One for all - Human kidney Caki-1 cells are highly susceptible to infection with corona- and other respiratory viruses -
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+Despite the vast increase in research activity in the coronavirus field over the past two years, researchers are still heavily reliant on non-human cells, for example Vero E6, highly heterogeneous or not fully differentiated cells, such as Calu-3, or not naturally susceptible cell lines overexpressing receptor ACE2 and other accessory factors, such as TMPRSS2. Complex cell models, such as primary cell-derived air-liquid interface epithelial models are highly representative of human tissues but are expensive and time-consuming to develop and maintain and have limited suitability for high-throughput analysis. In vitro investigations of host-pathogen interactions of viruses is highly reliant on suitable cell and tissue culture models and results are only as good as the model they have been validated in. Here, we show the use of a highly characterized human kidney cell line, Caki-1, for infection with three human coronaviruses: Betacoronaviruses severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and Middle Eastern respiratory syndrome coronavirus (MERS-CoV) and Alphacoronavirus human coronavirus 229E (hCoV-229E). Caki-1 cells show equal or superior susceptibility to all three coronaviruses when compared to other commonly used cells lines for the cultivation of the respective virus. Furthermore, we used a panel of antibodies generated against 21 SARS-CoV-2-encoded proteins to identify their location in the infected Caki-1 cells using immunocytochemistry. Most importantly, Caki-1 cells are also susceptible to two other respiratory viruses, Influenza A virus and RSV, making them an ideal model for cross-comparison of not only a broad range of coronaviruses but respiratory viruses in general.
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Genomic diversity of SARS-CoV-2 can be accelerated by mutations in the nsp14 gene -
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+Coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), encode a proofreading exonuclease, nonstructural protein 14 (nsp14), that helps ensure replication competence at a low evolutionary rate compared with other RNA viruses. In the current pandemic, SARS-CoV-2 has accumulated diverse genomic mutations including in nsp14. Here, to clarify whether amino acid substitutions in nsp14 affect the genomic diversity and evolution of SARS-CoV-2, we searched for amino acid substitutions in nature that may interfere with nsp14 function. We found that viruses carrying a proline-to-leucine change at position 203 (P203L) have a high evolutionary rate and that a recombinant SARS-CoV-2 virus with the P203 mutation acquired more diverse genomic mutations than wild-type virus during its replication in hamsters. Our findings suggest that substitutions, such as P203L, in nsp14 may accelerate the genomic diversity of SARS-CoV-2, contributing to virus evolution during the pandemic.
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Impact of sample clarification by size exclusion on virus detection and diversity in wastewater-based epidemiology -
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+The use of wastewater-based epidemiology (WBE) for early detection of virus circulation and response during the SARS-CoV-2 pandemic increased interest in and use of virus concentration protocols that are quick, scalable, and efficient. One such protocol involves sample clarification by size fractionation using either low-speed centrifugation to produce a clarified supernatant or membrane filtration to produce an initial filtrate depleted of solids, eukaryotes and bacterial present in wastewater (WW), followed by concentration of virus particles by ultrafiltration of the above. While this approach has been successful in identifying viruses from WW, it assumes that majority of the viruses of interest should be present in the fraction obtained by ultrafiltration of the initial filtrate, with negligible loss of viral particles and viral diversity. We used WW samples collected in a population of ~700,000 in southwest USA between October 2019 and March 2021, targeting three non-enveloped viruses (enteroviruses [EV], canine picornaviruses [CanPV], and human adenovirus 41 [Ad41]), to evaluate whether size fractionation of WW prior to ultrafiltration leads to appreciable differences in the virus presence and diversity determined. We showed that virus presence or absence in WW samples in both portions (filter trapped solids [FTS] and filtrate) are not consistent with each other. We also found that in cases where virus was detected in both fractions, virus diversity (or types) captured either in FTS or filtrate were not consistent with each other. Hence, preferring one fraction of WW over the other can undermine the capacity of WBE to function as an early warning system and negatively impact the accurate representation of virus presence and diversity in a population.
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Immunogenicity of the BA.5 Bivalent mRNA Vaccine Boosters -
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+Waning immunity following mRNA vaccination and the emergence of SARS-CoV-2 variants has led to reduced mRNA vaccine efficacy against both symptomatic infection and severe disease. Bivalent mRNA boosters expressing the Omicron BA.5 and ancestral WA1/2020 Spike proteins have been developed and approved, because BA.5 is currently the dominant SARS-CoV-2 variant and substantially evades neutralizing antibodies (NAbs). Our data show that BA.5 NAb titers were comparable following monovalent and bivalent mRNA boosters.
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Fever temperatures modulate intraprotein dynamics and enhance the binding affinity between monoclonal antibodies and the Spike protein from SARS-CoV-2 -
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+Fever is a typical symptom of most infectious diseases. While prolonged fever may be clinically undesirable, mild reversible fever (< 39, 312K) can potentiate the immune responses against pathogens. Here, using molecular dynamics, we investigated the effect of febrile temperatures (38 to 40, 311K to 313K) on the immune complexes formed by the SARS-CoV-2 spike protein with two neutralizing antibodies. We found that, at mild fever temperatures (311-312K), the binding affinities of the two antibodies improve when compared to the physiological body temperature (37, 310K). Furthermore, only at 312K, antibodies exert distinct mechanical effects on the receptor binding domains of the spike protein that may hinder SARS-CoV-2 infectivity. Enhanced antibody binding affinity may thus be obtained using appropriate temperature conditions.
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Adaptive trends of sequence compositional complexity over pandemic time in the SARS-CoV-2 coronavirus -
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+During the spread of the COVID-19 pandemic, the SARS-CoV-2 coronavirus underwent mutation and recombination events that altered its genome compositional structure, thus providing an unprecedented opportunity to check an evolutionary process in real time. The mutation rate is known to be lower than expected for neutral evolution, suggesting purifying selection and convergent evolution. We begin by summarizing the compositional heterogeneity of each viral genome by computing its Sequence Compositional Complexity (SCC). To analyze the full range of SCC diversity, we select random samples of high quality coronavirus genomes covering the full span of the pandemic. We then search for evolutionary trends that could inform us on the adaptive process of the virus to its human host by computing the phylogenetic ridge regression of SCC against time (i.e., the collection date of each viral isolate). In early samples, we find no statistical support for any trend in SCC values, although the viral genome appears to evolve faster than Brownian Motion (BM) expectation. However, in samples taken after the emergence of high fitness variants, and despite the brief time span elapsed, a driven decreasing trend for SCC and an increasing one for its absolute evolutionary rate are detected, pointing to a role for purifying selection in the evolution of SCC in the coronavirus. The higher fitness of variant genomes leads to adaptive trends of SCC over pandemic time in the coronavirus.
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NC-COVID: A Time-Varying Compartmental Model for Estimating SARS-CoV-2 Infection Dynamics in North Carolina, US -
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+Efforts to track and model SARS-CoV-2 infection dynamics in the population have been complicated by certain aspects of the transmission characteristics, which include a pre-symptomatic infectious phase as well as asymptomatic infectious individuals. Another problem is that many models focus on case count, as there there has been (and is) limited data regarding infection status of members of the population, which is the most important aspect for constructing transmission models. This paper describes and explain the parameterization, calibration, and revision of the NC-COVID model, a compartmental model to estimate SARS-CoV-2 infection dynamics for the state of North Carolina, US. The model was developed early in the pandemic to provide rapid, up-to-date state-level estimates of the number of people who were currently infected, were immune from a prior infection, and remained susceptible to infection. As a post modeling exercise, we assessed the veracity of the model by comparing its output to SARS-CoV-2 viral particle concentrations detected in wastewater data and to estimates of people infected using COVID-19 deaths. The NC-COVID model was highly correlated with these independently derived estimates, suggesting that it produced accurate estimates of SARS-CoV-2 infection dynamics in North Carolina.
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Development of criteria for cognitive dysfunction in post-COVID syndrome: the IC-CoDi-COVID approach -
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+Background. We aimed to develop objective criteria for cognitive dysfunction associated with the post-COVID syndrome. Methods. Four hundred and four patients with post-COVID syndrome from two centers were evaluated with comprehensive neuropsychological batteries. The International Classification for Cognitive Disorders in Epilepsy (IC-CoDE) framework was adapted and implemented. A complementary data-driven approach based on unsupervised machine-learning clustering algorithms was also used to evaluate the optimal classification and cutoff points. Results. According to the developed criteria, 41.2% and 17.3% of the sample were classified as having at least one cognitive domain impaired using -1 and -1.5 standard deviations as cutoff points. Attention/processing speed was the most frequently impaired domain. There were no differences in base rates of cognitive impairment between the two centers. Clustering analysis revealed two clusters according to the severity of cognitive impairment, but there was no difference in cognitive profiles. Cognitive impairment was associated with younger age and lower education levels, but not hospitalization. Conclusions. We propose a harmonization of the criteria to define and classify cognitive impairment in the post-COVID syndrome. These criteria may be extrapolated to other neuropsychological batteries and settings, contributing to the diagnosis of cognitive deficits after COVID-19 and facilitating multicenter studies to guide biomarker investigation and therapies.
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Impact of vaccination on the presence and severity of symptoms of hospitalised patients with an infection by the Omicron variant (B.1.1.529) of the SARS-CoV-2 (subvariant BA.1). -
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+Objectives: The emergence of SARS-CoV-2 variants raised questions over the extent to which vaccines designed in 2020 have remained effective. We aimed to assess whether vaccine status was associated with the severity of Omicron SARS-CoV-2 infection in hospitalised patients. Methods: We conducted an international, multicentric, retrospective study in 14 centres (Bulgaria, Croatia, France, Turkey). We collected data on patients hospitalised ≥24 hours between 01/12/2021 and 03/03/2022, with PCR-confirmed infection at a time of exclusive Omicron circulation, with hospitalisation related or not to the infection. Patients who had received prophylaxis by monoclonal antibodies were excluded. Patients were considered fully vaccinated if they had received at least 2 injections of either mRNA and/or ChAdOx1-S, or 1 injection of Ad26.CoV2-S vaccines. Results: Among the 1215 patients (median [IQR] age 73.0 [57.0; 84.0]; 51.3% males), 746 (61.4%) were fully vaccinated. In multivariate analysis, being vaccinated was associated with lower 28-day mortality (RR=0.50 [0.32-0.77]), ICU admission (R=0.40 [0.26-0.62], and oxygen requirement (RR=0.34 [0.25-0.46]), independently of age and comorbidities. When co-analysing these Omicron patients with 948 Delta patients from a study we recently conducted, Omicron infection was associated with lower 28-day mortality (RR=0.53 [0.37-0.76]), ICU admission (R=0.19 [0.12-0.28], and oxygen requirements (RR=0.50 [0.38-0.67]), independently of age, comorbidities and vaccination status. Conclusions: mRNA- and adenovirus-based vaccines have remained effective on severity of Omicron SARS-CoV-2 infection. Omicron is associated with a lower risk of severe forms, independently of vaccination and patient characteristics.
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Rare predicted loss-of-function variants of type I IFN immunity genes are associated with critical COVID-19 -
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+Background We previously reported inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity in 1-5% of unvaccinated patients with life-threatening COVID-19, and autoantibodies against type I IFN in another 15-20% of cases. Methods We report here a genome-wide rare variant burden association analysis in 3,269 unvaccinated patients with life-threatening COVID-19 (1,301 previously reported and 1,968 new patients), and 1,373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. A quarter of the patients tested had antibodies against type I IFN (234 of 928) and were excluded from the analysis. Results No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI:1.5-528.7, P=1.1x10-4), in analyses restricted to biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70 [95%CI:1.3-8.2], P=2.1x10-4). Adding the recently reported TYK2 COVID-19 locus strengthened this enrichment, particularly under a recessive model (OR=19.65 [95%CI:2.1-2635.4]; P=3.4x10-3). When these 14 loci and TLR7 were considered, all individuals hemizygous (n=20) or homozygous (n=5) for pLOF or bLOF variants were patients (OR=39.19 [95%CI:5.2-5037.0], P=4.7x10-7), who also showed an enrichment in heterozygous variants (OR=2.36 [95%CI:1.0-5.9], P=0.02). Finally, the patients 13 with pLOF or bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68x10-5). Conclusions Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie lifethreatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.
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COVID-19 vaccine equity and the right to health for displaced Venezuelans in Latin America -
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+Given the magnitude of Venezuelan displacement in Latin America, there is a need to assess how migrants were, and will continue to be, addressed in COVID-19 vaccination policies. To explore migration status as a dimension of vaccine equity in Latin America and in relation to international human rights, we assessed national vaccination plans, peer-reviewed, and gray literature published between January 2020 and June 2021. Three key rights-related concerns were found to restrict the health rights of migrants in the region: 1) lack of prioritization of migrants in vaccine distribution; 2) onerous documentation requirements to be eligible for COVID-19 vaccination; and (3) how pervasive anti-migrant discrimination limited equitable health care access. While international human rights law prohibits against discrimination based on migration status, few countries analyzed realized their obligations to provide equal access to COVID-19 vaccines to non-citizens, including displaced Venezuelans. Especially for migrants and displaced people, effective and sustainable vaccination strategies for COVID-19 and future pandemics in Latin America must be guided not only by epidemiological risk but also seek to align with human rights obligations. To achieve this, States must also take special measures to facilitate vaccine access for communities facing systemic discrimination, exclusion, and marginalization.
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A Systematic Review on Medical Oxygen Ecosystem: Current State and Recent Advancements -
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+Background: Medical-grade oxygen is an essential component of modern healthcare, with a wide variety of applications ranging from supplemental use in surgery and trauma patients to the primary medication in oxygen therapy. This is the most effective treatment for any respiratory illness. Despite the importance of medicinal oxygen for public health and its demand as a life-saving drug, research on the subject is limited, with the majority of studies conducted following the outbreak of the COVID-19 pandemic. Due to the lack of empirical studies, we aimed to compile the recent research efforts with the current state of the field to guide the new researchers around the topic. Methods: We have performed a systematic review targeting the medical oxygen ecosystem, following the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P). For the study, we have limited our scope to healthcare facilities and domiciliary applications of medical oxygen and considered the articles published in the last thirty years. Results: Our systematic search resulted in forty-three scientific articles, with three more miscellaneous articles appended for painting a complete picture. Based on the selected articles, the complete oxygen ecosystem was categorized into five main fields. Conclusion: We have presented an in-depth analysis of the research works found through the systematic search, and a brief discussion on the current scenario of the subject referencing these studies. We hope to benefit researchers approaching this area through this study, and guide them around the topic.
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A SEIRD+V Model for the Effect of Vaccination and Social Distancing on SARS-CoV-2 Infection and Mortality -
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+We present a deterministic, calibrated Susceptible-Exposed-Infected-Recovered-Dead + Vaccinated (SEIRD+V) model that simulates the spread and containment of COVID-19. We use the model to compare the effectiveness of vaccination vs. social distancing on death prevention and total and peak infection reduction. We find that vaccination drastically reduces total deaths from COVID-19, as well as total and peak infections with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). We find that social distancing plays a role in reducing total COVID-19 deaths, but its impact is less pronounced when vaccine efficacy and vaccination fraction are both high. Social distancing also plays a role in reducing total and peak infections, which is attenuated in the presence of vaccination. We employed a thresholding methodology to assess the requirements of vaccine efficacy and the vaccination fraction to limit total COVID-19 deaths and peak infections to a 5% threshold. Our thresholding results quantify the impact of social distancing on total COVID-19 deaths and peak infections and are significant in their ability to inform public health policy for future outbreaks, as well as for SARS-CoV-2 itself as it continues to mutate and alter its transmissibility.
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Scoping review and meta-analysis of COVID-19 epidemiological parameters for modeling from early Asian studies -
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+Retrospective epidemiological models are powerful tools to understand its transmission dynamics and to assess the efficacy of different control measures. This study summarises key epidemiological parameters of COVID-19 for retrospective mathematical and clinical modeling. A review of scientific papers and preprints published in English between 1 January and 15 April 2020 in PubMed, MedRxiv and BioRxiv was performed to obtain epidemiological parameters of the initial stage of COVID-19 pandemic in Asia. After excluding articles with unacceptable risks of bias and those that remained as preprints as of 15 November 2021, meta-analyses were performed to derive summary effect estimates from the data collected using the statistical software R. Out of 4,893 articles identified, 88 provided data for 22 parameters for the overall population and 7 specifically for children. Meta-analyses were conducted considering time period as a categorical moderator when it was statistically significant. The results obtained are essential for building more reliable models to help clinicians and policymakers improve their knowledge on COVID-19 and apply it in future decisions.
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Integrating T-cell receptor and transcriptome for large-scale single-cell immune profiling analysis -
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+Recent advancements in single-cell immune profiling that enable the measurement of the transcriptome and T-cell receptor (TCR) sequences simultaneously have emerged as a promising approach to study immune responses at cellular resolution. Yet, combining these different types of information from multiple datasets into a joint representation is complicated by the unique characteristics of each modality and the technical effects between datasets. Here, we present mvTCR, a multimodal generative model to learn a unified representation across modalities and datasets for joint analysis of single-cell immune profiling data. We show that mvTCR allows the construction of large-scale and multimodal T-cell atlases by distilling modality-specific properties into a shared view, enabling unique and improved data analysis. Specifically, we demonstrated mvTCR’s potential by revealing and separating SARS-CoV-2-specific T-cell clusters from bystanders that would have been missed in individual unimodal data analysis. Finally, mvTCR can enable automated analysis of new datasets when combined with transfer-learning approaches. Overall, mvTCR provides a principled solution for standard analysis tasks such as multimodal integration, clustering, specificity analysis, and batch correction for single-cell immune profiling data.
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Recombinant Omicron-Delta COVID-19 Vaccine (CHO Cell) - Condition: COVID-19 Interventions: Biological: Recombinant Omicron-Delta COVID-19 Vaccine (CHO Cell); Biological: Inactivated COVID-19 vaccine (Vero Cell) Sponsors: Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd.; First Affiliated Hospital Bengbu Medical College Active, not recruiting
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COVID-19 Testing and Vaccine Literacy for Women With Criminal Legal System Involvement - Condition: COVID-19 Pandemic Intervention: Behavioral: Tri-City COVID Attitudes Study Sponsor: University of Kansas Medical Center Recruiting
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JT001 (VV116) for the Treatment of COVID-19 - Condition: Mild to Moderate COVID-19 Interventions: Drug: JT001; Drug: Placebo Sponsors: Shanghai Vinnerna Biosciences Co., Ltd.; Sponsor GmbH Not yet recruiting
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Boost Intentions and Facilitate Action to Promote COVID-19 Booster Take-up - Conditions: COVID-19; Vaccines Interventions: Behavioral: Eligibility reminder; Behavioral: Link to a narrow set of vaccine venues; Behavioral: Link to a broad set of vaccine venues; Behavioral: Doctors’ recommendation and value of vaccine Sponsor: University of California, Los Angeles Not yet recruiting
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Effects of Prompt to Bundle COVID-19 Booster and Flu Shot - Conditions: COVID-19; Vaccines Interventions: Behavioral: Reminder to boost protection against COVID-19; Behavioral: Flu Tag Along; Behavioral: COVID-19 Booster & Flu Bundle Sponsor: University of California, Los Angeles Not yet recruiting
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Information Provision and Consistency Framing to Increase COVID-19 Booster Uptake - Conditions: COVID-19; Vaccines Interventions: Behavioral: Reminder that facilitates action; Behavioral: Consistency framing; Behavioral: Information provision about the uniqueness of the bivalent booster; Behavioral: Information provision about bivalent booster eligibility; Behavioral: Information provision about the severity of COVID-19 symptoms Sponsor: University of California, Los Angeles Not yet recruiting
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Respiratory Muscles After Inspiratory Muscle Training After COVID-19 - Conditions: COVID-19; Diaphragm Injury Intervention: Device: Inspiratory Muscle Training (IMT) Sponsors: RWTH Aachen University; Philipps University Marburg Medical Center Recruiting
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COVID-19 Simulation Education on Nursing Students - Conditions: COVID-19 Pandemic; Simulation of Physical Illness Interventions: Behavioral: Simulation training; Other: Control Group Sponsor: Mehmet Akif Ersoy University Completed
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OPtimisation of Antiviral Therapy in Immunocompromised COVID-19 Patients: a Randomized Factorial Controlled Strategy Trial - Conditions: COVID-19; Immunodeficiency Interventions: Drug: Paxlovid 5 days; Drug: Paxlovid 10 days; Drug: Tixagevimab and Cilgavimab Sponsors: ANRS, Emerging Infectious Diseases; University Hospital, Geneva Not yet recruiting
A Preliminary Exploratory Study to Evaluate the Safety and Immunogenicity of Omicron Variant Bivalent Vaccine V-01-B5 - Condition: COVID-19 Pandemic Interventions: Biological: V-01/V-01-B5; Biological: V-01-351/V-01-B5; Biological: V-01 Sponsor: Livzon Pharmaceutical Group Inc. Active, not recruiting
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Exploratory Clinical Study to Evaluation of the Safety and Immunogenicity of Bivalent Vaccine V-01D-351 - Condition: COVID-19 Pandemic Interventions: Biological: V-01D-351; Biological: CoronaVac Sponsor: Livzon Pharmaceutical Group Inc. Active, not recruiting
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Safety and Immunogenicity of AdCLD-CoV19-1 OMI as a Booster: A SARS-CoV-2 (COVID-19) Preventive Vaccine - Conditions: COVID-19; Vaccines Interventions: Biological: AdCLD-CoV19-1 OMI (Part A); Biological: AdCLD-CoV19-1 OMI (Part B); Other: Placebo (Part B) Sponsor: Cellid Co., Ltd. Active, not recruiting
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Immunogenicity Evaluation of Omicron Variant-based Vaccine and a Trivalent Vaccine in Adults Against COVID-19 in Chile - Conditions: COVID-19; Vaccines Interventions: Biological: CoronaVac®; Biological: Omicron Vaccine; Biological: Trivalent Vaccine Sponsors: Pontificia Universidad Catolica de Chile; Sinovac Life Sciences Co., Ltd. Not yet recruiting
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From PubMed
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Favipiravir in early symptomatic COVID-19, a randomised placebo-controlled trial - BACKGROUND: Well tolerated antivirals administered early in the course of COVID-19 infection when the viremia is highest could prevent progression to severe disease. Favipiravir inhibits SARS-CoV-2 viral replication in vitro with evidence of clinical benefit in open label trials. Placebo controlled studies of people with early symptomatic COVID-19 with regular assessments of SARS-CoV-2 viral load can determine if it has an antiviral effect and improves clinical outcomes.
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Synthesis of bee venom loaded chitosan nanoparticles for anti-MERS-COV and multi-drug resistance bacteria - This study aims to fully exploit the natural compound; bee venom (BV) as a substance that can kill and inhibit the growth of microbes and viruses. For this target, BV was loaded onto a safe, natural, and economically inexpensive polymer, which is chitosan (Ch) in its nano-size form using the ionic gelation method and chemical crosslinking agent (sodium tripolyphosphate; TPP). The findings illustrated that chitosan nanoparticles (ChNPs) were prepared thru this method exhibited spherical shape and…
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Host protein kinases required for SARS-CoV-2 nucleocapsid phosphorylation and viral replication - Multiple coronaviruses have emerged independently in the past 20 years that cause lethal human diseases. Although vaccine development targeting these viruses has been accelerated substantially, there remain patients requiring treatment who cannot be vaccinated or who experience breakthrough infections. Understanding the common host factors necessary for the life cycles of coronaviruses may reveal conserved therapeutic targets. Here, we used the known substrate specificities of mammalian protein…
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Genome-wide Mendelian randomization and single-cell RNA sequencing analyses identify the causal effects of COVID-19 on 41 cytokines - The elevated levels of inflammatory cytokines have attracted much attention during the treatment of COVID-19 patients. The conclusions of current observational studies are often controversial in terms of the causal effects of COVID-19 on various cytokines because of the confounding factors involving underlying diseases. To resolve this problem, we conducted a Mendelian randomization analysis by integrating the GWAS data of COVID-19 and 41 cytokines. As a result, the levels of 2 cytokines were…
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A peptide array pipeline for the development of Spike-ACE2 interaction inhibitors - In humans, coronaviruses are the cause of endemic illness and have been the causative agents of more severe epidemics. Most recently, SARS-CoV-2 was the causative agent of the COVID19 pandemic. Thus, there is a high interest in developing therapeutic agents targeting various stages of the coronavirus viral life cycle to disrupt viral propagation. Besides the development of small-molecule therapeutics that target viral proteases, there is also interest molecular tools to inhibit the initial event…
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Comparison of three different COVID-19 vaccine platforms (CoronaVac, BTN162b2, and Ad5-nCoV) in individuals with and without prior COVID-19: Reactogenicity and neutralizing antibodies - Neutralizing antibodies (NAbs) can be indicators of collective immunity, vaccine efficacy, and the longevity of the humoral response. This study aimed to compare reactogenicity and NAbs generated by three different COVID-19 vaccine platforms in individuals with and without prior COVID-19. 336 individuals vaccinated (112 with CoronaVac [inactivated virus], 112 with BNT162b2 [messenger RNA], and 112 with Ad5-nCoV [non-replicating viral vector]) were included. NAbs were quantified with the cPass…
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Serial thrombin generation and exploration of alternative anticoagulants in critically ill COVID-19 patients: Observations from Maastricht Intensive Care COVID Cohort - CONCLUSION: In a sub-group of mechanically ventilated, critically ill COVID-19 patients, despite apparent adequate anti-coagulation doses evaluated by anti-Xa levels, thrombin generation potential remained high during ICU admission independent of age, sex, body mass index, APACHE II score, cardiovascular disease, and smoking status. These observations could, only partially, be explained by (anti)coagulation and thrombosis, inflammation, and multi-organ failure. Our in vitro data suggested that…
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Investigation of Embelin synthetic hybrids as potential COVID-19 and COX inhibitors: Synthesis, Spectral analysis, DFT calculations and Molecular docking studies - Embelin (2, 5-dihydroxy-3-undecyl-1,4-benzoquinone), a benzoquinone isolated from fruits of Embelia ribes has miscellaneous biological potentials including; anticancer, anti-inflammation, antibiotic, and anti-hyperglycemic activities. Also, embelin down-regulates the overexpression of inflammatory pathways like NF-kB, TACE, TNF-α, and other cytokines. Furthermore, embelin fascinated synthetic interest as a pharmacologically active compound. The present article involves the design, synthesis, DFT…
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Does Coronavirus Disease 2019 Kill More Elderly Men than Women Due to Different Hormonal Milieu - Preliminary data depicts a much greater prevalence and high case-fatality rate in advanced age males as compared to age-matched women with severe acute respiratory syndrome-coronavirus-2 infections with high morbidity, mortality, high referral, and admission to intensive care unit with severe sequelae. However, the literature search revealed both for and against studies in this context. Thus, at present, in light of the mixed studies, it cannot be established whether low testosterone levels in…
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Microwave Assisted Synthesis of 2-amino-4-chloro-pyrimidine Derivatives: Anticancer and Computational Study on Potential Inhibitory Action against COVID-19 - We report microwave synthesis of seven unique pyrimidine anchored derivatives (1-7) incorporating multifunctional amino derivatives along with their in vitro anticancer activity and their activity against COVID-19 in silico. 1-7 were characterized by different analytical and spectroscopic techniques. Cytotoxic activity of 1-7 was tested against HCT116 and MCF7 cell lines, whereby 6 exhibited highest anticancer activity on HCT116 and MCF7 with EC(50) values of 89.24±1.36 µM and 89.37±1.17 µM,…
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Integrated computational approach towards identification of HSPG and ACE2 mimicking moieties for SARS-CoV-2 inhibition - A key step to inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is to prevent the entry of the virus into the host cells. The receptor-binding domains (RBDs) of spike proteins of SARS-CoV and other human coronaviruses utilize heparan sulfate proteoglycans (HSPGs) as the primary receptors for their accumulation on the cell surface and then scan for binding to the main entry receptor angiotensin-converting enzyme 2 (ACE2). SARS-CoV and SARS-CoV-2 share structurally…
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The interplay between the airway epithelium and tissue macrophages during the SARS-CoV-2 infection - The first line of antiviral immune response in the lungs is secured by the innate immunity. Several cell types take part in this process, but airway macrophages (AMs) are among the most relevant ones. The AMs can phagocyte infected cells and activate the immune response through antigen presentation and cytokine release. However, the precise role of macrophages in the course of SARS-CoV-2 infection is still largely unknown. In this study, we aimed to evaluate the role of AMs during the SARS-CoV-2…
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Longitudinal cellular and humoral immune responses after triple BNT162b2 and fourth full-dose mRNA-1273 vaccination in haemodialysis patients - Haemodialysis patients respond poorly to vaccination and continue to be at-risk for severe COVID-19. Therefore, dialysis patients were among the first for which a fourth COVID-19 vaccination was recommended. However, targeted information on how to best maintain immune protection after SARS-CoV-2 vaccinations in at-risk groups for severe COVID-19 remains limited. We provide, to the best of our knowledge, for the first time longitudinal vaccination response data in dialysis patients and controls…
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microRNA 1307 Is a Potential Target for SARS-CoV-2 Infection: An in Vitro Model - microRNAs (miRs) are proposed as critical molecular targets in SARS-CoV-2 infection. Our recent in silico studies identified seven SARS-CoV-2 specific miR-like sequences, which are highly conserved with humans, including miR-1307-3p, with critical roles in COVID-19. In this current study, Vero cells were infected with SARS-CoV-2, and miR expression profiles were thereafter confirmed by qRT-PCR. miR-1307-3p was the most highly expressed miR in the infected cells; we, therefore, transiently…
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Recent advances in transition metal-catalyzed reactions of chloroquinoxalines: Applications in bioorganic chemistry - The importance of the quinoxaline framework is exemplified by its presence in the well-known drugs such as varenicline, brimonidine, quinacillin, etc. In the past few years, preparation of a variety of organic compounds containing the quinoxaline framework has been reported by several research groups. The chloroquinoxalines were successfully used as substrates in many of these synthetic approaches due to their easy availability along with the reactivity especially towards a diverse range of…
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From Patent Search
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What Voters Can and Can’t Learn from John Fetterman’s Stroke - Health is rarely the thing that differentiates a competent politician from an incompetent one. - link
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John Kerry Is Looking for Money (to Help Save the Climate) - Private capital may require some “concessions” before it helps developing countries transition to clean energy. - link
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Xi Jinping’s Historic Bid at the Communist Party Congress - In his efforts to escape the “cycles of order and disorder, rise and fall” that China’s emperors could not, is Xi himself slipping into them? - link
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Polls Suggest the Battle for the Senate Is Still a Cliffhanger - Recent surveys show a shift to Republicans, but in the key battleground states the outcomes remain highly uncertain. - link
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The Deer Who Lived Upstairs - Dillie, a whitetail from Ohio, defied many expectations during her unexpectedly long life. - link
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From Vox
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Everybody wants to be a LinkedInfluencer -
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+Getty Images
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+And the biggest power users are turning to ghostwriters.
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+In August, the CEO of Ohio-based marketing company HyperSocial decided that the best way to publicly deal with the layoffs he authorized at his company would be to post a photo of himself crying. “This will be the most vulnerable thing I’ll ever share,” wrote Braden Wallake in a LinkedIn post, then proceeded to detail the emotional toll that letting go of two of his employees had on … him, the CEO, who still had a job.
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+Within days, Wallake had become a meme, shorthand for the type of oversharing, virtue-signaling hustle bro who racks up thousands of followers on platforms like Twitter, Instagram, and, most especially, LinkedIn. LinkedIn has always had its own curious posting conventions; while ostensibly geared toward average white-collar professionals seeking job opportunities or a talent pool to hire from, this year the company has gone all-in on “creators.” That is, users hoping to build a personal brand by spouting entrepreneurial advice or nuggets of wisdom (LinkedInfluencers, if you will). When such tools are wielded with skill, those who succeed can nab book deals and speaking gigs.
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+When done sloppily, they may end up on, say, the very popular Twitter account called @StateOfLinkedIn, which is devoted to mocking the worst offenders. A scroll through its timeline reveals long-winded, self-congratulatory threads detailing anecdotes that probably/definitely didn’t happen, bizarrely poetic descriptions of a day in the life of an entrepreneur, and “subtle” flexes of luxury logos. Together they make up a new sort of business-speak — less jargony a la Office Space and more inspiration-porn a la Gary Vaynerchuk — that runs rampant on places like LinkedIn.
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+For aspiring LinkedInfluencers, the field has never been more competitive. LinkedIn told Vox that there are currently 13 million users with “creator mode” turned on (a setting that expands the kinds of features users can deploy in order to grow their audience). Perhaps unsurprisingly, its focus on making its users famous has made it look and feel quite a lot like Facebook, as many have pointed out. There have never been more people trying to become LinkedInfluencers, and there have never been so many resources they can pay for to do it.
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+That’s why many of them are turning to professional ghostwriters to spearhead their content strategies. “There’s this perception that ghostwriting is like having someone else do your homework for you, but it’s a collaborative process, and it frees up so much of [the client’s] time,” says Amelia Forczak, founder of the ghostwriting firm Pithy Wordsmithery. In the past few years, her business has doubled.
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+Forczak specializes in ghostwriting how-to books for her clients, but social media is often a crucial first step. A typical client might be an executive in the corporate world who’s well-respected within their company or industry but not widely known outside of it, and often, those who’ve been in business and tech for decades have no idea how to self-promote. “They’ve had PR training where they’ve learned not to talk about anything personal,” she explains, “or anything that can be used against you.”
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+Now, the standard advice for LinkedInfluencers is to do the exact opposite: avoid business jargon and sound like a person. Nothing has made this clearer than the pandemic, which forced white-collar workers to move their lives, and more importantly, their reputations, online. “It’s cliché, but it’s true that people want to work with people, people buy from people, people want to see the human side of who you are before they decide to work with you,” says Tara Horstmeyer, an Atlanta-based ghostwriter who offers packages for 12 LinkedIn posts for anywhere between $2,000 and $3,000.
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+In the same time span, ghostwriting for entrepreneurs has turned into a desirable and potentially lucrative career. Earlier this month, Business Insider published an anonymous account of a tech startup founder who makes $200,000 on his side hustle writing tweets for venture capitalists. “Funders have to build parasocial relationships with founders,” he explains. “A founder might read a tweet from a VC and say: ‘Wow, he’s a cool guy. He’s in on the joke. I want him on my board.’”
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+LinkedIn ghostwriters I spoke to say that they receive daily inquiries on how to break into the field. Horstmeyer says she’s constantly referring incoming work to other writers she knows, and is considering offering an online course to help aspiring writers build up a client base. Mishka Rana, a 22-year-old college student in India, says that she’s turned down several job offers because her ghostwriting business generates enough income to support her. “I know a lot of people who have left their corporate jobs to start their own agencies,” she says, attributing this in part to the favorable exchange rates (several of her clients are US- or UK-based). Her content packages, which start at $800 for one month and go up to $9,000 for multi-month commitments, have afforded her the ability to buy a car and travel domestically and internationally.
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+Ghostwriters, though, do more than just write; most of the writers I spoke to also describe their work as content strategy and marketing. Emily Crookston of the Pocket PhD was a philosophy professor before pivoting to ghostwriting; she says her LinkedIn services, for which she charges $2,500 per month, including blogging, strategy, and posts, had become particularly popular during the pandemic. Just like any other social media platform, there’s a little bit of gaming the algorithm, too. Many LinkedIn super users join “pods,” or groups of people who agree to like, comment on, and share each other’s posts in an attempt to increase their engagement. “LinkedIn is really savvy about pods — it knows, and it will hurt your engagement,” she warns. But the biggest mistake people make is “posting and ghosting,” failing to engage with other people’s posts and “using it like a billboard,” she explains.
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+It’s ironic, considering that one of the major benefits of having a career in tech and finance is the freedom not to have to do this kind of laborious self-promotion. That’s more typically reserved for artists and other people in creative industries, where the field is saturated and competitive and relies heavily on relationships and clout. Like probably any writer, I’ve briefly fantasized about what my life might look like if I worked in, say, finance, or some other high-paying but entirely anonymous job where I felt zero attachment to the numbers I entered into the screen every day and forgot about them on my way out the door. The idea that such a job may also require you to preen and maintain your digital profiles for maximum consumption makes the whole career seem far less enviable — but I suppose that’s why people hire ghostwriters.
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+Wallake, it seems, has not arrived at this same conclusion. A week ago, the crying CEO ended up on @StateOfLinkedIn again. “My grandma passed away today,” he began his post. The moral of his story was that perhaps hustle culture was making all of us miss out on the important things. A nice sentiment, of course — but not without ending with a plug for his own company.
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+This column was first published in The Goods newsletter. Sign up here so you don’t miss the next one, plus get newsletter exclusives.
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Cormac McCarthy’s two new novels are deliberately frustrating -
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+The Passenger and Stella Maris by Cormac McCarthy | Knopf
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+The Passenger is out now, and Stella Maris is out in December. They’re McCarthy’s first new books since 2006.
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+It’s been 16 years since Cormac McCarthy published his apocalyptic masterpiece The Road, won the Pulitzer, and then, having secured his place in literary history, apparently vanished into the mists. Now, at 89 years old, he’s returned with two new books: The Passenger, out now, and its companion novella Stella Maris, out in December. Together they form less a capstone to McCarthy’s storied career than they do a compelling if uneven coda.
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+Some of McCarthy’s most celebrated novels are page-turners, but that’s not on the agenda here. These books are built to stand apart from the reader, to withhold, to refuse to satisfy. You can almost feel McCarthy swaggering a bit as, with great skill and elegance, he chooses time and time again to frustrate any desire the reader might have for either narrative or story.
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+The Passenger and Stella Maris occur 10 years apart from one another, each told by a different sibling. The Passenger takes place in the 1980s and is narrated by Bobby Western, a taciturn tough guy who was once a race driver, is currently a salvage diver, and maintains a deep knowledge of theoretical physics. Stella Maris takes place in the 1970s and is narrated by Alicia Western, a diagnosed schizophrenic and math genius. Their surname is Western because that’s what they stand for: the western postwar world order, with all its prosperity and order and all its moral compromises. In The Passenger, Bobby is in love with Alicia, who is dead. In Stella Maris, Alicia is in love with Bobby, who is in a coma. Both maintain they never consummated their relationship, but McCarthy gives you just enough room to wonder if that’s the truth.
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+The official line from the publishers is that The Passenger and Stella Maris each stand alone, but don’t believe them. The Passenger would be maddeningly opaque without Stella Maris to elaborate on some of its most compelling plot threads, and Stella Maris would be dry as book binding without The Passenger to leaven its many philosophical arguments. Reading them separately would be a cramped and despairing experience.
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+Not that The Passenger is exactly a light read in and of itself. While it gestures at a pulpy thriller plot involving a passenger vanishing from a crashed plane and mysterious government agencies chasing Bobby Western down, McCarthy serenely declines to either solve or, indeed, provide real suspects for any of his mysteries. They seem to exist merely to create the paranoid murk through which Western (as McCarthy consistently calls Bobby) must dive as he encounters and has Socratic dialogues with a series of colorful characters.
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+With a trans woman, Western discusses the question of whether there is a God or a female soul. With a magician turned private detective, he talks about the tragedy of beauty. And with an absolute blank slate of a character — so blank it’s almost offensive, really, as if McCarthy’s staring us in the eye and daring us to call him on it — Western gets into the real issue of these two novels: the atom bomb, quantum mechanics, and the question of whether reality is knowable.
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+“It’s all right to say that the reason we cant fully grasp the quantum world is because we didnt evolve in that world,” Western explains. (McCarthy’s still doing his thing with leaving out apostrophes and quotation marks.) “But the real mystery is the one that plagued Darwin. How we can come to know difficult things that have no survival value.”
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+Western comes by his understanding of this mystery honestly. He and Alicia are the children of one of the makers of the atom bomb, born, like all the postwar west, to the knowledge that they owe their wealth and good fortune to an atrocity that might have stopped a bigger atrocity. Both of them got an education in physics from their father, and both of them are deeply aware of the implications of modern physics for reality: the way it shows us that reality does not match our understanding, that the universe is less stable and more eerie than we thought.
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+Western responds to this knowledge by briefly pursuing a career as a physicist before failing his subject: He decides he isn’t quite good enough to do really valuable physics. Alicia, meanwhile, decides to go into pure math before being failed by her subject: since math has no provable reality independent of the human mind, she decides it is not equal to solving the problem of what reality is. Alicia’s project is to try to hold the truth of what contemporary physics and pure mathematics tell her completely in her mind, and the implication is that either the effort has shattered her mind or that only a shattered mind could attempt to do so in the first place.
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+Alicia appears periodically throughout The Passenger. Her death by suicide opens the novel, and in flashbacks we see her conversing with her hallucinations: a raggedy carnival barker of a man she calls the Thalidomide Kid, with flippers instead of hands, and all his hangers-on. (These hallucinations, it must be said, are appallingly tedious.) She doesn’t take center stage, though, until Stella Maris, which is made up entirely of Alicia’s conversations with her psychiatrist in the last year of her life.
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+There is something pleasingly, shockingly bare about Stella Maris after the lushness of The Passenger’s rich, haunted atmosphere. The Passenger takes place in New Orleans in the summer, but Stella Maris is all cold, cold, midwest in the winter. Gone, too, are The Passenger’s showy and circuitous plotlines about the JFK assassination being a cover for the mob taking out RFK and secret caches of gold buried in a dead grandmother’s basement. In Stella Maris, McCarthy has stripped away all the flesh down to the bare bone, the part that he’s actually interested in talking about.
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+It turns out the bone is more theoretical physics and pure math, the cosmic questions they inspire, and the creative work entailed in thinking them through.
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+“I knew what my brother did not,” Alicia explains to her shrink. “That there was an ill-contained horror beneath the surface of the world and there always had been. That at the core of reality lies a deep and eternal demonium.” The inexplicable void at the core of quantum physics is the demonium.
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+Writing women has never been McCarthy’s strong suit, and Alicia doesn’t exactly hold up as a rich and three-dimensional character. Her voice is appealingly spiky, but she’s more philosophical construct than whole human being. Yet halfway through Stella Maris, it becomes clear that she’s also an avatar for McCarthy himself, and for anyone who finds their unconscious mind doing their creative work for them.
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+“The core question is not how you do the math but how does the unconscious do it,” she says. “How is it that it’s demonstrably better at it than you are? You work on a problem and then you put it away for a while. But it doesnt go away. It reappears at lunch. Or while you’re taking a shower. It says: Take a look at this. What do you think? Then you wonder why the shower is cold. Or the soup. Is this doing math? I’m afraid it is. How is it doing it?” (Punctuation original.) You can slot in writing for math in that paragraph without changing the meaning a jot.
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+Speaking of writing, it’s just as great here as you would expect. Sometimes I think the reason literary criticism got obsessed with evaluating prose as “sentences” over the past few decades is simply that McCarthy’s are so good. They rattle out at you like little bullets, mean and punchy and precise.
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+Here he is on what it means that our reality is dependent on our observations: “In the beginning always was nothing. The novae exploding silently. In total darkness. The stars, the passing comets. Everything at best of alleged being. Black fires. Like the fires of hell. Silence. Nothingness. Night. Black Suns herding the planets through a universe where the concept of space was meaningless for want of any end to it. For want of any concept to stand it against.” The rat-a-tat-tat of those terse and isolated clauses; the easy richness of the phrase “alleged being” against the showy imagery of hellish black fire and silent black planets: When you’re as good as McCarthy, you make it look easy.
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+Still, McCarthy is stingy with the pleasures of his prose. In this pair of novels, his most ravishing sentences tend to evoke horrors, either cosmic or personal. He is stingy, too, with the possibility of sweetness or joy. The only true tenderness in these novels comes from Alicia and Bobby’s incestuous love, which McCarthy treats as both redemptive and destructive.
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+Neither The Passenger nor Stella Maris is designed to be anyone’s gateway to Cormac McCarthy. They lack the visceral emotional intensity McCarthy can conjure at his best; they are pointedly spare and withholding. But taken together, they offer an intellectual experience that’s not quite like anything else out there, laced with the eerie beauty that only Cormac McCarthy can offer.
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Biden has ambitious infrastructure goals. Made-in-America rules could slow them. -
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+Matt Dunne/Vox
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+New rules could hold back $1 trillion in infrastructure spending that extends to housing, broadband, and electric vehicle charging projects.
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+Nearly two years ago, the Tri-Valley Transit agency started to construct a new bus facility in Bradford, Vermont. The agency’s fleet, which residents across eight towns used to get to work, school, and medical appointments each day, was outgrowing the building it had been renting for 16 years. New buses were bigger than the vehicles they used to have, and they didn’t have the equipment to efficiently wash and maintain them.
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+Soon after breaking ground, officials ran into complications. The agency had planned to install a solar-powered heat pump system, which would have been cleaner for the environment and less expensive to maintain, said Jim Moulton, the agency’s executive director. But officials couldn’t find an American manufacturer to build a large enough system. Although two Italian companies could have fulfilled the order, the project was receiving federal funds, meaning that it was subject to “Buy America” rules that required manufactured products to be made domestically.
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+Moulton said the agency applied for a waiver from the federal government but was denied, so officials redesigned the $3.4 million project and purchased a wood pellet boiler system manufactured in the United States. Although the agency moved into the facility in August 2021, the debacle delayed the project for nearly three months and added on about $100,000 in extra costs.
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+“It was a little bit frustrating,” Moulton said. “We were anticipating that were would be a better balance of these rules.”
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+It was a logistical headache that could soon become more common — and extend to areas far beyond transit projects.
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+The $1 trillion infrastructure law passed last year expanded Buy America rules, which require state and local agencies to buy certain materials made in the United States for federally funded infrastructure projects. Rules that iron, steel, and manufactured products be made in America have been in place for decades, but they’ve traditionally applied to transportation and water-related projects, such as highways, rail, and public transit.
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+The Infrastructure Investment and Jobs Act’s new rules broadened the scope of goods that have to be produced in the United States by creating a new category for “construction materials.” It also expanded the types of infrastructure projects subject to the requirements to permanently include housing, broadband, and new programs for electric vehicle charging projects for the first time.
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+Ahead of the midterm elections, President Biden has hailed the bill as a once-in-a-generation investment in the nation’s infrastructure, promising that it would rebuild miles of crumbling roads and bridges, expand access to clean drinking water, and deploy broadband to communities that have long lacked high-speed internet.
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+“Instead of infrastructure week, which was a punchline for four years under my predecessor, it’s infrastructure decade,” Biden said in Pennsylvania last week.
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+ Mandel Ngan/AFP via Getty Images
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+President Joe Biden greets carpenter Gregory Allen Stahl before speaking about rebuilding the nation’s infrastructure on October 20 in Pittsburgh, Pennsylvania.
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+Biden has also highlighted the package’s Buy America provisions, which the administration has said will help create American manufacturing jobs and improve the resiliency of the nation’s supply chain. During his first State of the Union address in March, Biden vowed that the country would “buy American to make sure everything from the deck of an aircraft carrier to the steel on highway guardrails are made in America.”
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+But many state and local officials across the country say the new rules could delay much-needed infrastructure projects and significantly drive up costs amid the fastest inflation in 40 years. Some say they’re already struggling to deal with supply-chain disruptions that have emerged during the pandemic and worry that material shortages could worsen if they’re limited to domestic manufacturers. Higher costs could also lead to fewer projects and soften the impact of the package, officials say.
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+The effect could be felt beyond stalled roadway projects. Housing advocates worry the packages’ broader Buy America requirements mean it could take longer to build public housing. Broadband internet expansions could be delayed for the millions of Americans without reliable internet access.
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+Many state agencies, local officials, and industry groups have urged federal officials to delay implementation or provide more clarity surrounding the new rules. Individual federal agencies are tasked with enforcing the new rules, and several have granted waivers temporarily delaying them.
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+Mitch Landrieu, a senior advisor to Biden and the infrastructure coordinator, said it wouldn’t be reasonable to expect state and local officials to completely “turn on a dime” and that the administration would try to be flexible by evaluating waivers on a case-by-case basis.
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+“When you pressure test the system, you’re going to find holes in it,” Landrieu said. “We’re building a system that can actually implement these new rules and regulations, and of course, that takes time.”
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+Still, Landrieu said waivers would be limited and the administration would apply “downward pressure pretty aggressively on states and cities” to implement the requirements, which he said would help bolster the American manufacturing sector and the nation’s long-term economic prosperity.
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+“The imperative is to lean in, not to lean back,” Landrieu said.
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+Transportation projects will be subject to stricter rules
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+Before the infrastructure law passed last year, Buy America rules were mostly a collection of laws enforced by various agencies within the Transportation Department (although they sound similar, they’re different from “Buy American” rules, which deal with materials and products the federal government purchases directly).
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+Because there was no blanket rule across the Transportation Department, each agency formed its own interpretations of the laws and issued different waivers that were tailored to its own programs. The Federal Highway Administration (FHWA), for example, has had a waiver for manufactured products since 1983, meaning that roadway and bridge projects have only been required to use domestically made iron and steel products if they’re incorporated into the project permanently.
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+Under the new rules, three categories of materials have to be produced in the United States: iron and steel, manufactured products, and construction materials.
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+ Spencer Platt/Getty Images
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+Pedestrians walk by a construction site in Pawtucket, Rhode Island, in April 2021.
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+To be considered “produced in the United States,” manufactured goods now have to contain at least 55 percent domestic content and be manufactured in America. Construction materials, which have to be manufactured entirely in the United States, include plastic and polymer-based products, glass, lumber, drywall, and non-ferrous metals with the exception of cement and aggregate products like sand and gravel.
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+But the new requirements for transportation projects largely haven’t been in effect yet. In May, the Transportation Department issued a temporary waiver for construction materials to give state and local agencies time to adjust to the new category. The waiver, which is set to expire on November 10, should not be expected to be extended, a DOT spokesperson said in a statement. The FHWA also plans to initiate a review of its waiver for manufactured products by November 15.
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+Although many state and local agencies say they support the policy goals of Buy America, some have urged the Transportation Department to extend the construction materials waiver in recent months.
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+The American Association of State Highway and Transportation Officials, which represents transportation departments in the 50 states, the District of Columbia, and Puerto Rico, said in a public comment that domestic manufacturing was currently “unable to ensure the availability and timely delivery of many materials needed for transportation projects” and urged federal officials to extend the waiver period by 12 to 18 months.
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+Jim McDonnell, the association’s director of engineering, said state officials were fully supportive of boosting American jobs, but worried about how the new rules would be implemented and how they could increase costs if demand exceeds available supply. He said that officials, for instance, import many glass beads and metals like zinc from other countries since supply is limited in the United States.
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+“Six months isn’t enough time for a new industry to start churning out products or even for existing industries to ramp up production enough for a whole country,” McDonnell said. “We’re still concerned, even though we’ve got this six-month waiver, that state DOTs are going to have trouble figuring out where to get products.”
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+Jimmy Christianson, the vice president of government relations at the Associated General Contractors of America, said the organization wanted clearer final guidance from the federal government since there is confusion about what constitutes a construction material versus a manufactured product.
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+“Fiber optic glass is a construction material, but fiber optic glass is usually covered in some sort of rubber or plastic to prevent it from getting ruptured,” Christianson said. “If it’s covered in plastic, is it a construction material now or is it a manufactured product? We don’t know the answer.”
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+The Office of Management and Budget (OMB) released initial guidelines in April, which said that any item that consists of two or more construction materials listed and combined through a manufacturing process would be considered a manufactured product. The OMB is expected to issue more guidance in the coming months.
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+Christianson also urged the federal government to be flexible with future waiver requests. Although state and local agencies can submit individual waiver requests that are reviewed on a case-by-case basis, some say they’ve been discouraged by the process and told that waivers would unlikely be granted. Requests are eligible if certain materials aren’t produced in sufficient quantities in the United States, if the overall project cost would increase by more than 25 percent, or if the rules aren’t in the “public interest.”
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+A recent Associated General Contractors of America survey found that 93 percent of respondents were experiencing material shortages and most construction firms believed that meeting the new Buy America requirements would be difficult. Steel, non-ferrous metal, plastic products, electrical equipment, and HVAC systems would likely be the most difficult to source domestically, the respondents said. Lead times for some electrical equipment were reported to be nearly two years, and deliveries of ductile iron pipe and roofing materials were also reported to have waiting periods of more than a year.
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+ Sarah Rice for The Washington Post via Getty Images
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+Construction workers work on the expansion of IMCO Carbide Tool in Perrysburg, Ohio, on October 7.
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+In some cases, the rules have discouraged officials from pursuing federal grants to buy equipment that could help reduce emissions. Ryan McFarland, the senior manager of government affairs at the Northwest Seaport Alliance, a marine cargo operating partnership of the Port of Seattle and Port of Tacoma, said the authority wants to purchase zero and near-zero emissions equipment — such as electric terminal yard tractors, hydrogen top handlers, and hybrid rubber-tired gantry cranes — to increase the efficiency of handling cargo.
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+But in most cases, the ports can’t find an American manufacturer that can certify that their equipment is Buy America compliant. Even though some manufacturers have production facilities in the United States, parts that are used to make the equipment are often sourced overseas or companies don’t track the sources of steel that are used in parts, McFarland said.
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+Because the equipment is more expensive than traditional diesel versions, it’s difficult for the ports to purchase without federal funds, meaning that it would be challenging for them to phase out emissions from port operations by 2050, McFarland said.
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+“We simply can’t afford to meet those goals by ourselves,” he said.
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+Domestic content requirements have gained support from both Democrats and Republicans in recent years, said Jeff Davis, a senior fellow at the Eno Center for Transportation who has researched the topic extensively. But there is limited research on how the Buy America rules have directly impacted domestic job creation.
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+A 2014 Duke University study found that projects subject to Buy America preferences “mitigate the safety risks of using potentially inferior-quality foreign inputs while delivering more economic benefits to the US economy than outsourced projects.” In a case study of two large-scale bridge projects, the researchers — Lukas Brun, G. Jason Jolley, Andrew Hull, and Stacey Frederick — found that the project not subject to Buy America rules outsourced 27 percent of the funds spent.
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+Scott Paul, the president of the Alliance for American Manufacturing, which sponsored the Duke study, said he was confident that steel and iron manufacturers could meet the demand. He urged the federal government to allow current blanket waivers to expire, which he said could lead to manufacturers investing more in domestic production if federal officials fully enforce the rules.
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+“It’s time to get on with it,” Paul said. “Some of these waivers can just get extended indefinitely, and that certainly isn’t the intent of the law or what Congress had in mind when it passed.”
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+Other research has found that the rules don’t create a significant amount of American jobs. A 2018 study from Victoria University concluded that Buy America rules did provide a small boost to American manufacturing jobs, but they led to fewer jobs in other parts of the economy and made projects more costly.
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+The authors — Peter Dixon, Maureen Rimmer, and Robert Waschik — estimated that eliminating the domestic content requirements could result in a loss of about 57,000 manufacturing jobs, but lead to a net gain of about 306,000 jobs in industries like retail, restaurants, and nursing homes. The researchers found that eliminating the rules could allow the federal government to fund more projects or “return the savings to the private sector in the form of tax cuts,” which could increase consumption.
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+“These sorts of policies do generate jobs in manufacturing,” said Dixon, an economics professor at Victoria University. “But not many, and they come at a great cost.”
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+Housing, broadband, and EV charging projects are newly eligible
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+The expanded Buy America rules are also affecting new projects beyond traditional transportation programs. The law broadened the scope of infrastructure projects that are now subject to the rules, meaning that housing, broadband, and new programs for electrical vehicle charging projects are now permanently covered.
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+ Emily Elconin/Bloomberg via Getty Images
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+President Biden speaks during a visit to General Motors’ all-electric vehicle assembly plant in Detroit, Michigan, on November 17, 2021.
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+Some housing groups have objected to the new rules and called on the federal government to exclude public housing projects, since they say the requirements could increase costs and delay the construction of affordable housing units when there is already a nationwide shortage of homes. They’ve also said housing authorities lack staff members who could investigate whether all materials and products they purchase meet domestic content requirements.
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+That has caused uncertainty among housing authorities, said Sunia Zaterman, the executive director of the Council of Large Public Housing Authorities. HUD has issued a waiver delaying the implementation of the new rules for its financial assistance programs, but it’s set to expire on November 14.
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+“We think that we’re clearly exempt because we’re operating residential properties,” Zaterman said. “These aren’t school buildings. They aren’t courthouses. These are properties used for private residential purposes.”
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+Brien Thane, the executive director of the Bellingham and Whatcom County Housing Authorities in Washington, said officials were already struggling to deal with supply shortages. Thane said the authority is trying to replace about 100 windows in one of its properties for senior citizens and people with disabilities but they’ve struggled to procure them because lead times are about four to six months, significantly longer than before the pandemic, when it would have taken about 30 to 45 days to get a shipment. Ahead of the winter season, Thane said officials were worried about water intrusion since the windows are about 50 years old and “starting to fail.”
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+Thane said the authority ran into similar issues when Buy America rules were tied to funding in the Obama administration’s American Recovery and Reinvestment Act, which resulted in officials having an “extremely hard time” sourcing toilets, refrigerators, and other materials.
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+“The infrastructure bill does not include one cent for public housing,” Thane said. “So why are we extending the domestic procurement requirements to public housing?”
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+Some broadband groups have also praised the infrastructure law’s $65 billion in funding to build out the nation’s access to reliable internet, but have said Buy America rules could impede projects. In January, a coalition of organizations urged federal officials to consider a waiver for broadband infrastructure programs since the rules do not “reflect the realities of the global” supply chain. A broadband network contains dozens of elements — including switching and routing equipment — and devices used in each of those elements often include hundreds of components that are sourced from around the world, according to the letter.
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+Shirley Bloomfield, the chief executive officer of NTCA–The Rural Broadband Association, which signed the letter, said many rural communities are often served by smaller broadband providers who might struggle to procure supplies if they’re limited to domestic manufacturers and competing with larger companies. Bloomfield said some of the association’s members were already seeing delays of “well over a year” for fiber optic cable deliveries, and other equipment like handholes and pedestals were experiencing shortages. Bloomfield said she hoped to see the federal government further incentivize American suppliers to ramp up production.
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+“They’re going to have to make sure that the large guys aren’t able to grab up all the supplies so that the small carriers who are the ones building out into these rural communities don’t get stuck with the short end of the stick,” Bloomfield said.
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+Some contractors have said the new Buy America rules have made them hesitant to pursue federally funded projects, said Ben Brubeck, the vice president of regulatory, labor, and state affairs at Associated Builders and Contractors. Brubeck said contractors are mostly concerned about potential delays in receiving materials and how that could impact costs, especially since input prices are already up more than 40 percent since the pandemic’s start.
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+“There is work in the private sector, and if they can make profit in the private sector and not have to wade into all this uncertainty and added costs and regulatory risk, they will do that,” Brubeck said.
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+Patrick Murphy, the sustainability and innovations project manager at the Vermont Agency of Transportation, said he was worried that every state would be seeking EV chargers and necessary equipment like transformers and switchgear at the same time, which could strain supplies and increase costs. Vermont, which is set to receive $21.2 million over five years to build out its network, has so far identified 15 locations that will host chargers.
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+The FHWA has proposed initially waiving all Buy America requirements for EV chargers and components until January 1 and then gradually phasing out parts of the waiver through 2024. Still, Murphy said he was worried that it could take more time for American manufacturers to ramp up capacity.
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+“We’re already experiencing extreme aspects of climate change throughout the country,” Murphy said. “We need to build out the infrastructure that encourages more people to adopt electric vehicles as quickly as possible. Anything that hinders that will be an issue.”
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From The Hindu: Sports
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Mojito and Agostini Carracci excel -
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Peyo, Evaldo, The Sovereign Orb, Douglas, Stormy Ocean and Worldly Wise please -
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Koneru Humpy off to winning start in Women’s Candidates chess -
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T20I rankings | Kohli storms into top 10; Bhuvneshwar, Pandya also rise - Virat Kohli climbed five spots to ninth in the ICC T20I batting rankings, Bhuvneshwar Kumar jumped two spots to the 10th spot in the bowlers' rankings and Hardik Pandya rose three places to third in the all-rounders chart
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T20 World Cup | Rain washes out New Zealand-Afghanistan clash - The no-result at the Melbourne Cricket Ground leaves last year's runners-up New Zealand top of Group 1 on three points and Afghanistan remain bottom of the group on one point
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From The Hindu: National News
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Use of square mesh cod-ends evokes mixed response from fishermen - Fishers complain of non-availability of new gear, poor catch; Puthuvype fisherman says its use helped him save fuel
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Man held for throwing beer bottles at women football players from Ghana - The arrested is a lower division clerk in Kozhikode Corporation office
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Kodenchery panchayat to deploy native shooters to hunt down wild boars - Financial constraints prevent the local body from engaging shooters from Telangana on a regular basis
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Watch | ‘Britain has outgrown its racism’: Shashi Tharoor on Rishi Sunak’s elevation as UK Prime Minister - A video of Shashi Tharoor’s reaction to Rishi Sunak’s appointment as UK’s new PM
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SCR to run 14 special trains between Tirupati and various stations from Nov.4 to Dec. 30 - According to the Railway officials, SCR will run 100 special trains from November 4 to December 30 for the convenience of passengers
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From BBC: Europe
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Ukraine war: Russia troop deployment to Belarus prompts speculation - Russia is sending thousands more troops to Belarus. Is the country going to join the war in Ukraine?
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China accused of illegal police stations in the Netherlands - A Dutch media report says China is running an undeclared police operation to pressure dissidents.
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Macron-Scholz: Difficult Paris summit awaits German chancellor - Relations between France and Germany are strained as the two countries pull in different directions.
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Turkey arrests doctors’ chief for ‘terror propaganda’ - Sebnem Fincanci is held after calling for an inquiry into claims that the army used chemical weapons.
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Mercedes-Benz becomes latest Western company to pull out of Russia - The company said it did not expect the move to have a significant effect on profitability.
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From Ars Technica
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2022 iPad Pro review: Impressively, awkwardly fast and capable - This year’s iPad Pro has even more power. It’s nice, but a true upgrade beckons. - link
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2022 iPad review: The best one—except for all the others - Apple’s latest tablet doesn’t quite justify its price compared to other iPads. - link
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The feds’ new open-access policy: Who’s gonna pay for it? - Currently, researchers often have to choose between publishing and science. - link
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With shots and infections, the most common COVID symptoms have shifted - Beware of unexplained sneezing, which is becoming a more common COVID symptom. - link
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Apple releases patch for iPhone and iPad 0-day reported by anonymous source - Freshly released iOS 16.1 and iPadOS 16 also fix 19 other vulnerabilities. - link
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From Jokes Subreddit
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The sex position formerly known as 69 is now called 96. -
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+Due to the economy, the cost of eating out has gone up.
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