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1.  Islet Transplantation as a Treatment for Diabetes 
PMCID: PMC4152959  PMID: 15141057
2.  Peginterferon Alfa-2a plus Ribavirin versus Interferon Alfa-2a plus Ribavirin for Chronic Hepatitis C in HIV-Coinfected Persons 
The New England journal of medicine  2004;351(5):451-459.
Chronic hepatitis C virus (HCV) infection is a cause of major complications in persons who are also infected with the human immunodeficiency virus (HIV). However, the treatment of HCV infection in such persons has been associated with a high rate of intolerance and a low rate of response. We conducted a multicenter, randomized trial comparing peginterferon plus ribavirin with interferon plus ribavirin for the treatment of chronic hepatitis C in persons coinfected with HIV.
A total of 66 subjects were randomly assigned to receive 180 μg of peginterferon alfa-2a weekly for 48 weeks, and 67 subjects were assigned to receive 6 million IU of interferon alfa-2a three times weekly for 12 weeks followed by 3 million IU three times weekly for 36 weeks. Both groups received ribavirin according to a dose-escalation schedule. At week 24, subjects who did not have a virologic response (those who had an HCV RNA level greater than or equal to 60 IU per milliliter) underwent liver biopsy, and medications were continued in subjects with either a virologic response or histologic improvement.
Treatment with peginterferon and ribavirin was associated with a significantly higher rate of sustained virologic response (an HCV RNA level of less than 60 IU per milliliter 24 weeks after completion of therapy) than was treatment with interferon and ribavirin (27 percent vs. 12 percent, P=0.03). In the group given peginterferon and ribavirin, only 14 percent of subjects with HCV genotype 1 infection had a sustained virologic response (7 of 51), as compared with 73 percent of subjects with an HCV genotype other than 1 (11 of 15, P<0.001). Histologic responses were observed in 35 percent of subjects with no virologic response who underwent liver biopsy.
In persons infected with HIV, the combination of peginterferon and ribavirin is superior to the combination of interferon and ribavirin in the treatment of chronic hepatitis C. These regimens may provide clinical benefit even in the absence of virologic clearance. The marked discrepancy in the rates of sustained virologic response between HCV genotypes indicates that strategies are needed to improve the outcome in persons infected with HCV genotype 1.
PMCID: PMC4113392  PMID: 15282352
3.  Prostate Cancers in Men with Low PSA Levels — Must We Find Them? 
The New England journal of medicine  2004;350(22):2292-2294.
PMCID: PMC3474980  PMID: 15163780
4.  Relation of Serial Changes in Childhood Body-Mass Index to Impaired Glucose Tolerance in Young Adulthood 
The New England journal of medicine  2004;350(9):865-875.
The risk of type 2 diabetes mellitus is increased in people who have low birth weights and who subsequently become obese as adults. Whether their obesity originates in childhood and, if so, at what age are unknown. Understanding the origin of obesity may be especially important in developing countries, where type 2 diabetes is rapidly increasing yet public health messages still focus on reducing childhood “undernutrition.”
We evaluated glucose tolerance and plasma insulin concentrations in 1492 men and women 26 to 32 years of age who had been measured at birth and at intervals of three to six months throughout infancy, childhood, and adolescence in a prospective, population-based study.
The prevalence of impaired glucose tolerance was 10.8 percent, and that of diabetes was 4.4 percent. Subjects with impaired glucose tolerance or diabetes typically had a low body-mass index up to the age of two years, followed by an early adiposity rebound (the age after infancy when body mass starts to rise) and an accelerated increase in body-mass index until adulthood. However, despite an increase in body-mass index between the ages of 2 and 12 years, none of these subjects were obese at the age of 12 years. The odds ratio for disease associated with an increase in the body-mass index of 1 SD from 2 to 12 years of age was 1.36 (95 percent confidence interval, 1.18 to 1.57; P<0.001).
There is an association between thinness in infancy and the presence of impaired glucose tolerance or diabetes in young adulthood. Crossing into higher categories of body-mass index after the age of two years is also associated with these disorders.
PMCID: PMC3408694  PMID: 14985484
6.  Impaired Mitochondrial Activity in the Insulin-Resistant Offspring of Patients with Type 2 Diabetes 
The New England journal of medicine  2004;350(7):664-671.
Insulin resistance appears to be the best predictor of the development of diabetes in the children of patients with type 2 diabetes, but the mechanism responsible is unknown.
We performed hyperinsulinemic–euglycemic clamp studies in combination with infusions of [6,6-2H2]glucose in healthy, young, lean, insulin-resistant offspring of patients with type 2 diabetes and insulin-sensitive control subjects matched for age, height, weight, and physical activity to assess the sensitivity of liver and muscle to insulin. Proton (1H) magnetic resonance spectroscopy studies were performed to measure intramyo-cellular lipid and intrahepatic triglyceride content. Rates of whole-body and subcutaneous fat lipolysis were assessed by measuring the rates of [2H5]glycerol turnover in combination with microdialysis measurements of glycerol release from subcutaneous fat. We performed 31P magnetic resonance spectroscopy studies to assess the rates of mitochondrial oxidative-phosphorylation activity in muscle.
The insulin-stimulated rate of glucose uptake by muscle was approximately 60 percent lower in the insulin-resistant subjects than in the insulin-sensitive control subjects (P<0.001) and was associated with an increase of approximately 80 percent in the intramyocellular lipid content (P=0.005). This increase in intramyocellular lipid content was most likely attributable to mitochondrial dysfunction, as reflected by a reduction of approximately 30 percent in mitochondrial phosphorylation (P=0.01 for the comparison with controls), since there were no significant differences in systemic or localized rates of lipolysis or plasma concentrations of tumor necrosis factor α, interleukin-6, resistin, or adiponectin.
These data support the hypothesis that insulin resistance in the skeletal muscle of insulin-resistant offspring of patients with type 2 diabetes is associated with dysregulation of intramyocellular fatty acid metabolism, possibly because of an inherited defect in mitochondrial oxidative phosphorylation.
PMCID: PMC2995502  PMID: 14960743
7.  Was Rembrandt Stereoblind? 
The New England journal of medicine  2004;351(12):1264-1265.
PMCID: PMC2634283  PMID: 15371590
8.  Angiotensin-Converting-Enzyme Inhibition in Stable Coronary Artery Disease 
The New England journal of medicine  2004;351(20):2058-2068.
Angiotensin-converting-enzyme (ACE) inhibitors are effective in reducing the risk of heart failure, myocardial infarction, and death from cardiovascular causes in patients with left ventricular systolic dysfunction or heart failure. ACE inhibitors have also been shown to reduce atherosclerotic complications in patients who have vascular disease without heart failure.
In the Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) Trial, we tested the hypothesis that patients with stable coronary artery disease and normal or slightly reduced left ventricular function derive therapeutic benefit from the addition of ACE inhibitors to modern conventional therapy. The trial was a double-blind, placebo-controlled study in which 8290 patients were randomly assigned to receive either trandolapril at a target dose of 4 mg per day (4158 patients) or matching placebo (4132 patients).
The mean (±SD) age of the patients was 64±8 years, the mean blood pressure 133±17/78±10 mm Hg, and the mean left ventricular ejection fraction 58±9 percent. The patients received intensive treatment, with 72 percent having previously undergone coronary revascularization and 70 percent receiving lipid-lowering drugs. The incidence of the primary end point — death from cardiovascular causes, myocardial infarction, or coronary revascularization — was 21.9 percent in the trandolapril group, as compared with 22.5 percent in the placebo group (hazard ratio in the trandolapril group, 0.96; 95 percent confidence interval, 0.88 to 1.06; P=0.43) over a median follow-up period of 4.8 years.
In patients with stable coronary heart disease and preserved left ventricular function who are receiving “current standard” therapy and in whom the rate of cardiovascular events is lower than in previous trials of ACE inhibitors in patients with vascular disease, there is no evidence that the addition of an ACE inhibitor provides further benefit in terms of death from cardiovascular causes, myocardial infarction, or coronary revascularization.
PMCID: PMC2556374  PMID: 15531767
9.  Shedding Light on Immunotherapy for Cancer 
The New England journal of medicine  2004;350(14):1461-1463.
PMCID: PMC2275326  PMID: 15070799
10.  Human Metapneumovirus and Lower Respiratory Tract Disease in Otherwise Healthy Infants and Children 
The New England journal of medicine  2004;350(5):443-450.
We sought to determine the role of human metapneumovirus in lower respiratory tract illness in previously healthy infants and children.
We tested nasal-wash specimens, obtained over a 25-year period from otherwise healthy children presenting with acute respiratory tract illness, for human metapneumovirus.
A viral cause other than human metapneumovirus was determined for 279 of 687 visits for acute lower respiratory tract illness (41 percent) by 463 children in a population of 2009 infants and children prospectively seen from 1976 to 2001. There were 408 visits for lower respiratory tract illness by 321 children for which no cause was identified. Of these 321 children, specimens from 248 were available. Forty-nine of these 248 specimens (20 percent) contained human metapneumovirus RNA or viable virus. Thus, 20 percent of all previously virus-negative lower respiratory tract illnesses were attributable to human metapneumovirus, which means that 12 percent of all lower respiratory tract illnesses in this cohort were most likely due to this virus. The mean age of human metapneumovirus–infected children was 11.6 months, the male:female ratio was 1.8:1, 78 percent of illnesses occurred between December and April, and the hospitalization rate was 2 percent. The virus was associated with bronchiolitis in 59 percent of cases, pneumonia in 8 percent, croup in 18 percent, and an exacerbation of asthma in 14 percent. We also detected human metapneumovirus in 15 percent of samples from 261 patients with upper respiratory tract infection but in only 1 of 86 samples from asymptomatic children.
Human metapneumovirus infection is a leading cause of respiratory tract infection in the first years of life, with a spectrum of disease similar to that of respiratory syncytial virus.
PMCID: PMC1831873  PMID: 14749452
11.  Discordant Sexual Identity in Some Genetic Males with Cloacal Exstrophy Assigned to Female Sex at Birth 
The New England journal of medicine  2004;350(4):333-341.
BACKGROUND Cloacal exstrophy is a rare, complex defect of the entire pelvis and its contents that occurs during embryogenesis and is associated with severe phallic inadequacy or phallic absence in genetic males. For about 25 years, neonatal assignment to female sex has been advocated for affected males to overcome the issue of phallic inadequacy, but data on outcome remain sparse.
METHODS We assessed all 16 genetic males in our cloacal-exstrophy clinic at the ages of 5 to 16 years. Fourteen underwent neonatal assignment to female sex socially, legally, and surgically; the parents of the remaining two refused to do so. Detailed questionnaires extensively evaluated the development of sexual role and identity, as defined by the subjects' persistent declarations of their sex.
RESULTS Eight of the 14 subjects assigned to female sex declared themselves male during the course of this study, whereas the 2 raised as males remained male. Subjects could be grouped according to their stated sexual identity. Five subjects were living as females; three were living with unclear sexual identity, although two of the three had declared themselves male; and eight were living as males, six of whom had reassigned themselves to male sex. All 16 subjects had moderate-to-marked interests and attitudes that were considered typical of males. Follow-up ranged from 34 to 98 months.
CONCLUSIONS Routine neonatal assignment of genetic males to female sex because of severe phallic inadequacy can result in unpredictable sexual identification. Clinical interventions in such children should be reexamined in the light of these findings.
PMCID: PMC1421517  PMID: 14736925
12.  A Factorial Trial of Six Interventions for the Prevention of Postoperative Nausea and Vomiting 
The New England journal of medicine  2004;350(24):2441-2451.
Untreated, one third of surgical patients suffer postoperative nausea and vomiting (PONV). The relative benefit of prophylactic interventions remains unknown, as does the efficacy of combining interventions. We therefore compared the efficacy of six antiemetic interventions and their combinations.
5199 patients at high risk for PONV participated in a randomized, controlled trial of factorial design powered to evaluate interactions between up to three antiemetic interventions. 4123 patients were randomly assigned to one of 64 possible combinations of six prophylactic interventions: 1) 4 mg vs. no ondansetron; 2) 4 mg vs. no dexamethasone; 3) 1.25 mg vs. no droperidol; 4) propofol vs. a volatile anesthetic; 5) nitrogen vs. nitrous oxide; and 6) remifentanil vs. fentanyl. An additional 796 patients were randomized to 4 of all 6 interventions and an additional 280 patients were randomized to 80% oxygen in nitrogen as a third alternative to intervention 5. The blindly evaluated primary outcome was PONV within 24 hours.
5123 (99%) patients randomized to four interventions and 4086 of the 4123 patients (99%) randomized to all six interventions completed the study. Based on 4086 patients, ondansetron, dexamethasone, and droperidol each reduced PONV risk by about 26%. Propofol reduced risk by 19% and nitrogen by 12%; risk reduction with total intravenous anesthesia was thus similar to that resulting from antiemetics. All interventions acted independently, so that relative risk reduction for combined interventions could be estimated by the product of individual relative risk reductions. Similar results were obtained when all 5123 patients were analyzed.
Since each antiemetic drug and the total intravenous anesthesia similarly reduce relative risk, it seems sensible to use the least expensive or safest intervention first. Absolute risk is reduced less by additional interventions since the apparent baseline risk is already reduced. It is the patient’s initial risk therefore, which determines whether and how many interventions will produce a clinically relevant absolute risk reduction in PONV.
PMCID: PMC1307533  PMID: 15190136
randomized controlled trial; factorial design; postoperative nausea and vomiting; antiemetics; propofol; PONV

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