Prostate Symptom Score (–8.02 vs placebo, –6.19, P=.003) and QOL item (–1.61 vs –1.17, P=.003). All interventions were well tolerated. The incidence of acute urinary retention requiring catheterization was low (tolterodine ER plus tamsulosin, 0.4%; tolterodine ER, 0.5%; tamsulosin, 0%; and placebo, 0%). Conclusions  These results suggest that treatment with tolterodine ER plus tamsulosin for 12 weeks provides benefit for men with moderate to severe lower urinary tract symptoms including overactive bladder. Clinical Trials Registration  clinicaltrials.gov Identifier: NCT00147654      

Long-term Effects of Nurse Home Visitation on Children's Criminal and Antisocial Behavior: 15-Year Follow-up of a Randomized Controlled Trial

Context.— A program of home visitation by nurses has been shown to affect the rates of maternal welfare dependence, criminality, problems due to use of substances, and child abuse and neglect. However, the long-term effects of this program on children's antisocial behavior have not been examined. Objective.— To examine the long-term effects of a program of prenatal and early childhood home visitation by nurses on children's antisocial behavior. Design.— Fifteen-year follow-up of a randomized trial. Interviews were conducted with the adolescents and their biological mothers or custodial parents. Setting.— Semirural community in New York. Participants.— Between April 1978 and September 1980, 500 consecutive pregnant women with no previous live births were recruited, and 400 were enrolled. A total of 315 adolescent offspring participated in a follow-up study when they were 15 years old; 280 (89%) were born to white mothers, 195 (62%) to unmarried mothers, 151 (48%) to mothers younger than 19 years, and 186 (59%) to mothers from households of low socioeconomic status at the time of registration during pregnancy. Intervention.— Families in the groups that received home visits had an average of 9 (range, 0-16) home visits during pregnancy and 23 (range, 0-59) home visits from birth through the child's second birthday. The control groups received standard prenatal and well-child care in a clinic. Main Outcome Measures.— Children's self-reports of running away, arrests, convictions, being sentenced to youth corrections, initiation of sexual intercourse, number of sex partners, and use of illegal substances; school records of suspensions; teachers' reports of children's disruptive behavior in school; and parents' reports of the children's arrests and behavioral problems related to the children's use of alcohol and other drugs. Results.— Adolescents born to women who received nurse visits during pregnancy and postnatally and who were unmarried and from households of low socioeconomic status (risk factors for antisocial behavior), in contrast with those in the comparison groups, reported fewer instances (incidence) of running away (0.24 vs 0.60; P=.003), fewer arrests (0.20 vs 0.45; P=.03), fewer convictions and violations of probation (0.09 vs 0.47; P<.001), fewer lifetime sex partners (0.92 vs 2.48; P=.003), fewer cigarettes smoked per day (1.50 vs 2.50; P=.10), and fewer days having consumed alcohol in the last 6 months (1.09 vs 2.49; P=.03). Parents of nurse-visited children reported that their children had fewer behavioral problems related to use of alcohol and other drugs (0.15 vs 0.34; P=.08). There were no program effects on other behavioral problems. Conclusions.— This program of prenatal and early childhood home visitation by nurses can reduce reported serious antisocial behavior and emergent use of substances on the part of adolescents born into high-risk families.      

Zinc Gluconate Lozenges for Treating the Common Cold in Children: A Randomized Controlled Trial

Context.— The common cold is one of the most frequently occurring illnesses and is responsible for substantial morbidity and economic loss. Biochemical evidence suggests that zinc may be an effective treatment, and zinc gluconate glycine (ZGG) lozenges have been shown to reduce the duration of cold symptoms in adults. Objective.— To determine the efficacy of ZGG treatment of colds in children and adolescents. Design.— A randomized, double-masked, placebo-controlled study. Setting.— Two suburban school districts in Cleveland, Ohio. Patients.— A total of 249 students in grades 1 through 12 were enrolled within the first 24 hours of experiencing at least 2 of 9 symptoms of the common cold. Intervention.— Zinc lozenges, 10 mg, orally dissolved, 5 times a day (in grades 1-6) or 6 times a day (in grades 7-12). Main Outcome Measures.— Time to resolution of cold symptoms based on subjective daily symptom scores for cough, headache, hoarseness, muscle ache, nasal congestion, nasal drainage, scratchy throat, sore throat, and sneezing. Results.— Time to resolution of all cold symptoms did not differ significantly between students receiving zinc (n=124) and those receiving placebo (n=125) (median, 9 days; 95% confidence interval [CI], 8-9 days; median, 9 days, 95% CI, 7-10 days, respectively; P=.71). There were no significant differences in the time to resolution of any of the 9 symptoms studied. Compared with controls, more students in the zinc group reported adverse effects (88.6% vs 79.8%; P=.06); bad taste (60.2% vs 37.9%; P=.001); nausea (29.3% vs 16.1%; P=.01); mouth, tongue, or throat discomfort (36.6% vs 24.2%; P=.03); and diarrhea (10.6% vs 4.0%; P=.05). Conclusions.— In this community-based, randomized controlled trial, ZGG lozenges were not effective in treating cold symptoms in children and adolescents. Further studies with virologic testing are needed to clarify what role, if any, zinc may play in treating cold symptoms.      

Bartenders' Respiratory Health After Establishment of Smoke-Free Bars and Taverns

Context.— The association between environmental tobacco smoke (ETS) exposure and respiratory symptoms has not been well established in adults. Objective.— To study the respiratory health of bartenders before and after legislative prohibition of smoking in all bars and taverns by the state of California. Design.— Cohort of bartenders interviewed before and after smoking prohibition. Setting and Participants.— Bartenders at a random sample of bars and taverns in San Francisco. Main Outcome Measures.— Interviews assessed respiratory symptoms, sensory irritation symptoms, ETS exposure, personal smoking, and recent upper respiratory tract infections. Spirometric assessment included forced expiratory volume in 1 second (FEV₁) and forced vital capacity (FVC) measurements. Results.— Fifty-three of 67 eligible bartenders were interviewed. At baseline, all 53 bartenders reported workplace ETS exposure. After the smoking ban, self-reported ETS exposure at work declined from a median of 28 to 2 hours per week (P<.001). Thirty-nine bartenders (74%) initially reported respiratory symptoms. Of those symptomatic at baseline, 23 (59%) no longer had symptoms at follow-up (P<.001). Forty-one bartenders (77%) initially reported sensory irritation symptoms. At follow-up, 32 (78%) of these subjects had resolution of symptoms (P<.001). After prohibition of workplace smoking, we observed improvement in mean FVC (0.189 L; 95% confidence interval [CI], 0.082-0.296 L; 4.2% change) and, to a lesser extent, mean FEV₁ (0.039 L; 95% CI, -0.030 to 0.107 L; 1.2% change). Complete cessation of workplace ETS exposure (compared with continued exposure) was associated with improved mean FVC (0.287 L; 95% CI, 0.088-0.486; 6.8% change) and mean FEV₁ (0.142 L; 95% CI, 0.020-0.264 L; 4.5% change), after controlling for personal smoking and recent upper respiratory tract infections. Conclusion.— Establishment of smoke-free bars and taverns was associated with a rapid improvement of respiratory health.      

Sodium Reduction and Weight Loss in the Treatment of Hypertension in Older Persons: A Randomized Controlled Trial of Nonpharmacologic Interventions in the Elderly (TONE)

Context.— Nonpharmacologic interventions are frequently recommended for treatment of hypertension in the elderly, but there is a paucity of evidence from randomized controlled trials in support of this recommendation. Objective.— To determine whether weight loss or reduced sodium intake is effective in the treatment of older persons with hypertension. Design.— Randomized controlled trial. Participants.— A total of 875 men and women aged 60 to 80 years with systolic blood pressure lower than 145 mm Hg and diastolic blood pressure lower than 85 mm Hg while receiving treatment with a single antihypertensive medication. Setting.— Four academic health centers. Intervention.— The 585 obese participants were randomized to reduced sodium intake, weight loss, both, or usual care, and the 390 nonobese participants were randomized to reduced sodium intake or usual care. Withdrawal of antihypertensive medication was attempted after 3 months of intervention. Main Outcome Measure.— Diagnosis of high blood pressure at 1 or more follow-up visits, or treatment with antihypertensive medication, or a cardiovascular event during follow-up (range, 15-36 months; median, 29 months). Results.— The combined outcome measure was less frequent among those assigned vs not assigned to reduced sodium intake (relative hazard ratio, 0.69; 95% confidence interval [CI], 0.59-0.81; P<.001) and, in obese participants, among those assigned vs not assigned to weight loss (relative hazard ratio, 0.70; 95% CI, 0.57-0.87; P<.001). Relative to usual care, hazard ratios among the obese participants were 0.60 (95% CI, 0.45-0.80; P<.001) for reduced sodium intake alone, 0.64 (95% CI, 0.49-0.85; P=.002) for weight loss alone, and 0.47 (95% CI, 0.35-0.64; P<.001) for reduced sodium intake and weight loss combined. The frequency of cardiovascular events during follow-up was similar in each of the 6 treatment groups. Conclusion.— Reduced sodium intake and weight loss constitute a feasible, effective, and safe nonpharmacologic therapy of hypertension in older persons.      

Effects of Sodium Restriction on Blood Pressure, Renin, Aldosterone, Catecholamines, Cholesterols, and Triglyceride: A Meta-analysis

Context.— One of the controversies in preventive medicine is whether a general reduction in sodium intake can decrease the blood pressure of a population and thereby reduce the number of strokes and myocardial infarctions. In recent years the debate has been extended by studies indicating that reduced sodium intake has adverse effects. Objective.— To estimate the effects of reduced sodium intake on systolic and diastolic blood pressure (SBP and DBP), body weight, and plasma or serum levels of renin, aldosterone, catecholamines, cholesterols, and triglyceride, and to evaluate the stability of the blood pressure effect in relation to additional trials. Data Sources.— MEDLINE search from 1966 through December 1997 and reference lists of relevant articles. Study Selection.— Studies randomizing persons to high-sodium and low-sodium diets were included if they evaluated at least one of the effect parameters. Data Extraction.— Two authors independently recorded data. Data Synthesis.— In 58 trials of hypertensive persons, the effect of reduced sodium intake as measured by urinary sodium excretion (mean, 118 mmol/24 h) on SBP was 3.9 mm Hg (95% confidence interval [CI], 3.0-4.8 mm Hg) (P<.001) and on DBP was 1.9 mm Hg (95% CI, 1.3-2.5 mm Hg) (P<.001). In 56 trials of normotensive persons, the effect of reduced sodium intake (mean, 160 mmol/24 h) on SBP was 1.2 mm Hg (95% CI, 0.6-1.8 mm Hg) (P<.001) and on DBP was 0.26 mm Hg (95% CI, -0.3-0.9 mm Hg) (P=.12). The cumulative analysis showed that this effect size has been stable since 1985. In plasma, the renin level increased 3.6-fold (P<.001), and the aldosterone level increased 3.2-fold (P<.001); the increases were proportional to the degree of sodium reduction for both renin (r=0.66; P<.001) and aldosterone (r=0.64; P<.001). Body weight decreased significantly, and noradrenaline, cholesterol, and low-density lipoprotein cholesterol levels increased. There was no effect on adrenaline, triglyceride, and high-density lipoprotein cholesterol. Conclusion.— These results do not support a general recommendation to reduce sodium intake. Reduced sodium intake may be used as a supplementary treatment in hypertension. Further long-term studies of the effects of high reduction of sodium intake on blood pressure and metabolic variables may clarify the disagreements as to the role of reduced sodium intake, but ideally trials with hard end points such as morbidity and survival should end the controversy.      

Prevention of Estrogen Deficiency-Related Bone Loss With Human Parathyroid Hormone-(1-34): A Randomized Controlled Trial

Context.— Short-term intermittent administration of parathyroid hormone (PTH) prevents bone loss from the spine in women treated with a gonadotropin-releasing hormone (GnRH) analog. However, the effects of a longer period of PTH administration on bone mass in estrogen-deficient women, particularly on the hip and on cortical bone of the total body, are unknown. Objective.— To determine whether more prolonged PTH administration can prevent estrogen deficiency bone loss from the hip, spine, and total body in young women with endometriosis receiving GnRH analog (nafarelin acetate) therapy. Design.— Randomized controlled trial. Setting.— General Clinical Research Center of a tertiary care, university-affiliated hospital. Patients.— Forty-three women between the ages of 21 and 45 years with symptomatic endometriosis. Intervention.— Nafarelin alone (200 µg intranasally twice daily) or nafarelin plus human parathyroid hormone–(1-34) (hPTH-[1-34]) (40 µg subcutaneously daily). Main Outcome Measures.— The primary end points were bone mineral density (BMD) of the anterior-posterior and lateral spine, femoral neck, trochanter, radial shaft, and total body at 12 months of treatment. Results.— In the women who received nafarelin alone, the mean (SEM) BMDs of the anterior-posterior spine, lateral spine, femoral neck, trochanter, and total body were 4.9% (0.6%) (P<.001), 4.9% (0.8%) (P<.001), 4.7% (1.1%) (P<.001), 4.3% (0.9%) (P<.001), and 2.0% (0.6%) (P=.003) lower than at baseline after 12 months of therapy. In contrast, coadministration of hPTH-(1-34) increased BMD of the anterior-posterior spine by 2.1% (1.1%) (P=.09) and lateral spine by 7.5% (1.9%) (P=.002) and prevented bone loss from the femoral neck, trochanter, and total body, despite severe estrogen deficiency. Radial shaft BMD did not change significantly in either group. Serum bone-specific alkaline phosphatase and osteocalcin concentrations and urinary excretion of hydroxyproline and deoxypyridinoline increased 2-fold to 3-fold during the first 6 to 9 months of therapy in the women who received nafarelin plus hPTH-(1-34) and then declined. Changes in urinary deoxypyridinolone excretion were strongly predictive (r=0.85) of changes in spinal BMD in the women who received nafarelin plus hPTH-(1-34). Conclusions.— Parathyroid hormone prevents bone loss from the proximal femur and total body and increases lumbar spinal BMD in young women with GnRH analog–induced estrogen deficiency.      

Primary Care Physician Compensation Method in Medical Groups: Does It Influence the Use and Cost of Health Services for Enrollees in Managed Care Organizations?

Context.— Growth of at-risk managed care contracts between health plans and medical groups has been well documented, but less is known about the nature of financial incentives within those medical groups or their effects on health care utilization. Objective.— To test whether utilization and cost of health services per enrollee were influenced independently by the compensation method of the enrollee's primary care physician. Design.— Survey of medical groups contracting with selected managed care health plans, linked to 1994 plan enrollment and utilization data for adult enrollees. Setting.— Medical groups, major managed care health plans, and their patients/enrollees in the state of Washington. Study Participants.— Sixty medical groups in Washington, 865 primary care physicians (internal medicine, pediatrics, family practice, or general practice) from those groups and affiliated with 1 or more of 4 managed care health plans, and 200931 adult plan enrollees. Intervention.— The effect of method of primary care physician's compensation on the utilization and cost of health services was analyzed by weighted least squares and random effects regression. Main Outcome Measures.— Total visits, hospital days, and per member per year estimated costs. Results.— Compensation method was not significantly (P>.30) related to utilization and cost in any multivariate analyses. Patient age (P<.001), female gender (P<.001), and plan benefit level (P<.001) were significantly positively related to visits, hospital days, and per member per year costs. The primary care physician's age was significantly negatively related (P<.001) to all 3 dependent measures. Conclusions.— Compensation method was not significantly related to use and cost of health services per person. Enrollee, physician, and health plan benefit factors were the prime determinants of utilization and cost of health services.      

Chronic conditions, functional limitations, and special health care needs of school-aged children born with extremely low-birth-weight in the 1990s

Context  Information on the school-age functioning and special health care needs of extremely low-birth-weight (ELBW, <1000 g) children is necessary to plan for medical and educational services. Objective  To examine neurosensory, developmental, and medical conditions together with the associated functional limitations and special health care needs of ELBW children compared with normal-birth-weight (NBW) term-born children (controls). Design, Setting, and Participants  A follow-up study at age 8 years of a cohort of 219 ELBW children born 1992 to 1995 (92% of survivors) and 176 NBW controls of similar sociodemographic status conducted in Cleveland, Ohio. Main Outcome Measures  Parent Questionnaire for Identifying Children with Chronic Conditions of 12 months or more and categorization of specific medical diagnoses and developmental disabilities based on examination of the children. Results  In logistic regression analyses adjusting for sociodemographic status and sex, ELBW children had significantly more chronic conditions than NBW controls, including functional limitations (64% vs 20%, respectively; odds ratio [OR], 8.1; 95% confidence interval [CI], 5.0-13.1; P<.001), compensatory dependency needs (48% vs 23%, respectively; OR, 3.0; 95% CI, 1.9-4.7; P<.001), and services above those routinely required by children (65% vs 27%, respectively; OR, 5.4; 95% CI, 3.4-8.5; P<.001). These differences remained significant when the 36 ELBW children with neurosensory impairments were excluded. Specific diagnoses and disabilities for ELBW vs NBW children included cerebral palsy (14% vs 0%, respectively; P<.001), asthma (21% vs 9%; OR, 3.0; 95% CI, 1.6-5.6; P = .001), vision of less than 20/200 (10% vs 3%; OR, 3.1; 95% CI, 1.2-7.8; P = .02), low IQ of less than 85 (38% vs 14%; OR, 4.5; 95% CI, 2.7-7.7; P<.001), limited academic skills (37% vs 15%; OR, 4.2; 95% CI, 2.5-7.3; P<.001), poor motor skills (47% vs 10%; OR, 7.8; 95% CI, 4.5-13.6; P<.001), and poor adaptive functioning (69% vs 34%; OR, 6.5; 95% CI, 4.0-10.6; P<.001). Conclusion  The ELBW survivors in school at age 8 years who were born in the 1990s have considerable long-term health and educational needs.      

Human Cardiovascular and Metabolic Response to Acute, Severe Isovolemic Anemia

Context.— Although concern over the risks of red blood cell transfusion has resulted in several practice guidelines for transfusion, lack of data regarding the physiological effects of anemia in humans has caused uncertainty regarding the blood hemoglobin (Hb) concentration requiring treatment. Objective.— To test the hypothesis that acute isovolemic reduction of blood Hb concentration to 50 g/L in healthy resting humans would produce inadequate cardiovascular compensation and result in tissue hypoxia secondary to inadequate oxygen transport. Design.— Before and after interventional study. Setting.— Academic tertiary care medical center. Participants.— Conscious healthy patients (n=11) prior to anesthesia and surgery and volunteers not undergoing surgery (n=21). Interventions.— Aliquots of blood (450-900 mL) were removed to reduce blood Hb concentration from 131 (2) g/L to 50 (1) g/L [mean (SE)]. Isovolemia was maintained with 5% human albumin and/or autologous plasma. Cardiovascular parameters, arterial and mixed venous oxygen content, oxyhemoglobin saturation, and arterial blood lactate were measured before and after removal of each aliquot of blood. Electrocardiogram and, in a subset, Holter monitor were monitored continuously. Main Outcome Measures.— "Critical" oxygen delivery (TO₂) as assessed by oxygen consumption (O₂), plasma lactate concentration, and ST changes on electrocardiogram. Results.— Acute, isovolemic reduction of Hb concentration decreased systemic vascular resistance and TO₂ and increased heart rate, stroke volume, and cardiac index (each P<.001). We did not find evidence of inadequate oxygenation: O₂ increased slightly from a mean (SD) of 3.07 (0.44) mL of oxygen per kilogram per minute (mL O₂·kg^-1·min^-1) to 3.42 (0.54) Ml O₂·kg^-1·min^-1 (P<.001) and plasma lactate concentration did not change (0.81 [0.11] mmol/L to 0.62 [0.19] mmol/L;P=.09). Two subjects developed significant ST changes on Holter monitor: one apparently related to body position or activity, the other to an increase in heart rate (at an Hb concentration of 46-53 g/L); both occurred in young women and resolved without sequelae. Conclusions.— Acute isovolemic reduction of blood Hb concentration to 50 g/L in conscious healthy resting humans does not produce evidence of inadequate systemic TO₂, as assessed by lack of change of O₂ and plasma lactate concentration. Analysis of Holter readings suggests that at this Hb concentration in this resting healthy population, myocardial ischemia would occur infrequently.