Antiretroviral therapy (ART) to treat and pre-exposure prophylaxis (PrEP) to prevent HIV infection are effective tools to help end the HIV epidemic. However, their use could affect HIV ...transfusion-transmission risk. Three different ART/PrEP prevalence analyses in blood donors were conducted. First, blood samples from HIV-positive and a comparison group of infection-nonreactive donors were tested under blind using liquid chromatography-tandem mass spectrometry for ART. Second, blood donor samples from infection-nonreactive, 18- to 45-year-old, male, first-time blood donors in 6 US locations were tested for emtricitabine and tenofovir. Third, in men who have sex with men (MSM) participating in the 2017 Centers for Disease Control and Prevention National HIV Behavioral Surveillance (NHBS) from 5 US cities, self-reported PrEP use proximate to donation was assessed. In blind testing, no ART was detected in 300 infection-nonreactive donor samples, but in 299 HIV confirmed-infected donor samples, 46 (15.4%; 95% confidence interval CI, 11.5% to 20.0%) had evidence of ART. Of the 1494 samples tested from first-time male donors, 9 (0.6%; 95% CI, 0.03% to 1.1%) had tenofovir and emtricitabine. In the NHBS MSM survey, 27 of 591 respondents (4.8%; 95% CI, 3.2% to 6.9%) reported donating blood in 2016 or 2017 and PrEP use within the same time frame as blood donation. Persons who are HIV positive and taking ART and persons taking PrEP to prevent HIV infection are donating blood. Both situations could lead to increased risk of HIV transfusion transmission if blood screening assays are unable to detect HIV in donations from infected donors.
•Fifteen percent of HIV-positive donors in the United States took ART within a few days before donating.•PrEP use proximate to donation was found in 0.6% of first-time male blood donors and by survey in 5% of MSM.
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The NLST reported a significant 20% reduction in lung cancer mortality with three annual low-dose CT (LDCT) screens and the Dutch-Belgian NELSON trial indicates a similar reduction. We present the ...results of the UKLS trial.
From October 2011 to February 2013, we randomly allocated 4 055 participants to either a single invitation to screening with LDCT or to no screening (usual care). Eligible participants (aged 50–75) had a risk score (LLPv2) ≥ 4.5% of developing lung cancer over five years. Data were collected on lung cancer cases to 31 December 2019 and deaths to 29 February 2020 through linkage to national registries. The primary outcome was mortality due to lung cancer. We included our results in a random-effects meta-analysis to provide a synthesis of the latest randomised trial evidence.
1 987 participants in the intervention and 1 981 in the usual care arms were followed for a median of 7.3 years (IQR 7.1–7.6), 86 cancers were diagnosed in the LDCT arm and 75 in the control arm. 30 lung cancer deaths were reported in the screening arm, 46 in the control arm, (relative rate 0.65 95% CI 0.41–1.02; p=0.062). The meta-analysis indicated a significant reduction in lung cancer mortality with a pooled overall relative rate of 0.84 (95% CI 0.76–0.92) from nine eligible trials.
The UKLS trial of single LDCT indicates a reduction of lung cancer death of similar magnitude to the NELSON and NLST trials and was included in a meta-analysis of nine randomised trials which provides unequivocal support for lung cancer screening in identified risk groups.
NIHR Health Technology Assessment programme; NIHR Policy Research programme; Roy Castle Lung Cancer Foundation.
ABSTRACT
A common focus among molecular and cellular biologists is the identification of proteins that interact with each other. Yeast two‐hybrid, cDNA expression library screening, and ...coimmunoprecipitation experiments are powerful methods for identifying novel proteins that bind to one's favorite protein for the purpose of learning more regarding its cellular function. These same techniques, coupled with truncation and mutagenesis experiments, have been used to define the region of interaction between pairs of proteins. One conclusion from this work is that many interactions occur over short regions, often less than 10 amino acids in length within one protein. For example, mapping studies and 3‐dimensional analyses of antigen‐antibody interactions have revealed that epitopes are typically 4–7 residues long (1). Other examples include protein‐interaction modules, such as Src homology (SH) 2 and 3 domains, phosphotyrosine binding domains (PTB), postsynaptic density/disc‐large/ZO1 (PDZ) domains, WW domains, Eps15 homology (EH) domains, and 14–3–3 proteins that typically recognize linear regions of 3–9 amino acids. Each of these domains has been the subject of recent reviews published elsewhere (2–7). Among the primary structures of many ligands for protein–protein interactions, the amino acid proline is critical. In particular, SH3, WW, and several new protein‐interaction domains prefer ligand sequences that are proline‐rich. In addition, even though ligands for EH domains and 14–3–3 domains are not proline‐rich, they do include a single proline residue. This review highlights the analysis of those protein‐protein interactions that involve proline residues, the biochemistry of proline, and current drug discovery efforts based on proline peptidomimetics.—Kay, B. K., Williamson, M. P., Sudol, M. The importance of being proline: the interaction of proline‐rich motifs in signaling proteins with their cognate domains. FASEB J. 14, 231–241 (2000)
Six months into the COVID-19 pandemic, college campuses faced uncertainty regarding the likely prevalence and spread of disease, necessitating large-scale testing to help guide policy following ...re-entry.
A SARS-CoV-2 testing program combining pooled saliva sample surveillance leading to diagnosis and intervention surveyed over 112,000 samples from 18,029 students, staff and faculty, as part of integrative efforts to mitigate transmission at the Georgia Institute of Technology in Fall 2020.
Cumulatively, we confirmed 1,508 individuals diagnostically, 62% of these through the surveillance program and the remainder through diagnostic tests of symptomatic individuals administered on or off campus. The total strategy, including intensification of testing given case clusters early in the semester, was associated with reduced transmission following rapid case increases upon entry in Fall semester in August 2020, again in early November 2020, and upon re-entry for Spring semester in January 2021. During the Fall semester daily asymptomatic test positivity initially peaked at 4.1% but fell below 0.5% by mid-semester, averaging 0.84% across the Fall semester, with similar levels of control in Spring 2021.
Owing to broad adoption by the campus community, we estimate that the program protected higher risk staff and faculty while allowing some normalization of education and research activities.
Carbon monoxide (CO)-releasing molecules (CORMs) are used to deliver CO, a biological ‘gasotransmitter’, in biological chemistry and biomedicine. CORMs kill bacteria in culture and in animal models, ...but are reportedly benign towards mammalian cells. CORM-2 (tricarbonyldichlororuthenium(II) dimer, Ru2Cl4(CO)6), the first widely used and commercially available CORM, displays numerous pharmacological, biochemical and microbiological activities, generally attributed to CO release. Here, we investigate the basis of its potent antibacterial activity against Escherichia coli and demonstrate, using three globin CO sensors, that CORM-2 releases negligible CO (<0.1 mol CO per mol CORM-2). A strong negative correlation between viability and cellular ruthenium accumulation implies that ruthenium toxicity underlies biocidal activity. Exogenous amino acids and thiols (especially cysteine, glutathione and N-acetyl cysteine) protected bacteria against inhibition of growth by CORM-2. Bacteria treated with 30 μM CORM-2, with added cysteine and histidine, exhibited no significant loss of viability, but were killed in the absence of these amino acids. Their prevention of toxicity correlates with their CORM-2-binding affinities (Cys, Kd 3 μM; His, Kd 130 μM) as determined by 1H-NMR. Glutathione is proposed to be an important intracellular target of CORM-2, with CORM-2 having a much higher affinity for reduced glutathione (GSH) than oxidised glutathione (GSSG) (GSH, Kd 2 μM; GSSG, Kd 25,000 μM). The toxicity of low, but potent, levels (15 μM) of CORM-2 was accompanied by cell lysis, as judged by the release of cytoplasmic ATP pools. The biological effects of CORM-2 and related CORMs, and the design of biological experiments, must be re-examined in the light of these data.
Puerto Rico began screening blood donations for Zika virus RNA with nucleic acid amplification tests (NAATs) on April 3, 2016, because of an emerging Zika virus outbreak. We followed up positive ...donors to assess the dynamics of viral and serological markers during the early stages of Zika virus infection and update the estimate of infection incidence in the Puerto Rican population during the outbreak.
Blood donations from volunteer donors in Puerto Rico were screened for the presence of Zika virus RNA using the cobas Zika NAAT. Positive donations were further tested to confirm infection, estimate viral load, and identify Zika virus-specific IgM antibodies. Individuals with positive blood donations were invited to attend follow-up visits. Donations with confirmed infection (defined as detection of Zika virus RNA or IgM on additional testing of index or follow-up samples) were assessed for stage of infection according to Zika virus RNA detectability in simulated minipools, viral load, and Zika virus IgM status. A three-step process was used to estimate the mean duration of NAAT reactivity of Zika virus in human plasma from individuals identified pre-seroconversion with at least one follow up visit and to update the 2016 incidence estimate of Zika virus infection.
Between April 3 and Dec 31, 2016, 53 112 blood donations were screened for Zika virus, of which 351 tested positive, 339 had confirmed infections, and 319 could be staged. Compared with IgM-positive index donations (n=110), IgM-negative index donations (n=209) had higher mean viral loads (1·1 × 106vs 8·3 × 104 international units per mL) and were more likely to be detected in simulated minipools (93% n=194 vs 26% n=29). The proportions of donations with confirmed infections that had viral RNA detected only in individual-donation NAATs (ie, not in simulated minipools) and were IgM positive increased as the epidemic evolved. The estimated mean duration of NAAT detectability in the 140 donors included in the follow-up study was 11·70 days (95% CI 10·06–14·36). Applying this detection period to the observed proportion of donations that were confirmed NAAT positive yielded a Zika virus seasonal incidence estimate of 21·1% (95% CI 18·1–24·1); 768 101 infections in a population of 3 638 773 in 2016.
Characterisation of early Zika virus infection has implications for blood safety because infectivity of blood donations and utility of screening methods likely correlate with viral load and serological stage of infection. Our findings also have implications for diagnostic testing, public health surveillance, and epidemiology, and we estimate that around 21% of the Puerto Rican population was infected during the 2016 outbreak.
Biomedical Advanced Research and Development Authority, National Heart, Lung, and Blood Institute.
Abstract
Background
To inform public health policy, it is critical to monitor coronavirus disease 2019 vaccine effectiveness (VE), including against acquiring infection.
Methods
We estimated VE using ...self-reported vaccination in a retrospective cohort of repeat blood donors who donated during the first half of 2021, and we demonstrated a viable approach for monitoring VE via serological surveillance.
Results
Using Poisson regression, we estimated an overall VE of 88.8% (95% confidence interval, 86.2–91.1), adjusted for demographic covariates and variable baseline risk.
Conclusions
The time since first reporting vaccination, age, race and/or ethnicity, region, and calendar time were statistically significant predictors of incident infection.
Abstract
Background
Previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) vaccination, independently and combined (“hybrid ...immunity”), result in partial protection from subsequent infection and strong protection from severe disease. Proportions of the US population who have been infected, vaccinated, or have hybrid immunity remain unclear, posing a challenge for assessing effective pandemic mitigation strategies.
Methods
In this serial cross-sectional study, nationwide blood donor specimens collected during January–December 2021 were tested for anti-spike and anti-nucleocapsid antibodies, and donor COVID-19 vaccination history of ≥1 dose was collected. Monthly seroprevalence induced from SARS-CoV-2 infection, COVID-19 vaccination, or both, were estimated. Estimates were weighted to account for demographic differences from the general population and were compared temporally and by demographic factors.
Results
Overall, 1 123 855 blood samples were assayed. From January to December 2021, the weighted percentage of donations with seropositivity changed as follows: seropositivity due to vaccination without previous infection, increase from 3.5% (95% confidence interval, 3.4%–3.7%) to 64.0%, (63.5%–64.5%); seropositivity due to previous infection without vaccination, decrease from 15.6% (15.2%–16.0%) to 11.7% (11.4%–12.0%); and seropositivity due to hybrid immunity, increase from 0.7% (0.6%–0.7%) to 18.9% (18.5%–19.3%). Combined seroprevalence from infection, vaccination, or both increased from 19.8% (19.3%–20.2%) to 94.5% (93.5%–94.0%). Infection- and vaccination-induced antibody responses varied significantly by age, race-ethnicity, and region, but not by sex.
Conclusions
Our results indicate substantial increases in population humoral immunity from SARS-CoV-2 infection, COVID-19 vaccination, and hybrid immunity during 2021. These findings are important to consider in future COVID-19 studies and long-term pandemic mitigation efforts.
During January–December 2021, among 1 123 855 blood donations, monthly population-weighted seroprevalence estimates due to coronavirus disease 2019 vaccination increased from 3.5% to 64.0%, previous severe acute respiratory syndrome coronavirus 2 infection decreased from 15.6% to 11.7%, and both previous infection and vaccination increased from 0.7% to 18.9%.
BACKGROUND
Zika virus (ZIKV) is transmitted by Aedes mosquitos and can result in severe congenital and adult neurologic abnormalities. ZIKV has rapidly spread northward through Central America and ...the Caribbean and autochthonous cases have been identified in the continental United States. High rates of ZIKA RNA positivity were detected in blood donors during previous epidemics. ZIKV transmission by transfused blood from healthy donor components has been a growing concern.
STUDY DESIGN AND METHODS
Individual‐donation aliquots of plasma from volunteer blood donors were tested individually with an investigational Procleix ZIKV assay. Initially reactive samples were tested for ZIKV RNA in plasma and red blood cells (RBCs) and for ZIKV‐specific antibodies in serum. A confirmed positive classification required confirmation of RNA and/or detection of ZIKV antibodies in index and/or follow‐up samples.
RESULTS
Between September 19 and November 30, 2016, a total of 466,834 donations were screened for ZIKV RNA. Five donors (one in approx. 93,000) were reactive for ZIKV RNA by both the Procleix ZIKV assay and supplemental testing. The donations were collected outside areas considered as having active transmission, and all five donors had travel exposures. A lookback case demonstrated no infection despite transfusion of a Zika IgG–positive platelet (PLT) component with probable low levels of ZIKV RNA.
CONCLUSIONS
This report describes the first ZIKV‐positive donors detected outside areas with active transmission. These donors most likely represent travel‐acquired “tail‐end infections” with prolonged RBC‐associated ZIKV RNA. The lack of transmission to the recipient of an apheresis PLT may suggest that these units are not infectious.
Certain serum proteins, including C-reactive protein (CRP) and D-dimer, have prognostic value in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Nonetheless, these factors ...are non-specific, providing limited mechanistic insight into the peripheral blood mononuclear cell (PBMC) populations that drive the pathogenesis of severe COVID-19. To identify cellular phenotypes associated with disease, we performed a comprehensive, unbiased analysis of total and plasma-membrane PBMC proteomes from 40 unvaccinated individuals with SARS-CoV-2, spanning the whole disease spectrum. Combined with RNA sequencing (RNA-seq) and flow cytometry from the same donors, we define a comprehensive multi-omic profile for each severity level, revealing that immune-cell dysregulation progresses with increasing disease. The cell-surface proteins CEACAMs1, 6, and 8, CD177, CD63, and CD89 are strongly associated with severe COVID-19, corresponding to the emergence of atypical CD3+CD4+CEACAM1/6/8+CD177+CD63+CD89+ and CD16+CEACAM1/6/8+ mononuclear cells. Utilization of these markers may facilitate real-time patient assessment by flow cytometry and identify immune populations that could be targeted to ameliorate immunopathology.
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•Proteomic analysis of immune cells across the COVID-19 severity spectrum•Both whole-cell and plasma-membrane proteomes are quantified•Surface markers associated with severe COVID-19 include CEACAMs, CD177, CD63, CD89•Unusual marker-expressing T cell and monocyte populations emerge in severe disease
Potts et al. describe a multiplexed proteomic analysis of immune cells obtained from individuals with COVID-19, identifying CEACAMs 1/6/8, CD177, CD63, and CD89 as cell-surface markers upregulated in severe disease. Phenotyping identifies emergence of unusual CD4+ T cell and CD16+ monocyte populations expressing these markers in severe disease.
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