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<title>27 April, 2023</title>
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<title>Covid-19 Sentry</title><meta content="width=device-width, initial-scale=1.0" name="viewport"/><link href="styles/simple.css" rel="stylesheet"/><link href="../styles/simple.css" rel="stylesheet"/><link href="https://unpkg.com/aos@2.3.1/dist/aos.css" rel="stylesheet"/><script src="https://unpkg.com/aos@2.3.1/dist/aos.js"></script></head>
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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>Association between SARS-CoV-2 and metagenomic content of samples from the Huanan Seafood Market</strong> -
<div>
The role of the Huanan Seafood Market in the early SARS-CoV-2 outbreak remains unclear. Recently the Chinese CDC released data from deep sequencing of environmental samples collected from the market after it was closed on January-1-2020 (Liu et al, 2023). Prior to this release, Crits-Christoph et al (2023) analyzed data from a subset of the samples. Both studies concurred that the samples contained genetic material from a variety of species, including some like raccoon dogs that are susceptible to SARS-CoV-2. However, neither study systematically analyzed the relationship between the amount of genetic material from SARS-CoV-2 and different animal species. Here I implement a fully reproducible computational pipeline that jointly analyzes the number of reads mapping to SARS-CoV-2 and the mitochondrial genomes of chordate species across the full set of samples. I validate the presence of genetic material from numerous species, and calculate mammalian mitochondrial compositions similar to those reported by Crits-Christoph et al (2023). However, the number of SARS-CoV-2 reads is not consistently correlated with reads mapping to any non-human susceptible species. For instance, 14 samples have &gt;20% of their chordate mitochondrial material from raccoon dogs, but only one of these samples contains any SARS-CoV-2 reads, and that sample only has 1 of ~200,000,000 reads mapping to SARS-CoV-2. Instead, SARS-CoV-2 reads are most correlated with reads mapping to various fish, such as catfish and largemouth bass. These results suggest that while metagenomic analysis of the environmental samples is useful for identifying animals or animal products sold at the market, co-mingling of animal and viral genetic material is unlikely to reliably indicate whether any animals were infected by SARS-CoV-2.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.04.25.538336v1" target="_blank">Association between SARS-CoV-2 and metagenomic content of samples from the Huanan Seafood Market</a>
</div></li>
<li><strong>A systematic review of the prevalence of persistent gastrointestinal symptoms and incidence of new gastrointestinal illness after acute SARS-CoV-2 infection</strong> -
<div>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
It is known that SARS-CoV-2 infection can result in gastrointestinal symptoms. For some, these symptoms may persist beyond acute infection, in what is known as post-COVID syndrome. We conducted a systematic review to examine the prevalence of persistent gastrointestinal symptoms and the incidence of new gastrointestinal illness following acute SARS-CoV-2 infection. We searched scientific literature using MedLine, SCOPUS, Embase, Europe PubMed Central, medRxiv and Google Scholar from December 2019 to October 2022. Two reviewers independently identified 28 eligible articles which followed participants for various gastrointestinal outcomes after acute SARS-CoV-2 infection. Study quality was assessed using the Joanna Briggs Institute Critical Appraisal Tools. The weighted pooled prevalence for persistent gastrointestinal symptom of any nature and duration was 10.7%, compared to 4.9% in healthy controls. For six studies at a low risk of methodological bias, the symptom prevalence ranged from 0.2% to 24.1% with a median follow-up time of 13 weeks. We also identified the presence of functional gastrointestinal disorders in historically SARS-CoV-2 exposed individuals. Our review has shown that, from a limited pool of mostly low-quality studies, previous SARS-CoV-2 exposure may be associated with ongoing gastrointestinal symptoms and the development of functional gastrointestinal illness. Furthermore, we show the need for high-quality research to better understand the SARS-CoV-2 association with gastrointestinal symptoms, particularly as population exposure to enteric infections returns to pre-COVID-19-restriction levels.
</p>
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.04.26.23289142v1" target="_blank">A systematic review of the prevalence of persistent gastrointestinal symptoms and incidence of new gastrointestinal illness after acute SARS-CoV-2 infection</a>
</div></li>
<li><strong>Comparative Cohort Study of Post-Acute Covid-19 Infection with a Nested, Randomized Controlled Trial of Ivabradine for Those With Postural Orthostatic Tachycardia Syndrome (The COVIVA Study)</strong> -
<div>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
Background: Significant clinical similarities have been observed between the recently described Long-Haul COVID-19 (LHC) syndrome, Postural Orthostatic Tachycardia Syndrome (POTS) and Inappropriate Sinus Tachycardia (IST). Shared symptoms include light-headedness, palpitations, tremulousness, generalized weakness, blurred vision, chest pain, dyspnea, brain-fog, and fatigue. Ivabradine is a selective sinoatrial node blocker FDA-approved for management of tachycardia associated with stable angina and heart failure not fully managed by beta blockers. In our study we aim to identify risk factors underlying LHC, as well as the effectiveness of ivabradine in controlling heart rate dysregulations and POTS/IST related symptoms. Methods/Design: A detailed prospective phenotypic evaluation combined with multi-omic analysis of 200 LHC volunteers will be conducted to identify risk factors for autonomic dysfunction. A comparator group of 50 volunteers with documented COVID-19 but without LHC will be enrolled to better understand the risk factors for LHC and autonomic dysfunction. Those in the cohort who meet diagnostic criteria for POTS or IST will be included in a nested prospective, randomized, placebo-controlled trial to assess the impact of ivabradine on symptoms and heart rate, assessed non-invasively based on physiologic response and ambulatory electrocardiogram. Additionally, studies on catecholamine production, mast cell and basophil degranulation, inflammatory biomarkers, and indicators of metabolic dysfunction will be measured to potentially provide molecular classification and mechanistic insights. Discussion: Optimal therapies for dysautonomia, particularly associated with LHC, have yet to be defined. In the present study, ivabradine, one of numerous proposed interventions, will be systematically evaluated for therapeutic potential in LHC-associated POTS and IST. Additionally, this study will further refine the characteristics of the LHC-associated POTS/IST phenotype, genotype and transcriptional profile, including immunologic and multi-omic analysis of persistent immune activation and dysregulation. The study will also explore and identify potential endotheliopathy and abnormalities of the clotting cascade.
</p>
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.04.25.23289110v1" target="_blank">Comparative Cohort Study of Post-Acute Covid-19 Infection with a Nested, Randomized Controlled Trial of Ivabradine for Those With Postural Orthostatic Tachycardia Syndrome (The COVIVA Study)</a>
</div></li>
<li><strong>Surveillance of Vermont wildlife in 2021-2022 reveals no detected SARS-CoV-2 viral RNA</strong> -
<div>
Previous studies have documented natural infections of SARS-CoV-2 in various domestic and wild animals. More recently, studies have been published noting the susceptibility of members of the Cervidae family, and infections in both wild and captive cervid populations. In this study, we investigated the presence of SARS-CoV-2 in mammalian wildlife within the state of Vermont. 739 nasal or throat samples were collected from wildlife throughout the state during the 2021 and 2022 harvest season. Data was collected from red and gray foxes (Vulpes vulples and Urocyon cineroargentus, respectively), fishers (Martes pennati), river otters (Lutra canadensis), coyotes (Canis lantrans), bobcats (Lynx rufus rufus), black bears (Ursus americanus), and white-tailed deer (Odocoileus virginianus). Samples were tested for the presence of SARS-CoV-2 via quantitative RT-qPCR using the CDC N1/N2 primer set and/or the WHO-E gene primer set. Our results indicate that no sampled wildlife were positive for SARS-CoV-2. This finding is surprising, given that most published North America studies have found SARS-CoV-2 within their deer populations. The absence of SARS-CoV-2 RNA in populations sampled here may provide insights in to the various environmental and anthropogenic factors that reduce spillover and spread in North American’s wildlife populations.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.04.25.538264v1" target="_blank">Surveillance of Vermont wildlife in 2021-2022 reveals no detected SARS-CoV-2 viral RNA</a>
</div></li>
<li><strong>Intranasal VLP-RBD vaccine adjuvanted with BECC470 confers immunity against Delta SARS-CoV-2 challenge in K18-hACE2-mice</strong> -
<div>
As the COVID-19 pandemic transitions to endemic, seasonal boosters are a plausible reality across the globe. We hypothesize that intranasal vaccines can provide better protection against asymptomatic infections and more transmissible variants of SARS-CoV-2. To formulate a protective intranasal vaccine, we utilized a VLP-based platform. Hepatitis B surface antigen-based virus like particles (VLP) linked with receptor binding domain (RBD) antigen were paired with the TLR4-based agonist adjuvant, BECC 470. K18-hACE2 mice were primed and boosted at four-week intervals with either VLP-RBD-BECC or mRNA-1273. Both VLP-RBD-BECC and mRNA-1273 vaccination resulted in production of RBD-specific IgA antibodies in serum. RBD-specific IgA was also detected in the nasal wash and lung supernatants and were highest in VLP-RBD-BECC vaccinated mice. Interestingly, VLP-RBD-BECC vaccinated mice showed slightly lower levels of pre-challenge IgG responses, decreased RBD-ACE2 binding inhibition, and lower neutralizing activity in vitro than mRNA-1273 vaccinated mice. Both VLP-RBD-BECC and mRNA-1273 vaccinated mice were protected against challenge with a lethal dose of Delta variant SARS-CoV-2. Both vaccines limited viral replication and viral RNA burden in the lungs of mice. CXCL10 is a biomarker of severe SARS-CoV-2 infection and we observed both vaccines limited expression of serum and lung CXCL10. Strikingly, VLP-RBD-BECC when administered intranasally, limited lung inflammation at early timepoints that mRNA-1273 vaccination did not. VLP-RBD-BECC immunization elicited antibodies that do recognize SARS-CoV-2 Omicron variant. However, VLP-RBD-BECC immunized mice were protected from Omicron challenge with low viral burden. Conversely, mRNA-1273 immunized mice had low to no detectable virus in the lungs at day 2. Together, these data suggest that VLP-based vaccines paired with BECC adjuvant can be used to induce protective mucosal and systemic responses against SARS-CoV-2.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.04.25.538294v1" target="_blank">Intranasal VLP-RBD vaccine adjuvanted with BECC470 confers immunity against Delta SARS-CoV-2 challenge in K18-hACE2-mice</a>
</div></li>
<li><strong>Remote Aerosol SARS-CoV-2 Transmission from Clinical COVID Patients to Rodent Sentinels</strong> -
<div>
We performed studies investigating the feasibility of human to animal (H2A) model system to test whether patient generated respiratory bioaerosols hold infective capacity when traversing long distance airborne transport within the built environment. South African patients, clinically confirmed by facemask sampling to be exhaling SARS-CoV-2 genomic sequence, were recruited and housed for multiple days in a clinical ward with a uniquely designed building ventilation system continuously channeling exhaust airflow to individual microisolator animal caging units located proximal but segregated from clinic space (University of Pretoria AIR facility).
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://osf.io/cre2w/" target="_blank">Remote Aerosol SARS-CoV-2 Transmission from Clinical COVID Patients to Rodent Sentinels</a>
</div></li>
<li><strong>Conventional and Bayesian workflows for clinical prediction modelling of severe Covid-19 outcomes based on clinical biomarker test results: LabMarCS: Laboratory Markers of COVID-19 Severity - Bristol Cohort</strong> -
<div>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
We describe several regression models to predict severe outcomes in COVID-19 and challenges present in complex observational medical data. We demonstrate best practices for data curation, cross-validated statistical modelling, and variable selection emphasizing recent Bayesian methods. The study follows a retrospective observational cohort design using multicentre records across National Health Service (NHS) trusts in southwest England, UK. Participants included hospitalised adult patients positive for SARS-CoV 2 during March to October 2020, totalling 843 patients (mean age 71, 45% female, 32% died or needed ICU stay), split into training (n=590) and validation groups (n=253). Models were fit to predict severe outcomes (ICU admission or death within 28-days of admission to hospital for COVID-19, or a positive PCR result if already admitted) using demographic data and initial results from 30 biomarker tests collected within 3 days of admission or testing positive if already admitted. Cross-validation results showed standard logistic regression had an internal validation median AUC of 0.74 (95% Interval [0.62,0.83]), and external validation AUC of 0.68 [0.61, 0.71]; a Bayesian logistic regression (with horseshoe prior) internal AUC of 0.79 [0.71, 0.87], and external AUC of 0.70 [0.68, 0.71]. Variable selection performed using Bayesian predictive projection determined a four variable model using Age, Urea, Prothrombin time and Neutrophil-Lymphocyte ratio, with a median internal AUC of 0.79 [0.78, 0.80], and external AUC of 0.67 [0.65, 0.69]. We illustrate best-practices protocol for conventional and Bayesian prediction modelling on complex clinical data and reiterate the predictive value of previously identified biomarkers for COVID-19 severity assessment.
</p>
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2022.09.16.22279985v4" target="_blank">Conventional and Bayesian workflows for clinical prediction modelling of severe Covid-19 outcomes based on clinical biomarker test results: LabMarCS: Laboratory Markers of COVID-19 Severity - Bristol Cohort</a>
</div></li>
<li><strong>Genomic epidemiology reveals the dominance of Hennepin County in transmission of SARS-CoV-2 in Minnesota from 2020-2022</strong> -
<div>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
SARS-CoV-2 has had an unprecedented impact on human health and highlights the need for genomic epidemiology studies to increase our understanding of virus evolution and spread, and to inform policy decisions. We sequenced viral genomes from over 22,000 patient samples tested at Mayo Clinic Laboratories between 2020-2022 and use Bayesian phylodynamics to describe county and regional spread in Minnesota. The earliest introduction into Minnesota was to Hennepin County from a domestic source around January 22, 2020; six weeks before the first confirmed case in the state. This led to the virus spreading to Northern Minnesota, and eventually, the rest of the state. International introductions were most abundant in Hennepin (home to the Minneapolis/St. Paul International (MSP) airport) totaling 45 (out of 107) over the two-year period. Southern Minnesota counties were most common for domestic introductions with 19 (out of 64), potentially driven by bordering states such as Iowa and Wisconsin as well as Illinois which is nearby. Hennepin also was, by far, the most dominant source of in-state transmissions to other Minnesota locations (n=772) over the two-year period. We also analyzed the diversity of the location source of SARS-CoV-2 viruses in each county and noted the timing of state-wide policies as well as trends in clinical cases. Neither the number of clinical cases or major policy decisions, such as the end of the lockdown period in 2020 or the end of all restrictions in 2021, appeared to have impact on virus diversity across each individual county.
</p>
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2022.07.24.22277978v3" target="_blank">Genomic epidemiology reveals the dominance of Hennepin County in transmission of SARS-CoV-2 in Minnesota from 2020-2022</a>
</div></li>
<li><strong>Variability in excess deaths across countries with different vulnerability during 2020-2023</strong> -
<div>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
Importance: Excess deaths provide estimates of total impact of major crises, such as the COVID-19 pandemic. Objective: To evaluate excess deaths trajectories during 2020-2023 across countries with accurate death registration and population age structure data; and to assess how excess death patterns and trajectories correlate with economic indicators of vulnerability overall and in different age strata. Methods: Data were used from the Human Mortality Database on 34 countries. Excess deaths were calculated for 2020-2023 (to 2/26/2023) using 2017-2019 as baseline reference, with weekly expected death calculations and adjustment for 5 age strata. Countries were divided into less and more vulnerable; the latter had per capita nominal GDT&lt;$30,000, Gini&gt;0.35 for income inequality and/or at least 2.5% of their population living in poverty. Results: Excess deaths (as proportion of expected deaths, p% ) were strongly inversely correlated with per capita GDP (r=-0.61), strongly correlated with proportion living in poverty (r=0.65) and modestly correlated with income inequality (r=0.42). The 17 less vulnerable countries had 201,471 excess deaths versus 2,005,380 among the 17 more vulnerable countries. The USA would have had 1.50 million fewer deaths if it had the performance of Sweden, 1.13 million fewer deaths if it had the performance of Finland, and 0.93 million fewer deaths if it had the performance of France. Excess deaths started deviating in the two groups after the first wave when correlational patterns with the 3 economic indicators also started to emerge. Between-country heterogeneity diminished over time within each of the two groups. Less vulnerable countries had mean p%=-0.4% and 0.9% in 0-64 and &gt;65 year-old strata while more vulnerable countries had mean p%=8.3% and 9.0%, respectively. Certain countries performed substantially worse (USA, Canada, Chile, UK) or better (France, Poland, Slovenia) in the non-elderly than in the elderly. Usually lower death rates were seen in children 0-14 years old during 2020-2023 versus pre-pandemic years. Conclusion: While the pandemic hit some countries earlier than others, country vulnerability dominated eventually the cumulative impact. Half of the analyzed countries witnessed no substantial excess deaths versus pre-pandemic levels, while the other half suffered major death tolls.
</p>
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.04.24.23289066v1" target="_blank">Variability in excess deaths across countries with different vulnerability during 2020-2023</a>
</div></li>
<li><strong>Estimation of Near-kink Reproduction Numbers During the Emergent Variants of the COVID-19 Pandemic: Log-quadratic and Forward-imputation Approach</strong> -
<div>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
Background: Sketching the major portraits of the COVID-19 epidemic when variants of the pathogen emerge is critical to inform the dynamics of disease transmission, reproduction (i.e., the average counts of individuals of secondary infections generated by an index individual infected by the virus) strength of the pathogen, and countermeasure strategies. Multiple approaches, including log-linear, EpiEstim (an R package generally utilized to estimate the evolution traits of epidemics), and near-log-linear techniques, have been exploited to evaluate the principal parameters such as basic and effective reproduction numbers of an epidemic outbreak. Objective: This study focuses on the kink corner (i.e., sharp alternation of direction of the transmission curve) presenting differentiated log-quadratic traits where more infectious variants of viruses emerge at the diminishing transmission phase of an infectious disease. Methods: A novel log-quadratic trending framework was proposed to project potentially unidentified cases (i.e., forward imputing approximately one week ahead) of COVID-19 around the kink, where the transmission of the pandemic initially lowered and accelerated subsequently, and exercised with the updated framework of classic EpiEstim and Log-linear model. I first compared the performance near the kink using the proposed technique versus the two traditional models taking into account a variety of levels of transmissibility, data distribution (Weibull, Gamma, and Lognormal distributions), and reporting rates (0.2, 0.4, 0.6, 0.8 and 1.0 respectively). Thereafter I utilized the revised framework on the outbreak data of four settings including Bulgaria, Japan, Poland, and South Korea from June to August 2022. Results: The proposed framework reduced the estimation bias versus traditional EpiEstim and log-linear methods near the kink. The coverage estimates of 95% confidence intervals improved. The proposed forward-imputation method implied generally a consistent ascending trend of effective reproduction number estimation applying to a precipitous transition from diminishing to diverging scenarios versus the irregular zigzagging outcomes in classic methods when more contagious variants of the virus were present in the absence of effective vaccines. Conclusions: The log-quadratic correction accounting for transmissibility, data distribution, reporting rates, sliding windows, and generation intervals improved the basic and effective reproduction numbers estimation at the kink corner versus the classic EpiEstim and log-linear models by refined amendment of curve fitting. This is of concern when essentially the fundamental transmission traits of a pandemic alter expeditiously and countermeasures are needed at the earlier variant phases of the transiting climax with the advancement of the pandemic.
</p>
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<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.04.24.23289029v1" target="_blank">Estimation of Near-kink Reproduction Numbers During the Emergent Variants of the COVID-19 Pandemic: Log-quadratic and Forward-imputation Approach</a>
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<li><strong>Aerosol Jet Printing Enabled Dual-Function Electrochemical and Colorimetric Biosensor for SARS-CoV-2 Detection</strong> -
<div>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
An aerosol jet printing enabled dual-function biosensor for the sensitive detection of pathogens using SARS-CoV-2 RNA as an example has been developed. A CRISPR-Cas13: guide-RNA complex is activated in the presence of a target RNA, leading to the collateral trans-cleavage of ssRNA probes that contain a horseradish peroxidase (HRP) tag. This, in turn, catalyzes the oxidation of 3,3′,5,5′-tetramethylbenzidine (TMB) by HRP, resulting in a color change and electrochemical signal change. The colorimetric and electrochemical sensing protocol does not require complicated target amplification and probe immobilization and exhibits a detection sensitivity in the femtomolar range. Additionally, our biosensor demonstrates a wide dynamic range of 5 orders of magnitude. This low-cost aerosol inkjet printing technique allows for an amplification-free and integrated dual-function biosensor platform, which operates at physiological temperature and is designed for simple, rapid, and accurate point-of-care (POC) diagnostics in either low-resource settings or hospitals.
</p>
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.04.20.23288904v1" target="_blank">Aerosol Jet Printing Enabled Dual-Function Electrochemical and Colorimetric Biosensor for SARS-CoV-2 Detection</a>
</div></li>
<li><strong>Immune signature of patients with cardiovascular disease - in-depth immunophenotyping predicts increased risk for a severe course of COVID-19</strong> -
<div>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
Objective: SARS-CoV-2 infection can lead to life-threatening clinical manifestations. Patients with cardiovascular disease (CVD) are at higher risk for severe courses of COVID-19. However, strategies to predict the course of SARS-CoV-2 infection in CVD patients at hospital admission are still missing. Here, we investigated whether the severity of SARS-CoV-2 infection can be predicted by analyzing the immunophenotype in the blood of CVD patients. Approach and Results: We prospectively analyzed the peripheral blood of 94 participants, including CVD patients with acute SARS-CoV-2 infection, uninfected CVD patients, and healthy donors using a 36-color spectral flow cytometry panel. Clinical assessment included blood sampling, echocardiography, and electrocardiography. Patients were classified by their ISARIC WHO 4C-Mortality-Score on the day of admission into three subgroups of an expected mild, moderate, or severe course of COVID-19. Unsupervised data analysis revealed 40 clusters corresponding to major circulating immune cell populations. This revealed little differences between healthy donors and CVD patients, whereas the distribution of the cell populations changed dramatically in SARS-CoV-2-infected CVD patients. The latter had more mature NK cells, activated monocyte subsets, central memory CD4<sup>+</sup> T cells, and plasmablasts than uninfected CVD patients. In contrast, fewer dendritic cells, CD16<sup>+</sup> monocytes, innate lymphoid cells, and CD8<sup>+</sup> T cell subsets were detected in SARS-CoV-2-infected CVD patients. We identified an immune signature characterized by low frequencies of MAIT and intermediate effector CD8<sup>+</sup> T cells in combination with a high frequency of NKT cells that is predictive for CVD patients with a severe course of SARS-CoV-2 infection on hospital admission. Conclusion: Acute SARS-CoV-2 infected CVD patients revealed marked changes in abundance and phenotype of several immune cell populations associated with COVID-19 severity. Our data indicate that intensified immunophenotype analyses can help identify patients at risk of severe COVID-19 at hospital admission, improving clinical outcomes through specific treatment.
</p>
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<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.04.24.23288921v1" target="_blank">Immune signature of patients with cardiovascular disease - in-depth immunophenotyping predicts increased risk for a severe course of COVID-19</a>
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<li><strong>Anxiety due to Long COVID is partially driven by activation of the tryptophan catabolite (TRYCAT) pathway</strong> -
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This study examines whether activation of the tryptophan catabolite (TRYCAT) pathway is associated with anxiety symptoms due to Long COVID. We selected 90 participants, 60 Long COVID patients and 30 individuals without any symptoms following acute CIVID-19 infection. Using cluster analysis and the Hamilton Anxiety Rating scale (HAMA) score, the pure HAMA anxiety score, serum tryptophan (TRP) and kynurenine (KYN), the KYN/TRP ratio (all measured during Long COVID), and oxygen saturation (SpO2) (measured during the acute phase of COVID-19), we were able to classify Long COVID patients into two distinct clusters with an adequate silhouette cohesion and separation index (0.58): cluster 1 (n=61) and cluster 2 (n=29). Cluster 2 patients had lower SpO2 and TRP levels, as well as higher KYN, KYN/TRP ratio, and HAMA scores than cluster 1. Regression analysis revealed that the KYN/TRP ratio explained 14.4% of the variance in the HAMA score (F=14.81, df=1/88, p=0.001). In addition, regression analysis revealed that SpO2 partially explained the variance in serum TRP (r=0.396, p=0.005), KYN/TRP ratio (r=-0.248, p=0.018), and the HAMA score (r=-0.279, p=0.008). The current data imply that decreased SpO2 during the acute phase of COVID-19 infection is predictive of anxiety caused by Long COVID. Our data reveal that around 32% of Long COVID patients have elevated IDO activity in association with elevated anxiety.
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<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.04.24.23288115v1" target="_blank">Anxiety due to Long COVID is partially driven by activation of the tryptophan catabolite (TRYCAT) pathway</a>
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<li><strong>Is Covid-19 Mortality “Like the Flu”? A Cumulative Death Rates Comparison</strong> -
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It has been common both to make and to resist comparisons that equate the Covid-19 pandemic to influenza. We take the comparison between Covid-19 and flu seriously by asking how many years of influenza and pneumonia deaths are needed for cumulative deaths to those two causes to equal the cumulative toll of the Covid-19 pandemic between March 2020 and February 2023 – that is, three years of pandemic deaths. We find that in one state alone – Hawaii – three years of Covid-19 mortality is equivalent to influenza and pneumonia mortality in the three years preceding the Covid-19 pandemic. For all other states, at least nine years of flu and pneumonia are needed to match Covid-19; for the United States as a whole, seventeen years are needed; and for four states, more than 21 years (the maximum observable) are needed. These results provide an easy-to-understand calibration of flu as a heuristic for Covid-19, and vice versa.
</p>
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<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.04.24.23289045v1" target="_blank">Is Covid-19 Mortality “Like the Flu”? A Cumulative Death Rates Comparison</a>
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<li><strong>Increased consumption despite fewer occasions: A longitudinal analysis of COVID-19 lockdown effects on soft drink consumption in England</strong> -
<div>
We examined the impact of a COVID-19 lockdown in England on the frequency of consumption occasions and amount of soft drinks consumed. Beverage consumption is strongly associated with specific, often social, consumption situations (e.g., going out). We reasoned that lockdown would affect consumption behaviour because it removed typical soft drink consumption situations. Specifically, we hypothesised that soft drink consumption occasions and amount would be reduced during lockdown compared to before and after lockdown, especially in typical soft drink consumption situations. In two surveys (Dec. 2020 and May 2021) among the same participants (N = 211, N = 160; consuming soft drinks at least once/week), we assessed the frequency of soft drink and water consumption occasions before, during, and after the November/December 2020 lockdown, across typical soft drink and water drinking situations. This presents a detailed picture of the situations in which participants drink soft drinks and water, and how this was affected by a lockdown. We also assessed the daily amount of soft drinks and water consumed in each period, and perceived habitualness of drinking soft drinks and water. As predicted, participants reported fewer occasions of drinking soft drinks during lockdown compared to before and after, especially in typical soft drink consumption situations. Unexpectedly, however, the daily amount of soft drinks consumed increased during lockdown, compared to before and after, especially among participants with stronger perceived habitualness of soft drink consumption. Exploratory analyses suggest that during lockdown, participants increased their soft drink consump¬¬tion at home. Water consumption, on the other hand, was not systematically affected by the lockdown. These findings suggest that even if some typical consumption situations disappear, consumption may be hard to disrupt if the behaviour is rewarding.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://psyarxiv.com/wdx5k/" target="_blank">Increased consumption despite fewer occasions: A longitudinal analysis of COVID-19 lockdown effects on soft drink consumption in England</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>Efficacy and Safety of Nirmatrelvir/Ritonavir for Treating Omicron Variant of COVID-19</strong> - <b>Condition</b>:   Omicron Variant of COVID-19<br/><b>Intervention</b>:   Drug: Nirmatrelvir/Ritonavir<br/><b>Sponsor</b>:   Xiangao Jiang<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>A Study of mRNA-1283.222 Injection Compared With mRNA-1273.222 Injection in Participants ≥12 Years of Age to Prevent COVID-19</strong> - <b>Condition</b>:   COVID-19<br/><b>Interventions</b>:   Biological: mRNA-1283.222;   Biological: mRNA-1273.222<br/><b>Sponsor</b>:   ModernaTX, Inc.<br/><b>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>Evaluation of the RD-X19 Treatment Device in Individuals With Mild COVID-19</strong> - <b>Condition</b>:   COVID-19<br/><b>Interventions</b>:   Device: RD-X19;   Device: Sham<br/><b>Sponsor</b>:   EmitBio Inc.<br/><b>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>Assessment of Immunogenicity, Safety and Reactogenicity of a Booster Dose of Various COVID-19 Vaccine Platforms in Individuals Primed With Several Regimes.</strong> - <b>Condition</b>:   COVID-19<br/><b>Interventions</b>:   Biological: SCB-2019/Clover;   Biological: AstraZeneca/Fiocruz;   Biological: Pfizer/Wyeth<br/><b>Sponsors</b>:   D’Or Institute for Research and Education;   Bill and Melinda Gates Foundation<br/><b>Active, not 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>Postoperative Sugammadex After COVID-19</strong> - <b>Conditions</b>:   General Anesthesia;   COVID-19<br/><b>Interventions</b>:   Drug: Sugammadex Sodium;   Drug: neostigmine 50µg/kg + glycopyrollate 0.01mg/kg<br/><b>Sponsor</b>:   Korea University Ansan Hospital<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 Randomized, Double-Blind, Placebo-Controlled Phase 2/3 Study to Determine the Safety and Effectiveness of Azeliragon in the Treatment of Patients Hospitalized for Coronavirus Disease 2019 (COVID-19)</strong> - <b>Condition</b>:   COVID-19<br/><b>Interventions</b>:   Drug: Azeliragon;   Drug: Placebo<br/><b>Sponsor</b>:   Salim S. Hayek<br/><b>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>To Evaluate the Safety and Efficacy of Meplazumab in Treatment of Post-COVID-19</strong> - <b>Condition</b>:   Post-COVID-19<br/><b>Interventions</b>:   Biological: Meplazumab for injection;   Other: Normal saline<br/><b>Sponsor</b>:   Jiangsu Pacific Meinuoke Bio Pharmaceutical Co Ltd<br/><b>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>Cognitive-behavioral Therapy for Mental Disorder in COVID-19 Survivors</strong> - <b>Condition</b>:   Post Acute COVID-19 Syndrome<br/><b>Intervention</b>:   Behavioral: mindfulness-based stress reduction (MBSR) and cognitive behavioral therapy (CBT)<br/><b>Sponsor</b>:   Azienda Socio Sanitaria Territoriale di Lecco<br/><b>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>Efficacy of Lactobacillus Paracasei PS23 for Patients With Post-COVID-19 Syndrome</strong> - <b>Condition</b>:   Post-COVID-19 Syndrome<br/><b>Intervention</b>:   Dietary Supplement: PS23 heat-treated<br/><b>Sponsors</b>:   Mackay Memorial Hospital;   Bened Biomedical Co., Ltd.<br/><b>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 Coping and Resilience Intervention for Adolescents</strong> - <b>Condition</b>:   COVID-19 Pandemic<br/><b>Interventions</b>:   Behavioral: Coping and Resilience Intervention for Adolescents;   Other: Printing materials of Coping and Resilience Intervention for Adolescents<br/><b>Sponsor</b>:   Taipei Medical 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>Effect of Telerehabilitation Practice in Long COVID-19 Patients</strong> - <b>Conditions</b>:   Long COVID-19;   Long COVID;   Post COVID-19 Condition;   Post-COVID-19 Syndrome;   Post-COVID Syndrome<br/><b>Interventions</b>:   Behavioral: Telerehabilitation;   Behavioral: Standard rehabilitation care<br/><b>Sponsor</b>:   Indonesia University<br/><b>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>The Safety, Tolerability and Pharmacokinetics Study of RAY1216 in Healthy Adult Participants</strong> - <b>Condition</b>:   COVID-19 (Coronavirus Disease 2019)<br/><b>Interventions</b>:   Drug: RAY1216 dose 1;   Drug: RAY1216 dose 2;   Drug: RAY1216 dose 3;   Drug: RAY1216 dose 4 &amp;ritonavir   Drug: RAY1216 dose 5;   Drug: RAY1216 dose 6;   Drug: RAY1216 dose 7;   Drug: RAY1216 dose 8;   Drug: RAY1216 dose 9;   Drug: RAY1216 dose 10<br/><b>Sponsor</b>:   Guangdong Raynovent Biotech Co., Ltd<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>Computerized Training of Attention and Working Memory in Post COVID-19 Patients With Cognitive Complaints</strong> - <b>Conditions</b>:   COVID-19;   Cognitive Impairment;   Cognition Disorder;   Memory Disorders;   Attention Deficit;   Memory Impairment;   Memory Loss;   Attention Impaired<br/><b>Intervention</b>:   Device: RehaCom<br/><b>Sponsor</b>:   Erasmus 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>Strategies and Treatments for Respiratory Infections &amp;Amp; Viral Emergencies (STRIVE): Immune Modulation Strategy Trial</strong> - <b>Condition</b>:   COVID-19<br/><b>Interventions</b>:   Drug: abatacept infusion;   Drug: Placebo group<br/><b>Sponsor</b>:   University of Minnesota<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 Study of Silmitasertib (CX-4945) in Healthy Subject</strong> - <b>Condition</b>:   COVID-19<br/><b>Intervention</b>:   Drug: CX-4945<br/><b>Sponsor</b>:   Senhwa Biosciences, Inc.<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>Well-Defined Heparin Mimetics Can Inhibit Binding of the Trimeric Spike of SARS-CoV-2 in a Length-Dependent Manner</strong> - The emergence of new SARS-CoV-2 variants and the dangers of long-covid necessitate the development of broad-acting therapeutics that can reduce viral burden. SARS-CoV-2 employs heparan sulfate (HS) as an initial cellular attachment factor, and therefore, there is interest in developing heparin as a therapeutic for SARS-CoV-2. Its use is, however, complicated by structural heterogeneity and the risk of causing bleeding and thrombocytopenia. Here, we describe the preparation of well-defined…</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><em>Cichorium intybus</em> L. “hairy” roots as a rich source of antioxidants and anti-inflammatory compounds</strong> - The present study aimed to determine the bioactive profile of various extracts of Cichorium intybus L. “hairy” roots. In particular, the total content of flavonoids as well as the reducing power, antioxidant and anti-inflammatory activity of the aqueous and ethanolic (70%) extracts were evaluated. The total content of flavonoids the ethanolic extract of the dry “hairy” root reached up to 121.3 mg (RE)/g, which was twofold greater than in the aqueous one. A total of 33 diverse polyphenols 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>Ethanol vapor inhalation treatment inhibits lethal respiratory viral infection with Influenza A</strong> - Ethanol (EtOH) effectively inactivates enveloped viruses in vitro, including influenza and SARS-CoV-2. Inhaled EtOH vapor may inhibit viral infection in mammalian respiratory tracts, but this has not yet been demonstrated. Here we report that unexpectedly low EtOH concentrations in solution, approximately 20% (v/v), rapidly inactivate influenza A virus (IAV) at mammalian body temperature (37°C) and are not toxic to lung epithelial cells upon apical exposure. Furthermore, brief exposure to 20%…</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>Inhibition of Exchange Proteins Directly Activated by cAMP (EPAC) as a Strategy for Broad-Spectrum Antiviral Development</strong> - The recent SARS-CoV-2 and mpox outbreaks have highlighted the need to expand our arsenal of broad-spectrum antiviral agents for future pandemic preparedness. Host-directed antivirals are an important tool to accomplish this as they typically offer protection against a broader range of viruses than direct-acting antivirals and have a lower susceptibility to viral mutations that cause drug resistance. In this study, we investigate the Exchange Protein Activated by cAMP (EPAC) as a target for…</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>Curcumin attenuates hydroxychloroquine-mediated apoptosis and oxidative stress via the inhibition of TRPM2 channel signalling pathways in a retinal pigment epithelium cell line</strong> - CONCLUSION: HCQ-mediated overload Ca^(2+) influx and retinal oxidative toxicity were induced in an ARPE19 cell line through the stimulation of TRPM2, although they were attenuated by treatment with CRC. Hence, CRC may be a potential therapeutic antioxidant for TRPM2 activation and HCQ treatment-induced retinal oxidative injury and apoptosis.</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>Novel pseudonucleosides and sulfamoyl-oxazolidinone <em>β</em>-<em>D</em>-glucosamine derivative as anti-COVID-19: design, synthesis, and <em>in silico</em> study</strong> - New pseudonucleosides containing cyclic sulfamide moiety and sulfamoyl β-D-glucosamine derivative are described. These pseudonucleosides are synthesized in good yields starting from chlorosulfonyl isocyanate and β-D-glucosamine hydrochloride in five steps; (protection, acetylation, removal of the Boc group, sulfamoylation, and cyclization). Further, novel glycosylated sulfamoyloxazolidin-2-one is prepared in three steps; carbamoylation, sulfamoylation, and intramolecular cyclization. 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>RAAS inhibition and beyond-cardiovascular medications in patients at risk of or affected by COVID-19</strong> - The COVID-19 pandemic led to an enormous burden on healthcare systems worldwide. Causal therapy is still in its infancy. Contrary to initial views that the use of angiotensin-converting enzyme inhibitors (ACEi)/angiotensin II receptor blockers (ARBs) may increase the risk for a deleterious disease course, it has been shown that these agents may actually be beneficial for patients affected by COVID-19. In this article, we provide an overview of the three most commonly used classes of drugs in…</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 and Comparison of the Sialic Acid-Binding Domain Characteristics of Avian Coronavirus Infectious Bronchitis Virus Spike Protein</strong> - Infectious bronchitis virus (IBV) infections are initiated by the transmembrane spike (S) glycoprotein, which binds to host factors and fuses the viral and cell membranes. The N-terminal domain of the S1 subunit of IBV S protein binds to sialic acids, but the precise location of the sialic acid binding domain (SABD) and the role of the SABD in IBV-infected chickens remain unclear. Here, we identify the S1 N-terminal amino acid (aa) residues 19 to 227 (209 aa total) of IBV strains SD (GI-19) 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>Antiviral Nanobiologic Therapy Remodulates Innate Immune Responses to Highly Pathogenic Coronavirus</strong> - Highly pathogenic coronavirus (CoV) infection induces a defective innate antiviral immune response coupled with the dysregulated release of proinflammatory cytokines and finally results in acute respiratory distress syndrome (ARDS). A timely and appropriate triggering of innate antiviral response is crucial to inhibit viral replication and prevent ARDS. However, current medical countermeasures can rarely meet this urgent demand. Here, an antiviral nanobiologic named CoVR-MV is developed, which…</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>The human E3 ligase RNF185 is a regulator of the SARS-CoV-2 envelope protein</strong> - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) hijacks multiple human proteins during infection and viral replication. To examine whether any viral proteins employ human E3 ubiquitin ligases, we evaluated the stability of SARS-CoV-2 proteins with inhibition of the ubiquitin proteasome pathway. Using genetic screens to dissect the molecular machinery involved in the degradation of candidate viral proteins, we identified human E3 ligase RNF185 as a regulator of protein stability for…</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>Production and optimization of novel Sphorolipids from Candida parapsilosis grown on potato peel and frying oil wastes and their adverse effect on Mucorales fungal strains</strong> - CONCLUSION: The findings demonstrated the potential application of the SLs produced economically from agricultural waste as an effective and safer alternative for the treatment of infection caused by black fungus.</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>Preventive and therapeutic benefits of nelfinavir in rhesus macaques and human beings infected with SARS-CoV-2</strong> - Effective drugs with broad spectrum safety profile to all people are highly expected to combat COVID-19 caused by SARS-CoV-2. Here we report that nelfinavir, an FDA approved drug for the treatment of HIV infection, is effective against SARS-CoV-2 and COVID-19. Preincubation of nelfinavir could inhibit the activity of the main protease of the SARS-CoV-2 (IC(50) = 8.26 μM), while its antiviral activity in Vero E6 cells against a clinical isolate of SARS-CoV-2 was determined to be 2.93 μM (EC(50))….</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>Hemoptysis after COVID-19 and the importance of differential diagnosis: Birt-Hogg-Dubé syndrome</strong> - Birt-Hogg-Dubé syndrome is a genodermatosis of autosomal dominant inheritance characterized by mutations in the folliculin (FLCN) gene. There is an inappropriate inhibition/activation of a protein, the foliculin, which may cause tumor lesions in skin, renal and lung lesions; they could have more risk of developing pneumothorax compared to the normal population. A 38-year-old male patient with bronchial asthma who consulted for hemoptysis three weeks after recovery from COVID-19 infection. 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>Bioactive compounds from Huashi Baidu decoction possess both antiviral and anti-inflammatory effects against COVID-19</strong> - The coronavirus disease 2019 (COVID-19) pandemic is an ongoing global health concern, and effective antiviral reagents are urgently needed. Traditional Chinese medicine theory-driven natural drug research and development (TCMT-NDRD) is a feasible method to address this issue as the traditional Chinese medicine formulae have been shown effective in the treatment of COVID-19. Huashi Baidu decoction (Q-14) is a clinically approved formula for COVID-19 therapy with antiviral and anti-inflammatory…</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>Role of Cytochrome P450 2C9 in COVID-19 Treatment: Current Status and Future Directions</strong> - The major human liver drug metabolising cytochrome P450 (CYP) enzymes are downregulated during inflammation and infectious disease state, especially during coronavirus disease 2019 (COVID-19) infection. The influx of proinflammatory cytokines, known as a ‘cytokine storm’, during severe COVID-19 leads to the downregulation of CYPs and triggers new cytokine release, which further dampens CYP expression. Impaired drug metabolism, along with the inevitable co-administration of drugs or ’combination…</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>India’s Quest to Build the World’s Largest Solar Farms</strong> - Pavagada Ultra Mega Solar Park, a clean-power plant the size of Manhattan, could be a model for the world—or a cautionary tale. - <a href="https://www.newyorker.com/news/dept-of-energy/indias-quest-to-build-the-worlds-largest-solar-farms">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Israel Turns Seventy-five as a Nation Divided</strong> - Two worlds are ostensibly looking for a way forward together, as demonstrators once again take to the streets. - <a href="https://www.newyorker.com/news/daily-comment/israel-turns-seventy-five-as-a-nation-divided">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Joe Biden’s 2024 Opening Argument: It’s Me or the Abyss</strong> - The President’s calling card—as a Trump-slayer, and an upholder of normality and sanity—remains his biggest advantage. - <a href="https://www.newyorker.com/news/our-columnists/joe-bidens-2024-opening-argument-its-me-or-the-abyss">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Is It Sexist to Want Dianne Feinstein to Retire?</strong> - Debbie Stabenow, a Democratic colleague in the Senate, sees a double standard at work. - <a href="https://www.newyorker.com/news/q-and-a/is-it-sexist-to-want-dianne-feinstein-to-retire">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>The Climate Crisis Gives Sailing Ships a Second Wind</strong> - Cargo vessels are some of the dirtiest vehicles in existence. Can a centuries-old technology help to clean them up? - <a href="https://www.newyorker.com/news/annals-of-a-warming-planet/the-climate-crisis-gives-sailing-ships-a-second-wind">link</a></p></li>
</ul>
<h1 data-aos="fade-right" id="from-vox">From Vox</h1>
<ul>
<li><strong>What could actually kill us all?</strong> -
<figure>
<img alt="Nuclear explosion and atomic mushroom cloud. over French Polynesia" src="https://cdn.vox-cdn.com/thumbor/hRrv3nW8sLafxOx96_t6QT18xmo=/300x0:5040x3555/1310x983/cdn.vox-cdn.com/uploads/chorus_image/image/72222306/GettyImages_618367168.0.jpg"/>
<figcaption>
Nuclear explosion and atomic mushroom cloud over French Polynesia. | Sygma via Getty Images
</figcaption>
</figure>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
Nuclear war, AGI, and the importance of understanding what makes an existential risk.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="TNiyLR">
Four years ago, I wrote one of my most controversial articles. It argued that climate change — while it will make the world we live in much worse and lead directly and indirectly to the deaths of millions — <a href="https://www.vox.com/future-perfect/2019/6/13/18660548/climate-change-human-civilization-existential-risk">won’t end human life on Earth</a>.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="Ipn8JU">
This isn’t <em>scientifically </em>controversial. It’s <a href="https://www.washingtonpost.com/climate-environment/2023/01/06/climate-change-scenarios-extremes/">consistent with IPCC projections</a>, and with the perspective of most climate scientists. Some researchers <a href="https://www.pnas.org/doi/10.1073/pnas.2108146119">study extreme tail-risk scenarios</a> where planetary warming is far more catastrophic than projected. I think studying that is worthwhile, but these are very unlikely scenarios — not anyone’s best guess of what will happen.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="lpjgwb">
So the reason that arguing that climate change is likely not a species-ending threat is so controversial isn’t because of science. It’s because the argument can feel like intellectual hair-splitting and hand-waving, like a way of diminishing the severity of the challenge that unquestionably lies ahead of us.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="N1LWee">
Millions of people will die with climate change, and that’s horrendous; it feels almost like selling those victims out to tell comfortable people in rich countries that they will probably not be personally affected and will probably get to continue in their comfortable lives.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="6SaFmT">
But fundamentally, I believe in our ability to solve problems without exaggerating about them, and I don’t believe in our ability to solve problems while exaggerating about them. You need a clear picture of what’s going to happen to fix it. Climate action addressed with the wrong understanding of the threat is unlikely to save the people who actually need saving.
</p>
<h3 id="zxnB1X">
AI, nuclear war, and the end of the world
</h3>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="je007l">
This has been on my mind recently as the case that AI poses an existential risk to humanity — which I’ve written about <a href="https://www.vox.com/future-perfect/2018/12/21/18126576/ai-artificial-intelligence-machine-learning-safety-alignment">since 2018</a> — has gone mainstream.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="HEn2Or">
In an <a href="https://time.com/6266923/ai-eliezer-yudkowsky-open-letter-not-enough/">article in Time</a>, AI safety researcher Eliezer Yudkowsky wrote that “the most likely result of building a superhumanly smart AI, under anything remotely like the current circumstances, is that literally everyone on Earth will die.” New international treaties against building powerful AI systems are part of what it’ll take to save us, he argued, even if enforcing those treaties means acts of war against noncomplying nations.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="46IKyf">
This struck a lot of people as fairly outrageous. Even if you’re convinced that AI might be quite dangerous, you might need more convincing that it’s extraordinarily deadly indeed to consider it worth risking a war. (Wars are also dangerous to the future of human civilization, especially wars with the potential to escalate to a nuclear exchange.)
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="e2nR1T">
Yudkowsky doubled down: Uncontrolled superhuman AI will likely end all life on Earth, he <a href="https://twitter.com/ESYudkowsky/status/1643800261599825921">argued</a>, and a nuclear war, while it would be extremely bad, wouldn’t do that. We should not court a nuclear war, but it’d be a mistake to let fear of war stop us from putting teeth in international treaties about AI.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="doOFLz">
Both parts of that are, of course, controversial. A nuclear war would be devastating and kill millions of people directly. It could be even more catastrophic if <a href="https://www.vox.com/future-perfect/2022/8/17/23306861/nuclear-winter-war-climate-change-food-starvation-existential-risk-russia-united-states">firestorms from nuclear explosions</a> lowered global temperatures over a long period of time, a possibility that is contested among experts in the relevant atmospheric sciences.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="6Dg4kl">
Avoiding a nuclear war seems like it should be one of humanity’s highest priorities regardless, but the debate over whether “nuclear winter” would result from a nuclear exchange isn’t meaningless hairsplitting. One way we can reduce the odds of billions of people dying of mass starvation is to decrease nuclear arsenals, which for <a href="https://www.vox.com/future-perfect/2022/8/17/23306861/nuclear-winter-war-climate-change-food-starvation-existential-risk-russia-united-states">both the US and Russia are much smaller</a> than they were at the height of the Cold War but are recently on the rise again.
</p>
<h3 id="DfaBs9">
Is AI an existential risk?
</h3>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="1CIr3o">
As for whether AI would kill us all, the truth is that reporting on this question is honestly extraordinarily difficult. Climate scientists broadly agree that climate change won’t kill us all, though there’s substantial uncertainty about which tail-risk scenarios are plausible and how plausible. Nuclear war researchers have substantial, heated disagreement about whether a nuclear winter would ensue from a nuclear war.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="rnXVDF">
But both of those disagreements pale in comparison to the degree of disagreement over the impacts of AI. CBS <a href="https://www.cbsnews.com/news/godfather-of-artificial-intelligence-weighs-in-on-the-past-and-potential-of-artificial-intelligence/">recently asked</a> Geoffrey Hinton, called the godfather of AI, about claims that AI could wipe out humanity. “It’s not inconceivable, that’s all I’ll say,” Hinton said. I’ve heard the same thing from many other experts: Stakes that high seem to be genuinely on the table. Of course, other experts insist there is no cause for worry whatsoever.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="xFrd9s">
The million-dollar question, then, is how AI could wipe us out, if even a nuclear war or a massive pandemic or substantial global temperature change wouldn’t do it. But even if humanity is pretty tough, there are many other species on Earth that can tell you — or could have told you before they went extinct — that an intelligent civilization that doesn’t care about you can absolutely grind up your habitat for its highways (or the AI equivalent, maybe grinding up the whole biosphere to use for AI civilization projects).
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="WxwrBP">
It seems extraordinarily difficult to navigate high-stakes trade-offs like these in a principled way. Policymakers don’t know which experts to turn to to understand the stakes of AI development, and there’s no scientific consensus to guide them. One of my biggest takeaways here is that we need to know more. It’s impossible to make good decisions without a clearer grasp of what we’re building, why we’re building it, what might go wrong, and how wrong it could possibly go.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="LUK3Gd">
<em>A version of this story was initially published in the Future Perfect newsletter. </em><a href="https://confirmsubscription.com/h/d/A2BA26698741513A"><em><strong>Sign up here to subscribe!</strong></em></a>
</p></li>
<li><strong>What gets lost in the AI debate: It can be really fun</strong> -
<figure>
<img alt="Drake and The Weeknd perform onstage at Nottingham Capital FM Arena on March 16, 2014, in Nottingham, England." src="https://cdn.vox-cdn.com/thumbor/w3C7--j44XvqPtWqnySZl0aXf7I=/0x0:2663x1997/1310x983/cdn.vox-cdn.com/uploads/chorus_image/image/72222216/GettyImages_479173485.0.jpg"/>
<figcaption>
A viral fake Drake and The Weeknd song, which an anonymous user posted online and claimed to make using AI, shows how good AI is getting at entertaining us. | Ollie Millington/WireImage
</figcaption>
</figure>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
The viral fake Drake and The Weeknd song tells us a lot about the future of AI.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="ZTzb1I">
You’ve probably heard a lot lately about AI.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="TrOP4w">
Everyone from <a href="https://www.cnn.com/2023/04/17/tech/elon-musk-ai-warning-tucker-carlson/index.html">Elon Musk</a> to <a href="https://www.reuters.com/technology/biden-discuss-risks-ai-tuesday-meeting-with-science-advisers-2023-04-04/">Joe Biden</a> has been worried that AI could take over our jobs, spread misinformation, or even — if we’re not careful — one day kill us all. Meanwhile, some AI experts say instead of fixating on hypothetical doomsday scenarios in the long term, we should <a href="https://techcrunch.com/2023/03/31/ethicists-fire-back-at-ai-pause-letter-they-say-ignores-the-actual-harms/">focus on how AI is actively harming us</a> right now and <a href="https://www.technologyreview.com/2023/04/18/1071727/generative-ai-risks-concentrating-big-techs-power-heres-how-to-stop-it/">the concentration of power in a handful</a> of companies that are controlling its development. Already, the error-prone technology has been used to <a href="https://decrypt.co/125712/chatgpt-wrongly-accuses-law-professor-sexual-assault">invent slanderous lies about people</a>, <a href="https://www.vice.com/en/article/dy7axa/how-i-broke-into-a-bank-account-with-an-ai-generated-voice">hack bank accounts</a>, and mistakenly <a href="https://www.wired.com/story/face-recognition-software-led-to-his-arrest-it-was-dead-wrong/#:~:text=to%20His%20Arrest.-,It%20Was%20Dead%20Wrong,else%E2%80%94feeding%20debate%20over%20regulation.&amp;text=Carronne%20Sawyer%20took%20the%20week,husband%20Alonzo%20out%20of%20jail.">arrest</a> criminal suspects.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="HgwqTj">
But near-term and long-term concerns aside, there’s a major component to why it feels like AI is suddenly taking the world by storm: It’s fun.
</p>
<aside id="zglOob">
<div>
</div>
</aside>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="OU3QNA">
Over the past few weeks, I’ve been playing around with the latest AI tools and talking to people who use them. I’ve found that the most exciting forms of AI right now are not the kind people are using to increase productivity by crunching spreadsheets or writing emails. (Although bosses love that idea!) They’re the kind being used to entertain us.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="UELAih">
In just the past six months, AI has come an incredibly long way in helping people essentially create all kinds of media. With varying degrees of instruction, AI can craft photorealistic illustrations, design video games, or come up with catchy tunes with top-40 potential.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="ptG09K">
So what should we make of the fact that people are enthusiastic about using a technology that clearly has serious flaws and consequences?
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="CsNXys">
“I think it’s <em>completely</em> reasonable for people to be excited and having fun,” Margaret Mitchell, chief ethics scientist for AI platform Hugging Face, wrote in a text. Mitchell <a href="https://www.theinformation.com/articles/an-ai-researcher-tries-to-build-good-ai-while-burning-down-the-bad?rc=eh9iin">formerly</a> founded the Ethical AI team at Google, where she was controversially fired after <a href="https://www.theverge.com/2021/2/19/22292011/google-second-ethical-ai-researcher-fired">co-authoring</a> a <a href="https://dl.acm.org/doi/10.1145/3442188.3445922">paper</a> calling out the risks associated with large language models that power many AI apps. Mitchell and her co-authors were prescient early critics of the shortcomings of recent AI technology — but she acknowledges its potential, too.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="emGXL0">
Pietro Schirano is a design lead at financial services startup Brex. He was also an early adopter of GPT-4, the latest iteration of the technology from the company behind the viral ChatGPT app, OpenAI.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="whrJyG">
When <a href="https://www.vox.com/2023/3/15/23640640/gpt-4-chatgpt-openai-generative-ai">GPT-4 came out in March</a>, Schirano couldn’t wait to use it. He decided to test its ability to write working lines of code from simple prompts. So Schirano set out to recreate the video game Pong because, in his words, “it was the first video game ever, and it would be cool to do it.”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="8EnCsq">
In less than 60 seconds, after feeding GPT-4 a few sentences, copying the code, and pasting it into a code engine, Schirano had a working Pong he could play with. He was amazed.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="G28V4q">
“That was the first time that I had this sort of, like, ‘oh shoot’ moment where I’m like, oh my god,” he said. “This is different.”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="mqvhxR">
His <a href="https://twitter.com/skirano/status/1635736107949195278?lang=en">tweet posting a video</a> of the process went viral.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="HOvwli">
When I asked Schirano if he worries about AI replacing the jobs of people like him, he said he wasn’t too concerned. He says he uses ChatGPT at work to help him be more productive and focus on higher-level decision-making.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="Zc28Iu">
“The way that I see these tools is actually not necessarily replacing us, but basically making us superhuman, in a way,” said Schirano.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="JnmseM">
As my colleague Rani Molla has reported, <a href="https://www.vox.com/technology/23673018/generative-ai-chatgpt-bing-bard-work-jobs">many workers are in the same camp</a><strong> </strong>as Schirano. They don’t think their jobs can fully be replaced by AI, and they aren’t particularly terrified of it — for now.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="rWJ7e2">
I talked to Ethan Mollick, a professor at the University of Pennsylvania’s Wharton business school, about the wide range of reactions to new AI tools. Any kind of new “general purpose technology” Mollick said — think electricity, steam power, or the computer — has the potential for major disruption, but it also catches on because of unexpected, novel, and often entertaining use cases. New advancements in AI like GPT-4, he added, fit very well into that general-purpose technology category.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="GFU4bj">
AI is “absolutely supercharging creativity,” said Mollick. “How can you not spend every minute trying to make this thing do stuff? It’s incredible. I think it could both be incredible and terrifying.”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="KSPeHQ">
These fun creative ways to use AI also bring up the question of authenticity: Will it replace human creativity or merely help us in the production of it?
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="qCUXF3">
Last week, a hip-hop song that sounded like a mashup of the artists Drake and The Weeknd <a href="https://www.nytimes.com/2023/04/19/arts/music/ai-drake-the-weeknd-fake.html">went viral on social media</a>. The song, posted by the anonymous user “ghostwriter,” claimed to be made with AI, and got millions of plays before it was taken down by major platforms.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="wXaGGb">
The proliferation of this kind of AI-generated media has spooked record labels enough that Universal Music Group <a href="https://www.ft.com/content/aec1679b-5a34-4dad-9fc9-f4d8cdd124b9">asked streaming services</a> like Spotify to stop AI companies from using its music to train their models, citing intellectual property concerns. And last month, a coalition of record industry unions and trade groups launched the “Human Artistry Campaign” to make <a href="https://variety.com/2023/music/news/ai-copyright-human-artistry-campaign-musicians-songwriters-artificial-intelligence-1235557582/">sure AI doesn’t “replace or erode”</a> artists.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="E5ec7Z">
A few artists, though, have <a href="https://datebook.sfchronicle.com/music/grimes-ai-royalties-elon-musk-artificial-fake-17916049">embraced the AI concept</a>. The musician Grimes even asked fans to co-create music with her likeness and offered to split 50 percent of the royalties.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="Vey7z9">
Mollick compared the debate around whether AI will replace artists to the introduction of the synthesizer to modern music. When the synthesizer first came out, people debated whether it was “ruining music,” and whether people who used the instrument were real musicians.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="TQY95M">
Ultimately, the real dangers of AI may not lie so much in the technology but in who controls it and how it’s used, Mitchell said.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="aDn56T">
“My issues are more with tech leaders who mislead and push out tech inappropriately rather than creative people exploring new technology,”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="7u9HIt">
<em>A version of this story was first published in the Vox technology newsletter. </em><a href="https://www.vox.com/pages/newsletters"><em><strong>Sign up here</strong></em></a><em> so you don’t miss the next one!</em>
</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Are You There God? It’s Me, Margaret is about far more than periods</strong> -
<figure>
<img alt="Four preteen girls form a kick line in front of a painted stage background." src="https://cdn.vox-cdn.com/thumbor/o0hSY7cCJtGo7zISSWEWoA9id1k=/0x0:2638x1979/1310x983/cdn.vox-cdn.com/uploads/chorus_image/image/72222166/aytg_unit_02452rc2.0.jpg"/>
<figcaption>
The Pre-Teen Sensations! From left, Abby Ryder Fortson as Margaret, Amari Price as Janie, Elle Graham as Nancy, and Katherine Kupferer as Gretchen in Kelly Fremon Craig’s <em>Are You There God? It’s Me, Margaret</em>. | Dana Hawley/Lionsgate
</figcaption>
</figure>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
A new movie adaptation captures the sneaky complexity of what Judy Blume’s classic gets right about being 11.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="qQzX1R">
In my mental catalog of Judy Blume books, everything is filed according to the adolescent trope it taught me about. <em>It’s Not the End of the World</em> is the divorce book. <em>Forever…</em> is the sex book. <em>Then Again, Maybe I Won’t</em> is the wet dreams book, which in the fifth grade read like an intelligence report sent from behind enemy lines. <em>Are You There God? It’s Me, Margaret</em>, first published in 1970, is, of course, the period book.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="62K1Po">
Or at least that’s how I remembered it from being 10 years old: Margaret and her friends competing to see who will get their periods first; that awful Nancy lying about getting it and then crying in the bathroom of a fancy restaurant when it actually came; Margaret alone in her room, fumbling with the mysterious belt that sanitary napkins used to have in the ’70s. Girls read <em>Are You There God</em> as a supplement to middle school health classes, was what I vaguely concluded, so they would know what it felt like when their periods came. (I could not imagine a boy reading this book for any reason whatsoever.)
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="xSq0Ex">
So I was startled, when I watched Kelly Fremon Craig’s excellent new film adaptation of <em>Are You There God</em>, to see that there were so many other plotlines at work in the story. There was all this stuff about bras, which I did vaguely recall. But then there were also friendship dynamics and family dynamics and new town stuff and religion stuff — my god! How had I forgotten the religion stuff? It’s right there in the title!
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="1toJ7p">
It didn’t make sense to me. The damn book is only about 30,000 words long. Could Blume possibly have fit that much in there besides the period plotline? Had Craig added something new?
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="NAS76J">
Not really, I discovered upon returning to the book for the first time in 25 years. Nearly everything in Craig’s film is in Blume’s book, too. As it turns out, <em>Are You There God? It’s Me, Margaret</em> is a lot more than just the period book. It hits all the tweenage low points, and it welcomes adult readers with a surprising amount of grace.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="Ok11b4">
<em>Are You There God</em> begins with Margaret Simon, 11 years old, moving out of New York’s Upper West Side and into the suburbs of New Jersey. In a gently understated subversion of the city kid stereotype, she finds when she arrives that she seems younger for her age than the jaded suburbanites all around her. Queen Bee Nancy, who immediately takes Margaret under her wing, already plays with makeup and practices kissing boys, while Margaret does neither. Nancy seems, Margaret notes, impressed and resentful, “to know a lot.”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="tp53m4">
Toxic girl friendships are one of the great themes of Blume’s oeuvre (explored in their darkest form in the harrowing <em>Blubber</em>). Accordingly, once Nancy enters the picture, <em>Are You There God</em> becomes the story of Margaret’s education and corruption. Nancy pushes Margaret to buy a training bra and sanitary napkins, teaches her to perform her crushes, tells her which boys are acceptable crush objects. She plies Margaret with cruel gossip to turn her against the girl in their class who already wears bras.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="gnmxHK">
It’s Nancy who informs Margaret that her secular existence is a problem. The Simons identify as neither Jewish nor Christian after Margaret’s mother, Barbara, was disowned by her Christian parents for marrying a Jewish man. In New York this wasn’t an issue, but in the suburbs, Nancy tells Margaret, everyone joins either the Y or the Jewish Community Center.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="8ZGQTG">
Desperate to follow Nancy’s instructions, Margaret embarks on a research project to try to find what religion is best for her. She isn’t looking to be shown how to talk to God: She already does that every night, alone in her room, pouring out her dreams and worries to God as though she’s writing in her diary. (“Please help me grow God. You know where.”) Instead, Margaret wants organized religion to codify her relationship with God, to turn it into something that Nancy will be able to categorize neatly away in the same way she does everything else.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="g8FYv0">
Picking a religion wouldn’t only help Margaret with her school friends. It would also help her with her family. Simmering mostly below the surface of Margaret’s naive narration is a proxy war between her parents and her grandparents, with Margaret’s life as the battlefield.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="4FMGf3">
Margaret is devoted to her paternal grandmother, Sylvia, who dotes on her, paying for her New York City private school tuition and her New Hampshire summer camp. Sylvia feels fiercely that Margaret should grow up as a New York Jew, in culture if not in religious belief, and to that end shows up uninvited at the Simons’ new house with bags of deli food to make sure Margaret will remember what it should taste like. “Mmm … nothing like the real thing!” she says every time she bites into a pickle.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="Itl4Gi">
Margaret is vaguely aware that her mother doesn’t particularly like for Sylvia to be so involved in Margaret’s life, and she’s pretty sure that they moved to New Jersey specifically to get Margaret away from Sylvia. She’s less aware of how many times Sylvia tells her to do something and then follows it up by instructing her not to tell her parents. It all explodes, though, when Barbara’s parents show up in town to check up on their granddaughter, forcing Margaret to miss a planned visit to Sylvia.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="Ljs4BK">
“Margaret is a Christian!” says Barbara’s mother.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="elvXC8">
“You’re a Jewish girl,” Sylvia assures Margaret.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="5iurxo">
“I’m nothing, and you know it!” proclaims Margaret. “I don’t even believe in God!” (To us she adds, “I wanted to ask him did he hear that!” She is, at the time, in a fight with God.)
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="zl6YsF">
It’s this plotline that Craig gently expands, mostly through transforming Barbara (played here by Rachel McAdams at her warmest) into a point-of-view character. Craig’s take, though, is less an addition to Blume’s text than an excavation, working with what Margaret tells us to unearth new details in the story.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="S7xOI4">
Blume’s Barbara is an artist who seems a little scattered in the suburbs and lightly on edge around her mother-in-law. Craig’s Barbara, in turn, is a bohemian who moves to the suburbs because she thinks it will be best for her child and then finds herself losing her own identity; who would like her mother-in-law to stop trying to raise her daughter for her now, please. In the film, Barbara becomes a stand-in of sorts for all the women who grew up on Judy Blume and are watching Craig’s film now as adults. Through Barbara’s eyes, we watch Margaret care passionately about things like not wearing socks with loafers and buying a bra well before she needs one, and we remember what it was like to care so passionately.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="y2kt9K">
All of it is consistent with the characterization Blume gave us, back when she wrote <em>Margaret</em> as a newly suburban housewife herself, writing books in between caring for her children. It’s just the stuff that Margaret, with the complacent solipsism of childhood, never bothers to lay out for us. She’s too busy trying to figure out how to be the version of herself Nancy and her parents and her grandparents want her to be — until she figures out how to be a version of herself that she likes instead.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="Gij6wr">
Once she figures it out, you know what happens next: She gets her period.
</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>Wrestlers protesting on streets tarnishing India’s image, amounts to indiscipline, says IOA president P.T. Usha</strong> - IOA also instituted a three-member adhoc panel, including Suma Shirur, Bhupendra Singh Bajwa and headed by a yet-to-be-named retired high court judge</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>IPL 2023: PBKS vs LSG | Rahul’s strike rate in focus again as Lucknow faces Punjab in crucial mid-table clash</strong> - Halfway into the competition, both teams have four wins from seven games and would be aiming to find consistency in the tight race to the IPL play-offs.</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>SRH’s Washington Sundar ruled out of remainder of IPL 2023 due to hamstring injury</strong> - The Tamil Nadu player had also faced injury during the last IPL, suffering split webbing in his bowling hand.</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>Stuart Broad urges England to emulate 2005 Ashes success</strong> - England regained the famous urn for the first time in 18 years in 2005 with a 2-1 series victory, which is widely rated among the team’s greatest achievements in the longest format.</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>Watch | The rise of ‘Little Cuba’s’ new boxing star Nitu Ghanghas</strong> - A video on 22-year-old Nitu Ghanghas who bagged a gold medal in the 48 kg category at the 2023 Women’s Boxing World Championships</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>Target DMK, the common enemy: BJP top brass to AIADMK</strong> - At a meeting between Union Minister Amit Shah and AIADMK’s general secretary Edappadi K. Palaniswami, senior leaders of the BJP were of the view that the target of political attack in the State should be DMK</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>Mumbai-Pune Expressway pile-up after truck suffers brake failure injures 6, damages several vehicles</strong> - The incident took place near Khopoli in Raigad district, and the injured include a man, his wife and mother, the official said.</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>States clear all hurdles in path of projects listed for review under PRAGATI, says PM Modi</strong> - “In the last nine years, PRAGATI has made a huge contribution to “fast-paced development of the country,” the Prime Minister added.</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>Kerala govt. moves appeal for enhancing sentences in Madhu lynching case</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>Karnataka Assembly elections | Southern Karnataka emerges as crucial battleground for all three parties</strong> - The region has been a JD(S) bastion, but Congress State chief D.K. Shivakumar now poses a threat; the BJP is bringing in the PM and HM to campaign in the area in a bid to win a solo majority in the State for the first time</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>Ukraine war: Bakhmut defenders worry about losing support</strong> - Lack of ammunition is hampering Ukrainian fighters as they prepare an expected major offensive.</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>Turkey’s Erdogan falls ill on TV and cancels election rallies</strong> - Turkey’s president suspends election campaign events after a TV interview abruptly comes to a halt.</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>Sudan crisis: UK accused of delaying German evacuation efforts</strong> - German politicians tell the BBC that British actions in Sudan hampered efforts of other countries.</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>Pope Francis gives women historic right to vote at meeting</strong> - The move is being hailed as a “significant crack in the stained glass ceiling” of the Church.</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: Sniper kills fixer and wounds Italian reporter in Ukraine</strong> - Bogdan Bitik is killed and Corrado Zunino hit by suspected Russian fire in the Kherson region.</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>Man peddling vitamins as cancer therapy faces 5 felony counts</strong> - With allegedly fake title, Gevorkian sold unproven treatments for serious conditions. - <a href="https://arstechnica.com/?p=1934838">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Windows 11’s limited iMessage integration has publicly launched</strong> - The limitations are harsh, but it works. - <a href="https://arstechnica.com/?p=1934817">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Amazon will brick all Halo health trackers on August 1</strong> - The Halo Rise sleep tracker only came out 5 months ago. - <a href="https://arstechnica.com/?p=1934799">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Star Wars Jedi: Survivor review: An immense sequel that aims high and hits</strong> - A confident, deeper sequel that embraces Star Wars’ spirit of adventure. - <a href="https://arstechnica.com/?p=1934747">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Elizabeth Holmes gets bail extension one day before prison term start</strong> - Holmes’ last-ditch appeal triggered an automatic freeze on her previous bail denial. - <a href="https://arstechnica.com/?p=1934792">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>My wife asked me what would I do if she was choking…</strong> - <!-- SC_OFF --></p>
<div class="md">
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
I told her I would back up two inches…
</p>
</div>
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<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"> submitted by <a href="https://www.reddit.com/user/Amart1985"> /u/Amart1985 </a> <br/> <span><a href="https://www.reddit.com/r/Jokes/comments/1306wpw/my_wife_asked_me_what_would_i_do_if_she_was/">[link]</a></span> <span><a href="https://www.reddit.com/r/Jokes/comments/1306wpw/my_wife_asked_me_what_would_i_do_if_she_was/">[comments]</a></span></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Why don’t The Ants catch COVID?</strong> - <!-- SC_OFF --></p>
<div class="md">
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
They’ve got little Antibodies.
</p>
</div>
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<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"> submitted by <a href="https://www.reddit.com/user/4BDUL4Z1Z"> /u/4BDUL4Z1Z </a> <br/> <span><a href="https://www.reddit.com/r/Jokes/comments/130c8qm/why_dont_the_ants_catch_covid/">[link]</a></span> <span><a href="https://www.reddit.com/r/Jokes/comments/130c8qm/why_dont_the_ants_catch_covid/">[comments]</a></span></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>I’m starting to doubt my marriage</strong> - <!-- SC_OFF --></p>
<div class="md">
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
</p><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">A rich man, after 50 years of marriage, once looked at his wife and said:</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"></p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
</p><ul>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">50 years ago, we had a small house and an old car. We slept on the couch and watched a small black-and-white TV, but every night I went to bed with a beautiful 19-year-old girl. Now I have a huge expensive house, many expensive cars, a huge bed in a luxurious bedroom, and a wide-screen color TV, but I share a bed with a 69-year-old woman. I’m starting to doubt my marriage.
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"></p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
His wife suggested:
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
-You can find yourself a 19-year-old girl, and I will make sure that you live again in a small house, sleep on a sagging sofa, and watch black-and-white TV.
</p>
</li></ul></div>
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submitted by <a href="https://www.reddit.com/user/ThumbsUpJokes"> /u/ThumbsUpJokes </a> <br/> <span><a href="https://www.reddit.com/r/Jokes/comments/1308fy1/im_starting_to_doubt_my_marriage/">[link]</a></span> <span><a href="https://www.reddit.com/r/Jokes/comments/1308fy1/im_starting_to_doubt_my_marriage/">[comments]</a></span></li>
</ul>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Last night a local church was robbed. Miraculously the golden Jesus on the cross was left behind.</strong> - <!-- SC_OFF --></p>
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<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
They took everything that wasn’t nailed down.
</p>
</div>
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<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"> submitted by <a href="https://www.reddit.com/user/Glatzial"> /u/Glatzial </a> <br/> <span><a href="https://www.reddit.com/r/Jokes/comments/130edsn/last_night_a_local_church_was_robbed_miraculously/">[link]</a></span> <span><a href="https://www.reddit.com/r/Jokes/comments/130edsn/last_night_a_local_church_was_robbed_miraculously/">[comments]</a></span></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>A dentist goes out and buys the best car on the market, a brand-new Bugatti Chiron.</strong> - <!-- SC_OFF --></p>
<div class="md">
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
It is also the most expensive car in the world, and it costs him $1.5M. He takes it out for a spin and stops at a red light.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
An old man on a moped, looking about 90 years old, pulls up next to him.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
The old man looks over at the sleek shiny car and asks, “What kind of car ya got there, sonny?”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
The dentist replies, “A Bugatti Chiron. It cost one and a half a million dollars!”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
“That’s a lot of money,” says the old man. “Why does it cost so much?”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
“Because this car can do up to 250 miles an hour!” states the dentist proudly.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
The moped driver asks, “Mind if I take a look inside?”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
“No problem,” replies the dentist.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
So the old man pokes his head in the window and looks around.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
Then, sitting back on his moped, the old man says, “That’s a pretty nice car, all right, but I’ll stick with my moped!”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
Just then the light changes, so the dentist decides to show the old man just what his car can do.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
He floors it, and within 30 seconds, the speedometer reads 150 mph.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
Suddenly, he notices a dot in his rearview mirror – what it could be…and suddenly…
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
WHHHOOOOOOSSSSSHHH!
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
Something whips by him going much faster!
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
“What on earth could be going faster than my Bugatti?” the dentist asks himself.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
He floors the accelerator and takes the Bugatti up to 175 mph.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
Then, up ahead of him, he sees that it’s the old man on the moped!
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
Amazed that the moped could pass his Bugatti, he gives it more gas and passes the moped at 210 mph.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
WHOOOOOOOSHHHHH!
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
He’s feeling pretty good until he looks in his mirror and sees the old man gaining on him AGAIN!
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
Astounded by the speed of his old guy, he floors the gas pedal and takes the Bugatti all the way up to 250 mph.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
Not ten seconds later, he sees the moped bearing down on him again!
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
The Bugatti is flat out, and there’s nothing he can do!
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
Suddenly, the moped plows into the back of his Bugatti, demolishing the rear end.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
The dentist stops and jumps out and, unbelievably, the old man is still alive.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
He runs up to the mangled old man and says, “Oh my gosh! Is there anything I can do for you?”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
The old man whispers, “Unhook my suspenders from your side mirror.”
</p>
</div>
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<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"> submitted by <a href="https://www.reddit.com/user/pranavsundaram"> /u/pranavsundaram </a> <br/> <span><a href="https://www.reddit.com/r/Jokes/comments/130i3rp/a_dentist_goes_out_and_buys_the_best_car_on_the/">[link]</a></span> <span><a href="https://www.reddit.com/r/Jokes/comments/130i3rp/a_dentist_goes_out_and_buys_the_best_car_on_the/">[comments]</a></span></p></li>
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