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<title>15 August, 2023</title>
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<h1 data-aos="fade-down" id="covid-19-sentry">Covid-19 Sentry</h1>
<h1 data-aos="fade-right" data-aos-anchor-placement="top-bottom" id="contents">Contents</h1>
<ul>
<li><a href="#from-preprints">From Preprints</a></li>
<li><a href="#from-clinical-trials">From Clinical Trials</a></li>
<li><a href="#from-pubmed">From PubMed</a></li>
<li><a href="#from-patent-search">From Patent Search</a></li>
</ul>
<h1 data-aos="fade-right" id="from-preprints">From Preprints</h1>
<ul>
<li><strong>Revisiting the small-world property of co-enrollment networks: A network analysis of hybrid course delivery strategies</strong> -
<div>
Infectious disease outbreaks bring new challenges to campus operations at institutions of higher education (IHEs). At the beginning of the COVID-19 pandemic, as a precaution against COVID-19 transmission on their campuses, many IHEs shifted to entirely remote courses in the Spring 2020 semester. As these institutions prepared for the Fall 2020 semester, their administrations evaluated the extent to which remote courses should continue. While remote courses may reduce the number of students who interact on campus and thus mitigate the risk of disease spread, there may be academic and financial downsides. Methodology: With de-identified enrollment, course schedule, and student profile data from the Fall 2019 semester at Georgia Institute of Technology (Georgia Tech), we construct a co-enrollment network, which is a representation of student connections through courses. In this co-enrollment network, we observe the small-world property in which the average path length among reachable student pairs is short and nearly all students are connected to each other in the main component of the network through multiple independent paths. We also see high connectivity between different majors. Then, we apply various hybrid instructional mode strategies to this co-enrollment network and use network connectivity and in-person instruction metrics to compare these strategies from both health and academic perspectives, by their impacts on various groups of students, and based on the trade-off between network connectivity and in-person instruction. Results: Although these strategies result in decreased network connectivity, they do not remove the small-world property. When comparing the strategies in terms of network connectivity, we find three different strategy types to be the most favorable. Even under these strategies, the percentage of students with in-person courses that could be exposed rises quickly with initial infection rates. When comparing the strategies in terms of in-person instruction, the most favorable strategies select a fixed percentage of courses for each subject to be delivered remotely. We then consider the impacts of these strategies on various groups of students to evaluate if there may be disparate impacts across these groups. In general, we find that strategies with more remote courses result in less disparate impacts on network connectivity and in-person instruction across these groups. In addition, we generally see less in-person instruction for lower-level students (i.e. first-year students and sophomores) compared to upper-level students. Regarding the trade-off between network connectivity and in-person instruction, the only strategy that is suboptimal under all scenarios in this study is the 1000s and 4000s only strategy, which keeps all 1000- and 4000-level courses in-person. This is because of its large quantity of remote courses, the large 1000- and 4000- level courses, the highly central 1000- level courses, and the high connectivity among first-year students and seniors. Importance: By quantitatively comparing network connectivity and in-person instruction for these various strategies, campus administrators can weigh the physical health, academic performance, and mental health of students, along with the financial well-being of their academic institution when responding to infectious disease outbreaks.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://osf.io/jp6aq/" target="_blank">Revisiting the small-world property of co-enrollment networks: A network analysis of hybrid course delivery strategies</a>
</div></li>
<li><strong>SARS-CoV-2 Neutralizing Antibodies Following a Second BA.5 Bivalent Booster</strong> -
<div>
Bivalent COVID-19 mRNA vaccines expressing both the ancestral D614G and Omicron BA.5 spike proteins were introduced in August 2022 with the goal of broadening immunity to emerging SARS-CoV-2 Omicron subvariants. Subsequent studies on bivalent boosters found neutralizing antibody responses similar to boosters with the original monovalent vaccine, likely the result of immunological imprinting. Guidelines allow for administration of a second bivalent booster in high-risk groups, but it remains unknown whether this would broaden antibody responses. To address this question, we assessed longitudinal serum SARS-CoV-2-neutralizing titers in 18 elderly immunocompetent individuals (mean age 69) following a fourth monovalent booster and two BA.5 bivalent booster vaccines using pseudovirus neutralization assays against D614G, Omicron BA.5, and Omicron XBB.1.5. There was a small but significant increase in peak neutralizing antibody responses against Omicron BA.5 and XBB.1.5 following the first bivalent booster, but no significant increase in peak titers following the second bivalent booster. Omicron-specific neutralizing titers remained low after both doses of the BA.5 bivalent booster. Our results suggest that a second dose of the BA.5 bivalent booster is not sufficient to broaden antibody responses and to overcome immunological imprinting. A monovalent vaccine targeting only the spike of the recently dominant SARS-CoV-2 may mitigate the back boosting associated with the original antigenic sin.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.08.13.553148v1" target="_blank">SARS-CoV-2 Neutralizing Antibodies Following a Second BA.5 Bivalent Booster</a>
</div></li>
<li><strong>Impact of age and sex on neuroinflammation following SARS-CoV-2 infection in a murine model</strong> -
<div>
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiological agent for the worldwide COVID-19 pandemic, is known to infect people of all ages and both sexes. Senior populations have the greatest risk of severe disease, and sexual dimorphism in clinical outcomes has been reported in COVID-19. SARS-CoV-2 infection in humans can cause damage to multiple organ systems, including the brain. Neurological symptoms are widely observed in patients with COVID-19, with many survivors suffering from persistent neurological and cognitive impairment, potentially accelerating Alzheimer's disease. The present study aims to investigate the impact of age and sex on the neuroinflammatory response to SARS-CoV-2 infection using a mouse model. Wild-type C57BL/6 mice were inoculated, by intranasal route, with SARS-CoV-2 lineage B.1.351 variant known to infect mice. Older animals and in particular males exhibited a significantly greater weight loss starting at 4 dpi. In addition, male animals exhibited higher viral RNA loads and higher titers of infectious virus in the lung, which was particularly evident in males at 16 months of age. Notably, no viral RNA was detected in the brains of infected mice, regardless of age or sex. Nevertheless, expression of IL-6, TNF-, and CCL-2 in the lung and brain was increased with viral infection. An unbiased brain RNA-seq/transcriptomic analysis showed that SARS-CoV-2 infection caused significant changes in gene expression profiles in the brain, with innate immunity, defense response to virus, cerebravascular and neuronal functions, as the major molecular networks affected. The data presented in this study show that SARS-CoV-2 infection triggers a neuroinflammatory response despite the lack of detectable virus in the brain. Age and sex have a modifying effect on this pathogenic process. Aberrant activation of innate immune response, disruption of blood-brain barrier and endothelial cell integrity, and supression of neuronal activity and axonogenesis underlie the impact of SARS-CoV-2 infection on the brain. Understanding the role of these affected pathways in SARS-CoV-2 pathogenesis helps identify appropriate points of therapeutic interventions to alleviate neurological dysfunction observed during COVID-19.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.08.11.552998v1" target="_blank">Impact of age and sex on neuroinflammation following SARS-CoV-2 infection in a murine model</a>
</div></li>
<li><strong>Pandemic preparedness through genomic surveillance: Overview of mutations in SARS-CoV-2 over the course of COVID-19 outbreak</strong> -
<div>
Genomic surveillance is a vital strategy for preparedness against the spread of infectious diseases and to aid in development of new treatments. In an unprecedented effort, millions of samples from COVID-19 patients have been sequenced worldwide for SARS-CoV-2. Using more than 8 million sequences that are currently available in GenBank SARS-CoV-2 database, we report a comprehensive overview of mutations in all 26 proteins and open reading frames (ORFs) from the virus. The results indicate that the spike protein, NSP6, nucleocapsid protein, envelope protein and ORF7b have shown the highest mutational propensities so far (in that order). In particular, the spike protein has shown rapid acceleration in mutations in the post-vaccination period. Monitoring the rate of non-synonymous mutations (Ka) provides a fairly reliable signal for genomic surveillance, successfully predicting surges in 2022. Further, the external proteins (spike, membrane, envelope, and nucleocapsid proteins) show a significant number of mutations compared to the NSPs. Interestingly, these four proteins showed significant changes in Ka typically 2 to 4 weeks before the increase in number of human infections (surges). Therefore, our analysis provides real time surveillance of mutations of SARS-CoV-2, accessible through the project website http://pandemics.okstate.edu/covid19/. Based on ongoing mutation trends of the virus, predictions of what proteins are likely to mutate next are also made possible by our approach. The proposed framework is general and is thus applicable to other pathogens. The approach is fully automated and provides the needed genomic surveillance to address a fast-moving pandemic such as COVID-19.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.08.12.553079v1" target="_blank">Pandemic preparedness through genomic surveillance: Overview of mutations in SARS-CoV-2 over the course of COVID-19 outbreak</a>
</div></li>
<li><strong>Met58 and di-acidic motif located at C-terminal region of SARS-CoV-2 ORF6 plays a crucial role in its structural conformations</strong> -
<div>
Despite being mostly neglected in structural biology, the C-terminal Regions (CTRs) are studied to be multifunctional in humans as well as in viruses. Their role in cellular processes such as trafficking, protein-protein interactions, and protein-lipid interactions are known due to their structural properties. In our previous findings on SARS-CoV-2 Spike and NSP1 proteins, the C-terminal regions (CTRs) are observed to be disordered and experimental evidence showed a gain of structure properties in different physiological environments. In this line, we have investigated the structural dynamics of CTR (residues 38-61) of SARS-CoV-2 ORF6 protein, disrupting bidirectional transport between the nucleus and cytoplasm. Like Spike and NSP1-CTR, the ORF6-CTR is also disordered in nature but possesses gain of structure properties in minimal physiological conditions. As per studies, the residue such as Methionine at 58th position in ORF6 is critical for interaction with Rae1-Nup98. Therefore, along with M58, we have identified a few other mutations from the literature and performed extensive structure modelling and dynamics studies using computational simulations. The exciting revelations in CTR models provide evidence of its structural flexibility and possible capabilities to perform multifunctionality inside the host.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.08.14.553212v1" target="_blank">Met58 and di-acidic motif located at C-terminal region of SARS-CoV-2 ORF6 plays a crucial role in its structural conformations</a>
</div></li>
<li><strong>Transmission bottleneck size estimation from de novo viral genetic variation</strong> -
<div>
Sequencing of viral infections has become increasingly common over the last decade. Deep sequencing data in particular have proven useful in characterizing the roles that genetic drift and natural selection play in shaping within-host viral populations. They have also been used to estimate transmission bottleneck sizes from identified donor-recipient pairs. These bottleneck sizes quantify the number of viral particles that establish genetic lineages in the recipient host and are important to estimate due to their impact on viral evolution. Current approaches for estimating bottleneck sizes exclusively consider the subset of viral sites that are observed as polymorphic in the donor individual. However, allele frequencies can change dramatically over the course of an individual's infection, such that sites that are polymorphic in the donor at the time of transmission may not be polymorphic in the donor at the time of sampling and allele frequencies at donor-polymorphic sites may change dramatically over the course of a recipient's infection. Because of this, transmission bottleneck sizes estimated using allele frequencies observed at a donor's polymorphic sites may be considerable underestimates of true bottleneck sizes. Here, we present a new statistical approach for instead estimating bottleneck sizes using patterns of viral genetic variation that arose de novo within a recipient individual. Specifically, our approach makes use of the number of clonal viral variants observed in a transmission pair, defined as the number of viral sites that are monomorphic in both the donor and the recipient but carry different alleles. We first test our approach on a simulated dataset and then apply it to both influenza A virus sequence data and SARS-CoV-2 sequence data from identified transmission pairs. Our results confirm the existence of extremely tight transmission bottlenecks for these two respiratory viruses, using an approach that does not tend to underestimate transmission bottleneck sizes.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.08.14.553219v1" target="_blank">Transmission bottleneck size estimation from de novo viral genetic variation</a>
</div></li>
<li><strong>Mutational basis of serum cross-neutralization profiles elicited by infection or vaccination with SARS-CoV-2 variants</strong> -
<div>
A series of SARS-CoV-2 variants emerged during the pandemic under selection for neutralization resistance. Convalescent and vaccinated sera show consistently different cross-neutralization profiles depending on infecting or vaccine variants. To understand the basis of this heterogeneity, we modeled serum cross-neutralization titers for 165 sera after infection or vaccination with historically prominent lineages tested against 18 variant pseudoviruses. Cross-neutralization profiles were well captured by models incorporating autologous neutralizing titers and combinations of specific shared and differing mutations between the infecting/vaccine variants and pseudoviruses. Infecting/vaccine variant-specific models identified mutations that significantly impacted cross-neutralization and quantified their relative contributions. Unified models that explained cross-neutralization profiles across all infecting and vaccine variants provided accurate predictions of holdout neutralization data comprising untested variants as infecting or vaccine variants, and as test pseudoviruses. Finally, comparative modeling of 2-dose versus 3-dose mRNA-1273 vaccine data revealed that the third dose overcame key resistance mutations to improve neutralization breadth.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.08.13.553144v1" target="_blank">Mutational basis of serum cross-neutralization profiles elicited by infection or vaccination with SARS-CoV-2 variants</a>
</div></li>
<li><strong>Structural elucidation and antiviral activity of cathepsin L inhibitors with carbonyl and epoxide warheads</strong> -
<div>
Emerging RNA viruses including SARS-CoV-2 continue to be a major threat around the globe. The cell entry of SARS-CoV-2 particles via the endosomal pathway involves the cysteine protease cathepsin L (CatL) among other proteases. CatL is rendered as a promising drug target in the context of different viral and lysosome-related diseases. Hence, drug discovery and structure-based optimization of inhibitors is of high pharmaceutical interest. We herein verified and compared the anti-SARS-CoV-2 activity of a set of carbonyl and succinyl-epoxide-based inhibitors, which have previously been identified as cathepsin inhibitors. Calpain inhibitor XII (CI-XII), MG-101 and CatL inhibitor IV (CLI-IV) possess antiviral activity in the very low nanomolar IC50 range in Vero E6 cells. Experimental structural data on how these and related compounds bind to CatL are however notably lacking, despite their therapeutic potential. Consequently, we present and compare crystal structures of CatL in complex with 14 compounds, namely BOCA (N-BOC-2-aminoacetaldehyde), CLI-IV, CI-III, CI-VI, CI-XII, the main protease alpha-ketoamide inhibitor 13b, MG-101, MG-132 as well as E-64d (aloxistatin), E-64, CLIK148, CAA0225, TC-I (CID 16725315) and TPCK at resolutions better than 2 Angstrom. Overall, the presented data comprise a broad and solid basis for structure-guided understanding and optimization of CatL inhibitors towards protease drug development.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.08.11.552671v1" target="_blank">Structural elucidation and antiviral activity of cathepsin L inhibitors with carbonyl and epoxide warheads</a>
</div></li>
<li><strong>PRIEST - Predicting viral mutations with immune escape capability of SARS-CoV-2 using temporal evolutionary information</strong> -
<div>
The dynamic evolution of the SARS-CoV-2 virus is largely driven by mutations in its genetic sequence, culminating in the emergence of variants with increased capability to evade host immune responses. Accurate prediction of such mutations is fundamental in mitigating pandemic spread and developing effective control measures. In this study, we introduce a robust and interpretable deep-learning approach called PRIEST. This innovative model leverages time-series viral sequences to foresee potential viral mutations. Our comprehensive experimental evaluations underscore PRIEST's proficiency in accurately predicting immune-evading mutations. Our work represents a substantial step forward in the utilization of deep-learning methodologies for anticipatory viral mutation analysis and pandemic response.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.08.11.552988v1" target="_blank">PRIEST - Predicting viral mutations with immune escape capability of SARS-CoV-2 using temporal evolutionary information</a>
</div></li>
<li><strong>Lactobacillus rhamnosus (LR) ameliorates acute respiratory distress syndrome (ARDS) via modulating the lung Innate Lymphoid Cells (ILCs)-Mononuclear Phagocytic System (MPS)</strong> -
<div>
Acute-respiratory-distress-syndrome (ARDS), the ultimate manifestation of acute-lung-injury (ALI) is a life-threatening respiratory failure with a significantly higher incidence and mortality worldwide. Recent discoveries have emphasized the existence of a potential nexus between gut and lung-health wherein physiology of the gut is directly linked with the outcomes of the lung pathologies. These discoveries fuel novel approaches including probiotics for the treatment of several respiratory disorders including ALI/ARDS. Lactobacillus rhamnosus (LR) is a preferred probiotic of choice as it has been reported to exhibit potent anti-inflammatory activities in various inflammatory diseases. In the present study, we investigated the prophylactic-potential of LR in lipopolysaccharide (LPS)-induced ALI/ARDS mice model, which mimics the pathophysiology of several respiratory disorders including respiratory tract infections, COVID-19, influenza, pneumonia, asthma, tuberculosis, cystic fibrosis, chronic obstructive pulmonary disease (COPD) etc. Our in vivo findings revealed that pretreatment with LR significantly attenuated lung inflammation and improved the pathophysiology of lung-tissues in ALI/ARDS mice. We observed that LR-administration suppressed the LPS-induced inflammatory cell infiltration in the lungs via ameliorating vascular-permeability (edema) of the lungs. Acute and chronic lung-disorders, including ARDS, are largely governed by innate-immune response. Interestingly, we observed that LR via modulating different ILCs (first responder to infections) subsets viz. ILC1, ILC2 and ILC3 prevent lung-fibrosis and maintain vascular permeability in LPS induced ALI/ARDS mice model. Of note, we observed a significant-enhancement in the percentage of inflammatory IL-17 producing CD3-Roryt+NKp46- ILC3-fraction along with a significant reduction in IL-22 (responsible for vascular integrity) producing CD3-Roryt+NKp46+ ILC3 in both the BALF and lung-tissues. These ILCs would further augment the activation and recruitment of mononuclear phagocytic system (MPS-monocytes, macrophages and DCs) along with neutrophils and eosinophils in the lungs and BALF in ALI/ARDS mice model. Furthermore, gene expression and protein-analysis demonstrated that LR treatment significantly reduces the expression of inflammatory-cytokines in lung tissue and serum, thereby suggesting its potent immunomodulatory activity in attenuating ALI/ARDS. Summarily, our research convincingly establishes the prophylactic-role of LR in the prevention and management of respiratory-distress syndromes driven by the diverse inflammatory insults via modulating the lungs ILCs-MPS axis with significant clinical-implications for the management of COVID-19, Influenza, COPD etc.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.08.10.552899v1" target="_blank">Lactobacillus rhamnosus (LR) ameliorates acute respiratory distress syndrome (ARDS) via modulating the lung Innate Lymphoid Cells (ILCs)-Mononuclear Phagocytic System (MPS)</a>
</div></li>
<li><strong>Subphenotypes of Self-Reported Symptoms and Outcomes in Long COVID: a prospective cohort study with latent class analysis.</strong> -
<div>
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Objective: To characterize subphenotypes of self-reported symptoms and outcomes(SRSOs) in Post-acute sequelae of COVID-19(PASC). Design: Prospective, observational cohort study of PASC subjects. Setting: Academic tertiary center from five clinical referral sources. Participants: Adults with COVID-19 ≥ 20 days before enrollment and presence of any new self-reported symptoms following COVID-19. Exposures: We collected data on clinical variables and SRSOs via structured telephone interviews and performed standardized assessments with validated clinical numerical scales to capture psychological symptoms, neurocognitive functioning, and cardiopulmonary function. We collected saliva and stool samples for quantification of SARS-CoV-2 RNA via qPCR. Primary and Secondary outcomes of measure: Description of PASC SRSOs burden and duration, derivation of distinct PASC subphenotypes via latent class analysis (LCA), and relationship between viral load with SRSOs and PASC subphenotypes. Results: Baseline data for 214 individuals were analyzed. The study visit took place at a median of 197.5 days after COVID-19 diagnosis, and participants reported ever having a median of 9/16 symptoms (interquartile range 6-11) after acute COVID, with muscle-aches, dyspnea, and headache being the most common. Fatigue, cognitive impairment, and dyspnea were experienced for a longer time. Participants had a lower burden of active symptoms (median 3, interquartile range 1-6) than those ever experienced (p&lt;0.001). Unsupervised LCA of symptoms revealed three clinically-active PASC subphenotypes: a high burden constitutional symptoms (21.9%) , a persistent loss/change of smell and taste (20.6%) , and a minimal residual symptoms subphenotype (57.5%). Subphenotype assignments were strongly associated with self-assessments of global health, recovery and PASC impact on employment (p&lt;0.001). Viral persistence (5.6% saliva and 1% stool samples positive) did not explain SRSOs or subphenotypes. Conclusions: We identified distinct PASC subphenotypes and highlight that although most symptoms progressively resolve, specific PASC subpopulations are impacted by either high burden of constitutional symptoms or persistent olfactory/gustatory dysfunction, requiring prospective identification and targeted preventive or therapeutic interventions.
</p>
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<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.08.09.23293901v1" target="_blank">Subphenotypes of Self-Reported Symptoms and Outcomes in Long COVID: a prospective cohort study with latent class analysis.</a>
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<li><strong>Analysis of SARS-CoV-2 Variant-Specific Serum Antibodies Post-Vaccination Utilizing Immortalized Human Hepatocyte-like Cells (HLC) to Assess Development of Protective Immunity</strong> -
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Abstract Background: Our previous studies demonstrated that SARS-CoV-2 spike proteins could bind to hepatocytes via the asialoglycoprotein receptor-1 (ASGR-1) facilitating direct infection by the SARS-CoV-2 virus. Immortalized E12-HLC expressed the phenotypic and biological properties of primary human hepatocytes, including their ability to bind spike proteins via ASGR-1 with exception of the spike 1 protein. This binding could be inhibited by spike protein-specific monoclonal antibodies. We used the same spike-blocking analysis to determine if post-vaccination serum was capable of blocking spike protein binding to HLC. Samples collected from subjects prior to, and post-vaccination were quantified for anti-variant-specific antibody (original wild type, alpha (α), beta (β), gamma (γ), and delta (δ) variants by a flow cytometry based immunofluorescent assay. Inhibition of variant spike protein binding to HLC and AT-2 (as a known model for spike 1 binding to the ACE-2 receptor) was analyzed by confocal microscopy. This study was designed to investigate the ability of post-vaccination antibodies to mediate immunity to spike S2, and to validate the utility of the E12-HLC in analyzing that immunity. Methods: Serum was collected from 10 individuals pre- and post-vaccination with the J&amp;J, Moderna or Pfizer vaccines. The serum samples were quantified for variant-specific antibodies in a flow cytometry-based immunofluorescent assay utilizing beads coated with biotinylated variant spike proteins (α, β, γ, δ).Presence of variant-specific antibodies was visualized by anti-human IgG-Alexa 488. Inhibition of spike protein binding to cells was analyzed by immunofluorescent confocal analysis. Biotinylated variant spike proteins were preincubated with serum samples and then tested for binding to target cells. Binding was visualized by Streptavidin-Alexa 594. Results were compared to binding of unblocked spike variants. Results: All variant spike proteins tested bound to both the HLC and AT-2 cells. Pre-vaccination serum samples had no detectable reactivity to any of the variant spike proteins and were unable to inhibit binding of the variant spike proteins to either target cell. Post-vaccination serum samples demonstrated a progression of SARS-CoV-2 antibody levels from low early post-vaccination levels to higher levels at 2.5 months after vaccination. Concurrently, serum samples taken at those different timeframes demonstrated that serum obtained from shortly after vaccination were not as effective in blocking spike protein as serum obtained after 2.5 months post-vaccination. Antibody concentrations were not necessarily associated with better blocking of spike protein binding as spike variant-specific serum antibody concentrations varied significantly between subjects and within each subject. It was also demonstrated that vaccination with all the various available vaccines stimulated antibodies that inhibited binding of the available variant spike proteins to both HLC and AT-2 cells. Conclusion: HLC, along with AT-2 cells, provides a useful platform to study the development of protective antibodies that prevent the binding SARS-CoV-2 spike proteins to target cells. It was shown that vaccination with the three available vaccines all elicited serum antibodies that were protective against binding of each of the variant spike proteins to both AT-2 and HLC cells. This study suggests that analysis of immune serum to block spike binding to target cells may be a more useful technique to assess protective immunity than quantitation of gross antibody alone.
</p>
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<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.08.08.23293863v1" target="_blank">Analysis of SARS-CoV-2 Variant-Specific Serum Antibodies Post-Vaccination Utilizing Immortalized Human Hepatocyte-like Cells (HLC) to Assess Development of Protective Immunity</a>
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<li><strong>Immunogenicity of mRNA-1273 and BNT162b2 in Immunocompromised Patients: Systematic Review and Meta-Analysis Using GRADE</strong> -
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Aim: Immunocompromised (IC) patients mount poor immune responses to vaccination. Higher-dose COVID-19 vaccines may offer increased immunogenicity. Materials &amp; methods: A pairwise meta-analysis of 98 studies reporting comparisons of mRNA-1273 (50 or 100 mcg/dose) and BNT162b2 (30 mcg/dose) in IC adults was performed. Outcomes were seroconversion, total and neutralizing antibody titers, and cellular immune responses. Results: mRNA-1273 was associated with a significantly higher seroconversion likelihood (relative risk, 1.11 [95% CI, 1.08, 1.14]; P&lt;0.0001; I2=66.8%) and higher total antibody titers (relative increase, 50.45% [95% CI, 34.63%, 66.28%]; P&lt;0.0001; I2=89.5%) versus BNT162b2. mRNA-1273 elicited higher but statistically nonsignificant relative increases in neutralizing antibody titers and cellular immune responses versus BNT162b2. Conclusion: Higher-dose mRNA-1273 had increased immunogenicity versus BNT162b2 in IC patients.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.08.09.23293898v1" target="_blank">Immunogenicity of mRNA-1273 and BNT162b2 in Immunocompromised Patients: Systematic Review and Meta-Analysis Using GRADE</a>
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<li><strong>A community based cross-sectional study on impact assessment of COVID-19 on mental health in Central India</strong> -
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The current study is a cross-sectional survey that aims to assess the effect of COVID-19 on mental health in rural India. The study was conducted in the Durg district of Chhattisgarh state, and it used the Generalized Anxiety Disorder Assessment (GAD-7), PHQ-9, and IES-R to evaluate the prevalence of depression, anxiety, and PTSD among the community. Out of 431 participants, 44% were male, with a mean age of 41 years. The study found that 87% of the participants had health insurance, 40% had co-morbidities like hypertension or diabetes, and half of them experienced food shortage and change in income during the pandemic. One-third of the participants experienced death among one or more family members due to the pandemic. The study found that the mean scores of IES-R, GAD-7, and PHQ-9 were 23.59-24.91, 1.50, 2.07, and 1.06-1.58, respectively. Thirty percent of the participants observed some distress, 15% reported depression, and 12% reported anxiety. The adjusted effect of death in the family due to COVID-19 was found to be significantly associated with higher risk of mental distress, whereas education was associated with lower risk of distress. Depression and anxiety were more common among the elderly and less common among individuals living in nuclear families. Scarcity of food and change in income were significantly associated with anxiety. These findings highlight the need for increased support for mental health in rural communities in India, particularly in the face of the COVID-19 pandemic.
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<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.08.08.23293808v1" target="_blank">A community based cross-sectional study on impact assessment of COVID-19 on mental health in Central India</a>
</div></li>
<li><strong>To what extent are Chinese international students in Leuven influenced by the educational thoughts of Confucius when coping with the Covid-19 pandemic situation?</strong> -
<div>
The Chinese education market is the largest in Higher Education (HE) worldwide. The number of study-abroad Chinese students has experienced a constant growth throughout the previous decade. According to the Chinese Ministry of Education report, there were more than 660,000 Chinese students studying in different countries in 2018. This demonstrates the growing desire from Chinese students, as well as their parents, to integrate in multicultural contexts in order to broaden horizons in this modern era (Gao, 2018). However, recent studies revealed that Chinese overseas students have less affinity to different cultures and face many difficulties in integrating with students of different cultural backgrounds (Yu and Moskal, 2018). Both internal and external culture differences are the key factors behind Chinese students lacking ability for intercultural integration (Zhu and Gao, 2012), which is also associated with their difficulty in adapting in a different education system. Chinese overseas students come from a Confucian Heritage Culture where Confucianism has shaped the culture that has been deeply rooted in the Chinese education system. This has formed the students’ mind-set, resulting in certain personality traits related to social communication. Modesty, social and ritual propriety are the main tenets of Confucian traditionalism. It has become the standard for Chinese peoples’ social and moral behaviours, gives order to and strengthens the social connections between people. This mind-set influences Chinese international students’ cross-cultural communication, both in multilingual and multicultural contexts (Luo, Huang and Najjar, 2007). Taking the Covid-19 pandemic into consideration, it was observed that Chinese overseas students in different countries have proactively taken medical solutions for self-prevention in the crisis situation. In order to identify the role of Confucian Heritage Cultures influence in Chinese international students adapting to overseas education environments, this study examines the previous work on Confucian Heritage Culture involvement in Chinese education. It is designed to measure, to what extent are Chinese international students in Leuven influenced by Confucian Heritage Culture when coping with the Covid-19 pandemic situation during overseas study. The conducted thesis includes an academic review on Confucian Heritage Culture as a fundamental cultural factor in Chinese education system, a qualitative study and an analysis of Chinese international students in Leuven experience Confucian Heritage Culture to cope with lockdown situations. This thesis aims to explore the possible revelation of acculturation competence among Chinese international students within the coronavirus pandemic background.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://osf.io/q2afv/" target="_blank">To what extent are Chinese international students in Leuven influenced by the educational thoughts of Confucius when coping with the Covid-19 pandemic situation?</a>
</div></li>
</ul>
<h1 data-aos="fade-right" id="from-clinical-trials">From Clinical Trials</h1>
<ul>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>A Study to Evaluate the Safety and Immunogenicity of an (Omicron Subvariant) COVID-19 Vaccine Booster Dose in Previously Vaccinated Participants and Unvaccinated Participants.</strong> - <b>Condition</b>:   COVID-19<br/><b>Interventions</b>:   Biological: XBB.1.5 Vaccine (Booster);   Biological: XBB.1.5 Vaccine (single dose)<br/><b>Sponsor</b>:   Novavax<br/><b>Not yet recruiting</b></p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Effect of Natural Food on Gut Microbiome and Phospholipid Spectrum of Immune Cells in COVID-19 Patients</strong> - <b>Condition</b>:   COVID-19<br/><b>Intervention</b>:   Dietary Supplement: Freeze-dried Mare Milk (Saumal)<br/><b>Sponsor</b>:   Asfendiyarov Kazakh National Medical University<br/><b>Not yet recruiting</b></p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>EFFECT OF COGNITIVE BEHAVIORAL THERAPY ON DEPRESSION AND QUALITY OF LIFE IN PATIENTS WITH POST COVID-19</strong> - <b>Condition</b>:   Post-COVID-19 Syndrome<br/><b>Intervention</b>:   Behavioral: rehacom<br/><b>Sponsor</b>:   Cairo University<br/><b>Enrolling by invitation</b></p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Intradermal Administration of a COVID-19 mRNA Vaccine in Elderly</strong> - <b>Conditions</b>:   Vaccination; Infection;   COVID-19<br/><b>Intervention</b>:   Biological: Comirnaty<br/><b>Sponsor</b>:   Radboud University Medical Center<br/><b>Not yet recruiting</b></p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>A Safety and Immune Response Study to Evaluate Varying Doses of an mRNA Vaccine Against Coronavirus Disease 2019 (COVID-19) in Healthy Adults</strong> - <b>Condition</b>:   COVID-19<br/><b>Interventions</b>:   Biological: mRNA-CR-04 vaccine 10μg;   Biological: mRNA-CR-04 vaccine 30μg;   Biological: mRNA-CR-04 vaccine 100μg;   Drug: Placebo<br/><b>Sponsor</b>:   GlaxoSmithKline<br/><b>Not yet recruiting</b></p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Methylprednisolone in Patients With Cognitive Deficits in Post-COVID-19 Syndrome (PCS)</strong> - <b>Condition</b>:   Post-COVID-19 Syndrome<br/><b>Intervention</b>:   Drug: Methylprednisolone<br/><b>Sponsor</b>:   Charite University, Berlin, Germany<br/><b>Not yet recruiting</b></p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Phase 3 Adolescent Study for SARS-CoV-2 rS Variant Vaccines</strong> - <b>Condition</b>:   COVID-19<br/><b>Interventions</b>:   Biological: NVX-CoV2601 co-formulated Omicron XBB.1.5 SARS-CoV-2 rS vaccine;   Biological: Prototype/XBB.1.5 Bivalent Vaccine (5 µg)<br/><b>Sponsor</b>:   Novavax<br/><b>Not yet recruiting</b></p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Hyperbaric on Pulmonary Functions in Post Covid -19 Patients.</strong> - <b>Condition</b>:   Post COVID-19 Patients<br/><b>Interventions</b>:   Device: hyperbaric oxygen therapy;   Device: breathing exercise;   Drug: medical treatment<br/><b>Sponsor</b>:   Cairo University<br/><b>Completed</b></p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Dietary Intervention to Mitigate Post-Acute COVID-19 Syndrome</strong> - <b>Conditions</b>:   Post-Acute COVID-19 Syndrome;   Fatigue<br/><b>Interventions</b>:   Other: Dietary intervention to mitigate Post-Acute COVID-19 Syndrome;   Other: Attention Control<br/><b>Sponsor</b>:   University of Maryland, Baltimore<br/><b>Not yet recruiting</b></p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>A Phase II Trial to Evaluate the Safety and Immunogenicity of BIMERVAX® When Coadministered With Seasonal Influenza Vaccine (SIIV) in Adults Older Than 65 Years of Age Fully Vaccinated Against COVID-19</strong> - <b>Conditions</b>:   SARS CoV 2 Infection;   Influenza, Human<br/><b>Interventions</b>:   Biological: BIMERVAX;   Biological: SIIV<br/><b>Sponsor</b>:   Hipra Scientific, S.L.U<br/><b>Not yet recruiting</b></p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Directed Topical Drug Delivery for Treatment for PASC Hyposmia</strong> - <b>Condition</b>:   Post Acute Sequelae Covid-19 Hyposmia<br/><b>Interventions</b>:   Drug: Beclomethasone;   Other: Placebo;   Device: Microsponge<br/><b>Sponsor</b>:   Duke University<br/><b>Not yet recruiting</b></p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Preliminary Efficacy of a Technology-based Physical Activity Intervention for Older Korean Adults During the COVID-19 Pandemic</strong> - <b>Conditions</b>:   Cardiovascular Health;   Physical Function<br/><b>Intervention</b>:   Behavioral: Golden Circle<br/><b>Sponsor</b>:   University of Illinois at Urbana-Champaign<br/><b>Completed</b></p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Supported Employment COVID-19 Rapid Testing for PWID</strong> - <b>Condition</b>:   Health Behavior<br/><b>Intervention</b>:   Behavioral: Supported Employment<br/><b>Sponsor</b>:   University of Oregon<br/><b>Not yet recruiting</b></p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Telerehabilitation for Post COVID-19 Condition</strong> - <b>Conditions</b>:   Long COVID;   Chronic Fatigue Syndrome<br/><b>Intervention</b>:   Other: Telerehabilitation program based on cardiorespiratory principles<br/><b>Sponsors</b>:   Université de Sherbrooke;   Hotel Dieu Hospital<br/><b>Completed</b></p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Study of Tixagevimab/Cilgavimab and Regdanvimab Efficacy for Treatment of COVID-19</strong> - <b>Condition</b>:   Coronavirus Infections<br/><b>Interventions</b>:   Drug: tixagevimab/cilgavimab 150+150 mg;   Drug: tixagevimab/cilgavimab 300+300 mg;   Drug: regdanvimab<br/><b>Sponsors</b>:   City Clinical Hospital No.52 of Moscow Healthcare Department;   Gamaleya Research Institute of Epidemiology and Microbiology, Health Ministry of the Russian Federation<br/><b>Active, not recruiting</b></p></li>
</ul>
<h1 data-aos="fade-right" id="from-pubmed">From PubMed</h1>
<ul>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Identification of Promising Sulfonamide Chalcones as Inhibitors of SARS-CoV-2 3CL<sup>pro</sup> through Structure-Based Virtual Screening and Experimental Approaches</strong> - 3CL^(pro) is a viable target for developing antiviral therapies against the coronavirus. With the urgent need to find new possible inhibitors, a structure-based virtual screening approach was developed. This study recognized 75 pharmacologically bioactive compounds from our in-house library of 1052 natural product-based compounds that satisfied drug-likeness criteria and exhibited good bioavailability and membrane permeability. Among these compounds, three promising sulfonamide chalcones were…</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>TGF-β1 inhibition of ACE2 mediated by miRNA uncovers novel mechanism of SARS-CoV-2 pathogenesis</strong> - SARS-CoV-2 utilizes receptor binding domain (RBD) of spike glycoprotein to interact with angiotensin-converting enzyme 2 (ACE2). Decreased cell surface density of ACE2 contributes to mortality during COVID-19. Studies published early during the pandemic reported that people with cystic fibrosis (PwCF) treated with the high efficiency CFTR modulators ETI (elexacaftor-tezacaftor-ivacaftor) had higher ACE2 levels and milder COVID-19 symptoms, compared to people without CF. Subsequent studies did…</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Endogenous and Therapeutic 25-hydroxycholesterols May Worsen Early SARS-CoV-2 Pathogenesis in Mice</strong> - Oxysterols (i.e., oxidized cholesterol species) have complex roles in biology. 25-hydroxycholesterol (25HC), a product of activity of cholesterol-25-hydroxylase (CH25H) upon cholesterol, has recently been shown to be broadly antiviral, suggesting therapeutic potential against SARS-CoV-2. However, 25HC can also amplify inflammation and be converted by CYP7B1 to 7α,25HC, a lipid with chemoattractant activity via the G protein-coupled receptor, EBI2/GPR183. Here, using in vitro studies and two…</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Design of a bifunctional pan-sarbecovirus entry inhibitor targeting the cell receptor and viral fusion protein</strong> - Development of highly effective antivirals that are robust to viral evolution is a practical strategy for combating the continuously evolved severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Inspired by viral multistep entry process, we here focus on developing a bispecific SARS-CoV-2 entry inhibitor, which acts on the cell receptor angiotensin converting enzyme 2 (ACE2) and viral S2 fusion protein. First, we identified a panel of diverse spike (S) receptor-binding domains (RBDs) and…</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>A novel robust inhibitor of papain-like protease (PLpro) as a COVID-19 drug</strong> - Regarding the significance of SARS-CoV-2, scientists have shown considerable interest in developing effective drugs. Inhibitors for PLpro are the primary strategies for locating suitable COVID-19 drugs. Natural compounds comprise the majority of COVID-19 drugs. Due to limitations on the safety of clinical trials in cases of COVID, computational methods are typically utilized for inhibition studies. Whereas papain is highly similar to PLpro and is entirely safe, the current study aimed to examine…</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Growth media affects susceptibility of air-lifted human nasal epithelial cell cultures to SARS-CoV2, but not Influenza A, virus infection</strong> - Primary differentiated human epithelial cell cultures have been widely used by researchers to study viral fitness and virus-host interactions, especially during the COVID19 pandemic. These cultures recapitulate important characteristics of the respiratory epithelium such as diverse cell type composition, polarization, and innate immune responses. However, standardization and validation of these cultures remains an open issue. In this study, two different expansion medias were evaluated and the…</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Protegrin-2, a potential inhibitor for targeting SARS-CoV-2 main protease M<sup>pro</sup></strong> - CONCLUSIONS: Our in silico and experimental studies identified Protegrin-2 as a potent inhibitor of M^(pro) that could be pursued further towards drug development against COVID-19 infection.</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Real-world effectiveness of mRNA COVID-19 vaccines in the elderly during the Delta and Omicron variants: Systematic review</strong> - CONCLUSION: Because of the natural diminishing effectiveness of the vaccine, the need for booster dose to restore its efficacy is vital. From a research perspective, the use of highly heterogeneous outcome measures inhibits the comparison, contrast, and integration of the results which makes data pooling across different studies problematic. While pharmaceutical intervention like vaccination is important to fight an epidemic, utilizing common outcome measurements or carrying out studies with…</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>A pan-coronavirus peptide inhibitor prevents SARS-CoV-2 infection in mice by intranasal delivery</strong> - Coronaviruses (CoVs) have brought serious threats to humans, particularly severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), which continually evolves into multiple variants. These variants, especially Omicron, reportedly escape therapeutic antibodies and vaccines, indicating an urgent need for new antivirals with pan-SARS-CoV-2 inhibitory activity. We previously reported that a peptide fusion inhibitor, P3, targeting heptad repeated-1 (HR1) of SARS-CoV-2 spike (S) protein, could…</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Age differential CD13 and interferon expression in airway epithelia affect SARS-CoV-2 infection - effects of vitamin D</strong> - Young age and high vitamin D plasma levels have been associated with lower SARS-CoV-2 infection risk and favourable disease outcomes. This study investigated mechanisms associated with differential responses to SARS-CoV-2 across age groups and effects of vitamin D. Nasal epithelia were collected from healthy children and adults and cultured for four weeks at air-liquid interface with and without vitamin D. Gene expression (NanoString) and DNA methylation (Illumina EPIC850K) were investigated….</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Spike protein mutations and structural insights of pangolin lineage B.1.1.25 with implications for viral pathogenicity and ACE2 binding affinity</strong> - Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of COVID -19, is constantly evolving, requiring continuous genomic surveillance. In this study, we used whole-genome sequencing to investigate the genetic epidemiology of SARS-CoV-2 in Bangladesh, with particular emphasis on identifying dominant variants and associated mutations. We used high-throughput next-generation sequencing (NGS) to obtain DNA sequences from COVID-19 patient samples and compared these…</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Identification of a drug binding pocket in TMEM16F calcium-activated ion channel and lipid scramblase</strong> - The dual functions of TMEM16F as Ca^(2+)-activated ion channel and lipid scramblase raise intriguing questions regarding their molecular basis. Intrigued by the ability of the FDA-approved drug niclosamide to inhibit TMEM16F-dependent syncytia formation induced by SARS-CoV-2, we examined cryo-EM structures of TMEM16F with or without bound niclosamide or 1PBC, a known blocker of TMEM16A Ca^(2+)-activated Cl^(-) channel. Here, we report evidence for a lipid scrambling pathway along a groove…</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>CYP19A1 mediates severe SARS-CoV-2 disease outcome in males</strong> - Male sex represents one of the major risk factors for severe COVID-19 outcome. However, underlying mechanisms that mediate sex-dependent disease outcome are as yet unknown. Here, we identify the CYP19A1 gene encoding for the testosterone-to-estradiol metabolizing enzyme CYP19A1 (also known as aromatase) as a host factor that contributes to worsened disease outcome in SARS-CoV-2-infected males. We analyzed exome sequencing data obtained from a human COVID-19 cohort (n = 2,866) using a…</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Molnupiravir, a ribonucleoside antiviral prodrug against SARS-CoV-2, alters the voltage-gated sodium current and causes adverse events</strong> - Molnupiravir (MOL) is a ribonucleoside prodrug for oral treatment of COVID-19. Common adverse effects of MOL are headache, diarrhea, and nausea, which may be associated with altered sodium channel function. Here, we investigated the effect of MOL on voltage-gated Na^(+) current (I(Na)) in pituitary GH(3) cells. We show that MOL had distinct effects on transient and late I(Na), in combination with decreased time constant in the slow component of I(Na) inactivation. The 50% inhibitory…</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Expression and immunogenicity of recombinant porcine epidemic diarrhea virus Nsp9</strong> - Porcine epidemic diarrhea virus (PEDV) causes acute diarrhea, vomiting, dehydration, and high mortality in newborn piglets, which leads to significant economic losses. Coronavirus nonstructural protein 9 (Nsp9) is an essential RNA binding protein for coronavirus replication, which renders it a promising candidate for developing antiviral drugs and diagnosis targeting PEDV. In this study, PEDV Nsp9 protein fused with MBP protein and His-tag were expressed and purified in Escherichia coli….</p></li>
</ul>
<h1 data-aos="fade-right" id="from-patent-search">From Patent Search</h1>
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<h1 data-aos="fade-down" id="daily-dose">Daily-Dose</h1>
<h1 data-aos="fade-right" data-aos-anchor-placement="top-bottom" id="contents">Contents</h1>
<ul>
<li><a href="#from-new-yorker">From New Yorker</a></li>
<li><a href="#from-vox">From Vox</a></li>
<li><a href="#from-the-hindu-sports">From The Hindu: Sports</a></li>
<li><a href="#from-the-hindu-national-news">From The Hindu: National News</a></li>
<li><a href="#from-bbc-europe">From BBC: Europe</a></li>
<li><a href="#from-ars-technica">From Ars Technica</a></li>
<li><a href="#from-jokes-subreddit">From Jokes Subreddit</a></li>
</ul>
<h1 data-aos="fade-right" id="from-new-yorker">From New Yorker</h1>
<ul>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Is the F.B.I. Truly Biased Against Trump?</strong> - An agent turned whistle-blower claims that the Bureau was eager to investigate Hunter Biden—but protected Rudy Giuliani. - <a href="https://www.newyorker.com/news/news-desk/is-the-fbi-truly-biased-against-trump">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Can “Cop City” Be Stopped at the Ballot Box?</strong> - The fight over a massive police-training complex, set to be built outside Atlanta, has lasted more than two years. Now many people hope the proposal will be put to a vote. - <a href="https://www.newyorker.com/news/letter-from-the-south/can-cop-city-be-stopped-at-the-ballot-box">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>An Ambassador Without a Country</strong> - The Afghan statesman Zalmai Rassoul is recognized by the governments of the United Kingdom and Ireland—but not by the Taliban. - <a href="https://www.newyorker.com/news/a-reporter-at-large/an-ambassador-without-a-country">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>A Witness’s Strange Day at the Trump Grand Jury in Georgia</strong> - The journalist George Chidi saw a Georgia Republican walk into a conference room and became a significant witness in a potentially historic prosecution. - <a href="https://www.newyorker.com/news/letter-from-the-south/a-witnesss-strange-day-at-the-trump-grand-jury-in-georgia">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Why Republicans Are Complaining About the Hunter Biden Special Counsel That They Asked For</strong> - Eager to shift attention from the crimes and malfeasances of their own likely Presidential candidate, Republicans are more than happy to move the goalposts on the Hunter Biden case. - <a href="https://www.newyorker.com/news/our-columnists/why-republicans-are-complaining-about-the-hunter-biden-special-counsel-that-they-asked-for">link</a></p></li>
</ul>
<h1 data-aos="fade-right" id="from-vox">From Vox</h1>
<ul>
<li><strong>The story about Ambien and sex differences in medication isn’t what you think</strong> -
<figure>
<img alt="A prescription of bottle of Ambien&amp;nbsp;" src="https://cdn.vox-cdn.com/thumbor/OoGVFwnkiXPPepWLJ6QIh-7w88w=/228x0:2773x1909/1310x983/cdn.vox-cdn.com/uploads/chorus_image/image/72545618/GettyImages_57542990.0.jpg"/>
<figcaption>
A prescription of bottle of Ambien  | Getty Images
</figcaption>
</figure>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
The risks of sex-based drug dosing recommendations.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="ctqk4T">
Zolpidem tartrate is infamous. It walks the street with many names: “A-minus,” “zombie pills,” “no-go pills.” It has been blamed for a range of strange and disastrous incidents in the news over the years, including Roseanne Barr’s <a href="https://time.com/5295104/roseanne-barr-ambien/">racist tweeting</a> in 2018 and Tiger Woods’s <a href="https://www.washingtonpost.com/sports/2021/04/10/tiger-woods-crash-report-pill-bottle/">terrible car accident</a> in 2021. But you probably know zolpidem tartrate best by its brand moniker: Ambien, which hit the markets in 1992.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="jlQEjA">
Ambien, a drug commonly prescribed as a short-term solution for people experiencing insomnia, is famous not only for its association with celebrity fiascos and faux pas, but also for being the first and only drug sold under an FDA-mandated sex-specific dosing regime in the United States. In a <a href="https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-approves-new-label-changes-and-dosing-zolpidem-products-and">landmark 2013 decision</a>, the Food and Drug Administration recommended that women take half the dose of men, citing new data on women’s higher risk for next-day cognitive impairment that posed dangers for activities like driving.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="xTl5Fx">
This dosing regime put sex differences on the scientific and regulatory radar. In the eyes of many biomedical scientists, Ambien became a “textbook example” of how neglecting sex as a variable leads to disastrous consequences. This coincided with increasing recognition of the medical establishment’s long history of assuming the white male body as default (women and minority groups weren’t legally required to be included in clinical trials until the 1993 <a href="https://www.congress.gov/bill/103rd-congress/senate-bill/1">NIH Revitalization Act</a>). It also aligned with a growing prioritization of women’s health as its own area deserving of funding and resources. When the FDA came out with its recommendation to halve Ambien dosage for women in 2013, biomedical scientists from many fields took it as an urgent warning.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="4R2l43">
In a <a href="https://www.cbsnews.com/news/sex-matters-drugs-can-affect-sexes-differently/"><em>60 Minutes</em> segment</a>, journalist Lesley Stahl sat down with Larry Cahill, neuroscientist and professor at the University of California Irvine, about the importance of the decision. “If science got Ambien so wrong, does that tell you we really need to go back and review —” “Yes,” Cahill interjected. “Everything?” Stahl continued with her eyebrows raised. “Pretty much everything,” Cahill insisted.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="BJBbLQ">
For many researchers like Cahill, Ambien presented the perfect example to motivate wider changes, specifically the National Institutes of Health’s 2016 <a href="https://orwh.od.nih.gov/sex-gender/nih-policy-sex-biological-variable">Sex as a Biological Variable policy,</a> which mandated the incorporation of male and female sexes into the analyses of all federally funded, model organism preclinical research.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="Jx5xlw">
But is Ambien really a textbook example of sex differences? As researchers at the <a href="https://www.genderscilab.org/">Harvard GenderSci Lab</a>, an interdisciplinary lab that studies the methodologies, empirical claims, and sociopolitical context of studies of gender and sex differences in biomedicine (including areas like <a href="https://www.genderscilab.org/blog/q-and-a-sarah-richardson-on-sex-contextualism">preclinical science</a>, <a href="https://www.sciencedirect.com/science/article/pii/S0277953622000193#bib31">Covid-19</a>, and <a href="https://www.tandfonline.com/doi/full/10.1080/14647273.2021.1917778">sperm count science</a>), we know that this area of science is deeply contested, with a history of bias and overstatement of sex differences tinged with stereotypes. We think about questions such as: How do scientists, the government, and the public(s) determine what constitutes a fact about differences between the sexes? What is the role of law and policy in validating the authority of scientific claims about sex and gender? And, conversely, how do <a href="https://www.vox.com/policy">policies</a> and interventions take up such claims? We track how ideas about the nature of gender categories transform as they traverse domains as varied as laboratories, courtrooms, and business pitches.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="W9Pyz5">
Our collaborative team of scholars analyzed the scientific and public life of Ambien’s sex-based dosing claims, the results of which were recently <a href="https://journals.sagepub.com/doi/10.1177/03063127231168371">published</a> in the journal <em>Social Studies of Science</em>. We show that what seems a straightforward fact about pharmacological sex differences is not so simple, and what was widely hailed as a victory for women’s health and equity is not obviously so. Troublingly, this Ambien “fact” might actually be encouraging imprecise science and reinforcing a set of harmful assumptions about binary sex.
</p>
<h3 id="c4oNxS">
Unpacking the FDA decision process
</h3>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="zfywwT">
How did the FDA’s 2013 recommendation come about? The agency’s regulatory approval process for pharmaceuticals is notoriously intense. Regulatory decision-makers incorporate many forms of scientific evidence, and they also make judgment calls about how to weigh efficacy and risk, which metrics to use, and when to exercise extra caution.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="PVKCVM">
When Ambien was originally approved in 1992, the recommended dosing was sex-neutral. That changed in 2011 during the approval of a new formulation of Ambien called Intermezzo. As the name suggests, Intermezzo was supposed to be taken in the middle of the night, for patients who <a href="https://www.vox.com/culture/21437879/stay-woke-wokeness-history-origin-evolution-controversy">woke</a> up and couldn’t fall back asleep. Taking a sleep aid in the dead of night left less time for the drug to be metabolized before patients woke up, leaving them potentially drowsy and dangerous drivers the next morning. Because of this, the FDA was especially worried about both how quickly patients metabolized the drug and the real-time effects of the new formulation.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="PpBSZI">
This resulted in a drawn-out approval process for Intermezzo in which the FDA demanded that the drug company perform a study to examine the effects of Intermezzo on drivers at three and four hours post-dose, reflecting their broader concern about the <a href="https://www.nytimes.com/2007/03/15/business/15drug.ready.html">safety of sleep aids</a>. This study did not find that Intermezzo interfered with driving four hours after dosing. But the FDA remained worried about high levels of zolpidem in the bloodstream at this time interval, and pushed the drug company to find a way to lower morning drug levels in the blood for all patients below a cutoff point associated with driving impairment at three hours post-dose. Because other studies showed that female patients metabolized the drug more slowly than male patients, the drug company acquiesced by lowering the dose for female patients to half of that for males.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="Q25PbI">
Importantly, the Intermezzo <a href="https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022328Orig1s000MedR.pdf">evaluation</a> wasn’t based on direct evidence that slower clearance rates <em>caused </em>driving impairment. Furthermore, when adjusted for weight, sex differences in clearance rates themselves were reduced or even, in one case, reversed. (However, the FDA rejected this adjustment because it found that weight alone did not statistically predict clearance rates.) Ultimately, sex was a convenient way to reanalyze existing data, saving Intermezzo’s manufacturer, Transcept, from another cycle of regulatory scrutiny and from having to perform additional studies.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="Nju7AD">
Shortly after this decision, the FDA used the zolpidem blood level cutoff from the Intermezzo approval process to reanalyze data for other formulations of Ambien. On the basis of the Intermezzo review, together with additional reanalysis evidence that high levels of zolpidem correlated with next-day cognitive impairment, the FDA extended this sex-based dosing scheme to all formulations, including those meant to be taken before bed.
</p>
<h3 id="6fdkRS">
A sticky and compelling sex difference “fact”
</h3>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="uUE1cj">
References to the FDA’s sex-based dosing recommendation rapidly populated teaching materials for scientists, academic papers, and popular media like <a href="https://well.blogs.nytimes.com/2013/01/28/the-drug-dose-gender-gap/">the New York Times</a>, <a href="https://www.npr.org/2017/02/10/514153036/when-does-medicine-leave-women-behind"><em>TED Radio Hour</em></a>, and <a href="https://abcnews.go.com/Health/fda-recommends-slashing-sleeping-pill-dosage-half-women/story?id=18182165">ABC News</a>. Many scientists underscored Ambien as a canary warning of the wider problem of preclinical and clinical science’s neglect of sex: Who knows how many other biological sex differences in drugs we remain ignorant of, because female biology is ignored in research? In the <a href="https://archive.nytimes.com/well.blogs.nytimes.com/2013/01/28/the-drug-dose-gender-gap/">words</a> of Janine Clayton, director for the NIH Office for Women’s Health, Ambien was “just the tip of the iceberg.”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="FP8Bzu">
In academic papers, Ambien served as a touchstone for researchers advocating for application of the NIH’s Sex as a Biological Variable policy across fields as diverse as <a href="https://www.nature.com/articles/npp2016215">neuropsychopharmacology,</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9733431/">surgery</a>, and preclinical studies of <a href="https://onlinelibrary.wiley.com/doi/abs/10.1111/acer.13072">alcoholism</a> and <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877795/">neurodegenerative diseases</a>. These researchers used Ambien to argue that scientists need to incorporate sex as a variable in their statistical analyses, disaggregate by male/female groups, and look for differences in sex-based biology. Non-scientific bodies took notice, too. The Bill and Melinda Gates Foundation made Ambien <a href="https://www.gatesgenderequalitytoolbox.org/wp-content/uploads/2.-BMGF_Case-Study-Ambien_Aug2020.pdf">a case study</a> in its “Gender Equality Toolbox” designed to inform grant funding bodies, and McKinsey cited the drug as a harbinger of sex-based <a href="https://www.vox.com/health-care">health care</a> and treatment, and <a href="https://www.mckinsey.com/industries/healthcare-systems-and-services/our-insights/unlocking-opportunities-in-womens-healthcare">their ripe investment opportunities</a>.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="bTocdZ">
In these literatures, the sex difference fact was conveyed as the following: Female patients experience higher rates of adverse reactions to zolpidem due to their slower metabolism of the drug, and the FDA recommendation, long overdue, corrects for this by halving the dose. This Ambien story, now common parlance in biomedical literature, oversimplifies both the FDA evidence and state of the research.
</p>
<h3 id="PXFe0C">
A fact detached from the scientific debate
</h3>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="A5187R">
Sex-based dosing for Ambien reflects neither scientific nor international regulatory consensus. In fact, since Ambien’s approval in the 1990s, researchers have studied the effects of sex, age, and race/ethnicity on zolpidem tartrate. Although they found that women generally had slower clearance (metabolism) rates of zolpidem than men, there was much individual variability, and adjusting for body weight in the analysis reduced much of the observed sex difference, often rendering it statistically insignificant. In <a href="https://doi.org/10.1046/j.0306-5251.2003.01852.x">one study</a>, older men actually had the slowest clearance rates (and the FDA has <a href="https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/019908s038lbl.pdf">suggested</a> that older people of all genders are at higher risk of cognitive impairment).
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="XgZU3r">
Although the FDA was partially motivated to regulate on the basis of its internal reanalysis data, there has been no clear scientific consensus that slower clearance rates are primarily responsible for sex differences in impaired driving or auto accidents. Moreover, if adverse effects from high zolpidem blood levels are a concern for women, we should also worry about the men who have higher zolpidem levels in the morning.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="MDkUVs">
In other words, if the goal of the FDA recommendation was to reduce cognitive impairment and driving accidents for everyone, it’s not clear that halving the dose for women achieved that. Factors like taking multiple concurrent drugs and interactions with age and body weight might also be salient. As we <a href="https://journals.sagepub.com/doi/10.1177/03063127231168371">describe</a> in greater detail in the journal <em>Social Studies of Science</em>, like all regulatory policies, the FDA decision reflected a confluence of scientific and political judgment in the face of uncertainty, including a choice to minimize bloodstream levels and rely on sex categories to manage the general risk of automobile accidents.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="YHfnAX">
Pharmacology and sleep medicine researchers have since challenged the reasoning behind the FDA’s 2013 recommendation, suggesting that it was <a href="https://doi.org/10.1038/s41598-021-98689-z">missing “concrete evidence”</a> and might have <a href="https://doi.org/10.1097/JCP.0000000000001026">caused undermedication</a> for many women with sleep disorders, which poses its own <a href="https://www.vox.com/public-health">public health</a> risk. Significantly, aside from Canada and the United States, no other national drug agency has implemented sex-specific dosing for zolpidem.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="nH2Y2v">
In spite of this, Ambien has become a touchstone example for the public and those advocating for sex-specific medicine in the name of women’s health. As elaborated in our paper, our team found that academic and public-facing references to zolpidem sex differences often misrepresent the evidence. For instance, researchers have mistakenly suggested that <a href="https://www.clinicaltherapeutics.com/article/S0149-2918(16)30920-1/fulltext">emergency room visits and car accidents were primarily responsible</a> for the FDA’s decision (rather than reanalyses of existing data and driving studies), or that <a href="https://doi.org/10.1002/lary.27498">zolpidem was removed from the market</a> (only the label’s dosing language was changed). Authors almost never mention the possible relevance of body weight and the <a href="https://wayback.archive-it.org/7993/20170404172106/https://www.fda.gov/Drugs/DrugSafety/ucm334033.htm#:~:text=The%20drug%20labeling%20should%20recommend%20that%20health%20care%20professionals%20consider%20prescribing%20a%20lower%20dose%20of%205%20mg%20for%20men.%20In%20many%20men%2C%20the%205%20mg%20dose%20provides%20sufficient%20efficacy.">FDA’s concurrent suggestion</a> that men also start off with half doses. Some authors cite publications without original data or which do not support their claim, and other authors don’t provide a citation at all, treating zolpidem’s sex difference as an established, canonical fact, one with regulators’ and policymakers’ seal of approval. While it is not uncommon for scientists to disagree about regulatory decisions, the Ambien claim has miraculously transcended both ongoing disagreement and the complexities of its original context.
</p>
<h3 id="9yrk44">
Faulty facts and their fallout
</h3>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="WTys5J">
It matters when a faulty sex-difference “fact” persists and circulates unquestioned. Once such a “fact”<strong> </strong>is out in the world, it can be very difficult to unseat or revise. This phenomenon has been documented in the case of <a href="https://journals.sagepub.com/doi/full/10.1177/0306312714535679">misconceptions about spinach’s high iron content</a>, as well as more loaded claims like <a href="https://www.hup.harvard.edu/catalog.php?isbn=9780674725324">testosterone’s association with violence</a>. Scholars have termed these “academic urban legends” and “<a href="https://lithub.com/it-turns-out-theres-not-a-lot-of-science-linking-testosterone-to-violence/">zombie facts</a>” (which cannot be killed no matter how many times they are refuted).
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="9VAPg8">
How can we make sense of the uptake and proliferation of claims about sex differences in Ambien? Why is it so sticky, while other textbook facts <a href="https://www.vox.com/science-and-health/2018/8/27/17761466/psychology-replication-crisis-nature-social-science">are being knocked down</a>? For one, the FDA’s decision carried the weight and credibility of a federal regulatory authority. Even though the decision involved a contextual assessment to exercise caution and use sex-based dosage to lower morning blood levels, that nuance was lost as it was communicated to diverse audiences and used in different rhetorical settings. And once it was regarded as a “textbook” fact, the claim no longer received as much scrutiny.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="3As71R">
In addition, the story of Ambien sex differences strongly aligned with the platforms of existing advocacy groups. Over the past 25 years, women’s health advocates have elevated the problem of <a href="https://pubmed.ncbi.nlm.nih.gov/30015551/">androcentrism</a> and bias in medical research, emphasizing sex differences. Ambien seems like a clean, “<a href="https://www.northwell.edu/katz-institute-for-womens-health/articles/standard-of-care-treating-women-like-little-men">perfect example</a>” of women’s intrinsic biological difference from men, validating something that people often already feel to be true and what women’s health advocates have often argued: that sex differences are ubiquitous and clinically relevant. As Stahl commented on CBS after the <em>60 Minutes</em> special: “Now we are learning that [men and women] are pervasively different at every level. Our lungs are different, our skin is different, our cells are different.”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="nNRwSZ">
This way of looking at gender and sex — as two distinct types carving up the human population and producing distinctions at every biological level that explain health disparities — is what scholars call <a href="https://doi.org/10.3998/ptpbio.2096">binary biological sex essentialism</a>, and it has serious limitations.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="LFJ0cM">
Numerous scientific studies show that a sex binary of male and female just doesn’t work to explain the range of variability in <a href="https://linkinghub.elsevier.com/retrieve/pii/S0149763420306540">humans</a>, <a href="https://www.biorxiv.org/content/10.1101/2023.01.26.525769v1">animals</a>, and <a href="http://www.journals.uchicago.edu/doi/full/10.1086/688181">cellular mechanisms</a>. It also privileges intrinsic biological differences as an explanation over social and structural factors or interactions between the environment and biology. Ultimately, this makes science and medicine worse for everyone, including people who don’t fall neatly onto one side of the supposed binary — <a href="https://www.vox.com/lgbtq">trans</a> and gender-expansive individuals, people with intersex conditions, and anyone who departs from the average body weight or testosterone/estrogen level for their sex.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="VuADKh">
Certainly, sex-related variables like hormones, gonadal physiology, and chromosomes are important to account for in scientific research such as drug reactions. But if the aim is rigorous science, we need to discard the simplistic notion of sex as merely male or female, stop using sex as a coarse proxy for other mechanistically relevant features like body weight or hormones, and examine interactions between age, other drugs taken, lifetime stress levels, and other social variables to develop medicines that work for everyone, not just the imagined average “male” or “female” patient.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="bviP0c">
Sex-difference claims can also reify culturally embedded notions of two discrete, intrinsically different sexes. Although science that applies a binary sex framework has been championed as a win for women’s health, bad-faith actors have used a similar framework to support trans-exclusionary agendas. Sex-essentialist science has been <a href="https://www.science.org/doi/10.1126/science.abo1102">exploited</a> by those seeking to invalidate trans identities by appealing to the alleged naturalness of the sex binary, whether an XX/XY binary in chromosomes or a penis-vulva binary in genital anatomy. Many anti-trans platforms draw specifically on language from research advancing binary sex differences (e.g., <a href="https://www.emerald.com/insight/content/doi/10.1108/978-1-80262-985-920221007/full/html">in sports</a>, <a href="https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3207728">federal laws about public bathroom access</a>, and <a href="https://blog.lareviewofbooks.org/essays/transphobia-cloaked-science/">federal level health services</a>), thereby claiming that scientific legitimacy and biological reality are on their side.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="2RUbs5">
The consequences are grave and imminent: At the time of writing, <a href="https://translegislation.com/">563 anti-trans bills have been proposed in 49 states, with 80 having already passed</a>, in a historic legislative assault on the existence of trans people, particularly via restrictions on gender-affirming health care for trans youth. While many researchers share a laudable vision of sex and gender equity, sex essentialist approaches may concretize an oversimplified understanding of sex that runs counter to this goal, particularly in this political context.
</p>
<h3 id="RVEnLy">
<strong>Ambien isn’t the cautionary tale we think</strong>
</h3>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="gVivlx">
Cahill was right in a sense: Ambien provides a cautionary tale. Rather than offering a paragon example of biological differences between men and women, it instead illustrates how a distorted fact about pharmaceutical sex differences became common knowledge, as well as how hype, advocacy platforms, and assumed authority enabled its proliferation and misrepresentation. Sex difference facts are notoriously sticky, and they powerfully shape the concepts and frameworks in experiments, funding agendas, and policy justifications — so we need to make sure we get them right.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="b6rnLu">
To do that, we need a science that embraces the complexity of sex-related variables and their interaction with other biological and social factors in producing human variation in drug response. Comparing men and women is not enough, and we need caution and awareness about the potential bias and overstatement of such claims.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="b64LMV">
Before appealing to a textbook sex difference claim, it might be best to sleep on it.
</p>
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</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="KA8Nal">
</p></li>
<li><strong>The new “science of reading” movement, explained</strong> -
<figure>
<img alt="Four scientists in lab coats are observing various shapes and beakers, taking notes, and running tests. The shapes have letters on them, which collectively spell out the word “phonics.”" src="https://cdn.vox-cdn.com/thumbor/Jk9IDWSwpk-Q3F2K7Zhh1o5g240=/240x0:1680x1080/1310x983/cdn.vox-cdn.com/uploads/chorus_image/image/72545539/VOX_PhonicsWonReadingWars.0.jpg"/>
<figcaption>
Nicole Miles for Vox
</figcaption>
</figure>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
A huge shift in how kids are taught to read is underway. But the reading wars probably aren’t gone for good.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="Kvcl2O">
For over a century, a pendulum has swung back and forth on the best way to teach kids to read. On one side are advocates of phonics, an instructional approach focused on the relationships between sounds and letters; on the other, various methods, championed by educators, that emphasize word recognition and context clues.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="pYLG6K">
This fight has occasionally grown so vicious it’s been dubbed <a href="https://www.theatlantic.com/magazine/archive/1997/11/the-reading-wars/376990/">the Reading Wars</a>.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="f8pscI">
But in the last five years, one camp has scored a victory that, if not permanent, is at least decisive.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="FM83El">
Since 2019, <a href="https://www.shankerinstitute.org/resource/reading-viz">45 states and Washington, DC</a>, have passed at least one bill related to reforming reading instruction. The new rules apply to areas like school curriculum, professional development for teachers, screenings for dyslexic students, and requirements for testing. New York City — the largest public school system in the nation — has <a href="https://ny.chalkbeat.org/2023/5/9/23717292/eric-adams-david-banks-nyc-school-reading-curriculum-mandate-literacy">also ordered change</a> for its 700 elementary schools.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="PK4EeJ">
These new <a href="https://www.vox.com/policy">policies</a> — met with a mix of excitement and skepticism — are typically accompanied by<strong> </strong>bold promises. “These changes to our education system will actually educate our kids better in the future than we did before the pandemic,” Tennessee’s Republican Gov. Bill Lee <a href="https://www.psrmemphis.org/politics-of-phonics-how-a-skill-becomes-a-law/#:~:text=Right%20after%20SCORE's%20%E2%80%9CScience%20of,awareness%2C%20phonics%2C%20and%20fluency.">declared</a>. “This is the beginning of a massive turnaround,” <a href="https://www.nytimes.com/2023/05/09/nyregion/reading-nyc-schools.html">said</a> the New York City Schools chancellor.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="lTUwWV">
A life with poor literacy skills is a hard life. Not being able to read means countless social, <a href="https://epionline.org/studies/r127/">economic</a>, and <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1492599/">physical</a> challenges, making the stakes of these new reading reforms tremendously high. Coming out of the pandemic, as students <a href="https://amplify.com/index.php?amp-pdf-file=/wp-content/uploads/2023/07/mCLASS_EOY_Report_2023_071923.pdf">still struggle</a> with learning loss, policymakers are especially aware of the need to get these new literacy interventions right. Though some critics have claimed we <a href="https://journals.sagepub.com/doi/full/10.1177/01614681231155688">have no national reading crisis at all</a>, for the millions of kids and adults who struggle to read in America, there is no question that each day brings about new isolating, draining, and avoidable challenges.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="FP71lq">
Momentum for these reading laws traces its roots to four main factors.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="vb6c7s">
The first came five years ago, when a journalist named Emily Hanford released <a href="https://www.apmreports.org/episode/2018/09/10/hard-words-why-american-kids-arent-being-taught-to-read">an influential radio series</a> that looked critically at reading instruction, and specifically how popular strategies employed by American teachers conflicted with decades-old research in <a href="https://www.vox.com/neuroscience">neuroscience</a> and cognitive <a href="https://www.vox.com/psychology">psychology</a> about how kids best learn to read. Hanford’s reporting helped launch a movement dedicated to advancing the “science of reading” — a shorthand for applying these brain-focused studies to instruction.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="HBhPP2">
The second factor came a year later, when Mississippi, a high-poverty state that overhauled its own reading policies back in 2013, soared in national test score rankings. Mississippi fourth graders went from being 49th in the nation for reading on a major exam known as the National Assessment of Educational Progress (NAEP), to 29th, and one of the reforms Mississippi had embraced in 2013 was a focus on the “science of reading.”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="DlfuXV">
The third factor was the emergence in the 2010s of national grassroots networks of parents of children with dyslexia, who have more recently brought their organizing prowess to bear for new state policies they felt could better serve their children’s needs.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="pOUJOw">
And lastly, but no less important, was the pandemic, which fueled a major drop in student achievement and sparked an infusion of new federal funds for schools.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="jiwail">
This is not the first or even second time our country has quickly moved to revamp literacy instruction, and some worry that history is about to repeat itself with failed or misguided policy changes.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="vZusJE">
“I’ve been doing this for more than 50 years and I’ve been through three of these,” said Tim Shanahan, who once served as president of the International Literacy Association and <a href="https://www.nichd.nih.gov/sites/default/files/publications/pubs/nrp/Documents/report.pdf">on a federal study</a> into the scientific evidence behind reading instruction.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="owGX0J">
Reading Wars veterans like Shanahan say this wave of reform has some new elements<strong>. </strong>Still, some problems that have undermined past waves threaten these new laws too, like a lack of funding<strong> </strong>and the challenge of maintaining political support if (and likely when) some<strong> </strong>standardized test scores go down.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="KXJj3L">
Indeed, not all teachers and <a href="https://www.nytimes.com/2023/05/25/nyregion/nyc-public-schools-reading.html">school administrators</a> are on board. Many have resented the pendulum that has swung back and forth over decades, with competing rules and ideas and sometimes teacher-bashing to boot. Some educators reject the idea that they’ve been teaching reading incorrectly and note that the new materials they’re being told to use now lack a strong track record, either.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="L8cjWd">
One of the most prominent cognitive scientists studying how kids learn to read has emerged as a vocal critic of many of the curriculum guides now being marketed as adhering to the “science of reading.”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="pt7GIU">
Even the more enthusiastic champions of the new reading reforms recognize that passing laws is only the first step, and there’s a long road ahead to making these changes lasting and successful, as schools deal with other intense challenges including <a href="https://osf.io/bfg3p/">chronic absenteeism</a>, a <a href="https://www.nytimes.com/2022/10/06/education/learning/student-mental-health-crew.html">student mental health crisis</a>, and unusually <a href="https://www.chalkbeat.org/2023/6/27/23774375/teachers-turnover-attrition-quitting-morale-burnout-pandemic-crisis-covid">high staff turnover</a>.
</p>
<h3 id="g49uqH">
The science behind the science of reading
</h3>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="7vKPkl">
The definition of “science of reading” —<strong> </strong>a term <a href="https://cdn.vox-cdn.com/uploads/chorus_asset/file/24849291/What_Constitutes_a_Science_of_Reading_Instruction_.pdf">first used</a> in reading instruction in the 1830s — has evolved over the decades.<strong> </strong>Today, it primarily refers to cognitive research that pertains to what happens in the brains of strong and poor readers, and is frequently a shorthand for deploying more classroom time on phonics, with its emphasis on learning to sound out words. Past research has found that most kids need systematic phonics instruction when they’re young to ultimately read well.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="sGeaAJ">
Sometimes this phonics research gets overstated by proponents. The best studies have shown that teaching phonics is moderately better than other approaches — translating to about a few months of extra school instruction. Experts caution against forgetting that at its core, phonics is a means to an end: “Programs that focus too much on the teaching of letter-sounds relations and not enough on putting them to use are unlikely to be very effective,” stated <a href="https://www.nichd.nih.gov/sites/default/files/publications/pubs/nrp/Documents/report.pdf">the National Reading Panel report in 2000</a>, a seminal federally funded investigation into science-based reading instruction.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="7Y8OPq">
And not everyone needs explicit phonics instruction at school to read well; indeed tens of millions of children have acquired strong literacy skills without it for generations, either learning through osmosis at home or through other classroom approaches that have waxed and waned in popularity like “<a href="https://readinghorizons.website/reading-strategies/teaching/phonics-instruction/reading-wars-phonics-vs-whole-language-reading-instruction">whole language</a>” and “<a href="https://k12teacherstaffdevelopment.com/tlb/what-is-the-balanced-literacy-approach/">balanced literacy</a>.”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="SHzMUC">
But what reading experts generally agree on is that <em>most </em>students — <a href="https://www.nancyyoung.ca/_files/ugd/ff7f1a_0907efb358234fde9dc8f78c9d9f89e2.pdf">roughly 60 percent of children</a> — will benefit from more systematic phonics instruction, especially in kindergarten, first grade, and second grade. A school’s average reading performance will likely go up, and it could be especially helpful for students from disadvantaged backgrounds or those struggling with dyslexia.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="xvekQo">
Sometimes “the science of reading” is invoked as a way to signal what’s <em>not </em>considered scientific. The most prominent example of that today is a popular reading instruction strategy known as “three-cueing” or MSV, an acronym for meaning, syntax, and visual information. Popularized in the 1960s and ’70s, these methods encourage<strong> </strong>students to look at context clues to guess the meaning of unknown words; for example, a picture of a house in a story about the country might help a struggling reader guess the word “cottage.”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="WylIyG">
But studies have shown that these sorts of predictive approaches are ineffective in helping students actually learn to read specific words. Strong readers, rather than guessing a word’s meaning based on adjacent clues, will work to decode letters in the unfamiliar word itself. Have students who rely on cueing generally understood the meaning of a passage? Yes. But they haven’t read the passage <em>well. </em>
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="qL7GIL">
These debates around phonics instruction can grow contentious, especially over the last few years. Many academics argue there should be <a href="https://ila.onlinelibrary.wiley.com/doi/10.1002/rrq.349">a broader</a>, <a href="https://kappanonline.org/science-of-reading-amanda-goodwin/">more inclusive definition</a> of “science of reading” that encompasses research fields beyond just the brain.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="5LauXs">
“There isn’t shared language with thinking and talking about this with any precision,” said Rachael Gabriel, a professor of literacy education at the University of Connecticut. “A lot of the language is dog whistle-y, and everyone gets really deep in the weeds and then confuses each other.”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="2akzNI">
For example, though some reading experts defend context-based strategies like cueing, <a href="https://cdn.vox-cdn.com/uploads/chorus_asset/file/24849296/Using_Context_as_an_Assist_in_Word_Solving__The_Contributions_of_25_Years_of_Research_on_the_Interactive_Strategies_Approach.pdf">pointing to experimental studies</a> showing they could be complementary to phonics, others believe it’s a mistake to encourage teaching the strategies of poor readers at all.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="BYtaQx">
“Being a reader isn’t like being pregnant where you either are or you aren’t,” said Shanahan, who supports the move away from cueing. “We care how good a reader are you, and we know that strong readers don’t try and guess the meaning.”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="rxFn86">
In 2019, a <a href="https://www.edweek.org/research-center/research-center-reports/early-reading-instruction-results-of-a-national-survey">nationally representative EdWeek Research Center survey</a> found 75 percent of K–2 teachers said they teach students to read using the three-cueing method, and 65 percent of postsecondary instructors who teach courses on reading instruction said they did too. As the “science of reading” movement has picked up steam, popular school curriculum providers who endorse these strategies have come under intense scrutiny, blasted for teaching young children strategies that could delay or derail their reading.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="7Od1E6">
The tide is seemingly turning. Three states — <a href="https://www.edweek.org/teaching-learning/4-more-states-pass-science-of-reading-mandates/2023/05">Indiana, Arkansas, and Louisiana</a> have recently gone so far as to ban “three-cueing” in legislation, and ExcelInEd, a national advocacy group founded by former Florida Gov. Jeb Bush, holds eliminating three-cueing <a href="https://earlyliteracymatters.org/comprehensive-policy/">as essential for any model reading policy</a>. Last year Lucy Calkins, a longtime proponent of the “balanced literacy” approach to reading instruction, revamped her popular school curriculum program to include class-wide daily phonics lessons. “All of us are imperfect,” Calkins <a href="https://www.nytimes.com/2022/05/22/us/reading-teaching-curriculum-phonics.html">told the New York Times</a>. “The last two or three years, what I’ve learned from the science of reading work has been transformational.”
</p>
<h3 id="fbIkDi">
The problem is we don’t know how to teach the “science of reading” well yet, either
</h3>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="UUyVdA">
Though states have moved to replace <a href="https://www.edweek.org/teaching-learning/new-curriculum-review-gives-failing-marks-to-popular-early-reading-programs/2021/11">poorly rated</a> curricula or ban<strong> </strong>weak instructional approaches, figuring out exactly what schools should do instead is harder. Politicians have falsely declared that experts know what science-backed alternatives teachers should use, and education companies have rushed to meet the demand for new materials, selling school districts their own questionable curricula and teacher trainings.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="0VgbEn">
“We think we have some sort of tentative answers, that various kinds of instructional approaches work better than others, but that evidence is definitely far from ironclad,” said Morgan Polikoff, an education professor at the University of Southern California and an expert in K–12 curriculum standards. “Generally speaking there is not a lot of good research on the effectiveness of core curriculum materials, and that’s true both in reading and for other subjects.”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="rfK7Tg">
For example, LETRS, an acronym for Language Essentials for Teachers of Reading and Spelling, has become one of the most popular training courses claiming to adhere to the “science of reading.” Mississippi embraced it beginning in 2014 as part of its statewide reading reforms, and following Mississippi’s impressive gains on the 2019 NAEP exam, <a href="https://www.edweek.org/teaching-learning/letrs-program-teacher-training#:~:text=Twenty%2Dthree%20states%20have%20contracted,from%202019%2C%20the%20company%20says.">other states rushed to follow</a>. (It’s a <a href="https://www.edweek.org/teaching-learning/letrs-program-teacher-training#:~:text=Twenty%2Dthree%20states%20have%20contracted,from%202019%2C%20the%20company%20says.">pricey</a> professional development course that can take teachers up to 160 hours over two years to complete.)
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="lbSBy1">
Despite its close associations with the “science of reading”<strong> </strong>— LETRS has its own <a href="https://docs.google.com/document/d/1HVs7h-18km68jirWvkiEDQIyA6GV02JP9LxKt6D_QJU/edit">middling track record</a><strong> </strong>of effectiveness. One <a href="https://ies.ed.gov/ncee/pubs/20084030/index.asp">experimental study</a> found teachers who were trained by LETRS did improve in their knowledge of reading science, but their students did not have statistically higher differences in achievement than teachers in the control group. (A spokesperson for LETRS told Vox, “we<strong> </strong>know it has <a href="https://cdn.vox-cdn.com/uploads/chorus_asset/file/24849293/LETRS_Evidence_Base_2023_07_FINAL.pdf">been</a> <a href="https://cdn.vox-cdn.com/uploads/chorus_asset/file/24849292/LETRS_Suite_Brochure_Option_4.pdf">proven</a> <a href="https://cdn.vox-cdn.com/uploads/chorus_asset/file/24849294/LETRS_Talking_Points_2023_0201_FINAL.pdf">to drive</a> positive student outcomes when coupled with other educational interventions.”)
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="Sw6qRg">
Likewise, studies of reading interventions known as <a href="https://www.ortonacademy.org/resources/what-is-the-orton-gillingham-approach/">Orton-Gillingham</a>, which have been promoted by many literacy reform<strong> </strong>advocates, have yielded <a href="https://psycnet.apa.org/record/2006-20541-005">mixed results</a> so far. One<a href="https://pubmed.ncbi.nlm.nih.gov/34629488/#:~:text=Findings%20suggested%20Orton%2DGillingham%20reading,Orton%2DGillingham%2Dbased%20approaches."> 2021 meta-analysis</a> found the approach did not generate statistically significant improvements in foundational skill areas like phonics. Even<strong> </strong>for students with some forms of reading disability, Orton-Gillingham wasn’t found to significantly boost comprehension or vocabulary.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="bCElkA">
Generally reading experts say the policies included in the new state reading laws <a href="https://www.edweek.org/teaching-learning/states-are-pushing-changes-to-reading-instruction-but-old-practices-prove-hard-to-shake/2022/07">are a “real mixed bag.”</a> Some laws incorporate more research-backed ideas <a href="https://files.eric.ed.gov/fulltext/ED610423.pdf">like coaching,</a> while other endorsed approaches are more suspect. There is <a href="https://psycnet.apa.org/record/2010-19654-001">no clear</a> <a href="https://pubmed.ncbi.nlm.nih.gov/24704662/">amount of time</a> <a href="https://www.nichd.nih.gov/sites/default/files/publications/pubs/nrp/Documents/report.pdf">that research shows</a> should be spent daily on phonics, no established curriculum for the “science of reading” and studies on so-called <a href="https://www.edweek.org/teaching-learning/decodable-books-boring-useful-or-both/2020/03">decodable books</a> — <a href="https://www.readingrockets.org/topics/curriculum-and-instruction/articles/what-are-decodable-books-and-why-are-they-important">strongly endorsed</a> by some phonics advocates to help young students practice letter-sound combinations — <a href="https://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.525.9315&amp;rep=rep1&amp;type=pdf">have</a> <a href="https://psycnet.apa.org/record/2004-11017-004">their own mixed</a> <a href="http://backseatlinguist.com/blog/the-shaky-scienceofreading-on-decodable-texts/">research</a> <a href="https://link.springer.com/article/10.1007/s10643-019-00970-4">track</a> <a href="https://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.873.560&amp;rep=rep1&amp;type=pdf">record</a>.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="6UKjR2">
“Often phonics advocates promote the use of research since research supports phonics instruction … but when it comes to specific prescriptions about how phonics should be taught, they make all kinds of claims that come down to: do it my way, I know best, don’t worry about what the science has to say,” said Shanahan. “There are features of effective phonics instruction suggested by the research and there are aspects on which there is either no research or the research rejects the advocate’s prescription.”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="Ffp9z7">
Mark Seidenberg, a cognitive neuroscientist and author of<em> </em><a href="https://www.amazon.com/Language-Speed-Sight-Can%C2%92t-About/dp/0465019323"><em>Language at the Speed of Sight</em></a>, <a href="https://seidenbergreading.net/2023/03/31/about-the-science-in-the-science-of-reading/">has emerged as a critic</a> of some of the new materials being promoted under the banner of the “science of reading.” He’s <a href="https://seidenbergreading.net/2023/05/26/decoding-the-simple-view-of-reading/">blasted “influencers”</a> leading the movement whose own background in cognitive science is limited. (Seidenberg’s book on reading research heavily shaped <a href="https://www.apmreports.org/episode/2018/09/10/hard-words-why-american-kids-arent-being-taught-to-read">Hanford’s reporting</a>.)
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="8XJgaA">
In an interview with Vox, Seidenberg expounded on his criticism<strong>: </strong>“It’s a difficult situation because people want to adopt better practices, they understand the idea that what was done before was not really based on solid ideas … but now you have a huge demand for science-based practices pursued by advocacy groups and people who don’t have a great understanding of the science.”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="TToWRC">
Seidenberg believes that moving away from strategies like three-cueing is important. But he warned that a simplistic reliance on some of the foundational reading science research can lead to some misinformed instructional conclusions, like the idea that children should learn units of sound (or “phonemes” ) before letters, and letters before syllables and words.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="oQX5k4">
“That’s a basic misunderstanding,” said Seidenberg. “Phonemes are abstract units that are results of being exposed to an alphabet, they’re not a precursor.” He also lamented that some leaders have incorrectly cited his research to suggest there’s no downside to teaching kids phonics in the early grades for too long. “There are big opportunity costs and the clock to fourth grade is ticking,” he said. “You only want to do a lot of instruction on these components enough to get off the ground.”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="QM3q80">
The UK offers a cautionary tale. Last year reading researchers <a href="https://bera-journals.onlinelibrary.wiley.com/doi/epdf/10.1002/rev3.3314">published a major study</a> that concluded England’s present emphasis on phonics instruction came at the expense of other needed literacy skills. They attributed the country’s heavy prioritization in part to <a href="https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1142992/2023_Phonics_screening_check_administration_guidance.pdf">a national phonics screening test</a> introduced by the government in 2012, which incentivized in some cases up to three years of daily hour-long phonics lessons.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="sYTfN6">
“There’s no question that phonics instruction is important,” Dominic Wyse, the study’s lead author and an education professor at the University of College London, told Vox. “But let’s be clear, there are risks to overdoing it. You’re wasting their time and damaging their time to develop reading comprehension.”
</p>
<h3 id="0QAwv8">
Getting implementation right
</h3>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="VWCvBe">
The success of the new reading instruction laws will depend primarily on how well they’re implemented on the ground in schools and individual classrooms.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="Z9MRRj">
This past spring researchers from Michigan State <a href="https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4427675">presented a study</a> assessing the impact of the new reading reform laws on test scores. The research, which has not been peer-reviewed, <a href="https://www.edweek.org/teaching-learning/early-literacy-laws-some-seem-to-work-better-than-others/2023/04">found students in states with more “comprehensive” supports</a> — like coaching for teachers, adequate funding, and summer tutoring — had larger gains on test scores and on the NAEP than students in states with less comprehensive reading laws.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="OeVB6E">
One concern for advocates is the great variability in how states might hold schools accountable to the new laws. Some worry that without more proactive <a href="https://co.chalkbeat.org/2022/3/31/23005102/colorado-reading-curriculum-transparency-data">transparency</a> and <a href="https://fordhaminstitute.org/ohio/commentary/how-will-ohio-ensure-schools-are-actually-following-science-reading">enforcement provisions</a>, the reforms could wither on the vine. Others worry about unfunded mandates in a year or two once Covid-19 aid dries up.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="aePbtK">
Still, others point to the fact that many colleges of education are still teaching methods to prospective teachers like three-cueing, <a href="https://www.nytimes.com/2023/05/25/nyregion/nyc-public-schools-reading.html">and the New York Times quoted Lucy Calkins</a> at a conference in March telling educators they can join other school leaders in rejecting these new approaches. “You can say no,” Calkins had said. “And people all over the country are doing so.”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="ECMsZJ">
To encourage more successful implementation, Gabriel of the University of Connecticut and Sarah Woulfin, a professor of <a href="https://www.vox.com/education">education policy</a> at UT Austin, have been encouraging <a href="https://ila.onlinelibrary.wiley.com/doi/abs/10.1002/rrq.339">more focus on school systems, structures, and leadership</a>, rather than a narrow focus on what individual teachers know about reading. “It is not enough to deliver new materials that may sit in boxes in a closet without strong leadership for their integration,” <a href="https://nepc.colorado.edu/blog/infrastructure">they write</a>. “It is not enough to press teachers to use new tools, without providing high-quality opportunities.”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="gfCMhM">
In some states, such as North Carolina, lawmakers have rolled out new policies but provided little support for educators to incorporate the new mandates into their existing workflow, fueling backlash.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="fTAwIu">
Ginny Sharpless and Amanda Harrison, co-founders of <a href="https://www.facebook.com/groups/175241973895861/">Literacy Moms NC</a>, a group for parents of students with reading disabilities, told Vox they’ve been deeply disappointed by the lack of investment lawmakers have made in building teacher buy-in for the new policies.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="bNIaMg">
“If you’re already working crazy hours, already not getting paid enough, and then someone says, ‘Oh, we want you to do 200 hours of extra training on your own time,’ well, you’re going to be pissing off people who are already burnt out,” said Harrison.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="RETVyt">
“State lawmakers did absolutely nothing to try to change [educators’] views, you can’t just show people the data and expect them to be converted,” added Sharpless. “Leaders should have gone out there and had meeting after meeting to talk to teachers to bring them on board.”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="Er2H2D">
Polikoff, of the University of Southern California, said the history of US education policy reform suggests that building teacher buy-in and avoiding overly punitive mandates will be important to helping the new “science of reading” laws actually stick. He also warned against hinging hopes to specific state test score gains. When scores trended down <a href="https://www.vox.com/2014/10/7/18088680/common-core">following the introduction of the federal Common Core</a> standards, opponents used those declining results to then water down the policies.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="6qiwnC">
“There’s the risk of setting yourself with unrealistic expectations, and states that go up in test scores also go down,” he said. “One of the states that could go down is Mississippi, which has a lot of conditions that make it likely to have educational difficulty.”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="pIokqo">
As teachers embark on the 2023–24 academic year, eager to educate students using the best reading materials available, they’ll have to wade through this morass of information, hoping to do the best job possible but waiting for more clarity on exactly how. And in the meantime, there are real disagreements over what instructional strategies to use in schools, what emphasis each should get, what counts as evidence, and who gets to decide.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="zmbA7j">
“Policymakers don’t necessarily want to hear that the science is more complex and less certain than we thought,” <a href="https://kappanonline.org/science-of-reading-amanda-goodwin/">said Amanda Goodwin</a>, the co-editor of <em>Reading Research Quarterly</em> and a professor of literacy at Vanderbilt University. “It’s much easier to get public support for a handful of ‘proven’ practices.”
</p></li>
<li><strong>Trump’s 4 indictments, ranked by the stakes</strong> -
<figure>
<img alt="Trump’s face in silhouette, dark against blurry background lights." src="https://cdn.vox-cdn.com/thumbor/3nTfhHPf6ITqWGz9UawwPlrra7M=/302x0:5091x3592/1310x983/cdn.vox-cdn.com/uploads/chorus_image/image/72545491/1610278973.0.jpg"/>
<figcaption>
Donald Trump at the Iowa State Fair on August 12, 2023. | Brandon Bell/Getty Images
</figcaption>
</figure>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
A quick guide to Trump’s 4 indictments and why they matter.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="1M1Pr3">
<a href="https://www.vox.com/donald-trump">Donald Trump</a>’s<a href="https://www.vox.com/politics/2023/4/4/23664866/donald-trump-indictment-alvin-bragg-jack-smith-stormy-daniels-new-york-georgia"> legal web</a> has grown more tangled than ever. The former president is facing 91 criminal charges across four jurisdictions — Georgia, Florida, New York, and the District of Columbia. He has two trial dates set for 2024 so far. And all this is unfolding as he runs for the presidency again.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="xIKXLV">
The cases — involving allegations of attempted election theft, mishandling classified documents, and hush money payments — have grown so sprawling that it’s tough for anyone but the most die-hard political obsessive to follow them in detail.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="otO7jO">
But in some, the stakes — for our democracy and for Trump personally — are higher than others.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="hRqCrC">
The two prosecutions about Trump’s efforts to overturn <a href="https://www.vox.com/joe-biden">Joe Biden</a>’s 2020 victory (in DC and Georgia) both come with the possibility of serious criminal penalties. They also have enormous implications for the future of American elections, and for whether Trump or someone like him will respect the results next time around.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="txfVBA">
The classified documents prosecution, in Florida, is also significant in that it involves sensitive intelligence material. However, prosecutors have presented no evidence that this sensitive material leaked out from Trump’s possession. The prosecution is mainly about his efforts to defy the government’s demands that he return the documents.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="UQc1F6">
Then, in the New York case, Trump is charged with falsifying business records related to hush money payments he’d made. The core violation here is, basically, that the Trump Organization logged these payments improperly as “legal expenses.” This is not the highest-stakes issue in the world.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="VvyhmT">
It’s all a lot to keep track of, so in this guide, we’ll walk through the charges and potential sentences in each prosecution in more detail, and we’ve ranked the indictments in order of importance based on the stakes and potential implications of each case.
</p>
<h3 id="aeuJqB">
<strong>1) Federal </strong><a href="https://www.vox.com/2020-presidential-election"><strong>2020 election</strong></a><strong> case</strong> (District of Columbia)
</h3>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="NjPXUL">
<strong>How important is this indictment? </strong>Very important. <a href="https://www.vox.com/politics/2023/8/1/23800704/trump-indicted-criminal-charges-jack-smith-jan-6-insurrection">As Vox’s Nicole Narea previously explained</a>, this case “will legally define what a politician is able to do to reverse a defeat.” The outcome of this case could have major implications for the <a href="https://www.vox.com/2024-elections">2024 election</a> and every race that follows: If Trump isn’t held accountable for the actions he took on January 6 and leading up to it, he and others could try to pull the same schemes in the future.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="XpyjU3">
Ultimately, this case has a significant bearing on the future of US democracy.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="mmv5lT">
<strong>Number of charges: </strong>Four felony counts. They include:
</p>
<ul>
<li id="fS3iDI">
Charge of conspiracy to defraud the United States, which includes plotting to overturn the results of the <a href="https://www.vox.com/2020-presidential-election">2020 election</a>
</li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="fbmXO8">
Conspiracy to obstruct an official proceeding, including plotting to prevent the 2020 election certification
</li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="bCzNI5">
Obstruction of and attempt to obstruct an official proceeding, which includes actually blocking the certification of the 2020 election results
</li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="m2cyff">
Conspiracy against rights, which includes a plan to deprive someone of a constitutional right (in this case, that is the ability to vote)
</li>
</ul>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="Er37rO">
<strong>Potential jail time per count (these are maximum sentences that are unlikely to be imposed): </strong>
</p>
<ul>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="9yJujS">
Conspiracy to defraud the United States: 5 years
</li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="1nxqcZ">
Conspiracy to obstruct an official proceeding: 20 years
</li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="Ejq1dw">
Obstructing an official proceeding: 20 years
</li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="60i7eR">
Conspiracy against the right to vote: 10 years
</li>
</ul>
<aside id="znLwWu">
<div>
</div>
</aside>
<h3 id="Kh79zF">
<ol start="2" type="1">
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">Georgia election indictment
</li></ol></h3>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="aNuF9S">
<strong>How important is this indictment?</strong> Very important. Fulton County District Attorney Fani Willis accused Trump and several of his associates of a sprawling racketeering conspiracy related to their efforts to overturn Biden’s win in the state. In contrast to the federal election indictment, where Trump is the only one charged so far, here 18 others were also charged for participating in this alleged conspiracy. These include famous names like Rudy Giuliani and former White House chief of staff Mark Meadows, notorious Trump lawyers like John Eastman and Sidney Powell, and lower-level Georgia players.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="FxOdmZ">
Significantly, if Trump wins the presidency again in 2024, he would not be able to thwart this prosecution, since it is being carried out under state law.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="heWEEj">
<strong>Number of charges:</strong> 13 felony counts. They are:
</p>
<ul>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="zlszYj">
1 count of violating the Georgia RICO (Racketeer Influenced and Corrupt Organizations) Act, which is basically a catchall charge for the larger conspiracy to overturn the outcome
</li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="8pm5rx">
3 counts of solicitation of violation of oath by a public officer, which are about Trump’s attempts to convince Georgia officials to overturn the results
</li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="ANsFwp">
1 count of conspiracy to commit impersonating a public officer
</li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="gQCIOx">
2 counts of conspiracy to commit forgery
</li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="rFql3O">
2 counts of conspiracy to commit false statements and writings
</li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="rTPdOK">
1 count of conspiracy to commit filing false documents
</li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="pgCIUt">
1 count of filing false documents
</li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="bMDMoy">
2 counts of making false statements and writings
</li>
</ul>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="yD6iPf">
Most of those counts relate to the Trump campaign’s effort to put together a slate of “alternate” electors from Georgia who would purport to cast electoral votes for Trump rather than the actual winner, Biden.
</p>
<aside id="vySNSz">
<div>
</div>
</aside>
<h3 id="CE9n7t">
<strong>3) Federal documents case</strong> (Florida)
</h3>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="Rh2pOA">
<strong>How important is this indictment? </strong>Important. This case centers on a president’s ability to endanger the country’s <a href="https://www.vox.com/defense-and-security">national security</a> by taking and mishandling classified documents after leaving office. Documents that Trump kept addressed everything from US nuclear programs to the country’s defense and weapons capabilities to how America could respond in the face of a possible attack. Additionally, the case looks at how Trump obstructed FBI efforts to take back the documents.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="G0QjDH">
<strong>Number of charges: </strong>40 felony counts. They include:
</p>
<ul>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="wrvBwz">
32 counts of willful retention of national defense information, which includes keeping classified documents related to military activities and nuclear weapons
</li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="J03uy4">
1 count of conspiracy to obstruct justice, which includes Trump working with an aide to hold on to classified documents and hide them from a grand jury
</li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="KdL50T">
1 count of withholding a document or record from an official proceeding, which included efforts to hide documents from a grand jury
</li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="yEcHkz">
1 count of corruptly concealing a document or record from an official proceeding, which included hiding boxes with classified documents
</li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="kWxH1f">
1 count of concealing a document in a federal investigation, which included covering up Trump’s ongoing possession of classified documents at Mar-a-Lago
</li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="xtDBPo">
1 count of scheming to conceal information the government is seeking, which includes hiding the fact that Trump still possessed classified documents
</li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="yOAOFT">
1 count of making false statements, which includes directing his attorneys to lie about returning all the classified documents in his possession
</li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="2KhZOf">
2 counts of altering, destroying, or concealing information the government is seeking, which includes plans to delete security footage
</li>
</ul>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="zQE5Bi">
<strong>Potential jail time per count (these are maximum sentences that are unlikely to be imposed): </strong>
</p>
<ul>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="1LOFUx">
Willful retention of defense information: 10 years
</li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="FO8GYr">
Conspiracy to obstruct justice: 20 years
</li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="kQqgdF">
Withholding documents from an official proceeding: 20 years
</li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="N2HZir">
Concealing documents from an official proceeding: 20 years
</li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="peH8nC">
Concealing documents from federal investigators: 20 years
</li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="FbpeVT">
Scheme to conceal: 5 years
</li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="1CbCef">
Making false statement to the US government: 5 years
</li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="t89cAz">
Altering, destroying, or hiding something the government is looking for: 20 years
</li>
</ul>
<aside id="tlDlVG">
<div>
</div>
</aside>
<h3 id="WSxszy">
<strong>4) New York state case related to hush money to Stormy Daniels</strong>
</h3>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="6IcuRE">
<strong>How important is this indictment? </strong>Less important. This case is significant for the ways it addresses alleged wrongdoing by Trump, but it has fewer sweeping implications than the other indictments. It essentially highlights Trump’s recurring lies and falsehoods, but doesn’t really have the same broader democracy or <a href="https://www.vox.com/defense-and-security">national security</a> stakes that the other cases have. Primarily, it centers on efforts by Trump to conceal hush money that was paid to porn actress Stormy Daniels so she wouldn’t go public about their affair.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="aDYTKV">
<strong>Number of charges: </strong>34 felony counts. All counts are centered on falsifying business records, which Trump is accused of doing to cover up the hush money payments to Daniels.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="7dPZ3A">
<strong>Potential jail time per count (these are maximum sentences that are unlikely to be imposed): </strong>
</p>
<ul>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="6twDX7">
Falsifying business records: 4 years
</li>
</ul>
<aside id="Kpgy6O">
<div>
</div>
</aside>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="tFDekU">
All of this leads to two big questions: Will these indictments derail Trump’s presidential bid? And do they mean Trump’s going to jail?
</p>
<h3 id="dBHaKh">
<strong>What do the four indictments mean for Trump’s chances of becoming president again? </strong>
</h3>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="9QvoEz">
Amid all this, Trump is running for president again and facing several challengers in the Republican primary. He retains a<a href="https://projects.fivethirtyeight.com/polls/president-primary-r/2024/national/"> massive poll lead</a>. These multiple indictments haven’t hurt him just yet; if anything,<a href="https://www.politico.com/news/2023/03/31/donald-trump-indictment-00090001"> they’ve helped</a>, as GOP voters have rallied around him.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="XTkvNU">
Currently, Trump’s New York trial is scheduled for March 25, 2024, and his Florida trial is scheduled for May 20, 2024. Unless one of his challengers surges before then, he could have the nomination mostly wrapped up before either trial begins.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="zCdHHP">
Then, even if he’s found guilty, or even if he’s jailed, he technically wouldn’t be disqualified from taking office. If he wins the GOP nomination, he’ll still be on the ballot in the general election. So only the voters can stop Trump from becoming president again.
</p>
<h3 id="IaulXK">
<strong>Will Trump go to prison? How long could his sentence be?</strong>
</h3>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="nb42xm">
The technical “maximum sentence” Trump could face if convicted of everything he’s been charged with<a href="https://www.politico.com/news/2023/08/02/trump-prison-sentence-risk-00109544"> is absurdly high</a> — hundreds of years — but in practice, such high sentences are almost never given. Yet — though we’re a long way off from Trump actually being behind bars — he really is in danger of getting serious time.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="sTdxSs">
His eventual sentence, if he is convicted, will depend on several factors in each jurisdiction, none more important than whether the juries will even convict him. The strength of each case and the politics of each area could well influence this — given political polarization, winning a conviction may well be easier in DC and New York than in the<a href="https://www.nytimes.com/2023/06/22/us/politics/trump-trial-documents-florida-jury.html"> mostly conservative area of Florida</a> where he will be tried. (Recall it only takes one holdout juror to block a conviction.)
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="xlVgev">
Then, if he is convicted, what sentence will the judge hand down? Judges have broad discretion to hand down a sentence they feel is appropriate. Judge Tanya Chutkan of DC will hear the federal case against Trump for trying to steal the 2020 election, and she has been<a href="https://apnews.com/article/capitol-siege-only-on-ap-donald-trump-government-and-politics-sentencing-de394dd56b3251aac5a50014f4d6afa7"> the toughest sentencer</a> for January 6 rioters, suggesting she may lean more toward the maximum if given the chance. Meanwhile, Judge Aileen Cannon of Florida has the documents case, and she is a Trump appointee who has already<a href="https://www.vox.com/2023/6/13/23757893/aileen-cannon-donald-trump-jack-smith-indictment-mar-a-lago-maga"> arguably stretched the law</a> to try and help him out; a conviction in her courtroom could be on the lighter side.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="c580tM">
Once he’s sentenced, will higher court judges rescue him on appeal? Some of the cases against him use novel legal reasoning that hasn’t been tested before. So far, the Florida case appears the clearest and best grounded in precedent, while the election cases are more novel (no president has tried to do what Trump did before, after all) and the New York hush money case has been <a href="https://www.vox.com/politics/2023/4/1/23664751/trump-indictment-alvin-bragg-stormy-daniels">somewhat legally controversial</a>. If Trump is convicted, then, his eventual fate may end up in the <a href="https://www.vox.com/scotus">Supreme Court</a>.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="preXqw">
Finally, any Trump sentence could be scuttled if he wins the presidency. If Trump is back in power, he would likely use executive power to end the federal prosecutions against him (the DC and Florida ones), and perhaps even pardon himself. He could not end the state prosecutions — the Georgia and New York ones — but if he wins the presidency, he could likely put off serving prison time until after his term concludes. So, again, it’s the voters who ultimately have the power to maximize, or minimize, Trump’s chances of going to prison.
</p></li>
</ul>
<h1 data-aos="fade-right" id="from-the-hindu-sports">From The Hindu: Sports</h1>
<ul>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Synthesis, Last Wish, Stravinsky, Dedicate, Imperial Gesture and Golden Time impress</strong> -</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Star Romance and Buckley show out</strong> -</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Photos | Independence Day 2023 in Bengaluru</strong> - Images from the Independence Day celebrations in Karnataka</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>FIFA Women’s World Cup | Carmona’s fires Spain into first-ever final with 2-1 win over Sweden</strong> - Carmona’s 90th-minute strike from long-range pinged off the crossbar and into the goal two minutes after Rebecka Blomqvist had levelled the match for Sweden</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Australia captain Pat Cummins eyes return during ODI series against India in September</strong> - Australia captain Pat Cummins has been advised rest for six weeks</p></li>
</ul>
<h1 data-aos="fade-right" id="from-the-hindu-national-news">From The Hindu: National News</h1>
<ul>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Palaniswami criticises DMK govt. over treatment in State-run hospitals</strong> -</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>MLA M.K Muneer admitted to hospital due to physical discomfort</strong> -</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Mulapeta port will spur economic activity in Srikakulam district: Botcha Satyanarayana</strong> - New industries which are being set up with an estimated cost of ₹1,170 crore would create 1,500 job opportunities in Srikakulam district, says the Minister</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Sulabh International founder Bindeshwar Pathak passes away at 80</strong> - Pathak was the founder of Sulabh International, an India-based social service organisation which works to promote human rights, environmental sanitation, waste management and reforms through education</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Congress, Uddhav-led Sena begin review of Maharashtra Lok Sabha seats, with uncertainty over Sharad Pawar’s NCP faction</strong> - Sharad Pawar’s meetings with his nephew and rebel NCP leader Ajit Pawar has prompted the Sena (UBT) and the Congress to think ahead in case Pawar senior’s faction allies with the BJP, despite his denials of it</p></li>
</ul>
<h1 data-aos="fade-right" id="from-bbc-europe">From BBC: Europe</h1>
<ul>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>At least 35 die in inferno at petrol station in Dagestan southern Russia</strong> - Fire engulfs an area of 600 sq m (6,460 sq ft) in Makhachkala, in the southern region of Dagestan.</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Ukraine war: Three killed after blasts in Lutsk and Lviv</strong> - Ukrainian officials have blamed Russia for air strikes near the country’s border with Poland.</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Russia hikes interest rates to 12% as rouble falls</strong> - The Bank of Russia raises rates sharply in an attempt to boost the currency and lower inflation.</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Canadian couple win damages from Italian ruling party</strong> - The far-right party has been ordered to pay damages over a photo used in an anti-surrogacy campaign.</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Russian rouble falls to 16-month low against US dollar</strong> - The currency has been hit by rising imports and higher military spending for the Ukraine war.</p></li>
</ul>
<h1 data-aos="fade-right" id="from-ars-technica">From Ars Technica</h1>
<ul>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>What happens when you test the real-world efficiency of hybrids and EVs?</strong> - 18 drivers and 18 hybrids and EVs, tested on the same day on the same route. - <a href="https://arstechnica.com/?p=1959340">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>US picks the first two sites for carbon-capture hubs</strong> - Up to $1.2 billion in funding for handling “legacy” carbon emissions. - <a href="https://arstechnica.com/?p=1960812">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Real estate markets scramble following cyberattack on listings provider</strong> - No estimate when crucial MLS listings provided by Rapattoni will be restored. - <a href="https://arstechnica.com/?p=1960824">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Dell fined $6.5M after admitting it made overpriced monitors look discounted</strong> - Dell Australia is paying for something many of its peers are guilty of. - <a href="https://arstechnica.com/?p=1960737">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Netflix’s test of streaming games is small, but it’s poised to be a big deal</strong> - Some UK and Canadian subscribers can test the streaming giant’s first titles. - <a href="https://arstechnica.com/?p=1960735">link</a></p></li>
</ul>
<h1 data-aos="fade-right" id="from-jokes-subreddit">From Jokes Subreddit</h1>
<ul>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>A perfectly normal couple has a baby, but, very unexpectedly, the baby is born without arms. Or legs. Or even a body. It’s just a head…</strong> - <!-- SC_OFF --></p>
<div class="md">
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
Nevertheless, the couple embrace their roles as parents and, as unusual as it is, they raise their baby, trying to make his life as normal as possible. Obviously, it’s a struggle, but they manage… and they love and treat their son like any other normal kid. Well, as much as possible.
</p>
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On the day of their son’s 21st birthday, the father decides to take his son for his first official real drink as an adult. So they go to the local pub, where the father proudly puts the head on the bar and orders two shots of the finest. The bartender can’t believe what he’s seeing, but goes and gets the drinks.
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The father takes the drinks, cheers the glasses together, and takes down his shot while pouring it into his son’s mouth. Lo and behold, the head starts wiggling and shaking and suddenly, dramatically, it sprouts an entire torso!!
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“What the hell!?”, screams the dad… “Bartender!! Two more shots!!”
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And they do it again, and the torso and head start wiggling and shaking and BOOM, the son sprouts two arms!!
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“Unbelievable!!”, screams the dad… “Two more shots!!!”
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And this time, of course, the son, delirious with happiness, does his own shot… and the subsequent shaking and wiggling leads to him instantly sprouting two legs!!
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“Two more shots!!”, screams the dad!!
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“Holy shit!! Wait!!”, screams the son, “Look! I can walk!! I can run!!” – and with that, the son goes running out the door, straight into traffic, and gets obliterated by a bus.
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“Hmmm…”, says the bartender… “Should’ve quit while he was a head.”
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​
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<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"> submitted by <a href="https://www.reddit.com/user/canada11235813"> /u/canada11235813 </a> <br/> <span><a href="https://www.reddit.com/r/Jokes/comments/15r8hw6/a_perfectly_normal_couple_has_a_baby_but_very/">[link]</a></span> <span><a href="https://www.reddit.com/r/Jokes/comments/15r8hw6/a_perfectly_normal_couple_has_a_baby_but_very/">[comments]</a></span></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>I asked my teenage son to pass me the phone book</strong> - <!-- SC_OFF --></p>
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He laughed, called me a dinosaur and handed me his iPhone.
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​
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So, the spider is dead. The iPhone is broken and my son is furious.
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<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"> submitted by <a href="https://www.reddit.com/user/Alpha-Studios"> /u/Alpha-Studios </a> <br/> <span><a href="https://www.reddit.com/r/Jokes/comments/15rbznd/i_asked_my_teenage_son_to_pass_me_the_phone_book/">[link]</a></span> <span><a href="https://www.reddit.com/r/Jokes/comments/15rbznd/i_asked_my_teenage_son_to_pass_me_the_phone_book/">[comments]</a></span></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>A guy walks into a talent agent’s office</strong> - <!-- SC_OFF --></p>
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The talent agent looks up from his paperwork and says, “All right, buddy, what’s your schtick?”
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The gentleman says, “I do it all! I sing, I dance, I tell jokes, I act, I do magic tricks, you name it!” The man proceeds to sing one of the most complex tunes the agent had ever heard, and in perfect pitch. While singing, he breaks into a soft shoe routine, then starts kicking items from the floor up into the air and proceeds to juggle them. He stops singing and acts out a soliloquy from MacBeth. In the middle of the soliloquy he adroitly lands all the juggled items on the agent’s desk, and then pulls the Ace of Spades from behind the agent’s ear.
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“Wow, that’s amazing!” the agent exclaims. “We’ll get you on the circuit immediately, you’ll make millions! What’s your name?”
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“Penis van Lesbian.”
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“What? That’s ridiculous. You’ll have to change your name.”
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“I refuse to. The Van Lesbian family has a proud tradition stretching back centuries, and the Penis name belonged to several generations on my mother’s side. I would break my parents’ hearts if I changed it.”
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“Well, if you don’t change your name, you’ll never make it in this town. I can’t be your agent.”
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The man storms out of the agent’s office. “You’ll see! I’ll make it big in spite of you!”
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Three years later the agent is sitting at his desk, opening the mail. He opens a manila envelope to find a headshot picture of the gentleman from three years prior, along with $1000 and a letter.
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“Dear Mr. Agent,” the letter read. "After storming out of your office I tried to make it on my own in the business, but I was kicked out of every venue the moment I told them my name. I finally took your advice, and now I’m on a country-wide tour and I’ve been signed on to my own television show, as well as headlining several motion pictures! Enclosed is $1000 as a way to say thank you for being so honest to me. My apologies for doubting you.
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"Sincerely,
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“Dick van Dyke”
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<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"> submitted by <a href="https://www.reddit.com/user/donquixote235"> /u/donquixote235 </a> <br/> <span><a href="https://www.reddit.com/r/Jokes/comments/15r7mut/a_guy_walks_into_a_talent_agents_office/">[link]</a></span> <span><a href="https://www.reddit.com/r/Jokes/comments/15r7mut/a_guy_walks_into_a_talent_agents_office/">[comments]</a></span></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>So I was out having beers with the boys the other day . . .</strong> - <!-- SC_OFF --></p>
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The wife calls and says, “If you’re not home in ten minutes I’m feeding the dinner I cooked to the dog!”
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I was home in five minutes! I’d hate for anything to happen to that dog.
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<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"> submitted by <a href="https://www.reddit.com/user/Gerry1of1"> /u/Gerry1of1 </a> <br/> <span><a href="https://www.reddit.com/r/Jokes/comments/15qwer4/so_i_was_out_having_beers_with_the_boys_the_other/">[link]</a></span> <span><a href="https://www.reddit.com/r/Jokes/comments/15qwer4/so_i_was_out_having_beers_with_the_boys_the_other/">[comments]</a></span></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>A wealthy, but stingy father was trying to put a birthday party together for his 18 y/o daughter.</strong> - <!-- SC_OFF --></p>
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He wanted the party to be extravagant, but wanted to spend as little money as possible. He had finished all of the other decorations, and he was left to work on the cake.
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“Why not get it ordered from an upscale bakery?” his wife said.
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So the father visited a ton of different bakeries and did research, but found the prices to be too high.
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<em>My daughter is inviting all of her friends, and I’ll look bad if I don’t put together a good cake</em>, he thought. Then, he stumbled upon a shop that opened once a year to provide free cake to its customers.
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<em>How quaint,</em> the father thought, but desperate, he walked inside to see if they could provide a cake for his daughter’s birthday.
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He was met by a Buddhist monk chanting and lighting incense.
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“Hello,” the father asked, “I would like to buy a cake.”
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“Of course,” the monk replied, “just draw a picture of the cake you would like on the notepad on the desk.”
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The father thought this to be weird, but wanting to save as much money as possible, he gave him the address and told him to come in the backdoor, just in case the cake was bad.
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The day of the party arrived and the monk visited the house with the most extravagant cake the family had ever seen. All of the guests were in awe, and whispered to each other about how much the cake could have cost.
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The monk became the guest of honor and at the end of the party, the father approached the monk and asked,
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“Why do you do this for free? You should take money for your services!”
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The monk smiled and said, “I do this for free because a cake day is the best way to earn karma.”
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<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"> submitted by <a href="https://www.reddit.com/user/zeckem"> /u/zeckem </a> <br/> <span><a href="https://www.reddit.com/r/Jokes/comments/15rivlg/a_wealthy_but_stingy_father_was_trying_to_put_a/">[link]</a></span> <span><a href="https://www.reddit.com/r/Jokes/comments/15rivlg/a_wealthy_but_stingy_father_was_trying_to_put_a/">[comments]</a></span></p></li>
</ul>
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