Annals of Internal Medicine

Published by American College of Physicians
Online ISSN: 1539-3704
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Article
Researchers are increasingly interested in examining costs of care, and large administrative and clinical databases have made relevant data readily available. Because a few patients incur high costs relative to most patients, the distribution of cost data is often skewed. How robust are the usual methods of cost analysis against the skewed distribution of cost data? To determine the methods commonly used for comparing cost data, describe their limitations, and provide an alternate method of analysis. Review of statistical methods used in studies of medical costs published in medical journals between January 1991 and January 1996. Description of a Z-score method appropriate for testing the equality of mean costs between two log-normal samples; and reanalysis of published two-sample comparison results done by using the Z-score method. For two-sample comparisons, three methods were commonly used: the Student t-test on untransformed costs, the Wilcoxon test on untransformed costs, and the Student t-test on log-transformed costs. The t-test on untransformed costs ignores the skewness in cost data, the Wilcoxon test ignores unequal variances, and the t-test on log-transformed costs tests the wrong null hypothesis unless variances in the log-scale are equal. Eleven articles included two-sample tests and had enough information to allow reanalysis of the data using the Z-score method. These articles described a total of 23 Wilcoxon tests and 24 t-tests on untransformed costs. Most results did not change on reanalysis, but six results changed enough to alter conclusions. Specifically, reanalysis of data for which one Wilcoxon test had shown statistically significant results showed nonsignificant results; reanalysis of data for which two Wilcoxon tests had shown nonsignificant results showed statistically significant results. In articles that used t-tests on untransformed costs, two statistically significant results became nonsignificant on reanalysis and one nonsignificant result became statistically significant on reanalysis. The methods commonly used to compare costs of two groups have limitations. Some limitations may change some conclusions, and the direction of the change cannot be predicted. The Z-score method is designed to adjust for skewness in cost data and is appropriate for comparing means of log-normally distributed cost data.
 
Article
Humoral regulation of somatic and hematopoietic cell growth has been intensely investigated during the past decade. Growth hormone is unique because it regulates the size of the person within the constraints of the genetic program. The somatomedins and insulin growth factors are low molecular weight polypeptides believed to mediate some functions of growth hormone. Epithelial growth factor and nerve growth factor are well-characterized polypeptides that influence the growth and differentiation of epithelial and neural tissues and interact with specific cell surface receptors. The hematopoietins are a family of polypeptide hormones that specifically regulate the proliferation and differentiation of stem cells giving rise to erythrocytes, granulocytes, monocytes, megakaryocytes, and B and T lymphocytes. Platelet-derived growth factor modulates the proliferation of fibroblasts in vitro and may have a role in the development of atherosclerosis and myelofibrosis. New knowledge on the biochemistry and physiology of growth factors will probably have a substantial impact on our understanding of human diseases involving abnormal cell growth.
 
Article
The safety of delaying highly active antiretroviral therapy (HAART) in HIV-infected patients is uncertain when the CD4+ cell count declines below 0.350 x 10(9) cells/L. To evaluate the effect of baseline CD4+ cell count and adherence to HAART on survival rates. Prospective observational study. Province-wide Canadian HIV/AIDS treatment program. 1422 HIV-infected persons initiating HAART between 1 August 1996 and 31 July 2000 and followed through 31 March 2002. Patients were stratified by baseline CD4+ cell count and adherence level. Cumulative mortality rates were evaluated by using Kaplan-Meier methods and Cox regression-estimated adjusted relative hazards. Kaplan-Meier analyses showed no survival benefit of starting HAART at a CD4+ count of 0.200 x 10(9) cells/L or greater among adherent patients. Adjusted analysis showed that compared with adherent patients who initiated HAART at a CD4+ cell count of 0.350 x 10(9) cells/L or greater, nonadherent patients who initiated HAART when the CD4+ cell count was 0.200 to 0.349 x 10(9) cells/L had statistically elevated mortality rates (adjusted relative hazard, 2.56 [95% CI, 1.36 to 4.84]; P = 0.004). However, compared with adherent patients who initiated HAART at a CD4+ cell count of 0.350 x 10(9) cells/L or greater, adherent patients who initiated HAART when the CD4+ cell count was 0.200 to 0.349 x 10(9) cells/L had statistically similar mortality rates (adjusted relative hazard, 0.82 [CI, 0.45 to 1.49]; P > 0.2). Delaying HAART until the CD4+ cell count falls to 0.200 x 109 cells/L does not increase the mortality rate in HIV-infected patients with good medication adherence. Mortality rates increase if HAART is initiated below 0.200 x 10(9) cells/L. Also, nonadherent patients have higher mortality rates than adherent patients with similar CD4+ cell counts. Above a CD4+ cell count of 0.200 x 10(9) cells/L, medication adherence is the critical determinant of survival, not the CD4+ cell count at which HAART is begun.
 
Article
Does self-monitoring of blood glucose improve glycemic control in patients with type 2 diabetes who are not treated with insulin? REVIEW SCOPE: Included studies compared self-monitoring of blood glucose with no self-monitoring in patients with non-insulin-treated type 2 diabetes, included ≥ 80 patients, and had ≥ 6 months of follow-up. Primary outcome was HbA1c level; secondary outcomes were blood pressure and serum cholesterol level. MEDLINE and EMBASE/Excerpta Medica (Apr 2009 to Jun 2010), the reference list of a systematic review that included studies from January 2000 to April 2009, reference lists of other reviews, conference proceedings, and a current controlled trials register were searched for randomized controlled trials (RCTs). Authors of included studies were contacted for individual patient data. 6 RCTs (n = 2552, mean age 60 y, 54% men) met inclusion criteria. 3 RCTs described randomization, and all had allocation concealment and blinded outcome assessors. Loss to follow-up ranged from 2% to 31% (mean 15%). Analysis was by intention-to-treat. Meta-analysis of individual patient data showed that self-monitoring blood glucose reduced HbA1c levels at 3, 6, and 12 months compared with no self-monitoring (Table). Mean pooled reduction in HbA1c was 9.6 mmol/mol (0.88%) in the intervention group and 7.5 mmol/mol (0.69%) in the usual care group. Groups did not differ for blood pressure or total cholesterol (Table). Results were similar across patients with different levels of HbA1c at baseline (P = 0.3), including those with HbA1c > 64 mmol/mol (> 8%). Self-monitoring of blood glucose in patients with non-insulin-treated type 2 diabetes reduces HbA1c by 0.25% at 6 months compared with no self-monitoring.
 
Article
QUESTION In critically ill adults, what are the efficacy and safety of 6% hydroxyethyl starch (HES) 130/0.4 compared with saline for fluid resuscitation? METHODS DESIGN Randomized controlled trial (RCT) (Crystalloid versus Hydroxyethyl Starch Trial [CHEST]). ClinicalTrials.gov NCT00935168. ALLOCATION Concealed.* BLINDING Blinded* (patients, clinicians, {data collectors, outcome assessors, and data analysts}†). FOLLOW-UP PERIOD 90 days. SETTING 32 adult medical-surgical intensive care units (ICUs) in Australia and New Zealand. PATIENTS 7000 ICU patients ≥ 18 years of age (mean age 63 y, 60% men) requiring fluid resuscitation (IV fluid bolus above that needed for maintenance or fluid replacement) at any time during ICU stay, determined by the treating clinician and supported by ≥ 1 physiologic criterion. Exclusion criteria were administration of > 1000 mL of HES before screening, impending or current dialysis-dependent renal failure, or intracranial hemorrhage. INTERVENTION 6% HES (130/0.4) in 0.9% saline (Voluven, Fresenius Kabi) (n = 3500) or 0.9% saline (n = 3500) to a maximum dose of 50 mL/kg of body weight per day, followed by 0.9% saline for the remaining 24 hours. Study fluid was stopped if renal replacement therapy was started. OUTCOMES Primary outcome was all-cause mortality at 90 days. Secondary outcomes included renal replacement therapy; and kidney dysfunction, kidney injury, and kidney failure (all using RIFLE criteria, based on increase in serum creatinine levels and decrease in urine output). 7000 patients were required to detect a 3.5% absolute difference in 90-day mortality with a power of 90% (α = 0.05) and an estimated 26% baseline mortality. PATIENT FOLLOW-UP 95% (intention-to-treat analysis). MAIN RESULTS The main results are in the Table. CONCLUSION In critically ill adults, 6% hydroxyethyl starch 130/0.4 and saline for fluid resuscitation did not differ for mortality at 90 days.6% hydroxyethyl starch (HES) (130/0.4) in 0.9% saline vs 0.9% saline in critically ill adults‡OutcomesEvent ratesAt 90 dHESSalineRRI (95% CI)NNH (CI)Mortality18%17%6% (-4 to 18)Not significantRenal replacement therapy7.0%5.8%21% (0 to 45)84 (42 to 3031)Kidney failure§10%9.2%12% (-3 to 30)Not significantRRR (CI)NNT (CI)Kidney dysfunction||54%57%6% (2 to 10)30 (18 to 88)Kidney injury¶35%38%9% (3 to 15)30 (18 to 88)‡Abbreviations defined in Glossary. RRI, RRR, NNH, NNT, and CI calculated from control event rates and relative risks in article.§3-fold increase in serum creatinine from baseline, or urine output < 0.3 mL/kg/h for 24 h, or creatinine ≥ 350 µmol/L with an acute increase ≥ 44 µmol/L in < 24 h.||1.5-fold increase in serum creatinine from baseline or urine output < 0.5 mL/kg/h for 6 h.¶2-fold increase in serum creatinine from baseline or urine output < 0.5 mL/kg/h for 12 h.
 
Article
QUESTION In adults with severe sepsis, what are the relative efficacy and safety of hydroxyethyl starch (HES) 130/0.42 and Ringer's acetate for fluid resuscitation? METHODS DESIGN Randomized controlled trial (RCT) (Scandinavian Starch for Severe Sepsis/Septic Shock [6S] trial). ClinicalTrials.gov NCT00962156. ALLOCATION Concealed.* BLINDING Blinded* (patients, clinicians, research staff, safety committee, manuscript writers, and statisticians). FOLLOW-UP PERIOD 90 days. SETTING 26 intensive care units (ICUs) in Denmark, Norway, Finland, and Iceland. PATIENTS 804 ICU patients ≥ 18 years of age (median age 67 y, 61% men) who had severe sepsis (defined focus of infection and ≥ 2 systemic inflammatory response syndrome criteria) in the previous 24 hours and needed fluid resuscitation. Exclusion criteria included > 1000 mL of synthetic colloid in the previous 24 hours; renal replacement therapy; acute burn injury to > 10% of body surface; severe hyperkalemia; or liver or kidney transplantation or intracranial bleeding during current hospitalization. INTERVENTION 6% HES 130/0.42 in Ringer's acetate (Tetraspan 6%, B Braun) (n = 400) or Ringer's acetate (Sterofundin ISO, B Braun) (n = 400) to a maximum daily dose of 33 mL/kg ideal body weight administered intravenously for ≤ 90 days. OUTCOMES Primary outcome was a composite of death or dependence on dialysis (any renal replacement therapy from 86 to 94 d after randomization) at 90 days. Secondary outcomes included components of the composite endpoint, any renal replacement therapy, and severe bleeding (≥ 3 units of packed red cells within 24 h). PATIENT FOLLOW-UP 99% (modified intention-to-treat analysis). MAIN RESULTS The main results are in the Table. CONCLUSION In patients with severe sepsis needing fluid resuscitation, hydroxyethyl starch 130/0.42 increased death at 90 days and need for renal replacement therapy compared with Ringer's acetate.Hydroxyethyl starch (HES) 130/0.42 vs Ringer's acetate for fluid resuscitation in patients with severe sepsis†OutcomesEvent ratesAt 90 dHESRinger's acetateRRI (95% CI)NNH (CI)Death or dependence on dialysis‡51%43%17% (1 to 36)14 (7 to 232)Death51%43%17% (1 to 36)14 (7 to 233)Any renal replacement therapy22%16%35% (1 to 80)18 (8 to 616)Severe bleeding§10%6%52% (-6 to 148)NS†NS = not significant; other abbreviations defined in Glossary. RRI, NNH, and CI calculated from control event rates and relative risks in article.‡1 patient in each group was dependent on dialysis at 90 days.§≥ 3 units of packed red cells within 24 h.
 
Article
QUESTIONS In patients receiving oral anticoagulant therapy, how well do scores predict major bleeding? How do they compare with each other and with subjective physician assessment? METHODS DESIGN Cohort study. SETTING Academic hospital, Switzerland. PATIENTS 515 internal medicine patients ≥ 18 years of age (median age 71 y, 64% men) receiving oral anticoagulant therapy (acenocoumarol or phenprocoumon) for any indication at hospital discharge or at presentation in the ambulatory clinic. 96% of patients were hospitalized at enrollment, and 64% started anticoagulant therapy ≥ 3 months before. DESCRIPTION OF PREDICTION GUIDES Prediction scores were Outpatient Bleeding Risk Index (OBRI) (age ≥ 65 y; stroke; gastrointestinal bleeding; recent myocardial infarction, anemia, diabetes, or creatinine > 1.5 mg/dL), Kuijer (age ≥ 60 y, female, cancer), Shireman (age ≥ 70 y; female; gastrointestinal bleeding > 10 d or < 10 d; anemia; diabetes; alcohol or drug abuse; antiplatelet therapy), modified HEMORR2HAGES (age ≥ 75 y; gastrointestinal bleeding; anemia; glomerular filtration rate [GFR] < 30 mL/min or hepatic disease; cancer; hypertension; alcohol abuse; low platelet count; fall risk), Registry of Patients with Venous Thromboembolism (RIETE) (age ≥ 75 y, major bleeding < 15 d, anemia, creatinine > 1.2 mg/dL, cancer, pulmonary embolism), modified HAS-BLED (age ≥ 65 y, stroke, gastrointestinal bleeding, creatinine ≥ 2.3 mg/dL, hepatic disease, hypertension, alcohol abuse, drug abuse), Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) (anemia, GFR < 30 mL/min, age ≥ 75 y, prior bleeding, hypertension), and physician's subjective assessment of risk at discharge (0% to 100%). OUTCOMES First-time major bleeding event (fatal bleeding, with death within 7 d of bleeding episode and no alternative cause of death; symptomatic bleeding in a critical area or organ; or ≥ 20 g/L decrease in hemoglobin level or transfusion of ≥ 2 units of whole or red blood cells). MAIN RESULTS 35 first-time major bleeding events occurred during the study; 12-month cumulative incidence was 6.8%. C-statistics ranged from 0.54 to 0.61 and did not differ among the 7 scores (P = 0.84) or between the scores and physician assessment (P = 0.94) (Table). Only 1 score (ATRIA) predicted major bleeding better than chance (Table). CONCLUSION In patients receiving anticoagulant therapy, performance of clinical prediction scores for bleeding was poor (c-statistic ≤ 0.61) and did not differ for 7 scores and physician assessment.Clinical prediction scores for bleeding in patients receiving oral anticoagulant therapy*Prediction scoreC-statistic† (95% CI) at 12 moOBRI0.56 (0.50 to 0.62)Kuijer0.54 (0.48 to 0.60)Shireman0.57 (0.48 to 0.65)HEMORR2HAGES0.58 (0.50 to 0.67)RIETE0.57 (0.49 to 0.65)HAS-BLED0.57 (0.49 to 0.65)ATRIA0.61 (0.52 to 0.70)‡Physician assessment0.55 (0.46 to 0.65)*Scale descriptions and expanded abbreviations can be found under "Description of prediction guides"; other abbreviations defined in Glossary.†Area under the receiver-operating characteristic curve.‡Significantly better than chance.
 
Article
To compare the safety and efficacy of didanosine with that of continued zidovudine therapy in persons with human immunodeficiency virus (HIV) infection who had received zidovudine for at least 6 months and had CD4 cell counts of 200 to 500 CD4 cells/mm3. Double-blind, randomized controlled trial. 10 Canadian university-affiliated specialty clinics. 246 patients were assigned to receive standard doses of either zidovudine or didanosine. The primary clinical end point was the occurrence of a new, previously undiagnosed acquired immunodeficiency syndrome (AIDS)-defining illness or death. 245 of 246 patients were eligible (118 receiving didanosine and 127 receiving zidovudine). Sixty-six percent were asymptomatic, 30% had AIDS-related complex, and 4% had AIDS. The median baseline CD4 count was 320 cells/mm3. The median previous duration of zidovudine therapy was 471 days. Nine new AIDS-defining illnesses developed during the study; all but one were in the zidovudine group (relative risk, 7.9 [95% CI, 1.0 to 63.3; P = 0.02]). A change to didanosine led to a statistically significant increase in CD4 counts by week 2 that persisted until the end of the study at week 48 (P < or = 0.01). Viral sensitivity studies (done in 102 patients) showed that 28% of the zidovudine group and 21% of the didanosine group had high-level in vitro resistance to zidovudine (50% inhibitory concentration greater than 0.8 microM) at baseline (P = 0.49). Only one patient in the didanosine group developed high-level resistance to zidovudine during the study. In the zidovudine group, the cumulative probability of developing high-level resistance to zidovudine was 59% at 1 year (P = 0.01). Abdominal pain, leukopenia, and neutropenia were more frequent in the zidovudine group, and hyperuricemia was more frequent in the didanosine group (P < 0.05). In clinically stable patients with 200 to 500 CD4 cells/mm3 who had tolerated zidovudine for at least 6 months, a change to didanosine led to a decrease in the rate of disease progression, a sustained increase in CD4 counts, and a decrease in the chances of developing high-level resistance to zidovudine. Both drugs were generally well tolerated.
 
Article
The incidence of second primary colorectal cancer in patients with a history of colon cancer, compared with patients with a history of adenomatous polyps, is unknown. It is unclear whether guidelines for colonoscopy screening in patients with polyps are appropriate for patients with previous colon cancer. To determine the incidence of second primary colorectal cancer after treatment for localized colon cancer and to compare this incidence with that of first primary colorectal cancer in both the general population and high-risk patients. Historical cohort study. An international, multi-institutional trial of adjuvant 5-fluorouracil-based chemotherapy for localized colon cancer. 3278 patients with resected stage II and stage III colon cancer. Occurrence of endoscopic or radiologic colon surveillance and incidence of second primary colorectal cancer. Forty-two cases of second primary invasive colon cancer were found over 15 345 person-years of follow-up, yielding an incidence rate of 274 per 100 000 person-years (95% CI, 196 to 369 per 100 000 person-years) and a cumulative incidence of 1.5% (CI, 1.1% to 2.0%) at 5 years. This rate was compared with rates of first colon cancer in two reference groups: the general population and patients who had undergone frequent colonoscopy and polypectomy because of a history of adenomatous polyps; standardized incidence ratios were 1.6 (CI, 1.2 to 2.2) and 6.8 (CI, 2.7 to 22.0), respectively. The incidence of second primary colorectal cancer remains high despite intensive surveillance strategies.
 
Article
To determine the benefits of switching to didanosine compared with continuing zidovudine among patients infected with human immunodeficiency virus (HIV) who have previously used zidovudine and have signs of clinical deterioration. Randomized, double-blind, two-armed, parallel, comparative clinical trial with a blinded, compassionate crossover provision at 12 weeks. Outpatient clinics at 19 tertiary care medical centers. 312 patients infected with HIV who had received zidovudine for 6 months or more, had CD4 cell counts of 300/mm3 or less, and had signs of clinical deterioration within 12 weeks before study entry. Peroral didanosine tablets (600 mg/d adjusted for weight, "high dose") or zidovudine capsules (600 mg/d). Primary study end points were death, a new acquired immunodeficiency syndrome (AIDS)--defining event, or the combination of two new or recurrent HIV-related diagnoses with a 50% decrease in CD4 cells. Switching to didanosine was associated with fewer end points than continuing zidovudine (relative risk [RR] for zidovudine:didanosine = 1.5; 95% Cl, 1.1 to 2.0). This benefit was consistent across subgroups of patients with either AIDS-related complex or AIDS and was most apparent among those with a CD4 count at entry of 100/mm3 or more (RR = 2.2; Cl, 1.1 to 4.4). This study shows a positive treatment effect for switching from zidovudine to didanosine among patients with either AIDS-related complex or AIDS and validates the common practice of using clinical signs or a decrease in the CD4 count as an indication for changing therapy.
 
Article
To describe the spectrum of illnesses associated with Escherichia coli O157:H7 infections. Described an outbreak that showed the broad spectrum of these infections. Reviewed the clinical findings in the other eight major outbreaks reported between 1982 and 1986. Also reviewed reports of sporadic cases. Outbreaks in communities, nursing homes, a day care center, and a kindergarten. Persons identified in outbreaks of E. coli O157:H7 infections. Escherichia coli O157:H7 infection causes bloody diarrhea (hemorrhagic colitis), nonbloody diarrhea, the hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura. Infection can be asymptomatic, can involve extraintestinal sites, and can be fatal. Bloody diarrhea is the commonest symptom. Most patients have severe abdominal cramps; fever is documented in less than half. Findings from fecal leukocyte examinations often suggest a noninfectious cause. Results of radiologic and colonoscopic examinations can be consistent with a diagnosis of inflammatory bowel disease or ischemic colitis. Patients at the extremes of age are at increased risk for E. coli O157:H7-associated diarrhea, the hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, and death. Antimicrobial agents have not been shown to modify the illness, but there are few data on individual agents. Infection with E. coli O157:H7 should be considered in all patients with bloody diarrhea, the hemolytic uremic syndrome, or thrombotic thrombocytopenic purpura because the infection can masquerade as gastrointestinal bleeding of noninfectious cause, the antecedent diarrhea may be resolved and forgotten by the time the hemolytic uremic syndrome or thrombotic thrombocytopenic purpura is diagnosed, and the detection of E. coli O157:H7 requires specific stool culture techniques.
 
Article
After two outbreaks of hemorrhagic colitis associated with a previously unrecognized pathogen, Escherichia coli O157:H7, a surveillance system was established to identify and study sporadic cases of this distinct clinical illness in the United States. Between August 1982 and April 1984, we identified 28 persons from 11 states who met our case definition and whose stool specimens yielded E. coli O157:H7. Patients ranged in age from 1 to 80 years. Seventeen patients required hospitalization. All patients recovered, although one developed hemolytic-uremic syndrome 7 days after the onset of bloody diarrhea. Detection of E. coli O157:H7 in stools from persons with hemorrhagic colitis was highly associated with collection of stool specimens within the first 6 days after onset of illness. All E. coli O157:H7 isolates produced a Vero cytotoxin. Hemorrhagic colitis caused by E. coli O157:H7 is widely distributed in the United States as a sporadic illness; clinicians should be aware of its distinctive clinical presentation, and should collect specimens promptly when the diagnosis is suspected.
 
Article
Empirical scores, computerized ST-segment measurements, and equations have been proposed as tools for improving the diagnostic performance of the exercise test. To compare the diagnostic utility of these scores, measurements, and equations with that of visual ST-segment measurements in patients with reduced workup bias. Prospective analysis. 12 university-affiliated Veterans Affairs Medical Centers. 814 consecutive patients who presented with angina pectoris and agreed to undergo both exercise testing and coronary angiography. Digital electrocardiographic recorders and angiographic calipers were used for testing at each site, and test results were sent to core laboratories. Although 25% of patients had previously had testing, workup bias was reduced, as shown by comparison with a pilot study group. This reduction resulted in a sensitivity of 45% and a specificity of 85% for visual analysis. Computerized measurements and visual analysis had similar diagnostic power. Equations incorporating nonelectrocardiographic variables and either visual or computerized ST-segment measurement had similar discrimination and were superior to single ST-segment measurements. These equations correctly classified 5 more patients of every 100 tested (areas under the receiver-operating characteristic curve, 0.80 for equations and 0.68 for visual analysis; P < 0.001) in this population with a 50% prevalence of disease. Standard exercise tests had lower sensitivity but higher specificity in this population with reduced work-up bias than in previous studies. Computerized ST-segment measurements were similar to visual ST-segment measurements made by cardiologists. Considering more than ST-segment measurements can enhance the diagnostic power of the exercise test.
 
Article
Stavudine is a promising antiretroviral agent, but its clinical efficacy has not been determined. To evaluate the clinical effect of stavudine (2',3'-didehydro-3'-deoxythymidine) monotherapy in patients with human immunodeficiency virus (HIV) infection. Randomized, controlled, double-blind trial. 56 outpatient clinics in private practices, universities, and contract research organizations in the United States, France, and Italy. 822 HIV-infected adults who had 50 to 500 CD4+ cells/mm3 and had previously received at least 6 months of zidovudine treatment. Monotherapy with peroral stavudine capsules or peroral zidovudine capsules. The primary end point was clinical progression, which was defined as all occurrences of acquired immunodeficiency syndrome (AIDS)-defining events or death. Patients receiving stavudine reached clinical end points at a rate of 26 per 100 person-years, compared with 32 per 100 person-years for patients receiving zidovudine (relative risk, 0.75 [95% CI, 0.58 to 0.98]; P = 0.03). The risk for death alone was 26% lower in the stavudine group than in the zidovudine group, but the comparison was not statistically significant (relative risk, 0.74 [CI, 0.53 to 1.02]; P = 0.066). The benefit of stavudine therapy was seen in all CD4+ cell strata (< or = 100 cells/mm3, 101 to 300 cells/mm3, and > 300 cells/mm3) and clinical stages of HIV disease (asymptomatic, symptomatic, and AIDS). Four weeks after treatment began, CD4+ cell counts were 30 cells/mm3 higher in the stavudine group than in the zidovudine group; this difference was sustained for 96 weeks (P < 0.001). Nausea and vomiting were more common in patients receiving zidovudine (P < 0.01), and neuropathy occurred more frequently in those receiving stavudine (12% in the stavudine group compared with 4% in the zidovudine group; P < 0.001). Neuropathy resolved completely in many patients (63%) after interruption of stavudine treatment; these patients could resume stavudine therapy at a lower dose. Stavudine was well tolerated and delayed progression of HIV disease in patients who had previously received 6 or more months of zidovudine treatment. Benefits were apparent in all CD4+ cell strata and clinical stages of HIV disease. Stavudine is an important agent to consider for trials of combination chemotherapy.
 
Article
To determine the association between HLA class II genes and methimazole-induced agranulocytosis in patients with Graves disease. Case-control study. Kuma Hospital, which specializes in thyroid diseases, in Kobe, Japan. 24 patients with Graves disease who had methimazole-induced agranulocytosis diagnosed by peripheral granulocyte counts of less than 0.5 x 10(9)/L, and 68 patients with Graves disease treated with methimazole, who were free from agranulocytosis. Controls were 525 healthy, unrelated Japanese student volunteers at Kyushu University in Japan. All HLA class II genes were analyzed for polymorphisms at the DNA level by using the polymerase chain reaction sequence-specific oligonucleotide probes method. The allele frequencies in the agranulocytotic Graves disease group were compared with those in the nonagranulocytotic Graves disease and control groups. A strong positive association was seen in DRB1*08032 between the agranulocytotic group and both the control and nonagranulocytotic Graves disease groups. The HLA DRB1*08032 allele was strongly associated with susceptibility to methimazole-induced agranulocytosis, suggesting that cellular autoimmunity may be involved in its development.
 
Article
1,25 dihydroxycholecalciferol [1,25(OH)2D3] was studied in a double-blind controlled fashion in patients on chronic dialysis. Serum calcium was unchanged in 16 patients on vitamin D3 (D3) (400 to 1200 IU/day). In 15 patients on 1,25(OH)2D3 (0.5 to 1.5 microgram/day), serum calcium increased from 9.05 +/- .15 to 10.25 +/- .20 mg/dl (p less than 0.001), returning to 9.37 +/- .16 mg/dl (p less than 0.001) in the post control period. Patients on D3 showed no reversible decrease in immunoreactive parathyroid hormone levels, but patients on 1,25(OH)2D3 did, from a control of 1077 +/- 258 to 595 +/- 213 microliter equivalents/ml (p less than 0.01), and returned to 1165 +/- 271 microliter equivalents/ml (p less than 0.005). Nine of 12 patients on D3 who underwent serial iliac-crest biopsies showed histologic deterioration, and six of seven who received 1,25(OH)2D3 were improved or unchanged (p less than 0.025). Bone mineral and calcium decreased in patients on D3 (p less than 0.05) but not in those on 1,25(OH)2D3. Hypercalcemia occurred in five of 15 patients. We conclude that 1,25(OH)2D3 has a calcemic effect in chronic dialysis patients, decreases levels of immunoreactive parathyroid hormone, and is associated with histologic improvement in bone disease. Thus, 1,25(OH)2D3 is a valuable adjunct to the management of renal osteodystrophy but requires monitoring of serum calcium to avoid hypercalcemia.
 
Top-cited authors
Josef Coresh
  • Johns Hopkins University
Christopher H Schmid
  • School of Public Health- Brown University
Douglas Altman
  • University of Oxford
Lesley A Inker
  • Tufts Medical Center
Harold I Feldman
  • University of Pennsylvania