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<title>18 June, 2023</title>
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<h1 data-aos="fade-down" id="covid-19-sentry">Covid-19 Sentry</h1>
<h1 data-aos="fade-right" data-aos-anchor-placement="top-bottom" id="contents">Contents</h1>
<ul>
<li><a href="#from-preprints">From Preprints</a></li>
<li><a href="#from-clinical-trials">From Clinical Trials</a></li>
<li><a href="#from-pubmed">From PubMed</a></li>
<li><a href="#from-patent-search">From Patent Search</a></li>
</ul>
<h1 data-aos="fade-right" id="from-preprints">From Preprints</h1>
<ul>
<li><strong>Personality Psychology in Times of Crisis: Profile-specific Recommendations on how to deal with COVID-19</strong> -
<div>
The early stages of the COVID-19 pandemic posed a twofold global health threat: Besides the evident danger to human life, the corona crisis is also a psychological crisis. Psychologists worldwide have contributed to cushion the distress that is laid on many societies and enforce adaptive coping strategies. However, psychological support in the past has often been broadly applied, has not been particularly parsimonious and has often been focused on severe psychological stressors. In this brief report we describe the development and application of a low-threshold tool that generates personality-specific recommendations on how to functionally cope with the psychological challenges of the corona crisis. The tool gained widespread attention in Germany and many other countries and was well received by users. It demonstrates how psychological knowledge from personality and health psychology can be combined to be of very concrete use for many people in a threatening situation.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://psyarxiv.com/r9q6g/" target="_blank">Personality Psychology in Times of Crisis: Profile-specific Recommendations on how to deal with COVID-19</a>
</div></li>
<li><strong>SARS-CoV-2 Delta Variant Remains Viable in Environmental Biofilms found in Meat Packaging Plants</strong> -
<div>
To determine why SARS-CoV-2 appears to thrive specifically well in meat packaging plants, we used SARS-CoV-2 Delta variant and meat packaging plant drain samples to develop mixed-species biofilms on materials commonly found within meat packaging plants (stainless steel (SS), PVC, and ceramic tile). Our data provides evidence that SARS-CoV-2 Delta variant remained viable on all the surfaces tested with and without an environmental biofilm. We observed that SARS-CoV-2 Delta variant was able to remain infectious with each of the environmental biofilms, however, we detected a significant reduction in viability post-exposure to Plant B biofilm on SS, PVC, and on ceramic tile chips, and to Plant C biofilm on SS and PVC chips. The numbers of viable SARS-CoV-2 Delta viral particles was 1.81 - 4.57-fold high than the viral inoculum incubated with the Plant B and Plant C environmental biofilm on SS, and PVC chips. We did not detect a significant difference in viability when SARS-CoV-2 Delta variant was incubated with the biofilm obtained from Plant A on any of the materials tested and SARS-CoV-2 Delta variant had higher plaque numbers when inoculated with Plant C biofilm on tile chips, with a 2.75-fold difference compared to SARS-CoV-2 Delta variant on tile chips by itself. These results indicate a complex virus-environmental biofilm interaction which correlates to the different bacteria found in each biofilm. Our results also indicate that there is the potential for biofilms to protect SARS-CoV-2 from disinfecting agents and remaining prevalent in meat packaging plants.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.06.15.545172v1" target="_blank">SARS-CoV-2 Delta Variant Remains Viable in Environmental Biofilms found in Meat Packaging Plants</a>
</div></li>
<li><strong>High-confidence placement of difficult-to-fit fragments into electron density by using anomalous signals - a case study using hits targeting SARS-CoV-2 non-structural protein 1</strong> -
<div>
The identification of multiple simultaneous orientations of small molecule inhibitors binding to a protein target is a common challenge. It has recently been reported that the conformational heterogeneity of ligands is widely underreported in the Protein Data Bank, which is likely to impede optimal exploitation to improve affinity of these ligands. Significantly less is even known about multiple binding orientations for fragments (&lt; 300 Da) although this information would be essential for subsequent fragment optimisation using growing, linking or merging and rational structure-based design. Here we use recently reported fragment hits for the SARS-CoV-2 non-structural protein 1 (nsp1) N-terminal domain to propose a general procedure for unambiguously identifying binding orientations of 2-dimensional fragments containing either sulphur or chloro substituents within the wavelength range of most tunable beamlines. By measuring datasets at two energies, using a tuneable beamline operating in vacuum and optimised for data collection at very low X-ray energies, we show that the anomalous signal can be used to identify multiple orientations in small fragments containing sulphur and/or chloro substituents or to verify recently reported conformations. Although in this specific case we identified the positions of sulphur and chlorine in fragments bound to their protein target, we are confident that this work can be further expanded to additional atoms or ions which often occur in fragments. Finally, our improvements in the understanding of binding orientations will also serve to improve the rational optimisation of SARS-CoV-2 nsp1 targeting fragment hits.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.06.16.545251v1" target="_blank">High-confidence placement of difficult-to-fit fragments into electron density by using anomalous signals - a case study using hits targeting SARS-CoV-2 non-structural protein 1</a>
</div></li>
<li><strong>Evaluation of 3-D printed swabs for respiratory sampling and testing for SARS-CoV-2 during the early pandemic period</strong> -
<div>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
Appropriate collection of respiratory samples is essential for accurate diagnostic testing of respiratory pathogens such as, SARS-CoV-2. Early in the pandemic, there was a shortage of nasopharyngeal (NP) swabs and difficulty in sampling suspected cases. Therefore, we developed a 3D printed nasal swab for anterior nares, paired with in-house viral transport medium (VTM). The utility of this 3D swab kit was investigated in comparison with the standard NP commercial swab and VTM, in 200 individuals between August and September 2021. Subjects were those presenting for diagnostic testing for SARS-CoV-2 using the RT- PCR (cobas Roche assay) assay. NP samples were taken from each subject using the standard NP and 3D swabs followed by RT-PCR on paired specimens. CT values for amplification of gene targets were evaluated to determine assay parameters based on viral load cut offs of ≤ CT 35 or, ≤ CT 37. For high to medium viral loads, 3D swab based PCR testing had a sensitivity of 93%, specificity of 99%, positive predictive value (PPV) of 98.5% and negative predictive value (NPV) of 96.2% respectively. For low viral loads, 3D swab testing had a sensitivity of 88%, specificity of 99%, with a PPV of 98.5% and NPV of 93.2%.%. 3D swab sampling of anterior nares was comparable with NP sampling using standard swabs for SARS-CoV-2 specimens with a medium to high viral load. Therefore, 3D swab based sampling is a reliable and convenient local solution for collecting respiratory samples for SARS-CoV-2 diagnostic testing.
</p>
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.06.14.23291367v1" target="_blank">Evaluation of 3-D printed swabs for respiratory sampling and testing for SARS-CoV-2 during the early pandemic period</a>
</div></li>
<li><strong>Determinants of post-acute COVID-19 syndrome among hospitalized severe COVID-19 patients: a 2-year follow-up study</strong> -
<div>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
Abstract Background: Coronavirus disease–19 (COVID–19), emerged as a public health threat in December 2019. The number of COVID–19 cases worldwide is now more than 765 million with more than 6.9 million dead. During follow–up visits following discharge, a large percentage of patients were discovered to still be suffering from health issues that lower their quality of life and ability to return to work. This study assessed the prevalence and associated risk factors of post-acute COVID–19 syndrome (PACS) among severe COVID–19 patients who were discharged from Millennium COVID–19 care center, Addis Ababa, Ethiopia. Methods: A cross–sectional study using data collected from patient charts and a follow–up telephone interview after two years of discharge. Systematic random sampling was used to select a total of 400 patients. A structured questionnaire developed from the case report form for PACS of WHO was used. Frequency and cross–tabulation were used for descriptive statistics. Predictor variables with a p–value &lt;0.25 in bivariate analyses were included in the logistic regression. Result: Out of the 400 patients, 20 patients were dead, 14 patients refused to give consent, and 26 patients could not be reached because their phone was not working. Finally, 340 were included in the study. The majority (68.5%) were males and the mean age was 53.9 (±13.3 SD) years. Most of the patients (60%) has one or more comorbidity. The most common symptom at presentation was cough (93.5%), followed by shortness of breath (82.1%) and fatigue (69.7%). The mean duration of hospital admission was 12.3 (±6.5 SD) days. More than a third (38.1%) of the patients reported the persistence of at least one symptom after hospital discharge. The most common symptoms were fatigue (27.5%) and Cough (15.3%). older age (AOR 1.04, 95% CI 1.02 – 1.07), female sex (AOR 1.82, 95% CI 1.00 – 3.29), presence of comorbidity (AOR 2.38, 95% CI 1.35 – 4.19), alcohol use (AOR 3.05, 95% CI 1.49 – 6.26), fatigue at presentation (AOR 2.18, 95% CI 1.21 – 3.95), and longer hospital stay (AOR 1.06, 95% CI 1.02 – 1.10) were foundto increase the odds of developing post–acute COVID-19 syndrome. Higher hemoglobin level was found to decrease the risk of subsequent post–acute COVID–19 syndrome (AOR 0.84, 95% CI 0.71 – 0.99). Conclusion: establishing a dedicated PACS followup clinic, especially for those with a higher risk can help to provide comprehensive care for the patients and improve their quality of life. Keywords: Post –acute COVID –19 syndrome, Long COVID, Chronic COVID –19
</p>
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.06.13.23290674v1" target="_blank">Determinants of post-acute COVID-19 syndrome among hospitalized severe COVID-19 patients: a 2-year follow-up study</a>
</div></li>
<li><strong>Omicron vs. the Rest: Assessing the Competitive Dynamics and Coinfection Scenarios of COVID-19 Strains on a Social Network</strong> -
<div>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
The rapid spread and evolving nature of COVID-19 variants have raised concerns regarding their competitive dynamics and coinfection scenarios. In this study, we assess the competitive interactions between the Omicron variant and other prominent variants (Alpha, Beta, and Delta) on a social network, considering both single infection and coinfection states. Using the SIRS model, we simulate the progression of these variants and analyze their impact on infection rates, mortality, and overall disease burden. Our findings demonstrate that the Alpha and Beta strains exhibit comparable contagion levels, with the Alpha strain displaying higher infection and mortality rates. Moreover, the Delta strain emerges as the most prevalent and virulent strain, surpassing the other variants. When introduced alongside the less virulent Omicron strain, the Delta strain results in higher infection and mortality rates. However, the Omicron strain9s dominance leads to an overall increase in disease statistics. Remarkably, our study highlights the efficacy of the Omicron variant in supplanting more virulent strains and its potential role in mitigating the spread of infectious diseases. The Omicron strain demonstrates a competitive advantage over the other variants, suggesting its potential to reduce the severity of the disease and alleviate the burden on healthcare systems. These findings underscore the importance of monitoring and understanding the dynamics of COVID-19 variants, as they can inform effective prevention and mitigation strategies, particularly with the emergence of variants that possess a relative advantage in controlling disease transmission.
</p>
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.06.13.23291332v1" target="_blank">Omicron vs. the Rest: Assessing the Competitive Dynamics and Coinfection Scenarios of COVID-19 Strains on a Social Network</a>
</div></li>
<li><strong>The relative effectiveness of a high-dose quadrivalent influenza vaccine vs standard-dose quadrivalent influenza vaccines in older adults in France: a retrospective cohort study during the 2021-22 influenza season</strong> -
<div>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
<b>Background:</b> High-dose quadrivalent influenza vaccine (HD-QIV) was introduced during the 2021/22 influenza season in France for adults aged ≥65 years as an alternative to standard-dose quadrivalent influenza vaccines (SD-QIV). This is the first study to estimate the relative vaccine effectiveness (rVE) of HD-QIV versus SD-QIV against influenza-related hospitalizations in France. <b>Methods:</b> Community-dwelling individuals aged ≥65 years with reimbursed influenza vaccine claims during the 2021/22 influenza season were included from the French national health insurance database. Individuals were followed up from vaccination day to 30 June 2022, nursing home admission or death date. Baseline socio-demographic and health characteristics were identified from medical records over the 5 previous years. Hospitalizations due to influenza and other causes were recorded from 14 days after vaccination to end of follow-up. HD-QIV and SD-QIV vaccinees were matched using 1:4 propensity score matching with an exact constraint on age group, sex, week of vaccination and region. Incidence rate ratios (IRR) were estimated using zero-inflated Poisson or zero-inflated negative binomial regression models. <b>Results:</b> We matched 405,385 (99.9%) HD-QIV to 1,621,540 SD-QIV vaccinees. HD-QIV was associated with a 23.3% (95%CI: 8.4–35.8) lower rate of influenza hospitalizations compared to SD-QIV. Post-matching, we observed higher rates in the HD-QIV group for hospitalizations non-specific to influenza and for negative control outcomes, suggesting residual confounding by indication. <b>Conclusions:</b> HD-QIV was associated with lower influenza-related hospitalization rates versus SD-QIV, consistent with existing evidence, in the context of high SARS-CoV-2 circulation in France and likely prioritization of HD-QIV for older/more comorbid individuals.
</p>
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.06.15.23291345v1" target="_blank">The relative effectiveness of a high-dose quadrivalent influenza vaccine vs standard-dose quadrivalent influenza vaccines in older adults in France: a retrospective cohort study during the 2021-22 influenza season</a>
</div></li>
<li><strong>Tracking SARS-CoV-2 seropositivity in rural communities using blood-fed mosquitoes</strong> -
<div>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
The spread of SARS-CoV-2 cannot be well monitored and understood in areas without capacity for effective disease surveillance. Countries with a young population will have disproportionately large numbers of asymptomatic or pauci-symptomatic infections, further hindering detection of infection in the population. Sero-surveillance on a country-wide scale by trained medical professionals may be limited in scope in resource limited setting such as Mali. Novel ways of broadly sampling the human population in a non-invasive method would allow for large-scale surveillance at a reduced cost. Here we evaluate the collection of naturally bloodfed mosquitoes to test for human anti-SARS-CoV-2 antibodies in the laboratory and at five field locations in Mali. Immunoglobulin-G antibodies were found to be readily detectable within the mosquito bloodmeals by a bead-based immunoassay at least through 10 hours post-feeding with high sensitivity (0.900 STD=0.059) and specificity (0.924 STD=0.080), respectively, indicating that most blood-fed mosquitoes collected indoors during early morning hours (and thus, have likely fed the previous night) are viable samples for analysis. We find that reactivity to four SARS-CoV-2 antigens rose during the pandemic from pre-pandemic levels. Consistent with other sero-surveillance studies in Mali, crude seropositivity of blood sampled via mosquitoes was 6.3% in October/November 2020 over all sites, and increased to 25.1% overall, with the town closest to Bamako reaching 46.7% in February of 2021. Mosquito bloodmeals a viable target for conventional immunoassays, and therefore country-wide sero-surveillance of human diseases (both vector-borne and non-vector-borne) is attainable in areas where human-biting mosquitoes are common, and is an informative, cost-effective, non-invasive sampling option.
</p>
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.06.13.23291267v1" target="_blank">Tracking SARS-CoV-2 seropositivity in rural communities using blood-fed mosquitoes</a>
</div></li>
<li><strong>(PREPRINT PAPER) A Moderated Mediation Model of Self-Construal, Social Trust, and Compliance on Covid-19 Public Health Regulation: A Cross-country Analysis</strong> -
<div>
To address the global Covid-19 pandemic, governments around the world require on the collective cooperation of their citizens to comply with public health regulation. Earlier studies examined the extent to which self-construal has an impact on individual compliance to law. However, existing literature has paid little significant attention to behavioural outcome of self-construal in the pandemic context across countries and cultures. The aim of this study was; 1) to determine whether interdependent self-construal predicts compliance of Covid-19 public health regulation, 2) to examine if the association was mediated by individual social trust, and 3) to test whether these associations were moderated by respondent’s country of residence (US x Indonesia). General adult respondents from US (N=231) and Indonesia (N=440) were voluntary participated in a survey measuring their trust to the government, interdependent self-construal orientation and compliance toward Covid-19 public health regulation. While our moderated mediation model involving respondent’s country residence did not support the hypothesis, the mediation analysis demonstrated significant association between interdependent self-construal and compliance via social trust. Our additional simple moderation analysis on direct effect of interdependent self-construal and compliance showed significant findings. Further, theoretical and practical implications of these findings were discussed in the following paper.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://psyarxiv.com/hjz6n/" target="_blank">(PREPRINT PAPER) A Moderated Mediation Model of Self-Construal, Social Trust, and Compliance on Covid-19 Public Health Regulation: A Cross-country Analysis</a>
</div></li>
<li><strong>M3NetFlow: a novel multi-scale multi-hop modular graph AI model for multi-omics data integration and signaling network inference</strong> -
<div>
The integration and interpretation of multi-omics data play a crucial role in systems biology for prioritizing key molecular targets and deciphering core signaling pathways of complex diseases, such as cancer, covid-19 and Alzheimer's disease. However, it remains a challenge that has not been adequately addressed. Graph neural networks (GNN) have been emerged as powerful artificial intelligence models for analyzing data with a graphical structure. Nevertheless, GNN models have not been sufficiently designed for integrative and interpretable analysis of multi-omics data. In this study, we propose a novel multi-scale multi-hop modular GNN model, M3NetFlow, to integrate and interpret multi-omics data to rank key targets and infer core signaling pathways. Specifically, we applied the M3NetFlow model to infer cell-line specific core signaling networks explaining drug combination response. The evaluation and comparison results on drug combination prediction showed that the M3NetFlow model achieved significantly higher prediction accuracy than existing GNN models. Furthermore, M3NetFlow can predict key targets and infer essential signaling networks regulating drug combination response. It is critical for investigating mechanisms of synergy, and guiding the development of personalized precision medicine for patients with drug resistance. This model can be applied to general multi-omics data-driven research.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.06.15.545130v1" target="_blank">M3NetFlow: a novel multi-scale multi-hop modular graph AI model for multi-omics data integration and signaling network inference</a>
</div></li>
<li><strong>Mapping SARS-CoV-2 antigenic relationships and serological responses</strong> -
<div>
During the SARS-CoV-2 pandemic, multiple variants escaping pre-existing immunity emerged, causing concerns about continued protection. Here, we use antigenic cartography to analyze patterns of cross-reactivity among a panel of 21 variants and 15 groups of human sera obtained following primary infection with 10 different variants or after mRNA-1273 or mRNA-1273.351 vaccination. We find antigenic differences among pre-Omicron variants caused by substitutions at spike protein positions 417, 452, 484, and 501. Quantifying changes in response breadth over time and with additional vaccine doses, our results show the largest increase between 4 weeks and &gt;3 months post-2nd dose. We find changes in immunodominance of different spike regions depending on the variant an individual was first exposed to, with implications for variant risk assessment and vaccine strain selection.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2022.01.28.477987v3" target="_blank">Mapping SARS-CoV-2 antigenic relationships and serological responses</a>
</div></li>
<li><strong>Perceptions Matter: Quasi-Experimental Evidence on the Effects of Spain’s New Minimum Income on Households’ Financial Wellbeing</strong> -
<div>
This paper examines how minimum income schemes (MISs) affect households’ financial wellbeing and whether this effect differs across objective material conditions and households’ perceptions. Two reasons motivate this study. First, while the Covid-19 pandemic, the ecological transition and the cost-of-living crisis have all prompted a renewed interest in MISs, no consensus exists on how effective these schemes are in improving households’ financial wellbeing. Second, when evaluating MISs, the literature focuses on objective measures of financial wellbeing, namely monetary poverty. Yet, peoples’ perceptions of their own situation can be instrumental in affecting their health, productivity and decision-making and can reveal important information about adaptation mechanisms or spillovers to non-recipients. This paper examines the case study of Spain, a country that introduced a new MIS in 2020. The study uses Eurostat survey data for the 2010-2022 period in a Synthetic Control Method analysis. The results show that, while the policy had no significant effect on objective financial wellbeing measures (i.e. the poverty rate, the poverty gap and mean income) for its first year and a half of existence, it did considerably improve subjective financial wellbeing after two years and a half, as it helped households feel less pessimistic about the evolution of their finances during the Covid-19 and cost-of-living crises. The paper discusses several mechanisms explaining this differentiated impact of the policy, such as its lagged rollout, the improvements made to the benefit from 2022 as well as anticipation, placebo and positive spillover effects of the MIS. The findings highlight the importance for practitioners to consider subjective measures when assessing income support schemes.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://osf.io/preprints/socarxiv/wv7xt/" target="_blank">Perceptions Matter: Quasi-Experimental Evidence on the Effects of Spain’s New Minimum Income on Households’ Financial Wellbeing</a>
</div></li>
<li><strong>Measuring short-term mobility patterns in North America using Facebook Advertising data, with an application to adjusting Covid-19 mortality rates</strong> -
<div>
Patterns and trends in short-term mobility are important to understand, but data required to measure such movements are often not available from traditional sources. We collected daily data from Facebook’s Advertising Platform to measure short-term mobility across all states and provinces in the United States and Canada. We show that rates of short-term travel vary substantially over geographic area, but also by age and sex, with the highest rates of travel generally for males. Strong seasonal patterns are apparent in travel to many areas, with different regions experiencing either increased travel or decreased travel over winter, depending on climate. Further, some areas appear to show marked changes in mobility patterns since the onset of the pandemic. We used the traveler rates constructed from Facebook to adjust Covid-19 mortality rates over the period July 2020 to July 2021, and showed that accounting for travelers leads to on average a 3 per cent difference in implied mortality rates, with substantial variation across demographic groups and regions.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://osf.io/preprints/socarxiv/bev4p/" target="_blank">Measuring short-term mobility patterns in North America using Facebook Advertising data, with an application to adjusting Covid-19 mortality rates</a>
</div></li>
<li><strong>Are patterns of discounting choices stable over time?</strong> -
<div>
Few studies have examined the stability of discounting responses over time. We examined delay and probabilistic discounting of losses at two time points, 13-16 months apart. We found that people do change over time in the frequency with which they select immediate and certain losses. These changes in discounting steepness for delayed and probabilistic losses were predicted by different profiles of state-dependent factors (i.e., local numbers of COVID-19 cases and deaths, anxiety, and depression). We also identified subgroups of individuals with different loss response patterns, and although the tendency to switch between subgroups over time was below chance, it was not negligible, particularly for delay discounting. Further, subgroup changes for delay, but not probabilistic, discounting were influenced by age as well as instability of income and intolerance of uncertainty. Together, these findings indicate the importance of considering temporal stability and the role of state-dependent factors in discounting research.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://osf.io/4d7ny/" target="_blank">Are patterns of discounting choices stable over time?</a>
</div></li>
<li><strong>Repurposing Remdesivir for COVID-19: Computational Drug Design Targeting SARS-CoV-2 RNA Polymerase and Main Protease using Molecular Dynamics Approach</strong> -
<div>
The coronavirus disease of 2019 (COVID-19) is a highly contagious respiratory illness that has become a global health crisis with new variants, an unprecedented number of infections, and deaths and demands urgent manufacturing of potent therapeutics. Despite the success of vaccination campaigns around the globe, there is no particular therapeutics approved to date for efficiently treating infected individuals. Repositioning or repurposing previously effective antivirals against RNA viruses to treat COVID-19 patients is a feasible option. Remdesivir is a broad-spectrum antiviral drug that the Food and Drug Administration (FDA) licenses for treating COVID-19 patients who are critically ill patients. Remdesivir's low efficacy, which has been shown in some clinical trials, possible adverse effects, and dose-related toxicities are issues with its use in clinical use. Our study aimed to design potent derivatives of remdesivir through the functional group modification of the parent drug targeting RNA-dependent RNA polymerase (RdRp) and main protease (MPro) of SARS-CoV-2. The efficacy and stability of the proposed derivatives were assessed by molecular docking and extended molecular dynamics simulation analyses. Furthermore, the pharmacokinetic activity was measured to ensure the safety and drug potential of the designed derivatives. The derivatives were non-carcinogenic, chemically reactive, highly interactive, and stable with the target proteins. D-CF3 is one of the designed derivatives that finally showed stronger interaction than the parent drug, according to the docking and dynamics simulation analyses, with both target proteins. However, in vitro and in vivo investigations are guaranteed to validate the findings in the future. Keywords: SARS-CoV-2; RNA-dependent RNA polymerase (RdRp); Main protease (MPro); Remdesivir; Modified derivatives; Molecular docking; Molecular dynamics simulation.
</div>
<div class="article-link article-html-link">
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.06.15.545129v1" target="_blank">Repurposing Remdesivir for COVID-19: Computational Drug Design Targeting SARS-CoV-2 RNA Polymerase and Main Protease using Molecular Dynamics Approach</a>
</div></li>
</ul>
<h1 data-aos="fade-right" id="from-clinical-trials">From Clinical Trials</h1>
<ul>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Community-engaged Optimization of COVID-19 Rapid Evaluation And TEsting Experiences</strong> - <b>Conditions</b>:   COVID-19;   COVID-19 Pandemic<br/><b>Interventions</b>:   Behavioral: COVID-19 walk-up, on-site testing strategy;   Behavioral: Community Health Worker (CHW) leading testing navigation and general preventive care reminders;   Behavioral: No-cost self-testing kit vending machines<br/><b>Sponsors</b>:   University of California, San Diego;   San Ysidro Health Center<br/><b>Not yet recruiting</b></p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Influence of Manual Diaphragm Release on Pulmonary Functions in Women With COVID-19</strong> - <b>Condition</b>:   COVID-19 Pneumonia<br/><b>Interventions</b>:   Other: manual therapy;   Other: breathing exercise and prone position alone<br/><b>Sponsor</b>:   Cairo University<br/><b>Completed</b></p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Safety Study of COVID19 Vaccine on the Market</strong> - <b>Condition</b>:   COVID-19<br/><b>Intervention</b>:   Biological: Recombinant new coronavirus vaccine (CHO cell)<br/><b>Sponsors</b>:   Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd.;   Hunan Provincial Center for Disease Control and Prevention;   Guizhou Center for Disease Control and Prevention;   Hainan Center for Disease Control &amp; Prevention<br/><b>Recruiting</b></p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>ACTIV-6: COVID-19 Study of Repurposed Medications - Arm F (Montelukast)</strong> - <b>Condition</b>:   Covid19<br/><b>Interventions</b>:   Other: Placebo;   Drug: Montelukast<br/><b>Sponsors</b>:   Susanna Naggie, MD;   National Center for Advancing Translational Sciences (NCATS);   Vanderbilt University Medical Center<br/><b>Recruiting</b></p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>ACTIV-6: COVID-19 Study of Repurposed Medications - Arm B (Fluvoxamine)</strong> - <b>Condition</b>:   Covid19<br/><b>Interventions</b>:   Drug: Fluvoxamine;   Other: Placebo<br/><b>Sponsors</b>:   Susanna Naggie, MD;   National Center for Advancing Translational Sciences (NCATS);   Vanderbilt University Medical Center<br/><b>Completed</b></p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>ACTIV-6: COVID-19 Study of Repurposed Medications - Arm D (Ivermectin 600)</strong> - <b>Condition</b>:   Covid19<br/><b>Interventions</b>:   Drug: Ivermectin;   Other: Placebo<br/><b>Sponsors</b>:   Susanna Naggie, MD;   National Center for Advancing Translational Sciences (NCATS);   Vanderbilt University Medical Center<br/><b>Completed</b></p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>ACTIV-6: COVID-19 Study of Repurposed Medications - Arm E (Fluvoxamine 100)</strong> - <b>Condition</b>:   Covid19<br/><b>Interventions</b>:   Drug: Fluvoxamine;   Other: Placebo<br/><b>Sponsors</b>:   Susanna Naggie, MD;   National Center for Advancing Translational Sciences (NCATS);   Vanderbilt University Medical Center<br/><b>Completed</b></p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Pycnogenol® in Post-COVID-19 Condition</strong> - <b>Conditions</b>:   Post COVID-19 Condition;   Long COVID<br/><b>Interventions</b>:   Drug: Pycnogenol®;   Drug: Placebo<br/><b>Sponsor</b>:   University of Zurich<br/><b>Recruiting</b></p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Efficacy of Bailing Capsule on Pulmonary Fibrosis After COVID-19</strong> - <b>Conditions</b>:   Pulmonary Fibrosis;   COVID-19 Pneumonia<br/><b>Intervention</b>:   Drug: Bailing capsule<br/><b>Sponsor</b>:   Second Affiliated Hospital, School of Medicine, Zhejiang University<br/><b>Not yet recruiting</b></p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Evaluating Emetine for Viral Outbreaks (EVOLVE)</strong> - <b>Condition</b>:   COVID-19<br/><b>Interventions</b>:   Drug: Emetine Hydrochloride;   Drug: Placebo<br/><b>Sponsors</b>:   Johns Hopkins University;   Nepal Health Research Council;   Bharatpur Hospital Chitwan;   Stony Brook University;   Rutgers University<br/><b>Not yet recruiting</b></p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>A Study to Evaluate the Safety and Efficacy of COVID-19 Convalescent Plasma (CCP) Transfusion to Prevent COVID-19 in Adult Recipients Following Hematopoietic Stem Cell Transplantation</strong> - <b>Conditions</b>:   COVID-19;   Hematopoietic Stem Cell Transplantation<br/><b>Intervention</b>:   Biological: COVID Convalescent Plasma<br/><b>Sponsor</b>:   Institute of Hematology &amp; Blood Diseases Hospital<br/><b>Recruiting</b></p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Cupping Therapy on Immune System in Post Covid -19</strong> - <b>Condition</b>:   Covid-19 Patients<br/><b>Interventions</b>:   Combination Product: Cupping therapy with convential medical treatment;   Drug: Convential medical treatment<br/><b>Sponsor</b>:   Cairo University<br/><b>Completed</b></p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>To Evaluate the Immunogenicity and Safety of Sequential Booster Immunization of Recombinant Novel Coronavirus Vaccine (CHO Cells) for SARS-CoV-2</strong> - <b>Condition</b>:   COVID-19<br/><b>Intervention</b>:   Biological: Recombinant Novel Coronavirus vaccine (CHO Cells)<br/><b>Sponsor</b>:   Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd.<br/><b>Completed</b></p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Immunogenicity and Safety Study of SARS-CoV-2 DNA Vaccine (ICCOV)</strong> - <b>Condition</b>:   COVID-19<br/><b>Intervention</b>:   Biological: SARS-CoV-2 DNA Vaccine (ICCOV)<br/><b>Sponsors</b>:   Immuno Cure 3 Limited;   The University of Hong Kong<br/><b>Recruiting</b></p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Phase 3 Study of S-217622 in Prevention of Symptomatic SARS-CoV-2 Infection</strong> - <b>Condition</b>:   SARS-CoV-2 Infection<br/><b>Interventions</b>:   Drug: S-217622;   Drug: Placebo<br/><b>Sponsor</b>:   Shionogi<br/><b>Recruiting</b></p></li>
</ul>
<h1 data-aos="fade-right" id="from-pubmed">From PubMed</h1>
<ul>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Covalent-reversible peptide-based protease inhibitors. Design, synthesis, and clinical success stories</strong> - Dysregulated human peptidases are implicated in a large variety of diseases such as cancer, hypertension, and neurodegeneration. Viral proteases for their part are crucial for the pathogens’ maturation and assembly. Several decades of research were devoted to exploring these precious therapeutic targets, often addressing them with synthetic substrate-based inhibitors to elucidate their biological roles and develop medications. The rational design of peptide-based inhibitors offered a rapid…</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Hybrid immunity in older adults is associated with reduced SARS-CoV-2 infections following BNT162b2 COVID-19 immunisation</strong> - CONCLUSIONS: Hybrid immunity in older adults was associated with considerably higher antibody titres, neutralisation and inhibition capacity. Instances of high anti-RBD titre with lower inhibition suggests antibody quantity and quality as independent potential correlates of protection, highlighting added value of measuring inhibition over antibody titre alone to inform vaccine strategy.</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Multivalent bicyclic peptides are an effective antiviral modality that can potently inhibit SARS-CoV-2</strong> - COVID-19 has stimulated the rapid development of new antibody and small molecule therapeutics to inhibit SARS-CoV-2 infection. Here we describe a third antiviral modality that combines the drug-like advantages of both. Bicycles are entropically constrained peptides stabilized by a central chemical scaffold into a bi-cyclic structure. Rapid screening of diverse bacteriophage libraries against SARS-CoV-2 Spike yielded unique Bicycle binders across the entire protein. Exploiting Bicycles’ inherent…</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Tocilizumab for the treatment of COVID-19</strong> - INTRODUCTION: Since the beginning of the COVID-19 pandemic, the repurposing of medicines has been pursued to find interventions effective in preventing fatal outcome of the disease. One of these drugs was tocilizumab, an interleukin-6 inhibiting monoclonal antibody, previously used to treat several immune-related disorders.</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Preventative and therapeutic potential of animal milk components against COVID-19: A comprehensive review</strong> - The global pandemic of COVID-19 is considered one of the most catastrophic events on earth. During the pandemic, food ingredients may play crucial roles in preventing infectious diseases and sustaining people’s general health and well-being. Animal milk acts as a super food since it has the capacity to minimize the occurrence of viral infections due to inherent antiviral properties of its ingredients. SARS-CoV-2 virus infection can be prevented by immune-enhancing and antiviral properties of…</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>COVID-19 PCR: frequency of internal control inhibition in clinical practice</strong> - CONCLUSIONS: This study showed a low percentage of inhibition using RNase P as an internal control in COVID-19 PCRs using the CDC protocol, thus proving the effectiveness of this protocol for identification of SARS-CoV-2 in clinical samples. Re-extraction was efficacious for samples that showed little or no fluorescence for the RNase P gene.</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>A suitable drug structure for interaction with SARS-CoV-2 main protease between boceprevir, masitinib and rupintrivir; a molecular dynamics study</strong> - In recent years, more than 200 countries of the world have faced a health crisis due to the epidemiological disease of COVID-19 caused by the SARS-CoV-2 virus. It had a huge impact on the world economy and the global health sector. Researchers are studying the design and discovery of drugs that can inhibit SARS-CoV-2. The main protease of SARS-CoV-2 is an attractive target for the study of antiviral drugs against coronavirus diseases. According to the docking results, binding energy for…</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Combining virtual screening with cis-/trans-cleavage enzymatic assays effectively reveals broad-spectrum inhibitors that target the main proteases of SARS-CoV-2 and MERS-CoV</strong> - The main protease (M^(pro)) of SARS-CoV-2 is essential for viral replication, which suggests that the M^(pro) is a critical target in the development of small molecules to treat COVID-19. This study used an in-silico prediction approach to investigate the complex structure of SARS-CoV-2 M^(pro) in compounds from the United States National Cancer Institute (NCI) database, then validate potential inhibitory compounds against the SARS-CoV-2 M^(pro) in cis- and trans-cleavage proteolytic assays….</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Structure-Based Drug Design of RdRp Inhibitors against SARS-CoV-2</strong> - The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide pandemic since 2019, spreading rapidly and posing a significant threat to human health and life. With over 6 billion confirmed cases of the virus, the need for effective therapeutic drugs has become more urgent than ever before. RNA-dependent RNA polymerase (RdRp) is crucial in viral replication and transcription, catalysing viral RNA synthesis and serving as a promising therapeutic target for developing…</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>An allosteric inhibitor of sirtuin 2 deacetylase activity exhibits broad-spectrum antiviral activity</strong> - Most drugs used to treat viral disease target a virus-coded product. They inhibit a single virus or virus family, and the pathogen can readily evolve resistance. Host-targeted antivirals can overcome these limitations. The broad-spectrum activity achieved by host targeting can be especially useful in combating emerging viruses and for treatment of diseases caused by multiple viral pathogens, such as opportunistic agents in immunosuppressed patients. We have developed a family of compounds that…</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Recent advances in RNA sample preparation techniques for the detection of SARS-CoV-2 in saliva and gargle</strong> - Molecular detection of SARS-CoV-2 in gargle and saliva complements the standard analysis of nasopharyngeal swabs (NPS) specimens. Although gargle and saliva specimens can be readily obtained non-invasively, appropriate collection and processing of gargle and saliva specimens are critical to the accuracy and sensitivity of the overall analytical method. This review highlights challenges and recent advances in the treatment of gargle and saliva samples for subsequent analysis using reverse…</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>An efflux pump in genomic island GI-M202a mediates the transfer of polymyxin B resistance in Pandoraea pnomenusa M202</strong> - CONCLUSIONS: These findings demonstrated that GI-M202a along with the MFS transporter FKQ53_RS21695 in P. pnomenusa M202 could mediate the transmission of polymyxin B resistance.</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Dimethyl fumarate and 4-octyl itaconate are anticoagulants that suppress Tissue Factor in macrophages via inhibition of Type I Interferon</strong> - Excessive inflammation-associated coagulation is a feature of infectious diseases, occurring in such conditions as bacterial sepsis and COVID-19. It can lead to disseminated intravascular coagulation, one of the leading causes of mortality worldwide. Recently, type I interferon (IFN) signaling has been shown to be required for tissue factor (TF; gene name F3) release from macrophages, a critical initiator of coagulation, providing an important mechanistic link between innate immunity and…</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Verbenalin alleviates acute lung injury induced by sepsis and IgG immune complex through GPR18 receptor</strong> - Acute lung injury is significantly associated with the aberrant activation and pyroptosis of alveolar macrophages. Targeting the GPR18 receptor presents a potential therapeutic approach to mitigate inflammation. Verbenalin, a prominent component of Verbena in Xuanfeibaidu (XFBD) granules, is recommended for treating COVID-19. In this study, we demonstrate the therapeutic effect of verbenalin on lung injury through direct binding to the GPR18 receptor. Verbenalin inhibits the activation of…</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Synthesis, Characterization, and Antibacterial Activity of New Isatin Derivatives</strong> - 1H-indol-2,3-dione (isatin) class of biologically active compounds have analgesic, anti-microbial, anti-inflammatory, anti-tubercular, anti-proliferative properties, and is also useful for the treatment of SARS-CoV. Schiff bases containing isatin moiety are known to have broad spectrum of biological activities like anti-viral, anti-tubercular, anti-fungal, and anti-bacterial. In this work, several Schiff base derivatives have been synthesized using two methods (synthetic and microwave) by…</p></li>
</ul>
<h1 data-aos="fade-right" id="from-patent-search">From Patent Search</h1>
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<h1 data-aos="fade-down" id="daily-dose">Daily-Dose</h1>
<h1 data-aos="fade-right" data-aos-anchor-placement="top-bottom" id="contents">Contents</h1>
<ul>
<li><a href="#from-new-yorker">From New Yorker</a></li>
<li><a href="#from-vox">From Vox</a></li>
<li><a href="#from-the-hindu-sports">From The Hindu: Sports</a></li>
<li><a href="#from-the-hindu-national-news">From The Hindu: National News</a></li>
<li><a href="#from-bbc-europe">From BBC: Europe</a></li>
<li><a href="#from-ars-technica">From Ars Technica</a></li>
<li><a href="#from-jokes-subreddit">From Jokes Subreddit</a></li>
</ul>
<h1 data-aos="fade-right" id="from-new-yorker">From New Yorker</h1>
<ul>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>“I Am the Only One”: Trump’s Messianic 2024 Message</strong> - Under threat of prison, the master of fear and anger takes another dark political turn. - <a href="https://www.newyorker.com/news/letter-from-bidens-washington/i-am-the-only-one-trumps-messianic-2024-message">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Ukraine’s Counter-Offensive, and What Comes After</strong> - Zelensky has mounted a major effort to take back territory seized by the Russians. But he’ll have to do more than prevail on the battlefield. - <a href="https://www.newyorker.com/news/q-and-a/ukraines-counter-offensive-and-what-comes-after">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Is Donald Trump Scared?</strong> - At the former President’s arraignment in Miami on Tuesday, it was impossible to say whether his fate was more likely to be a return to the White House—or prison. - <a href="https://www.newyorker.com/news/dispatch/is-donald-trump-scared">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Why Isn’t Joe Biden Getting More Credit for a Big Drop in Inflation?</strong> - Throughout the past year, the rate at which prices are rising has fallen dramatically, but public perceptions are lagging, perhaps because many prices are still a lot higher than they were in 2020. - <a href="https://www.newyorker.com/news/our-columnists/why-isnt-joe-biden-getting-more-credit-for-a-big-drop-in-inflation">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>What Can Joe Biden Do About Benjamin Netanyahu?</strong> - The President is clearly displeased by the Prime Minister’s anti-democratic turn but seems wary of testing his influence. - <a href="https://www.newyorker.com/news/daily-comment/what-can-joe-biden-do-about-benjamin-netanyahu">link</a></p></li>
</ul>
<h1 data-aos="fade-right" id="from-vox">From Vox</h1>
<ul>
<li><strong>The epic story of our best malaria drug</strong> -
<figure>
<img alt="A medical worker prepares paperwork alongside documents and medical supplies including a box of injectable artesunate vials." src="https://cdn.vox-cdn.com/thumbor/debCLHPGzSOAQtYV1UkIkaCD0D8=/326x0:4675x3262/1310x983/cdn.vox-cdn.com/uploads/chorus_image/image/72380712/174644273.0.jpg"/>
<figcaption>
Artesunate is the leading effective anti-malaria treatment, and was made from a plant used in traditional Chinese medicine. | Thierry Falise/LightRocket via Getty Images
</figcaption>
</figure>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
How the Vietnam War and ancient Chinese medicine led to a malaria treatment.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="T94VfP">
Let’s talk about artesunate.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="On0hUy">
This drug is now the <a href="https://www.sciencedirect.com/science/article/pii/S1876034114000720">standard, World Health Organization-recommended treatment</a> for severe malaria. It was <a href="https://www.mmv.org/sites/default/files/uploads/docs/access/Injectable_Artesunate_Tool_Kit/INJartesunate_60mg_booklet_ENG.pdf">only in 2011</a> that it officially displaced the old treatment, quinine, which you may know better as the thing in tonic water that makes G&amp;Ts delicious. Artesunate is one of a class of anti-malarials developed as part of <a href="https://www.sciencedirect.com/science/article/pii/S0092867411009500">Project 523</a>, an effort launched by Chinese leaders Zhou Enlai and Mao Zedong in the middle of the Cultural Revolution as a favor to North Vietnamese leader Ho Chi Minh.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="qJBgkS">
Ho was in the midst of a brutal guerrilla war with the Americans, and his soldiers were falling sick and <a href="https://www.google.com/books/edition/A_Detailed_Chronological_Record_of_Proje/fFaxhXYg8uAC?hl=en&amp;gbpv=1&amp;pg=PA4&amp;printsec=frontcover">dying of malaria at alarming rates</a>. He wanted a better class of treatments, but his country, which had been fighting the Japanese, the French, South Vietnam, and the Americans for a quarter-century by that point, didn’t exactly have the manpower or money to develop them itself. So he <a href="https://www.chemistryworld.com/features/50-years-of-artemisinin/4016074.article">asked his comrades</a> in Beijing to help.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="RHf2dd">
Tu Youyou, a chemist and expert on Chinese traditional medicine, <a href="http://www.lavierebelle.org/IMG/pdf/the_discovery_of_artemisinin_qinghaosu_and_gifts_from_chinese_medicine.pdf">led a team that combed through ancient medical guides</a> for hints at compounds that could fight malaria. She found that Artemisia annua, a type of wormwood, was mentioned as fighting malaria in <em>A Handbook of Prescriptions for Emergencies</em>, written by the 4th-century traditional Chinese doctor Ge Hong (284-346). Tu’s team developed an extract from the plant (known as “artemisinin”) that they found effective in treating severe malaria cases. A whole class of treatments, known as “artemisinin derivatives,” comes out of this work. Tu would eventually <a href="https://www.nobelprize.org/prizes/medicine/2015/tu/facts/">win the 2015 Nobel Prize in Medicine</a> for her achievements.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="gi624X">
Liu Xu, a scientist at the Guilin Pharmaceutical Factory in southern China, <a href="https://www.google.com/books/edition/Artemisinin_Based_and_Other_Antimalarial/EuxjDwAAQBAJ?hl=en&amp;gbpv=1&amp;pg=PA20&amp;printsec=frontcover">attended a meeting</a> in 1977 held by Project 523, and heard about artemisinin derivatives for the first time. He began experimenting in rodents and found that one specific derivative was up to seven times more effective than ordinary artemisinin against severe malaria. It could also be formulated as an intravenous treatment. It became known as artesunate.
</p>
<h2 id="j2KA70">
The long road to treatment
</h2>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="U1liS5">
But, as a <a href="https://rethinkpriorities.org/publications/historical-global-health-rd-hits">new report from the research group Rethink Priorities</a> written by analyst Bruce Tsai details, that was just the start of the story. It took decades for Tu and Liu’s discoveries to translate into a change in the worldwide treatment of malaria, a disease that still kills over <a href="https://www.who.int/news-room/fact-sheets/detail/malaria#:~:text=Disease%20burden&amp;text=cases%20in%202020.-,The%20estimated%20number%20of%20malaria%20deaths%20stood%20at%20619%20000,63%20000%20more%20malaria%20deaths.">600,000 people per year</a>.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="Dem2vm">
As late as 1998, Tsai writes, “there was no particular interest in artesunate specifically.” A <a href="https://doi.org/10.1002/14651858.CD000527">Cochrane review</a> that year found that artemisinin derivatives generally were “no worse” than quinine at treating malaria. The main derivative tested at that point was artemether, which seemed a viable alternative to quinine, but not clearly superior.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="MD2qxk">
So what changed? Tsai gives primary credit to a series of randomized controlled trials (RCTs) funded by the Wellcome Trust, the British medical foundation. First a <a href="https://academic.oup.com/cid/article/37/1/7/474970">small 113-person study</a> found lower mortality when intravenous artesunate was used than with quinine. While not statistically significant, this result was promising enough to prompt a <a href="https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(05)67176-0/fulltext">much larger, multicountry study of 1,461 patients</a> across India, Bangladesh, Myanmar, and Indonesia. It concluded that mortality with artesunate was 34.7 percent lower than with quinine, and also had fewer harmful side effects. A <a href="https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)61924-1/fulltext">still larger study</a> in nine African countries with 5,425 child patients also showed a huge advantage (22.5 percent lower mortality), and demonstrated that the results generalized outside of adults in South Asia.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="73d8MT">
At the same time, the Medicines for Malaria Venture, a nonprofit funded <a href="https://www.mmv.org/about-us">by foreign aid agencies and foundations</a>, funded an RCT that found a <a href="https://academic.oup.com/jid/article/205/2/312/2192412?login=false">lower-dose, cheaper regimen of artesunate</a> was just as effective as a bigger dose. It also worked with Guilin, the pharma company where Liu had developed artesunate, to get “prequalified” by the WHO. <a href="https://www.who.int/news-room/fact-sheets/detail/prequalification-of-medicines-by-who">Prequalification</a> is a kind of quality check involving pharmaceutical factory inspections and other steps meant to signal to governments that prequalified products are safe and legitimate, and can greatly increase uptake.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="n7LSn5">
Tsai and the Rethink Priorities team estimate that the 2011 introduction of injectable artesunate has prevented at least 785,716 deaths so far. Projecting forward, it estimates the drug could save as many as 4 million lives total.
</p>
<h2 id="tmqhDz">
Philanthropic investment in drugs pays off in lives
</h2>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="tX0GxQ">
The tale of artesunate is a wild story that jumps from the Vietnam War to 4th-century Chinese medicine to modern randomized trial-based medical research. Its main lesson, for me, is a simple one, widely known to experts on global health but probably underemphasized outside that world: we cannot rely on businesses alone to protect us from disease.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="yAlNns">
At each step in the artesunate story, the key funders and actors have been governments, foundations, and NGOs. Even Guilin, the pharmaceutical company that invented the drug, existed in the context of pre-reform China, where few enterprises were truly “private” and the state was heavily, heavily involved. (It still is, to a lesser extent, today.)<strong> </strong>
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="pg7rci">
The delay in the drug’s rollout seems attributable in part to the lack of much commercial incentive to develop better malaria treatments, given how poor most people who get malaria are. If malaria was killing 190,000 Americans a year — which is the <a href="https://www.who.int/news-room/fact-sheets/detail/malaria">number of Nigerians who died from the disease in 2021</a> — I’d guess artesunate would have become a standard treatment within a couple years of discovery, not over three decades later. Americans would be able to pay for it, and pharma firms would rush to soak up that money.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="GxoR1J">
Though maybe even that is too optimistic —<strong> </strong>a paper examining cancer drug trials from 1973 to 2011 in the United States found that <a href="https://drive.google.com/file/d/1yYFwDH8MEpmyBC-jMdmnzgChdFfT9xDe/view">drug companies systematically underinvested in research and development</a>, and that proper investment would have led to patients living longer, cumulatively adding millions of years of additional life. The US invests heavily in health research through the National Institutes of Health and public universities. But there’s a strong case we should be doing still more.
</p></li>
<li><strong>People are using abortion medication later in their pregnancies. Here’s what that means.</strong> -
<figure>
<img alt="A single pill, inscribed with an S, is perched on its edge atop a translucent pink block." src="https://cdn.vox-cdn.com/thumbor/nOyA94sDAMX4VIz-_Q53EzAKReA=/0x0:2880x2160/1310x983/cdn.vox-cdn.com/uploads/chorus_image/image/72380692/GettyImages_1481452347.0.jpg"/>
<figcaption>
Mifepristone, pictured, is one step in the most common medication abortion regimen. Access to it, and to clinical abortion, has become increasingly limited in the year since <em>Roe v. Wade</em> was overturned. | Getty Images/iStockphoto
</figcaption>
</figure>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
The regimen is common and considered safe after 10 weeks, but the delays are cause for concern.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="QDNQXd">
Medication abortion is a simple procedure.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="84rIjC">
A patient takes one medication, <a href="https://www.vox.com/policy/23678597/mifepristone-safety-abortion-pill-ruling-misoprostol-kacsmaryk-fda-rems">mifepristone</a>, which stops the pregnancy from developing, followed one to two days later by another medication, <a href="https://www.vox.com/23672829/what-is-misoprostol-abortion-medication-mifepristone-kacsmaryk">misoprostol</a>, which induces contractions that empty the uterus. The regimen, approved for abortions in the US since 2000, is <a href="https://www.vox.com/policy/23678597/mifepristone-safety-abortion-pill-ruling-misoprostol-kacsmaryk-fda-rems">effective and very safe</a>, according to physicians and researchers, with a low incidence of serious side effects, and it’s the <a href="https://www.guttmacher.org/article/2022/02/medication-abortion-now-accounts-more-half-all-us-abortions">most common method of abortion</a> in the US. It’s approved by the Food and Drug Administration for the first 70 days, or 10 weeks, of pregnancy, though the World Health Organization recommends medication abortion for <a href="https://srhr.org/abortioncare/chapter-3/abortion-3-4/medical-management-of-induced-abortion-recommendations-27-30-3-4-2/">up to 12 weeks</a>.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="FgjIy1">
Since <a href="https://www.vox.com/2022/6/24/23181720/supreme-court-dobbs-jackson-womens-health-samuel-alito-roe-wade-abortion-marriage-contraception">the Supreme Court overturned <em>Roe v. Wade</em></a> last summer, however, nothing about abortion is simple anymore. With near-total <a href="https://www.guttmacher.org/state-policy/explore/state-policies-later-abortions">abortion bans in place</a> in more than a dozen states and gestational limits in several others, the procedure is growing harder to access by the day. Meanwhile, a federal court case is casting further doubt on <a href="https://www.vox.com/policy/23679121/mifepristone-abortion-pill-legal">the future of mifepristone’s availability</a> in the US.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="GDNEoD">
That ongoing march of bans and restrictions is causing delays for many patients — because they have to travel to other states to receive care, because the remaining clinics are overwhelmed with patients, or because they’re using pills <a href="https://www.vox.com/23056530/aid-access-abortion-roe-wade-pills-mifepristone">mailed from overseas</a>, which can take weeks to arrive.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="2zLR7F">
“Up until the fall of <em>Roe</em>, we had maybe two calls ever asking for advice on using pills in a pregnancy that was over 12 or 13 weeks,” said Linda Prine, a family physician and co-founder of the <a href="https://www.mahotline.org/">Miscarriage and Abortion Hotline</a>, which advises callers about <a href="https://www.guttmacher.org/gpr/2018/10/self-managed-medication-abortion-expanding-available-options-us-abortion-care">self-managing their abortions</a>. Now, she said, the hotline gets such calls as frequently as once a day.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="D1GOoa">
So far, there is little hard data on how many people are using medication abortion after the first trimester. Counting abortions is difficult in an environment where they are often illegal, and <a href="https://societyfp.org/research/wecount/">existing efforts</a> often do not track how far along a patient is in pregnancy. The increasingly limited access to abortion around the country, however, has experts considering a future in which people use the medications later in pregnancies, beyond the 10 weeks approved by the FDA and outside of clinical settings.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="MZtbtx">
Abortion medications still work past 12 weeks — <a href="https://pubmed.ncbi.nlm.nih.gov/15327617/#full-view-affiliation-1">one study</a> of 224 women between 12 and 20 weeks’ gestation found efficacy rates of 91 to 95 percent — and outside the US, medication abortion after 10 weeks is not uncommon. But the process comes with more severe side effects and slightly higher risk of complications, experts say, and can be frightening for patients who have to go through it alone and without guidance — a more common scenario as more people self-manage their abortions, and as stories of bans and <a href="https://www.vox.com/policy-and-politics/23021104/texas-abortion-murder-charge-starr-county">prosecutions</a> have patients unsure who they can trust.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="a1VNKh">
“It’s infuriating and outrageous to me,” Prine said. “These laws are not stopping people from getting abortions; they’re stopping them from getting timely abortions.”
</p>
<h3 id="VY5bX8">
Medication abortions after 10 weeks are safe, according to doctors, but come with more severe side effects
</h3>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="fpdm6m">
Around the world, there is plenty of precedent for medication abortions later in pregnancy. This method is the norm for second-trimester procedures in Scandinavian countries, said Daniel Grossman, a physician and a professor of obstetrics and gynecology at the University of California San Francisco.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="VDKyT6">
Even in the US, doctors are able to prescribe medication abortion <a href="http://webmd.com/a-to-z-guides/features/off-label-drug-use-what-you-need-to-know">off-label</a> after 10 weeks — in <a href="https://www.ansirh.org/sites/default/files/2022-06/Trends%20in%20Abortion%20Care%20in%20the%20United%20States%2C%202017-2021.pdf">one 2022 study</a>, 33 percent of clinics provided medication abortion after that time period. In <a href="https://blog.utp.edu.co/maternoinfantil/files/2012/04/135-Aborto-2-trimestre.pdf">its most recent practice bulletin</a> on the topic, the American College of Obstetricians and Gynecologists lists medication as one of the recommended methods of second-trimester abortion; the recommended regimen includes more doses of misoprostol than a first-trimester abortion but is otherwise similar.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="H3TBbe">
Researchers have also studied the method into the third trimester, with some research conducted at up to 28 weeks. They’ve found that mifepristone and misoprostol “are very safe and effective medications and they remain so throughout pregnancy,” said Heidi Moseson, a senior research scientist at Ibis Reproductive Health, a research group focused on reproductive autonomy.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="0BhrT2">
The FDA, for its part, does not continuously review the latest research, instead relying on pharmaceutical companies to submit applications to expand approval of their drugs. The agency expanded its approval of mifepristone from seven weeks’ gestation to 10 weeks in 2016, but has not acted to lengthen the period in which it can be used since then. “Just because the evidence is published in a peer-reviewed journal or even because practice is changing,” Grossman said, “it doesn’t happen automatically.”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="9RGITI">
Online pharmacies and other groups vary in their policies toward abortions later in pregnancy. Aid Access does not prescribe medication to people who say they are more than 11 weeks pregnant, but instead directs them to abortion funds or other resources, said founder Rebecca Gomperts. Plan C, which provides information and links to online stores that sell abortion medication, does not collect data on how far along visitors are in pregnancy, said co-founder and co-director Elisa Wells. (The website had 209,000 visitors this April, up from 76,000 in April 2022, before the <em>Dobbs</em> decision was announced.)
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="wzgEt5">
Complications such as hemorrhage or a retained placenta are slightly more likely after 10 weeks than when the medication is taken earlier. However, <a href="https://pubmed.ncbi.nlm.nih.gov/18772097/">one review</a> of the available research found that less than 1 percent of patients had heavy bleeding that required transfusion. “For the most part, in our experience, the pills work very well, and it isn’t common to need to get extra care,” Prine said.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="jl8o8T">
Still, the process of undergoing a second-trimester abortion with medication can be challenging, especially at home. “People who are further in gestation have more pain associated with medication abortions,” Grossman said. Because of the pain and the elevated complication risk, the standard of care in the US has been for medication abortions in the second trimester to take place in medical facilities.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="E9thGV">
The experience can also look different from a first-trimester abortion. Earlier procedures tend to produce fairly consistent cramping and bleeding over the course of several hours, while later medication abortions more often result in “a big gush of fluid and then passage of the fetus and then some bleeding after that,” Prine said.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="rOFUlL">
Sometimes patients call the hotline frightened, saying things like, “I just passed my pregnancy and it’s the size of my fist.” Others call because the umbilical cord is still connected, or because they haven’t passed the placenta yet and want to know what to do. Much of what they’re experiencing is expected for a second-trimester abortion, but patients don’t necessarily know that.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="QQYwGZ">
For now, most callers to the hotline are using a combination of mifepristone and misoprostol. People can self-manage second-trimester abortions with misoprostol alone if mifepristone becomes unavailable, but it is harder to determine when a misoprostol-only abortion is finished. Patients could end up having to take several additional doses of misoprostol, each of which comes with side effects like nausea and diarrhea, Prine said.
</p>
<h3 id="1fTcnl">
Bans and restrictions could push more people to use medication abortion later in pregnancy
</h3>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="LN0V7O">
Today, <a href="https://www.guttmacher.org/state-policy/explore/state-policies-later-abortions">13 states ban abortion</a>, and several others impose strict gestational limits — restrictions that apply to both <a href="https://www.kff.org/womens-health-policy/fact-sheet/the-availability-and-use-of-medication-abortion/">surgical and medication abortions</a>.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="49NDJV">
That has left patients there scrambling to access reproductive options. Some are able to travel elsewhere to seek care: In the six months following <em>Dobbs</em>, states such as North Carolina and Illinois, which border states with bans and have fewer restrictions, experienced surges in the number of abortions performed, according to <a href="https://www.societyfp.org/wp-content/uploads/2023/03/WeCountReport_April2023Release.pdf">the abortion reporting effort #WeCount</a>. That influx of patients has caused an <a href="https://sentinelcolorado.com/1gridhome/dobbs-effect-as-demand-for-abortions-in-colorado-goes-up-so-do-wait-times-for-in-person-care/">increase in wait times</a> for clinic appointments in the states that still allow abortion, a phenomenon that can push patients past the legal limits as some states without bans still <a href="https://www.reuters.com/world/us/north-carolina-lawmakers-vote-overriding-veto-12-week-abortion-ban-2023-05-16/">shrink the window</a> in which people can get care.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="xdbofa">
Faced with fewer options within the US, more patients are turning to pharmacies and other groups that provide abortion medication from overseas. <a href="https://www.nytimes.com/2022/11/01/upshot/abortion-pills-mail-overseas.html">One study</a>, for example, found an almost 120 percent increase in orders through the Austria-based nonprofit Aid Access in the two months after <em>Dobbs</em>. “Most people can’t travel to other states,” Prine said. So their only option is to get pills “either from underground community networks or online.”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="nADpkO">
Overseas groups get around US abortion law because they are outside the American legal system and thus more difficult to prosecute or sue. However, the pills can take longer to arrive than if they were shipped or prescribed domestically, meaning that patients will potentially have abortions later in pregnancy.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="JkB25j">
The confusion and logistical difficulties caused by new abortion restrictions may be causing more delays, too. Patients may first seek an abortion nearby and go online only when that’s impossible to access. “When we see bans go into effect, it delays people,” Moseson said. “Many people will still obtain care, but it pushes them later in pregnancy.”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="nTD5pF">
It also means that clinical care may not be an option, particularly in states with bans. Patients in these areas are often on their own, unsure of what to expect or how to get medical care if they need it — or whether they’ll be criminalized for doing so.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="QExj4H">
Only two states have laws explicitly banning self-managed abortion, and there are no laws requiring health care providers to report to law enforcement if they believe such an abortion took place, Moseson said. There’s also no blood test or other screening that can determine if someone took abortion medication.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="6kuT5p">
However, many patients remain afraid of legal repercussions if they do end up needing to go to a doctor or hospital for complications. Prosecutors have used laws against mishandling human remains and other crimes to prosecute people suspected of self-managing abortions. In a <a href="https://www.ifwhenhow.org/resources/self-care-criminalized-preliminary-findings/">2022 analysis</a> of such criminalization by the reproductive justice legal group If/When/How, the vast majority of abortions that led to investigation or arrest took place in the second or third trimester. <a href="https://www.vox.com/policy-and-politics/23021104/texas-abortion-murder-charge-starr-county">High-profile cases of criminalization</a> in the news can also make people afraid of going to the hospital. “There are real instances when people need care quickly to save their lives and the confusion around these laws and the real legal repercussions have a very harmful chilling effect,” Moseson said.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="UI5kxT">
“People are just living in such fear in these restricted states,” Prine said. “They just don’t know what’s safe.”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="Eeuoad">
<a href="https://www.vox.com/the-goods/23580117/linda-prine-abortion-pills-medication-dobbs-roe">Prine and other abortion rights advocates</a> are calling for <a href="https://www.nytimes.com/2023/01/20/opinion/new-york-abortion-rights-legislation.html">shield laws</a> to protect doctors in blue states who want to prescribe abortion medication by telemedicine to patients in red states. Massachusetts already has such a law, and New York state is considering one. The laws could allow more patients to get the medication through US mail, avoiding the long waits sometimes associated with shipping from overseas.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="c2ZEar">
For now, however, legal barriers and logistical hurdles are combining to leave some patients with few options other than a medication abortion later in pregnancy. “I feel for the people who are experiencing this,” Prine said. “This should not be having to happen.”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="RIs2ye">
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="T5deHB">
</p></li>
<li><strong>Mali’s referendum can’t guarantee a democratic transition</strong> -
<figure>
<img alt="MALI-GUINEA-POLITICS-DIPLOMACY-GOITA-DOUMBOUYA" src="https://cdn.vox-cdn.com/thumbor/K-RNHLqe-52Jx7ugXJ5mi9ASYEA=/0x69:1600x1269/1310x983/cdn.vox-cdn.com/uploads/chorus_image/image/72379903/1243425166.0.jpg"/>
<figcaption>
Malis interim leader and head of Junta, Colonel Assimi Goïta looks on, in Bamako, Mali, on September 22, 2022 during Mali’s Independence Day military parade.  | Ousmane Makaveli/AFP via Getty Images
</figcaption>
</figure>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
The junta’s constitutional amendments could let it consolidate power over an unstable nation
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="gL8imE">
The ruling junta in Mali is <a href="https://www.reuters.com/world/africa/malians-divided-ahead-referendum-vote-paving-way-elections-2023-06-16/">holding a constitutional referendum</a> as part of a transition back toward civilian rule, but experts and political opponents say the true aim<strong> </strong>is consolidating its power in the increasingly violent and unstable Sahel region, which runs through Mali and several other countries.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="J38yXo">
The junta, which came to power in an August 2020 coup, has promised to stabilize the country where violent insurgent Islamist groups compete with it and<strong> </strong>each other for control. Instead, violence on the part of the Islamists and the junta — backed by<a href="https://www.vox.com/world-politics/2023/3/21/23622615/ukraine-war-bakhmut-wagner-group-russia"> the Russian mercenary Wagner group </a>— has increased exponentially, with civilians bearing the brunt of the horror.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="6DEJaS">
The vote has been delayed several times, most recently in February of this year, <a href="https://www.reuters.com/world/africa/mali-junta-delays-referendum-needed-democratic-transition-2023-03-10/">citing logistical</a> reasons. Presidential elections are to be held in February 2024, though it’s unclear whether the junta will adhere to that timeframe.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="71BlOB">
Some of the proposed constitutional amendments give more power to the president, rather than than the parliament — hence the political opposition. Though it’s unclear whether the current leader, Col. Assimi Goïta, will stand in any future election, certainly an ally or proxy for the junta will. That could effectively legitimize the junta’s control and perpetuate the current violence and instability.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="rN1z5K">
“The fear I have for Mali is that we might see, effectively, the restoration of military power which is kind of like going back to the ‘70s and ‘80s, which are commonly referred to in the African politics literature as the ‘Dark Decades,’” according to Daniel Eizenga of the Africa Center for Strategic Studies. “That was a really terrible time, but [the current situation] looks kind of like a prelude to re-experiencing that,” he told Vox in an interview.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="IUfCDN">
<a href="https://www.africanews.com/2023/06/12/mali-soldiers-cast-ballots-during-early-voting-in-constitution-referendum//#:~:text=06%20%2D%2011%3A49-,Mali,in%20Bamako%20in%20early%20voting.">Security forces have already voted</a>, and civilians are set to vote Sunday, June 18 — a simple “yes” or “no” in response to whether they approve of the changes the junta has proposed to the 1992 Malian constitution, created by civilian leadership after the overthrow of dictator Moussa Traoré in 1991. Opposition to the changes include a contingent of influential imams who oppose the idea of Mali as a secular country, as well as political parties and civil society groups that reject mechanisms for the junta to consolidate power under the guise of the democratic process.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="hrPH6h">
However, the international community has pushed for the referendum as part of Mali’s path back to civilian governance; regardless of the flaws in the process, it’s a necessary step in the transition, Leonardo Villalon, a professor of political science and African studies at the University of Florida told Vox. “This referendum is going to be limited and flawed, in the sense that the vote is going to be very difficult to hold in some areas,” he said. “There’s precedent for that, and there’s precedent for widespread acceptance of that,” particularly given the security challenges that Mali faces and its fragile electoral apparatus.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="LglyKP">
“I’m assuming [the referendum is] going to pass, and the government will make sure it passes,” Villalon told Vox.
</p>
<h3 id="0HRb2D">
The junta promised stability, but violence has only accelerated in Mali
</h3>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="t7b5Td">
<a href="https://www.aljazeera.com/news/2021/6/7/coup-leader-assimi-goita-set-to-be-sworn-in-as-malis-president">Goïta’s leadership</a> is actually the result of a second coup that he staged in May 2021, seizing power from the transitional president and prime minister. Goïta had previously taken power from Mali’s last elected civilian, <a href="https://www.washingtonpost.com/local/obituaries/ibrahim-boubacar-keita-dead/2022/01/16/2d74da48-ed25-11ea-b4bc-3a2098fc73d4_story.html">President Ibrahim Boubacar Keïta</a> — commonly referred to as IBK — over allegations of corruption and worsening security and economic conditions.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="dsZ1rA">
Though the coup sparked international outcry, thousands of Malians had protested IBK’s poor handling of the country’s crises, and supported the military forces as they took the capital Bamako. Islamist terrorist groups and separatist groups flush with weapons and insurgents after Libya’s collapse in 2011 have wreaked havoc across the Sahel region, particularly in <a href="https://www.cfr.org/global-conflict-tracker/conflict/violent-extremism-sahel">Mali, Burkina Faso, and Niger</a>.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="s3Xq9U">
“[IBK’s] government was not particularly effective on the security front,” Eizenga told Vox. “The situation has gotten much worse, and it’s gotten worse faster since the junta came to power, and I think they bear a lot of responsibility for that, particularly the violence against civilians. But the situation was trending badly before they came to power, too.”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="teT2oL">
United Nations peacekeeping forces and French military forces had been in Mali since 2013,<strong> </strong>in an effort to help the government combat extremist forces. However, the junta effectively forced French forces out in 2022 and on Friday demanded that UN peacekeepers leave the country “<a href="https://www.france24.com/en/africa/20230616-mali-calls-for-immediate-withdrawal-of-un-peacekeeping-mission">without delay.</a>”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="nmoyTK">
Though the efficacy of both forces in containing the violence has been dubious at best, the calls for their removal has more to do with the junta’s efforts to whip up populist, nationalist, and anti-colonial sentiment than it does with the military’s own efforts to stabilize areas where insurgent groups are in control.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="ci2zdY">
Indeed, under the present government, the security situation has rapidly deteriorated, Eizenga told Vox. According to data from the Armed Conflict Location and Event Data Project (ACLED) and the<a href="https://africacenter.org/spotlight/debunking-the-malian-juntas-claims/"> Africa Center for Strategic Studies</a> shared in an email, in 2022 there were 996 violent events involving Islamist groups, which resulted in 3,635 fatalities. As Eizenga told Vox, that makes violence in 2022 “by far the worst on record.” Furthermore, “based on the available data through the first quarter of 2023, we anticipate roughly a doubling of violence since the junta took power.”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="VqPOVp">
That is primarily due to the <a href="https://www.hrw.org/news/2022/04/05/mali-massacre-army-foreign-soldiers">Moura massacre</a> in Mali’s southern-central Mopti region. As Vox’s Jen Kirby wrote in a <a href="https://www.vox.com/world-politics/2023/3/21/23622615/ukraine-war-bakhmut-wagner-group-russia">March report</a> on the Wagner mercenary group:
</p>
<blockquote>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="GZ4OZh">
In January, <a href="https://www.ohchr.org/en/press-releases/2023/01/mali-un-experts-call-independent-investigation-possible-international-crimes"><strong>a group of independent United Nations experts</strong></a> called for an investigation into reported abuses in Mali, including a potential mass execution in Moura. Malian troops and Russian mercenaries — who are fighting an insurgency — were accused of murdering hundreds of people last March, <a href="https://www.nytimes.com/2022/05/31/world/africa/mali-massacre-investigation.html"><strong>many of them likely civilians with no apparent ties to insurgent groups</strong></a>.
</p>
</blockquote>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="oZ4tFX">
The junta has defended its actions in Moura, decrying a <a href="https://www.ohchr.org/en/press-releases/2023/05/malian-troops-foreign-military-personnel-killed-over-500-people-during">recent United Nations report</a> on the event and claiming that it was protecting civilians in the area from Islamist violence. But, Eizenga said via email, “part of the logic seems to be to alienate international forces like those comprising [the UN peacekeepping forces], so as to limit scrutiny of the military’s operations particularly with Wagner support.”
</p>
<h3 id="ZiD8l1">
The referendum is a difficult start to any potential democratic transition
</h3>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="f9jaaK">
Despite its failures to stamp out Islamic extremism and the alleged atrocities it’s committed, the junta does have supporters, Villalon said. “They have support and they have a lot of ambivalence — maybe people who aren’t sure about them, but they’re also really dissatisfied with the old guard, the old parties that ruled Mali for so long.”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="N9LMaq">
Some of the opposition to the referendum does come from those “old guard” entrenched political parties, particularly the Parti Pour la Renaissance Nationale, or PARENA and Solidarité Africaine pour la Démocratie et l’Indépendance, or SADI, which were established in the 1990s.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="Sl5VNL">
“Too much power in the hands of the future president will squash all the other institutions,” Sidi Toure, a PARENA spokesperson, <a href="https://www.reuters.com/world/africa/malians-divided-ahead-referendum-vote-paving-way-elections-2023-06-16/">told Reuters Friday</a>. PARENA is encouraging Malians to vote “no” to the changes, but, Toure said, it’s unclear what the outcome will be. “Mali and Malians are profoundly divided.”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="TknaOY">
The referendum has brought about a serious debate about the role of <a href="https://www.vox.com/religion">religion</a> in society and politics in the majority-Muslim country, particularly as a rejection of the French model of secularism. Imams are a major force of opposition to the draft constitution, which designates Mali as an “independent, sovereign, unitary, indivisible, democratic, secular and social republic.” Some of the most <a href="https://www.barrons.com/news/rallies-grip-bamako-before-mali-constitutional-referendum-eadd899f">vocal opponents to the referendum</a> are <a href="https://www.tandfonline.com/doi/full/10.1080/23802014.2022.2108893">imam Mahmoud Dicko</a>, one of the leaders of the opposition to IBK in 2020, and the <a href="https://www.rfi.fr/fr/afrique/20230506-mali-des-associations-islamiques-se-l%C3%A8vent-contre-l-inscription-de-la-la%C3%AFcit%C3%A9-dans-la-constitution">Ligue Islamique des Imams du Mali</a>, an association of about 20 Muslim groups. Separatist groups in the north, including the <a href="https://www.maliweb.net/politique/mali-les-principaux-mouvements-signataires-de-laccord-dalger-recommandent-le-report-du-referendum-constitutionnel-3024750.html">Cadre Stratégique Permanant pour la Paix, la Sécurité et le Développement</a> (CSP-PSD), have also opposed the referendum, saying that the changes are not sufficiently inclusive.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="RDF6Ee">
Though Villalon referred to Sunday’s vote as a “referendum on the regime,” Eizenga told Vox that “the hopes for emboldened democracy in Mali, I think, are pretty low.”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="Le8eZY">
Results of Sunday’s referendum are expected within 72 hours after the election, according <a href="https://www.barrons.com/news/rallies-grip-bamako-before-mali-constitutional-referendum-eadd899f">to Agence France-Presse</a>.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="gLsvP5">
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom" id="VzmVeZ">
</p></li>
</ul>
<h1 data-aos="fade-right" id="from-the-hindu-sports">From The Hindu: Sports</h1>
<ul>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Wrestlers protest | Sakshi Malik, Babita Phogat engage in a war of words</strong> - While Malik accused Babita of siding with the government, the latter claimed that the Malik has become a “Congress’ puppet”</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Badminton | India’s Rankireddy and Shetty triumph in Indonesia Open, create history</strong> - The Indians, who were also Asian champions, defeated the current world champions in 43 minutes.</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Morning Digest | From one eruption to another, day and night spread equal dread in Manipur; Railways to review operations on safety of trains, and more</strong> - Here’s a select list of stories to read before you start your day</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Inter-state Athletics Championships: AFI president Sumariwalla defends hosting event amid heat wave</strong> -</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Jamari, who is in fine nick, may score an encore in the Fillies Championship Stakes</strong> -</p></li>
</ul>
<h1 data-aos="fade-right" id="from-the-hindu-national-news">From The Hindu: National News</h1>
<ul>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Heatwave in U.P. and Bihar kill nearly 100 die as India struggles with a sweltering</strong> - Indian officials say at least 96 people have died in the two States over the last several days with swaths of the country reeling from scorching heat</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>EESL pledges support to Energy Efficiency projects in State</strong> - The projects are aimed at mitigating the impact of climate change, especially in the MSME sector</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Gandhi Peace Prize 2021 to be conferred on Gita Press</strong> - “Gandhi Peace Prize 2021 recognises the important and unparalleled contribution of Gita Press, in contributing to collective upliftment of humanity, which personifies Gandhian living in true sense”</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Manipur women hit the streets for peace</strong> - Women raised slogans demanding implementation of the National Register of Citizens (NRC).</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Congress blames BJP for violence against minorities</strong> - APCC says PM Modi and Home Minister Amit Shah failed to reach out to States shaken by violence and initiate confidence-building measures</p></li>
</ul>
<h1 data-aos="fade-right" id="from-bbc-europe">From BBC: Europe</h1>
<ul>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Ukraine war must end, South African President Ramaphosa tells Putin</strong> - Cyril Ramaphosa and other African leaders met the Ukrainian and Russian presidents in their peace bid.</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Poland: Thousands march in Warsaw for LGBT rights ahead of elections</strong> - Same-sex relationships are not legally recognised in Poland and gay couples cannot adopt children.</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Rare earthquake damages French homes, schools and churches</strong> - Hundreds of buildings in western France are declared uninhabitable following the rare earthquake.</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Ukraine war: Putin confirms first nuclear weapons moved to Belarus</strong> - Russia’s leader says the move is to remind anyone “thinking of inflicting a strategic defeat on us”.</p></li>
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Spain drought forces Fuente de Piedra flamingos to find new home</strong> - Spain has witnessed its hottest spring since 1961, with high temperatures likely to continue for months.</p></li>
</ul>
<h1 data-aos="fade-right" id="from-ars-technica">From Ars Technica</h1>
<ul>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>The sleeper hits of Summer Game Fest 2023</strong> - Games about time travel, foam spraying guns, and… space hospitals? - <a href="https://arstechnica.com/?p=1948256">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Scientists conduct first test of a wireless cosmic ray navigation system</strong> - System could be used to guide underwater robots or underground autonomous vehicles - <a href="https://arstechnica.com/?p=1948491">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Neanderthal adhesives were made through a complex synthesis process</strong> - Birch bark was heated in underground chambers to create a tougher adhesive. - <a href="https://arstechnica.com/?p=1948666">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>The US Navy, NATO, and NASA are using a shady Chinese company’s encryption chips</strong> - US government warns encryption chipmaker Hualan has suspicious ties to China’s military. - <a href="https://arstechnica.com/?p=1948695">link</a></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Weirdly, a NASA official says fixed-price contracts do the agency “no good”</strong> - “What really makes me worried is that I think it shows where the heart of the agency is.” - <a href="https://arstechnica.com/?p=1948558">link</a></p></li>
</ul>
<h1 data-aos="fade-right" id="from-jokes-subreddit">From Jokes Subreddit</h1>
<ul>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Reddit is killing third-party applications (and itself). Read more in the comments.</strong> - submitted by <a href="https://www.reddit.com/user/JokeSentinel"> /u/JokeSentinel </a> <br/> <span><a href="https://i.redd.it/1j5nee06kx5b1.png">[link]</a></span> <span><a href="https://www.reddit.com/r/Jokes/comments/1490rmv/reddit_is_killing_thirdparty_applications_and/">[comments]</a></span></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Did you know that 20 pirahnas can demolish a small child down to the bone in under 30 seconds?</strong> - <!-- SC_OFF --></p>
<div class="md">
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
In other news, I lost my job at the aquarium today.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
(My nephew told me this joke yesterday, totally deadpan! Thought it was worth sharing!)
</p>
</div>
<!-- SC_ON -->
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"> submitted by <a href="https://www.reddit.com/user/smelliepoo"> /u/smelliepoo </a> <br/> <span><a href="https://www.reddit.com/r/Jokes/comments/14ceu9q/did_you_know_that_20_pirahnas_can_demolish_a/">[link]</a></span> <span><a href="https://www.reddit.com/r/Jokes/comments/14ceu9q/did_you_know_that_20_pirahnas_can_demolish_a/">[comments]</a></span></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>NSFW A teacher asked her class if anyone could use the word contagious in a sentence. One girl raiser her hand and said, “The mumps are contagious” “Very good”, said the teacher, “Would anyone else like to try?” A boy raised his hand and said,</strong> - <!-- SC_OFF --></p>
<div class="md">
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
“Our next-door neighbor was painting her house by herself, and my dad said it would take the contagious.”
</p>
</div>
<!-- SC_ON -->
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"> submitted by <a href="https://www.reddit.com/user/bebobbaloola"> /u/bebobbaloola </a> <br/> <span><a href="https://www.reddit.com/r/Jokes/comments/14buh8h/nsfw_a_teacher_asked_her_class_if_anyone_could/">[link]</a></span> <span><a href="https://www.reddit.com/r/Jokes/comments/14buh8h/nsfw_a_teacher_asked_her_class_if_anyone_could/">[comments]</a></span></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Two men were washed ashore during WWI.</strong> - <!-- SC_OFF --></p>
<div class="md">
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
Their ship, an aging minesweeping model, had wrecked off the coast of an uninhabited island. As the older veteran worked to build a makeshift camp, the younger soldier managed to salvage a radio, and quickly telegraphed an SOS with their coordinates.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
To their surprise, a ship responded within the hour, confirming that it could arrive at their position in approximately two weeks.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
The old vet sighed and shook his head, saying he’d rather take his chances swimming out to the wrecked ship and trying to repair it.
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
The young soldier scoffed. “You’d really rather play with that old mine craft all day?”
</p>
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
The older man shrugged. “It’s better than a fortnight.”
</p>
</div>
<!-- SC_ON -->
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"> submitted by <a href="https://www.reddit.com/user/KairuSmairukon"> /u/KairuSmairukon </a> <br/> <span><a href="https://www.reddit.com/r/Jokes/comments/14bzhya/two_men_were_washed_ashore_during_wwi/">[link]</a></span> <span><a href="https://www.reddit.com/r/Jokes/comments/14bzhya/two_men_were_washed_ashore_during_wwi/">[comments]</a></span></p></li>
<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Is your refrigerator running?</strong> - <!-- SC_OFF --></p>
<div class="md">
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
If so, I may vote for it.
</p>
</div>
<!-- SC_ON -->
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"> submitted by <a href="https://www.reddit.com/user/HelpingHandsUs"> /u/HelpingHandsUs </a> <br/> <span><a href="https://www.reddit.com/r/Jokes/comments/14c4is9/is_your_refrigerator_running/">[link]</a></span> <span><a href="https://www.reddit.com/r/Jokes/comments/14c4is9/is_your_refrigerator_running/">[comments]</a></span></p></li>
</ul>
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