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Biomedical subjects

J M Raboud

Publications and source records attributed to J M Raboud.

At least 19 recordsLinked to original sources

Assay of HIV gp41 amino acid sequence to identify baseline variation and mutation development in patients with virologic failure on enfuvirtide.

In this study, we retrospectively assessed a gp41 genotypic assay in 404 enfuvirtide-naïve individuals (340 clade B, 64 non-B clade) to determine the prevalence of baseline polymorphisms and in 41 patients virologically failing enfuvirtide to determine correlates of resistance to this agent. Conserved and polymorphic regions of gp41 were identified in clade B isolates, with 127 of 328 codons (38.7%) being highly conserved (<1.0% variation) and 74 of 328 codons (22.6%) being partially conserved (1.0-5.0% variation). Polymorphisms were observed throughout gp41 in non-B clade virus sequences compared to the clade B reference strain, ranging from 53 natural substitutions in clade D to 76 in clade A. Insertions were common at positions 3, 105, 215 and 276. In the patients failing enfuvirtide, mutations were detected in the 10 amino acid region at positions 36-45 in all plasma virus sequences. Six additional mutations were selected outside of the common region which may be clinically significant at positions 33, 73, 75, 126, and 138. Two or three mutations at positions 36-45 were observed in the majority of plasma virus sequences from patients with virologic failure following the use of enfuvirtide. Further study is required to determine the clinical relevance of the clade related polymorphisms and the new mutations identified in the patients with virologic failure.

Adult↗

Accuracy of healthcare worker recall and medical record review for identifying infectious exposures to hospitalized patients.

OBJECTIVE: To determine the validity of using healthcare worker (HCW) recall of patient interactions and medical record review for contact tracing in a critical care setting. DESIGN: Trained observers recorded the interactions of nurses, respiratory therapists, and service assistants with study patients in a medical-surgical intensive care unit. These observers' records were used as the reference standard to test the criterion validity of using HCW recall data or medical record review data to identify exposure characteristics. We assessed the effects of previous quarantine of the HCW (because of possible exposure) and the availability of patients' medical records for use as memory aids on the accuracy of HCW recall. SETTING: A 10-bed medical-surgical intensive care unit at Mount Sinai Hospital in Toronto, Ontario. PATIENTS: Thirty-six HCWs observed caring for 16 patients, for a total of 55 healthcare worker shifts. RESULTS: Recall accuracy was better among HCWs who were provided with patient medical records as memory aids (P<.01). However, HCWs tended to overestimate exposures when they used patient medical records as memory aids. For 6 of 26 procedures or care activities, this tendency to overestimate was statistically significant (P<.05). Most HCWs with true exposures were identified by means of this technique, despite the overestimations. Documentation of the activities of the 4 service assistants could not be found in any of the patients' medical records. Similarly, the interactions between 6 (19%) of 32 other patient-HCW pairs were not recorded in patients' medical records. CONCLUSIONS: Data collected from follow-up interviews with HCWs in which they are provided with patient medical records as memory aids should be adequate for contact tracing and for determining exposure histories. Neither follow-up interviews nor medical record review alone provide sufficient data for these purposes.

Disease Transmission, Infectious↗

Preventing type 2 diabetes using combination therapy: design and methods of the CAnadian Normoglycaemia Outcomes Evaluation (CANOE) trial.

Several studies have demonstrated that type 2 diabetes mellitus (DM) can be prevented/delayed in subjects with impaired glucose tolerance (IGT) by using pharmacologic agents and/or lifestyle interventions. However, a number of challenges remain, including the translation of lifestyle programmes to the general population and the need to achieve greater risk reductions by using pharmacologic approaches. IGT, like DM, is characterized by insulin resistance, beta-cell dysfunction and increased hepatic glucose production. We believe that the use of combination diabetes therapy would be a particularly effective diabetes prevention strategy. In this context, we initiated the Canadian Normoglycemia Outcomes Evaluation (CANOE) study, a moderately sized, randomized, double-blind, controlled trial. The primary objective of CANOE is to determine whether treatment with metformin plus rosiglitazone, in addition to a healthy living lifestyle programme, will prevent the development of DM. The secondary objective of CANOE is to determine whether this treatment approach will improve cardiovascular risk factors associated with IGT. A total of 200 patients will be recruited in Toronto and London, Ontario, and followed for an average of 4 years (range 3-5 years). Active treatment with metformin (500 mg) plus rosiglitazone (2 mg), administered as one capsule twice daily, will be compared to matched placebo. Subjects will be eligible for randomization if they have IGT and are between the ages of 30-75 years. The primary outcome will be the development of new-onset DM, diagnosed by either two fasting plasma glucose values of >or=7 mmol/l or one positive oral glucose tolerance test with a 2-h plasma glucose value of >11.0 mmol/l during the active drug phase of the trial. With a sample size of 100 participants per group, we will be able to detect a relative risk reduction of 45%, with a two-sided log-rank test with a significance level of 0.05 and 80% power, assuming that the median time to progression is 8 years in the control group and that participants will be recruited over 2 years and followed for an average of 4 years. In conclusion, the CANOE study will determine whether combination pharmacological therapy combined with a lifestyle intervention programme can significantly modify the development of diabetes in high-risk Canadians.

Combined Modality Therapy↗

The impact of needle-exchange programs on the spread of HIV among injection drug users: a simulation study.

OBJECTIVE: To determine the impact of the implementation of a needle-exchange program (NEP) on the spread of human immunodeficiency virus (HIV) in an injection drug user (IDU) community. We conducted a Monte Carlo simulation study of a theoretical population of 10000 IDUs. The population was followed monthly from 1984 to 2000. HIV was assumed to be transmitted only by needle sharing. The NEP was introduced in 1989 and evaluated over a period of 11 years. The impacts of the proportion of the population attending the NEP, the risk level of IDUs attending the NEP, the reduction in needle-sharing frequency, and the number of new needle-sharing partners acquired at the NEP on prevalence and incidence of HIV were determined. Increasing the proportion of the population who always attend the NEP and eliminating needle-sharing incidents among IDUs who always attended the NEP were the most effective ways of reducing the spread of HIV. Attracting high-risk users instead of lower risk users to the NEP also reduced the spread of HIV, but to a lesser extent. NEPs are effective at reducing the spread of HIV; even under the worst case scenario of low risk users more likely to attend the NEP, one additional partner per month as a result of attending the NEP, and poor NEP attendance, the estimated prevalence was still less than that from the scenario without an NEP. Under our model, NEPs were shown to reduce the spread of HIV significantly. Efforts should be focused on getting as many IDUs as possible to become regular NEP attenders and stop sharing needles rather than partially reducing the frequency of sharing by a larger number of IDUs.

British Columbia↗

Impact of adherence on duration of virological suppression among patients receiving combination antiretroviral therapy.

OBJECTIVE: To assess the effect of adherence to antiretroviral therapy on the duration of virological suppression after controlling for whether or not the patient ever attained a plasma viral load below the limit of detection of sensitive HIV-1 RNA assays. METHODS: Data were combined from three randomized, blinded clinical trials (INCAS, AVANTI-2, and AVANTI-3) that compared the antiviral effects of two- and three-drug antiretroviral regimens. Virological suppression was defined as maintaining a plasma viral load below 1000 copies/mL. Adherence was defined prospectively and measured by patient self-report. RESULTS: Adherence did not have a major impact on the probability of achieving virological suppression for patients receiving dual therapy. However, for patients receiving triple therapy, adherence increased the probability of virological suppression, whether the plasma viral load nadir was above or below the lower limit of quantification. Compared to adherent patients with a plasma viral load nadir below the lower limit of quantification, the relative risk of virological failure was 3.0 for non-adherent patients with a nadir below the limit, 18.1 for adherent patients with a nadir above the limit, and 32.1 for non-adherent patients with a nadir above the limit. CONCLUSION: For patients receiving current three-drug antiretroviral regimens, adherence to therapy and plasma viral load nadir are important factors determining the duration of virological suppression.

Anti-HIV Agents↗

A computer model to simulate family history of breast/ovarian cancer in BRCA1 mutation carriers.

The BRCA1 gene and its relationship to family history of breast/ovarian cancer are difficult to study in a population because of practical and ethical issues. The paucity of information on BRCA1 in the general population was a major theme in a recent review of genetic testing in Canada. We develop a simulation model to mimic genetic inheritance and cancer incidence in the family of someone with a germline BRCA1 mutation. Given someone's age and family structure, our model simulates his or her family history in three steps: (1) determine which family members have the mutation, (2) determine the ages of family members and (3) determine which family members have breast/ovarian cancer. Each step involves random variation. Some parameters in our model are estimated using local (British Columbia, Canada) population data. The breast/ovarian cancer risk associated with BRCA1 mutations is estimated using values published in the literature. An example is provided to illustrate the model's application. The model incorporates results from genetics, demography and epidemiology, but requires several additional assumptions. Research to address these assumptions is recommended.

Adult↗

Predicting HIV RNA virologic outcome at 52-weeks follow-up in antiretroviral clinical trials. The INCAS and AVANTI Study Groups.

OBJECTIVE: To determine the ability of intermediate plasma viral load (pVL) measurements to predict virologic outcome at 52 weeks of follow-up in clinical trials of antiretroviral therapy. METHODS: Individual patient data from three clinical trials (INCAS, AVANTI-2 and AVANTI-3) were combined into a single database. Virologic success was defined to be plasma viral load (pVL) <500 copies/ml at week 52. The sensitivity and specificity of intermediate pVL measurements below the limit of detection, 100, 500, 1000, and 5000 copies/ml to predict virologic success were calculated. RESULTS: The sensitivity, specificity, and positive and negative predictive values of a pVL measurement <1000 copies/ml at week 16 to predict virologic outcome at week 52 were 74%, 74%, 48%, and 90%, respectively, for patients on double therapy. For patients on triple therapy, the sensitivity, specificity, and positive and negative predictive values of a pVL measurement <50 copies/ml at week 16 to predict virologic outcome were 68%, 68%, 80%, and 47%, respectively. CONCLUSIONS: For patients receiving double therapy, a poor virologic result at an intermediate week of follow-up is a strong indicator of virologic failure at 52 weeks whereas intermediate virologic success is no guarantee of success at 1 year. For patients on triple therapy, disappointing intermediate results do not preclude virologic success at 1 year and intermediate successes are more likely to be sustained.

Anti-HIV Agents↗

Human immunodeficiency virus-infected persons with mutations conferring resistance to zidovudine show reduced virologic responses to hydroxyurea and stavudine-lamivudine.

The baseline predictors of poor virologic response (<0.5 log decrease in plasma virus load) were examined in two 1996 pilot trials of combination nucleoside-analogue therapy. One trial examined the addition of hydroxyurea to didanosine therapy; the other examined stavudine-lamivudine in combination. In both, predictors of virologic response included the presence of mutations associated with zidovudine resistance. For hydroxyurea, the odds ratio (OR) of failure to achieve a short-term (4 weeks) virologic response in a bivariate logistic regression model was 30.8 (95% confidence interval [CI], 1.75-543; P=.02) for use of lower dose hydroxyurea (500 mg/day) and 14.7 (95% CI, 1.1-200; P=.04) for the presence of a zidovudine-related mutation. For the stavudine-lamivudine study, the OR of failure to achieve a virologic response at 4 weeks in a multivariate logistic regression model was 23 (95% CI, 2.7-199; P=.004) for the presence of a mutation at codon 215.

Anti-HIV Agents↗

Can pooling be used for seroprevalence studies of hepatitis C?

Two hepatitis C antibody assays were used to test diluted positive sera. Dilutions of 1 in 5, 1 in 10, and 1 in 20 all resulted in loss of reactivity, with the greatest losses occurring in samples with low and moderate reactivities. These results disqualify pooling as a strategy for seroprevalence studies and screening programs.

Blood Specimen Collection↗

Symptomatic and health status outcomes in the Canadian randomized MAC treatment trial (CTN010). Canadian HIV Trials Network Protocol 010 Study Group.

Our objective was to compare the effect of 2 regimens for treatment of Mycobacterium avium complex (MAC) bacteraemia in an HIV-positive population on symptoms and health status outcomes using a substudy of an open-label randomized controlled trial. The study was conducted in 24 hospital-based human immunodeficiency virus (HIV) clinics in 16 Canadian cities. Patients had HIV infection and MAC bacteraemia and were given either rifampin 600 mg, ethambutol 15 mg/kg daily, clofazimine 100 mg daily and ciprofloxacin 750 mg twice daily (4-drug arm) or rifabutin 600 mg daily (amended to 300 mg daily in mid-trial), ethambutol 15 mg/kg daily and clarithromycin 1000 mg twice daily (3-drug arm). The primary health status outcome was the change on the 8-item symptom subscale of the Medical Outcome Study (MOS)-HIV Health Survey adapted for MAC. Changes on other MOS-HIV subscales and on the Karnofsky score were also evaluated. Patients on the 3-drug arm had better outcomes on the MOS-HIV symptom subscale at 16 weeks (P=0.06), with statistically significant differences restricted to night sweats and fever and chills (P < 0.001). The proportion of patients improving on the symptom subscale relative to baseline was 55% on the 3-drug arm and 40% on the 4-drug arm. Patients on the 3-drug arm also had better Karnofsky score at 16 weeks (P < 0.001) and better outcomes on the social function, mental health, energy/fatigue, health distress and cognitive function subscales of the MOS-HIV. The 3-drug arm is superior to the 4-drug arm in terms of impact on MAC-associated symptoms, functional status and other aspects of health status.

AIDS-Related Opportunistic Infections↗

Violence in the emergency department: a survey of health care workers.

BACKGROUND: Violence in the workplace is an ill-defined and underreported concern for health care workers. The objectives of this study were to examine perceived levels of violence in the emergency department, to obtain health care workers' definitions of violence, to determine the effect of violence on health care workers and to determine coping mechanisms and potential preventive strategies. METHODS: A retrospective written survey of all 163 emergency department employees working in 1996 at an urban inner-city tertiary care centre in Vancouver. The survey elicited demographic information, personal definition of violence, severity of violence, degree of stress as a result of violence and estimate of the number of encounters with violence in the workplace in 1996. The authors examined the effects of violence on job performance and job satisfaction, and reviewed coping and potential preventive strategies. RESULTS: Of the 163 staff, 106 (65%) completed the survey. A total of 68% (70/103) reported an increased frequency of violence over time, and 60% (64/106) reported an increased severity. Most of the respondents felt that violence included witnessing verbal abuse (76%) and witnessing physical threats or assaults (86%). Sixty respondents (57%) were physically assaulted in 1996. Overall, 51 respondents (48%) reported impaired job performance for the rest of the shift or the rest of the week after an incident of violence. Seventy-seven respondents (73%) were afraid of patients as a result of violence, almost half (49%) hid their identities from patients, and 78 (74%) had reduced job satisfaction. Over one-fourth of the respondents (27/101) took days off because of violence. Of the 18 respondents no longer working in the emergency department, 12 (67%) reported that they had left the job at least partly owing to violence. Twenty-four-hour security and a workshop on violence prevention strategies were felt to be the most useful potential interventions. Physical exercise, sleep and the company of family and friends were the most frequent coping strategies. INTERPRETATION: Violence in the emergency department is frequent and has a substantial effect on staff well-being and job satisfaction.

Adaptation, Psychological↗

Meta-analysis of two randomized controlled trials comparing combined zidovudine and didanosine therapy with combined zidovudine, didanosine, and nevirapine therapy in patients with HIV. INCAS study team.

OBJECTIVES: To extend the range of CD4 counts in which a plasma viral load nadir (pVL) <20 copies/ml was known to be predictive of the duration of virologic response. To determine whether baseline pVL is predictive of virologic response during the study periods. METHODS: A meta-analysis was conducted of the original individual patient data from two randomized controlled trials comparing zidovudine (ZDV)/didanosine (ddI) with ZDV/ddI/nevirapine (NVP). RESULTS: In total, 87 patients received ZDV/ddI and 83 received ZDV/ddI/NVP. Study subjects on triple therapy with baseline pVL <100,000 copies/ml were more likely to achieve a pVL <400 copies/ml (odds ratio [OR] = 2.49; p = .02) and <20 copies/ml (OR = 4.76; p = .001) during the trial than those with baseline pVL > 100,000 copies/ml. Among triple therapy patients, the relative risk of virologic failure was higher for patients with higher baseline pVL (rate ratio [RR] = 2.51/log10 copies/ ml; p = .01), after controlling for compliance and pVL nadir. The relative risks of virologic failure associated with pVL nadir <20 copies/ml and between 21 and 400 copies/ml were .04 (p = .0001) and .56 (p = .26), respectively, compared with patients with a pVL nadir >400 copies/ml. CONCLUSIONS: We have extended our earlier results that achieving a pVL nadir <20 copies/ml is important for maintaining virologic suppression. In particular, we have demonstrated that a pVL nadir <20 copies/ml is at least fivefold more protective against virologic failure than achieving a pVL nadir between 20 and 400 copies/ml. Baseline pVL is significantly associated with the probability of achieving and sustaining virologic suppression.

Adult↗

Suppression of plasma virus load below the detection limit of a human immunodeficiency virus kit is associated with longer virologic response than suppression below the limit of quantitation.

Suppression of human immunodeficiency virus type 1 plasma virus load (PVL) to <20 copies/mL is associated with a longer virologic response after initiation of antiretroviral therapy. The relationship between duration of virologic response and PVL nadir according to a less sensitive assay was explored. When compared with subjects with a PVL nadir >500 copies/mL, the relative risks of PVL rising above 1000 copies/mL for participants in the INCAS trial and the British Columbia Drug Treatment Program with a PVL nadir below the limit of detection (LOD) were 0.04 (95% confidence interval [CI], 0.02-0.09) and 0.06 (95% CI, 0.03-0.12), respectively. The corresponding relative risks for persons with a detectable but not quantifiable PVL nadir were 0.25 (95% CI, 0.13-0.50) and 0.54 (95% CI, 0.25-1.19). The relative risks of virologic failure associated with a PVL nadir detectable but not quantifiable and a PVL nadir below the LOD were statistically different (P<.0001) in both data sets.

Acquired Immunodeficiency Syndrome↗

Burkholderia cepacia in cystic fibrosis. Variable disease course.

Variable clinical course has been reported with the acquisition of Burkholderia cepacia in patients who have cystic fibrosis (CF). We hypothesized that the perceived worsening with B. cepacia may reflect the underlying severity of pulmonary disease at the time of acquisition. To test this hypothesis, we matched CF patients colonized with B. cepacia with CF patients not colonized with the organism. Two-year pre- and postacquisition data and long-term data were compared. Patients were matched for gender, age (+/- 1 yr), height (+/- 5 cm), weight (+/- 8 kg), percent predicted forced expiratory volume in one second (% pred FEV(1)) (+/- 10%), and pancreatic sufficiency status. Differences in rates of change pre- and postacquisition for FEV(1), FVC, weight, and frequency of intravenous courses were compared within pairs with the Wilcoxon signed rank test. Two-year and long-term survival was compared within pairs with the McNemar test. No significant differences were observed in mean annual rates of change in weight (0.33 and -0.28 kg/yr), % pred FEV(1) (-0.36 and -1.74%/yr), and percent predicted forced vital capacity (% pred FVC) (-3.80 and -2.32%/yr) between B. cepacia and control pairs in 2-yr and long-term postacquisition interval, respectively. Similar rates of change were noted for pre- to postacquisition intervals within pairs for weight (0.17 kg/yr), % pred FEV(1) (-0.16%/yr), % pred FVC (5.02 %/yr). There was a significantly higher rate of intravenous antibiotic courses in B. cepacia cases in the 2-yr and long-term postacquisition interval. Higher mortality was observed in the B. cepacia cases in the long term (p < 0.05). We conclude that colonization with B. cepacia does not necessarily adversely affect pulmonary status, but is associated with reduced long term survival. Whereas previous associations may be attributed to a propensity to colonize those who had more advanced disease, specific strain types of B. cepacia may have enhanced pathogenicity.

Adolescent↗

Estimates of the virological benefit of antiretroviral therapy are both assay- and analysis-dependent.

OBJECTIVE: To assess the potential discrepancies in reported changes in plasma viral load (PVL) depending on how values below the detection limit of the assay are handled in the data analysis phase of a randomized controlled clinical trial. DESIGN: Data from a recently completed clinical trial comparing combinations of zidovudine, didanosine and nevirapine were analysed. In this trial, PVL was measured using an assay with a lower quantification limit of 400 HIV-1 RNA copies/ml initially. All PVL values less than 500 copies/ml were retested with a more sensitive assay with a lower quantification limit of 20 copies/ml. METHODS: Several summary measures for assessing change in PVL were calculated using three different methods to adjust for PVL values less than the quantification limit of the assay. The differences between these measures were evaluated. RESULTS: We found that the magnitude of the discrepancy between summary measures used to report changes in PVL depended on the proportion of subjects with PVL less than the quantification limit of the assay, how those observations were handled in the data analysis, and the relative difference between the quantification limits of the conventional and more sensitive assay. CONCLUSION: The lack of consensus in reporting of PVL data in the literature makes the interpretation of published trial results difficult. In the absence of agreement on the most appropriate summary measure of PVL data, we recommend that all summaries include information on the quantification limit of the assay used, the proportion of observations at or below the quantification limit and how these observations were handled in the data analysis.

Analysis of Variance↗

Suppression of plasma viral load below 20 copies/ml is required to achieve a long-term response to therapy.

BACKGROUND: Current guidelines state that the goal of antiretroviral therapy for HIV-infected individuals is to suppress plasma viral load (pVL) to below 400 copies/ml. METHODS: Predictors of achieving and maintaining pVL suppression were examined in a randomized trial of combinations of zidovudine, nevirapine and didanosine in patients with CD4+ T cell counts of between 200 and 600 x 10(6) cells/l who were naive to antiretroviral therapy and AIDS-free at enrolment. RESULTS: One hundred and four patients had pVL > 500 copies/ml at baseline and a pVL nadir below 500 copies/ml. Of these, 77 patients experienced an increase in pVL above 500 copies/ml. The median number of days of pVL suppression to below 500 copies/ml was 285 (42) for patients with pVL nadir < or = (>) 20 copies/ml (P = 00.0001). The relative risk of an increase in pVL above 500 copies/ml associated with a pVL nadir below 20 copies/ml was 0.11 (P = 0.0001). The relative risks of an increase in pVL above 5000 copies/ml associated with a pVL nadir below 20 copies/ml or between 20 and 400 copies/ml were 0.05 [95% confidence interval (CI), 0.02-0.12] and 0.37 (95% CI, 0.23-0.61) respectively, compared with individuals with a pVL nadir > 400 copies/ml. Individuals with a pVL nadir < or = 20 copies/ml were at a significantly lower risk of virologic failure than individuals with a pVL nadir of between 21 and 400 copies/ml (P = 0.0001). CONCLUSIONS: Our results demonstrate that suppression of pVL below 20 copies/ml is necessary to achieve a long-term antiretroviral response. Our data support the need for a revision of current therapeutic guidelines for the management of HIV infection.

Anti-HIV Agents↗

Estimating the effect of treatment on quality of life in the presence of missing data due to drop-out and death.

Quality of life was measured in a study of two multidrug regimens for mycobacterium avium complex MAC bactaeremia using the MOS-HIV questionnaire. The effect of treatment on quality of life was estimated at each follow-up time in three ways: (1) using only the observed data, (2) after assigning the worst possible quality of life scores for individuals who died, and (3) after imputing missing scores for patients who either died or dropped out of the study. The overall quality of life scores were also compared between treatment groups with categorical generalized estimating equation models and three-dimensional graphs. Of the 179 patients included in these analyses, 84 (47%) either died or dropped out during the 16 week study period. When the quality of life scores were compared between the treatment groups with the Wilcoxon rank sum test using only the observed data, there was no significant difference between the groups at 16 weeks of follow-up. When the worst possible quality of life scores were assumed for patients who had died, both the magnitude and the statistical significance of the difference in the quality of life scores between the groups increased. Imputing missing data for patients who either dropped out or died resulted in even larger differences in quality of life between the treatment groups. We conclude that ignoring missing data due to drop-outs and death can result in an underestimation of the treatment effect and overly optimistic statements about the outcome of the participants on both treatment arms due to the selective drop-out of participants with poorer quality of life. To obtain a valid assessment of the effect of treatment on quality of life, the experience of the patients who died or dropped out of the study must be considered.

AIDS-Related Opportunistic Infections↗

Comparison of costs of strategies for measuring levels of human immunodeficiency virus type 1 RNA in plasma by using Amplicor and Ultra Direct assays.

The costs of four algorithms for monitoring plasma human immunodeficiency virus type 1 RNA were compared. For patients with strong virologic responses, the use of Ultra Direct exclusively was the cheapest strategy. For patients with weak virologic responses, small savings could be obtained by using Amplicor and retesting only samples with values below 500 copies/ml with Ultra Direct.

Algorithms↗