Bound by the Bounty: Collaboratively Shaping Evaluation Processes for Queer AI Harms

Bias evaluation benchmarks and dataset and model documentation have emerged as central processes for assessing the biases and harms of artificial intelligence (AI) systems. However, these auditing processes have been criticized for their failure to integrate the knowledge of marginalized communities and consider the power dynamics between auditors and the communities. Consequently, modes of bias evaluation have been proposed that engage impacted communities in identifying and assessing the harms of AI systems (e.g., bias bounties). Even so, asking what marginalized communities want from such auditing processes has been neglected. In this paper, we ask queer communities for their positions on, and desires from, auditing processes. To this end, we organized a participatory workshop to critique and redesign bias bounties from queer perspectives. We found that when given space, the scope of feedback from workshop participants goes far beyond what bias bounties afford, with participants questioning the ownership, incentives, and efficacy of bounties. We conclude by advocating for community ownership of bounties and complementing bounties with participatory processes (e.g., co-creation).Comment: To appear at AIES 202

Safety, immunogenicity, and reactogenicity of BNT162b2 and mRNA-1273 COVID-19 vaccines given as fourth-dose boosters following two doses of ChAdOx1 nCoV-19 or BNT162b2 and a third dose of BNT162b2 (COV-BOOST): a multicentre, blinded, phase 2, randomised trial

Background Some high-income countries have deployed fourth doses of COVID-19 vaccines, but the clinical need, effectiveness, timing, and dose of a fourth dose remain uncertain. We aimed to investigate the safety, reactogenicity, and immunogenicity of fourth-dose boosters against COVID-19.Methods The COV-BOOST trial is a multicentre, blinded, phase 2, randomised controlled trial of seven COVID-19 vaccines given as third-dose boosters at 18 sites in the UK. This sub-study enrolled participants who had received BNT162b2 (Pfizer-BioNTech) as their third dose in COV-BOOST and randomly assigned them (1:1) to receive a fourth dose of either BNT162b2 (30 µg in 0·30 mL; full dose) or mRNA-1273 (Moderna; 50 µg in 0·25 mL; half dose) via intramuscular injection into the upper arm. The computer-generated randomisation list was created by the study statisticians with random block sizes of two or four. Participants and all study staff not delivering the vaccines were masked to treatment allocation. The coprimary outcomes were safety and reactogenicity, and immunogenicity (antispike protein IgG titres by ELISA and cellular immune response by ELISpot). We compared immunogenicity at 28 days after the third dose versus 14 days after the fourth dose and at day 0 versus day 14 relative to the fourth dose. Safety and reactogenicity were assessed in the per-protocol population, which comprised all participants who received a fourth-dose booster regardless of their SARS-CoV-2 serostatus. Immunogenicity was primarily analysed in a modified intention-to-treat population comprising seronegative participants who had received a fourth-dose booster and had available endpoint data. This trial is registered with ISRCTN, 73765130, and is ongoing.Findings Between Jan 11 and Jan 25, 2022, 166 participants were screened, randomly assigned, and received either full-dose BNT162b2 (n=83) or half-dose mRNA-1273 (n=83) as a fourth dose. The median age of these participants was 70·1 years (IQR 51·6–77·5) and 86 (52%) of 166 participants were female and 80 (48%) were male. The median interval between the third and fourth doses was 208·5 days (IQR 203·3–214·8). Pain was the most common local solicited adverse event and fatigue was the most common systemic solicited adverse event after BNT162b2 or mRNA-1273 booster doses. None of three serious adverse events reported after a fourth dose with BNT162b2 were related to the study vaccine. In the BNT162b2 group, geometric mean anti-spike protein IgG concentration at day 28 after the third dose was 23 325 ELISA laboratory units (ELU)/mL (95% CI 20 030–27 162), which increased to 37 460 ELU/mL (31 996–43 857) at day 14 after the fourth dose, representing a significant fold change (geometric mean 1·59, 95% CI 1·41–1·78). There was a significant increase in geometric mean anti-spike protein IgG concentration from 28 days after the third dose (25 317 ELU/mL, 95% CI 20 996–30 528) to 14 days after a fourth dose of mRNA-1273 (54 936 ELU/mL, 46 826–64 452), with a geometric mean fold change of 2·19 (1·90–2·52). The fold changes in anti-spike protein IgG titres from before (day 0) to after (day 14) the fourth dose were 12·19 (95% CI 10·37–14·32) and 15·90 (12·92–19·58) in the BNT162b2 and mRNA-1273 groups, respectively. T-cell responses were also boosted after the fourth dose (eg, the fold changes for the wild-type variant from before to after the fourth dose were 7·32 [95% CI 3·24–16·54] in the BNT162b2 group and 6·22 [3·90–9·92] in the mRNA-1273 group).Interpretation Fourth-dose COVID-19 mRNA booster vaccines are well tolerated and boost cellular and humoral immunity. Peak responses after the fourth dose were similar to, and possibly better than, peak responses after the third dose

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Multiple Functions of the Type II Thioesterase Associated with the Phoslactomycin Polyketide Synthase

Polyketide synthases (PKSs) are molecular assembly lines that condense basic chemical building blocks for the production of structurally diverse polyketides. Many PKS biosynthetic gene clusters contain a gene encoding for a type II thioesterase (TEII). It is believed that TEIIs exert a proofreading function and restore or increase the productivity of PKSs by removing aberrant modifications on the acyl-carrier proteins (ACPs) of the PKS assembly line. Yet biochemical evidence is still sparse. Here, we investigated the function of PnG, the TEII of the phoslactomycin PKS (Pn PKS), in the context of its cognate assembly line in vitro. Biochemical analysis revealed that PnG preferentially hydrolyzes alkyl-ACPs over (alkyl)malonyl-ACPs by up to three orders of magnitude, supporting a proofreading role of the enzyme. We further demonstrate that PnG increases the in vitro production of different native and non-native tetra-, penta-, and hexaketide derivatives of phoslactomycin by more than one order of magnitude and show that these effects are caused by the initial clearing of the Pn PKS, as well as proofreading of the active assembly line. Finally, we demonstrate that PnG is able to release intermediate but notably also terminal polyketides from the Pn PKS. This allows PnG to functionally replace and overcome the terminal TEI activity of chimeric in vitro Pn PKS systems, as showcased with a phoslactomycin hexaketide system. Altogether, our experiments provide detailed insights into the molecular mechanisms and the multiple functions of PnG in its native context, as well as their potential use in future applications

CIED malfunction in patients receiving radiation is a rare event that could be detected by remote monitoring

INTRODUCTION: An increasing number of patients with cardiac devices require radiation therapy for treatment of a variety of cancers. This study aimed to identify the incidence and predictors of cardiac implantable electronic devices (CIED) malfunction in a real-world population that has received radiation therapy. METHODS: This retrospective cohort study included 109 adult patients who received radiation therapy at the University of Rochester Medical Center, Radiation Oncology Department, between 2000 and 2015. Sixty patients had pacemakers and 49 had automatic implantable cardioverter defibrillators. Subjects received either high energy (16 MV) and/or low energy (6 MV) photon beams with or without electron beams (6-16 MeV). We included interrogations done from first day of radiation and up to 3 months\u27 postradiation therapy. Outcomes analyzed were device-related malfunctions and device-related clinical events. Fisher\u27s exact, Wilcoxon, and Kruskall-Wallis tests were used for bivariate analysis. Logistic regression with robust adjustment was used for multivariate analysis. RESULTS: We identified six device-related malfunctions. All events were minor and included partial settings reset leading to loss of historical data, pacing thresholds changes, lead impedance changes, and LV output increase. Two patients had device-related clinical events, including dyspnea and diaphragmatic-stimulation. In bivariate analysis, CIED malfunction was associated with CIED duration in situ. In multivariate analysis, there was no significant statistical association between adverse events and beam energy type, CIED location, or dose of radiation delivered to the target. CONCLUSIONS: CIED malfunctions are uncommon in real-world patients and associated with minor clinical events. In our cohort, remote CIED monitoring would have identified all events

Heterogeneity in leukemia cells that escape drug-induced senescence-like state

Abstract Erythropoietin (EPO) suppresses drug-induced apoptosis in EPO-receptor-positive leukemia cells and allows cells to persist after drug treatment by promoting cellular senescence. Importantly a small proportion of senescent cells can re-enter the cell cycle and resume proliferation after drug treatment, resulting in disease recurrence/persistence. Using a single-cell assay to track individual cells that exit a drug-induced senescence-like state, we show that cells exhibit asynchronous exit from a senescent-like state, and display different rates of proliferation. Escaped cells retain sensitivity to drug treatment, but display inter-clonal variability. We also find heterogeneity in gene expression with some of the escaped clones retaining senescence-associated gene expression. Senescent leukemia cells exhibit changes in gene expression that affect metabolism and senescence-associated secretory phenotype (SASP)-related genes. Herein, we generate a senescence gene signature and show that this signature is a prognostic marker of worse overall survival in AML and multiple other cancers. A portion of senescent leukemia cells depend on lysosome activity; chloroquine, an inhibitor of lysosome activity, promotes senolysis of some senescent leukemia cells. Our study indicates that the serious risks associated with the use of erythropoietin-stimulating agents (ESAs) in anemic cancer patients may be attributed to their ability to promote drug-tolerant cancer cells through the senescence program

Blood Lead Concentrations and Antibody Levels to Measles, Mumps, and Rubella among U.S. Children

Child blood lead concentrations have been associated with measures of immune dysregulation in nationally representative study samples. However, response to vaccination—often considered the gold standard in immunotoxicity testing—has not been examined in relation to typical background lead concentrations common among U.S. children. The present study estimated the association between blood lead concentrations and antigen-specific antibody levels to measles, mumps, and rubella in a nationally representative sample of 7005 U.S. children aged 6–17 years. Data from the 1999–2004 cycles of the National Health and Nutrition Examination Survey (NHANES) were used. In the adjusted models, children with blood lead concentrations between 1 and 5 µg/dL had an 11% lower anti-measles (95% CI: −16, −5) and a 6% lower anti-mumps antibody level (95% CI: −11, −2) compared to children with blood lead concentrations <1 µg/dL. The odds of a seronegative anti-measles antibody level was approximately two-fold greater for children with blood lead concentrations between 1 and 5 µg/dL compared to children with blood lead concentrations <1 µg/dL (OR = 2.0, 95% CI: 1.4, 3.1). The adverse associations observed in the present study provide further evidence of potential immunosuppression at blood lead concentrations <5 µg/dL, the present Centers for Disease Control and Prevention action level