Corette B. Parker

Male circumcision for HIV prevention in young men in Kisumu, Kenya: a randomised controlled trial

BACKGROUND Male circumcision could provide substantial protection against acquisition of HIV-1 infection. Our aim was to determine whether male circumcision had a protective effect against HIV infection, and to assess safety and changes in sexual behaviour related to this intervention. METHODS We did a randomised controlled trial of 2784 men aged 18-24 years in Kisumu, Kenya. Men were randomly assigned to an intervention group (circumcision; n=1391) or a control group (delayed circumcision, 1393), and assessed by HIV testing, medical examinations, and behavioural interviews during follow-ups at 1, 3, 6, 12, 18, and 24 months. HIV seroincidence was estimated in an intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, with the number NCT00059371. FINDINGS The trial was stopped early on December 12, 2006, after a third interim analysis reviewed by the data and safety monitoring board. The median length of follow-up was 24 months. Follow-up for HIV status was incomplete for 240 (8.6%) participants. 22 men in the intervention group and 47 in the control group had tested positive for HIV when the study was stopped. The 2-year HIV incidence was 2.1% (95% CI 1.2-3.0) in the circumcision group and 4.2% (3.0-5.4) in the control group (p=0.0065); the relative risk of HIV infection in circumcised men was 0.47 (0.28-0.78), which corresponds to a reduction in the risk of acquiring an HIV infection of 53% (22-72). Adjusting for non-adherence to treatment and excluding four men found to be seropositive at enrollment, the protective effect of circumcision was 60% (32-77). Adverse events related to the intervention (21 events in 1.5% of those circumcised) resolved quickly. No behavioural risk compensation after circumcision was observed. INTERPRETATION Male circumcision significantly reduces the risk of HIV acquisition in young men in Africa. Where appropriate, voluntary, safe, and affordable circumcision services should be integrated with other HIV preventive interventions and provided as expeditiously as possible.

The effect of diabetes mellitus on prognosis and serial left ventricular function after acute myocardial infarction: Contribution of both coronary disease and diastolic left ventricular dysfunction to the adverse prognosis☆

Abstract Patients with diabetes mellitus experience a more adverse outcome after acute myocardial infarction compared with nondiabetic patients, although the mechanisms responsible for these findings are not clear. From the Multicenter Investigation of the Limitation of Infarct Size (MILIS) study, the course of acute infarction in 85 diabetic patients was compared with that in 415 nondiabetic patients, all of whom had serial assessments of left ventricular function. The diabetic patients experienced a more complicated in-hospital and postdischarge course than did the nondiabetic patients, including a higher incidence of postinfarction angina, infarct extension, heart failure and death, despite the development of a smaller infarct size and similar levels of left ventricular ejection fraction. Although diabetic patients had a worse profile of cardiovascular risk factors at the time of the index infarction, the increased incidence of adverse outcomes among them persisted despite adjustment for these baseline imbalances. Diabetic women had a poor baseline risk profile compared with the other groups categorized by gender and diabetic status, and experienced an almost twofold increase in cardiac mortality despite development of the smallest infarct size during the index event. The duration of diabetes and the use of insulin at the time of the index infarction were associated with a better in-hospital mortality rate, but the duration of diabetes did not exert a major influence on the outcome of the diabetic patients. The factors responsible for the increased incidence of adverse outcomes among diabetic patients may be related to an acceleration of the atherosclerotic process, diastolic left ventricular dysfunction associated with diabetic cardiomyopathy or other unidentified unfavorable processes.

A randomized controlled trial of a reduced daily dose of zidovudine in patients with the acquired immunodeficiency syndrome

Abstract Background. The initially tested dose of zidovudine for the treatment of patients with advanced disease caused by the human immunodeficiency virus type 1 (HIV) was 1500 mg. Although this dose is effective, it is associated with substantial toxicity. Methods. To evaluate the efficacy and safety of a reduced dose, we conducted a randomized controlled trial in 524 subjects who had had a first episode of Pneumocystis carinii pneumonia. The subjects were assigned to receive zidovudine in either a dose of 250 mg taken orally every four hours (the standard-treatment group, n = 262) or a dose of 200 mg taken orally every four hours for four weeks and thereafter 100 mg taken every four hours (the low-dose group, n = 262). Results. The median length of follow-up was 25.6 months. At 18 months the estimated survival rates were 52 percent for the standard-treatment group and 63 percent for the low-dose group (P = 0.012 by the log-rank test). At 24 months the estimated survival rates were 27 percent for the st...

Electrocardiographic and clinical criteria for recognition of acute myocardial infarction based on analysis of 3,697 patients.

Over a 34.5-month period, all admissions to 5 university hospital coronary care units were screened for eligibility for the Multicenter Investigation of the Limitation of Infarct Size (MILIS), an ongoing study of the effects of hyaluronidase, propranolol and placebo on myocardial infarct (MI) size. Of 3,697 patients with greater than or equal to 30 minutes of discomfort that was thought to reflect myocardial ischemia who were assessed for the presence or absence of certain electrocardiographic abnormalities at the time of hospital admission, the electrocardiogram was considered predictive of acute MI if greater than or equal to 1 of the following abnormalities was present: new or presumably new Q waves (greater than or equal to 30 ms wide and 0.20 mV deep) in at least 2 of the 3 diaphragmatic leads (II, III, aVF), or in at least 2 of the 6 precordial leads (V1 to V6), or in I and aVL; new or presumably new ST-segment elevation or depression of greater than or equal to 0.10 mV in 1 of the same lead combinations; or complete left bundle branch block. In the screened population, the diagnostic sensitivity of the electrocardiographic criteria was 81%, whereas the overall infarct rate in the total population screened was 49%. The diagnostic specificity of these entry criteria was 69% and the predictive value 72%.(ABSTRACT TRUNCATED AT 250 WORDS)

The in-hospital development of cardiogenic shock after myocardial infarction: Incidence, predictors of occurrence, outcome and prognostic factors

The incidence, outcome and predictors of the in-hospital development of cardiogenic shock and its prognostic significance were analyzed in 845 patients presenting with acute myocardial infarction. Cardiogenic shock developed after hospitalization in 60 patients (7.1%). In half of these patients, cardiogenic shock developed at least 24 h after hospital admission. The in-hospital mortality rate was greater than 15 times higher for patients with cardiogenic shock than for patients without shock (65.0% versus 4.3%, respectively, p less than 0.001). Enzymatic evidence of infarct extension occurred in 23.3% of the patients with shock compared with 7.4% of those without shock (p less than 0.0001). Multivariate analysis indicated that independent predictors for the in-hospital development of cardiogenic shock were age greater than 65 years (p = 0.007), left ventricular ejection fraction on hospital admission less than 35% (p = 0.007), large infarct as estimated from serial enzyme determinations (that is, peak creatine kinase-MB isoenzyme greater than 160 IU/liter (p = 0.008), history of diabetes mellitus (p = 0.011) and previous myocardial infarction (p = 0.012). Patients with three, four or five of these risk factors had a 17.9%, 33.7% or 54.4% probability, respectively, of developing cardiogenic shock after hospital admission. Left ventricular function, as reflected by left ventricular ejection fraction (p = 0.04) and severity of left ventricular wall motion abnormality (p = 0.04), was the most important determinant of in-hospital mortality in the patients with cardiogenic shock.

Ventricular septal and free wall rupture complicating acute myocardial infarction: experience in the Multicenter Investigation of Limitation of Infarct Size.

Left ventricular rupture was studied in 849 patients enrolled in the Multicenter Investigation of Limitation of Infarct Size. Although documented rupture occurred in only 14 cases (1.7%), it accounted for 14% of in-hospital mortality. Seven of the 14 ruptures occurred within 2 days and 10 within 4 days of the MB-creatine kinase-determined onset of infarction. Three easily determined baseline characteristics defined a set of patients with a markedly increased risk of myocardial rupture. Rupture was 9.2 times more likely to occur in patients with all of the following characteristics than in the remaining patients: (1) no history of previous angina or myocardial infarction, (2) ST segment elevation or signs of Q wave development on the initial ECG, and (3) peak MB-creatine kinase value (greater than or equal to 150 IU/L). The risk of myocardial rupture with these three characteristics was 5.5%. Although these predictors are likely to be of little therapeutic value for free wall rupture, since most patients with that complication die within minutes of its onset, they may aid in alerting physicians to the early diagnosis and timely surgical correction of ventricular septal rupture.

Comparison of enzymatic and anatomic estimates of myocardial infarct size in man.

Enzymatic estimates of myocardial infarct size based on plasma levels of MB creatine kinase (MB-CK) were compared with anatomic infarct size in 49 human hearts obtained at autopsy. The patients studied had been enrolled in the Multicenter Investigation of Limitation of Infarct Size (MILIS) study program within 18 hr of the onset of acute infarction and were treated at one of five participating hospitals. Infarct size was estimated from serial measurements of plasma MB-CK made at the core laboratory for CK analysis. Hearts obtained at autopsy were studied independently by the core pathology laboratory without knowledge of the MB-CK levels or clinical results. Data from the two laboratories were compared at the data coordinating center. Of 49 hearts, 12 were excluded either because anatomic infarct size could not be established or because the infarct occurring at the time of enrollment in the MILIS study could not be distinguished with certainty from other infarcts. Of the remaining 37 hearts, peak MB-CK level was available in 36, but samples sufficient for estimation of infarct size were available in only 25. The overall correlation coefficient (Spearman) was .87 for these 25 hearts, indicating that enzymatic estimates of infarct size correlate closely with anatomic measurements. The results indicate that CK estimates of myocardial infarct size represent a valid clinical end point for assessing myocardial infarct size, and the effect of therapy thereon, in groups of treated and control patients.

Implications for acute intervention related to time of hospital arrival in acute myocardial infarction.

The time from onset of symptoms to arrival in the hospital emergency room (ER) was studied in 778 patients randomized into a study of acute myocardial infarction (AMI) size limitation. Patients at relatively high risk of death after AMI (including those with preexisting diabetes mellitus, systemic hypertension or congestive heart failure), women and older patients arrived significantly later in the ER than did patients without these characteristics. A significantly higher mortality rate was observed in patients who arrived late, i.e., those who arrived more than 2 hours after the onset of chest pain, even though patients with hemodynamic compromise (bradycardia, hypotension) tended to arrive earlier. The difference in long-term mortality between those who arrived early (within 2 hours of onset of chest pain) and those who arrived late was accounted for by the baseline differences between these 2 groups. These baseline differences may influence the effects of early interventions in AMI. In addition, these findings have implications for education of high-risk patients who could benefit the most from aggressive early intervention.

Karyotype versus Microarray Testing for Genetic Abnormalities after Stillbirth

BACKGROUND Genetic abnormalities have been associated with 6 to 13% of stillbirths, but the true prevalence may be higher. Unlike karyotype analysis, microarray analysis does not require live cells, and it detects small deletions and duplications called copy-number variants. METHODS The Stillbirth Collaborative Research Network conducted a population-based study of stillbirth in five geographic catchment areas. Standardized postmortem examinations and karyotype analyses were performed. A single-nucleotide polymorphism array was used to detect copy-number variants of at least 500 kb in placental or fetal tissue. Variants that were not identified in any of three databases of apparently unaffected persons were then classified into three groups: probably benign, clinical significance unknown, or pathogenic. We compared the results of karyotype and microarray analyses of samples obtained after delivery. RESULTS In our analysis of samples from 532 stillbirths, microarray analysis yielded results more often than did karyotype analysis (87.4% vs. 70.5%, P<0.001) and provided better detection of genetic abnormalities (aneuploidy or pathogenic copy-number variants, 8.3% vs. 5.8%; P=0.007). Microarray analysis also identified more genetic abnormalities among 443 antepartum stillbirths (8.8% vs. 6.5%, P=0.02) and 67 stillbirths with congenital anomalies (29.9% vs. 19.4%, P=0.008). As compared with karyotype analysis, microarray analysis provided a relative increase in the diagnosis of genetic abnormalities of 41.9% in all stillbirths, 34.5% in antepartum stillbirths, and 53.8% in stillbirths with anomalies. CONCLUSIONS Microarray analysis is more likely than karyotype analysis to provide a genetic diagnosis, primarily because of its success with nonviable tissue, and is especially valuable in analyses of stillbirths with congenital anomalies or in cases in which karyotype results cannot be obtained. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.).

A new system for determining the causes of stillbirth.

OBJECTIVE: To describe the methods for assigning the cause of death for stillbirths enrolled in the Stillbirth Collaborative Research Network (SCRN). METHODS: A complete evaluation, including postmortem examination, placental pathology, medical record abstraction, and maternal interview was available on 512 stillbirths among 500 women. These 512 stillbirths were evaluated for cause of death using the definitions outlined in this report. Using the best available evidence, SCRN investigators developed a new methodology to assign the cause of death of stillbirths using clinical, postmortem, and placental pathology data. This new tool, designated the Initial Causes of Fetal Death, incorporates known causes of death and assigns them as possible or probable based on strict diagnostic criteria, derived from published references and pathophysiologic sequences that lead to stillbirth. RESULTS: Six broad categories of causes of death are accounted for, including maternal medical conditions; obstetric complications; maternal or fetal hematologic conditions; fetal genetic, structural, and karyotypic abnormalities; placental infection, fetal infection, or both; and placental pathologic findings. Isolated histologic chorioamnionitis and small for gestational age were not considered causes of death. CONCLUSION: A new system, Initial Causes of Fetal Death, to assign cause of death in stillbirths was developed by the SCRN investigators for use in this study but has broader applicability. Initial Causes of Fetal Death is a standardized method to assign probable and possible causes of death of stillbirths based on information routinely collected during prenatal care and the clinical evaluation of fetal death.