Evolution and neutralization escape of the SARS-CoV-2 BA.2.86 subvariant -
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+Omicron BA.2.86 subvariant differs from Omicron BA.2 as well as recently circulating variants by over 30 mutations in the spike protein alone. Here we report on the first isolation of the live BA.2.86 subvariant from a diagnostic swab collected in South Africa which we tested for escape from neutralizing antibodies and viral replication properties in cell culture. BA.2.86 did not have significantly more escape than Omicron XBB.1.5 from neutralizing immunity elicited by infection of Omicron subvariants ranging from BA.1 to XBB, either by infection alone or as breakthrough infection in vaccinated individuals. Neutralization escape was present relative to earlier strains: BA.2.86 showed extensive escape both relative to ancestral virus in sera from pre-Omicron vaccinated individuals and relative to Omicron BA.1 in sera from Omicron BA.1 infected individuals. We did not observe substantial differences in viral properties in cell culture relative to XBB.1.5. Both BA.2.86 and XBB.1.5 produced infection foci of similar size, had similar cytopathic effect (both lower than ancestral SARS-CoV-2), and had similar replication dynamics. We also investigated the relationship of BA.2.86 to BA.2 sequences and found that the closest were BA.2 samples from Southern Africa circulating in early 2022. These observations suggest that BA.2.86 is more closely related to sequences from Southern Africa than other regions and so may have evolved there, and that evolution led to escape from neutralizing antibodies similar in scale to recently circulating strains of SARS-CoV-2.
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How immunity shapes the long-term dynamics of seasonal influenza -
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+Since its emergence in 1968, influenza A H3N2 has caused yearly epidemics in temperate regions. While infection confers immunity against antigenically similar strains, new antigenically distinct strains that evade existing immunity regularly emerge (9antigenic drift9). Immunity at the individual level is complex, depending on an individual9s lifetime infection history. An individual9s first infection with influenza typically elicits the greatest response with subsequent infections eliciting progressively reduced responses (9antigenic seniority9). The combined effect of individual-level immune responses and antigenic drift on the epidemiological dynamics of influenza are not well understood. Here we develop an integrated modelling framework of influenza transmission, immunity, and antigenic drift to show how individual-level exposure, and the build-up of population level immunity, shape the long-term epidemiological dynamics of H3N2. Including antigenic seniority in the model, we observe that following an initial decline after the pandemic year, the average annual attack rate increases over the next 80 years, before reaching an equilibrium, with greater increases in older age-groups. Our analyses suggest that the average attack rate of H3N2 is still in a growth phase. Further increases, particularly in the elderly, may be expected in coming decades, driving an increase in healthcare demand due to H3N2 infections. We anticipate our findings and methodological developments will be applicable to other antigenically variable pathogens. This includes the recent pandemic pathogens influenza A H1N1pdm09, circulating since 2009, and SARS-CoV-2, circulating since 2019. Our findings highlight that following the short-term reduction in attack rates after a pandemic, if there is any degree of antigenic seniority then a resurgence in attack rates should be expected over the longer-term. Designing and implementing studies to assess the dynamics of immunity for H1N1pdm09, SARS-CoV-2, and other antigenically variable pathogens may help anticipate any long-term rises in infection and health burden.
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Disease trajectories in hospitalized COVID-19 patients are predicted by clinical and peripheral blood signatures representing distinct lung pathologies. -
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+Linking clinical biomarkers and lung pathology still is necessary to understand COVID-19 pathogenesis and the basis of progression to lethal outcomes. Resolving these knowledge gaps enables optimal treatment approaches of severe COVID-19. We present an integrated analysis of longitudinal clinical parameters, blood biomarkers and lung pathology in COVID-19 patients from the Brazilian Amazon. We identified core signatures differentiating severe recovered patients and fatal cases with distinct disease trajectories. Progression to early death was characterized by rapid and intense endothelial and myeloid activation, presence of thrombi, mostly driven by SARS-CoV-2 + macrophages. Progression to late death was associated with systemic cytotoxicity, interferon and Th17 signatures and fibrosis, apoptosis, and abundant SARS-CoV-2 + epithelial cells in the lung. Progression to recovery was associated with pro-lymphogenic and Th2-mediated responses. Integration of antemortem clinical and blood biomarkers with post-mortem lung-specific signatures defined predictors of disease progression, identifying potential targets for more precise and effective treatments.
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+The virus severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, is the causative agent of the current COVID-19 pandemic. It possesses a large 30 kilobase (kb) genome that encodes structural, non-structural, and accessory proteins. Although not necessary to cause disease, these accessory proteins are known to influence viral replication and pathogenesis. Through the synthesis of novel infectious clones of SARS-CoV-2 that lack one or more of the accessory proteins of the virus, we have found that one of these accessory proteins, ORF8, is critical for the modulation of the host inflammatory response. Mice infected with a SARS-CoV-2 virus lacking ORF8 exhibit increased weight loss and exacerbated macrophage infiltration into the lungs. Additionally, infection of mice with recombinant SARS-CoV-2 viruses encoding ORF8 mutations found in variants of concern reveal that naturally occurring mutations in this protein influence disease severity. Our studies with a virus lacking this ORF8 protein and viruses possessing naturally occurring point mutations in this protein demonstrate that this protein impacts pathogenesis.
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Early combination with remdesivir, nirmatrelvir/ritonavir and sotrovimab for the treatment of COVID-19 in immunocompromised hosts -
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+Background: Immunocompromised patients with COVID-19 have higher morbidity and mortality than general population. Some authors have successfully used antiviral combination, but never in the early phase of the infection. Methods: Retrospective cohort study to describe efficacy and safety of the combination of 2 antivirals, with or without a mAb, both in early (within 10 days from symptoms) and in later phase (after 10 days) of SARS-CoV-2 infection in immunocompromised patients admitted to our facility. Results: We treated 11 patients (7 in early phase and 4 in later phase of COVID-19) with 10 days of intravenous remdesivir plus 5 days of oral nirmatelvir/ritonavir, also combined with sotrovimab in 10/11 cases. Notably, 100% of the <early> patients reached virological clearance at day 30 from the end of the therapy and were alive and well at follow-up, whereas corresponding figures in the <late> patients were 50% and 75%. Patients in late group more frequently needed oxygen supplementation (p=0.015) and steroid therapy (p=0.045) during admission and reached higher a COVID-19 severity (p=0.017). Discussion: The combination of antiviral and sotrovimab in early phase of COVID-19 in immunocompromised patients is well tolerated and associated with 100% of virological clearance. Patients treated later have lower response rate and higher disease severity, but a causative role of the therapy in such finding is yet to be demonstrated.
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Uncovering the implications of IFN-I in severe COVID-19 neutrophil inflammasome -
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+Excessive inflammation defines COVID-19 pathophysiology. Neutrophils represent a critical arm of the innate immune response and are major mediators of inflammation. We conducted transcriptomic profiling of polymorphonuclear cells (PMNs), consisting mainly of mature neutrophils, which revealed a pronounced type I interferon (IFN-I) gene signature in severe COVID-19, compared to mild COVID-19 and healthy controls. Notably, low-density granulocytes (LDGs) from severe COVID-19 did not exhibit this signature and displayed a distinct immature neutrophil phenotype. PMNs from severe COVID-19 patients showed heightened nigericin-induced caspase1 activation but reduced responsiveness to exogenous inflammasome priming. Interestingly, while mature neutrophils efficiently released IL-1? upon inflammasome activation, they were poor producers of IL-18. Furthermore, IFN-I emerged as a priming stimulus for neutrophil inflammasomes, which was confirmed in a COVID-19 mouse model. Overall, these findings underscore the crucial role of neutrophil inflammasomes in driving inflammation during severe COVID-19 and opens promising avenues for targeted therapeutic interventions to mitigate the pathological processes associated with the disease.
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Comparison of Different PCR Methods for the Detection of SARS-CoV-2 RNA in Wastewater Based on the Reported Incidence of COVID-19 in Finland -
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+The spatial and temporal changes of the COVIDâ19 pandemic have been monitored with wastewaterâbased surveillance, which many countries have applied to their national public health monitoring measures. The most commonly used methods for the detection of SARSâCoVâ2 in wastewater are RTâqPCR and RTâddPCR. Previous comparisons of the two methods have produced conflicting results; some found RTâddPCR to be more sensitive, one found RTâqPCR to be more sensitive, and others found them to be equal in sensitivity. This research was conducted to further study these two methods as well as two different RNA extraction methodologies and gene assays for the detection of SARSâCoVâ2 in wastewater. We compared two RTâqPCR kits and RTâddPCR based on sensitivity, variability, and the correlation of SARSâCoVâ2 gene copy numbers in wastewater with the incidence of COVIDâ19. Our results indicate that the most sensitive and lowâvariance method to detect SARSâCoVâ2 in wastewater was RTâddPCR. However, we obtained the best correlation between COVID-19 incidence and SARSâCoVâ2 gene copy number in wastewater using RTâqPCR (CC = 0.697, p < 0.001). We found a significant difference in sensitivity between the two RTâqPCR kits, one having a significantly lower limit of detection and a higher percentage of positive samples than the other. Furthermore, the CDC N1 primers and probe were the most sensitive for both RTâqPCR kits, while there was no significant difference between the tested gene targets using RTâddPCR. For the most sensitive RTâqPCR, the use of different RNA extraction kits affected the result. All methods showed a trend between COVIDâ19 incidence and SARSâCoVâ2 gene copy numbers in wastewater. In addition, we tested an isothermal amplification method for the detection of SARSâCoVâ2 RNA in wastewater. It proved to be a viable option if results are expected quickly, resources are limited, and presenceâabsence information is sufficient.
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Effectiveness of BNT162b2 COVID-19 Vaccination in Children Aged 5â17 Years in the United States -
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+Importance: COVIDâ19 vaccines are authorized for use in children in the United States; realâworld assessment of vaccine effectiveness in children is needed. Objective: To estimate the effectiveness of receiving a complete primary series of monovalent BNT162b2 (PfizerâBioNTech) COVID-19 vaccine in US children. Design: A cohort study of children aged 5â17 years vaccinated with BNT162b2 matched with unvaccinated children. Setting: Participants identified in Optum and CVS Health insurance administrative claims databases were linked with Immunization Information System (IIS) COVID-19 vaccination records from 16 US jurisdictions between December 11, 2020, and May 31, 2022 (end date varied by database and IIS). Participants: Vaccinated children were followed from their first BNT162b2 dose and matched to unvaccinated children on calendar date, US county of residence, and demographic and clinical factors. Censoring occurred if vaccinated children failed to receive a timely dose 2 or if unvaccinated children received any dose. Exposure: BNT162b2 vaccinations were identified using IIS vaccination records and insurance claims. Main Outcomes and Measures: Two COVIDâ19 outcome definitions were evaluated: COVIDâ19 diagnosis in any medical setting and COVIDâ19 diagnosis in hospitals/emergency departments (EDs). Propensity scoreâweighted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with Cox proportional hazards models, and vaccine effectiveness (VE) was estimated as 1 minus HR. VE was estimated overall, within age subgroups, and within variantâspecific eras. Sensitivity, negative control, and quantitative bias analyses evaluated various potential biases. Results: There were 453,655 eligible vaccinated children oneâtoâone matched to unvaccinated comparators (mean age 12 years; 50% female). COVID-19 hospitalizations/ED visits were rare in children, regardless of vaccination status (Optum, 41.2 per 10,000 personâ years; CVS Health, 44.1 per 10,000 personâ years). Overall, vaccination was associated with reduced incidence of any medically diagnosed COVIDâ19 (metaâanalyzed VE = 38% [95% CI, 36%â40%]) and hospital/EDâdiagnosed COVID-19 (metaâanalyzed VE = 61% [95% CI, 56%â65%]). VE estimates were lowest among children 5â11 years and during the omicron variant era. Conclusions and Relevance: Receipt of a complete BNT162b2 vaccine primary series was associated with overall reduced medically diagnosed COVIDâ19 and hospital/EDâdiagnosed COVIDâ19 in children; observed VE estimates differed by age group and variant era.
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Effect of the 2022 COVID-19 booster vaccination campaign in 50 year olds in England: regression discontinuity analysis in OpenSAFELY -
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+Background: SARS-CoV-2 vaccines are highly effective in preventing severe COVID-19 but require boosting to maintain protection. Changes to circulating variants and prevalent natural immunity may impact on real-world effectiveness of boosters in different time periods and in different populations. Methods: With NHS England approval, we used linked routine clinical data from >24 million patients to evaluate the effectiveness of the 2022 combined COVID-19 autumn booster and influenza vaccine campaign in non-clinically vulnerable 50-year-olds in England using a regression discontinuity design. Our primary outcome was a composite of 6-week COVID-19 emergency attendance, COVID-19 unplanned hospitalisation, or death. The secondary outcomes were: respiratory hospitalisations or death; any unplanned hospitalisation; and any death. Results: Our study included 1,917,375 people aged 45-54 years with no evidence of being in a high-risk group prioritised for vaccination. By 26 November 2022, booster vaccine coverage was 11.1% at age 49.75 years increasing to 39.7% at age 50.25 years. The estimated effect of the campaign on the risk of the primary outcome in 50-year-olds during weeks 7-12 after the campaign start was -0.4 per 100,000 (95% CI -7.8, 7.1). For the secondary outcomes the estimated effects were: -0.6 per 100,000 (95%CI -13.5, 12.3) for respiratory outcomes; 5.0 per 100,000 (95%CI -40.7, 50.8) for unplanned hospitalisations; and 3.0 per 100,000 (95%CI -2.7, 8.6) for any death. The results were similar when using different follow-up start dates, different bandwidths, or when estimating the effect of vaccination (rather than the campaign). Conclusion: This study found little evidence that the autumn 2022 vaccination campaign in England was associated with a reduction in severe COVID-19-related outcomes among non-clinically vulnerable 50-year-olds. Possible explanations include the low risk of severe outcomes due to substantial pre-existing vaccine- and infection-induced immunity. Modest booster coverage reduced the precision with which we could estimate effectiveness. The booster campaign may have had effects beyond those estimated, including reducing virus transmission and incidence of mild or moderate COVID-19.
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Epidemiological insight into the possible drivers of Lassa fever in an endemic area of Southwestern Nigeria from 2017 and 2021 -
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+Background Lassa fever (LF) is a viral disease transmitted between animals and humans, commonly found in West Africa, including Nigeria. The region experiences an estimated annual total of about 2 million LF cases in humans, leading to 5,000 to 10,000 deaths. Strikingly, up to 80% of LF-infected individuals show no symptoms, making its true incidence hard to determine in endemic populations. We investigated LF distribution, mortality, survival patterns, and contributing factors during a local outbreak in Nigeria, from 2017 to 2021. Method Data from the Integrated Disease Surveillance and Response weekly line list for 2017 to 2021 were extracted. The survival pattern of LF patients was visualized with the Kaplan-Meier curve, binary logistic regression model was employed to explore LF-associated factors and level of statistical significance (α) was set at 5%. Result Overall, 4,554 participants were recruited between 2017 and 2021. Their average age varied from 31.82 ± 20.0 to 37.85 ± 17.89. LF-positive patients decreased from 26.9% in 2017 to 17.7% in 2021, paralleling the mortality trend. In 2021, patient survival ranged from 5 to 30 days. Male patients had lower survival odds in the initial 10 days of hospitalization, improved chances from days 10 to 20, and reduced probabilities beyond day 20. Residence location and age were significant factors (p<0.05) associated with LF in Ondo State. Conclusion The decline in LF cases in 2021 could be attributed to the ongoing intervention by Nigerian Centre for Disease Control or the disruption caused by the COVID-19 pandemic in 2020. To address LF challenges in hotspot areas, we propose Community Action Networks that would operate using the One Health approach involving local stakeholders sustainably to promote Early Warning/Early Response system in high-risk settings and mitigate LF-related issues.
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Predictors of SARS-CoV-2 anti-Spike IgG antibody levels following two COVID-19 vaccine doses among children and adults in the Canadian CHILD Cohort -
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+Background: Vaccination helps prevent SARS-CoV-2 infection and severe COVID-19. However, vaccine-induced humoral immune responses vary among individuals and wane over time. We aimed to describe the SARS-CoV-2 anti-spike IgG antibody response to vaccination and identify health and demographic factors associated with this response among children and adults. Methods: We studied a subset of double-vaccinated children (n= 151; mean age: 12 ±1.5 years, 46% female) and adults (n= 995; 44 ±6.0 years, 60% female) from the Canadian CHILD Cohort. Dried blood spots were collected over two time periods (March 2021 to September 2021; October 2021 to January 2022). Antibody levels were quantified using automated chemiluminescent ELISAs. Demographic, vaccination, and health data were collected via online questionnaires. Associations were determined using multivariable regression. Results: Our cohort had SARS-CoV-2 anti-spike seropositivity rate of 97% following two COVID-19 vaccine doses. In both children and adults, the highest antibody levels were observed around three months post-vaccination and did not differ by biological sex. Higher antibody levels were associated with: prior SARS-CoV-2 infection (ÎČ=0.15 scaled luminescence units, 95%CI, 0.06-0.24), age <18 years (ÎČ=0.15, 95%CI 0.05-0.26) and receiving the Moderna mRNA (ÎČ=0.23, 95%CI 0.11-0.34) or Pfizer-BioNTech mRNA vaccines (ÎČ= 0.10, 95%CI, 0.02-0.18) vs. a combination of mRNA and Oxford-AstraZeneca viral vector vaccines. There were no differences in antibody levels when comparing a 3-8 vs. 9-16-week interval between vaccine doses. Interpretation: We identified key factors associated with post-vaccination antibody responses in children and adults, which could help improve future vaccine development and deployment among different population subgroups.
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Computational Methods for Characterizing Research Outputs, Collaborative Networks and Thematic Concentration: a Case Study in Primary Care Research Evaluation -
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+Objective: Research impact is difficult to measure, evaluate and report. This study aims to demonstrate how computational scientometric methods, including bibliometric, network analytic, and thematic summary measures can efficiently characterize complex scientific disciplines, such as primary care research. Methods: We used a retrospective cohort design. The study included N=17 international academic primary care research departments. A scientometric database was curated using a bottom-up methodology, which included peer-reviewed research articles/reviews, and associated meta-data, published between 01/01/2017 and 31/12/2022. Publication-level bibliometric information was queried from the Scopus application programming interface (API). The Altmetrics API was used to extract publication-level indicators of social engagement. Network analytic visualizations and statistics characterized research collaboration. Topic models and keyword mining characterized the main thematic areas of primary care research. At an author-level, we investigated correlations between bibliometric, altmetric, network analytic and topical summary measures. Results: Our analysis included N=591 primary care researchers (from 17 institutions) who produced 13,047 unique peer-reviewed articles over the study timeframe. These 13,047 research articles were published in 2,237 unique journal titles; cited 231,121 times; and received broad social uptake (605,349 Twitter tweets, 36,982 mainstream media mentions, 884 Wikipedia references, and 1,127 policy document citations). The 591 researchers collaborated with 35,585 unique co-authors resulting in 20,808,886 pair-wise collaborations. The median number of authors per publication was 7 (IQR: 4-10; min=1; max=3,391). Frequently occurring keywords/n-grams and latent topical vectors, highlighted the diversity of primary care research. Clinical research themes included: physical/mental health conditions, disease prevention and screening, issues in primary/obstetric/emergency/palliative-care, and public health. Methodological research themes included: research synthesis/appraisal, statistical/epidemiological inference, study design, qualitative research, mixed methods, health economics, medical education, and quality improvement. Many themes were stable over the study timeframe. COVID-19 emerged as an important research theme from 2020 through 2022. Topic vectors encoding clinical medicine were positively correlated with bibliometric, altmetric and network centrality measures, whereas, vectors encoding qualitative methods, medical education, and public health were negatively correlated with these same metrics. Conclusions: Multi-metric, computational scientometric methods offer an efficient, transparent, and reproducible means for characterizing the research output of complex scientific disciplines, such as primary care research.
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Systematical assessment of the impact of single spike mutations of SARS-CoV-2 Omicron sub-variants on the neutralization capacity of post-vaccination sera -
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+The evolution of novel SARS-CoV-2 variants significantly affects vaccine effectiveness. While these effects can only be studied retrospectively, neutralizing antibody titers are most used as correlates of protection. However, studies assessing neutralizing antibody titers often show heterogeneous data. To address this, we investigated assay variance and identified virus infection time and dose as factors affecting assay robustness. We next measured neutralization against Omicron sub-variants in cohorts with hybrid or vaccine induced immunity, identifying a gradient of immune escape potential. To evaluate the effect of individual mutations on this immune escape potential of Omicron variants, we systematically assessed the effect of each individual mutation specific to Omicron BA.1, BA.2, BA.2.12.1, and BA.4/5. We cloned a library of pseudo-viruses expressing spikes with single point mutations, and subjected it to pooled sera from vaccinated hosts, thereby identifying multiple mutations that independently affect neutralization potency. These data might help to predict antigenic features of novel viral variants carrying these mutations and support the development of broad monoclonal antibodies.
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ACE-2-like enzymatic activity is associated with immunoglobulin in COVID-19 patients -
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+Many mechanisms responsible for COVID-19 pathogenesis are well-established, but COVID-19 includes features with unclear pathogenesis, such as autonomic dysregulation, coagulopathies, and high levels of inflammation. The receptor for SARS-CoV-2 spike protein9s receptor binding domain (RBD) is angiotensin converting enzyme 2 (ACE2). We hypothesized that some COVID-19 patients may develop antibodies that have negative molecular image of RBD sufficiently similar to ACE2 to yield ACE2-like catalytic activity â ACE2-like abzymes. To explore this hypothesis, we studied patients hospitalized with COVID-19 who had plasma samples available obtained about 7 days after admission. ACE2 is a metalloprotease that requires Zn2+ for activity. However, we found that the plasma from some patients studied could cleave a synthetic ACE2 peptide substrate, even though the plasma samples were collected using disodium ethylenediaminetetraacetate (EDTA) anticoagulant. When we spiked plasma with synthetic ACE2, no ACE2 substrate cleavage activity was observed unless Zn2+ was added or the plasma was diluted to decrease EDTA concentration. After processing samples by 100 kDa size exclusion columns and protein A/G adsorption, which depleted immunoglobulin by >99.99%, the plasma samples did not cleave the ACE2 substrate peptide. The data suggest that some patients with COVID-19 develop antibodies with abzyme-like activity capable of cleaving synthetic ACE2 substrate. Since abzymes can exhibit promiscuous substrate specificities compared to the enzyme whose active site image they resemble, and since proteolytic cascades regulate many physiologic processes, anti-RBD abzymes may contribute to some otherwise obscure COVID-19 pathogenesis.
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Assessing the importance of demographic risk factors across two waves of SARS-CoV-2 using fine-scale case data -
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+For the long term control of an infectious disease such as COVID-19, it is crucial to identify the most likely individuals to become infected and the role that differences in demographic characteristics play in the observed patterns of infection. As high-volume surveillance winds down, testing data from earlier periods are invaluable for studying risk factors for infection in detail. Observed changes in time during these periods may then inform how stable the pattern will be in the long term. To this end we analyse the distribution of cases of COVID-19 across Scotland in 2021, where the location (census areas of order 500â1,000 residents) and reporting date of cases are known. We consider over 450,000 individually recorded cases, in two infection waves triggered by different lineages: B.1.1.529 (âOmicronâ) and B.1.617.2 (âDeltaâ). We use random forests, informed by measures of geography, demography, testing and vaccination. We show that the distributions are only adequately explained when considering multiple explanatory variables, implying that case heterogeneity arose from a combination of individual behaviour, immunity, and testing frequency. Despite differences in virus lineage, time of year, and interventions in place, we find the risk factors remained broadly consistent between the two waves. Many of the observed smaller differences could be reasonably explained by changes in control measures.
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A 2nd Generation E1/E2B/E3-Deleted Adenoviral COVID-19 Vaccine: The TCELLVACCINE TRIAL - Condition:  COVID-19 Interventions:  Biological: hAd5-S-Fusion+N-ETSD;  Biological: Placebo (0.9% (w/v) saline) Sponsor:  ImmunityBio, Inc. Completed
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Aerobic Training for Rehabilitation of Patients With Post Covid-19 Syndrome - Conditions:  Post-COVID-19 Syndrome;  Long-COVID-19 Syndrome Intervention:  Behavioral: Aerobic Exercise Training Sponsors:  University of Witten/Herdecke;  Institut fĂŒr Rehabilitationsforschung Norderney Completed
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Additional Recombinant COVID-19 Humoral and Cell-Mediated Immunogenicity in Immunosuppressed Populations - Conditions:  Immunosuppression;  COVID-19 Intervention:  Biological: NVX-CoV2372 Sponsors:  University of Wisconsin, Madison;  Novavax Not yet recruiting
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Comparative Immunogenicity of Concomitant vs Sequential mRNA COVID-19 and Influenza Vaccinations - Conditions:  Influenza;  COVID-19;  Influenza Immunogencity;  COVID-19 Immunogenicity Interventions:  Biological: Simultaneous Vaccination (Influenza Vaccine and mRNA COVID booster);  Biological: Sequential Vaccination (Influenza vaccine then mRNA COVID booster);  Biological: Sequential Vaccination (mRNA COVID booster then Influenza vaccine) Sponsors:  Duke University;  Centers for Disease Control and Prevention;  Arizona State University;  University Hospitals Cleveland Medical Center;  University of Pittsburgh;  Washington University School of Medicine;  Valleywise Health;  VA Northeast Ohio Health Care;  Senders Pediatrics Not yet recruiting
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Bronchoalveolar Lavage in Recovered From COVID-19 Pneumonia - Condition:  Bronchoalveolar Lavage Intervention:  Procedure: Bronchoalveolar Lavage Sponsors:  Mohamed Abd Elmoniem Mohamed;  Marwa Salah Abdelrazek Ghanem;  Mohammad Khairy El-Badrawy;  Tamer Ali Elhadidy;  Dalia Abdellateif Abdelghany Completed
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Phase I Safety Study of B/HPIV3/S-6P Vaccine Via Nasal Spray in Adults - Condition:  SARS-CoV-2 Infection Intervention:  Biological: B/HPIV3/S-6P Sponsors:  National Institute of Allergy and Infectious Diseases (NIAID);  Johns Hopkins Bloomberg School of Public Health;  National Institutes of Health (NIH) Recruiting
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Effects of Cognitive-behavioral Therapy for Insomnia in Nurses With Post Covid-19 Condition - Condition:  Cognitive Behavioral Therapy Intervention:  Behavioral: cognitive behavioral therapy Sponsor:  Tri-Service General Hospital Not yet recruiting
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The Effectiveness of Natural Resources for Reducing Stress - Conditions:  Distress, Emotional;  COVID-19 Interventions:  Combination Product: Balneotherapy plus complex;  Combination Product: Combined nature resources treatment;  Other: Nature therapy procedure Sponsors:  KlaipÄda University;  Research Council of Lithuania Active, not recruiting
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Pre-probiotic Supplementation for Post-covid Fatigue Syndrome - Condition:  Long COVID Interventions:  Dietary Supplement: Dietary Supplement: Experimental;  Dietary Supplement: Dietary Supplement: Placebo Sponsor:  University of Novi Sad, Faculty of Sport and Physical Education Active, not recruiting
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Long COVID Immune Profiling - Conditions:  Long COVID;  POTS - Postural Orthostatic Tachycardia Syndrome;  Autonomic Dysfunction Interventions:  Diagnostic Test: IL-6;  Diagnostic Test: cytokines (IL-17, and IFN-ɣ);  Behavioral: Compass 31 Sponsors:  Vanderbilt University Medical Center;  American Heart Association Not yet recruiting
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A Study of Healthy Microbiome, Healthy Mind - Conditions:  Critical Illness;  COVID-19;  PICS;  Cognitive Impairment;  Mental Health Impairment;  Weakness, Muscle;  Dysbiosis Intervention:  Behavioral: Fermented Food Diet Sponsor:  Mayo Clinic Not yet recruiting
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From PubMed
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Broad-Spectrum Antiviral Effect of Cannabidiol Against Enveloped and Nonenveloped Viruses - Introduction: Cannabidiol (CBD), the main non-psychoactive cannabinoid of the Cannabis sativa plant, is a powerful antioxidant compound that in recent years has increased interest due to causes effects in a wide range of biological functions. Zika virus (ZIKV) is a virus transmitted mainly by the Aedes aegypti mosquitoes, which causes neurological diseases, such as microcephaly and Guillain-Barre syndrome. Although the frequency of viral outbreaks has increased recently, no vaccinations orâŠ
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SARS-CoV-2 Nsp15 suppresses type I interferon production by inhibiting IRF3 phosphorylation and nuclear translocation - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes 2019 coronavirus disease (COVID-19), poses a significant threat to global public health security. Like other coronaviruses, SARS-CoV-2 has developed various strategies to inhibit the production of interferon (IFN). Here, we have discovered that SARS-CoV-2 Nsp15 obviously reduces the expression of IFN-ÎČ and IFN-stimulated genes (ISG56, CXCL10), and also inhibits IRF3 phosphorylation and nuclear translocation byâŠ
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Plasma tissue-type plasminogen activator is associated with lipoprotein(a) and clinical outcomes in hospitalized patients with COVID-19 - CONCLUSION: High Lp(a) concentration provides a possible explanation for low endogenous tPA enzymatic activity, and poor clinical outcomes in patients with COVID-19.
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The Power of Molecular Dynamics Simulations and Their Applications to Discover Cysteine Protease Inhibitors - A large family of enzymes with the function of hydrolyzing peptide bonds, called peptidases or cysteine proteases (CPs), are divided into three categories according to the peptide chain involved. CPs catalyze the hydrolysis of amide, ester, thiol ester, and thioester peptide bonds. They can be divided into several groups, such as papain-like (CA), viral chymotrypsin-like CPs (CB), papain-like endopeptidases of RNA viruses (CC), legumain-type caspases (CD), and showing active residues of His,âŠ
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Investigating the Superiority of Chitosan/ D-alpha-tocopheryl Polyethylene Glycol Succinate Binary Coated Bilosomes in Promoting the Cellular Uptake and Anti-SARS-CoV-2 Activity of Polyphenolic Herbal Drug Candidate - The evolution of a safe and effective therapeutic system to conquer SAR-CoV-2 infection deemed to be a crucial worldwide demand. Curcumin (CUR) is a phytomedicinal polyphenolic drug that exhibited a well-reported anti-SAR-CoV-2. However, the therapeutic activity of CUR is hindered by its poor intestinal permeability and diminished aqueous solubility. Therefore, this study strived to develop D-alpha-tocopheryl polyethylene glycol succinate (TPGS) bilosomes (TPGS-Bs) adopting 2Âł full factorialâŠ
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Activation of Nrf2/ARE pathway by Anisodamine (654-2) for Inhibition of cellular aging and alleviation of Radiation-Induced lung injury - CONCLUSION: 654-2 can activate the Nrf2/ARE pathway, enhance cellular antioxidant capacity, and inhibit cellular senescence, thereby exerting a protective effect against RILI.
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Evidence of a Sjögrenâs disease-like phenotype following COVID-1 19 in mice and human - CONCLUSION: Overall, our study shows a direct association between SARS-CoV-2 and SjD. Hallmark features of SjD salivary glands were histologically indistinguishable from convalescent COVID-19 subjects.The results potentially implicate that SARS-CoV-2 could be an environmental trigger for SjD.
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DNase analysed by a novel competitive assay in patients with complications after ChAdOx1 nCoV-19 vaccination and in normal unvaccinated blood donors - Increased levels of neutrophil extracellular traps (NETs) have been detected in individuals with vaccine complications after the ChAdOx1 nCov vaccine with a correlation between the severity of vaccine side effects and the level of NETosis. DNases may disrupt NETs by degrading their content of DNA, and a balance has been reported between NETs and DNases. Because of this and since the inflammatory marker NETs may be used as a confirmatory test in diagnosing VITT, it is of interest to monitorâŠ
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Extracts of Thesium chinense inhibit SARS-CoV-2 and inflammation in vitro - CONCLUSION: T. chinense can be a potential candidate to fight SARS-CoV-2, and is becoming a traditional Chinese medicine candidate for treating COVID-19.
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Primary exposure to SARS-CoV-2 via infection or vaccination determines mucosal antibody-dependent ACE2 binding inhibition - CONCLUSIONS: Our study provides new insights into the relationship between antibody isotypes and neutralization by using a sensitive and high-throughput ACE2 binding inhibition assay. Key differences are highlighted between vaccination and infection at the mucosal level, showing that despite differences in the quantity of the response, post-infection and post-vaccination ACE2 binding inhibition capacity did not differ.
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Outcomes of MIS-C patients treated with anakinra: a retrospective multicenter national study - CONCLUSIONS: In this retrospective cohort of severe MIS-C patients treated with anakinra we report favorable clinical outcomes with a low incidence of side effects. The simultaneous use of steroids ± IVIG in these patients hinders definitive conclusions regarding the need of IL-1 inhibition in MIS-C treatment.
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Unleashing the link between the relaxation of the COVID-19 control policy and residentsâ mental health in China: the mediating role of family tourism consumption - CONCLUSION: Based on the findings, the study proposes that government and policymakers should strengthen mental health intervention, improve access to mental health counseling, stimulate economic development, expand the employment of residents, and track the mutation of the novel coronavirus.
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Alpha-1 antitrypsin protects against phosgene-induced acute lung injury by activating the ID1-dependent anti-inflammatory response - Phosgene is widely used as an industrial chemical, and phosgene inhalation causes acute lung injury (ALI), which may further progress into pulmonary edema. Currently, an antidote for phosgene poisoning is not known. Alpha-1 antitrypsin (α1-AT) is a protease inhibitor used to treat patients with emphysema who are deficient in α1-AT. Recent studies have revealed that α1-AT has both anti-inflammatory and anti-SARS-CoV-2 effects. Herein, we aimed to investigate the role of α1-AT in phosgene-inducedâŠ
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RNA-dependent RNA polymerase of SARS-CoV-2 regulate host mRNA translation efficiency by hijacking eEF1A factors - The RNA-dependent RNA polymerase (NSP12) of COVID-19 plays a significant role in the viral infection process, which promotes viral RNA replication by cooperating with NSP7 and NSP8, but little is known about its regulation on the function of host cells. We firstly found that overexpression of NSP12 had little effect on host mRNAs transcription. Using iCLIP technology, we found that NSP12 can bind a series of host RNAs with the conserved binding motif G(C/A/G)(U/G/A)UAG, especially ribosomal RNAâŠ.
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Antiviral Activity of Cinchona officinalis, a Homeopathic Medicine, against COVID-19 - CONCLUSION: Based on this in silico and in vitro evidence, we propose CO-MT as a promising antiviral medicine candidate for treating COVID-19. In vivo investigation is required to clarify the therapeutic potential of CO-MT in COVID-19.
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From Patent Search
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+ 09 September, 2023
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+Daily-Dose
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Narendra Modiâs New New Delhi - A multibillion-dollar revamp of Indiaâs capital complex reflects the Prime Ministerâs vision for the countryâs futureâand what he wants to erase from its past. - link
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Did Authoritarianism Cause Chinaâs Economic Crisis? - An erosion of trust between the government and its people now threatens the countryâs decades-long boom. - link
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Can Teachers and Parents Get Better at Talking to One Another? - Families are more anxious than ever to find out what happens in school. But there may be value in a measure of not-knowing and not-telling. - link
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David Grann on Turning Best-Sellers Into Movies - The author of âKillers of the Flower Moonâ and âThe Wagerâ on his reporting process and adapting his work to the screen. Plus, Richard Brody makes the case for keeping your DVDs. - link
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Why âAloneâ Is the Best Reality Show Ever Made - As contestants devolve into hunger and desolation, the camera proves to be as uncaring as the wilderness itself. - link
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From Vox
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The Southern Hemisphere, where itâs winter, has been really hot too -
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+SĂŁo Paulo, Brazil experienced 90-degree temperatures last month, during winter. | Cris Faga/NurPhoto via Getty Images
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+Brazil, Argentina, South Africa, and Australia had heat waves in the past few months. Now spring begins.
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+Itâs been a hot, brutal, record-breaking summer across much of the world, and itâs not quite ready to let go as late-season heat waves bake parts of the United States, the United Kingdom, North Africa, and the Middle East.
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+But at least people north of the equator can look forward to some relief as autumn and winter set in. The 850 million people in the Southern Hemisphere, on the other hand, are emerging from some of their hottest winter temperatures on record and bracing for even more heat as the warmer seasons begin.
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+In fact, the weather was pretty much like summer in June, July, and August across parts of South America, Africa, and Australia. Peruvians went to the beach last month as temperatures reached 82 degrees Fahrenheit. Similarly balmy weather engulfed Paraguay and Chile. Buenos Aires, Argentina, reached 86°F, the hottest August temperature in at least 117 years. The heat was downright dangerous in Brazil as thermometers ticked above 100°F. Australiaâs Bureau of Meteorology confirmed this month that Australia experienced its hottest winter since record keeping began more than a century ago. Even down near the South Pole, warmer air and water have led to the lowest sea ice extent on record around Antarctica.
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+âSome of these set new records by a large margin, also known as ârecord shatteringâ extremes,â explained Michael Grose, a senior research scientist at CSIRO, Australiaâs government science agency, in an email.
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+Record-breaking winter heat in the Southern Hemisphere.
Perth airport in Western Australia just recorded its hottest winter day on record (records go back 79 years here).
Cape Town Observatory, South Africa records its hottest August day on record with 32.9°C. Records⊠pic.twitter.com/O7kK1yZCLI
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+Winters tend to be milder in the Southern Hemisphere than in the North, and many of the factors that cranked up the heat across North America, Europe, and Asia in recent months are doing the same thing below the equator: Ocean temperature cycles like El Niño are in their warm phases, while greenhouse gasses from burning fossil fuels are accumulating in the atmosphere, warming the planet and changing its climate. So the hot winter across the Southern Hemisphere this year lined up with what scientists expected.
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+âThe seasonal forecast told us that we will have a warm winter time, so we were not surprised,â said Matilde Rusticucci, a professor of atmospheric sciences at the University of Buenos Aires and a researcher at CONICET, Argentinaâs national science research council. But âit wasnât normal.â
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+Now that spring is in the air, researchers expect that Australia, Africa, and South America will experience even more extreme weather â not just high temperatures, but more intense rainfall. As the Northern Hemisphere cools off, this year of record-breaking weather is only heating up in the south.
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+First, a quick trip back to elementary school: Earth has seasons because the axis it spins on as it revolves around the sun every 365 days is tilted, rather than completely vertical. That tilt means that for about half of the year, the Northern Hemisphere is pointed more toward the sun than the Southern Hemisphere, leading to longer days and more accumulated heat, thus creating summer. The process then reverses in the Northern Hemisphereâs winter, which is also summer in the south.
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+But there are other factors at play when it comes to how the seasons manifest across the planet, namely the distribution of land and water.
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+âThe biggest difference between the Northern and Southern hemispheres as a whole is that the North contains more large continents with an Arctic Ocean, whereas the Southern features fewer large land areas, the Southern Ocean and then Antarctica,â Grose said.
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+The oceans act like shock absorbers for weather and have a moderating effect on the climate. The Southern Hemisphere, with proportionately more ocean than land, tends to have a less drastic swing between seasons than places above the equator. That also means that winters in the south start from a warmer baseline than winters in the north.
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+So countries like Brazil rarely get chilly weather in the winter. âItâs dry and mild,â said FĂĄbio Luiz Teixeira Gonçalves, a professor of geosciences at the University of SĂŁo Paulo. Temperatures typically range between 53°F and 78°F, but they have been about 3.6°F higher on average since May around SĂŁo Paulo. Those higher average temperatures fueled more extreme heat.
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+Extraordinary heat in South America is rewriting climatic books: Last 2 days #Paraguay had stations with Tmin >30C Yesterday the min. temp. at Base Aerea Jara was 30.6C this is the highest minimum temperature ever recorded in September in the whole Southern Hemisphere. pic.twitter.com/LLRX0KXjx0
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+â Extreme Temperatures Around The World (@extremetemps) September 4, 2023
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+Part of the reason is that the oceans that typically keep big temperature swings in check have been really hot over these past few months. The Pacific Ocean is experiencing a strong El Niño this year, so warm water is moving west to east across the equator. This has the effect of heating up the oceanâs surface while channeling evaporation and rainfall. The ripple effects of El Niño tend to heat up the whole planet. The Atlantic Ocean also goes through temperature cycles and this year has reached record-high temperatures. The warm oceans have helped maintain warm air over the land in the Southern Hemisphere.
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+The background factor here is climate change. Average temperatures are rising all over the world and all throughout the year, but in general, winters are warming faster than summers. In fact, scientists say that higher temperatures in the cold seasons are a more robust indicator of humanityâs influence on the climate. âWe can say with very high confidence that the recent warm seasons and weather contains a climate change signal,â Grose said.
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+Warm winters have important consequences
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+Hotter weather in the winter can have a lot of important consequences, even if temperatures donât reach the triple-digit peaks of the summer. Plants, for instance, rely on temperature signals to time their life-cycles, and warmer winters throw this off. âWe can say they are cuckoo, and not in a good way,â Gonçalves said. âItâs confusing.â
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+Specifically, as warm seasons get longer and cool seasons get shorter, plants can germinate earlier and grow longer throughout the year. This is a boon for some species, but it can create a misalignment for plants that need pollinators like bees if they blossom too early. It also leads to longer and more intense pollen seasons, creating misery for allergy sufferers. Warm winters can also change the timing of when plants bear fruit, which can affect the animals that depend on them for food.
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+Cold temperatures also keep dangerous insects in check, and the higher temperatures this year have allowed for more mosquito-borne diseases to spread in cities like Buenos Aires. âWe had a dengue situation out of the season because dengue is more of a summertime problem here,â Rusticucci said.
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+Warmer, drier winters also mean that there is less water recharging rivers and groundwater supplies, and thus less water available for agriculture the following season. Hard, dry soil doesnât absorb water quickly, so when rain does occur, itâs more likely to run off and create flash floods. And if it doesnât rain, dry soil can lead to dust storms.
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+ Mauricio Zina/Bloomberg via Getty Images
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+In Uruguay, drought this winter left the Paso Severino reservoir at 10 percent of its capacity.
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+This is all converging on top of other ways that humans have changed the environment. Dense urban areas like SĂŁo Paulo and Buenos Aires form heat islands that trap more heat than surrounding areas. And deforestation of critical rainforests like the Amazon has disrupted vital rainfall patterns, worsening droughts, increasing regional warming, and creating conditions for wildfires.
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+A warm winter in the Southern Hemisphere can have global impacts too. The reduced sea ice around Antarctica can alter ocean circulation patterns, changing the flow of vital nutrients needed to nourish fisheries. Sea ice also shields ice on land, so losing it can cause ice sheets to melt more. That in turn can contribute to sea level rise along shorelines around the world.
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+Spring and summer will only get hotter down south
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+Researchers expect that the factors that heated up the winter across the Southern Hemisphere will continue to play out and amplify over the next few months as the seasons change. âIn fact we expect the biggest effect of the El Niño to emerge as it fully forms and then plays out over coming months and into next year,â Grose said. The Indian Ocean Dipole, another ocean cycle, is also moving toward its positive phase, which tends to reduce clouds and rainfall over Australia. âIn Australia, the warm winter was a new record and the seasonal forecast is for a warm spring as well,â Grose added.
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+In South America, the warmer season will also bring more precipitation, likely in torrential downpours. During past El Niño years, countries like Paraguay and Uruguay experienced deadly flooding, so the region is anticipating similar or worse conditions. âWe will probably have a hot summer and a rainy summer,â Gonçalves said.
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+As a result, more weather records are poised to fall this year as the planet continues to experience what will likely be the hottest year ever recorded. Figuring out all the ways this will affect us is, as scientists like to say, an âactive area of research.â Weâre learning in real time what happens when the world reaches an unprecedented state. And with the climate changing, humanity will see more changes it has never witnessed before.
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The worldâs brutal climate change report card, explained -
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+An oil refinery in France is one example of the kind of infrastructure that would need to transition to clean energy or capture its carbon emissions to meet global climate goals. | AFP via Getty Images
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+The first international climate change stocktake says trying is not enough.
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+Just about every country in the world committed to keeping climate change in check in 2015. This week, the United Nations issued its first report card for this goal and found that the world is falling behind while time is running out.
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+Under the 2015 Paris climate agreement, countries agreed to pitch in what they could to slash greenhouse gas emissions. Their initial proposals were nowhere near enough, so the accord created a mechanism called the global stocktake to keep everyone accountable.
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+Unlike other UN climate change reports that are meant to be informative and shy away from policy recommendations, the stocktake is explicitly meant to spur countries to act. Itâs a blunt progress assessment, and it lays out how much further countries must go in their emissions commitments the next time they come to the negotiating table at COP28, which will be held in the United Arab Emirates this December.
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+âThe Paris Agreement has driven near-universal climate action,â the report notes, but âmuch more is needed now on all fronts.â
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+The task ahead is immense: According to the report, global emissions need to be slashed 43 percent by 2030 to limit warming to 1.5 degrees Celsius, one of the main goalposts of the Paris agreement. But the world has already warmed about 1.2 degrees so far above preindustrial averages and is on track to pass the key threshold in the next few years. So when negotiators reconvene at the next climate summit, the stocktake will shape the discussion.
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+âIt carries a lot of weight,â said European Climate Foundation CEOLaurence Tubiana, who helped negotiate the Paris agreement. âThe [stocktake] is looking backwards, but even more importantly setting the direction for the next phase of climate policymaking.â
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+Among its recommendations, the report unapologetically calls for âphasing out all unabated fossil fuelsâ and for a âradical decarbonization of all sectors of the economy.â
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+But in a world facing economic turmoil, energy shocks, and unrelenting opposition from the biggest polluters, there are open questions about whether leaders will heed the message at all, and what theyâll actually do about it.
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+Coal, oil, and natural gas need to go
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+The stocktake says in stark terms that there can be no new fossil fuel infrastructure in a world committed to keeping warming in check, including phasing out the existing coal industry before 2050.
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+The exact language here is important. At previous climate conferences, countries fought over every word around fossil fuels, whether they should call for a âphase outâ or a more watered-down phrase like âenergy transition.â The latter leaves room for new fossil fuels without looking like governments are going back on their word.
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+But the stocktake, which will inform the political process from here on out, echoes the findings of other global bodies that no new fossil fuel infrastructure should be built in a world aligned with 1.5 degrees.
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+Thereâs some vagueness in what âunabatedâ means, however, and itâs likely to be a contentious topic at the next COP. The language leaves room, Tubiana explained, for remaining fossil fuels to rely on technology like carbon capture and storage. âBy 2050 weâll still have fossil fuels in the pipeline, the question is how much,â Tubiana said.
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+One key barrier to transitioning from fossil fuels is the trillions of dollars in subsidies that governments pour into the industry year after year. A recent analysis from the International Monetary Fund found these subsidies have only grown; they surged to $7 trillion last year, $2 trillion more than in 2021.
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+âThe removal of fossil fuel subsidies is a key strategy for addressing structural economic barriers that can perpetuate inertia to change and prevent cost-effective low-carbon alternatives from being adopted at scale,â the report says.
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+The stocktake also emphasizes the need to address emissions across the entire economy. Governments canât overlook the role of sectors like industry, which contributes to 25 percent of global emissions, and transportation, which contributes 15 percent.
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+Reducing these emissions requires targeting the demand and the supply in these sectors. For example, in transportation, regulations and incentives will help to phase out the internal combustion engine and push manufacturers to offer electric vehicles at a vast scale, but governments also need to think about reducing the need for private vehicles altogether through tactics like public transit. This extends to sectors like international shipping and aviation, both areas that are hard to decarbonize and have often been ignored in international climate negotiations.
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+The stocktake is clear that the time for small, incremental change is over: We need to think in terms of systems-wide change, and a wide breadth of policies to make deeper emissions cuts. âIf youâre rowing and you can turn your oar faster and faster, but if itâs not really going deep enough, you wonât get anywhere,â said David Waskow, director of the World Resources Instituteâs International Climate Initiative. âWe need to think in pace and speed, of course, but we also need depth.â
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+Everyone is doing something, but everyone needs to do more
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+The test now is whether countries will make the ârapid and deepâ greenhouse gas cuts the report says are required, delivering more financing and even deeper emissions cuts in the next round of pledges in 2025. But countries are dealing with other challenges too, and that will also shape what they bring to the table at COP28.
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+Shocks to food and energy prices, along with inflation, may mean there is less money to invest in clean energy. Major fossil fuel companies are also trying to influence the discussions and maintain their market share.
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+Meanwhile, many nations are still struggling to meet their own self-imposed pledges. The US, for example, has set a goal of slashing carbon pollution 50 percent from 2005 levels by 2030 while contributing $3 billion to the Green Climate Fund. But itâs struggling to meet both goals, even after the passage of historic climate legislation last year. Some countries have even seen their fossil fuel emissions go up.
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+So mustering the political will to make these drastic changes is going to be an immense challenge. But at the same time, cleaner energy is more affordable than ever and the stocktake says a transition away from fossil fuels is within our grasp. In many parts of the world, wind and solar power are the cheapest sources of new energy, sometimes undercutting existing fossil fuel sources. âThere are now sufficient cost-effective opportunities to address the 2030 emissions gap,â the report says. The challenges are entirely political hurdles.
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Suits is an unlikely time capsule for a troubled decade -
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+Gabriel Macht as Harvey Specter in Suits. | Shane Mahood/USA Network/NBCU Photo Bank/NBCUniversal via Getty Images
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+Suits is half comfort watch, half reckoning â and America canât stop streaming.
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+Itâs 2023, and everyone is watching Suits. The question is, which Suits are they watching?
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+In one corner, we have Suits, seasons one through four, the absurdist morality play. The concept: a high-powered Manhattan law firm and the cutthroat corporate lawyers who do their clientsâ bidding. The title: A reference to the sleazy characters, the glitzy aesthetic, and the fact that, unlike most legal dramas, Suits rarely ends up in a courtroom.
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+The catch: One of these hard-charging lawyers, bushy-tailed eager beaver Mike Ross, apprentice to the dashing artful dodger Harvey Specter, isnât actually an attorney at all.
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+In the other corner, we have Suits, seasons five through eight (just ignore season nine and the short-lived one-season spinoff, Pearson, neither of which is included on Netflix where this culture-wide rewatch is taking place): in which the show becomes self-aware, jettisons the moral antipathy of previous seasons, and puts itself on trial.
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+Suits never got its cultural due during the nine seasons it aired on the USA network. Until 2023, its main claim to fame was boosting the career of one-time princess Meghan Markle. Yet it currently stands poised to become Netflixâs biggest streaming hit of all time, after a viral TikTok video that made the rounds in May sparked renewed interest in the show â which has since been setting streaming records so wild they sound like theyâre completely made up.
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+The TikTok clip showcases the key scene of the entire show: The moment Harvey (Gabriel Macht) and Mike (Patrick J. Adams) meet, and Harvey falls in love at first recitation with Mike, his polymath brain, and his photographic memory. Although Mike is a dropout bike messenger whoâs literally in the middle of running a drug deal when they meet, Harvey hires him on the spot to work for his law firm, Pearson. The two of them construct an elaborate lie to create the illusion that Mike graduated from Harvard Law. Harveyâs drive to keep Mike by his side against all odds fuels the plot for most of the showâs eight-year run.
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+Suits may be the unexpected hit show of 2023, but it premiered in 2011, in a world that felt profoundly different from the one it finished with, in 2019. The result is an odd little time capsule. Over the course of the show, the world changed rapidly, and Suits responded to and evolved with that change â so much so that we can follow the trajectory of our own cultural evolution within its seasons. Suits was born out of an era when nihilistic absurdism dominated TV across a broad range of shows, from Always Sunny to Scandal. The oblivious ethos of that early-season Suits may be key to its renewed popularity: Philosophically, itâs escapist comfort food mixed with geeky pop culture refs and far too much reverence for Aaron Sorkin.
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+Yet itâs the latter era of the show thatâs really fascinating. Suits was born out of a society that memed performative uncaring, and it was all too fun and silly to take seriously â until it wasnât. As it progressed, Suits absorbed the ripples of political and cultural unease that characterized the â10s. In the showâs highest-rated episode (per IMDb votes), âFaith,â Mikeâs childhood priest tells him that he might think of âGodâ as âconsequences.â Suitsâ gods are capricious, but when they demand tithes, a bitch better pay up.
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+Suitsâ first half: A slick legal buddy drama that becomes an epistemic looking-glass
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+ Shane Mahood/USA Network/NBCU Photo Bank/NBCUniversal via Getty Images
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+Patrick J. Adams as Mike Ross and Gabriel Macht as Harvey Specter in Suits.
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+Suitsâ first half follows a law firm full of clearly drawn office character tropes: no-nonsense boss Jessica Pearson (Gina Torres), ultimate secretary Donna (Sarah Rafferty), volatile wannabe partner Louis Litt (Rick Hoffman), and long-suffering paralegal turned ultimate girlfriend Rachel (Markle). They all have one thing in common: Their lives revolve around the firm, eventually known as Pearson Specter Litt, or PSL.
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+That means that whether they know it or not, their lives revolve around keeping Mikeâs secret. Despite the flimsiness of the premise and the complete lack of logic about, well, anything, the first half of Suits fully milks the tension between Mikeâs go-getter enthusiasm for the law and the fact that heâs flagrantly breaking it.
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+Between this (silly) high-stakes drama, Suitsâ procedural formula deals in high-powered pettiness. Each episode sees the firm defending a shady corporation against another shady corporation, going back and forth over a series of legal maneuverings that allow them to trade quips and drop highly improbable interpretations of the law. Our antiheroes usually finagle their way into some kind of moral high ground, but not without stretching their credibility and our credulity. This Suits is a frothy treat in the pantheon of self-serious legal dramas. And thanks to the increasingly outlandish things Harvey and Mike do to get away with Mikeâs crime, like hacking the Harvard database and printing a fake Harvard degree, we never have to take any of it too seriously.
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+Except then we do!
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+Season four begins a gradual tonal shift characterized by forewarnings of disaster for the firm, as well as increased dysfunctionality among the ensemble. The showâs blatantly antisemitic early-season portrayal of Louis Litt actually gets worse for a while because seasons four and five double down on all of his worst traits in the name of drama. Those traits are all heinous stereotypes: Despite Rick Hoffmanâs best efforts at humanizing Louis, heâs mean-tempered, buffoonish, weak, disloyal, effeminate, and selfish above all else. The show presents him as spiteful and vindictive, a cheap, greedy, money-hoarding backstabber whoâs obsessed with power. At one point, he plays the role of Shylock, as if the theme couldnât get more explicit. Any time the screws are put to him, Louis turns volatile and vengeful. Itâs a tired, troubling routine, and unfortunately, even after the show writers finally realize what theyâve done and rapidly rehabilitate his character in later seasons, the subtext that he could be the firmâs weak link â more of an existential threat even than Mike whoâs literally not a lawyer!â never fully goes away.
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+Seasons five and six: The game changes
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+In season five, which aired in 2015â2016, the tonal change becomes even more pronounced: Harvey, whoâs hitherto prided himself on his weaponized superficiality, starts going to therapy to deal with his many abandonment issues. And someone finally prosecutes Mike for fraud. This development forces Suits into a much darker iteration of its implied âethics schmethics!â worldview. By the time Mike is finally facing trial in the latter half of season five, he and Harvey have gone from season one lawyers (and âlawyersâ) who proudly draw their moral lines and refuse to cross them to people willing to commit blackmail, forgery, perjury, and beyond. âDo whatever you have to do,â Harvey tells Mike as they get more and more desperate to avoid prison. âJust donât get caught.â
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+However, any time Mike and Harvey use their typical tactics â strong-arming, bargaining, one-upmanship â to shut down the case, opposing prosecuting attorney Gibbs (Leslie Hope) surmounts them by relying on the unshakeable truth: Mike isnât a lawyer. Mike isnât a lawyer! Yet one by one, all the other players at Pearson Specter line up behind him, committing to performing the lie that he is. The world of that lie keeps expanding; by the time Mike is finally exposed, no fewer than 13 recurring cast members know he never went to Harvard and are casually walking around covering for him.
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+Suits thus becomes an apt and revealing, if entirely unwitting, metaphor for the broader epistemic crisis thatâs come to define much of the modern age, in which people who are otherwise rational find themselves moving in an entirely different version of reality, from climate change denialism to Covid skepticism to the factual outcome of elections. Just as many of Trumpâs supporters started out espousing extremist nonsense for laughs yet wound up believing their own rhetoric, Mike and Harvey, who get together initially almost as a troll, ultimately come to believe their own reality distortion.
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+Mike becomes so convinced that heâs an actual lawyer that he tries to take on a new case while he is on trial for pretending to be a lawyer. Every time he careens into the fact that no one will testify to knowing him at Harvard because no one knew him because he never went to Harvard, he reacts with a dazed headshake, as though he canât quite believe theyâre inconveniencing him by refusing to help him bend the truth. Itâs difficult to watch him spend the back half of season five frantically trying and failing to coerce, beg, extort, and bribe witnesses to help him without being reminded of Trump asking the Georgia Secretary of State to âfind 11,780 votes.â
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+For all the writers clearly want us to root for Harvey and Mike to agree that Mike is, as one clientâs mother insists, âinnocent in [his] heart,â itâs harder for a post-Trump audience to do that than it would be for the sweet summer children of the Obama era. Harvey and Mike might deserve mercy after their sins have been acknowledged and confessed. But innocent they are not â and Suits, for its first six seasons, isnât interested in rehabilitating them. It only takes them a few episodes after Harvey finally engineers an early prison release for Mike in season six before the two of them are back to doing highly unethical things to get what they want.
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+Suits tries to create a world where the law isnât reality because it can always be manipulated for the right price. The show wants us to believe that since everyone in this universe is cutthroat and amoral by default, these guys are heroic for at least trying to do the right thing some of the time â except when they donât. In other words, itâs vibes, not truth, that really matter.
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+Which makes its entire abrupt turnaround in season seven such an interesting reveal â not for what it says about Suits butwhat it says about the rest of us.
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+Season seven of Suits tries to right its wrongs
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+Throughout Suitsâ first six seasons, its characters are essentially caricatures whose relationships with themselves and each other are mainly shallow and undeveloped. The showâs female characters suffer the most from this underwritten tendency, particularly Gina Torresâ Jessica, who never really gets to be more than a plot device. (Torres captained a spinoff, Pearson, launched from Suitsâ seventh-season finale, but it only lasted a single season, and itâs hard not to wonder if that was partly because the writers had so little to build on.) And though the show lives and dies with the lighthearted chemistry between Mike and Harvey, not even Gabriel Machtâs deep commitment to sending flirtatious smiles in Adamsâs direction can fully convince us that Mike deserves to be where heâs at.
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+Season sevenâs writers seem to have realized all of this abruptly. (Itâs probably no coincidence it was the first full season to follow the 2016 election.) Once it has straightened out the giant plot wrinkle it started with, the show goes full-throttle redemption arc, working overtime to deepen its characters and repair all of its negatives at once. Newly born again and (somehow) (nonsensically) admitted to the bar for real-real, Mike begins tackling large-scale pro bono cases with a social justice edge. Louis, we learn, has actually been in therapy all along; the show fast-tracks him through a personal growth arc that sees him almost instantly learning to put other people before himself. Donna, whose whole character til now has been âbeing loyal to Harvey,â suddenly gets dreams and lines like, âI think I regret putting Harvey over myself.â Season seven canât stop telling you how feminist it is: âA man canât swing a dead cat around here without hitting a strong-willed woman,â Rachelâs father says at one point.
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+When, in the seventh-season finale, Mike finally tells Harvey, âThis is who I am, itâs who Iâve always beenâ â meaning that heâs an ethical do-good lawyer who only wants to take pro-bono work for the betterment of humanity â Harvey is too good to remind him what a giant retcon this is, for both him and for Suits.
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+It helps that the show doesnât have to keep Mike on the straight and narrow for long: Instead, it gives Mike and Rachel a season seven finale send-off, providing them both with a chance to sail into the sunset as pro-bono lawyers. (Rachelâs fictional wedding aired in April 2018, just three weeks before Markleâs actual fairy tale wedding.) That send-off also doubles as another reset: As season eight rolls around, the remaining crew is right back to corporate schemes and stratagems, now headed up by Rachelâs dad (Wendell Pierce), who manages to be both fun and terrifying as the new top brass. Still, Suits, now self-aware, can never completely retreat into its former malaise of substituting movie quotes and pop culture cred for human connection and empathy.
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+By the showâs end, itâs all grown up; and if we all liked it a little better when it was younger, obnoxious, and oblivious â well, perhaps we all liked ourselves a little better in 2011, too.
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From The Hindu: Sports
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Sumit Nagal ousts top seed Ramos-Vinolas in Challenger quarterfinals -
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Not facing Pakistani bowlers enough makes difference at big events: Shubman Gill - India get to play Pakistan only during Asia Cup or at the ICC events
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Asia Cup 2023 | India seeks answer to Rahul-Kishan riddle ahead of high-voltage Pakistan clash - Pakistan has an edge on paper in this department, but India will believe that they have the ammunition to strike back in kind.
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As an all-rounder, I carry double or triple workload compared to specialists: Hardik Pandya - The ODI vice-captain explained that he reads the match situation and then takes a call on whether to bowl his full quota of 10 overs or not
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Bopanna-Ebden lose U.S. Open menâs doubles final to Ram-Salisbury - Playing only his second menâs doubles final at a Major tournament, Bopanna and his Australian teammate lost the title clash 6-2 3-6 4-6
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From The Hindu: National News
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G-20 New Delhi Leadersâ Declaration â Highlights -
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SiRST inks MoU with Edappal-based IDTR for road safety research -
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BSF jawan posted near LoC is reported missing in Poonch - Search operation is underway but he had not been located till Saturday afternoon
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Mallikarjun Kharge sees BJPâs pushing for âBharatâ as afterthought of INDIA coalition - Kharge pointed to the Constitution of India which called the country as India as well as âBharatâ and asserted that both meant the same land.
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G-20 adopts New Delhi Leadersâ Declaration in significant victory for India - The announcement about the consensus on the declaration and its subsequent adoption came hours after India circulated a new text to the G-20 countries to describe the Ukraine conflict
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From BBC: Europe
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Greek floods: PM Mitsotakis warns of very unequal battle with nature - Rescuers try to reach hundreds of people trapped by floods in Greece where 10 people have died.
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Elon Musk says he withheld Starlink over Crimea to avoid escalation - A senior Ukrainian official says this enabled Russian attacks and accuses him of âcommitting evilâ.
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Ukraine condemns âshamâ elections in Russian-occupied regions - Many taking part in early polling have been asked to vote in the presence of armed Russian soldiers.
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Thodex cryptocurrency boss jailed for 11,196 years in Turkey for fraud - Faruk Fatih Ozer was found guilty of defrauding millions of dollars from investors in his collapsed Thodex platform.
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Luis Rubiales: Spanish prosecutor files complaint with high court - A prosecutor files a complaint with Spainâs high court against suspended football federation president Luis Rubiales for sexual assault.
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From Ars Technica
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Microsoft offers legal protection for AI copyright infringement challenges - âSome customers are concerned about the risk of IP infringement claims,â says Microsoft. - link
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Teenâs death after eating a single chip highlights risks of ultra-spicy foods - The hot pepper linked to teenâs death can cause arteries in the brain to spasm. - link
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The MonsterVerse comes to Apple TV+ with Monarch: Legacy of Monsters teaser - âIf you come with me, youâll know everything, I promise.â - link
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X sues Calif. to avoid revealing how it makes âcontroversialâ content decisions - X decried lawâs âdraconian financial penaltiesâ up to $15K per violation per day. - link
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FTC judge rules Intuit broke law, must stop advertising TurboTax as âfreeâ - Intuit plans appeal, slams FTCâs âpredetermined decision.â - link
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From Jokes Subreddit
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Blonde Wife -
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+One winter morning during breakfast a husband and wife in Northern Minnesota were listening to the radio.
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+They heard the announcer say, âWe are going to have 8 to 10 inches of snow today. You must park your car on the even-numbered side of the street, so the snowplows can get through.â
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+So the good wife went out and moved her car.
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+A week later while they are eating breakfast again, the radio announcer said, âWe are expecting 10 to 12 inches of snow today. You must park your car on the odd-numbered side of the street so the snowplows can get through.â
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+The good wife went out and moved her car again.
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+The next week they were again having breakfast, when the radio announcer said, âWe are expecting 12 to 14 inches of snow today. You must parkâŠâ Then the electric power went out.
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+The good wife was very upset, and with a worried look on her face she said, âHoney, I donât know what to do. Which side of the street do I need to park on so the snowplows can get through?â
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+With the love and understanding in his voice that all men who are married to blondes exhibit, the husband replied,
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+"Why donât you just leave it in the garage this time?
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A young widow goes to the funeral parlour to plan her husbandâs funeral -
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+She met with the mortician who asked her how she wants the body dressed.
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+âHe always looked so good in blue. I want him to be buried in a blue suit.â
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+This posed a problem as he had been delivered to the funeral parlour in the black suit he was wearing when he died. However, the wife was adamant.
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+âI donât care what it costs!â she said, handing the mortician a blank cheque. âDo whatever it takes.â
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+The mortician agrees and the next day called the widow back. When she arrived, the mortician revealed her husband in very sharp blue suit. The wife is very pleased.
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+âThank you so much, this is perfect. Whatever it cost, it was worth it.â
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+The mortician handed her back the blank cheque.
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+âThere is no charge, madam,â he said.
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+âI donât understand,â the widow said. âHow did you manage this for free?â
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+âWell, shortly after you left yesterday, another gentleman was delivered. He was similar in size and build to your husband and he was wearing a blue suit. I asked his next of kin if they would object to him being buried in a black suit instead of the blue one, and they said they didnât care.â
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+âSo you undressed them, and swapped the suits?â the widow said. âThat must have been difficult.â
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+âOh no,â said the mortician. âI just swapped the heads.â
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A priest opens his confessional panel to a young boy. -
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+The boy says, âForgive me Father for I have sinned.â The priest asked, âWhat have you done, my son?â He replies, âI threw pickles into the well.â The priest seems a little confused but says, âVery well. Say three Hail Marys and you will be forgiven.â
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+Four more boys follow and say the same thing, the priest wondering eventually if heâs being pranked. Finally, a young boy looking very upset steps into the confessional.
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+âLet me guess,â says the priest, âYou threw pickles into the well?â
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+The boy sniffs and said, âNo Father, I AM pickles!â
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Mauricio Zina/Bloomberg via Getty Images
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Shane Mahood/USA Network/NBCU Photo Bank/NBCUniversal via Getty Images
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