Vulnerability to APOBEC3G linked to the pathogenicity of deltaretroviruses.

Human retroviruses are derived from simian ones through cross-species transmission. These retroviruses are associated with little pathogenicity in their natural hosts, but in humans, HIV causes AIDS, and human T-cell leukemia virus type 1 (HTLV-1) induces adult T-cell leukemia-lymphoma (ATL). We analyzed the proviral sequences of HTLV-1, HTLV-2, and simian T-cell leukemia virus type 1 (STLV-1) from Japanese macaques (Macaca fuscata) and found that APOBEC3G (A3G) frequently generates G-to-A mutations in the HTLV-1 provirus, whereas such mutations are rare in the HTLV-2 and STLV-1 proviruses. Therefore, we investigated the mechanism of how HTLV-2 is resistant to human A3G (hA3G). HTLV-1, HTLV-2, and STLV-1 encode the so-called antisense proteins, HTLV-1 bZIP factor (HBZ), Antisense protein of HTLV-2 (APH-2), and STLV-1 bZIP factor (SBZ), respectively. APH-2 efficiently inhibits the deaminase activity of both hA3G and simian A3G (sA3G). HBZ and SBZ strongly suppress sA3G activity but only weakly inhibit hA3G, suggesting that HTLV-1 is incompletely adapted to humans. Unexpectedly, hA3G augments the activation of the transforming growth factor (TGF)-ß/Smad pathway by HBZ, and this activation is associated with ATL cell proliferation by up-regulating BATF3/IRF4 and MYC. In contrast, the combination of APH-2 and hA3G, or the combination of SBZ and sA3G, does not enhance the TGF-ß/Smad pathway. Thus, HTLV-1 is vulnerable to hA3G but utilizes it to promote the proliferation of infected cells via the activation of the TGF-ß/Smad pathway. Antisense factors in each virus, differently adapted to control host cellular functions through A3G, seem to dictate the pathogenesis.

HTLV-1 and blood donation.

Human T-cell leukaemia virus type 1 (HTLV-1) is a human retrovirus that causes adult T-cell lymphoma and HTLV-associated myelopathy. In this issue, Rosadas et al. use data from a recent WHO report to describe how blood banks test for HTLV-1 and how this testing contributes to public health surveillance for the virus. Commentary on: Rosadas et al. HTLV-1 screening of blood donations: we are systematically missing opportunities. Br J Haematol 2023;202:1220-1223.

Systemic cytokines and GlycA discriminate disease status and predict corticosteroid response in HTLV-1-associated neuroinflammation.

BACKGROUND: HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is an incapacitating neuroinflammatory disorder for which no disease-modifying therapy is available, but corticosteroids provide some clinical benefit. Although HAM/TSP pathogenesis is not fully elucidated, older age, female sex and higher proviral load are established risk factors. We investigated systemic cytokines and a novel chronic inflammatory marker, GlycA, as possible biomarkers of immunopathogenesis and therapeutic response in HAM/TSP, and examined their interaction with established risk factors. PATIENTS AND METHODS: We recruited 110 People living with HTLV-1 (PLHTLV-1, 67 asymptomatic individuals and 43 HAM/TSP patients) with a total of 946 person-years of clinical follow-up. Plasma cytokine levels (IL-2, IL-4, IL-6, IL-10, IL-17A, IFN-γ, TNF) and GlycA were quantified by Cytometric Bead Array and 1NMR, respectively. Cytokine signaling and prednisolone response were validated in an independent cohort by nCounter digital transcriptomics. We used multivariable regression, machine learning algorithms and Bayesian network learning for biomarker identification. RESULTS: We found that systemic IL-6 was positively correlated with both age (r = 0.50, p < 0.001) and GlycA (r = 0.45, p = 0.00049) in asymptomatics, revealing an 'inflammaging" signature which was absent in HAM/TSP. GlycA levels were higher in women (p = 0.0069), but cytokine levels did not differ between the sexes. IFN-γ (p = 0.007) and IL-17A (p = 0.0001) levels were increased in untreated HAM/TSP Multivariable logistic regression identified IL-17A and proviral load as independent determinants of clinical status, resulting in modest accuracy of predicting HAM/TSP status (64.1%), while a machine learning-derived decision tree classified HAM/TSP patients with 90.7% accuracy. Pre-treatment GlycA and TNF levels significantly predicted clinical worsening (measured by Osame Motor Disability Scale), independent of proviral load. In addition, a poor prednisolone response was significantly correlated with higher post-treatment IFN-γ levels. Likewise, a transcriptomic IFN signaling score, significantly correlated with previously proposed HAM/TSP biomarkers (CASP5/CXCL10/FCGR1A/STAT1), was efficiently blunted by in vitro prednisolone treatment of PBMC from PLHTLV-1 and incident HAM/TSP. CONCLUSIONS: An age-related increase in systemic IL-6/GlycA levels reveals inflammaging in PLHTLV-1, in the absence of neurological disease. IFN-γ and IL-17A are biomarkers of untreated HAM/TSP, while pre-treatment GlycA and TNF predict therapeutic response to prednisolone pulse therapy, paving the way for a precision medicine approach in HAM/TSP.

A novel high performing multiplex immunoassay Multi-HTLV for serological confirmation and typing of HTLV infections.

BACKGROUND: Human T-Cell Lymphotropic Viruses (HTLV) type 1 and type 2 account for an estimated 5 to 10 million infections worldwide and are transmitted through breast feeding, sexual contacts and contaminated cellular blood components. HTLV-associated syndromes are considered as neglected diseases for which there are no vaccines or therapies available, making it particularly important to ensure the best possible diagnosis to enable proper counselling of infected persons and avoid secondary transmission. Although high quality antibody screening assays are available, currently available confirmatory tests are costly and have variable performance, with high rates of indeterminate and non-typable results reported in many regions of the world. The objective of this project was to develop and validate a new high-performance multiplex immunoassay for confirmation and discrimination of HTLV-1 and HTLV-2 strains. METHODOLOGY/PRINCIPAL FINDINGS: The multiplex platform was used first as a tool to identify suitable antigens and in a second step for assay development. With data generated on over 400 HTLV-positive blood donors sourced from USA and French blood banks, we developed and validated a high-precision interpretation algorithm. The Multi-HTLV assay demonstrated very high performance for confirmation and strain discrimination with 100% sensitivity, 98.1% specificity and 100% of typing accuracy in validation samples. The assay can be interpreted either visually or automatically with a colorimetric image reader and custom algorithm, providing highly reliable results. CONCLUSIONS/SIGNIFICANCE: The newly developed Multi-HTLV is very competitive with currently used confirmatory assays and reduces considerably the number of indeterminate results. The multiparametric nature of the assay opens new avenues to study specific serological signatures of each patient, follow the evolution of infection, and explore utility for HTLV disease prognosis. Improving HTLV diagnostic testing will be critical to reduce transmission and to improve monitoring of seropositive patients.

Undisclosed HIV status and antiretroviral therapy use among South African blood donors.

BACKGROUND: Undisclosed antiretroviral drug (ARV) use among blood donors who tested HIV antibody positive, but RNA negative, was previously described by our group. Undisclosed ARV use represents a risk to blood transfusion safety. We assessed the prevalence of and associations with undisclosed ARV use among HIV-positive donors who donated during 2017. STUDY DESIGN AND METHODS: South African National Blood Service (SANBS) blood donors are screened by self-administered questionnaire, semi-structured interview, and individual donation nucleic acid amplification testing for HIV. Stored samples from HIV-positive donations were tested for ARV and characterized as recent/longstanding using lag avidity testing. RESULTS: Of the 1462 HIV-positive donations in 2017, 1250 had plasma availability for testing of which 122 (9.8%) tested positive for ARV. Undisclosed ARV use did not differ by gender (p = .205) or ethnicity (p = .505) but did differ by age category (p < .0001), donor (p < .0001), clinic type (p = .012), home province (p = .01), and recency (p < .0001). Multivariable logistic regression found older age (adjusted odds ratio [aOR] 3.73, 95% confidence interval [CI] 1.98-7.04 for donors >40 compared with those <21), first-time donation (aOR 5.24; 95% CI 2.48-11.11), and donation in a high HIV-prevalence province (aOR 9.10; 95% CI 2.70-30.72) compared with Northern Rural provinces to be independently associated with undisclosed ARV use. DISCUSSION: Almost 1 in 10 HIV-positive blood donors neglected to disclose their HIV status and ARV use. Demographic characteristics of donors with undisclosed ARV use differed from those noted in other study. Underlying motivations for nondisclosure among blood donors remain unclear and may differ from those in other populations with significant undisclosed ARV use.

Phenotypic and Functional Analyses Guiding Combination Immune Checkpoint Immunotherapeutic Strategies in HTLV-1 Infection.

Human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) develops in 1-5% of HTLV-1-infected individuals. Previous studies by us and others have shown that the expression of negative immune checkpoint receptors (NCRs) is significantly increased on CD8 T cells in various chronic viral infections and are associated with poor anti-viral immunity. We have previously identified the differential expression of NCRs on CD8 T cells in blood from patients with HAM/TSP and in central nervous system (CNS) tissues of HTLV-1 infected humanized mice and defined the association with neurological complications. In this study, we determined the co-expression patterns of several key NCRs (PD-1, TIGIT, TIM-3, and LAG-3) and their cognate ligands in HTLV-1 infection and assessed how combination strategies targeting these pathways would impact HTLV-1-specific CD8 T-cell effector functions as an approach to reduce CNS disease outcomes. We found that global CD8 T cells from HAM/TSP patients co-express multiple NCRs at significantly higher frequencies than asymptomatic carriers (AC). Moreover, NCR ligands (PVR and PD-LI) on both plasmacytoid and myeloid dendritic cells were also expressed at higher frequencies in HAM/TSP compared to AC. In both AC and HAM/TSP subjects, combination dual PD-L1/TIGIT or triple PD-L1/TIGIT/TIM-3 blockade with monoclonal antibodies resulted in increases in intracellular cytokine expression in CD8 T cells after virus stimulation, particularly CD107a, a marker of degranulation, and TNF-α, a key cytokine that can directly inhibit viral replication. Interestingly, almost all blockade combinations resulted in reduced IL-2+ HTLV-1-specific CD8 T cell frequencies in HAM/TSP subjects, but not in AC. These results define a novel combinatorial NCR immunotherapeutic blockade strategy to reduce HAM/TSP disease burden.

A Multiancestry Sex-Stratified Genome-Wide Association Study of Spontaneous Clearance of Hepatitis C Virus.

BACKGROUND: Spontaneous clearance of acute hepatitis C virus (HCV) infection is more common in women than in men, independent of known risk factors. METHODS: To identify sex-specific genetic loci, we studied 4423 HCV-infected individuals (2903 male, 1520 female) of European, African, and Hispanic ancestry. We performed autosomal, and X chromosome sex-stratified and combined association analyses in each ancestry group. RESULTS: A male-specific region near the adenosine diphosphate-ribosylation factor-like 5B (ARL5B) gene was identified. Individuals with the C allele of rs76398191 were about 30% more likely to have chronic HCV infection than individuals with the T allele (OR, 0.69; P = 1.98 × 10-07), and this was not seen in females. The ARL5B gene encodes an interferon-stimulated gene that inhibits immune response to double-stranded RNA viruses. We also identified suggestive associations near septin 6 and ribosomal protein L39 genes on the X chromosome. In box sexes, allele G of rs12852885 was associated with a 40% increase in HCV clearance compared with the A allele (OR, 1.4; P = 2.46 × 10-06). Septin 6 facilitates HCV replication via interaction with the HCV NS5b protein, and ribosomal protein L39 acts as an HCV core interactor. CONCLUSIONS: These novel gene associations support differential mechanisms of HCV clearance between the sexes and provide biological targets for treatment or vaccine development.

The use of the GeeniusTM HIV-1/2 Rapid confirmatory test for the enrolment of patients and blood donors in the WHO Universal Test and Treat Strategy in Cameroon, Africa.

BACKGROUND AND OBJECTIVE: In the WHO Universal test and treat strategy, false-positive HIV blood donors and patients may be unnecessarily put under antiretroviral treatment and false-negative subjects may be lost to follow-up. This study assessed the false positivity rate of the Cameroonian national HIV screening testing algorithm and the benefit of a confirmation test in the enrolment of patients and donors in the HIV care programme. METHODS: We included initial HIV reactive blood donors and patients in a cross-sectional study conducted in two Cameroonian hospitals. Samples were retested according to the Cameroon national algorithm for HIV diagnosis. A positive or discordant sample was retested with the Geenius Bio-Rad HIV 1&2 (Bio-Rad, Marnes-la-Coquette, France) for confirmation. The Geenius HIV-1-positive results with 'poor' profiles were retested for RNA as well as the Geenius indeterminate results. RESULTS: Of the 356 participants, 190/225 (84·4%) patients and 76/131 (58%) blood donors were declared positive with the national algorithm; 257 participants (96·6%) were confirmed HIV-1-positive. The study revealed that about 34/1000 blood donors and patients are false-positive and unnecessarily put on treatment; 89/1000 blood donors and patients declared discordant could have been included immediately in the HIV care programme if confirmatory testing was performed. The second test of the algorithm had a false-negative rate of 3%. Eleven samples (3·1%) were Geenius poor positive and NAT negative. CONCLUSION: The universal test and treat strategy may identify and refer more individuals to HIV care if a third rapid confirmatory test is performed for discordant cases.

Association of donor age, body mass index, hemoglobin, and smoking status with in-hospital mortality and length of stay among red blood cell-transfused recipients.

BACKGROUND: Recent publications have reported conflicting findings regarding associations of blood donor demographics and mortality of transfused patients. We hypothesized that the analysis of additional donor characteristics and consideration of alternative outcomes might provide insight into these disparate results. STUDY DESIGN AND METHODS: We analyzed data from a retrospective cohort of transfused patients from the Recipient Epidemiology and Donor Evaluation Study-III (REDS-III). We used stratified Cox regression models to estimate associations between blood donor characteristics and hospital mortality and posttransfusion length of stay among patients transfused red blood cell (RBC) units. Donor characteristics evaluated included age, body mass index, hemoglobin levels, and smoking status. The statistical analyses were adjusted for recipient factors, including total number of transfusions. RESULTS: We studied 93,726 patients in 130,381 hospitalizations during which 428,461 RBC units were transfused. There were no associations between blood donor characteristics and hospital mortality. Receipt of RBC units from donors less than 20 years of age was associated with a shorter hospital length of stay (hazard ratio for discharge per transfused unit, 1.03; 95% confidence interval, 1.02-1.04; p < 0.001) but not for other donor characteristics. CONCLUSION: We found no evidence of associations between blood donor factors and in-hospital mortality. Our finding of shorter hospital length of stay in patients transfused RBCs from younger donors is intriguing but requires confirmation. Future collaborations are needed to develop a framework of appropriate methodologic approaches to be used in linked analyses across large cohorts.

Proficiency Testing of Viral Marker Screening in African Blood Centers - Seven African Countries, 2017.

A 2014 report evaluating accuracy of serologic testing for transfusion-transmissible viruses at African blood center laboratories found sensitivities of 92%, 87%, and 90% for detecting infections with human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV), respectively (1). Following substantial investments in national blood transfusion service (NBTS) laboratories, in 2017 investigators tested proficiency at 84 blood center laboratories (29 NBTS and 55 non-NBTS) in seven African countries. A blinded panel of 25 plasma samples was shipped to each participating laboratory for testing with their usual protocols based on rapid diagnostic tests (RDTs) (2) and third and fourth generation enzyme immunoassays (EIA-3 and EIA-4). Sensitivity and specificity were estimated using separate regression models that clustered assays by laboratory and adjusted for assay type and NBTS laboratory status. Mean specificities were ≥95% for all three viruses; however, mean sensitivities were 97% for HIV-positive, 76% for HBV-positive, and 80% for HCV-positive samples. Testing sensitivities for all viruses were high when EIA-3 assays were used (≥97%). Lower sensitivities for HBV-positive samples and HCV-positive samples were associated with assay types other than EIA-3, used primarily by non-NBTS laboratories. Proficiency for HIV testing has improved following international investments, but proficiency remains suboptimal for HBV and HCV testing. In sub-Saharan African blood centers, the quality of rapid tests used for HBV and HCV screening needs to be improved or their use discouraged in favor of EIA-3 tests.

The impact of recipient factors on the lower-than-expected hemoglobin increment in transfused outpatients with hematologic diseases.

BACKGROUND: Patients with cancer or chronic hematologic disorders frequently receive red blood cell (RBC) transfusions. Based on long-standing assumptions, each RBC unit is thought to increase recipient hemoglobin by 1 g/dL, but smaller increments can occur. A better understanding of recipient factors affecting hemoglobin increments could help providers manage these patients. METHODS: Data were collected as a part of the observational Red Cells in Outpatients Transfusion Outcomes (RETRO) study of outpatients with hematologic or cancer-related diagnoses. Hemoglobin was measured before transfusion and 30 minutes after transfusion. A classification and regression tree (CART) analysis was performed to identify statistically significant associations with clinical variables. A corresponding prediction equation was developed and validated using linear regression. RESULTS: A total of 195 participants had both pre- and posttransfusion hemoglobin values for analysis. The median age was 66 years, and patients received one (73%) or two (27%) RBC units during the transfusion episode. The overall median change in hemoglobin was 0.6 g/dL per RBC unit. Both CART analysis and linear regression identified the following significant predictors of hemoglobin increment: number of units received (positive correlation), patient estimated circulating blood volume (negative correlation), pretransfusion hemoglobin (negative correlation), and patient age (negative correlation). CONCLUSION: In this study of outpatients with hematologic disease, most patients had a hemoglobin increment of less than 1 g/dL/unit. Recipient-specific factors influenced the hemoglobin increment at 30 minutes, and providers should consider circulating blood volume, pretransfusion hemoglobin, and recipient age, when developing patient-specific RBC transfusion plans for this unique cohort.

The prevalence of human T-lymphotropic virus type 1 & 2 (HTLV-1/2) in South African blood donors.

BACKGROUND AND OBJECTIVES: Donated blood is not currently screened for human T-cell lymphotropic virus (HTLV) in South Africa. Several small studies have detected HTLV-1 in South Africa, but prevalence by geographic region or population group is unavailable. MATERIALS AND METHODS: We performed a large seroprevalence study of South African blood donors during 3 months in 2013. All geographic regions except the Western Cape were included, and Black and Coloured (local term for mixed race) donors were oversampled. Identity-unlinked plasma samples were screened with the Abbott Prism HTLV-1/2 assay, and repeatedly reactive samples were tested by the Inno-LIA HTLV-1/2 Score confirmatory assay. Odds ratios were calculated with multivariable logistic regression. RESULTS: Of 46 752 donors tested, 133 (0·28%) were initially reactive, 111 (0·24%) repeatedly reactive and 57 (0·12%) confirmed positive for HTLV-1; none were HTLV-2 positive. Prevalence was 0·062% weighted to annual blood donations but highly concentrated in the Black population group (OR = 20·24 CI: 2·77-147·88); higher in females than males (OR = 1·81 CI: 1·06-3·08); and in donors aged >50 years compared to ages 16-19 (OR = 6·4 CI: 2·95-13·86). After controlling for age, sex and population group, there was no difference in prevalence between new and repeat blood donors or among geographic regions within South Africa. CONCLUSIONS: We conclude that HTLV-1 infection is widespread among the Black population of South Africa and its epidemiology is similar to other endemic areas. Because South Africa is increasing its recruitment of Black blood donors, the implications for blood screening require further consideration.

Discovery of False Elite Controllers: HIV Antibody-Positive RNA-Negative Blood Donors Found To Be on Antiretroviral Therapy.

BACKGROUND: An increase in potential HIV elite controllers (EC) and anecdotal reports of antiretroviral therapy (ART) use among South African blood donors led us to verify EC status. METHODS: Stored plasma samples from potential EC were tested for ART drugs. Demographic and temporal associations were examined using multivariable logistic regression. RESULTS: Of 226 potential EC, 150 (66.4%) had detectable ART with increasing prevalence by year (OR = 7.57 for 2016 vs 2010, 95% confidence interval, 1.96-32.17). DISCUSSION: False presumptive EC status due to undisclosed ART represents a growing proportion of potential EC donors in South Africa coincident with the country's ART rollout.

Therapeutic impact of red blood cell transfusion on anemic outpatients: the RETRO study.

BACKGROUND: Patients with cancer or other diagnoses associated with chronic anemia often receive red blood cell (RBC) transfusion as outpatients, but the effect of transfusion on functional status is not well demonstrated. STUDY DESIGN AND METHODS: To estimate the effect of transfusion on functional status and quality of life, we measured 6-minute walk test distance and fatigue- and dyspnea-related quality-of-life scores before and 1 week after RBC transfusion in 208 outpatients age ≥50 with at least one benign or malignant hematology/oncology diagnosis. To account for potential confounding effects of cancer treatment, patients were classified into two groups based on cancer treatment within 4 weeks of the study transfusion. Minimum clinically important improvements over baseline were 20 meters in walk test distance, 3 points in fatigue score, and 2 points in dyspnea score. RESULTS: The median improvement in unadjusted walk test distance was 20 meters overall and 30 meters in patients not receiving recent cancer treatment. Fatigue scores improved overall by a median of 3 points and by 4 points in patients without cancer treatment. There was no clinically important change in dyspnea scores. In multiple linear regression analysis, patients who maintained hemoglobin (Hb) levels of 8 g/dL or greater at 1 week posttransfusion, who had not received recent cancer treatment, and who did not require hospitalization during the study showed clinically important increases in mean walk test distance. CONCLUSIONS: Red blood cell transfusion is associated with a modest, but clinically important improvement in walk test distance and fatigue score outcomes in adult hematology/oncology outpatients.

In vivo and in vitro immunogenicity of novel MHC class I presented epitopes to confer protective immunity against chronic HTLV-1 infection.

Human T-cell leukemia virus type 1 (HTLV-1) has infected as many as 10 million people worldwide. While 90% are asymptomatic, 5% develop severe diseases including adult T-cell leukemia/lymphoka (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). No vaccine against HTLV-1 exists, and screening programs are not universal. However, patients with chronic HTLV-1 infection have high frequencies of HTLV-1-activated CD8+ T cells, and the two main HLA alleles (A2, A24) are present in 88% of infected individuals. We thus utilized an immunoproteomics approach to characterize MHC-I restricted epitopes presented by HLA-A2+, A24+ MT-2 and SLB-1 cell lines. Unlike traditional motif prediction algorithms, this approach identifies epitopes associated with cytotoxic T-cell responses in their naturally processed forms, minimizing differences in antigen processing and protein expression levels. Out of nine identified peptides, we confirmed six novel MHC-I restricted epitopes that were capable of binding HLA-A2 and HLA-A24 alleles and used in vitro and in vivo methods to generate CD8+ T cells specific for each of these peptides. MagPix MILLIPLEX data showed that in vitro generated epitope-specific CD8+ T cells secreted IFN-É£, granzyme B, MIP-1α, TNF-α, perforin and IL-10 when cultured in the presence of MT-2 cell line. Degranulation assay confirmed cytotoxic response through surface expression of CD107 on CD8+ T cells when cultured with MT-2 cells. A CD8+ T-cell killing assay indicated significant antiviral activity of CD8+ T cells specific against all identified peptides. In vivo generated CD8+ T cells similarly demonstrated immunogenicity on ELISpot, CD107 degranulation assay, and MagPix MILLIPLEX analysis. These epitopes are thus candidates for a therapeutic peptide-based vaccine against HTLV-1, and our results provide preclinical data for the advancement of such a vaccine.

Contemporary Risk Factors and Outcomes of Transfusion-Associated Circulatory Overload.

OBJECTIVES: Transfusion-associated circulatory overload is characterized by hydrostatic pulmonary edema following blood transfusion. Restrictive transfusion practice may affect the occurrence and severity of transfusion-associated circulatory overload in critically ill patients. We sought to examine contemporary risk factors and outcomes for transfusion-associated circulatory overload. DESIGN: Case-control study. SETTING: Four tertiary care hospitals. PATIENTS: We prospectively enrolled 200 patients with transfusion-associated circulatory overload identified by active surveillance and 405 controls matched by transfusion intensity. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 20,845 transfused patients who received 128,263 blood components from May 2015 until July 2016, transfusion-associated circulatory overload incidence was one case per 100 transfused patients. In addition to cardiovascular comorbidities, multivariable analysis identified the following independent predictors of transfusion-associated circulatory overload: acute kidney injury, emergency surgery, pretransfusion diuretic use, and plasma transfusion-the latter especially in females. Compared with matched controls, transfusion-associated circulatory overload cases were more likely to require mechanical ventilation (71% vs 49%; p < 0.001), experienced longer intensive care and hospital lengths of stay following transfusion, and had higher mortality (21% vs 11%; p = 0.02) even after adjustment for other potentially confounding variables. CONCLUSIONS: Despite restrictive transfusion practice, transfusion-associated circulatory overload remains a frequent complication of transfusion and is an independent risk factor for in-hospital morbidity and mortality. In addition to cardiovascular and renal risk factors, plasma transfusion was associated with transfusion-associated circulatory overload after controlling for other covariates. Additional research is needed to examine the benefit of reduced erythrocyte or plasma exposure in patients at high risk for transfusion-associated circulatory overload.

Use of Blood Donor Screening to Monitor Prevalence of HIV and Hepatitis B and C Viruses, South Africa.

Among 397,640 first-time blood donors screened in South Africa during 2012-2015, HIV prevalence was 1.13%, hepatitis B virus prevalence 0.66%, and hepatitis C virus prevalence 0.03%. Findings of note were a high HIV prevalence in Mpumalanga Province and the near absence of hepatitis C virus nationwide.

Telomere Length, Proviral Load and Neurologic Impairment in HTLV-1 and HTLV-2-Infected Subjects.

Short or damaged telomeres have been implicated in degenerative conditions. We hypothesized that analysis of telomere length (TL) in human T-cell lymphotropic virus (HTLV) infection and HTLV-associated neuropathy might provide clues to the etiology of HTLV-associated disease and viral dynamics. A subset of 45 human T-cell lymphotropic virus type 1 (HTLV-1), 45 human T-cell lymphotropic virus type 2 (HTLV-2), and 45 seronegative subjects was selected from the larger HTLV Outcomes Study (HOST) cohort, matched on age, sex and race/ethnicity. Telomere-to-single-copy gene (T/S) ratio (a measure of TL) and HTLV-1 and HTLV-2 proviral loads were measured in peripheral blood mononuclear cells (PBMCs) using quantitative PCR (qPCR). Vibration sensation measured by tuning fork during neurologic examinations performed as part of the HOST study allowed for an assessment of peripheral neuropathy. TL was compared between groups using t-tests, linear and logistic regression. Mean T/S ratio was 1.02 ± 0.16 in HTLV-1, 1.03 ± 0.17 in HTLV-2 and 0.99 ± 0.18 in HTLV seronegative subjects (p = 0.322). TL was not associated with HTLV-1 or -2 proviral load. Shorter TL was significantly associated with impaired vibration sense in the HTLV-2 positive group only. Overall, we found no evidence that telomere length was affected by chronic HTLV-1 and HTLV-2 infection. That TL was only associated with peripheral neuropathy in the HTLV-2-positive group is intriguing, but should be interpreted cautiously. Studies with larger sample size and telomere length measurement in lymphocyte subsets may clarify the relationship between TL and HTLV-infection.