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Biomedical subjects

David J Wright

Publications and source records attributed to David J Wright.

At least 19 recordsLinked to original sources
PubMed2004

Increased mortality associated with HTLV-II infection in blood donors: a prospective cohort study.

BACKGROUND: HTLV-I is associated with adult T-cell leukemia, and both HTLV-I and -II are associated with HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Several published reports suggest that HTLV-I may lead to decreased survival, but HTLV-II has not previously been associated with mortality. RESULTS: We examined deaths among 138 HTLV-I, 358 HTLV-II, and 759 uninfected controls enrolled in a prospective cohort study of U.S. blood donors followed biannually since 1992. Proportional hazards models yielded hazard ratios (HRs) for the association between mortality and HTLV infection, controlling for sex, race/ethnicity, age, income, educational level, blood center, smoking, injection drug use history, alcohol intake, hepatitis C status and autologous donation. After a median follow-up of 8.6 years, there were 45 confirmed subject deaths. HTLV-I infection did not convey a statistically significant excess risk of mortality (unadjusted HR 1.9, 95%CI 0.8-4.4; adjusted HR 1.9, 95%CI 0.8-4.6). HTLV-II was associated with death in both the unadjusted model (HR 2.8, 95%CI 1.5-5.5) and in the adjusted model (HR 2.3, 95%CI 1.1-4.9). No single cause of death appeared responsible for the HTLV-II effect. CONCLUSIONS: After adjusting for known and potential confounders, HTLV-II infection is associated with increased mortality among healthy blood donors. If replicated in other cohorts, this finding has implications for both HTLV pathogenesis and counseling of infected persons.

Blood Donors↗
PubMed2004

How special is a 'special' interval: modeling departure from length-biased sampling in renewal processes.

Length-biased sampling occurs in renewal processes when the probability that an interval is selected is proportional to the length of the interval. This can occur when intervals are selected because they contain an event that is independent of the renewal process and occurs with constant hazard. For example, if the times between donations for repeat blood donors are independent and identically distributed, and if the donor seroconverts to HIV (develops antibodies that indicate infection with human immunodeficiency virus), then the interval between the last HIV seronegative and first HIV seropositive test is expected to be longer than that donor's previous time intervals between donations. We develop hypothesis tests to determine if the relationship between the typical and length-biased intervals is as expected, or if there is departure from length-biased sampling. We further develop a regression method to determine if there are covariates that explain the departure from length-biased sampling. Our approach is motivated by the question of whether there is evidence that repeat blood donors who develop antibodies to HIV or other viral infections change their donation pattern in some way because of seroconversion.

Blood Donors↗
PubMed2003

Dynamics of HIV viremia and antibody seroconversion in plasma donors: implications for diagnosis and staging of primary HIV infection.

OBJECTIVES: The characterization of primary HIV infection by the analysis of serial plasma samples from newly infected persons using multiple standard viral assays. DESIGN: A retrospective study involving two sets of archived samples from HIV-infected plasma donors. (A) 435 samples from 51 donors detected by anti-HIV enzyme immunoassays donated during 1984-1994; (B) 145 specimens from 44 donors detected by p24 antigen screening donated during 1996-1998. SETTING: Two US plasma products companies. MAIN OUTCOME MEASURES: The timepoints of appearance of HIV-1 markers and viral load concentrations during primary HIV infection. RESULTS: The pattern of sequential emergence of viral markers in the 'A' panels was highly consistent, allowing the definition and estimation of the duration of six sequential stages. From the 'B' panels, the viral load at p24 antigen seroconversion was estimated by regression analysis at 10 000 copies/ml (95% CI 2000-93 000) and the HIV replication rate at 0.35 log copies/ml/day, corresponding to a doubling time in the preseroconversion phase of 20.5 h (95% CI 18.2-23.4 h). Consequently, an RNA test with 50 copies/ml sensitivity would detect HIV infection approximately 7 days before a p24 antigen test, and 12 days before a sensitive anti-HIV test. CONCLUSION: The sequential emergence of assay reactivity allows the classification of primary HIV-1 infection into distinct laboratory stages, which may facilitate the diagnosis of recent infection and stratification of patients enrolled in clinical trials. Quantitative analysis of preseroconversion replication rates of HIV is useful for projecting the yield and predictive value of assays targeting primary HIV infection.

Biomarkers↗
PubMed2003

Effect of a national disaster on blood supply and safety: the September 11 experience.

CONTEXT: An understanding of characteristics of blood donors donating in times of crisis may help predict blood supply safety and donor return patterns. OBJECTIVES: To characterize the volume of donations and prevalence of infectious disease markers in blood donated by US donors responding to the September 11, 2001, terrorist attacks, and to evaluate return rates in those who donated for the first time. DESIGN: Cross-sectional survey data from the National Heart, Lung, and Blood Institute Retrovirus Epidemiology Donor Study for 4 weeks before and 4 weeks starting with September 11, 2001, and the corresponding 8-week period in 2000. SETTING AND PARTICIPANTS: A total of 327065 volunteer blood donors making 373628 allogeneic donations at 5 large regional US blood centers. MAIN OUTCOME MEASURES: Changes in number of donations overall and by first-time and repeat status, prevalence of infectious disease markers, estimated risks of transfusion-transmitted viral infections, and first-time donor return rates. RESULTS: About 20000 allogeneic donations were collected weekly in the 4 weeks preceding September 11, whereas approximately 49 000 (2.5-fold increase) and approximately 26000 to 28000 (1.3-fold to 1.4-fold increases) donations were made per week in the first and in the second through fourth weeks starting with September 11, respectively. All demographic groups donated more than usual after the attacks, and after adjusting for seasonal and annual variation there was a 5.2-fold (95% confidence interval, 5.0-5.4) increase in the number of first-time donations vs a 1.5-fold (1.4-1.5) increase in the number of repeat donations made in the first week starting on September 11 vs the 4 weeks before. The weekly proportion of repeat donors returning after not donating for 10 or more years increased from 2% before September 11 to 6% in the first week starting with September 11. Donations confirmed positive for human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B surface antigen nearly tripled between 1 week before September 11 (0.1%) and 1 week after the attacks (0.3%), largely explained by the increase in first-time and lapsed repeat donors. Estimated viral residual risks increased slightly after the attacks (HIV, 1/1.5 million vs 1/1.8 million donations; HCV, 1/1.3 million vs 1/1.6 million; hepatitis B virus, 1/140000 vs 1/170000). First-time donor 12-month return rates for 2000 and 2001 were similar, approximately 28% (P =.37) for donors in the first week starting with September 11 (or September 12, 2000) and 30% (P =.69) for the second to fourth weeks. CONCLUSIONS: The September 11 events resulted in an influx of first-time donors without substantial increase in absolute risk of transfusion-transmissible viral infections. First-time donor return rates were equally relatively low before and after the attacks, suggesting that those donating in times of crisis have return behaviors similar to those of other first-time donors. Their relatively low return rates reinforce the need for education about the importance of donating regularly.

Blood Banks↗
PubMed2003

Development, implementation and cost-effectiveness of a protocol for review of combination diuretic prescribing.

AIMS: To determine the extent of inappropriate prescribing of combination diuretics and the cost implications of protocol implementation. METHODS: Pharmacist-run medication review clinics in two general practices in Bradford, UK. RESULTS: Sixty-one patients, mean +/- s.d. age 75.8 +/- 12.0 years, were reviewed. Thirty-six met protocol criteria; 30 (49.2%) patients had their potassium-sparing diuretics (PSDs) discontinued. Mean (95% confidence interval) reduction in serum potassium concentrations after intervention in these 30 patients was 0.26 (0.09, 0.43) mmol l(-1) (P < 0.01). Twenty-eight (93.3%) patients were within the reference range at follow-up; none was below. CONCLUSIONS: Of prescribed PSDs, 59% were found to be unnecessary. Using the developed protocol potentially improves drug safety and enables cost savings.

Adult↗
PubMed2003

Lapsed donors: an untapped resource.

BACKGROUND: There is a clear need for methods to recruit and retain donors without compromising blood safety. Although prior studies report lower viral prevalence rates in repeat donors than those in first-time donors, it is unknown if this relationship holds after a lapse of several years between donations. STUDY DESIGN AND METHODS: A total of 6.4 million allogeneic donations collected at five US blood centers from 1991 through 1998 were classified by donation history (first-time vs. repeat) and by length of time between donations (lapsed interval length). The prevalence of HCV, HIV, and HBsAg was compared by donation history and lapsed interval length. The relationship between lapsed interval length and donor demographics was explored. RESULTS: Repeat donors who delayed their return for over 5 years were significantly less likely to test positive for a viral infection than were first-time donors. The likelihood of a positive test result appeared to increase steadily with lapsed interval length for HCV and HBsAg, but not for HIV. Younger, less educated, and nonwhite donors were less likely to return than others. CONCLUSIONS: Recruitment of donors who have not returned for several years could be an effective way to increase the blood supply while preserving blood safety. Understanding the relationship of donor demographics to return behavior is important for recruitment efforts.

Adult↗
PubMed2003

Impact of changes in viral marker screening assays.

BACKGROUND: Monitoring the performance of routinely used infectious disease serologic tests is necessary to evaluate their effectiveness in identifying true-positive units and erroneously disqualifying safe blood donors. METHODS: With two large screening test data sets collected between 1991 and 1998 and between 1997 and 2000, the impact of changes in screening assays for HIV, HCV, and HBsAg was analyzed with regard to the prevalence of confirmed-positive, indeterminate, and confirmed-negative results and the deferral of donors with an indeterminate or negative results (donor loss). RESULTS: The prevalence of indeterminate results and donors loss increased significantly in the 6 months after introduction of an HIV-1/2 EIA. A second-generation HCV EIA increased the detection of confirmed-positive donations in repeat donors (p < 0.001) and increased the prevalence of indeterminate donations. Implementation of a third-generation HCV EIA resulted in a significant decrease in indeterminate results in first-time donors. Nonspecific test results increased when HBsAg test kits from a different manufacturer were introduced or different lots of HIV antibody screening test kits from the same manufacturer were used. CONCLUSION: Introduction of newly licensed versions of assays, switching kit manufacturers, and lot-to-lot variations have an impact on rates of deferrals of safe donors as well as sensitivity of routine screening. Before considering changes in screening tests, blood centers should be aware of, and evaluate, the potential impact on donor loss.

Antigens, Viral↗
PubMed2003

Increasing blood availability by changing donation patterns.

BACKGROUND: There is a declining margin between US blood collections and transfusions. Donation patterns were examined to characterize returning first-time donors and predict the impact on blood availability of decreasing the number of nonreturning donors. STUDY DESIGN AND METHODS: First-time donors giving between 1991 and 1994 were followed for 3 to 6 years. The impact of decreasing the number of nonreturning donors in a 12-month period was projected using the Poisson distribution to model the donation patterns of 539,063 donors who gave in 1995. Repeat donors were classified as "returning first-time" (gave a first-time donation within 12 months of their index donation), "established" (gave a repeat donation), and "inactive" (didn't donate in the 12 months before their index donation). RESULTS: A total of 49 percent of first-time donors did not return within 6 years. Returning first-time donors tended to be US born, white, and had more than a high school education. In 1995, 30 percent of donors were first time, 31 percent were established, 7 percent were returning first time, and 32 percent were inactive, giving 1.5, 2.4, 1.9, and 1.7 donations in 12 months, respectively. Reducing nonreturning donors by 5 percent could increase blood collections by 2.7 percent. Similarly, 15 or 25 percent reductions in nonreturns could increase collections by 8.6 or 16.0 percent, respectively. CONCLUSIONS: Most donors are not giving near the donation limit. A substantial increase in donations could be achieved by a relatively small decrease in donor nonreturn. Research is needed to understand why approximately half of first-time donors donate only once.

Behavior↗
PubMed2003

Comparative sensitivity of HBV NATs and HBsAg assays for detection of acute HBV infection.

BACKGROUND: A study was designed to estimate relative analytic sensitivity and window-period (WP) closure and to project incremental yield of newer HBsAg tests, pooled-sample NAT, and single-sample NAT, compared to currently licensed HBsAg tests. STUDY DESIGN AND METHODS: HBV DNA and HBsAg test results for 23 HBV seroconversion (SC) panels were first analyzed to construct a model of primary HBV viremia. One-hundred representative samples were then selected from 10 panels and coded with 28 analytical controls. All 128 samples were tested by seven HBsAg tests and by four pooled-sample and three single-sample NAT assay formats. Results were analyzed to obtain differential times to HBV detection and combined with HBV incidence rates to project comparative yields. RESULTS: HBV doubling time during the ramp-up phase was estimated at 2.56 days. HBsAg concentrations at cutoff for new tests ranged from 0.07 to 0.12 ng per mL, compared with 0.13 to 0.62 ng per mL for licensed tests. Estimated viral load at cutoff ranged from 102 to 267 IU per mL for new tests and from 363 to 1069 IU per mL for licensed tests. HBsAg tests detected 31 to 63 percent of early ramp-up phase samples in the 100-member seroconversion panel study, while pooled-sample NAT detected 55 to 71 percent and single-sample NAT, 82 to 99 percent. Compared with currently licensed HBsAg assays, newer HBsAg assays would reduce the WP by 2 to 9 days; pooled-sample NAT would reduce the WP by 9 to 11 days; and single-sample NAT would reduce the WP by 25 to 36 days. CONCLUSION: Newer HBsAg tests would be expected to detect an additional 15 to 21 infected units per 107 donations, compared to licensed HBsAg tests. Sensitivity, WP closure, and yield projections for newer HBsAg assays and pooled-sample NAT are comparable. Single-sample NAT would increase yield by 13 to 15 units per 107 donations over pooled-sample NAT and newer HBsAg assays and by 35 to 50 units per 107 donations over currently licensed HBsAg assays.

Acute Disease↗
PubMed2003

DNA sequencing using rolling circle amplification and precision glass syringes in a high-throughput liquid handling system.

An automated high-throughput method that employs rolling circle amplification (RCA) to generate template for large-scale DNA sequencing has been developed using liquid handling systems equipped with precision glass syringes. A protocol was designed to perform the sequencing analysis from template preparation to thermal cycle sequencing within the same vessel, thus minimizing the amount of liquid handling and transfer. The amplified DNA was directly used for cycle sequencing with no need for any purification procedures. Total RCA reaction volumes as low as 500 nL generated sufficient templates for successful sequencing. Reducing the RCA total reaction volumes by a 40-fold factor, from a total of 20 microL to 500 nL, resulted in a significant reduction in cost, from $1.25/reaction to less than $0.04/reaction. Additionally, the volume of the sequencing reactions was reduced from a total of 20 to 10 microL, thus generating a further cost advantage. This high-throughput DNA sequencing protocol maximizes the speed and precision of processing while significantly reducing the cost of amplification.

Algorithms↗
PubMed2002

DNA topoisomerase II is essential for preimplantation mouse development.

Topoisomerase II (topo II) is an essential enzyme that alters DNA topology. This activity is important for a variety of chromosome functions including DNA replication, transcription, recombination, and chromosome condensation and segregation. Previously we localized topo II in mouse gametes and preimplantation embryos using isoform-specific antibodies demonstrating the presence of the enzyme in oocytes and embryos, but not sperm. To probe functions of topo II during preimplantation development, we treated mouse zygotes with 100 nM teniposide, and assessed embryo morphology and DNA replication. Teniposide blocked cleavage in 69% embryos; the remainder cleaved once but had abnormal nuclei. Teniposide-treated embryos were devoid of topo II immunofluorescence. Teniposide also prevented DNA replication, implicating topo II in this process. Embryos treated with a 2 hr pulse of teniposide recovered and developed to the blastocyst stage, indicating 100 nM teniposide did not induce apoptosis. To more specifically analyze topo IIalpha function, we treated zygotes with topo IIalpha-targeted antisense oligodeoxynucleotides. Most zygotes arrested at the 2-cell stage while controls developed into blastocysts indicating topo IIalpha is essential for preimplantation development. The absence of topo IIalpha, but not beta immunofluorescence in antisense-treated embryos confirms the specificity and impact of the treatment. In addition, topo IIalpha is newly synthesized at the 2-cell stage. These results establish an essential function for topo II in mouse preimplantation embryonic development.

Animals↗
PubMed2002

DNA topoisomerase II distribution in mouse preimplantation embryos.

DNA topoisomerase II (topo II) is an essential enzyme that mediates a variety of chromosome activities including DNA replication, transcription, recombination, and chromosome condensation and segregation. Isoform-specific anti-topo II antibodies were used to determine the distribution of topo II alpha and beta in mouse gametes and embryos. Immunoblot analysis with two anti-topo IIalpha antibodies revealed that a 170 kDa topo IIalpha band was present in ovary and testis. Mature sperm exhibited an 89 kDa band only, which may be a degradation product of topo IIalpha. Immunoblots probed with a monoclonal antibody that recognizes both isoforms, showed bands at 170 and 180 kDa, which correspond to topo IIalpha and beta, respectively. An additional 100 kDa band was also present in ovary and testis. Mature sperm did not exhibit staining with this antibody. We also localized topo II in mouse gametes and embryos up to the blastocyst stage using immunofluorescence microscopy. While both isoforms were found in nuclei and nucleoli of germinal vesicle oocytes, topo IIalpha localized to metaphase chromosomes during meiosis, and only to nucleoli during embryonic interphase. Topo IIbeta was absent from chromosomes of metaphase II oocytes, but localized to embryonic interphase nuclei. Both full-length isoforms were absent from sperm, indicating topo II is stored maternally. These results identify topo II as an important component of mouse oocyte and embryonic chromatin, and suggest its involvement in oocyte maturation and preimplantation embryonic development. The different immunofluorescent staining patterns indicate topo IIalpha and beta may serve different roles during the embryonic cell cycle.

Animals↗
PubMed2002

Pharmacoeconomic evaluation of a patient education letter aimed at reducing long-term prescribing of benzodiazepines.

OBJECTIVE: To determine the economic implications of sending an educational letter to patients, aimed at reducing long-term BDZ prescribing. METHOD: Letters were sent to 242 patients from 2 general medical practices. BDZ usage and costs were compared in the years before and after intervention using numbers of defined daily dosages (DDDs) prescribed. The cost of intervention implementation was estimated using pharmacist, GP and administrative staff time, plus postage costs. MAIN OUTCOME MEASURES: Number of BDZ DDDs prescribed during the 12-month periods before and after intervention. The cost implications of intervention. RESULTS: Mean patient age was 67 years, 75% were female and the mean duration of BDZ usage was 19 years. A mean of 337 benzodiazepine DDDs per patient were prescribed during the baseline year. Overall BDZ usage at baseline was increasing by 13%. After receiving the letter, 31% of patients discussed BDZ usage with their GP and 10% had their drug or strength changed. During the year after intervention, a significant reduction of 17% in benzodiazepine usage was observed compared to baseline; 5% of patients ordered no more benzodiazepine prescriptions after receiving the letter. Mean BDZ costs reduced by 1.20 Pounds per patient after intervention. The cost of intervention implementation was 5.54 Pounds per patient, giving a net cost of 4.34 Pounds per patient, or 86.80 Pounds to obtain one BDZ discontinuation. CONCLUSION: This intervention is effective, simple, and inexpensive. Its minimal cost could be justified given the morbidity associated with the long-term prescribing of benzodiazepines, particularly in the elderly.

Adult↗
PubMedDate not supplied

An assessment of a multiplex PCR assay for differentiating clinically important mycobacteria based on pncA gene variation.

The pncA genes in mycobacteria are responsible for the production of pyrazinamidase (PZase). In Mycobacterium tuberculosis, PZase hydrolyses pyrazinamide (PZA) to pyrazonic acid, a compound that possesses bactericidal activity against tubercle bacilli. Nucleotide sequences of pncA genes found within mycobacteria where aligned in an effort to ascertain the significance of any variability in sequence. Three sets of primers (one degenerate and five consensus sequences) were designed and employed in a multiplex PCR assay to amplify the pncA region in seven clinically common mycobacteria. The banding patterns generated from each species in conjunction with PZase activity tests demonstrated that the mycobacterial species examined could be clearly identified and differentiated from one another. Although not yet tested with clinical isolates, the combination of these two assays has provided a promising discriminatory tool for the identification of commonly encountered clinical mycobacteria species.

Amidohydrolases↗