Distribution and determinants of QRS rotation of black and white persons in the general population.

BACKGROUND: The prevalence and determinants of QRS transition zones are not well established. METHODS: We examined the distributions of Normal, clockwise (CW) and counterclockwise (CCW)) QRS transition zones and their relations to disease, body size and demographics in 4624 black and white men and women free of cardiovascular disease and major ECG abnormalities enrolled in the NHANES-III survey. RESULTS: CW transition zones were least observed (6.2%) and CCW were most prevalent (60.1%) with Normal in an intermediate position (33.7%). In multivariable logistic regression analysis, the adjusted, significant predictors for CCW compared to Normal were a greater proportion of blacks and women, fewer thin people (BMI<20, thin), a greater ratio of chest depth to chest width, and an LVMass index <80g. By contrast, CW persons were older, had larger QRS/T angles, smaller ratio of chest depth to chest width, had a greater proportion of subjects with low voltage QRS, more pulmonary disease, a greater proportion with high heart rates, shorter QRS duration and were more obese (BMI≥30). CONCLUSIONS: Normal rather than being the most prevalent transition zone was intermediate in frequency between the most frequently encountered CCW and the least frequently encountered transition zone CW. Differences in the predictors of CW and CCW exist. This requires further investigation to examine how far these differences explain the differences in the published prognostic differences between CW and CCW.

Eradicating hepatitis B virus: The critical role of preventing perinatal transmission.

Prevention of hepatitis B virus (HBV) transmission from infected mothers to their newborns is critical to HBV control and eventual eradication. Mother-to-child perinatal transmission causes the highest chronic carrier rate (>85%) with a high rate of subsequent chronic liver disease and hepatocellular carcinoma. This risk is reduced by 90% with HBV vaccine given along with hepatitis B immune globulin (HBIG) starting at birth. New analyses of our data from US trials of HBIG and HBV vaccine in high-risk infants revealed better efficacy with yeast-recombinant vaccine than plasma-derived vaccine, especially in preventing late onset infections, with evidence that vaccine prevented transmission of maternal HBV infection with the glycine to arginine mutation in surface antigen codon 145 (sG145R). Most late infections with sG145R were in vaccine non-responders, suggesting escape from HBIG rather than from vaccine-induced antibody. Our findings also help explain survey results from Taiwan following universal childhood immunization implemented in the mid-1980s. We conclude that current vaccines will remain effective against surface antigen mutants. Anti-viral drugs in high-risk pregnant women, in combination with newborn HBIG and vaccine, show promise for eliminating residual breakthrough neonatal infections, critical to meeting WHO 2030 goals and for eradicating HBV.

Association between Nondominant Unit Total Nucleated Cell Dose and Engraftment in Myeloablative Double-Unit Cord Blood Transplantation.

Sustained hematopoiesis after double-unit cord blood transplantation (dCBT) is mediated by 1 unit in nearly all patients. To investigate the associations between nondominant unit characteristics and neutrophil engraftment, we studied 129 consecutive myeloablative dCBT recipients. Ninety-five percent (95% confidence interval, 90 to 98) of patients engrafted. Detection of the nondominant unit 21 to 28 days after dCBT was not associated with improved neutrophil engraftment. In univariate analyses, nondominant unit characteristics (infused total nucleated cell [TNC] and viable CD3(+) cell doses) were significantly associated with speed and success of neutrophil engraftment as were dominant unit characteristics (infused TNC; viable CD34(+), viable CD3(+), and viable CD3-56(+)16(+) cell doses; and post-thaw CD34(+) cell viability). In multivariate analysis, higher infused TNC dose of the nondominant unit was independently associated with improved neutrophil engraftment, even when this unit did not contribute to donor hematopoiesis. In further subgroup analysis, this association was only evident when the infused viable CD34(+) cell dose of the dominant unit was low (<1.20 × 10(5)/kg). These findings suggest nondominant units mediate a dose-dependent facilitation of engraftment in myeloablative dCBT and support continued investigation of dCBT biology and the clinical practice of dCBT in adults in whom low cell dose grafts are common.

Dominant unit CD34+ cell dose predicts engraftment after double-unit cord blood transplantation and is influenced by bank practice.

We investigated the unit characteristics associated with engraftment after double-unit cord blood (CB) transplantation (dCBT) and whether these could be reliably identified during unit selection. Cumulative incidence of neutrophil engraftment in 129 myeloablative dCBT recipients was 95% (95% confidence interval: 90-98%). When precryopreservation characteristics were analyzed, the dominant unit CD34(+) cell dose was the only characteristic independently associated with engraftment (hazard ratio, 1.43; P = .002). When postthaw characteristics were also included, only dominant unit infused viable CD34(+) cell dose independently predicted engraftment (hazard ratio, 1.95; P < .001). We then examined the determinants of infused viable CD34(+) cell dose (precryopreservation count, postthaw recovery, and postthaw viability) in 402 units thawed at our center. This revealed close correlation between precryopreservation and postthaw CD34(+) cell counts (r(2) = 0.73). Median CD34(+) cell recovery was 101%, although it ranged from 12% to 1480%. Notably, units from non-Netcord Foundation for the Accreditation of Cellular Therapy (Netcord-FACT)-accredited banks were more likely to have low recovery (P < .001). Furthermore, although median postthaw CD34(+) cell viability was 92%, 33 (8%) units had <75% viable CD34(+) cells. Units from non-Netcord-FACT-accredited banks and units with cryovolumes other than 24.5 to 26.0 mL were more likely to have poor postthaw viability. Precryopreservation CD34(+) cell dose and banking practices should be incorporated into CB unit selection.

Indirect evidence that maternal microchimerism in cord blood mediates a graft-versus-leukemia effect in cord blood transplantation.

During pregnancy women can develop B- and T-cell immunity against the inherited paternal antigens (IPAs) of the fetus, such as HLA, peptides of minor histocompatibilty antigens, and possibly onco-fetal antigens. The biological and pathological role of these pregnancy-induced immunological events is only understood in part. However, anti-IPA immunity in the mother persists for many decades after delivery and may reduce relapse in offspring with leukemia after HLA-haploidentical transplantation of maternal hematopoietic stem cells (HSC). We hypothesized that maternal anti-IPA immune elements cross the placenta and might confer a potent graft-versus-leukemia effect when cord blood (CB) is used in unrelated HSC transplantation. In a retrospective study of single-unit CB recipients with all grafts provided by the New York Blood Center, we show that patients with acute myeloid or lymphoblastic leukemia (n = 845) who shared one or more HLA-A, -B, or -DRB1 antigens with their CB donor's IPAs had a significant decrease in leukemic relapse posttransplantation [hazard ratio (HR) = 0.38, P < 0.001] compared with those that did not. Remarkably, relapse reduction in patients receiving CB with one HLA mismatch (HR = 0.15, P < 0.001) was not associated with an increased risk of severe acute graft-versus-host disease (HR = 1.43, P = 0.730). Our findings may explain the unexpected low relapse rate after CB transplantation, open new avenues in the study of leukemic relapse after HSC transplantation (possibly of malignancies in general), and have practical implications for CB unit selection.

HLA mismatch direction in cord blood transplantation: impact on outcome and implications for cord blood unit selection.

Donor-recipient human leukocyte antigen mismatch level affects the outcome of unrelated cord blood (CB) transplantation. To identify possible "permissive" mismatches, we examined the relationship between direction of human leukocyte antigen mismatch ("vector") and transplantation outcomes in 1202 recipients of single CB units from the New York Blood Center National Cord Blood Program treated in United States Centers from 1993-2006. Altogether, 98 donor/patient pairs had only unidirectional mismatches: 58 in the graft-versus-host (GVH) direction only (GVH-O) and 40 in the host-versus-graft or rejection direction only (R-O). Engraftment was faster in patients with GVH-O mismatches compared with those with 1 bidirectional mismatch (hazard ratio [HR] = 1.6, P = .003). In addition, patients with hematologic malignancies given GVH-O grafts had lower transplantation-related mortality (HR = 0.5, P = .062), overall mortality (HR = 0.5, P = .019), and treatment failure (HR = 0.5, P = .016), resulting in outcomes similar to those of matched CB grafts. In contrast, R-O mismatches had slower engraftment, higher graft failure, and higher relapse rates (HR = 2.4, P = .010). Based on our findings, CB search algorithms should be modified to identify unidirectional mismatches. We recommend that transplant centers give priority to GVH-O-mismatched units over other mismatches and avoid selecting R-O mismatches, if possible.

Combined effect of total nucleated cell dose and HLA match on transplantation outcome in 1061 cord blood recipients with hematologic malignancies.

Both total nucleated cell (TNC) dose and human leukocyte antigen (HLA)-match affect the outcome of cord blood (CB) transplantation. However, how to prioritize these characteristics in unit selection is not established. Therefore, we analyzed the outcomes of 1061 patients who received single-unit myeloablative CB transplantation for leukemia or myelodysplasia. TNC dose and HLA-match each affected survival via their effect on transplant-related mortality (TRM); neither was associated with relapse. Therefore, TRM was the focus of multivariate analyses combining dose and HLA-match. Compared with our 1 HLA-mismatch (MM) reference group with TNC 2.5 to 4.9 x 10(7)/kg, recipients of 0 MM units had the lowest TRM regardless of dose (relative risk [RR] = 0.4, P = .019). TRM for recipients of 1- or 2-MM units with TNC 5.0 x 10(7)/kg or greater was similar to the reference group (RR = 0.8, P = .391 and RR = 1.0, P = .847) despite their greater dose. Recipients of 2 MM units with TNC 2.5 to 4.9 x 10(7)/kg had a greater TRM (RR = 1.5, P = .014), and those with 1 or 2 MM and TNC less than 2.5 x 10(7)/kg or 3 MM did substantially worse. These findings support new unit selection criteria that take into account both TNC dose and HLA-match and have important implications for the size of the global CB inventory needed to find an optimum CB graft.

Reexposure of cord blood to noninherited maternal HLA antigens improves transplant outcome in hematological malignancies.

Cord blood (CB) hematopoietic stem cell transplantation can be successful even if donor and recipient are not fully matched for human leukocyte antigens (HLA). This may result from tolerance-inducing events during pregnancy but to date this concept has not been tested in CB transplantation. Hence we analyzed the impact of fetal exposure to noninherited maternal antigens (NIMA) of the HLA-A, -B antigens, or -DRB1 alleles on the outcome of CB transplants. The 1,121 patients studied were transplanted for hematological malignancy with a single CB unit: 1,059 received grafts mismatched for one or two HLA antigens. Of these patients, 79 patients had a mismatched antigen that was identical to a donor NIMA, 25 with one HLA mismatch (MM), and 54 with two. If there was a NIMA match, transplant-related mortality (TRM) was improved, especially in patients >or=10 years (P = 0.012) as were overall mortality and treatment failure (P = 0.022 and 0.020, respectively, in the older subset), perhaps related to improved neutrophil recovery, especially in patients who received a low total nucleated cell (TNC) dose (P = 0.031). Posttransplant relapse rate also tended to be reduced, especially in patients with myelogenous malignancies given units with a single HLA mismatch (P = 0.074). These findings represent unique evidence that donor exposure to NIMA can improve survival in unrelated CB transplantation and might reduce relapse, indicating that cord blood cells can mount an antileukemic effect. By matching for donor NIMAs in search algorithms of CB inventories, the probability of selecting a graft with an optimal outcome will increase significantly.

Extracellular DNA in cord blood plasma and applications in cord blood banking for sample identification.

BACKGROUND: Human cord blood (CB) units donated for transplantation require testing for various markers in blood and plasma aliquots. Although the identity link between the CB unit and the labeled aliquots with the same identifiers can be confirmed by HLA-DNA assays, these methods have not been used for CB plasma. We have previously reported that viral DNA sequences are present in the CB plasma of carrier babies and now hypothesize that human genomic DNA may also be present in CB plasma. STUDY DESIGN AND METHODS: The aim of the study was to determine whether human genomic DNA is also present in CB plasma in quality and quantity able to support human genetic identification by short tandem repeat analysis (STR). RESULTS: The presence of extracellular DNA (EC-DNA) in CB and adult peripheral blood plasma was confirmed by HLA-DR polymerase chain reaction (PCR) and real-time PCR of Alu (SB2) genes. High concentrations were seen in CB plasma (0.131 ng/mL vs. adult 0.005 ng/mL; p < 0.001). EC-DNA increased over time while CB was stored at room temperature; this increase was associated with decreasing cell viability. STR-PCR of EC-DNA showed good signal strength and accurate allele calling so that linkage between the infant donor, the collected CB unit, and CB plasma aliquots could be established. CONCLUSION: This study demonstrates that infant-derived EC-DNA is present in CB plasma and provides a useful tool for the unambiguous confirmation of plasma aliquot identity, as routinely used in CB banking, by the use of a sensitive and highly accurate DNA assay.

Umbilical cord blood transplantation and cytomegalovirus: Posttransplantation infection and donor screening.

This study assessed the incidence of cytomegalovirus (CMV) infection after transplantation of cord blood (CB) from unrelated donors and evaluated strategies for screening CB donors. Posttransplantation CMV infection, reported in 23% of 1221 CB recipients, was associated with patient pretransplantation CMV serology (P < .001), but not with CMV serology in CB donors or their mothers. A total of 26 988 infant CB donors were evaluated by viral culture of saliva. Subgroups were evaluated by polymerase chain reaction in CB (CB-PCR) in 2 case-control studies. In the first study, 33 of 47 saliva culture-positive CB donors were confirmed by CB-PCR. All mothers of the 33 infants with confirmed CMV infection were CMV-total antibody positive, but only 1 of 3 had CMV-IgM antibody. The second study evaluated infants born to mothers with CMV-IgM antibody. Of these, 5 of 170 saliva culture-negative infants were positive by CB-PCR. The incidence of congenital CMV infection in CB donors was low (0.12%). Maternal serology had poor predictive value for CMV infection in their infant CB donors and bore no detected relationship to CMV infection in CB recipients. Saliva culture for CMV had both false-positive and -negative results. CB-PCR was a useful alternative for detecting CMV in CB donors.

Obstetric predictors of placental/umbilical cord blood volume for transplantation.

OBJECTIVE: Umbilical cord blood is an effective alternative to bone marrow as a source of hematopoietic stem cells in transplantation. However, the amount of donor blood and the cell content that are collected may be insufficient for engraftment in some adult recipients. This study identifies obstetric factors that affect retrievable placental cord blood volume. STUDY DESIGN: A retrospective analysis of factors that were obtained by direct observation or medical record review that were related to harvested cord blood volume was conducted; the analysis involved 9205 deliveries from mothers who donated placental cord blood through the obstetric services of two New York City hospitals between 1993 and 1999. RESULTS: Obstetric factors that influenced significantly the total volume of blood that was collected were route of delivery, induction of labor, presence of a nuchal cord, infant birth weight, multiple births, placental weight, and duration of labor. The length of the umbilical cord from the venipuncture site and the length of time to cord blood collection also affected the volume that was retrieved. Maternal ethnicity was associated with cord blood yield; Caucasian mothers provided larger quantities than either African American or Asian mothers. CONCLUSION: Our results confirm that the volume of residual placental cord blood that is collected for hematopoietic stem cell transplantation is influenced by several factors, the presence of which predict the likelihood of an adequate collection. Collected volumes can be improved when a longer length of the cord is left with the placenta and when there is a shorter time between the delivery of the placenta and the collection.

Hematopoietic recovery after unrelated umbilical cord-blood allogeneic transplantation in adults treated with in vivo stem cell factor (R-MetHuSCF) and filgrastim administration.

Transplantation with unrelated umbilical cord blood (UCB) is marked by delayed hematologic recovery. This report summarizes two adults with chronic myelogenous leukemia (CML), who received myeloablative conditioning followed by infusion of a non-expanded single UCB graft. These CML patients were enrolled in a clinical trial incorporating concomitant in vivo administration of stem cell factor (R-MetHuSCF) and filgrastim from day of UCB infusion until attained hematopoietic recovery. Each patient engrafted fully with donor UCB, with days to absolute neutrophil count (ANC) >500/microl being 13 and 29 days, respectively. Both patients remain in cytogenetic remission at 28 months follow-up. 'In vivo UCB expansion' with administration of concomitant R-MetHuSCF and filgrastim may facilitate prompt hematologic engraftment.

Placental/umbilical cord blood for unrelated-donor bone marrow reconstitution: relevance of nucleated red blood cells.

Placental/umbilical cord blood (PCB) is a source of hematopoietic stem cells for bone marrow reconstitution. Engraftment speed and survival are related to the total nucleated cell (TNC) dose of the graft. This study explored the possible influence on engraftment of nucleated red blood cells (NRBCs) in the graft. Automated hematology analyzers were used to enumerate TNCs. NRBCs were counted by visual examination or by using an automated analyzer. Hematopoietic progenitor cells were enumerated as either colony-forming cells or CD34(+) cells. Transplant centers reported on transplant outcome in 1112 patients given PCB grafts through September 2001. NRBCs correlated with progenitor cell numbers. Both white blood cell and NRBC dose were independently predictive of myeloid engraftment speed. Because NRBC dose predicted engraftment speed, inclusion of NRBCs in the TNC count does not reduce the effectiveness of the prefreezing TNC count as an index of the quality of a PCB unit as a graft. The correlation between the number of NRBCs and the number of hematopoietic progenitor cells probably reflects the involvement of early stem cells in erythroid responses.

Genetic variation of hepatitis B surface antigen coding region among infants with chronic hepatitis B virus infection.

Variants in the amino acid composition of the primary antibody-binding site of hepatitis B surface antigen (HBsAg) have been identified in a number of populations with chronic hepatitis B virus (HBV) infection. Direct sequencing of amplified or cloned PCR products, solid phase detection of sequence-specific PCR products (SP-PCR), and limiting dilution cloning PCR (LDC-PCR) were compared to determine their sensitivity in detecting differing concentrations of HBsAg variants. LDC-PCR had the greatest sensitivity and could detect HBsAg variants at a concentration of 0.1% of the total viral population. HBsAg variants were detected in 51% of infants with chronic HBV infection acquired after postexposure prophylaxis, and more than half of the variants were detected only by the most sensitive methods.