Impact of SARS-CoV-2 spike efficacy on tolerability of spike-based Covid-19 Vaccinations -
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+Abstract: Knowledge about the efficacy of vaccine spikes has multiplied in recent years. The purpose of this review is to update the key findings from the scientific literature that provide explanations for many of the reported and analysed adverse effects associated with the spike-based Covid-19 vaccination. Principle results: An overwhelming body of evidence supports the main mode of action of spike-based Covid-19 vaccines, namely the downregulation of ACE2 by spikes. Direct spike effects, synergisms and RAAS-independent responses complement and multiply the already deleterious effects on tolerability. It has been repeatedly confirmed that the SARS-CoV spike protein alone is not only able to downregulate ACE2, but also to induce cell fusion, activation of TLR4, of co-receptors and gastrointestinal responses. The systemic and long-lasting detection of spikes after vaccination disproves the claimed regionally limited and short-lasting spike production and efficacy. The production volume of spikes, their dependencies and the non-neutralised spike proportion have so far remained unknown for unknown reasons. Conclusions: The exceptionally broad spectrum, frequency and severity of the reported side effects associated with spike-based Covid-19 vaccination exceed the known level of conventional vaccinations. According to my side effect analyses, the spike-based vaccines possess an unacceptable class-specific, unique side effect profile. From a pharmacological point of view, spikes are highly active substances, but not tolerable simple antigens. For this reason, they are not suitable for preventive immunisation to avoid comparatively harmless infections.
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Discovery and Characterization of a Pan-betacoronavirus S2-binding antibody -
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+Three coronaviruses have spilled over from animal reservoirs into the human population and caused deadly epidemics or pandemics. The continued emergence of coronaviruses highlights the need for pan-coronavirus interventions for effective pandemic preparedness. Here, using LIBRA-seq, we report a panel of 50 coronavirus antibodies isolated from human B cells. Of these antibodies, 54043-5 was shown to bind the S2 subunit of spike proteins from alpha-, beta-, and deltacoronaviruses. A cryo-EM structure of 54043-5 bound to the pre-fusion S2 subunit of the SARS-CoV-2 spike defined an epitope at the apex of S2 that is highly conserved among betacoronaviruses. Although non-neutralizing, 54043-5 induced Fc-dependent antiviral responses, including ADCC and ADCP. In murine SARS-CoV-2 challenge studies, protection against disease was observed after introduction of Leu234Ala, Leu235Ala, and Pro329Gly (LALA-PG) substitutions in the Fc region of 54043-5. Together, these data provide new insights into the protective mechanisms of non-neutralizing antibodies and define a broadly conserved epitope within the S2 subunit.
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Adsorption-driven deformation and landing-footprints of the RBD proteins in SARS-CoV-2 variants onto biological and inanimate surfaces -
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+Respiratory viruses, carried through airborne microdroplets, frequently adhere to surfaces, including plastics and metals. However, our understanding of the interactions between viruses and materials remains limited, particularly in scenarios involving polarizable surfaces. Here, we investigate the role of receptor-binding domain (RBD) mutations on the adsorption of SARS-CoV-2 to hydrophobic and hydrophilic surfaces employing molecular simulations. To contextualize our findings, we contrast the interactions on inanimate surfaces with those on native-biological interfaces, specifically the ACE2 receptor. Notably, we identify a twofold increase in structural deformations for the protein's receptor binding motif onto the inanimate surfaces, indicative of enhanced shock-absorbing mechanisms. Furthermore, the distribution of amino acids (landing-footprints) on the inanimate surface reveals a distinct regional asymmetry relative to the biological interface. In spite of the H-bonds formed at the hydrophilic substrate, the simulations consistently show a higher number of contacts and interfacial area with the hydrophobic surface, with the WT RBD adsorbed more strongly to than the delta or omicron RBDs. In contrast, the adsorption of delta and omicron to hydrophilic surfaces was characterized by a distinctive hopping-pattern. The novel shock-absorbing mechanisms identified in the virus adsorption on inanimate surfaces could lead current experimental efforts in the design of virucidal surfaces.
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Reference materials for SARS-CoV-2 molecular diagnostic quality control: validation of encapsulated synthetic RNAs for room temperature storage and shipping -
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+The Coronavirus pandemic unveiled the unprecedented need for diagnostic tests to rapidly detect the presence of pathogens in the population. Real-time RT-PCR and other nucleic acid amplification techniques are accurate and sensitive molecular techniques that necessitate positive controls. To meet this need, Twist Bioscience has developed and released synthetic RNA controls. However, RNA is an inherently unstable molecule needing cold storage, costly shipping, and resource-intensive logistics. Imagene provides a solution to this problem by encapsulating dehydrated RNA inside metallic capsules filled with anhydrous argon, allowing room temperature and eco-friendly storage and shipping. Here, RNA controls produced by Twist were encapsulated (RNAshells) and distributed to several laboratories that used them for COVID-19 detection tests by amplification. One RT-LAMP procedure, four different RT-PCR devices and 6 different PCR kits were used. The amplification targets were genes E, N; RdRp, Sarbeco-E and Orf1a/b. RNA retrieval was satisfactory, and the detection was reproducible. RNA stability was checked by accelerated aging. The results for a 10-year equivalent storage time at 25 {degrees}C were not significantly different from those for unaged samples. This room temperature RNA stability allows the preparation and distribution of large strategic batches which can be stored for a long time and used for standardization processes between detection sites. Moreover, it makes it also possible to use these controls for single use and in the field where large temperature differences can occur. Consequently, this type of encapsulated RNA controls, processed at room temperature, can be used as reference materials for the SARS-Cov-2 virus as well as for other pathogens detection.
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Lineage frequency time series reveal elevated levels of genetic drift in SARS-CoV-2 transmission in England -
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+Genetic drift in infectious disease transmission results from randomness of transmission and host recovery or death. The strength of genetic drift for SARS-CoV-2 transmission is expected to be high due to high levels of superspreading, and this is expected to substantially impact disease epidemiology and evolution. However, we donât yet have an understanding of how genetic drift changes over time or across locations. Furthermore, noise that results from data collection can potentially confound estimates of genetic drift. To address this challenge, we develop and validate a method to jointly infer genetic drift and measurement noise from time-series lineage frequency data. Our method is highly scalable to increasingly large genomic datasets, which overcomes a limitation in commonly used phylogenetic methods. We apply this method to over 490,000 SARS-CoV-2 genomic sequences from England collected between March 2020 and December 2021 by the COVID-19 Genomics UK (COG-UK) consortium and separately infer the strength of genetic drift for pre-B.1.177, B.1.177, Alpha, and Delta. We find that even after correcting for measurement noise, the strength of genetic drift is consistently, throughout time, higher than that expected from the observed number of COVID-19 positive individuals in England by 1 to 3 orders of magnitude, which cannot be explained by literature values of superspreading. Our estimates of genetic drift will be informative for parameterizing evolutionary models and studying potential mechanisms for increased drift.
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De novo-designed minibinders expand the synthetic biology sensing repertoire -
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+Synthetic and chimeric receptors capable of recognizing and responding to user-defined antigens have enabled "smart" therapeutics based on engineered cells. These cell engineering tools depend on antigen sensors which are most often derived from antibodies. Advances in the de novo design of proteins have enabled the design of protein binders with the potential to target epitopes with unique properties and faster production timelines compared to antibodies. Building upon our previous work combining a de novo-designed minibinder of the Spike protein of SARS-CoV-2 with the synthetic receptor synNotch (SARSNotch), we investigated whether minibinders can be readily adapted to a diversity of cell engineering tools. We show that the Spike minibinder LCB1 easily generalizes to a next-generation proteolytic receptor SNIPR that performs similarly to our previously reported SARSNotch. LCB1-SNIPR successfully enables the detection of live SARS-CoV-2, an improvement over SARSNotch which can only detect cell-expressed Spike. To test the generalizability of minibinders to diverse applications, we tested LCB1 as an antigen sensor for a chimeric antigen receptor (CAR). LCB1-CAR enabled CD8+ T cells to cytotoxically target Spike-expressing cells. Our findings suggest that minibinders represent a novel class of antigen sensors that have the potential to dramatically expand the sensing repertoire of cell engineering tools.
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mRNA-LNP COVID-19 vaccine lipids induce low level complement activation and production of proinflammatory cytokines: Mechanisms, effects of complement inhibitors, and relevance to adverse reactions -
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+Messenger RNA-containing lipid nanoparticles (mRNA-LNPs) enabled widespread COVID-19 vaccination with a small fraction of vaccine recipients displaying acute or sub-acute inflammatory symptoms. The molecular mechanism of these adverse events (AEs) remains undetermined. Here we report that the mRNA-LNP vaccine, Comirnaty, triggers low-level complement (C) activation and production of inflammatory cytokines, which may be key underlying processes of inflammatory AEs. In serum, Comirnaty and the control PEGylated liposome (Doxebo) caused different rises of C split products, C5a, sC5b-9, Bb and C4d, indicating stimulation of the classical pathway of C activation mainly by the liposomes, while a stronger stimulation of the alternative pathway was equal with the vaccine and the liposomes. Spikevax had similar C activation as Comirnaty, but viral or synthetic mRNAs had no such effect. In autologous serum-supplemented peripheral blood mononuclear cell (PBMC) cultures, Comirnaty caused increases in the levels of sC5b-9 and proinflammatory cytokines in the following order: IL-1 < IFN-{gamma} < IL-1{beta} < TNF- < IL-6 < IL-8, whereas heat-inactivation of serum prevented the rises of IL-1, IL-1{beta}, and TNF-. Clinical C inhibitors, Soliris and Berinert, suppressed vaccine-induced C activation in serum but did not affect cytokine production when applied individually. These findings suggest that the PEGylated lipid coating of mRNA-LNP nanoparticles can trigger C activation mainly via the alternative pathway, which may be causally related to the induction of some, but not all inflammatory cytokines. While innate immune stimulation is essential for the vaccine's efficacy, concurrent production of C- and PBMC-derived inflammatory mediators may contribute to some of the AEs. Pharmacological attenuation of harmful cytokine production using C inhibitors likely requires blocking the C cascade at multiple points.
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Primate-specific BTN3A2 protects against SARS-CoV-2 infection by interacting with and reducing ACE2 -
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+Coronavirus disease 2019 (COVID-19) is an immune-related disorder caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 invades cells via the entry receptor angiotensin-converting enzyme 2 (ACE2). While several attachment factors and co-receptors for SARS-CoV-2 have been identified, the complete pathogenesis of the virus remains to be determined. Unraveling the molecular mechanisms governing SARS-CoV-2 interactions with host cells is crucial for the formulation of effective prophylactic measures and the advancement of COVID-19 therapeutics. Here, we identified butyrophilin subfamily 3 member A2 (BTN3A2) as a potent inhibitor of SARS-CoV-2 infection. The mRNA level of BTN3A2 was correlated with COVID-19 severity. Upon re-analysis of a human lung single-cell RNA sequencing dataset, BTN3A2 expression was predominantly identified in epithelial cells. Moreover, this expression was elevated in pathological epithelial cells from COVID-19 patients and co-occurred with ACE2 expression in the same cellular subtypes in the lung. Additionally, BTN3A2 primarily targeted the early stage of the viral life cycle by inhibiting SARS-CoV-2 attachment through direct interactions with the receptor-binding domain (RBD) of the Spike protein and ACE2. Furthermore, BTN3A2 inhibited ACE2-mediated SARS-CoV-2 infection by reducing ACE2 in vitro and in a BTN3A2 transgenic mouse model. These results reveal a key role of BTN3A2 in the fight against COVID-19 and broaden our understanding of the pathobiology of SARS-CoV-2 infection. Identifying potential monoclonal antibodies that target BTN3A2 may facilitate disruption of SARS-CoV-2 infection, providing a therapeutic avenue for COVID-19.
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Intestinal helminth infection impairs vaccine-induced T cell responses and protection against SARS-CoV-2 -
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+Although vaccines have reduced COVID-19 disease burden, their efficacy in helminth infection endemic areas is not well characterized. We evaluated the impact of infection by Heligmosomoides polygyrus bakeri (Hpb), a murine intestinal hookworm, on the efficacy of an mRNA vaccine targeting the Wuhan-1 spike protein of SARS-CoV-2. Although immunization generated similar B cell responses in Hpb-infected and uninfected mice, polyfunctional CD4+ and CD8+ T cell responses were markedly reduced in Hpb-infected mice. Hpb-infected and mRNA vaccinated mice were protected against the ancestral SARS-CoV-2 strain WA1/2020, but control of lung infection was diminished against an Omicron variant compared to animals immunized without Hpb infection. Helminth mediated suppression of spike-specific CD8+ T cell responses occurred independently of STAT6 signaling, whereas blockade of IL-10 rescued vaccine-induced CD8+ T cell responses. In mice, intestinal helminth infection impairs vaccine induced T cell responses via an IL-10 pathway and compromises protection against antigenically shifted SARS-CoV-2 variants.
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Different vaccine platforms result in distinct antibody responses to the same antigen in haemodialysis patients -
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+Generalised immune dysfunction in chronic kidney disease, especially in patients requiring haemodialysis (HD), significantly enhances the risk of severe infections. Moreover, vaccine-induced immunity is typically reduced in HD populations, but the full mechanisms behind this remain unclear. The SARS-CoV-2 pandemic provided an opportunity to examine the magnitude and functionality of antibody responses in HD patients to a previously unencountered antigen, Spike (S)-glycoprotein, after vaccination with different vaccine platforms (viral vector (VV); mRNA (mRV)). Here, we compared total and functional anti-S antibody responses (cross-variant neutralisation and complement binding) in 187 HD patients and 43 healthy controls 21-28 days after serial immunisation. After 2 doses of the same vaccine, HD patients had anti-S antibody levels and complement binding capacity comparable to controls. However, 2 doses of mRV induced greater polyfunctional antibody responses than VV, yet previous SARS-CoV-2 infection or an mRV boost after 2 doses of VV significantly enhanced antibody functionality in HD patients. Therefore, HD patients can generate near-normal, functional antigen-specific antibody responses following serial vaccination to a novel antigen, suggesting largely intact B cell memory. Encouragingly, exploiting immunological memory by using mRNA vaccines and boosting may improve the success of vaccination strategies in this vulnerable patient population.
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Lipid nanoparticle composition for adjuvant formulation modulates disease after influenza virus infection in QIV vaccinated mice. -
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+Adjuvants can enhance vaccine effectiveness of currently licensed influenza vaccines. We tested influenza vaccination in a mouse model with two adjuvants: Sendai virus derived defective interfering (SDI) RNA, a RIG-I agonist, and an amphiphilic imidazoquinoline (IMDQ-PEG-Chol), TLR7/8 adjuvant. The negatively charged SDI RNA was formulated into lipid nanoparticles (LNPs) facilitating the direct delivery of a RIG-I agonist to the cytosol. We have previously tested SDI and IMDQ-PEG-Chol as standalone and combination adjuvants for influenza and SARS-CoV-2 vaccines. Here we tested two different ionizable lipids, K-Ac7-Dsa and S-Ac7-Dog, for LNP formulations. The adjuvanticity of IMDQ-PEG-Chol with and without empty or SDI-loaded LNPs was validated in a licensed vaccine setting (quadrivalent influenza vaccine or QIV) against H1N1 influenza virus, showing robust induction of antibody titres and T cell responses. Depending on the adjuvant combination and LNP lipid composition (K-Ac7-Dsa or S-Ac7-Dog lipids), humoral and cellular vaccine responses could be tailored towards type 1 or type 2 host responses with specific cytokine profiles that correlated with protection during viral infection. The extent of protection conferred by different vaccine/LNP/adjuvant combinations was examined against challenge with the vaccine-matching strain of H1N1 influenza A virus. Groups that received either LNP formulated with SDI, IMDQ-PEG-Chol or both showed very low levels of viral replication in their lungs at five days post virus infection. LNP ionizable lipid composition as well as loading (empty versus SDI) also skewed host responses to infection, as reflected in the cytokine and chemokine levels in lungs of vaccinated animals upon infection. These studies show the potential of LNPs as adjuvant delivery vehicles for licensed vaccines and illustrate the importance of LNP composition for subsequent host responses to infection, an important point of consideration for vaccine safety.
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Eliminating the missing cone challenge through innovative approaches -
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+Microcrystal electron diffraction (MicroED) has emerged as a powerful technique for unraveling molecular structures from microcrystals too small for X-ray diffraction. However, a significant hurdle arises with plate-like crystals that consistently orient themselves flat on the electron microscopy grid. If, as is typically the case, the normal of the plate correlates with the axes of the crystal lattice, the crystal orientations accessible for measurement are restricted because the grid cannot be arbitrarily rotated. This limits the information that can be acquired, resulting in a missing cone of information. We recently introduced a novel crystallization strategy called suspended drop crystallization and proposed that this method could effectively address the challenge of preferred crystal orientation. Here we demonstrate the success of the suspended drop crystallization approach in eliminating the missing cone in two samples that crystallize as thin plates: bovine liver catalase and the COVID-19 main protease (Mpro). This innovative solution proves indispensable for crystals exhibiting preferred orientations, unlocking new possibilities for structure determination by MicroED.
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Human mobility patterns to inform sampling sites for early pathogen detection and routes of spread: a network modeling and validation study -
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+Background: Detecting and foreseeing pathogen dispersion is crucial in preventing widespread disease transmission. Human mobility is a critical issue in human transmission of infectious agents. Through a mobility data-driven approach, we determined municipalities in Brazil that could make up an advanced sentinel network, allowing for early detection of circulating pathogens and their associated transmission routes. Methods: We compiled a comprehensive dataset on intercity mobility spanning air, road, and waterway transport, and constructed a graph-based representation of Brazil9s mobility network. The Ford-Fulkerson algorithm, coupled with centrality measures, were employed to rank cities according to their suitability as sentinel hubs. Findings: Our results disentangle the complex transportation network of Brazil, with flights alone transporting 79.9 million (CI 58.3 to 10.1 million) passengers annually during 2017-22, seasonal peaks occurring in late spring and summer, and roadways with a maximum capacity of 78.3 million passengers weekly. We ranked the 5,570 Brazilian cities to offer flexibility in prioritizing locations for early pathogen detection through clinical sample collection. Our findings are validated by epidemiological and genetic data independently collected during the SARS-CoV-2 pandemic period. The mobility-based spread model defined here was able to recapitulate the actual dissemination patterns observed during the pandemic. By providing essential clues for effective pathogen surveillance, our results have the potential to inform public health policy and improve future pandemic response efforts. Interpretation: Our results unlock the potential of designing country-wide clinical sample collection networks using data-informed approaches, an innovative practice that can improve current surveillance systems.
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+The prevalence of COVID-19 critical illness varies across ethnicities, with recent studies suggesting that genetic factors may contribute to this variation. The aim of this study was to investigate natural selection signals of genes associated with critically-ill COVID-19 in sub-Saharan Africans. Severe COVID-19 SNPs were obtained from the HGI website. Selection signals were assessed in 661 sub-Sahara Africans from 1000 Genomes Project using integrated haplotype score (iHS), cross-population extended haplotype homozygosity (xpEHH), and fixation index (Fst). Allele frequency trajectory analysis of ancient DNA samples were used to validate the existing of selection in sub-Sahara Africans. We also used Mendelian randomization to decipher the correlation between natural selection and critically-ill COVID-19. We identified that CCR3 exhibited significant natural selection signals in sub-Sahara Africans. Within the CCR3 gene, rs17217831-A showed both high iHS (Standardized iHS = 2) and high XP-EHH (Standardized XP-EHH = 2.5) in sub-Sahara Africans. Allele frequency trajectory of CCR3 rs17217831-A revealed natural selection occurring in the recent 1,500 years. Natural selection resulted in increased CCR3 expression in sub-Sahara Africans. Mendelian Randomization provided evidence that increased blood CCR3 expression and eosinophil counts lowered the risk of critically ill COVID-19. Our findings suggest that sub-Saharan Africans are less vulnerable to critically ill COVID-19 due to natural selection and identify CCR3 as a potential novel therapeutic target.
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Risk factors for experiencing Long-COVID symptoms: Insights from two nationally representative surveys -
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+Background: Long COVID (LC) is a complex and multisystemic condition marked by a diverse range of symptoms, yet its associated risk factors remain poorly defined. Methods: Leveraging data from the 2022 Behavioral Risk Factor Surveillance System (BRFSS) and National Health Interview Survey (NHIS), both representative of the United States population, this study aimed to identify demographic characteristics associated with LC. The sample was restricted to individuals aged 18 years and older who reported a positive COVID-19 test or doctor9s diagnosis. We performed a descriptive analysis comparing characteristics between participants with and without LC. Furthermore, we developed multivariate logistic regression models on demographic covariates that would have been valid at the time of the COVID-19 infection. Results: Among the 124,313 individuals in BRFSS and 10,131 in the NHIS reporting either a positive test or doctor9s diagnosis for COVID-19 (Table), 26,783 (21.5%) in BRFSS and 1,797 (17.1%) in NHIS reported LC. In the multivariate logistic regression model, we found middle age, female gender, Hispanic ethnicity, lack of a college degree, and residence in non-metropolitan areas associated with higher risk of LC. Notably, the initial severity of acute COVID-19 was strongly associated with LC risk. In contrast, significantly lower ORs were reported for Non-Hispanic Asian and Black Americans compared to Non-Hispanic White. Conclusions: In the United States, there is marked variation in the risk of LC by demographic factors and initial infection severity. Further research is needed to understand the underlying cause of these observations.
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A Study to Evealuate Safety, Reactogenicity, and Immunogenicity of TI-0010 Vaccine in Healthy Adults - Conditions: COVID-19; COVID-19 Immunisation Interventions: Biological: TI-0010; Biological: Placebo Sponsors: National Drug Clinical Trial Institute of the Second Affiliated Hospital of Bengbu Medical College; Therorna Recruiting
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Sodium Citrate in Smell Retraining for People With Post-COVID-19 Olfactory Dysfunction - Conditions: Long Haul COVID-19; Post-Acute COVID-19 Syndrome; Anosmia; Olfaction Disorders Interventions: Drug: Sodium Citrate; Drug: Normal Saline; Other: Olfactory Training Kit - âThe Olfactory Kit, by AdvancedRxâ Sponsors: University of North Carolina, Chapel Hill Recruiting
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Phase II, Double Blind, Randomized Trial of CX-4945 in Viral Community Acquired Pneumonia - Conditions: Community-acquired Pneumonia; SARS-CoV-2 -Associated Pneumonia; Influenza With Pneumonia Interventions: Drug: CX-4945 (SARS-CoV-2 domain); Drug: Placebo (SARS-CoV-2 domain); Drug: CX-4945 (Influenza virus domain); Drug: Placebo (Influenza virus domain) Sponsors: Senhwa Biosciences, Inc. Not yet recruiting
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Edge AI-deployed DIGItal Twins for PREDICTing Disease Progression and Need for Early Intervention in Infectious and Cardiovascular Diseases Beyond COVID-19 - Investigation of Biomarkers in Dermal Interstitial Fluid - Conditions: Heart Failure Interventions: Device: Use of the PELSA System for dISF extraction Sponsors: Charite University, Berlin, Germany Not yet recruiting
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Phase III Clinical Study Evaluating the Efficacy and Safety of WPV01 in Patients With Mild/Moderate COVID-19 - Conditions: Mild to Moderate COVID-19 Interventions: Drug: WPV01; Drug: Placebo Sponsors: Westlake Pharmaceuticals (Hangzhou) Co., Ltd. Recruiting
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Integrated Mindfulness-based Health Qigong Intervention for COVID-19 Survivors and Caregivers - Conditions: COVID-19 Infection Interventions: Other: Mindfulness-based Health Qigong Intervention Sponsors: The Hong Kong Polytechnic University Recruiting
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Effect of Aerobic Exercises Versus Incentive Spirometer Device on Post-covid Pulmonary Fibrosis Patients - Conditions: Lung Fibrosis Interstitial; Post-COVID-19 Syndrome Interventions: Other: Aerobic Exercises; Device: Incentive Spirometer Device; Other: Traditional Chest Physiotherapy Sponsors: McCarious Nahad Aziz Abdelshaheed Stephens; Cairo University Active, not recruiting
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SARS-CoV-2 and Influenza A/B in Point-of-Care and Non-Laboratory Settings - Conditions: SARS-CoV-2 Infection; Influenza A; Influenza B Interventions: Diagnostic Test: Aptitude Medical Systems Metrix COVID/Flu Test Sponsors: Aptitude Medical Systems; Biomedical Advanced Research and Development Authority Recruiting
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Can Doctors Reduce COVID-19 Misinformation and Increase Vaccine Uptake in Ghana? A Cluster-randomised Controlled Trial - Conditions: COVID-19 Interventions: Behavioral: Motivational Interviewing, AIMS; Behavioral: Facility engagement Sponsors: London School of Economics and Political Science; Innovations for Poverty Action; Ghana Health Services Not yet recruiting
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Long COVID Ultrasound Trial - Conditions: Long Covid Interventions: Device: Splenic Ultrasound Sponsors: SecondWave Systems Inc.; University of Minnesota; MCDC (United States Department of Defense) Recruiting
Donald Trump Coasts to Victory in the Iowa Republican Caucuses - About half of the stateâs caucus-goers went for the former President, leaving his closest challengersâNikki Haley and Ron DeSantisâin a desperate race for a distant second place. - link
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Iowa Caucuses: When Ron DeSantis Forgot His Coat - On the eve of the Iowa caucuses, the Florida governor faces blizzards, skeptical voters, and the chill of his own campaign. - link
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The Deadly Challenges of War Coverage in Gaza - Clarissa Ward, the first Western reporter to enter Gaza without an I.D.F. escort since October 7th, has faced accusations of pro-Israel bias even as she strives to highlight Arab suffering. - link
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For Iowa Voters, the Endless Caucuses Ended Too Soon - After months of G.O.P. candidates being photographed holding babies, eating ice cream, and gazing into hog pens, Donald Trump won the state with little effort. - link
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Trump Receives a Warm Embrace in Frigid Iowa - Before the caucuses, snow had kept the former President away from his enthusiastic crowds. On Saturday, he finally arrived in Des Moines. - link
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From Vox
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The Supreme Court is running away from transgender rights cases -
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+Trans rights protesters outside of the Supreme Court building in 2019. | Erik McGregor/LightRocket via Getty Images
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+For the third time in the last year, the Supreme Court turned away an opportunity to make life much worse for trans youth.
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+For the third time in the last year, the Supreme Court unexpectedly turned away a case asking it to diminish the rights of young transgender Americans in much of the country.
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+On Tuesday, the Court announced that it would not hear Metropolitan School District v. A.C., a case asking whether public school districts may require transgender students to use bathrooms that align with their sex assigned at birth, as opposed to their gender identity.
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+In A.C., the United States Court of Appeals for the Seventh Circuit ruled in favor of three trans students â so these students may use the bathroom that aligns with their identity. Because the Supreme Court decided not to hear this case, this Seventh Circuit ruling will stand, at least for now. The Seventh Circuit has jurisdiction over federal legal disputes in Illinois, Indiana, and Wisconsin.
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+The Court turned this case away, moreover, despite the fact that it fits the criteria the justices normally use to decide which cases to hear. Among other things, the question of whether trans students have a right to use the bathroom that aligns with their gender identity has dividedfederal appealscourts, and the Supreme Court frequently steps in to resolve such disagreements.
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+A.C. is also the second time in just over a month that the Court walked away from a major LGBTQ rights dispute that divided lower court judges. In December, the Court also announced that it would not hear Tingley v. Ferguson, a case challenging Washington stateâs restrictions on âconversion therapyâ â a technique that tries to turn LGBTQ patients into cisgender heterosexuals or prevent them from expressing their actual sexual orientation or gender identity.
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+As the lower court that upheld Washingtonâs restrictions noted in its opinion, âevery major medical, psychiatric, psychological, and professional mental health organization opposes the use of conversion therapy.â
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+Additionally, last April â in a case called West Virginia v. B.P.J. â the Court decided not to kick a transgender student off of her middle school girlâs cross-country team. A lower court had blocked a West Virginia state law forbidding her from competing with other girls, and the Supreme Court rejected a request to temporarily reinstate that law while the case is being litigated. (This case could potentially reach the justices again in the future.)
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+And, on top of all of this, in all three cases, the anti-LGBTQ side raised a plausible argument that existing law supports their preferred outcome. The Tingley case turns on contradictory language in a 2018 Supreme Court decision, which can be read to support either outcome in Tingley. Meanwhile, the A.C. and B.P.J. cases raise questions that the Court left open in its landmark LGBTQ rights decision in Bostock v. Clayton County (2020).
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+It sure appears, in other words, that the Court is running scared from transgender rights cases, at least for the moment.
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+Trans rights cases involving bathrooms and sports raise particularly challenging questions under current law
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+Bostock asked whether a federal law that forbids âsexâ discrimination in the workplace also forbids discrimination against LGBTQ people. Six justices concluded that it does, and the Court held that âit is impossible to discriminate against a person for being homosexual or transgender without discriminating against that individual based on sex.â If an employer fires a male employee for dating a man, for example, but permits female employees to date men, then thatâs just ordinary sex discrimination because this employer permits women to do something that men may not.
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+Similarly, Bostock held that if an employer penalizes an âemployee who was identified as female at birthâ for presenting as a man or otherwise engaging in stereotypically male behavior, but does not penalize âa person identified as male at birthâ for the same actions, that is also sex discrimination forbidden by federal law.
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+While this was a historic victory for transgender rights, it also left unresolved one of the most important questions that arises in such cases: whether the concept of âgenderâ exists separately, as a legal matter, from âstatus as either male or female [as] determined by reproductive biology.â Indeed, Bostock was decided âon the assumption thatâ the term âsexâ refers exclusively to âbiological distinctions between male and female.â
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+And yet, even if you assume that the law refers only to âbiologicalâ sex, Bostock still concluded that most forms of discrimination against trans people violate that law because they necessarily require treating men (or people assigned male at birth) differently than women (or people assigned female at birth).
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+Federal law, however, also permits sex discrimination in certain limited circumstances. The law forbidding sex discrimination in most educational facilities, for example, permits those facilities to maintain âseparate living facilities for the different sexes.â Federal regulations also permit schools to have âseparate toilet, locker room, and shower facilities on the basis of sex,â as long as the facilities âprovided for students of one sex [are] comparable to such facilities provided for students of the other sex.â
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+Similarly, federal bans on sex discrimination have long been understood to permit sex-segregated sports teams â otherwise, women-only teams could not exist.
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+If you want a deeper dive into the legal arguments for and against requiring schools to treat trans girls just like any other girl (or trans boys just like any other boy), I wrote that deeper dive here. For now, I will simply add that the Supreme Court appears determined not to resolve this question, even though lower courts are divided on how it should be answered.
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After Iowa, is it time to trust the polls again? -
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+Florida Gov. Ron DeSantis greets supporters at his caucus night event on January 15, 2024, in West Des Moines, Iowa. | Anna Moneymaker/Getty Images
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+The pollsters got Iowa spot on. That means trouble for Trumpâs rivals.
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+Donald Trumpâs resounding victory in the 2024 Iowa caucuses should have been expected by just about everyone. You could have seen it coming based on his fundraising numbers, his campaignâs presence in the state, his refusal to debate his primary opponents â or you could have looked at just about any poll.
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+Since 2016 (and 2020), however, thereâs been some apprehension about trusting polls. And even though the state-level polls were generally more accurate in the 2022 midterms than conventional wisdom holds, recent discourse about national polling of a Trump-Biden rematch has reignited those concerns.
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+Trump led the Republican field for the last year, hovering at about 50 percent in most polls in Iowa as far back as May 2023. And his final vote share, of 51 percent of the vote, is right in line with what most polls expected. And itâs not just Trump. Once all the votes were counted, it looks like the polling of Iowa was pretty accurate in the runup to Monday nightâs caucuses. The topline numbers are nearly identical to the final results. And for that to be true in Iowa, with its fickle weather, low turnout, and tedious caucus system, is a victory for pollsters, despite the widespread skepticism over public polling since 2016.
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+Primary polling across the country historically tends to be pretty inaccurate, G. Elliott Morris, a data journalist and the editorial director of data analytics at ABC Newsâs FiveThirtyEight, told me. âNot just in Iowa, but they tend to be off on average 7 points. So for any given candidate, their vote share is 7 points different from their polls, going back to 1999 or so. In reality, it might be a bit bigger.â
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+But looking at the mean average error (MAE), the average disparity between the polls and the final results, for the top three candidates â Trump, Florida Gov. Ron DeSantis, and former South Carolina Gov. Nikki Haley â that gap was just 2.3 points, by Morrisâs calculations. âYou can round that down to 2 if you want to be optimistic, but right off the bat, the top lines were a lot more accurate this year compared to the average primary, and even more accurate than the average Iowa caucus.â
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+Historically, Iowa caucus polling tends to be all over the place, reflecting the specific difficulties of polling in Iowa. The stateâs voting population is rather small (about 2 million people), turnout rates tend to be even smaller, weather can always throw a wrench into the actual caucus day, and the caucus process can give an edge to candidates benefiting from enthusiastic supporters.
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+Beyond Trump, the individual polls were pretty close to the final vote totals for DeSantis and Haley. Take the highest-profile polling operation of the caucus: the famed Iowa Poll, conducted by the highly respected pollster Ann Selzer in conjunction with the Des Moines Register, NBC News, and Mediacom. Its last two polls, conducted in December and early January, showed a pretty stable picture after an early fall surge for Nikki Haley and Ron DeSantis. Trump hovered around 50 percent in both polls â and the final read was of 48 percent of the electorate backing Trump, 20 percent backing Haley, and 16 percent backing DeSantis. The December poll showed Trump at 51 percent, Haley at 16 percent, and DeSantis at 19 percent.
+
+
+The final results? Trump at 51 percent, DeSantis at 21 percent, and Haley at 19 â a mean average error of 3 points.
+
+
+Morrisâs own poll aggregating operation was also close in line, logging Haleyâs support at 19 percent, DeSantisâs at 16 percent, and Trumpâs at 53 percent, or an MAE of 2.5.
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+âThe modest surprise was DeSantis, who beat his polling average by 5 points,â Morris said. âThat speaks to his edge on enthusiasm. He had a higher percentage of voters who really wanted to turn out and vote for him than Nikki Haley.â
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+Whether this matters for the future of the Republican primary is less clear. Candidates who do better than their polls suggest in Iowa tend to gain ground in national polls, Morris said. But DeSantis has all but abandoned his chances of performing well in New Hampshireâs primary next week, and instead is focusing his campaignâs work on doing better in South Carolina, where FiveThirtyEightâs average shows him trailing Trump and Haley.
+
+
+And the surprising accuracy of the Iowa polling does not mean that polls for the rest of the cycle will be just as accurate or that their crosstabs are as close to reality. Those national and general election polls are entirely different from polls of one partyâs voters in individual states, and they may be more susceptible to the kind of non-response bias and polling troubles showing up in national polls of young voters, for example.
+
+
+â2016 and 2020 were, of course, pretty bad for the pollsters. 2022 and 2023 were a little bit better,â Morris said. âSo when the news is good for them, and for the people like me who like to average polls, we like to share the good news and remind people that this tool that we all rely on for democracy is not as hopelessly broken as most of the commentary implies.â
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+
How Congress is planning to lift 400,000 kids out of poverty -
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+This kid got exactly the deal she wanted! | Tasos Katopodis/Getty Images for Economic Security Project
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+Weâre not bringing back the extended child tax credit. But this deal is better than nothing.
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+The child tax credit has had a roller coaster of a decade so far. In 2021, the Democratic Congress and Joe Biden enacted the largest-ever expansion of the provision, making it a monthly benefit of up to $300 (or up to $3,600 annually) paid to all parents, even those without income.
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+Then ⊠it ended. Despite widespread Democratic support for making that change permanent, the credit went back to a $2,000 annual benefit in 2022, with strings attached that limited how much poor families could get. The poorest families went from getting up to $3,600 per kid to getting $0.
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+Ever since, antipoverty activists have been strategizing about how to expand the credit again. The votes clearly werenât there in the Senate for the full proposal, and after the 2022 midterms, the votes werenât there in the House either. So hopes started to revolve around a tit-for-tat deal: Maybe an expanded credit with more benefits for poor children could pass if combined with some business tax breaks Republicans wanted. The GOP wouldnât necessarily want the expanded child credit, but theyâd stomach one if they got something in return.
+
+
+Efforts to cut a deal along these lines foundered at the end of 2022, as my colleague Rachel Cohen reported. A renewed push began at the end of last year, and for a while the outlook was similarly bleak.
+
+
+Then, on Tuesday, Congressâs two lead lawmakers on tax issues â Senate Finance chair Ron Wyden (D-OR) and House Ways and Means chair Jason Smith (R-MO) â announced they had come to a deal. The arrangement was exactly the same one that had been pitched for well over a year: a child tax credit boost in exchange for more favorable treatment of research and development expenses. Generally seen as a Republican priority, the provision has some bipartisan backing.
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+The technical details of the Wyden-Smith deal are now available. It includes some provisions besides the child and R&D provisions, like an extension of âbonus depreciationâ (which lets businesses deduct the cost of property they buy faster), some provisions on US-Taiwan tax issues, and payments for people affected by the East Palestine train derailment in Ohio. The much-covered rule requiring payments on apps like Venmo and Square Cash in excess of $600 to be reported to the IRS is amended, with the limit raised to $1,000. To pay for all this, the deal rolls back the Employee Retention Tax Credit, a business credit enacted to encourage employers to keep people in their jobs during the Covid pandemic.
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+For people who care about child poverty, though, the real action is in the child credit section.
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+How the bipartisan deal changes the child tax credit
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+
+The Wyden-Smith deal significantly expands the child tax credit, with changes designed mostly to benefit households earning around $20,000 to $40,000 a year. The details of how it does this are a little complicated.
+
+
+Currently, the credit is limited to 15 percent of a filerâs income in excess of $2,500 a year. Thatâs a rather slow phase-in, and it means that, for instance, a family with two children making $20,000 wonât get the creditâs full benefit (and a family making $10,000 would get still less). It also features a ârefundable maximumâ: While the credit is worth $2,000 per child for families earning enough money to owe income taxes, at most $1,600 per child is available to families that donât have a tax bill â that is, poor and working-class families. About 2 in 5 American households owe $0 in income taxes or get money back on net. The refundable maximum limits how much these families can benefit from the child credit.
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+The Wyden-Smith deal changes both of these aspects of the credit. The phase-in rate is still 15 percent but is now applied on a per-child basis. Right now, the way the credit works for a family with multiple kids is that the maximum refundable amount is multiplied by the number of kids and then phased in with income at 15 percent, so a family with three kids has a $4,800 total credit, which then gradually phases in. The Wyden-Smith approach treats the family as getting three separate $1,600 credits, which phase in simultaneously at 15 percent, resulting in much more money for low-income families.
+
+
+This change can be a little hard to grasp, so hereâs a chart showing how the phase-in works for families with two or three children, under both the old (dotted lines) and new (solid lines) provisions:
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+Effectively, the new credit means that everyone gets the full refundable credit once they earn $14,000 a year or more, whereas under previous law parents of three kids making as much as $34,000 a year still werenât getting the full benefit.
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+As the chart indicates, this change is targeted at families earning in the $20,000 to $40,000 a year range, not families with little or no income. The Tax Policy Center estimates that about 58 percent of the tax benefit goes to families earning $20,000 to $40,000 a year, with almost all of it (87.2 percent) going to families making $10,000 to $50,000. The average benefiting family gets $1,130 more a year from the change.
+
+
+The law also changes the refundable maximum. Under current law, the maximum is indexed for inflation. It had increased to $1,600 for 2023 and was due to keep increasing. The $2,000 maximum credit for families who owe income taxes, by contrast, was not indexed for inflation. Over time, observers expected the refundable maximum to reach $2,000 due to inflation and thus become irrelevant.
+
+
+The Wyden-Smith deal speeds up that convergence by increasing the 2023 maximum to $1,800, then setting it to $1,900 in 2024 and $2,000 in 2025. Both those numbers and the total $2,000 credit will be indexed for inflation. By 2025, the maximum is done away with, and poor taxpayers get the same $2,000 credit as everyone else from that year onward. Better yet, all taxpayers get a constantly increasing child credit thereafter. Like the change to the phase-in approach, most of the benefit from this policy goes to those making $20,000 to $40,000 a year, per the Tax Policy Center. The average affected household gets about $350 back a year.
+
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+Finally, the deal includes a âlookbackâ provision for tax years 2024 and 2025. This allows a taxpayer to use the previous yearâs income to qualify for the credit, if doing so results in a bigger benefit. This rule has been introduced in the past to account for emergencies (like Covid), and itâs generally beneficial to families enduring temporary difficulties. Under current law, a parent who earned $30,000 in 2023 but spent all of 2024 unemployed would get nothing from the child tax credit in the latter year. But with a lookback, they could get the full credit.
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+How big a deal is this?
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+
+Putting all the provisions together, the Center on Budget and Policy Priorities estimates that the deal will lift about 400,000 children out of poverty, and make another 3 million less poor, in its first year. By 2025, it will be keeping 500,000 children a year out of poverty.
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+While nothing to sneeze at, this is a far cry from the roughly 3 million children that would been lifted out of poverty in 2022 if the 2021 expansion of the credit had been extended. It is a dramatically more modest step. It also takes as a given that the credit will not be available to families with zero earnings, a key disagreement between Democratic and Republican legislators on which the latter have shown no flexibility.
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+All that being said, the CBPP authors note that the proposal is very well-targeted, and its CTC provisions âdirect all of their benefits to children in low-income families who receive less than the full credit under current law.â
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+Some Democratic legislators, notably House Ways and Means ranking member Richard Neal (D-MA) and longtime child credit champion and Appropriations ranking member Rosa DeLauro (D-CT), have signaled opposition to the deal, arguing it does not go far enough.
+
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+And, indeed, for supporters of the 2021 credit, it does not go nearly far enough. By some other standards, itâs also a bit of a disappointment. When I wrote about a possible compromise back in November, I envisioned a bill that increased the creditâs phase-in rate to 30 percent and reduced the earnings minimum from $2,500 to $0. Neither of those changes made it into the final deal. I think theyâre logical next steps for antipoverty advocates to demand.
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+But 400,000 children taken out of poverty is also nothing to sneeze at, and some business credits with bipartisan support are a pretty paltry price to pay. So too is the early expiration of a program intended for the dark days of 2020, when Covid was causing mass unemployment, and not 2024 when unemployment is under 4 percent.
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+I expect that as the measure reaches the House and Senate floors, supporters of the child credit will come around and back it. The alternative is a status quo that does even less for children.
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+
From The Hindu: Sports
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Vafadar, Stormy Ocean and Joon please -
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Endurance and Exuma please -
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Daily Quiz | On Muhammad Ali - A quiz on the iconic boxer Muhammad âThe Greatestâ Ali who would have turned 82 on January 17
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Redfern to be first ICC-appointed female neutral umpire for bilateral series - Redfernâs appointment follows the International Cricket Council (ICC) decision to appoint one neutral umpire for all ICC Womenâs Championship series as well as any T20I matches
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Praggnanandhaa stuns world champion Liren; surpasses Viswanathan Anand as No. 1 Indian chess player - Praggnanandhaa had also beaten Liren at the 2023 Tata Steel tournament
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From The Hindu: National News
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105 cases registered against rooster fight organisers in West Godavari - While 49 cases were registered in Narsapuram division, 28 cases each were registered in Bhimavaram and Tadepalligudem divisions
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Maramon Convention to begin on February 11 - The 129-year-old even will be inaugurated by Theodosius Mar Thoma, Metropolitan of the Malankara Mar Thoma Syrian Church at 2.30Â p.m. on February 12
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Congress springs surprise by picking up Mahesh Goud, Balamoor Venkat as MLC candidates - Party pitches for a youth leader and a seasoned BC leader as nominees
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Two persons including minor boy gored to death at Siravayal manjuvirattu in Sivaganga - Police said the bulls, which were outside the sporting arena, suddenly charged at spectators.
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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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From BBC: Europe
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Russia protest: Crowds clash with riot police as activist jailed - Riot police clash with protesters in small town in the Urals after Fail Alsynov was jailed.
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Frederik X: Danish monarch publishes âThe Kingâs Wordâ three days into reign - Frederik X discusses thoughts on Denmarkâs place in world and his relationship with his wife.
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Franceâs Macron shifts to right on schools and birth rate - The French president promotes school uniforms, a drug gang crackdown and raising the low birth rate.
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Polandâs journalists caught up in battle for airwaves - Public TV and radio are entangled in a political battle as Poland shifts away from the right.
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Doppelganger murder: German woman goes on trial accused of killing lookalike - Sharaban K is accused of selecting her victim because of her similar looks to fake her own death.
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From Ars Technica
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New UEFI vulnerabilities send firmware devs across an entire ecosystem scrambling - PixieFail is a huge deal for cloud and data centers. For the rest, less so. - link
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Twin Galaxies lawyer says settlement avoids âan inordinate amount of costsâ - Tashroudian: âI think the finality really is something that we wanted to achieve.â - link
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AI âBlack Boxâ placed in more hospital operating rooms to improve safety - Questions about liability linger, but fans say it offers a trove of useful surgical data. - link
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Google lays off âhundredsâ more as ad division switches to AI-powered sales - Googlers are now building AI tools so other Googlers can be laid off. - link
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Climate denialists find new ways to monetize disinformation on YouTube - Majority of climate-denial content posted now does not violate YouTubeâs policy. - link
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+
From Jokes Subreddit
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+
Three men met on a nude beach. Two of the three men were happy, but the third was sad. -
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+The three men broke into a conversation. Eventually, they started talking about their jobs, and why they were at the beach.
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+âIâm a construction worker,â said the first man. âAll day long I toil in the hot, hot sun, and do so wearing very heavy clothes. Itâs quite exhausting. But here, I can relax, and do so without any clothing at all.â
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+âIâm an accountant,â said the second man. âI just like how everyone here is dressed exactly the same.â
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+The first two men turned to the third, sad man. âWhat about you?â they asked. âWhy are you here?â
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+âMy doctor sent me here,â said the third man. âIâm a pickpocket.â
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So a guy with a nice suit walks into a diner, and an ostrich follows him. -
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+He orders eggs and bacon, the ostrich says âSame hereâ, they scarf down their meals, the waitress brings the bill, the guy pays it, with exact change, and both leave.
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+Next day this repeats, the guy orders a milkshake, the ostrich says âSameâ, etc. Again, exact change.
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+Next evening they order a steak and fries each, etc. The waitress asks: âHow come you wear such a nice suit but never tip, always having exact change down to a penny, and whatâs with the ostrich?â
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+The guy says âOh, thatâs a bit of a long story, but itâs kind of crazy. You see, Iâm a pilot. I was flying over the Sahara desert doing some aerial photography, but the engines gave out and the plane crashed. Miraculously I survived and strode through the desert for three days and three nights until I found some old ruins, where I took shelter from the scorching sun. In there, I found an old lamp, rubbed it, and a genie came out, promising me three wishes for freeing him. So for my first wish I asked to be returned from the desert back home.â
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+âThatâs right.â said the ostrich.
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+âFor the second wish, I asked to always have enough money for anything Iâd like to pay for. Now I always have just enough money in my back pocket, and not a penny more!â
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+âThat you do.â said the ostrich.
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+âThat sure sounds convenient.â said the waitress. âBut whatâs with the bird?â
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+âOh, for my third wish I asked to be followed everywhere by a talking ostrich.â
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+A study was being held to determine what people thought was the fastest thing in the world and were asking random people on yhe street what their answers were.
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+The first person replied âA blink! In the blink of an eye, you dont see yourself blink, blinking is the fastest thing in the world.â
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+The second person answered âThinking, is the fastest thing in the world. You think a thought and there it is, itâs instantaneous. Itâs thinking.â
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+The third person surveyed says âA light switch is pretty fast, you flick the switch and right away a light goes on. Turning on a light is the fastest thing in the world!â
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+The fourth man pondered the question for a long time before finally answering sincerely, âDiarrhea.â The person running the questionnaire looks up and says âDiarrhea? Really?â The man says, âYep. I was laying in bed the other night and before i could blink, think, or turn on a light, I shit myself.â
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