Universal protection against SARS-CoV-2 viruses by multivalent mRNA vaccine in mice -
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+The ongoing emergence of new strains of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants challenges available SARS-CoV-2 vaccines for adequate control of outbreaks. Currently, there is a lack of universal vaccines for SARS-CoV-2 variants that do not necessitate strain matching between mRNA vaccines and the viruses. In this study, a nucleoside-modified twenty-valent lipid nanoparticle mRNA vaccine was designed and manufactured. The primary objective is to provide protection against various recent variants via the twenty-valent mRNA vaccine after efficacy assessment. Furthermore, the protection efficiency of bivalent and quadrivalent mRNA vaccines was compared with the universal vaccine. The neutralizing antibody activity against BA.4/5, XBB.1.5, BQ.1.1, and EG.5.1 was evaluated using enzyme-linked immunosorbent assay, pseudovirus neutralization test, and a rapid fiber-optic biolayer interferometry-based biosensor. Our universal multivalent vaccine provided robust protection against both prevailing and emerging, previously unidentified SARS-CoV-2 strains.
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Predicting human and viral protein variants affecting COVID-19 susceptibility and repurposing therapeutics -
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+The COVID-19 disease is an ongoing global health concern. Although vaccination provides some protection, people are still susceptible to re-infection. Ostensibly, certain populations or clinical groups may be more vulnerable. Factors causing these differences are unclear and whilst socioeconomic and cultural differences are likely to be important, human genetic factors could influence susceptibility. Experimental studies indicate SARS-CoV-2 uses innate immune suppression as a strategy to speed-up entry and replication into the host cell. Therefore, it is necessary to understand the impact of variants in immunity-associated human proteins on susceptibility to COVID-19. In this work, we analysed missense coding variants in several SARS-CoV-2 proteins and its human protein interactors that could enhance binding affinity to SARS-CoV-2. We curated a dataset of 19 SARS-CoV-2: human protein 3D-complexes, from the experimentally determined structures in the Protein Data Bank and models built using AlphaFold2-multimer, and analysed impact of missense variants occurring in the protein-protein interface region. We analysed 468 missense variants from human proteins and 212 variants from SARS-CoV-2 proteins and computationally predicted their impacts on binding affinities to SARS-CoV-2 proteins, using 3D-complexes. We predicted a total of 26 affinity-enhancing variants from 14 human proteins implicated in increased binding affinity to SARS-CoV-2. These include key-immunity associated genes (TOMM70, ISG15, IFIH1, IFIT2, RPS3, PALS1, NUP98, RAE1, AXL, ARF6, TRIMM, TRIM25) as well as important spike receptors (KREMEN1, AXL and ACE2). We report both common (e.g., Y13N in IFIH1) and rare variants in these proteins and discuss their likely structural and functional impact, using information on known and predicted functional sites. Potential mechanisms associated with immune suppression implicated by these variants are discussed. Occurrence of certain predicted affinity-enhancing variants should be monitored as they could lead to increased susceptibility and reduced immune response to SARS-CoV-2 infection in individuals/populations carrying them. Our analyses aid in understanding the potential impact of genetic variation in immunity-associated proteins on COVID-19 susceptibility and help guide drug-repurposing strategies.
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Allosteric modulation by the fatty acid site in the glycosylated SARS-CoV-2 spike -
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+The trimeric spike protein plays an essential role in the SARS-CoV-2 virus lifecycle, facilitating virus entry through binding to the cellular receptor angiotensin-converting enzyme 2 (ACE2) and mediating viral and host membrane fusion. The SARS-CoV-2 spike contains an allosteric fatty acid (FA) binding site at the interface between two neighbouring receptor-binding domains. This site, also found in some other coronaviruses, binds free fatty acids such as linoleic and oleic acid, and other small molecules. Understanding allostery and how this site modulates the behaviour of different regions in this protein could potentiate the development of promising alternative strategies for new coronavirus therapies. Here, we apply dynamical nonequilibrium molecular dynamics (D-NEMD) simulations to investigate allosteric effects and identify the communication pathways in the fully glycosylated spike in the original SARS-CoV-2 ancestral variant. The results reveal the allosteric networks that connect the FA site to important functional regions of the protein, including some more than 40 Angstroms away. These regions include the receptor binding motif, an antigenic supersite in the N-terminal domain, the furin cleavage site, the regions surrounding the fusion peptide and a second allosteric site known to bind heme and biliverdin. The networks identified here highlight the complexity of the allosteric modulation in this protein and reveal a striking and unexpected connection between different allosteric sites. Notably, 65% of amino acid substitutions, deletions and insertions in the Alpha, Beta, Delta, Gamma and Omicron variants map onto or close to the identified allosteric pathways.
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+Waning immunity and continued virus evolution have limited the durability of protection from symptomatic infection mediated by intramuscularly (IM)-delivered mRNA vaccines against COVID-19 although protection from severe disease remains high. Mucosal vaccination has been proposed as a strategy to increase protection at the site of SARS-CoV-2 infection by enhancing airway immunity, potentially reducing rates of infection and transmission. Here, we compared protection against XBB.1.16 virus challenge 5 months following IM or mucosal boosting in non-human primates (NHP) that had previously received a two-dose mRNA-1273 primary vaccine regimen. The mucosal boost was composed of a bivalent chimpanzee adenoviral-vectored vaccine encoding for both SARS-CoV-2 WA1 and BA.5 spike proteins (ChAd-SARS-CoV-2-S) and delivered either by an intranasal mist or an inhaled aerosol. An additional group of animals was boosted by the IM route with bivalent WA1/BA.5 spike-matched mRNA (mRNA-1273.222) as a benchmark control. NHP were challenged in the upper and lower airways 18 weeks after boosting with XBB.1.16, a heterologous Omicron lineage strain. Cohorts boosted with ChAd-SARS-CoV-2-S by an aerosolized or intranasal route had low to undetectable virus replication as assessed by levels of subgenomic SARS-CoV-2 RNA in the lungs and nose, respectively. In contrast, animals that received the mRNA-1273.222 boost by the IM route showed minimal protection against virus replication in the upper airway but substantial reduction of virus RNA levels in the lower airway. Immune analysis showed that the mucosal vaccines elicited more durable antibody and T cell responses than the IM vaccine. Protection elicited by the aerosolized vaccine was associated with mucosal IgG and IgA responses, whereas protection elicited by intranasal delivery was mediated primarily by mucosal IgA. Thus, durable immunity and effective protection against a highly transmissible heterologous variant in both the upper and lower airways can be achieved by mucosal delivery of a virus-vectored vaccine. Our study provides a template for the development of mucosal vaccines that limit infection and transmission against respiratory pathogens.
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The α-dystroglycan N-terminus is a broad-spectrum antiviral agent against SARS-CoV-2 and enveloped viruses -
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+The COVID-19 pandemic has shown the need to develop effective therapeutics in preparedness for further epidemics of virus infections that pose a significant threat to human health. As a natural compound antiviral candidate, we focused on -dystroglycan, a highly glycosylated basement membrane protein that links the extracellular matrix to the intracellular cytoskeleton. Here we show that the N-terminal fragment of -dystroglycan (-DGN), as produced in E. coli in the absence of post-translational modifications, blocks infection of SARS-CoV-2 in cell culture, human primary gut organoids and the lungs of transgenic mice expressing the human receptor angiotensin I-converting enzyme 2 (hACE2). Prophylactic and therapeutic administration of -DGN reduced SARS-CoV-2 lung titres and protected the mice from respiratory symptoms and death. Recombinant -DGN also blocked infection of a wide range of enveloped viruses including the four Dengue virus serotypes, influenza A virus, respiratory syncytial virus, tick-borne encephalitis virus, but not human adenovirus, a non-enveloped virus in vitro. This study establishes soluble recombinant -DGN as a broad-band, natural compound candidate therapeutic against enveloped viruses.
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Combining models to generate a consensus effective reproduction number R for the COVID-19 epidemic status in England -
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+The effective reproduction number R was widely accepted as a key indicator during the early stages of the COVID-19 pandemic. In the UK, the R value published on the UK Government Dashboard has been generated as a combined value from an ensemble of fourteen epidemiological models via a collaborative initiative between academia and government. In this paper we outline this collaborative modelling approach and illustrate how, by using an established combination method, a combined R estimate can be generated from an ensemble of epidemiological models. We show that this R is robust to different model weighting methods and ensemble size and that using heterogeneous data sources for validation increases its robustness and reduces the biases and limitations associated with a single source of data. We discuss how R can be generated from different data sources and is therefore a good summary indicator of the current dynamics in an epidemic.
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Combining models to generate consensus medium-term projections of hospital admissions, occupancy and deaths relating to COVID-19 in England -
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+Mathematical modelling has played an important role in offering informed advice during the COVID-19 pandemic. In England, a cross government and academia collaboration generated Medium-Term Projections (MTPs) of possible epidemic trajectories over the future 4-6 weeks from a collection of epidemiological models. In this paper we outline this collaborative modelling approach and evaluate the accuracy of the combined and individual model projections against the data over the period November 2021-December 2022 when various Omicron subvariants were spreading across England. Using a number of statistical methods, we quantify the predictive performance of the model projections for both the combined and individual MTPs, by evaluating the point and probabilistic accuracy. Our results illustrate that the combined MTPs, produced from an ensemble of heterogeneous epidemiological models, were a closer fit to the data than the individual models during the periods of epidemic growth or decline, with the 90% confidence intervals widest around the epidemic peaks. We also show that the combined MTPs increase the robustness and reduce the biases associated with a single model projection. Learning from our experience of ensemble modelling during the COVID-19 epidemic, our findings highlight the importance of developing cross-institutional multi-model infectious disease hubs for future outbreak control.
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ASSESSMENT AND CHARACTERIZATION OF COVID-19 RELATED COGNITIVE DECLINE: RESULTS FROM A NATURAL EXPERIMENT -
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+Background: Cognitive impairment is the most common and disabling manifestation of post-acute sequelae of SARS-CoV-2. There is an urgent need for the application of more stringent methods for evaluating cognitive outcomes in research studies. Objective: To determine whether cognitive decline emerges with the onset of COVID-19 and whether it is more pronounced in patients with Post-Acute Sequelae of SARS-CoV-2 or severe COVID-19. Methods: This longitudinal cohort study compared the cognitive performance of 276 patients with COVID-19 to that of 217 controls across four neuroinflammation or vascular disease-sensitive domains of cognition using data collected both before and after the pandemic starting in 2015. Results: The mean age of the COVID-19 group was 56.04 (SD=6.6) years, while that of the control group was 58.1 (SD=7.3) years. Longitudinal models indicated a significant decline in cognitive throughput ((B=-0.168, P=.001) following COVID-19, after adjustment for pre-COVID-19 functioning, demographics, and medical factors. The effect sizes were large; the observed changes in throughput were equivalent to 10.6 years of normal aging and a 59.8% increase in the burden of mild cognitive impairment. Cognitive decline worsened with coronavirus disease 2019 severity and was concentrated in participants reporting post-acute sequelae of SARS-CoV-2. Conclusion: COVID-19 was most likely associated with the observed cognitive decline, which was worse among patients with PASC or severe COVID-19. Monitoring patients with post-acute sequelae of SARS-CoV-2 for declines in the domains of processing speed and visual working memory and determining the long-term prognosis of this decline are therefore warranted.
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Text Augmentations with R-drop for Classification of Tweets Self-Reporting Covid-19 -
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+This paper presents models created for the Social Media Mining for Health 2023 shared task. Our team addressed the first task, which involves automatically distinguishing tweets that self-report a Covid-19 diagnosis, for example, a positive test, clinical diagnosis, or hospitalization from tweets that merely state that the user has experienced Covid-19 without presenting any evidence and thus would not be considered a diagnosis. Our approach involves a classification model that incorporates diverse textual augmentations and utilizes R-drop to augment data and mitigate overfitting, boosting model efficacy. Our leading model, enhanced with R-drop and augmentations like synonym substitution, reserved words, and back translations, outperforms the task mean and median scores. Our system achieves an impressive F1 score of 0.877 on the test set.
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Beliefs in Conspiracy Theories and Online News Consumption during the onset of the COVID-19 pandemic -
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+Using an original survey covering 17 countries, this paper documents the prevalence of beliefs in theories related to the COVID-19 pandemic and characterizes the informational, demographic, and trust profiles of individuals who believe in conspiracy theories. There is considerable variation across countries in the level of conspiracy beliefs, with people in a set of countries like Romania, Poland, Greece, and Hungary being relatively more susceptible than respondents in northern Europe. We find several factors are correlated with conspiracy beliefs across countries. Relative to respondents who do not read news on social media, social media users tend to endorse more conspiracies, and this is the case for Facebook, Instagram, and YouTube users in particular. We also observe a link between distrust in medical experts or government and endorsement of conspiracy theories in most countries. In a subset of countries, we also find individuals with medium level of education and those who are younger to believe in a higher number of conspiracy theories.
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Global Sensitivity Analysis of the Onset of Nasal Passage Infection by SARS-CoV-2 With Respect to Heterogeneity in Host Physiology and Host Cell-Virus Kinetic Interactions -
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+Throughout the COVID-19 pandemic, positive nasal swab tests have revealed dramatic population heterogeneity in viral titers spanning 6 orders-of-magnitude. Our goal here is to probe potential drivers of infection outcome sensitivity arising from (i) physiological heterogeneity between hosts and (ii) host-variant heterogeneity in the detailed kinetics of cell infection and viral replication. Toward this goal, we apply global sensitivity methods (Partial Rank Correlation Coefficient analysis and Latin Hypercube Sampling) to a physiologically faithful, stochastic, spatial model of inhaled SARS-CoV-2 exposure and infection in the human respiratory tract. We focus on the nasal passage as the primary origin of respiratory infection and site of clinical testing, and we simulate the spatial and dynamic progression of shed viral load and infected cells in the immediate 48 hours post infection. We impose immune evasion, i.e., suppressed immune protection, based on the preponderance of clinical evidence that nasal infections occur rapidly post exposure, largely independent of immune status. Global sensitivity methods provide the de-correlated outcome sensitivities to each source of within-host heterogeneity, including the dynamic progression of sensitivities at 12, 24, 36, and 48 hours post infection. The results reveal a dynamic rank-ordering of the drivers of outcome sensitivity in early infection, providing insights into the dramatic population-scale outcome diversity during the COVID-19 pandemic. While we focus on SARS-CoV-2, the model and methods are applicable to any inhaled virus in the immediate 48 hours post infection.
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Integrated longitudinal multi-omics study identifies immune programs associated with COVID-19 severity and mortality in 1152 hospitalized participants -
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+Hospitalized COVID-19 patients exhibit diverse clinical outcomes, with some individuals diverging over time even though their initial disease severity appears similar. A systematic evaluation of molecular and cellular profiles over the full disease course can link immune programs and their coordination with progression heterogeneity. In this study, we carried out deep immunophenotyping and conducted longitudinal multi-omics modeling integrating ten distinct assays on a total of 1,152 IMPACC participants and identified several immune cascades that were significant drivers of differential clinical outcomes. Increasing disease severity was driven by a temporal pattern that began with the early upregulation of immunosuppressive metabolites and then elevated levels of inflammatory cytokines, signatures of coagulation, NETosis, and T-cell functional dysregulation. A second immune cascade, predictive of 28-day mortality among critically ill patients, was characterized by reduced total plasma immunoglobulins and B cells, as well as dysregulated IFN responsiveness. We demonstrated that the balance disruption between IFN-stimulated genes and IFN inhibitors is a crucial biomarker of COVID-19 mortality, potentially contributing to the failure of viral clearance in patients with fatal illness. Our longitudinal multi-omics profiling study revealed novel temporal coordination across diverse omics that potentially explain disease progression, providing insights that inform the targeted development of therapies for hospitalized COVID-19 patients, especially those critically ill.
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Dynamic gene expression analysis reveals distinct severity phases of immune and cellular dysregulation in COVID-19 -
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+Background: COVID-19 patients experience dynamic changes in immune and cellular function over time with potential clinical implications. However, there is insufficient research investigating, on a gene expression level, the mechanisms that become activated or suppressed over time as patients deteriorate or recover, which can inform use of repurposed and novel drugs as therapies. Objective: To investigate longitudinal changes in gene expression profiles throughout the COVID-19 disease timeline. Methods: Three-hundred whole blood samples from 128 adult patients were collected during hospitalization from COVID-19, with up to five samples per patient. Transcriptome sequencing (RNA-Seq), differential gene expression analysis and pathway enrichment was performed. Drug-gene set enrichment analysis was used to identify FDA-approved medications that could inhibit critical genes and proteins at each disease phase. Prognostic gene-expression signatures were generated using machine learning to distinguish 3 disease stages. Results: Samples were longitudinally grouped by clinical criteria and gene expression into six disease phases: Mild, Moderate, Severe, Critical, Recovery, and Discharge. Distinct mechanisms with differing trajectories during COVID-19 hospitalization were apparent. Antiviral responses peaked early in COVID-19, while heme metabolism pathways became active much later during disease. Adaptive immune dysfunction, inflammation, and metabolic derangements were most pronounced during phases with higher disease severity, while hemostatic abnormalities were elevated early and persisted throughout the disease course. Drug-gene set enrichment analysis predicted repurposed medications for potential use, including platelet inhibitors in early disease, antidiabetic medications for patients with increased disease severity, and dasatinib throughout the disease course. Disease phases could be categorized using specific gene signatures for prognosis and treatment selection. Disease phases were also highly correlated to previously developed sepsis endotypes, indicating that severity and disease timing were significant contributors to heterogeneity observed in sepsis and COVID-19. Conclusions: Higher temporal resolution of longitudinal mechanisms in COVID-19 revealed multiple immune and cellular changes that were activated at different phases of COVID-19. Understanding how a patient's gene expression profile changes over time can permit more accurate risk stratification of patients and provide time-dependent personalized treatments with repurposed medications. This creates an opportunity for timely intervention before patients transition to a more severe phase, potentially accelerating patients to recovery.
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Supply Chain Resilience and Medicine Availability in Saudi Arabian Pharmacies: A Case Study in Jeddah -
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+This article investigates the critical issue of supply chain resilience and its impact on medicine availability in Saudi Arabian pharmacies, focusing on a case study in Jeddah. During the COVID-19 pandemic, pharmacies in Jeddah experienced significant supply chain disruptions, leading to challenges in maintaining medicine availability. The study explores the resilience measures implemented by these pharmacies during the crisis and offers practical recommendations to enhance supply chain resilience. These recommendations include regulatory adjustments, the adoption of advanced technology, and strategic approaches to ensure uninterrupted access to essential medicines. This research underscores the crucial role of resilient supply chains in the context of public health and emphasizes the need for proactive measures to safeguard medicine availability in Saudi Arabian pharmacies and similar healthcare settings.
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Zheln.com: A protocol for a universal living overview of health-related systematic reviews -
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+BACKGROUND Objectives. 1. Identify and monitor most of published systematic reviews. 2. Tag the identified systematic records with medical specialties. 3. Select or crowdfund reviews for further appraisal. 4. Critically appraise and replicate the selected systematic reviews. 5. Disseminate practice implications of positively appraised reviews to both the public and evidence-based practitioners in health care and other fields associated with intervention into a human life, such as education, business, policy, or ecology. METHODS Eligibility criteria. Record eligibility is assessed by checking the record title and, if the title failed, abstract against the âtrue positive criteriaâ for systematic reviews taken from the publication by Shojania & Bero, 2001 (PMID 11525102). The record/study flow is as follows: All eligible records are amenable for tagging, selection, and crowdfunding process; Only those eligible records that have been selected or crowdfunded are subject to critical appraisal; For all records that have been selected, all relevant reports are collected; Reports are grouped into studies; Only for the studies appraised positively, practical implications are summarized and disseminated. COVID-19 publications are not selected. Crowdfunding an appraisal of any eligible record is possible for any individual or organization. Information sources. MEDLINE via PubMed. Adding other search sources, such as Scopus, OSF, and medRxiv, is planned in the future when more appraisers become available. The Replicated Version of the PubMed Systematic Review Subset Query Zheln Edition (DOI 10.17605/OSF.IO/Z3JU7) will be used. The searches are run daily. Risk of bias. Critical appraisal will feature: Duplication assessment; Replication; Assessment against the MECIR conduct standards; ROB-ME assessment; GRADE assessment. Synthesis of results. No across-studies synthesis is planned. Within-studies, I will formulate explicit practice-relevant statements based on the extracted health outcomes and quality-of-conduct assessment. Also, the process of each critical appraisal is video-recorded and published on YouTube daily. OTHER Funding. The review is crowdfunded; the details are available from the Zheln website (https://zheln.com). Crowd funders had no role in the design of the protocol. They will be able to request critical appraisal and additional critical appraisal (with new data provided) of any eligible record but will not influence the review process otherwise. Registration. The project is hosted on GitHub. Also, there is an umbrella Open Science Framework project that links repositories and preprints (DOI 10.17605/OSF.IO/EJKFC). The protocol for this overview of systematic reviews has been submitted for registration in PROSPERO.
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Brief Digital Intervention to Increase COVID-19 Vaccination Among Individuals With Anxiety or Depression - Conditions: Misinformation; Vaccine Hesitancy; Anxiety; Depression; COVID-19 Interventions: Behavioral: Attitudinal inoculation; Behavioral: Cognitive-behavioral therapy-informed intervention; Behavioral: Conventional public health messaging Sponsors: City University of New York, School of Public Health; University of North Carolina, Chapel Hill Not yet recruiting
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A Phaseâ Ą Study to Evaluate the Safety and Immunogenicity of SARS-CoV-2 (COVID-19) Vaccine( ZSVG-02-O) - Conditions: SARS-CoV-2 Infection Interventions: Biological: COVID-19 mRNA Vaccine (ZSVG-02-O); Biological: COVID-19 mRNA Vaccine (ZSVG-02-O); Biological: COVID-19 Vaccine (Vero Cell) ,Inactivated Sponsors: CNBG-Virogin Biotech (Shanghai) Ltd. Recruiting
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Pilot Randomized Study of RD-X19 Tx Device in Subjects With PCC (Long Covid) in the Outpatient Setting - Conditions: Post COVID-19 Condition (PCC) Interventions: Device: RDX-19 Sponsors: KNOWBio Inc.; NAMSA Recruiting
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CPAP Therapy Through a Helmet or a Full Face Mask in Patients With Acute Hypoxemic Respiratory Failure: Cross-over Study - Conditions: Pneumonia, Bacterial; Respiratory Failure; COVID-19 Pneumonia Interventions: Diagnostic Test: Arterial blood gases; Diagnostic Test: Respiratory rate (RR); Diagnostic Test: Pulseoximeter; Diagnostic Test: Assessment of accessory respiratory muscles work; Diagnostic Test: Esophageal pressure measurement; Diagnostic Test: Discomfort Visual Analog Scale (VAS); Diagnostic Test: Noninvasive blood pressure; Diagnostic Test: Heart rate Sponsors: I.M. Sechenov First Moscow State Medical University Recruiting
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A Phaseâ Study to Evaluate the Safety and Immunogenicity of SARS-CoV-2 (COVID-19) Vaccine( ZSVG-02-O) - Conditions: SARS-CoV-2 Infection Interventions: Biological: COVID-19 mRNA Vaccine (ZSVG-02-O); Biological: Placebo; Biological: COVID-19 Vaccine (Vero Cell) ,Inactivated Sponsors: CNBG-Virogin Biotech (Shanghai) Ltd.; Shulan (Hangzhou) Hospital Recruiting
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Investigation of Efficacy and Safety of Electrical Signal Therapy Provided by Dr BiolyseÂź Device in COVID-19 Disease - Conditions: COVID-19 Pneumonia; Virus Diseases; COVID-19 Interventions: Device: Signal Therapy provided by Dr.Biolyse device; Other: Liquid Support Treatment Sponsors: AVB Biotechnology Recruiting
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SAFE Workplace Intervention for People With IDD - Conditions: Developement of Infectious Airborne Disease Prevention Workplace Curriclulm Interventions: Behavioral: SAFE Employment Training Sponsors: Temple University; National Institute on Disability, Independent Living, and Rehabilitation Research Recruiting
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Effects of an EMDR Intervention on Traumatic and Obsessive Symptoms - Conditions: Adult ALL; Post-traumatic Stress Disorder; Obsessive-Compulsive Disorder; Disgust; Guilt; Shame Interventions: Behavioral: EMDR Sponsors: University of Pisa Completed
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Lithium Long COVID Dose-finding Study - Conditions: Long COVID Interventions: Dietary Supplement: Lithium Sponsors: State University of New York at Buffalo Not yet recruiting
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Pharmacokinetics and Safety of GST-HG171 Tablets in Subjects With Impaired and Normal Renal Function - Conditions: COVID-19 Pneumonia Interventions: Drug: GST-HG171 Tablets Sponsors: Fujian Akeylink Biotechnology Co., Ltd. Recruiting
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Preoperative Educational Videos on Maternal Stress Whose Children Received Congenital Heart Disease Surgery: During COVID-19 Panic - Conditions: COVID-19; Educational Videos; Maternal; Uncertainty; Anxiety; Depression; Congenital Heart Disease; Children Interventions: Other: Preoperative educational videos plus routine education; Other: Preoperative routine education Sponsors: Chung Shan Medical University Completed
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Pharmacokinetics and Safety of GST-HG171 Tablets in Subjects With Impaired and Normal Liver Function - Conditions: COVID-19 Pneumonia Interventions: Drug: GST-HG171 Tablets Sponsors: Fujian Akeylink Biotechnology Co., Ltd. Completed
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Evaluation of Concordance Between Exhaled Air Test (eBAM-CoV) and RT-PCR to Detect SARS-CoV-2 - Conditions: SARS-CoV-2 Infection; COVID-19; Coronavirus Interventions: Device: eBAM Cov Testing Sponsors: Centre Hospitalier Universitaire de NÄ«mes; University of Nimes; brainsâ laboratory sas, FRANCE Not yet recruiting
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Study to Safety, Tolerability and Immunogenicity of EG-COVII in Healthy Adult - Conditions: COVID-19 Interventions: Biological: EG-COVII Sponsors: EyeGene Inc. Recruiting
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From PubMed
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The prediction of main protease SARS-CoV-2 inhibition based on models of enzyme-inhibitor complexes - A set of linear regression equations predicting the IC50 values for SARS-CoV-2 main protease inhibitors was analyzed. For 180 competitive inhibitors, we have simulated the molecular dynamics of enzyme-inhibitor complexes with known structures or modeled using molecular docking. In the docking procedure, the selection of final poses was restricted by similarity to known structural analogs. The values of the energy contributions obtained by means of calculation of the free energy change of theâŠ
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Rituximab, but not other biologics, impairs humoral immunity in patients with rheumatoid arthritis-a study using CoVariant protein arrays - CONCLUSION: After receiving three doses of SARS-CoV-2 vaccination, RA patients who underwent rituximab treatment generated sufficient antibodies but exhibited lower neutralizing activities against wild-type and multiple variants, including current Omicron. Other biological DMARDs, e.g. TNF inhibitor, IL-6 inhibitor and CTLA4-Ig, did not show obvious inhibition.
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Inhibition of SARS-CoV-2 infection in human airway epithelium with a xeno-nucleic acid aptamer - CONCLUSIONS: Together, these results suggest that FANA-R8-9 effectively prevents infection by specific SARS-CoV-2 variants and indicate that aptamer technology could be utilized to target other clinically-relevant viruses in the respiratory mucosa.
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Broad spectrum post-entry inhibitors of coronavirus replication: Cardiotonic steroids and monensin - A small molecule screen identified several cardiotonic steroids (digitoxin and ouabain) and the ionophore monensin as potent inhibitors of HCoV-229E, HCoV-OC43, and SARS-CoV-2 replication with EC(50)s in the low nM range. Subsequent tests confirmed antiviral activity in primary cell models including human nasal epithelial cells and lung organoids. Addition of digitoxin, ouabain, or monensin strongly reduced viral gene expression as measured by both viral protein and RNA accumulationâŠ.
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Lipin-2 regulates the antiviral and anti-inflammatory responses to interferon - Interferons (IFN) are crucial antiviral and immunomodulatory cytokines that exert their function through the regulation of a myriad of genes, many of which are not yet characterized. Here, we reveal that lipin-2, a phosphatidic acid phosphatase whose mutations produce an autoinflammatory syndrome known as Majeed syndrome in humans, is regulated by IFN in a STAT-1-dependent manner. Lipin-2 inhibits viral replication both in vitro and in vivo. Moreover, lipin-2 also acts as a regulator ofâŠ
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Saying no to SARS-CoV-2: the potential of nitric oxide in the treatment of COVID-19 pneumonia - Nitric oxide (NO), a gaseous free radical produced from L-arginine catalyzed by NO synthase, functions as an important signaling molecule in the human body. Its antiviral activity was confirmed in the 1990s, and has been studied more extensively since the outbreak of the SARS pandemic in 2003. In the fight against the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, some recent studies have revealed the potential of NO in the treatment of coronavirus disease 2019âŠ
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Understanding psychology studentsâ perspective on video psychotherapy and their intention to offer it after graduation: a mixed-methods study - INTRODUCTION: Video psychotherapy (VPT) demonstrated strong clinical efficacy in the past, with patients and psychotherapists expressing satisfaction with its outcomes. Despite this, VPT only gained full recognition from the German healthcare system during the COVID-19 pandemic. As society increasingly relies on new media, it seems likely that VPT will become even more relevant. Previous studies surveyed practicing psychotherapists and patients about advantages and disadvantages of VPT. InâŠ
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Oral mucosa immunity: ultimate strategy to stop spreading of pandemic viruses - Global pandemics are most likely initiated via zoonotic transmission to humans in which respiratory viruses infect airways with relevance to mucosal systems. Out of the known pandemics, five were initiated by respiratory viruses including current ongoing coronavirus disease 2019 (COVID-19). Striking progress in vaccine development and therapeutics has helped ameliorate the mortality and morbidity by infectious agents. Yet, organism replication and virus spread through mucosal tissues cannot beâŠ
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Intracellular delivery of nuclear localization sequence peptide mitigates COVID-19 by inhibiting nuclear transport of inflammation associated transcription factors - The novel coronavirus SARS-CoV-2, responsible for COVID-19, can trigger dysregulated immune responses known as cytokine release syndrome (CRS), leading to severe organ dysfunction and respiratory distress. Our study focuses on developing an improved cell-permeable nuclear import inhibitor, iCP-NI, capable of blocking the nuclear transport of inflammation-associated transcription factors (IATFs), specifically nuclear factor kappa B (NF-ÎșB). By fusing advanced macromolecule transduction domainsâŠ
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Hyperbaric Oxygen Treatment for Long COVID: From Molecular Mechanism to Clinical Practice - Long COVID symptoms typically occur within 3 months of an initial COVID-19 infection, last for more than 2 months, and cannot be explained by other diagnoses. The most common symptoms include fatigue, dyspnea, coughing, and cognitive impairment. The mechanisms of long COVID are not fully understood, but several hypotheses have been put forth. These include coagulation and fibrosis pathway activation, inflammatory and autoimmune manifestations, persistent virus presence, and Epstein-Barr virusâŠ
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The extracellular polysaccharide inhibit porcine epidemic diarrhea virus with extract and gene editing Lacticaseibacillus - Lacticaseibacillus is one of the predominant microorganisms in gut from human and animal, and the lacticaseibacillus have effective applications against the viral diarrhea of piglets in the farm. However, the function and the concrete cell single pathways of the active ingredient from lacticaseibacillus was not clear within anti-infection in the postbiotics research. Here, we compared the biological function of extracellular polysaccharides (EPS) purified from lacticaseibacillus casei (L. casei)âŠ
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Selectivity, efficacy and safety of JAKinibs: new evidence for a still evolving story - Fundamental insight gained over the last decades led to the discovery of cytokines as pivotal drivers of inflammatory diseases such as rheumatoid arthritis, psoriasis/psoriasis arthritis, inflammatory bowel diseases, atopic dermatitis and spondylarthritis. A deeper understanding of the pro-inflammatory and anti-inflammatory effects of various cytokines has prompted new cytokine-targeting therapies, which revolutionised the treatment options in the last years for patients with inflammatoryâŠ
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Veratramine Inhibits Porcine Epidemic Diarrhea Virus Entry through Macropinocytosis by Suppressing PI3K/Akt Pathway - Porcine epidemic diarrhea (PED) is a contagious intestinal disease caused by α-coronavirus porcine epidemic diarrhea virus (PEDV). At present, no effective vaccine is available to prevent the disease. Therefore, research for novel antivirals is important. This study aimed to identify the antiviral mechanism of Veratramine (VAM), which actively inhibits PEDV replication with a 50% inhibitory concentration (IC(50)) of ⌠5 ”M. Upon VAM treatment, both PEDV-nucleocapsid (N) protein level and virusâŠ
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Promising role of Vitamin D and plant metabolites against COVID-19: Clinical trials review - Vitamin D possesses immunomodulatory qualities and is protective against respiratory infections. Additionally, it strengthens adaptive and cellular immunity and boosts the expression of genes involved in oxidation. Experts suggested taking vitamin D supplements to avoid and treat viral infection and also COVID-19, on the other hand, since the beginning of time, the use of plants as medicines have been vital to human wellbeing. The WHO estimates that 80 % of people worldwide use plants or herbsâŠ
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Plant-Derived Antioxidants for Management of COVID-19: A Comprehensive Review of Molecular Mechanisms - We aimed to review the literature to introduce some effective plant-derived antioxidants to prevent and treat COVID-19. Natural products from plants are excellent sources to be used for such discoveries. Among different plant-derived bioactive substances, components including luteolin, quercetin, glycyrrhizin, andrographolide, patchouli alcohol, baicalin, and baicalein were investigated for several viral infections as well as SARS-COV-2. The mechanisms of effects detected for these agents wereâŠ
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From Patent Search
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+ 08 November, 2023
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+Daily-Dose
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Where Does Antisemitism Come From? - Amid a dramatic increase in attacks on Jewish people and institutions, a historian traces the cultural and political forces at work. - link
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Donald Trumpâs Contentious Day on the Witness Stand - Appearing at his civil fraud trial, the former President made some potentially damaging admissions, even as he dismissed the case against him as a witch hunt. - link
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The Line Between Gaza and America - Fragments of life and death from Palestinians inside the Strip and their relatives abroad, four weeks into Israelâs war. - link
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Women Played an Unprecedented Role at the Popeâs Synod. Will It Make Any Difference? - What was clear going in was that the event could have been a capstone to Francisâs first decade as Pope. - link
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Why Josh Paul Lost Hope in Israel and Quit the U.S. State Department - For more than a decade, Josh Paul helped send American weapons overseas. After the Hamas attack, he resigned in protest of arming the Israeli response. - link
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From Vox
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3 winners and 1 loser from Election Day 2023 -
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+US President Joe Biden (right) and Kentucky Gov. Andy Beshear participate in a briefing on response efforts to the flooding at Marie Roberts Elementary School, in Lost Creek, Kentucky on August 8, 2022. | Jim Watson/AFP via Getty
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+Democrats had a good night. So did abortion rights. Glenn Youngkin, not so much.
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+The 2023 general election on Tuesday, November 7, featured only a grab-bag group of contests, but there was one clear overall theme in the results: Democrats did well.
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+Gov. Andy Beshear (D) won reelection in deep-red Kentucky. Democrats seemed set to hold onto the Virginia state Senate and take over the Virginia state House, blocking Republican Gov. Glenn Youngkinâs hopes of passing conservative policies (and perhaps his ambitions in national politics). Meanwhile, Ohio voters enshrined the protection of abortion rights in the state constitution and legalized recreational cannabis.
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+Strangely, all this happened while President Joe Biden has been getting some of his worst polling numbers yet. As in the 2022 midterms, though, national dissatisfaction with Biden did not lead to a red wave sweeping out Democrats across the country or to wins for conservative policy proposals in ballot initiatives.
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+If youâre looking for tea leaves about how 2024 will go, donât get carried away. Many of these outcomes were driven by local personalities, issues, and circumstances. And they took place in so few states that the results hardly present a clear picture of where opinion in the country is, or where it will be next year. But wins are wins, and Democrats got some significant ones on Tuesday.
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+Winner: Democrats
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+ Michael Swensen/Getty
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+Incumbent Democratic Gov. Andy Beshear speaks to the press and supporters on his last campaign stop before the election, on November 6, 2023, in Louisville, Kentucky.
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+Democrats had about as good a night on Tuesday as they could have reasonably expected.
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+Gov. Beshearâs reelection in Kentucky proves that Democrats can still win in Trump Country, especially if they happen to be the son of a popular former governor. Though Republicans won the other statewide races on the ballot in Kentucky, Beshear beat back the candidacy of Daniel Cameron (R), who had been hyped as a Republican rising star, to win a second term.
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+The other governorâs race on the ballot was in Mississippi, where Brandon Presley (D) put forth a surprisingly strong challenge to Gov. Tate Reeves (R) in this red state but ultimately conceded the race late Tuesday night.
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+Then, in Virginia, Democrats swept into control of both sides of the stateâs General Assembly, prevailing in an expensive contest against Gov. Youngkin and Virginia Republicans. Legislative races in the other states on the ballot this year â New Jersey, Louisiana, and Mississippi â appeared to show little change. A Democrat won in Pennsylvaniaâs state Supreme Court race as well, preserving the partyâs 5-2 majority in a court that heard many election-related challenges in 2020.
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+This wasnât a blue wave sweeping the nation, exactly. And the margins of key Virginia races looked more similar to 2021âs than 2020âs (when Biden won the state big). But considering how the incumbent presidentâs party usually suffers in off-year elections, and how bad Bidenâs national numbers have been, Democrats should be pretty pleased with these outcomes.
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+Winner: abortion rights
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+ AFP via Getty Images
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+Tuesday was an excellent night for supporters of abortion rights â again.
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+Their biggest victory was in the ballot referendum in Ohio, which both codified abortion access up to the point when a fetus is viable and made clear abortions would be permitted even after viability if a doctor deems it necessary to protect a patientâs health. Ohio Republicans had previously passed a law banning abortion after six weeks of pregnancy, but it had been blocked in court, with the state Supreme Court hearing arguments about it in September. Now thatâs off the table.
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+But abortion rights were a major theme in Beshearâs reelection campaign in Kentucky and Youngkinâs attempt to flip the state legislature in Virginia, as well as in the Pennsylvania Supreme Court race. In election after election and referendum after referendum in the post-Dobbs era, voters have made clear â even in many red states â that they are not enthusiastic about major abortion restrictions.
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+Yet Republicans remain beholden to right-wing voters and activists demanding such restrictions â and it keeps backfiring on them in elections.
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+Loser: Virginia Gov. Glenn Youngkin
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+ Nathan Howard/Bloomberg via Getty
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+Glenn Youngkin, governor of Virginia, speaks during a âGet Out the Voteâ rally in Richmond, Virginia, on November 5, 2023.
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+Every so often this year, a story would pop up claiming that Youngkin was consideringchallengingDonald Trump in the GOP presidential primary. However, these stories all claimed, Youngkin would wait to make up his mind until after his stateâs legislative elections, in which he was hoping to wrest control of the state Senate from Democrats. Big wins for Virginia Republicans, the theory went, would prove Youngkin was a political powerhouse who could win nationally too.
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+This never made a ton of sense, both because there are such things as ballot deadlines that would make the timing extremely difficult, and because national GOP voters have been quite loyal to Trump. More likely, Youngkin hoped that full control of Virginiaâs government could let him pass laws like a ban on abortions after 15 weeks of pregnancy, making himself a champion of the right and positioning him well for the 2028 presidential race. He made no secret of his abortion policy â hoping that he could show Republicans how to run on the issue and win.
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+But he didnât win. Republicans fell short of retaking the state Senate and they lost control of the House of Delegates, likely in part because Democrats campaigned on abortion. Those wins will prevent Youngkin from using the legislature to cozy up to the national right. And Youngkin wonât get another shot â Virginia governors canât run for reelection. So while it may be too sweeping to say his presidential ambitions have been squashed, theyâve certainly taken a serious hit.
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+Winner: Joe Biden
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+ Mark Makela/Getty Images
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+President Joe Biden speaks at Tioga Marine Terminal on October 13, 2023, in Philadelphia, Pennsylvania.
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+Biden was not on the ballot in any state this year, and it would be a mistake to think that Tuesdayâs results have any real connection to how heâll do in 2024.
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+But, as mentioned above, the president has been dogged by a series of brutal polls of late showing him trailing Donald Trump nationally and in most battleground states.
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+Democrats and political analysts have hotly debated what to make of these polls, with some arguing that they show Biden is a badly flawed candidate who might put Trump back into the White House if he persists in running again. Former Obama adviser David Axelrod tweeted this weekend that Biden needed to consider whether it would be âwiseâ for him to run again. Recent news reports spoke of some Democratsâ âworry,â âfrustrations,â and âpanic.â
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+But others have argued that these polls tell us little of value. After all, theyâre being taken a year in advance of the election at a time when Bidenâs likely opponent, Trump, has had a relatively minor (for him) role in the news cycle. Such a panic occurred before the 2022 midterms, they point out, and yet Democrats did better than expected there. Bidenâs numbers will likely recover once the choice is clearly framed for voters as Biden or Trump, the argument goes.
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+Democratsâ wins Tuesday will likely ease some of the pressure on Biden, feeding a sense that in the party, regardless of what the polls say, Democratsâ strategy and coalition turn out to be solid when people actually vote.
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+Now itâs not clear whether that inference would actually be correct. I said just a few paragraphs ago that it would be a mistake to connect these races to 2024, which will feature a very different electorate. (Itâs possible that Democrats are now the party that is structurally advantaged in non-presidential-year elections, since they now do so well among college-educated voters, who are more likely to vote consistently.) And even if Bidenâs party does well now, itâs still possible that he himself is a uniquely vulnerable candidate, either due to his age or his record in office.
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+Still, winning is better than losing. So regardless of what the future holds, Biden has good reason to be happy about Tuesdayâs results.
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+Update, November 8, 7:30 a.m.: This post has been updated to reflect the Virginia House of Delegates results.
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Hollywood is missing the big picture on the opioid crisis -
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+Emily Blunt and Chris Evans in Pain Hustlers. | Netflix
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+From Pain Hustlers to Dopesick to The Fall of the House of Usher, filmmakers are fascinated by the epidemic. But what are they saying?
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+From its first moments, Pain Hustlers sets out to distinguish itself from the pack of recent series and movies about the opioid crisis with one simple declaration: This is the one that isnât about the Sacklers.
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+The family most closely associated with the crisis â due to their company Purdue Pharmaâs misleading marketing of OxyContin and the ensuing lawsuits â are at the center of a number of high-profile Hollywood productions, many of which are based on books by journalists. Dopesick is the best of the scripted bunch, a multi-Emmy-winning limited Hulu series that splits its time between Purdue executives and Appalachian victims. There are more, including the Netflix series Painkiller, HBOâs documentary series The Crime of the Century, movies like Ben Is Back and Hillbilly Elegy, and a lot of others. Laura Poitrasâs excellent documentary All the Beauty and the Bloodshed, also on HBO, centers on photographer Nan Goldinâs activism against the Sacklers and was among 2022âs best films. Even the most recent Netflix series from horror master Mike Flanagan, The Fall of the House of Usher, is based on the Poe novel but patterned more or less explicitly on the Sacklers.
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+ Netflix
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+Mike Flanaganâs The Fall of the House of Usher is pretty clearly about the Sackler family.
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+Pain Hustlers, based on journalist Evan Hughesâs book, starts with mock-documentary footage introducing us to fictional characters from the story weâre about to watch, most of whom are composites of real people from Hughesâs reporting. Former pharmaceutical executive Pete Brenner (Chris Evans) says, with a touch of nonchalance, âWhat you need to remember is weâre not Purdue Pharma. We didnât kill America. This was 2011. Strictly speaking, weâre not even part of the opioid crisis.â
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+As images of people on stretchers appear on screen, he continues. âYou know, Lonafenâ â the movieâs fictional opioid, based on the drug Subsys â âwas never a street drug. But you know, people hear âfentanylâ and they lose all fucking perspective.â
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+Perspective is precisely what Pain Hustlers aims to provide, a goal it shares with others that weave together stories of the addicted with the addictors, with varying degrees of success. Pain Hustlers is the story of a single mother, Liza Drake (Emily Blunt), who is living a life of not-so-quiet desperation, strapped for cash and camping out with her daughter and mother in her disapproving sisterâs garage. One night, exasperated by her job as an exotic dancer, she plops down at the bar and meets Brenner, who drunkenly offers her a job. Turns out that Zanna, the (fictional, based on Insys) pharmaceutical company where he works, is also in desperate straits. So is everyone who works there. So are the doctors they approach in a barely legal attempt to entice them into prescribing Lonafen to desperate cancer patients. The whole thing reeks of panic, and even when Zannaâs coffers begin to swell, that feeling remains.
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+Pain Hustlers proclaims that the opioid crisis is at its core a story of American desperation: a desperate medical system that doesnât work for anyone, a desperate legal system that unevenly applies justice, and desperate people sucked into the orbit who need money or recognition or just to be able to get through the day without wanting to die. Tonally, though, itâs a weird movie, with overtones of Wolf of Wall Street but not quite the same level of commitment to the bit, meaning that Liza comes out as kind of a plucky but misguided heroine with a good heart.
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+ Netflix
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+Pain Hustlers has some Wolf of Wall Street vibes.
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+But in telling a story decoupled from the Sacklers, Pain Hustlers does get at something that can sometimes get lost in other media. That media has taken a variety of genre forms: Painkiller plays like a disaster story (and is directed by modern disaster auteur Peter Berg); Dopesick is a prestige drama; Fall of the House of Usher is gothic horror, with overt Succession vibes. Other movies have taken the form of addiction stories, a popular genre for a lot of Hollywoodâs history, with middling success. Pain Hustlers feels like one of this yearâs wildly popular business-guy movies, a tale of a rise and a fall that takes the suffering into account but has a different sort of arc.
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+That artists keep messing with genre in telling this story suggests a nation trying to figure out what, exactly, this story even is. What is the crisis ⊠about? Itâs about pain and our handling of it; itâs about desperation. Itâs about villains â the Sacklers, or maybe just pain itself â but not the kind who can, or will, be beaten by heroes.
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+Trying to fit the opioid crisis into a genre arc is especially hard, I think, because Hollywoodâs tendency is to point a finger at a single villain and make everyone else victims, and that doesnât quite work here. It would be heinously wrong to call Purdue, OxyContin, and especially the Sacklers âscapegoatsâ for the crisis; they are in fact largely responsible for it, thanks to incredible disregard for the lives of others, and should be treated accordingly.
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+Yet the half-million dead and their grieving families across America arenât suffering purely because some isolated rich people decided to take advantage of them. The tendency to overwhelmingly focus on the Sacklers risks suggesting that if they could be punished, the problem would be solved. But thereâs far more to it than that. This is not a war story.
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+ Netflix
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+Michael Stuhlbarg plays Richard Sackler in Dopesick.
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+Thatâs why, in the end, All the Beauty and the Bloodshed is such a monumental achievement and still by far the greatest of the current crop of opioid movies. Poitras and Goldin weave together Goldinâs activism and her addiction to opioids with some surprising strands. Thereâs Goldinâs photographs, particularly The Ballad of Sexual Dependency, in which she chronicled the lives of friends, many of whom died from drugs or HIV-related illnesses. Thereâs the story of Goldinâs family, and in particular her sister, who was repeatedly institutionalized and died at an early age due, in part, Goldin says, to her parentsâ unwillingness to acknowledge what their children needed to flourish.
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+These are not matters that obviously relate to one another, except that they all happened to Goldin. But the juxtaposition creates meaning, especially framed within Goldinâs (successful) attempts to force major art museums like the Guggenheim and the Tate to remove the Sackler name from their galleries and stop taking money from the family.
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+ HBO
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+All the Beauty and the Bloodshed is, in part, a film about trying to remove the Sackler name and money from the art world.
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+The Sacklers, and the kinds of people who profit in Pain Hustlers, can only be successful in the context of a social order that allows them to be. This requires systems that shield perpetrators from consequences, as long as theyâre rich enough. It requires a public villainization of addicts. It requires a kind of delirious American optimism bent on burying anything that isnât optimism, and a celebration of the wealthy. It of course requires a broken medical system that can be morally and ethically bankrupt. All the Beauty and the Bloodshed draws these themes through other sorts of public health crises, whether itâs HIV/AIDS or the (mis)treatment and deaths of queer people, or the immense need for better mental health care.
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+Poitrasâs documentary best captures all of this, putting the crisis into its larger social and, one might say, spiritual roots. A society that pathologizes rather than cares for the weak, that stuffs whatâs painful into a closet, canât help but foster a crisis. Add some highly addictive drugs that stand to make some people very rich and you have a flame held to a puddle of gasoline. Nobody escapes the conflagration.
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+Pain Hustlers, Painkiller, and The Fall of the House of Usher are streaming on Netflix. Dopesick is streaming on Hulu. All the Beauty and the Bloodshed is streaming on Max.
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The problem isnât inflation. Itâs prices. -
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+Prices arenât going up as fast as they were ⊠theyâre also arenât really moving downward. | OsakaWayne Studios via Getty Images
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+What goes up may not come down. Like, ever.
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+Life in 2023 means being in a constant state of sticker shock.
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+You walk out of the grocery store feeling like youâre not really sure what happened, but somehow, your normal fare ran you $50 more than you swear it should have. Did Diet Coke always cost that much? Or eggs? Maybe youâve been putting off buying that new car in the hope prices go back to where they were pre-pandemic, but youâre starting to feel like the wait is awfully long. Or, the morning after a post-work happy hour, youâre left scratching your head. You swear you had two glasses of wine, but the size of your credit card receipt makes you wonder if it wasnât four. âHow expensive everything is todayâ is a top theme of conversation. The whole situation can be infuriating.
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+The root of whatâs going on here can feel obvious: blame inflation, which picked up in mid-2021 and throughout 2022. But that isnât really the issue anymore, at least not at the current rate, because inflation is coming down. The actual problem here is prices.
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+Theyâre not going up nearly as much as they were in, say, the middle of last year, but theyâre by and large not declining en masse, either. And in most cases, they wonât get back to where they were in the Before Times.
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+âInflation in the US is falling relatively quickly compared to all of our other peer countries, and we have the strongest growth out of the recession,â said Felicia Wong, president and CEO of the Roosevelt Institute, a progressive think tank. âBut people donât just want falling inflation numbers, they actually want deflation.â
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+Deflation probably isnât in the cards (and the rub is we donât want it to be). Higher prices might just be the sort of thing weâve all got to get used to. The truth is weâre never going back to how things were in 2019 â we wonât be returning to the office at the same levels, weâll never hear âcoronaâ and only think of beer, and that night on the town is going to cost us more than it did before.
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+Paying more for stuff is the worst
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+Two things are true in the United States today: The economyisgood, and people hate it. Poll after poll shows that many Americans think the economy is in the gutter and that itâs getting worse. Thatâs even though the labor market is robust, economic growth is strong, and many people say their personal financial situations are just fine. Not to mention that the recession many economists have been predicting for over a year hasnât materialized. âWhy do people say the economy is bad even when itâs good?â is a question dogging economists, journalists, and the White House, which would very much like to convince people otherwise.
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+I donât pretend to have all the answers here, but I think one thing is quite clear: People really do not like paying more for stuff than they used to. That doesnât mean American consumers arenât still spending â they are â but theyâre mad about it.
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+In June 2022, consumer prices were up by 9.1 percent from the year before, hitting a 40-year high that summer. In September 2023, they were up by 3.7 percent over the previous 12 months. (The Federal Reserveâs inflation target is 2 percent over the long term.) In other words, prices arenât going up nearly as fast as they were before, but the cost landscape still stings.
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+âThat surge of inflation really reflected a very high growth of prices,â said Rob Rich, director of the Center for Inflation Research at the Cleveland Fed. âSince the pandemic, and since we started raising interest rates, weâve actually seen the inflation rate slow. Now ⊠it doesnât mean that prices have fallen. What it means is prices are not growing as quickly as they were before.â
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+If youâre looking at 2023 through a pre-pandemic lens, even if not intentionally, the situation feels pretty gross. âPeople might just be still annoyed that prices are high compared to where they were. Even if prices have stopped going up at the rate that they were, it still sucks if you still are anchored to what things were in 2019,â said Matthew Klein, the founder and publisher of The Overshoot, an economic research service.
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+The Fedâs interest rate hikes to combat inflation mean higher interest rates for consumers as well, meaning buying a house or a car or just paying your credit card bill is more expensive, too.
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+Some prices have declined and will likely bounce around and fall, such as for commodities and goods. Lumber prices, which soared in 2021, have settled. The same goes for eggs. Oil prices and many food prices depend on global factors, from weather to geopolitics, that are impossible to control. Airfare prices have fallen, but theyâre likely to pick back up again soon.
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+In many areas where prices have come down, theyâre not where they were pre-pandemic. As the Wall Street Journal noted in October, the prices of a number of items, from milk to gasoline to new cars, have declined from their recent peaks but are still above where they were ahead of the outset of the Covid-19 outbreak.
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+âThereâs a couple prices people might track that might decline, and some things might normalize here and there. But, in general, the level of spending in the economy is not going to decrease, and the level of spending supports a level of goods and prices,â said Mike Konczal, director of macroeconomic analysis at the Roosevelt Institute. âThat is unlikely to have a huge shift unless people start spending a lot less, at which point, there would be a recession.â
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+Prices tend to be âdownwardly rigid,â Konczal added, meaning they tend not to go down (the same goes for wages). On the consumer end, once companies increase a price for, say, shampoo or soda, they donât often revise them back down. Corporations have been quite open that people are largely hanging with them on price increases over the past couple of years, which has allowed them to hike more. There isnât much consumers can do about it. Many parts of the economy arenât competitive in a way that would force companies to price down, and itâs not clear how much corporate greed is at the heart of the issue anyway.
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+âThe things that people are very price sensitive about and that they really do think about â the price of gas, food prices, price of cars, the price of housing â is all pretty elevated. Cars and housing in particular saw a big shift up and have not declined very much,â Konczal said.
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+The situation is frustrating to consumers, but itâs important to note that prices suddenly dropping really isnât a desired outcome â deflation, meaning a broad decline in prices, is generally viewed as a negative by economists.
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+âEpisodes where prices actually fall can be really, really damaging to an economy,â Rich said. If consumers expect prices to fall further, they hold off on purchasing and pull back on spending, which can hurt businesses and impact hiring. Deflation is also a negative for contracts like mortgages and other debt instruments, he explained, because the amount of money borrowers have to pay is fixed, and if prices are falling, it becomes more of a burden. âWhile everyone may initially think, âOh, yeah, letâs let prices all fall,â that can actually be very problematic for an economy.â
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+Klein noted that deflation in the wake of World War I meant a depression. âPrices did go back down a lot, not all the way back to where they were before World War I,â he said. âBut you also had a huge increase in unemployment, and you had a huge decrease in wages.â
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+Thereâs a silver lining here that we could feel better about than many of us maybe do
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+Day-to-day life in America is more expensive than it used to be â and, itâs worth noting, around the globe, because inflation hasnât been just a US problem. Beyond pandemic-induced inflation, the problem of the cost of big-ticket items â health care, child care, higher education, housing â is far from being solved. Thereâs no denying the cost of living has gone up and that dealing with inflation is painful and a nuisance. The silver lining here is that many people have gotten a raise between then and now, and that 2019 paycheck isnât coming back either.
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+Better pay and even a better job hit differently, psychologically, than inflation.
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+One research paper Rich worked on from the Cleveland Fed found that people donât think their wages will keep up with expected inflation. âIf people change their inflation expectations, then what they report to us is they think that for every percentage point that expected inflation goes up, they would only expect a 20 percent commensurate increase in their wages,â he said.
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+When people do get a raise or find a better-paying job, they often donât attribute it to forces in the greater economy. They see it as a reflection of their own productivity and merits, their hard work paying off, not of macroeconomic conditions.
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+Basically, if I get a raise at work, I think itâs because Iâm awesome. That may be partly true, but thatâs not all thatâs going on â itâs also that the labor market is tight and wages broadly are going up. My current employer doesnât want to lose me, and my future employer would have to pay me a little more to lure me away.
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+While many people see their employment situations (good or bad) as something theyâve earned, they see inflation as something thatâs happening to them and that itâs the governmentâs fault. âThe reality is inflation takes away and it gives back. It takes away, prices go up, and it gives back, wages catch up,â said Justin Wolfers, an economist at the University of Michigan. âBut you code what it takes away as inflationâs fault but what it gives back as your own genius.â
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+Overall, people do just seem angrier at inflation than they are happy about jobs. A recent Blueprint/YouGov poll found that 64 percent of registered voters would most like to see lower prices on goods, services, and gas improved in the economy, compared to 20 percent who wanted higher wages, 9 percent who wanted lower interest rates, and just 7 percent who wanted more jobs.
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+The rate of inflation really is slowing (and, if all goes well, will continue to do so), and the disorienting nature of whatâs happened in the economy over the past few years will likely fade. Post-pandemic prices will eventually feel normal, and post-pandemic wages should make those prices more feasible â or at least not significantly less feasible than they were before. Sooner or later, sticker shock will feel a little less shocking.
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From The Hindu: Sports
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Hyderabad races for Nov. 12 and 13 cancelled -
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Son Of A Gun, Running Star, Esconido and Irish Gold show out -
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Priceless Gold, Peyo and Art Of Romance shine -
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Daily Quiz | On Angelo Mathews - On November 6, veteran Sri Lankan all-rounder Angelo Mathews became the first cricketer to be dismissed timed out in ODI cricket. Here is a quiz on various modes of dismissal in cricket.
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AIFF sacks its secretary general Shaji Prabhakaran due to breach of interest - Shaji Prabhakaranâs sacking comes 14 months after his appointment to the high-profile job even as the national federation did not mention what the breach of trust was that prompted the action.
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From The Hindu: National News
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Passport racket unearthed in Bengaluru; one arrested -
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ED raid at Kandala bank puts CPI and LDF on the defence - Enforcement Directorate officials inspect Kandala bank and houses of former office-bearers, most of them CPI leaders, simultaneously on Wednesday
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Here are the big stories from Karnataka today - Welcome to the Karnataka Today newsletter, your guide from The Hindu on the major news stories to follow today. Curated and written by Nalme Nachiyar.
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Modi slams Nitish Kumar over âderogatoryâ remarks, says will do whatever he can to ensure respect of women - He was addressing a rally in Madhya Pradeshâs Guna ahead of the November 17 assembly elections.
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Video of Karnataka minister being âhelpedâ by gunman to wear shoes goes viral - The incident happened during the ministerâs inspection of a hostel in Dharwad.
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From BBC: Europe
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Spanish fury at Pedro SĂĄnchezâ controversial amnesty plan for power - Right-wing protests against acting prime minister Pedro SĂĄnchez are growing increasingly violent.
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Holocaust survivor George Shefi retraces escape 85 years on - George Shefi was just six when Nazi mobs rampaged across Germany, killing Jewish people and attacking synagogues.
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G7 Summit: Bloc insists support for Ukraine âwill never waverâ - G7 bloc insists that the Israel-Gaza war will not weaken its resolve to back Kyiv.
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Portuguese PM AntĂłnio Costa resigns over lithium deal probe - AntĂłnio Costa says he handed in his resignation during a meeting with the Portuguese president.
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Global heat: Extreme autumn sets 2023 up to break records - Climate scientists say it is now âvirtually certainâ year will be the warmest on record.
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From Ars Technica
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The Legend of Zelda is getting a live-action film from Nintendo and Sony - Maze Runner director, Jurassic World writer, and no release date yet. - link
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Xbox moderation team turns to AI for help filtering a flood of user content - Automated language/vision models help evaluate player reports, Gamerpic uploads, and more. - link
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Chamberlain blocks smart garage door opener from working with smart homes - Chamberlain packed its app with ads while disabling third-party access. - link
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Data brokerâs âstaggeringâ sale of sensitive info exposed in unsealed FTC filing - Judge: Data brokerâs motion to sanction FTC âlong on hyperbole, short on facts.â - link
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PS5 âSlimâ teardowns suggest same chip, not much shrinking, but nifty disc drive - Itâs an improvement, but not like the notable gains of previous âslimâ models. - link
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From Jokes Subreddit
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A Union Steward goes to a brothel . . . -
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+. . . and asks the Madam âIs this a union house?â
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+âNo itâs notâ she replies.
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+âHow much do the girls earn?â the union man asks.
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+âYou pay me $500, the house gets $400 and the girl gets $100â
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+âThatâs crass exploitation!â the man yells and stomps out.
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+Eventually he finds a union brothel and asks âIf I give you $500, how much does the girl get?â
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+The Madam says âShe gets $400â.
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+âThatâs great!â the union man says. âIâd like Colleenâ
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+âIâm sure you wouldâ says the Madam âbut Theresa has seniorityâ.
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+Dave was bragging to his boss one day, âYou know, I know everyone there is to know. Just name someone, anyone, and I know them.â
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+Tired of his boasting, his boss called his bluff, âOK, Dave, how about Tom Cruise?â
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+âNo dramas boss, Tom and I are old friends, and I can prove it.â So Dave and his boss fly out to Hollywood and knock on Tom Cruiseâs door, and Tom Cruise shouts,
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+âDave! Whatâs happening? Great to see you! Come on in for a beer!â
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+Although impressed, Daveâs boss is still skeptical. After they leave Cruiseâs house, he tells Dave that he thinks him knowing Cruise was just lucky.
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+âNo, no, just name anyone else,â Dave says.
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+âPresident Obama,â his boss quickly retorts.
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+âYup,â Dave says, âOld buddies, letâs fly out to Washington,â and off they go.
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+At the White House, Obama spots Dave on the tour and motions him and his boss over, saying, âDave, what a surprise, I was just on my way to a meeting, but you and your friend come on in and letâs have a beer first and catch up.â
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+Well, the boss is very shaken by now but still not totally convinced. After they leave the White House grounds he expresses his doubts to Dave, who again implores him to name anyone else.
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+âPope Francis,â his boss replies.
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+âSure!â says Dave. âIâve known the Pope for years.â So off they fly to Rome.
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+Dave and his boss are assembled with the masses at the Vaticanâs St. Peterâs Square when Dave says, âThis will never work. I canât catch the Popeâs eye among all these people. Tell you what, I know all the guards so let me just go upstairs and Iâll come out on the balcony with the Pope.â He disappears into the crowd headed towards the Vatican.
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+Sure enough, half an hour later Dave emerges with the Pope on the balcony, but by the time Dave returns, he finds that his boss has had a heart attack and is surrounded by paramedics.
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+Making his way to his bossâ side, Dave asks him, âWhat happened?â
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+His boss looks up and says, "It was the final straw⊠you and the Pope came out on to the balcony and the man next to me said, âWho the fuck is that on the balcony with Dave?â
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An Italian guy is out picking up women in Rome. While at his favorite bar, he manages to attract one rather attractive-looking blonde. -
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+They go back to his place, and sure enough, they go at it. After a long while, he climaxes. Then he rolls over, lights up a cigarette and asks her, âSo⊠you finish?â
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+After a short pause, she replies, âNo.â
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+Surprised, but pleasantly, he puts out his cigarette, rolls back on top of her, and has his way with her again, this time lasting even longer than the first. Again he rolls over, lights a cigarette, and asks, âSo⊠you finish?â
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+And again, after a short pause, she just says âNo.â
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+Stunned, but still acting reflexively on his macho pride, he once again puts out the cigarette and entertains his companion du jour. This time, with all the strength he can muster up, he barely manages to end the task, but he does, after expending quite a lot of time and energy.
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+Barely able to roll over, he reaches for his cigarette, lights it again, and then asks tiredly, âSo⊠you finish?â
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+Three thieves are caught stealing fruits from the kingâs garden.
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+The king asks the first thief: âWhat have you stolen?â
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+âI have stolen 10 grapes, your majestyâ
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+âYour punishment is to have grapes shoved up your assâ
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+And so, the guards bent over the thief and shoved 10 grapes up his ass. The thief was crying in pain and begging them to stop
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+Next, the king asks the second thief: âWhat have you stolen?â
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+âI have stolen 10 apples, your majestyâ
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+âYour punishment is to have apples shoved up your assâ
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+And so, the guards bent over the thief and shoved 10 apples up his ass. The thief was crying in laughter and begging them to finish as fast as possible
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+The king asks the second thief: âWhy are you laughing? Arenât you in pain?â
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+âYes, Your Majesty, I am in pain, but the third thief stole watermelonsâ
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A guy dies and is standing before St. Peter at the Gates of Heaven⊠-
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+âŠSt. Peter tells him, âWeâre getting REALLY full in here, so please tell me something that you have done in your life thatâs completely unselfish and deserving of getting into Heaven.â
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+The guy says, âWell, one day I was driving along a backroad when I came across a young woman that was being threatened by a group of bikers. I got in between them and the woman and said, âIf you want you to touch her, youâll have to kill me first.
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+St. Peter says, âWow, thatâs pretty unselfish and caring of your fellow human! When did this happen?â
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+The guy responds with, âAbout five minutes ago.â
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Michael Swensen/Getty
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AFP via Getty Images
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Nathan Howard/Bloomberg via Getty
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Mark Makela/Getty Images
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Netflix
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Netflix
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Netflix
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HBO
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