'Information is information': a public perspective on incidental findings in clinical and research genome-based testing.

The potential for genomic incidental findings is increasing with the use of genome-based testing. At the same time approaches to clinical decision making are shifting to shared decision-making models involving both the healthcare community and the public. The public's voice has been nearly absent in discussions on managing incidental findings. We conducted nine focus groups and nine interviews (n = 63) with a broad cross-section of lay public groups to elucidate public viewpoints on incidental findings that could occur as a result of genome-based testing in clinical and research situations. Data were analyzed using qualitative content analysis. Participants wanted incidental findings disclosed to them whether or not these were clinical or research findings. Participants used different terms to define and describe incidental findings; they wanted to know that incidental findings are possible and be given a choice to learn about them. Personal utility was an important reason for disclosure, and participants believed that managing information is a shared responsibility between professionals and themselves. Broad public input is needed in order to understand and incorporate the public's perspective on management of incidental findings as disclosure guidelines, and policies are developed in clinical and research settings.

Correspondence between the effect of zidovudine plus lamivudine on plasma HIV level/CD4 lymphocyte count and the incidence of clinical disease in infected individuals. North American Lamivudine HIV Working Group.

OBJECTIVES: To investigate whether apparently beneficial changes in plasma HIV RNA level and CD4 lymphocyte count that are induced by antiretroviral therapy are associated with a corresponding clinical benefit. METHODS: For 620 patients in two randomized, double-blind trials of lamivudine (3TC) and zidovudine (ZDV) plasma HIV RNA and CD4 lymphocyte count changes were compared in patients randomized to 3TC plus ZDV and patients randomized to other treatment arms. The effect of therapy on the HIV RNA level and CD4 count was compared with the effect of therapy on clinical endpoints over the same time period. RESULTS: Median baseline values for all subjects were 42 420 copies/ml for HIV RNA and 277 x 10(6)/l for CD4 count. During the trial a significantly lower HIV RNA level and higher CD4 count was sustained in the ZDV/3TC group compared with the other group, with a difference in the median area under the curve from baseline per month of follow-up of 0.38 log10 copies/ml HIV RNA and 0.18 log2 x 10(6)/l CD4 cells (P < 0.001 in each case). For patients who were initially asymptomatic or in CDC stage B, the adjusted relative hazard (RH) of AIDS for a twofold lower CD4 count was 3.14 [95% confidence interval (CI), 1.44-6.83] and for a 10-fold higher HIV RNA level was 3.22 (1.20-8.59). The RH progression to AIDS expected with ZDV/3TC compared with the control treatments, given the observed effects of treatment on CD4 cell counts and HIV RNA levels, is 0.52, whereas the observed value was 0.16 (0.03-0.74). After adjustment for HIV RNA and CD4 changes over time the observed RH of progression to AIDS for ZDV/3TC treatment compared with controls was increased to 0.36 and was no longer significant (95% CI, 0.07-1.85). CONCLUSION: In this analysis of two trials, the effects of ZDV/3TC in reducing plasma HIV RNA and raising peripheral blood CD4 counts were associated with concurrent clinical benefits and the effect of treatment on these markers could account for at least part of the clinical benefits of therapy that were observed.

Multiple sites in HIV-1 reverse transcriptase associated with virological response to combination therapy.

OBJECTIVE: To determine whether analysis of sequence variation in reverse transcriptase at baseline can explain differences in response to combination antiretroviral therapy. METHODS: Amino acid sequences of reverse transcriptase obtained from baseline isolates from 55 patients included in a trial of zidovudine and didanosine versus zidovudine/didanosine/nevirapine (ACTG241) were analysed. Simple and multiple linear regression were used to determine the relationship between numbers and identity of mutations at baseline and virological response after 8 and 48 weeks. RESULTS: Numbers of baseline zidovudine resistance mutations were predictive of short-term response (week 8). Amino acid identity at position 215 explained > 20% of the variation in response at week 8, but less at week 48. Multiple regression identified the combinations: 215 + 44 and 41 + 202, each of which explained about 30% of the variation in week 8 response. A model incorporating amino acids 214 + 215 + 60 + 202 + baseline viral load explained > 40% of the variation in response at week 48. Unexpectedly, the mutant combination 601 + 215Y/F responded threefold better than 60V + 215Y/F over 48 weeks. CONCLUSIONS: Use of clinical data to analyse virological response to combination therapy has revealed effects of baseline amino acid mutations at sites not previously identified as being important in antiretroviral resistance. Predictors of long-term responses were different from those involved in the short term and may require more complex analysis.

Lamivudine in combination with zidovudine, stavudine, or didanosine in patients with HIV-1 infection. A randomized, double-blind, placebo-controlled trial. National Institute of Allergy and Infectious Disease AIDS Clinical Trials Group Protocol 306 Investigators.

OBJECTIVE: To study the antiviral activity of lamivudine (3TC) plus zidovudine (ZDV), didanosine (ddl), or stavudine (d4T). DESIGN: Randomized, placebo-controlled, partially double-blinded multicenter study. SETTING: Adult AIDS Clinical Trials Units. PATIENTS: Treatment-naive HIV-infected adults with 200-600x10(6) CD4 T lymphocytes/l. INTERVENTIONS: Patients were openly randomized to a d4T or a ddl limb, then randomized in a blinded manner to receive: d4T (80 mg/day), d4T plus 3TC (300 mg/day), or ZDV (600 mg/day) plus 3TC, with matching placebos; or ddl (400 mg/day), ddl plus 3TC (300 mg/day), or ZDV (600 mg/day) plus 3TC, with matching placebos. After 24 weeks 3TC was added for patients assigned to the monotherapy arms. MAIN OUTCOME MEASURE: The reduction in plasma HIV-1 RNA level at weeks 24 and 48. RESULTS: Two hundred ninety-nine patients were enrolled. After 24 weeks the mean reduction in plasma HIV-1 RNA copies/ml from baseline was 0.49 log10 (d4T monotherapy) versus 1.03 log10 (d4T plus 3TC; P = 0.001), and 0.68 log10 (ddl monotherapy) versus 0.82 log10 (ddl plus 3TC; P>0.22). After 48 weeks the mean reduction was 1.08 log10 (d4T plus 3TC) versus 1.01 log10 (ZDV plus 3TC) in the d4T limb (P = 0.66), and 0.94 log10 (ddl plus 3TC) versus 0.88 log10 (ZDV plus 3TC; P = 0.70) in the ddl limb. CONCLUSIONS: 3TC added significantly to the virologic effects of d4T, but not ddl, in treatment-naive patients. 3TC plus d4T produced virologic changes comparable to those of 3TC plus ZDV. These results support the use of 3TC with either ZDV or d4 as a component of initial combination antiretroviral therapy.

Continued lamivudine versus delavirdine in combination with indinavir and zidovudine or stavudine in lamivudine-experienced patients: results of Adult AIDS Clinical Trials Group protocol 370.

OBJECTIVE: To compare the virologic activity of continued lamivudine (3TC) versus a switch to delavirdine (DLV) when initiating protease inhibitor therapy in nucleoside-experienced patients. DESIGN: Randomized, open-label, multi-center study. SETTING: Adult AIDS clinical trials units. PATIENTS: Protease and non-nucleoside reverse transcriptase inhibitor-naive patients who had received 3TC plus zidovudine (ZDV), stavudine (d4T), or didanosine (ddl) for at least 24 weeks. INTERVENTIONS: Patients with plasma HIV-1 RNA levels > 500 copies/ml who previously received d4T + 3TC or ddI + 3TC were randomized to ZDV + 3TC + indinavir (IDV) or ZDV + DLV + IDV. MAIN OUTCOME MEASURES: Primary endpoints were the proportion of patients with plasma HIV-1 RNA levels < or = 200 copies/ml at 24 weeks, and occurrence of serious adverse events. The proportion of patients with plasma HIV-1 RNA levels < or = 200 copies/ml at week 48 was a secondary endpoint. RESULTS: At week 24, 58% of subjects in the ZDV + 3TC + IDV arm and 73% in the ZDV + DLV + IDV arm had plasma HIV-1 RNA levels < or = 200 copies/ml (P = 0.29). At week 48, plasma HIV-1 RNA levels were < or = 200 copies/ml in 48% and 83%, respectively (P = 0.007). Rash and hyperbilirubinemia occurred more frequently in the DLV arm than in the 3TC arm. Steady-state plasma IDV levels were higher among patients in the DLV arm as compared with the 3TC arm. CONCLUSIONS: Substituting DLV for 3TC when adding IDV improved virologic outcome in nucleoside-experienced patients. This result might be explained, in part, by the positive effect of DLV on IDV pharmacokinetics.

Symptomatic lactic acidosis in hospitalized antiretroviral-treated patients with human immunodeficiency virus infection: a report of 12 cases.

We retrospectively investigated the clinical and histopathologic features of hospitalized patients infected with human immunodeficiency virus who had symptomatic lactic acidosis syndrome at a university teaching hospital during 1995-2000. Twelve patients were identified, 11 during 1998-2000; of these, 5 died with rapid progression to otherwise unexplained multiple-organ failure. All had extensive prior exposure to nucleoside analog reverse-transcriptase inhibitors (NRTIs). At presentation, the most commonly identified NRTI component of antiretroviral regimens was stavudine plus didanosine. Eleven patients presented with abdominal pain, nausea, and/or emesis. Eight patients had prior acute weight loss (mean [+/-SD], 12+/-5.3 kg). Median venous plasma lactate levels were > or =2-fold greater than the upper limit of normal (2.1 mmol/L). Serum transaminase levels were near normal limits at presentation. Histopathologic studies confirmed hepatic macrovesicular and microvesicular steatosis in 6 patients. Concurrent chemical pancreatitis was identified in 6 patients. The increasing number of cases identified during the study period suggests that physicians better recognize symptomatic lactic acidosis and/or that cumulative NRTI exposure may increase the risk for this syndrome.

Patterns of care received by Medicaid recipients with urinary tract infections.

BACKGROUND: Urinary tract infections (UTIs) occur commonly in children and may lead to substantial morbidity. Most experts recommend urine cultures for diagnosing UTIs in children. In addition, most experts recommend imaging studies in a portion of children diagnosed with UTIs. PURPOSE: The purpose of this study was to assess how rates of performance of urine cultures and imaging studies for children in the Alabama Medicaid program diagnosed with a UTI vary by patient demographics, provider characteristics, and service locations. METHODS: The study design was a retrospective review of Alabama Medicaid claims data. Children were included as UTI cases if they had a Medicaid claim for urinary tract infections during 1991, were continuously enrolled in Medicaid for that year, and were younger than 8 years of age. Claims were grouped into episodes of care, and episodes were assigned to a diagnosing physician. Physician locations were classified as rural, suburban, or urban using demographic data. Specific laboratory and imaging procedures were identified using CPT codes (Physician's Current Procedural Technology Codes, 4th Edition). RESULTS: We identified 404 episodes of UTI occurring in 380 children. Only 47% of episodes were associated with claims for urine cultures. Claims for urine cultures were more frequently filed by pediatricians in urban locations. In the subset of 114 patients with multiple UTI episodes, only 68% had imaging studies specific for the urinary tract. Only 44% received both a voiding cystourethrogram and renal ultrasound. CONCLUSIONS: Claims data suggest that physicians underuse urine cultures in diagnosing UTIs in Alabama pediatric Medicaid recipients. Urban-based pediatricians perform better than other types of physicians. Imaging studies are also used less frequently than is commonly recommended.

Combination therapy: more effective control of HIV type 1?

The rationale for combining anti-HIV-1 agents is to provide more complete viral suppression, to limit the emergence of drug resistance during chronic viral replication, and to provide more effective antiretroviral treatment even when mixtures of drug-resistant and drug-sensitive strains are present. In vitro experiments reveal increased suppression with multiple-drug therapy, but viral breakthrough occurs after prolonged time in culture even during triple-drug therapy. Clinical results available to date indicate that drugs should be given simultaneously for optimal benefit. There appears to be a rationale for early initiation of combination therapy before the onset of increased viral burden and the emergence of syncytium-inducing viral variants. The results of ACTG protocol 155 revealed benefit of zidovudine and zalcitabine over monotherapy with either agent in patients with CD4+ cell counts > or = 150 cells/mm3. However, further clinical studies will be necessary before firm recommendations can be made about the indications for combination antiretroviral therapy in HIV-1-infected individuals at different stages of disease. Ultimately, we need better drugs, in combination, which significantly impact on HIV-1 burden to achieve more complete viral suppression and to reduce selection of drug-resistant viral variants.

Comparative analysis of HIV type 1 genotypic resistance across antiretroviral trial treatment regimens.

From data on HIV-1 genotypes collected from antiretroviral trial participants who fail virologically, we describe methods for comparing distributions of acquired HIV-1 mutations across different treatment regimens. Given a definition of a "mutational distance" that summarizes the genetic change of a subject's virus in a way that captures the resistance cost of exposure to an antiretroviral regimen, these comparative analyses inform about the relative treatability of emergent virus by next-line therapy directed to the same viral target. The utility of the methods is illustrated by application to data from AIDS Clinical Trials Group (ACTG) Study 241. We find that patients failing zidovudine/didanosine/nevirapine accumulated a 2.41-fold greater nonnucleoside reverse transcriptase inhibitor (RTI) mutational distance than patients failing zidovudine/didanosine [95% confidence interval (1.55, 5.26), p < 0.000001], quantitating expectations that adding a nonnucleoside RTI to a double nucleoside regimen may attenuate future effectiveness of nonnucleoside RTI therapy for nucleoside-experienced patients if viremia is not suppressed. We also find that persons with extensive prior experience with suboptimal nucleoside therapy who were virologically failing zidovudine/didanosine/nevirapine or zidovudine/didanosine accumulated a similar nucleoside RTI mutational distance, implying that the addition of the nonnucleoside RTI did not preserve future nucleoside options.

Flurbiprofen in post-partum women: plasma and breast milk disposition.

The plasma and milk disposition of flurbiprofen (FB) was assessed in healthy women during the early post-partum period after multiple doses of FB. The results confirmed that a pragmatic study design is an attainable requirement for definitive statements about the excretion of FB in transitional milk. Nine doses of FB (50 mg per dose) were administered during three days. Paired milk and plasma samples were obtained during this period of dosing as well as after the last dose. The plasma data were used to derive an equation, which was then used to simulate cumulative plasma profiles for multiple doses given at unequal time intervals. The observed data corresponded to the simulated cumulative profiles of FB in plasma. The plasma elimination half-life of FB during early lactation was slightly prolonged (mean 4.8 hrs) as compared to reported values for normal adult men. The peak plasma concentrations of FB were comparable to those reported for healthy volunteers. In 10 of 12 women (3-5 days post-partum) the FB concentration in breast milk was less than 0.050 micrograms/ml. In two women the milk concentrations of FB were 0.06, 0.07 and 0.07 micrograms/ml as found in only three samples. We conclude that, on the basis of dose found in milk, FB is safe for women breast feeding their infants in the early post-partum period.

Single-dose pharmacokinetics of ibuprofen and acetaminophen in febrile children.

The disposition of antipyretic drugs is central to the understanding of their action in children. Accordingly, the authors measured plasma levels of acetaminophen and ibuprofen in 153 febrile children for 6 hours after a single dose of either acetaminophen (12.5 mg/kg) or ibuprofen (5 or 10 mg/kg). Cmax occurred about 2 1/2 hours before maximum antipyresis, when plasma acetaminophen or ibuprofen was 25 to 50% less than Cmax. Most plasma level data fit a one-compartment open model, and this suggests a pharmacodynamic basis for the observed lag between Cmax and maximum antipyretic response. Plasma levels (and AUCO----infinity) of ibuprofen 10 mg/kg were less than expected for a two-fold increase in dose. For acetaminophen, the tlag was less than ibuprofen, Ka was more than ibuprofen, and beta was less than ibuprofen. The ibuprofen beta was not dose dependent, but the Vd was dose and model dependent. In contrast, ibuprofen Clp was dose and model independent. Acetaminophen pharmacokinetics were similar to those previously reported. Initial temperature, race, gender, prior medications, or diagnosis did not confound the results for ibuprofen or acetaminophen. Accordingly, a pharmacodynamic basis is a more likely explanation for the initial temperature effects found previously for antipyretic drugs in children. Ibuprofen (5 and 10 mg/kg) AUCO-----infinity was higher in the older (greater than or equal to 2.5 yrs) children and the Vd and Clp were lower in the older children, when discriminated by age or pharmacokinetic parameters. The observed dose dependency of AUCO----infinity and the effect of age on ibuprofen disposition must be considered if pharmacokinetic interpretations are used to develop the antipyretic dose of ibuprofen in children.

The ultimate prognosis after valve replacement: an assessment at twenty years.

Our experience over a 20-year period consists of 2,135 patients with initial caged-ball valve replacement: 52% aortic, 34% mitral, 12% double, and 2% triple-valve replacements, with 59.2, 39.8, 10.3, and 2.7 patient-centuries of follow-up, respectively. Fifteen-year actuarial survival (+/- standard error) was 43 +/- 2% for aortic and 44 +/- 3% for mitral valve replacement, and 27 +/- 5% for double-valve and 23 +/- 7% for triple-valve replacement. Restricting attention to patients operated on since 1973 divides the series almost in half and does not dramatically improve the 5-year actuarial survival (from 66 +/- 2% to 71 +/- 3% and from 70 +/- 2% to 78 +/- 3% for aortic valve replacement and mitral valve replacement, respectively). There was some alteration in the causes of late death: the largest percentage of deaths in both the earlier and current groups, 52%, was cardiac related whereas only 24% and 13%, respectively, were valve related. Over the past two decades operative mortality has declined and, to a lesser extent, late survival after mitral valve replacement has improved. The incidence of embolism has decreased significantly, most notably with the Silastic ball valves. Dramatic improvements in late results will occur primarily by modifying the cardiac-related death rate through earlier operation and improvements in the medical management of postoperative arrhythmias and congestive heart failure.

Development of on-line real-time menu management system.

An on-line, real-time menu management system was developed as a module of the integrated computer-assisted food management system implemented at the University of Missouri-Columbia Health Sciences Center Department of Nutrition and Dietetics. This system supplants a former automated form generating system and permits flexibility in menu design. The major data base in the system is the Master Menu File, which is updated using real-time processing. This file contains data about each occurrence of menu items and is interfaced with existing recipe files to produce numerous printed documents and to display the menu on a video display terminal. The major benefits of the system are flexibility and elimination of typing of worksheets. Entering a new menu or changes to the menu require only a brief amount of time; new revised documents relative to the menu can be generated on the same day. Some of the types of documents available from this system are: master menu, nutrient syllabi, menu audit, and food production forms. The menu is available on-line at all times for reference by dietitians and supervisors. The Master Menu File will be utilized more fully as new modules are designed to interface with the Menu Management System. Production forecasting, patient menu printing, and individualized diet planning are three potential enhancements to the system which will utilize data in the Master Menu File. The file was designed to accommodate additional data as the system in further matured.

Improvement of wheat protein quality and quantity by breeding.

Substantial genetic, variability for grain protein content in wheat has been identified. In appropriate combinations known genes can increase protein content of wheat grain by 5 percentage points. Productive high protein experimental lines with good agronomic traits and satisfactory processing attributes have been identified. A high protein hard red winter variety developed in Nebraska was released for commercial production in 1975 under the name "Lancota". The high protein of Lancota resides entirely in the starchy endosperm portion of the kernel and is fully transmissible to white milled flour. The high protein of Lancota results from elevated NO3 reductase activity, increased N-absorption by the roots, and more complete translocation of N to the grain. Despite strong environmental influence on wheat protein level, genes for high protein have been demonstrated to effectively increase protein content in many different production environments. Lysine % of protein decreases but lysine % of grain increases as protein is increased. Genetic variability for lysine of sufficient magnitude to overcome the normal depression of lysine % of protein as protein is increased has been uncovered. Experimental lines have been developed in the ARS-Nebraska program in which genes for high protein and high lysine were combined. The lines have been widely distributed for use in other breeding programs.

Comparative protein quality as measured by human and small animal bioassays of three lines of winter wheat.

Incomplete information on factors contributing to apparent protein quality and to value of food products as sources of protein and how these factors interact necessitate the use of bioassay procedures. Ideally bioassay procedures should be done using the animal species for which the protein is intended. Practical considerations dictate the use of small animal bioassay rather than human bioassays for routine use in protein product evaluation. To be of real value for routine use in protein product evaluation. To be of real value for assays of food products designed for human use, animal bioassays must accurately predict human performance. Surprisingly little information is available on this topic. In the current project three Nebraska winter wheats of similar genetic backgrounds were evaluated for protein value and for value of the wheats as sources of proteins. Chemical, weanling mouse, adult human and growing human bioassay techniques were employed. Rankings of the grains were similar regardless of species used for protein quality evaluations. Similar rankings were found regardless of species used for protein quality/quantity evaluations. However, ranking varied between methods designed to evaluate protein quality and those designed to measure protein quality/quantity interrelationships. The results stress the importance of matching appropriate methodology with information desired. In a latter project, wheats of dissimilar genetic background were not as uniformily evaluated. This suggests that other factors known to affect protein quality and value were more variable in these wheats.

How rural physicians compare on cost and quality measures for Medicaid ambulatory care episodes.

This study compares the costs and quality of episodes of care for two common childhood illnesses, urinary tract infections (UTI) and otitis media (OM), across providers practicing in rural, small town, and urban counties in Alabama in 1992. The data source is Medicaid claims data for children under age 8 who were treated for these conditions. The study found that episodes cared for by rural providers were less expensive than episodes cared for in other locations, both because fewer rural episodes included outpatient facility charges and because fewer ancillary services were provided in rural settings. Researchers also found that, even controlling for physician characteristics and patient demographic and utilization factors, rural episodes were significantly less likely to include two process measures of quality of care: fewer rural UTI episodes included urine cultures, and fewer rural OM episodes included follow-up visits. This study suggest that, as a group, rural physicians may have a favorable cost profile but a potentially unfavorable care content profile, compared with other physicians. Both practice profile data and explicit care recommendations need to be available to physicians so thy can monitor, defend, or alter their clinical practices.

Impact of care setting on cost and quality under Medicaid.

Medicaid claims data were used to compare the costs and care quality of ambulatory visits for two childhood illnesses, urinary tract infection (UTI) and suppurative otitis media (OM), in the fee-for-service Medicaid program in Alabama across three care settings: offices where patients had been seen before, offices where patients had not been seen before, and outpatient hospital departments. Forty percent of UTI visits and 46 percent of OM visits occurred in return office settings. Visits to outpatient hospital and first-time office settings were more expensive than those to return office settings, due to the billing of facility fees and the provision of additional services. Adherence to common measures of quality of care for both types of visits was low; 52 percent of UTI visits included urine cultures and 40 percent of OM visits included recheck visits. Adherence to these quality measures was significantly lower in visits occurring in hospital settings.