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HIV-1 persists as a latent reservoir in people receiving suppressive antiretroviral therapy (ART). When ART is interrupted (treatment interruption/TI), rebound virus re-initiates systemic infection in the lymphoid system. During TI, HIV-1 is also detected in cerebrospinal fluid (CSF), although the source of this rebound virus is unknown. To investigate whether there is a distinct HIV-1 reservoir in the central nervous system (CNS), we compared rebound virus after TI in the blood and CSF of 11 participants. Peak rebound CSF viral loads vary and we show that high viral loads and the appearance of clonally amplified viral lineages in the CSF are correlated with the transient influx of white blood cells. We found no evidence of rebound macrophage-tropic virus in the CSF, even in one individual who had macrophage-tropic HIV-1 in the CSF pre-therapy. We propose a model in which R5 T cell-tropic virus is released from infected T cells that enter the CNS from the blood (or are resident in the CNS during therapy), with clonal amplification of infected T cells and virus replication occurring in the CNS during TI.

The predominant approach for antibody generation remains animal immunization, which can yield exceptionally selective and potent antibody clones owing to the powerful evolutionary process of somatic hypermutation. However, animal immunization is inherently slow, not always accessible and poorly compatible with many antigens. Here, we describe 'autonomous hypermutation yeast surface display' (AHEAD), a synthetic recombinant antibody generation technology that imitates somatic hypermutation inside engineered yeast. By encoding antibody fragments on an error-prone orthogonal DNA replication system, surface-displayed antibody repertoires continuously mutate through simple cycles of yeast culturing and enrichment for antigen binding to produce high-affinity clones in as little as two weeks. We applied AHEAD to generate potent nanobodies against the SARS-CoV-2 S glycoprotein, a G-protein-coupled receptor and other targets, offering a template for streamlined antibody generation at large.

We show that SARS-CoV-2 spike protein interacts with both cellular heparan sulfate and angiotensin-converting enzyme 2 (ACE2) through its receptor-binding domain (RBD). Docking studies suggest a heparin/heparan sulfate-binding site adjacent to the ACE2-binding site. Both ACE2 and heparin can bind independently to spike protein in vitro, and a ternary complex can be generated using heparin as a scaffold. Electron micrographs of spike protein suggests that heparin enhances the open conformation of the RBD that binds ACE2. On cells, spike protein binding depends on both heparan sulfate and ACE2. Unfractionated heparin, non-anticoagulant heparin, heparin lyases, and lung heparan sulfate potently block spike protein binding and/or infection by pseudotyped virus and authentic SARS-CoV-2 virus. We suggest a model in which viral attachment and infection involves heparan sulfate-dependent enhancement of binding to ACE2. Manipulation of heparan sulfate or inhibition of viral adhesion by exogenous heparin presents new therapeutic opportunities.

The continued emergence of SARS-CoV-2 variants and the threat of future Sarbecovirus zoonoses have spurred the design of vaccines that can induce broad immunity against multiple coronaviruses. Here, we use computational methods to infer ancestral phylogenetic reconstructions of receptor binding domain (RBD) sequences across multiple Sarbecovirus clades and incorporate them into a multivalent adenoviral-vectored vaccine. Mice immunized with this pan-Sarbecovirus vaccine are protected in the upper and lower respiratory tracts against infection by historical and contemporary SARS-CoV-2 variants, SARS-CoV, and pre-emergent SHC014 and Pangolin/GD coronavirus strains. Using genetic and immunological approaches, we demonstrate that vaccine-induced protection unexpectedly is conferred principally by CD4+ and CD8+ T cell-mediated anamnestic responses. Importantly, prior mRNA vaccination or SARS-CoV-2 respiratory infection does not alter the efficacy of the mucosally delivered pan-Sarbecovirus vaccine. These data highlight the promise of a phylogenetic approach for antigen and vaccine design against existing and pre-emergent Sarbecoviruses with pandemic potential. [Display omitted] • Phylogenetically inferred RBDs are used to design a trivalent Sarbecovirus vaccine • Trivalent vaccine protects against pandemic and pre-emergent Sarbecoviruses • CD4+ and CD8+ T cell responses mediate vaccine protection • A mucosal booster enhances natural or vaccination-induced pre-existing immunity Case et al. use ancestral phylogenetic reconstructions of Sarbecovirus sequences to generate a pan-Sarbecovirus vaccine. In mice, the vaccine confers protection against all tested Sarbecoviruses, including SARS-CoV, multiple SARS-CoV-2 variants, and pre-emergent Sarbecovirus strains. Pre-existing SARS-CoV-2 immunity does not affect the immunogenicity or efficacy of mucosal boosting with this vaccine. [ABSTRACT FROM AUTHOR]

Pneumocystis species are opportunistic mammalian pathogens that cause severe pneumonia in immunocompromised individuals. These fungi are highly host specific and uncultivable in vitro Human Pneumocystis infections present major challenges because of a limited therapeutic arsenal and the rise of drug resistance. To investigate the diversity and demographic history of natural populations of Pneumocystis infecting humans, rats, and mice, we performed whole-genome and large-scale multilocus sequencing of infected tissues collected in various geographic locations. Here, we detected reduced levels of recombination and variations in historical demography, which shape the global population structures. We report estimates of evolutionary rates, levels of genetic diversity, and population sizes. Molecular clock estimates indicate that Pneumocystis species diverged before their hosts, while the asynchronous timing of population declines suggests host shifts. Our results have uncovered complex patterns of genetic variation influenced by multiple factors that shaped the adaptation of Pneumocystis populations during their spread across mammals.IMPORTANCE Understanding how natural pathogen populations evolve and identifying the determinants of genetic variation are central issues in evolutionary biology. Pneumocystis, a fungal pathogen which infects mammals exclusively, provides opportunities to explore these issues. In humans, Pneumocystis can cause a life-threatening pneumonia in immunosuppressed individuals. In analysis of different Pneumocystis species infecting humans, rats, and mice, we found that there are high infection rates and that natural populations maintain a high level of genetic variation despite low levels of recombination. We found no evidence of population structuring by geography. Our comparisons of the times of divergence of these species to their respective hosts suggest that Pneumocystis may have undergone recent host shifts. The results demonstrate that Pneumocystis strains are widely disseminated geographically and provide a new understanding of the evolution of these pathogens.

Purpose: Postoperative endophthalmitis is a relatively uncommon, but potentially visually devastating, complication associated with cataract surgery. Specific microbial causes of endophthalmitis are characteristically associated with particular disease time courses. Although Cutibacterium acnes is typically associated with an indolent course of inflammation, we report a case of C. acnes endophthalmitis with onset on postoperative day (POD) 1 and a positive culture from POD 2. Methods: This is a case report. Results: A 56-year-old man underwent cataract extraction and posterior chamber intraocular lens placement in his left eye. On POD 1, he presented with severe discomfort, reduced visual acuity, and significant inflammation. On POD 2, his anterior chamber was tapped and injected with broad-spectrum antibiotics and steroids. The inflammation ultimately resolved, and his visual acuity improved to 20/20. Conclusion: C. acnes is a rare cause of hyperacute-onset postoperative endophthalmitis. Maintaining a high clinical suspicion and initiating prompt treatment can help to optimize long-term visual outcomes. [ABSTRACT FROM AUTHOR]

This article examines inequality in different dimensions of student academic achievement (math, science, and reading) by family background and school context in three East Asian (Taiwan, Japan, and South Korea) and three Western (United States, Germany, and the Czech Republic) nations. Building on Hauser (2009), we develop a novel multiple-indicator multiple-cause (MIMIC) model with a two-level hierarchical linear modeling specification, which allows us to explicitly test whether the several academic achievement constructs respond similarly to variation in family background and variation among schools and countries. The two-level MIMIC model is specified in detail and applied to 2012 Programme for International Student Assessment data. The analysis reveals new empirical insights, such as substantive differences within countries in performance inequality by subject, particularly among East Asian countries. While the data do not support the view of a "virtuous" relationship between excellence and equity in education, nor do they lend strong support to a "vicious" relationship either.

BACKGROUND: Little is known about the distribution and outcomes of hip fractures in pediatric patients during the COVID-19 pandemic. OBJECTIVE: To study the clinical outcomes of both pediatric and adult patients who underwent hip fracture surgeries and determine the effects of changes surrounding the COVID-19 pandemic. METHODS: Both pediatric and adult surgical hip fracture cases were analyzed from the pandemic year (2020) and the control year (2019) using the American College of Surgeons National Surgical Quality Improvement Program database. RESULTS: Between the prepandemic (control) and pandemic years, a total of 2,438 pediatric and 28,180 adult cases were compared. Pediatric patients had similar perioperative characteristics and outcomes between the two years. Significantly fewer hip fractures were reported among adults during the pandemic (p <.001). Preoperatively, more adult patients had ventilator dependence (p =.020), transfusions (p =.029), and systemic inflammatory response syndrome (p <.001) in 2020. Adult operations were more likely to be emergent in 2020 (p <.001) and adults had more severe disease states. Length of stay (p <.001) and the time from operation to discharge (p <.001) were significantly longer for the adult cohort in 2020. Mortality was also higher for adults during the first year of the pandemic (p =.003), and superficial surgical site infections became more common (p =.036). CONCLUSION: Pediatric hip fracture patients had similar clinical outcomes between 2019 and 2020. Adults with hip fractures presented in more serious clinical conditions, which resulted in higher mortality in 2020. Further studies could better clarify the reasons as to why adult hip fracture patients had markedly worse clinical course during the COVID year than pediatric patients. [ABSTRACT FROM AUTHOR]

Sociologists have long used educational expectations to understand the complex mental processes underlying individuals' educational decision making. Yet, little research evaluates how students actually formulate their educational expectations. Status attainment theory asserts that students adopt their educational expectations early based on family background and social influences, and that their educational expectations are driven by a static mental construct as a result. In contrast, recent research based on Bayesian learning theory hypothesizes that students mostly adapt their educational expectations in light of new information about their academic potential. Comparing models of expectations formation in adolescence, we find that students' expectations do not derive from a static mental construct. However, students adapt their educational expectations only modestly and only in response to very large changes in grade point averages. Thus, adolescent educational expectations stabilize early and are rather persistent over time.

This article addresses a potentially serious problem with the widely used self-rated health (SRH) survey item: that different groups have systematically different ways of using the item's response categories. Analyses based on unadjusted SRH may thus yield misleading results. The authors evaluate anchoring vignettes as a possible solution to this problem. Using vignettes specifically designed to calibrate the SRH item and data from the Wisconsin Longitudinal Study (WLS; N = 2,625), the authors show how demographic and health-related factors, including sex and education, predict differences in rating styles. Such differences, when not adjusted for statistically, may be sufficiently large to lead to mistakes in rank orderings of groups. In the present sample, unadjusted models show that women have better SRH than men, but this difference disappears in models adjusting for women's greater health-optimism. Anchoring vignettes appear a promising tool for improving intergroup comparability of SRH. (Contains 9 notes, 7 tables, and 2 figures.)

Research on variation in cognitive abilities has focused largely on their genetic or experiential sources and on their economic consequences. This article takes a broader look at the consequences of cognitive ability--IQ--across the life course. Contrary to received wisdom, the effects of IQ on economic success are almost entirely mediated by educational attainment. Among persons with equal levels of schooling, IQ has little influence on job performance, occupational standing, earnings, or wealth. But there are other, sometimes surprising consequences of IQ throughout adult life. The long-term correlates of adolescent cognition include drinking behavior, survey participation, Internet use, and the timing of menopause. These are surveyed primarily using findings from the Wisconsin Longitudinal Study. (Contains 2 figures, 1 table, and 18 notes.)