Relationship of human herpesvirus 8 peripheral blood virus load and Kaposi's sarcoma clinical stage.

OBJECTIVE: To determine the relationship between human herpesvirus 8 (HHV-8 or Kaposi's sarcoma-associated herpesvirus) peripheral blood virus load and Kaposi's sarcoma (KS) clinical stage. DESIGN: Blinded, cross-sectional analysis of peripheral blood HHV-8 DNA levels in persons with AIDS-related KS in Harare, Zimbabwe. METHODS: Subjects were stratified by KS clinical stage. The amount of HHV-8 DNA in plasma and peripheral blood mononuclear cells (PBMC) was determined by quantitative real-time PCR amplification of the HHV-8 open reading frame 26. RESULTS: Thirty-one HIV-1/HHV-8-coinfected persons were studied: 26 subjects had histologically confirmed KS (one stage II, 11 stage III and 14 stage IV) and five subjects had antibodies to HHV-8 but did not have KS. The age, CD4 lymphocyte count and plasma HIV-1 RNA levels were similar in all groups. HHV-8 DNA was detected in the plasma of all HHV-8-infected subjects (range < 2.4 to 5.2 log10 copies/ml), but plasma HHV-8 DNA levels were not associated with KS disease stage. In contrast, the amount of HHV-8 DNA in PBMC (range < 0.7 to 4.5 log10 copies/microg) was strongly associated with KS clinical stage (P = 0.005). Among stage IV KS cases, there was a linear relationship between plasma and PBMC HHV-8 DNA levels (r2 = 0.42; P = 0.01). CONCLUSION: The strong association observed between the extent of KS disease and the levels of HHV-8 DNA in PBMC provides further evidence for a relationship between HHV-8 virus load and KS pathogenesis.

Age at AIDS diagnosis for children with perinatally acquired HIV.

The human immunodeficiency virus (HIV) can be transmitted from mother to child in utero, during birth, or after birth through breast milk. While the majority of children born to HIV-positive mothers are not infected, almost all carry maternal antibodies. The number of maternal or perinatal exposures can be determined by screening all newborns for these antibodies, while maintaining the anonymity of mother and child. Combining newborn screening results with traditional surveillance data from New York City, we estimate that among maternally infected children, almost 14% will be diagnosed in the 1st year of life and, approximately 11-12% each year after, through age 7. This implies a median diagnosis age of 4.1 years, and suggests that in the majority of infected children, AIDS will not develop until after the 1st few years of life. We also examine the diagnosis age distribution for all children (infected and not) with a positive screen. We conclude that by approximately 7 years of age, 17% of children who test positive will be diagnosed with clinical AIDS, according to a yearly rate of > 2%. Based on these results, the perinatally acquired pediatric epidemic can be projected from the newborn screening data.

Treatment of histoplasmosis with fluconazole in patients with acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases Acquired Immunodeficiency Syndrome Clinical Trials Group and Mycoses Study Group.

PURPOSE: This study assesses the efficacy and safety of fluconazole therapy in patients with acquired immunodeficiency syndrome (AIDS) and mild to moderately severe manifestations of disseminated histoplasmosis. PATIENTS AND METHODS: This was a multicenter, open-label, nonrandomized prospective trial. All patients had AIDS and disseminated histoplasmosis. Patients were treated with 1,200 mg of fluconazole given by mouth once on the first day, then 600 mg once daily for 8 weeks, and those patients who improved clinically were then assigned fluconazole maintenance therapy 200 mg once daily for at least 1 year. Interim analysis revealed a high failure rate (10 of 20, 50%), causing revision of the protocol to increase the fluconazole dose to 1,600 mg given once on the first day, then 800 mg once daily, and the duration to 12 weeks for induction therapy and then 400 mg daily for 1 year for maintenance therapy. MEASUREMENTS AND MAIN RESULTS: Thirty-six of 49 patients (74%; 95% confidence interval [CI]: 59% to 85%) with mild to moderately severe clinical manifestations who entered into the revised study responded to 800 mg of fluconazole daily for 12 weeks as induction therapy. Of the seven patients who failed induction therapy because of progression of histoplasmosis, one died of the infection. Of 36 patients who entered into the maintenance phase of the study receiving 400 mg of fluconazole daily for 1 year, 11 (30.5%) relapsed, including one who died (2.8%). Two of the 49 patients (4.1%) were removed because of grade 4 adverse events, alkaline phosphatase elevation for one and aspartate aminotransferase elevation in the other. The relapse-free rate at 1 year was 53% (95% CI: 32% to 89%), prompting closure of the study. CONCLUSIONS: Fluconazole 800 mg daily is a safe and moderately effective induction therapy for mild or moderately severe disseminated histoplasmosis in patients with AIDS. On the basis of historic comparison, fluconazole 400 mg daily is less effective than itraconazole 200 to 400 mg daily or amphotericin B 50 mg given weekly as maintenance therapy to prevent relapse.

Mild renal failure is associated with adverse outcome after cardiac valve surgery.

The present study was performed to ascertain whether the presence of mild renal failure (defined as a serum creatinine concentration of 1. 5 to 3.0 mg/dL) is an independent risk factor for adverse outcome after cardiac valve surgery. An extensive set of preoperative and postoperative data was collected in 834 prospectively evaluated patients undergoing cardiac valve surgery at 14 Veterans Affairs Medical Centers. Univariate and multivariable analyses were performed to determine whether an independent association of mild renal dysfunction with adverse outcomes was present. Patients with mild renal failure had significantly greater 30-day mortality rates (P = 0.001; 16% versus 6%) and frequency of postoperative bleeding (P = 0.023; 16% versus 8%), respiratory complications (P = 0.02, 29% versus 16%), and cardiac complications (P = 0.002; 18% versus 7%) than patients with normal renal function (serum creatinine <1.5 mg/dL) when controlling for multiple other variables. The presence of a serum creatinine concentration of 1.5 to 3.0 mg/dL is significantly and independently associated with adverse outcomes after cardiac valve surgery.

Changes in health-related quality of life following coronary artery bypass graft surgery.

BACKGROUND: There are limited data to help clinicians identify patients likely to have an improvement in quality of life following CABG surgery. We evaluated the relationship between preoperative health status and changes in quality of life following CABG surgery. METHODS: We evaluated 1,744 patients enrolled in the VA Cooperative Processes, Structures, and Outcomes in Cardiac Surgery study who completed preoperative and 6-month postoperative Short Form-36 (SF-36) surveys. The primary outcome was change in the Mental Component Summary (MCS) and Physical Component Summary (PCS) scores from the SF-36. RESULTS: On average, physical and mental health status improved following the operation. Preoperative health status was the major determinant of change in quality of life following surgery, independent of anginal burden and other clinical characteristics. Patients with MCS scores less than 44 or PCS scores less than 38 were most likely to have an improvement in quality of life. Patients with higher preoperative scores were unlikely to have an improvement in quality of life. CONCLUSIONS: Patients with preoperative health status deficits are likely to have an improvement in their quality of life following CABG surgery. Alternatively, patients with relatively good preoperative health status are unlikely to have a quality of life benefit from surgery and the operation should primarily be performed to improve survival.

Identification of risk factors for increased cost, charges, and length of stay for cardiac patients.

BACKGROUND: In this study we explored different risk model options to provide clinicians with predictions for resource utilization. The hypotheses were that predictors of mortality are not predictive of resource consumption, and that there is a correlation between cost estimates derived using a cost-to-charge ratio or a product-line costing approach. METHODS: From March 1992 to June 1995, 2,481 University of Colorado Hospital patients admitted for ischemic heart disease were classified by diagnosis-related group code as having undergone or experienced coronary bypass procedures (CBP), percutaneous cardiovascular procedures (PCVP), acute myocardial infarction (AMI), and other cardiac-related discharges (Other). For each diagnosis-related group, Cox proportional hazards models were developed to determine predictors of cost, charges, and length of stay. RESULTS: The diagnosis groups differed in the clinical factors that predicted resource use. As the two costing methods were highly correlated, either approach may be used to assess relative resource consumption provided costs are reconciled to audited financial statements. CONCLUSIONS: To develop valid prediction models for costs of care, the clinical risk factors that are traditionally used to predict risk-adjusted mortality may need to be expanded.

Fast-track cardiac surgery in a Department of Veterans Affairs patient population.

BACKGROUND: "Fast-track" (FT) cardiac surgery is popular in the private and university sectors. This study was designed to examine its safety and efficacy in the Department of Veterans Affairs elderly, male patient population, a population with multiple comorbid risk factors, often decreased social functioning, and impaired support systems. METHODS: Time to extubation, hospital length of stay, perioperative morbidity, and mortality were studied in two consecutive cohorts undergoing cardiac operations requiring cardiopulmonary bypass before (pre-FT: n = 255, January 1992 to September 1993) and after (FT: n = 304, October 1993 to October 1995) institution of an FT protocol at a university-affiliated teaching Department of Veterans Affairs medical center. Preoperative risk factors, including a Department of Veterans Affairs risk-adjusted estimate of operative mortality, and perioperative surgical and anesthetic processes of care were evaluated. RESULTS: The mean Department of Veterans Affairs risk estimate of perioperative mortality was not different between the pre-FT and FT cohorts (3.5% versus 3.7%, p = 0.13). In the FT cohort, median time to extubation decreased significantly (19.2 versus 10.2 hours; p < 0.001) along with median surgical intensive care unit stay (96 versus 49 hours; p < 0.001) and total postoperative length of stay (222 versus 167 hours; p < 0.001). Median postoperative day of hospital discharge decreased from day 10 to 7 (p < 0.001). One patient (0.3%) required emergent reintubation directly related to early extubation. Reintubation for medical reasons was unchanged between pre-FT and FT groups (6.3% versus 5.0%; p = 0.48). Postoperative morbidity was similar between groups except for nosocomial pneumonia, the rate of which decreased significantly in the FT cohort (14.7% versus 7.3%; p < 0.005). Thirty-day (3.9% versus 4.6%; p = 0.69) and 6-month mortality (6.7% versus 6.9%; p = 0.91) were unchanged. CONCLUSIONS: An FT cardiac surgery protocol has been instituted in a university-affiliated teaching Department of Veterans Affairs medical center, with decreased length of stay and no significant increase in postoperative morbidity, 30-day mortality, or 6-month mortality. It was associated with a lower rate of nosocomial pneumonia, a finding that must be validated in a prospective study.

Body composition, dietary intake, and energy expenditure in nonobese, prepubertal children of obese and nonobese biological mothers.

OBJECTIVE: To determine differences in dietary intake, resting energy expenditure, activity level, fat-free mass, and percentage body and abdominal fat in nonobese children of obese mothers compared with nonobese children of nonobese mothers. DESIGN: Cross-sectional comparison study. Children's food diaries were analyzed to determine average energy and nutrient content. Resting energy expenditure of children was measured by means of indirect calorimetry. Children's activity levels were estimated through questionnaires administered during interviews. Dual-energy x-ray absorptiometry was used to estimate body composition of children. SUBJECTS: Mothers of subjects responded to advertisements and were recruited as nonobese (body mass index = 20 to 25) or obese (body mass index > or = 30). Offspring included in the study were prepubertal and nonobese (10th to 90th percentile of weight for height by gender). Twelve pairs of children could be matched for weight, gender, and age. STATISTICAL ANALYSIS PERFORMED: Wilcoxon signed rank tests were used to determine differences between the 2 groups of children. RESULTS: Percentage abdominal fat was greater (median difference = 3.15, P = .001) and fat-free mass was lower (median difference = 1.19, P = .04) in children of obese mothers compared with children of nonobese mothers. No statistically significant differences between the 2 groups of children were found for dietary intake, resting energy expenditure, activity level, or percentage body fat. APPLICATIONS/CONCLUSIONS: The significantly higher percentage of abdominal fat and lower fat-free mass in children of obese mothers may contribute to obesity onset. Use of dual-energy x-ray absorptiometry as a screening tool for nonobese, prepubertal children with an obese parent will help to identify those at risk. Education and lifestyle changes can then be implemented to help prevent the onset of obesity.

Prior meal enhances the plasma glucose lowering effect of exercise in type 2 diabetes.

PURPOSE: To compare the changes in plasma glucose and insulin levels in response to 1 h of exercise performed at 60% of VO(2peak) either in the fasted state or 2 h after a standardized breakfast in subjects with type 2 diabetes. METHODS: Ten sedentary men with type 2 diabetes treated with oral agents and not under strict metabolic control were tested on two occasions (fasted and fed state) in a random order at a 1-wk interval. RESULTS: Plasma glucose was slightly but not significantly higher at the beginning of exercise performed in the fed state versus the fasted state (12.4 +/- 1.3 vs 11.1 +/- 1.1 mmol x L(-1) respectively; mean +/- SE, P = 0.06). However, after exercise, plasma glucose levels were much lower in the fed state (7.6 +/- 1.1 mmol x L(-1)) compared with the fasted state (10.0 +/- 1.0 mmol x L(-1); P = 0.009). Insulin levels were higher at the beginning of the exercise bout performed in the fed state (177 +/- 26 vs 108 +/- 19 pmol x L(-1); P < 0.05) and during exercise. Similar respiratory exchange ratio at identical workload indicated that the difference in glycemic response was not due to differences in whole body substrate utilization. Plasma concentrations of free fatty acids, glucagon, epinephrine, and norepinephrine were also similar during both experiments. CONCLUSIONS: One hour of aerobic exercise has a minimal impact on plasma glucose level when performed in fasted moderately hyperglycemic men with type 2 diabetes but induces an important decrease in plasma glucose level when performed 2 h after breakfast. Because glucose utilization increased similarly during exercise in both conditions, the higher insulin levels after the meal might have blunted glucose production, creating an imbalance between total glucose production and total peripheral utilization in the fed state in contrast to the fasted state.

Emergency department post-coital contraception in Northern Ireland.

BACKGROUND: The granting of a licence to Levonelle as an emergency hormonal contraceptive in the Republic of Ireland may require accident and emergency (A&E) departments to formally provide such a service. This article outlines the experiences of a Northern Ireland A&E unit. AIMS: To examine the pattern of attendance of patients requesting emergency contraception at an A&E department and to assess if adequate standards of care are achieved. METHOD: Retrospective case note review of 100 patients attending the A&E department requesting emergency contraception. RESULTS: Sixty-one per cent of requests for emergency contraception were outside normal pharmacy opening hours. Seventy-seven per cent of these patients were less than 26 years old. Most (63%) attended within 24 hours of unprotected sexual intercourse. Forty-three per cent of the patients studied had used no contraception prior to this request. Recording of menstrual details and sexual behaviour as part of the consultation was variable. CONCLUSIONS: A&E departments receive requests for emergency hormonal contraception particularly from younger women (<25 years). A&E staff must have appropriate training and support to manage these consultations effectively.

Requests for emergency contraception at an accident and emergency department--assessing the impact of a change in legislation.

The aim of this study was to examine the pattern of attendance of patients requesting Emergency Hormonal Contraception (EHC) at an accident and emergency department before and after a government driven change in legislation, which allowed EHC to be sold over-the-counter by trained pharmacists, to women aged 16 years and above. We employed retrospective comparative study using computer records of all accident and emergency attendances coded as requests for emergency contraception for the years 2000 and 2001. The number of patients requesting emergency contraception at the A&E department decreased after over-the-counter sales were introduced, from 196 in the year 2000 to 164 in 2001 (p = 0.037). Despite this, the number of teenagers requesting emergency contraception at the A&E department increased in 2001--from 63 in 2000 to 74 in 2001 (p = 0.0115). Most requests are received outside local pharmacy opening hours--63.77% in 2000 and 62.2% in 2001. This study raises concerns that the government initiative allowing emergency hormonal contraception to be sold in pharmacies is having little impact on teenagers most in need of this service. A&E departments can expect to continue to receive a significant number of requests for emergency contraception. Further measures will be required to reduce the U.K.'s high rate of unplanned pregnancies.

Distribution of the latency period for perinatally acquired AIDS.

In the United States, over 86 per cent of paediatric cases of acquired immunodeficiency syndrome (AIDS) were infected through maternal or perinatal transmission and current estimates suggest that approximately 6000 children are born to infected women each year. In industrialized countries, less than 25 per cent of infants maternally exposed to the human immunodeficiency virus (HIV) are infected. The exact time of infection is unknown. However an endpoint, birth, exists from which the latency period or the time to diagnosis with clinical AIDS can be measured. In New York City, 7 years of reliable surveillance data were available for children with perinatally acquired AIDS. Using these data, the only estimable aspect of the latency is a conditional distribution, which conditions on diagnosis occurring before age 7. Because newborns carry maternal antibodies, a positive antibody test at birth is only an indication of maternal infection. Screening all newborns for HIV antibodies, while maintaining the anonymity of the mother and child, provides data on the number of children maternally exposed. The above conditioning can be removed by combining the surveillance and newborn screening data to obtain the unconditional latency distribution. We estimate a median diagnosis age of 4.1 years, somewhat longer than previously believed.

Control and induction of ovulation in cattle.

The control and induction of ovulation in cattle are discussed with particular reference to use of progesterone-impregnated coils in heifers and beef cows. Progesterone treatment for 14 days was required to obtain precise onset of oestrus. With 7, 9 or 12 days of progesterone treatment a luteolytic agent in the form of a prostaglandin (PG) or oestradiol benzoate had to be used. Fertility was normal after treatment durations of 7, 9 or 12 days, but fertility after 14-day treatment requires further testing. The progesterone coil was not effective in maintaining luteal-phase levels of progesterone throughout a 12-day treatment and increasing the concentration of progesterone in the coil from 4 to 20% was not effective in elevating the progesterone concentrations in blood. When progesterone concentrations dropped below approximately 1.5 ng/ml the basal level of LH began to rise before removal of the coil. A 2-fold rise in the basal level of LH was observed following the removal of the progesterone coil. This early rise in LH was absent in cows which did not ovulate after they were given a 12-day progesterone treatment and GnRH 24-36 h after removal of coils to induce the main LH peak. Absence of this early rise suggests that frequency and amplitude of episodic LH release were inadequate in the post-partum anovulatory period. Ovariectomy in the early post-partum period was not followed by an abrupt LH release.

Regression analysis of censored and truncated data: estimating reporting-delay distributions and AIDS incidence from surveillance data.

AIDS surveillance provides a vital source of information for health departments to assess the AIDS epidemic and to plan for future health-care needs. However, the use of surveillance data requires proper adjustments for the underreporting of AIDS cases caused by the delay in reporting diagnosed AIDS cases to the surveillance system. The statistical problem of adjusting for this underreporting concerns making inferences about an unobservable random sample of which only a portion is observed in a chronologic time interval defined by the analysis. Most regression methods for making inferences using right-truncated data employ a reverse-time hazard function, which requires that the observed data be transformed so that methods for left-truncated data can be applied. In this paper, we discuss fitting regression models to data that can be truncated and even censored in arbitrary intervals. The proposed methodology was applied to the national AIDS surveillance data provided by the Centers for Disease Control to analyze the trend of delays over chronologic time and variation among different geographic regions as well as across risk groups.

Improving the fit of bivariate smoothing splines when estimating longitudinal immunological and virological markers in HIV patients with individual antiretroviral treatment strategies.

CD4+ lymphocyte count and HIV RNA plasma viral load are longitudinally monitored in patients with HIV infection. Because data collection intervals may be unequally spaced and these markers experience high within-patient variability, they may be smoothed before use in subsequent models. Estimation strategies must be able to accommodate the drastic changes in viral load which may occur when an individual's treatment strategy is updated. Because these treatment changes are not regimented, these dynamics cannot be modelled using standard methods. We propose univariate and bivariate cubic smoothing splines to fit CD4+ count and viral load over time. The method is developed using state space equations, and the Kalman filter is used to calculate the log-likelihood. Non-linear optimization is used to obtain the maximum likelihood estimates. A modification of the Kalman filter allows non-informative or diffuse priors at the initial observation. Since treatment changes are expected to alter the shape of the curve, we further extend the Kalman filter to permit greater flexibility in the smoothing spline at these time points. The method produces smoothed estimates of the viral load and CD4+ count curves over time.

In vitro effect of interleukin-12 on antigen-specific lymphocyte proliferative responses from persons infected with human immunodeficiency virus type 1.

The relationship between CD4 lymphocyte count and the in vitro effect of interleukin (IL)-12 on lymphocyte proliferative responses to Candida, tetanus toxoid, and streptokinase antigens was studied in peripheral blood mononuclear cells (PBMC from 30 human immunodeficiency virus (HIV)-infected persons and 10 seronegative controls. IL-12 significantly increased proliferative responses to microbial recall antigens of PBMC from HIV-infected persons with >200 CD4 lymphocytes/mm3 but had little effect on PBMC from patients with more advanced disease. The greatest increase was seen in patients with 200-500 CD4 cells/mm3. Results of limiting dilution analysis suggested that the increase in antigen-specific lymphocyte proliferation in the presence of IL-12 was due to an increase in the number of responding cells rather than an increase in the extent of proliferation of a fixed number of responder cells.

Human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus) infection in men receiving treatment for HIV-1 infection.

OBJECTIVE: To determine the prevalence of human herpesvirus 8 (HHV-8) infection in men treated for HIV-1 infection in Denver, Colorado. DESIGN: Cross-sectional analysis METHODS: Blood samples were obtained from 216 HIV-1-infected men. Antibody to latency-associated nuclear antigen (LANA) was detected by an immunofluorescent assay and the presence of HHV-8 in peripheral blood mononuclear cells (PBMC) was detected by polymerase chain reaction amplification. RESULTS: Among HIV-1-infected men who did not have Kaposi's sarcoma (KS), prevalence of HHV-8 infection was 46% (95% confidence interval [CI], 0.39-0.52). LANA seropositivity was common both among subjects with KS and subjects without KS (69% versus 42%; p = .06), but detection of HHV-8 DNA in peripheral blood was strongly associated with a diagnosis of KS (44% versus 10%; p = .001). In a univariate analysis of study subjects without KS, neither the odds of LANA seropositivity nor detection of HHV-8 DNA in PBMC was significant for CD4+ lymphocyte count, HIV-1 virus load, the use of three drug antiretroviral regimens or the prior occurrence of non-KS AIDS-related conditions. CONCLUSION: Although antibodies to HHV-8 are common among HIV-1-infected men, detection of HHV-8 DNA in PBMC is uncommon and is associated with a diagnosis of Kaposi's sarcoma.

In vitro effects of IL-12 on HIV-1-specific CTL lines from HIV-1-infected children.

We studied the in vitro effects of IL-12 on HIV-1-specific CTL lines derived from PBMC of HIV-1-infected children. HIV-1-specific CTL lines were derived by limiting dilution following Ag-specific stimulation of PBMC from HIV-1-infected children and were maintained with repeated anti-CD3 stimulation. Following incubation with IL-12 for 5 to 7 days, HIV-1-specific cytotoxicity was augmented in a dose-dependent fashion (mean increase, 94 +/- 83 lytic units; p = 0.0006). Experiments performed with CD3-blocking Abs and MHC-mismatched targets demonstrated that the IL-12-enhanced activity was MHC restricted and dependent on cells bearing CD3. The effect of IL-12 on proliferation of the CTL lines as tested by [3H]TdR uptake was minimal, with stimulation indexes ranging from 1.25 to 4.9. The effects of IL-12 on cytotoxicity were not significantly altered by addition of Ab to the IL-2R (anti-Tac) in quantities sufficient to block exogenous IL-2 (p = 0.15), demonstrating that endogenous IL-2 activity is not required for IL-12-enhanced cytolytic activity. Likewise, addition of neutralizing Ab specific for IFN-gamma did not change IL-12-enhanced cytotoxicity (p = 0.61). The in vivo role of IL-12 in the generation and the stimulation of CTL remains to be determined; however, its ability to augment HIV-1-specific CTL in vitro adds additional support for IL-12 as a candidate for immune-based therapy of HIV-1.