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+ + + ++Background Host immunity is critical in determining outcomes of acute respiratory viral infections (ARVIs). However, detailed kinetics of host immune responses following natural exposures are poorly understood. Investigating the host response during the preâsymptomatic phase of viral infection is challenging, and prior work has largely relied on human challenge studies. In this prospective longitudinal study, we utilized a self-blood collection tool (homeRNA) to profile the host response during preâsymptomatic ARVIs in recently exposed adults and present a study framework for the conduct of largeâscale longitudinal mechanistic studies. Methods We prospectively recruited nonâsymptomatic adults with recent exposure to ARVIs who subsequently tested negative (exposed uninfected) and positive for respiratory pathogens. Study participants performed selfâcollection of blood and nasal swabs across a 4âweek observation window. Daily monitoring of symptoms, viral load, and blood transcriptional responses was performed for the first week followed by weekly monitoring of blood transcriptional responses and symptoms. Nasal swabs were assayed for respiratory pathogens including SARSâCoVâ2. Immune kinetics from 132 longitudinal blood samples (8 SARSâCoVâ2 infected and 4 exposed uninfected) were profiled at high temporal resolution for 773 host response genes. Findings 68 participants across 26 U.S. states completed the study between June 2021 â April 2022, with 97.6% of scheduled longitudinal blood collections (n=691), 97.9% of nasal swabs (n=466) and 97.2% of symptom surveys (n=688) returned. SARS-CoV-2 infection was confirmed in 25% of the participants (n=17) Expression of host immediate early genes (IEGs) involved in AP-1 transcriptional complex and prostaglandin biosynthesis along with genes encoding the early T-cell activation antigen (CD69), pyrogenic cytokines (IL-6, MIP-1ÎČ, and IFN-Îł), cytotoxic cell receptors and granule proteins, and interferon-induced GTPases were detected in the periphery prior to onset of viral shedding in the nasal passage. Upon onset of viral shedding, robust induction of interferon stimulated genes (ISGs) were observed. We also observed elevated expression of the host defense peptides DEFA4, LCN2, LTF, BPI (HDPs) in exposed uninfected individuals. Interpretation Signatures of Tâcell responses prior to nasal viral shedding followed by robust induction of innate ISGs upon onset of viral shedding suggests that Tâcell derived immune memory may play a role in pathogen control during early phases of the infection. Elevated levels of HDPs in exposed uninfected individuals suggest a potential role for neutrophilâmediated immunity in host defense during pathogen exposure. Finally, we demonstrated that unsupervised selfâcollection and stabilization of blood using homeRNA can be used to study early host immune kinetics to natural ARVIs at a temporal resolution comparable to that of human challenge studies. +
++Oral antivirals have the potential to reduce the public health burden of COVID-19. However, now that we have exited the emergency phase of the COVID-19 pandemic, declining SARS-CoV-2 clinical testing rates (average testing rates = âȘ10 tests/100,000 people/day in low-and-middle income countries; <100 tests/100,000 people/day in high-income countries; September 2023) make the development of effective test-and-treat programs challenging. We used an agent-based model to investigate how testing rates and strategies affect the use and effectiveness of oral antiviral test-to-treat programs in four country archetypes of different income levels and demographies. We find that in the post-emergency phase of the pandemic, in countries where low testing rates are driven by limited testing capacity, significant population-level impact of test-and-treat programs can only be achieved by both increasing testing rates and prioritizing individuals with greater risk of severe disease. However, for all countries, significant reductions in severe cases with antivirals are only possible if testing rates were substantially increased with high willingness of people to seek testing. Comparing the potential population-level reductions in severe disease outcomes of test-to-treat programs and vaccination shows that test-and-treat strategies are likely substantially more resource intensive requiring very high levels of testing (>>100 tests/100,000 people/day) and antiviral use suggesting that vaccination should be a higher priority. +
++Abstract Introduction A virtual simulated placement (VSP) is a computer-generated version of a practice placement. COVID-19 drove increased adoption of virtual technology in clinical education. Accordingly, the number of VSP publications increased from 2020. This review aims to determine the scope of this literature to inform future research questions. Objective Assess the range and types of evidence related to VSPs across the healthcare professions. Inclusion criteria Studies that focussed on healthcare students participating in VSPs. Hybrid, augmented reality (AR) and mixed reality (MR) placements were excluded. Methods Fourteen databases were searched, limited to English, and dated from 1st January 2020. Supplementary searches were employed, and an updated search was conducted on 9th July 2023. Themes were synthesised using the PAGER framework to highlight patterns, advances, gaps, evidence for practice and research recommendations. Results Twenty-eight papers were reviewed. All VSPs were designed in response to pandemic restrictions. Students were primarily from medicine and nursing. Few publications were from developing nations. There was limited stakeholder involvement in the VSP designs and a lack of robust research designs, consistent outcome measures, conceptual underpinnings, and immersive technologies. Despite this, promising trends for student experience, knowledge, communication, and critical thinking skills using VSPs have emerged. Conclusion. This review maps the VSP evidence across medicine, nursing, midwifery and allied health. Before a systematic review is feasible across healthcare, allied health and midwifery research require greater representation. Based on the highlighted gaps, other areas for future research are suggested. +
++Background: The Global Burden of Disease study has provided key evidence to inform clinicians, researchers, and policy makers across common diseases, but no similar effort with single study design exists for hundreds of rare diseases. Consequently, many rare conditions lack population-level evidence including prevalence and clinical vulnerability. This has led to the absence of evidence-based care for rare diseases, prominently in the COVID-19 pandemic. Method: This study used electronic health records (EHRs) of more than 58 million people in England, linking nine National Health Service datasets spanning healthcare settings for people alive on Jan 23, 2020. Starting with all rare diseases listed in Orphanet, we quality assured and filtered down to analyse 331 conditions with ICD-10 or SNOMED-CT mappings clinically validated in our dataset. We report 1) population prevalence, clinical and demographic details of rare diseases, and 2) investigate differences in mortality with SARs-CoV-2. Findings: Among 58,162,316 individuals, we identified 894,396 with at least one rare disease. Prevalence data in Orphanet originates from various sources with varying degrees of precision. Here we present reproducible age and gender-adjusted estimates for all 331 rare diseases, including first estimates for 186 (56.2%) without any reported prevalence estimate in Orphanet. We identified 49 rare diseases significantly more frequent in females and 62 in males. Similarly we identified 47 rare diseases more frequent in Asian as compared to White ethnicity and 22 with higher Black to white ratios as compared to similar ratios in population controls. 37 rare diseases were overrepresented in the white population as compared to both Black and Asian ethnicities. In total, 7,965 of 894,396 (0.9%) of rare-disease patients died from COVID-19, as compared to 141,287 of 58,162,316 (0.2%) in the full study population. Eight rare diseases had significantly increased risks for COVID-19-related mortality in fully vaccinated individuals, with bullous pemphigoid (8.07[3.01-21.62]) being worst affected. Interpretation: Our study highlights that National-scale EHRs provide a unique resource to estimate detailed prevalence, clinical and demographic data for rare diseases. Using COVID-19-related mortality analysis, we showed the power of large-scale EHRs in providing insights to inform public health decision-making for these often neglected patient populations. +
++Background: Countries across Europe have faced similar evolutions of SARS-CoV-2 VOCs, including the Alpha, Delta, and Omicron variants. Materials and Methods: We used data from GISAID and applied a robust, automated mathematical substitution model to study the dynamics of COVID-19 variants across Europe over a period of more than two years, from late 2020 to early 2023. This model identifies variant substitution patterns and distinguishes between residual and dominant behavior. We used weekly sequencing data from 19 European countries to estimate the increase in transmissibility (âÎČ) between consecutive SARS-CoV-2 variants. In addition, we focused on large countries with separate regional outbreaks and complex scenarios of multiple competing variants. Results: Our model accurately reproduced the observed substitution patterns between the Alpha, Delta, and Omicron major variants. We estimated the daily variant prevalence and calculated âÎČ between variants, revealing that: (i) âÎČ increased progressively from the Alpha to the Omicron variant; (ii) âÎČ showed a high degree of variability within Omicron variants; (iii) a higher âÎČ was associated with a later emergence of the variant within a country; (iv) a higher degree of immunization of the population against previous variants was associated with a higher âÎČ for the Delta variant; (v) larger countries exhibited smaller âÎČ, suggesting regionally diverse outbreaks within the same country; and finally (vi) the model reliably captures the dynamics of competing variants, even in complex scenarios. Conclusions: The use of mathematical models allows for the precise and reliable estimation of daily cases of each variant. By quantifying âÎČ, we have tracked the spread of the different variants across Europe, highlighting a robust increase in transmissibility trend from Alpha to Omicron. On the other hand, we have shown that the country-level increases in transmissibility can always be influenced by the geographical characteristics of the country and the timing of the emergence of the variant. +
++At the beginning of 2021 the monitoring of the circulating variants of SARS-CoV-2 was established in Germany in accordance with the Corona Surveillance Act (discontinued after July 2023) to allow a better containment of the pandemic, because certain amino acid exchanges (especially) in the spike protein lead to higher transmission as well as a reduced vaccination efficacy. Therefore, our group performed whole genome sequencing applying the ARTIC protocol (currently V4) on Illumina9s NextSeq 500 platform (and starting in May 2023 on the MiSeq DX platform) for SARS-CoV-2 positive specimen from patients of the Heidelberg University Hospital (and associated hospitals) as well as the Public health office in Rhine-Neckar/Heidelberg region. Our group sequenced a total of 26,795 SARS-CoV-2-positive samples between January 2021 and July 2023 - valid sequences, according to the requirements for sequence upload to the German electronic sequencing data hub (DESH) operated by the Robert Koch Institute (RKI), could be determined for 24,852 samples, while the lineage/clade could be identified for 25,912 samples. While the year 2021 was very dynamic and changing regarding the circulating variants in the Rhine-Neckar/Heidelberg region with the initial non-variant of concerns, followed by A.27.RN and the rise of B.1.1.7 in winter/spring and its displacement by B.1.617.2 in spring/summer, which remained almost exclusive until the beginning of December and the first B.1.1.529 incidences, which rose to a proportion of 40 percent by the end of 2021 (and superseded B.1.617.2 by January 2022 with a proportion of over 90 percent). The years 2022 and 2023 were then dominated by B.1.1.529 and its numerous sublineages, especially BA.5 and BA.2, and more recently by the rise of recombinant variants, such as XBB.1.5. By the end of July 2023 (and since calendar week 20) the proportion of the recombinant variants amounted to 100 percent of all circulating variants in the Rhine-Neckar/Heidelberg region. +
++COVID-19 epidemic dynamics are driven by a complex interplay of factors including population behaviour, government interventions, new variants, vaccination campaigns and immunity from prior infections. We aimed to quantify the epidemic drivers of SARS-CoV-2 dynamics in the Dominican Republic, an upper-middle income country of 10.8 million people, and assess the impact of the vaccination campaign implemented in February 2021 in saving lives and averting hospitalisations. We used an age-structured, multi-variant transmission dynamic model to characterise epidemic drivers in the Dominican Republic and explore counterfactual scenarios around vaccination coverage and population mobility. We fit the model to reported deaths, hospital bed occupancy, ICU bed occupancy and seroprevalence data until December 2021 and simulated epidemic trajectories under different counterfactual vaccination scenarios. We estimate that vaccination averted 5040 hospital admissions (95% CrI: 4750 - 5350), 1500 ICU admissions (95% CrI: 1420 - 1590) and 544 deaths (95% CrI: 488 - 606) in the first 6 months of the campaign. We also found that early vaccination with Sinovac-CoronaVac was preferable to delayed vaccination using a product with higher efficacy. We investigated the trade-off between changes in vaccination coverage and population mobility to understand how much relaxation of social distancing measures vaccination was able to 9buy9 in the later stages of a pandemic. We found that if no vaccination had occurred, an additional decrease of 10-20% in population mobility would have been required to maintain the same death and hospitalisation outcomes. We found SARS-CoV-2 transmission dynamics in the Dominican Republic were driven by substantial accumulation of immunity during the first two years of the pandemic but that, despite this, vaccination was essential in enabling a return to pre-pandemic mobility levels without incurring considerable additional morbidity and mortality. +
+Improving Post COVID-19 Syndrome With Hyperbaric Oxygen Treatments - Conditions: Post COVID-19 Condition; Post-COVID-19 Syndrome; Post-COVID Syndrome; COVID-19; Fatigue; Fatigue Syndrome, Chronic
Interventions: Device: Monoplace Hyperbaric Chamber (Class III medical device).
Sponsors: Sunnybrook Health Sciences Centre
Not yet recruiting
Education of Medical Staff to Post Acute Covid susTained sYmptoms - Conditions: Post-acute COVID-19 Syndrome
Interventions: Other: Training in the management of functional disorders; Other: Reimbursement of 3 long consultations
Sponsors: Assistance Publique - HĂŽpitaux de Paris; ANRS, Emerging Infectious Diseases
Not yet recruiting
Pharmacist Management of Paxlovid eVisits - Conditions: COVID-19; Quality of Care
Interventions: Other: Pharmacist Care; Other: AFM Pool Care
Sponsors: Kaiser Permanente
Not yet recruiting
ACTIVATE in Public Housing - Conditions: Pneumonia; Influenza; Varicella Zoster; Meningitis; COVID-19; Vaccine Hesitancy
Interventions: Behavioral: Increasing Willingness and Uptake of Influenza, Pneumonia, Meningitis, HZV, and COVID-19 Vaccination
Sponsors: Charles Drew University of Medicine and Science
Not yet recruiting
Effects of a Home-Based Exercise Intervention in Subjects With Long COVID - Conditions: Long COVID-19; Post-COVID-19 Syndrome
Interventions: Other: home-based concurrent exercise
Sponsors: University of Vienna
Recruiting
Early Awake Alterning Prone Positioning Combined With Non-invasive Oxygen Therapy in Patients With COVID-19. - Conditions: COVID-19 Pneumonia
Interventions: Other: Prone position; Other: Standard treatment
Sponsors: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
Terminated
tDCS in the Management of Post-COVID Disorders - Conditions: Long COVID
Interventions: Device: Transcranial Direct Current Stimulation (tDCS); Behavioral: Motor Training; Behavioral: Cognitive Training
Sponsors: Universidade Federal de Pernambuco; SĂŁo Paulo State University
Recruiting
Equity Evaluation of Fact Boxes on Informed COVID-19 and Influenza Vaccination Decisions - Study Protocol - Conditions: COVID-19; Influenza
Interventions: Other: Fact box
Sponsors: Harding Center for Risk Literacy
Not yet recruiting
Study of the Vector Vaccine GamCovidVac-M (Altered Antigenic Composition) - Conditions: COVID-19
Interventions: Biological: GamCovidVac-M vector vaccine for the prevention of COVID-19 with altered antigenic composition
Sponsors: Gamaleya Research Institute of Epidemiology and Microbiology, Health Ministry of the Russian Federation
Not yet recruiting
Study of the Vector Vaccine GamCovidVac for the Prevention of COVID-19 With Altered Antigenic Profile With Participation of Adult Volunteers - Conditions: COVID-19
Interventions: Biological: GamCovidVac vector vaccine for the prevention of COVID-19 (with altered antigenic profile)
Sponsors: Gamaleya Research Institute of Epidemiology and Microbiology, Health Ministry of the Russian Federation
Not yet recruiting
Exercise Interventions in Post-acute Sequelae of Covid-19 - Conditions: COVID-19
Interventions: Behavioral: Exercise
Sponsors: University of Virginia
Not yet recruiting
Effects of Cacao FLAvonoids in LOng Covid Patients (FLALOC) - Conditions: Long Covid19; Fatigue Syndrome, Chronic
Interventions: Dietary Supplement: Flavonoids
Sponsors: Guillermo Ceballos Reyes; Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado
Recruiting
The Efficacy of the 2023-2024 Updated COVID-19 Vaccines Against COVID-19 Infection - Conditions: COVID-19; Vaccine-Preventable Diseases; SARS CoV 2 Infection; Upper Respiratory Tract Infection; Upper Respiratory Disease
Interventions: Biological: Novavax COVID-19 vaccine (2023-2024 formula XBB containing); Biological: Pfizer COVID-19 mRNA vaccine (2023-2024 formula XBB containing)
Sponsors: Sarang K. Yoon, DO, MOH; Westat; Novavax
Not yet recruiting
Motivational Interviewing for Vaccine Uptake in Latinx Adults - Conditions: Vaccine Hesitancy
Interventions: Other: EHR alert; Behavioral: Motivational Interviewing; Behavioral: Warm hand off to nurse
Sponsors: Boston College; East Boston Neighborhood Health Center; Harvard School of Public Health (HSPH); Boston Childrenâs Hospital; National Institute of Nursing Research (NINR)
Not yet recruiting
Clinical Trial to Evaluate the Safety of RQ-01 in SARS-CoV-2 Positive Subjects - Conditions: COVID-19; Infectious Disease; Symptomatic COVID-19 Infection Laboratory-Confirmed; SARS CoV 2 Infection
Interventions: Combination Product: RQ-001; Other: Placebo
Sponsors: Red Queen Therapeutics, Inc.; PPD
Recruiting
2-thiouridine is a broad-spectrum antiviral nucleoside analogue against positive-strand RNA viruses - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are causing significant morbidity and mortality worldwide. Furthermore, over 1 million cases of newly emerging or re-emerging viral infections, specifically dengue virus (DENV), are known to occur annually. Because no virus-specific and fully effective treatments against these or many other viruses have been approved, there is an urgent need for novel, effective therapeutic agents. Here, we identified 2-thiouridine (s2U) asâŠ
Distinct motifs in the E protein are required for SARS-CoV-2 virus particle formation and lysosomal deacidification in host cells - Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is a major public health concern, but the mechanisms underlying its viral particle formation are not well understood. In this study, we established a system for producing virus-like particles (VLPs) by expressing four structural proteins that make up SARS-CoV-2 virus particles in cells and used a spike (S) protein fused with the HiBiT peptide as a marker for evaluating VLP production. Using this system, we confirmed that the E proteinâŠ
Evaluation of in vitro SARS-CoV-2 inactivation by a new quaternary ammonium compound: Bromiphen bromide - The pneumonia (COVID-19) outbreak caused by the novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which unpredictably exploded in late December of 2019 has stressed the importance of being able to control potential pathogens with the aim of limiting their spread. Although vaccines are well known as a powerful tool for ensuring public health and controlling the pandemic, disinfection and hygiene habits remain crucial to prevent infection from spreading andâŠ
An aggregation-induced emission sensor combined with UHPLC-Q-TOF/MS for fast identification of anticoagulant active ingredients from traditional Chinese medicine - Xuebijing injection (XBJ) has a good therapeutic effect on the patients with severe coronavirus disease, but the material basis of XBJ with the anticoagulant effect to improve the coagulopathy and thromboembolism is still unclear. Herein, we developed a new strategy based on aggregation-induced emission (AIE) for monitoring thrombin activity and screening thrombin inhibitors from XBJ. The molecule AIE(603) and the thrombin substrate peptide S-2238 were formed into AIE nanoparticle (AIENP) whichâŠ
Targeting Cyclophilin A and CD147 to Inhibit Replication of SARS-CoV-2 and SARS-CoV-2-Induced Inflammation - Identification and development of effective therapeutics for COVID-19 are still urgently needed. The CD147/Spike interaction is involved in the SARS-CoV-2 invasion process, in addition to ACE2. Cyclophilin A (CyPA), the extracellular ligand of CD147, has been found to play a role in the infection and replication of coronaviruses. In this study, our results show that CyPA inhibitors such as Cyclosporine A (CsA) and STG-175 can suppress the intracellular replication of SARS-CoV-2 by inhibiting theâŠ
Multifunctional natural derived carbon quantum dots from Withania somnifera (L.) - Antiviral activities against SARS-CoV-2 pseudoviron - Natural carbon dots (NCQDs) are expediently significant in the photo-, nano- and biomedical spheres owing to their facile synthesis, optical and physicochemical attributes. In the present study, three NCQDs are prepared and optimized from Withania somnifera (ASH) by one-step hydrothermal (bottom-up) method: HASHP (without dopant), nitrogen doped HASHNH(3) (surface passivation using ammonia) and HASHEDA (surface passivation with ethylenediamine). The HR-TEM images reveal that HASHP, HASNH(3),âŠ
4-Octyl itaconate reduces influenza A replication by targeting the nuclear export protein CRM1 - In recent years, especially since the outbreak of the severe acute respiratory syndrome coronavirus 2 pandemic, the cell-permeable itaconate derivative 4-octyl itaconate (4-OI) has gained traction as a potential antiviral agent. Here, we demonstrate that 4-OI inhibits replication of multiple influenza A viruses (IAV) by restricting nuclear export of viral ribonucleoproteins, a key step in the IAV replication cycle. This nuclear retention is achieved by deactivation and subsequent degradation ofâŠ
Exploration of phenolic acid derivatives as inhibitors of SARS-CoV-2 main protease and receptor binding domain: potential candidates for anti-SARS-CoV-2 therapy - Severe acute respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) is the etiological virus of Coronavirus Disease 2019 (COVID-19) which has been a public health concern due to its high morbidity and high mortality. Hence, the search for drugs that incapacitate the virus via inhibition of vital proteins in its life cycle is ongoing due to the paucity of drugs in clinical use against the virus. Consequently, this study was aimed at evaluating the potentials of natural phenolics against the MainâŠ
The Apolipoprotein E neutralizing antibody inhibits SARS-CoV-2 infection by blocking cellular entry of lipoviral particles - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causal agent for coronavirus disease 2019 (COVID-19). Although vaccines have helped to prevent uncontrolled viral spreading, our understanding of the fundamental biology of SARS-CoV-2 infection remains insufficient, which hinders effective therapeutic development. Here, we found that Apolipoprotein E (ApoE), a lipid binding protein, is hijacked by SARS-CoV-2 for infection. Preincubation of SARS-CoV-2 with a neutralizing antibodyâŠ
Unnatural Endotype B PPAPs as Novel Compounds with Activity against Mycobacterium tuberculosis - Pre-SARS-CoV-2, tuberculosis was the leading cause of death by a single pathogen. Repetitive exposure of Mycobacterium tuberculosis(Mtb) supported the development of multidrug- and extensively drug-resistant strains, demanding novel drugs. Hyperforin, a natural type A polyprenylated polycyclic acylphloroglucinol from St. Johnâs wort, exhibits antidepressant and antibacterial effects also against Mtb. Yet, Hyperforinâs instability limits the utility in clinical practice. Here, we present photo-âŠ
In vitro reconstitution of SARS-CoV-2 Nsp1-induced mRNA cleavage reveals the key roles of the N-terminal domain of Nsp1 and the RRM domain of eIF3g - SARS CoV-2 nonstructural protein 1 (Nsp1) is the major pathogenesis factor that inhibits host translation using a dual strategy of impairing initiation and inducing endonucleolytic cleavage of cellular mRNAs. To investigate the mechanism of cleavage, we reconstituted it in vitro on ÎČ-globin, EMCV IRES, and CrPV IRES mRNAs that use unrelated initiation mechanisms. In all instances, cleavage required Nsp1 and only canonical translational components (40S subunits and initiation factors), arguingâŠ
Lipid droplets in Zika neuroinfection: Potential targets for intervention? - Lipid droplets (LD) are evolutionarily conserved lipid-enriched organelles with a diverse array of cell- and stimulus-regulated proteins. Accumulating evidence demonstrates that intracellular pathogens exploit LD as energy sources, replication sites, and part of the mechanisms of immune evasion. Nevertheless, LD can also favor the host as part of the immune and inflammatory response to pathogens. The functions of LD in the central nervous system have gained great interest due to their presenceâŠ
Tetherin antagonism by SARS-CoV-2 ORF3a and spike protein enhances virus release - The antiviral restriction factor, tetherin, blocks the release of several different families of enveloped viruses, including the Coronaviridae. Tetherin is an interferon-induced protein that forms parallel homodimers between the host cell and viral particles, linking viruses to the surface of infected cells and inhibiting their release. We demonstrate that SARS-CoV-2 infection causes tetherin downregulation and that tetherin depletion from cells enhances SARS-CoV-2 viral titres. We investigateâŠ
Characterization of pre-existing anti-PEG and anti-AGAL antibodies towards PRX-102 in patients with Fabry disease - Polyethylene glycol (PEG)ylated drugs are used for medical treatment, since PEGylation either decreases drug clearance or/and shields the protein from undesirable immunogenicity. PEGylation was implemented in a new enzyme replacement therapy for Fabry disease (FD), pegunigalsidase-alfa (PRX-102). However, exposure to PEG via life-style products and vaccination can result in the formation of anti-PEG antibodies. We demonstrate the de novo formation of functional anti-PEG antibodies in a healthyâŠ
W254 in furin functions as a molecular gate promoting anti-viral drug binding: Elucidation of putative drug tunneling and docking by non-equilibrium molecular dynamics - Furins are serine endoproteases that process precursor proteins into their biologically active forms, and they play essential roles in normal metabolism and disease presentation, including promoting expression of bacterial virulence factors and viral pathogenesis. Thus, furins represent vital targets for development of antimicrobial and antiviral therapeutics. Recent experimental evidence indicated that dichlorophenyl (DCP)-pyridine âBOSâ drugs (e.g., BOS-318) competitively inhibit human furinâŠ
The Luxury Office Development That Became a Horrific Migrant Shelter - In Brooklyn, hundreds of men have languished in a city-run facility, taking cold showers, eating bad food, and sleeping inches from one another. - link
The Chaos Party on the Hill Keeps On Chaos-ing - Even after Hamasâs attack on Israel, House Republicans are too busy fighting with themselves to get serious about the rest of the world. - link
Keir Starmer, the Man Who Would Be Britainâs Next Prime Minister - At the annual conference of the Labour Party this week, Keir Starmer laid out his plans to rebuild the United Kingdom after thirteen years of Conservative misrule. - link
What Was Hamas Thinking? - One of the groupâs senior political leaders explains its strategy. - link
The Tangled Grief of Israelâs Anti-Occupation Activists - Israelis who advocate for Palestinian rights are simultaneously absorbing two streams of traumatic news: the brutality and extent of Hamasâs attacks and the bombardment and siege of Gaza. - link
+Protests in the Middle East show the centrality of Palestine. +
++Demonstrations of solidarity with Palestinians have broken out across the Arab world this week, as Israel reels from Hamasâs massive attack and Palestinians in Gaza come under bombardment. +
++Moroccans, Jordanians, and Egyptians have rallied in protests large and small, even as the governments of these countries have built and maintained varying degrees of diplomatic ties with Israel. And while those demonstrations may seem jarring given the widespread deaths in Israel this week, the fact that some have cheered on violence against civilians may obscure the broader political dynamics at play â both within the Middle East and within the Arab countries themselves. +
++Hamasâs violence does not reflect the desire of all, or even most, Palestinians who seek rights and freedoms. But the solidarity expressed in these rallies reflects a broader dissatisfaction with how Israel, with Western support, has subjected Palestinians to military occupation since 1967. The protests also represent a rare space for political expression in largely autocratic states where regimes severely limit such speech. +
++In the Arab world, people have been as quick to show support for Palestine as most American politicians have for Israel. On Friday, after prayers at Egyptâs al-Azhar Mosque, protesters filled the streets. As did tens of thousands of Iraqis in Baghdadâs Tahrir Square, thousands of Jordanians protesting in the capital and in major cities, and hundreds who gathered outside a central mosque in Qatar, along with protesters in Lebanon, Oman, Tunisia, and Yemen. Demonstrators burned Israeli flags and chanted against Israelâs military campaign. +
+ ++Without understanding the full history of the conflict and the region, some American readers could dismiss everyone participating in these protests as âangry Arabs,â a repugnant trope that has permeated Western media for a century and was heightened after 9/11. It may still be jarring to watch for many, but the forces that drive the protests go deep â and will only deepen as the latest war unfolds. +
++For Palestinians and Arabs, the war did not begin on the morning of October 7 with Hamasâs attacks on Israel. Rather, for them, the war has been ongoing since 1948, when militias expelled Palestinians from their homes and killed tens of thousands in what is called the Nakba, or catastrophe. It continued with the 1967 setback â as the Six-Day War is called in Arabic â in which Israel began occupying the West Bank, Gaza, and East Jerusalem, and has carried on through waves of further conflicts and protests. +
++That support is rooted in a history of grassroots support for Palestinians and of Arab strongmen using the cause as a populist rallying point. âItâs the open wound, the festering sore, on the Arab conscience,â Mouin Rabbani, an analyst of Palestinian politics and co-editor of the web journal Jadaliyya, told me. âWhen you go back to the 1950s and the 1960s, the heyday of Arab nationalism, Palestine was the central Arab cause, so much so that many Arab leaders could use it, instrumentalize it, and exploit it to either help them achieve power or stay in power or improve their popularity at home.â +
+ ++The religious component is also important, with so many holy sites for Muslims within Jerusalem and throughout Israel and the occupied territories. The Arab-Israeli conflict is a political conflict over land, and it has never been primarily a religious war. (For centuries, Jews and Muslims had gotten along throughout the Middle East and beyond.) Yet images of Israeli security forces in mosques of significant historic meaning can indeed galvanize emotional response. And the same goes for churches in Jerusalem and Bethlehem, among other holy sites for Arab Christians. +
++Nonetheless, most Arabs, according to polling conducted over two decades by the Arab Barometer, would be willing to have diplomatic relations with Israel â but only after the establishment of a Palestinian state alongside Israel. âTheyâre not against coexisting with a Jewish-majority Israeli state, which is what exists now, but they will not do that until the Palestinians get their rights,â Rami Khouri, a Palestinian-Jordanian journalist and a policy fellow at the American University of Beirut, told me. +
++âThe popular sentiment across the whole region supporting Palestinian rights is very strong and very deep,â Khouri told me. +
++âMost Arab citizens are bludgeoned by their own autocratic systems, and increasingly by severe economic stress,â he explained. âSo the Palestine struggle is vicariously seen by many in the region as an anti-colonial struggle.â +
++As long as both Arab rulers and their populations remained united in the idea that there could be no progress with Israel without significant progress in the Palestinian cause, normalization of Israelâs ties with its Middle East neighbors â long a goal of politicians there and in the US â was off the table. But in recent years, that had begun to change. +
++Egypt made peace with Israel in 1979, and neighboring Jordan followed in 1993. Such deals were often far from popular at home â Egyptian President Anwar Sadat was assassinated in 1981 by Islamic militants who were against the peace deal. Other Arab states held out, insisting first on the creation of a sovereign Palestinian state. US policy since President George H.W. Bush has been focused on a peace process that would lead to that outcome, and the goal as set out by Presidents Bill Clinton, George W. Bush, and Barack Obama was two states for two peoples. +
+ ++When President Donald Trump focused on a series of normalization deals between Israel and Arab states in 2020, however, he sidelined the cause of Palestine. Saudi Arabia, which had long emphasized the importance of a Palestinian state, had already been quietly developing extensive business and military relationships with Israel. Suddenly it seemed possible that the Palestinian cause could be sacrificed by the Arab worldâs rulers. +
++But all of the countries involved in the normalization negotiations â the United Arab Emirates, Bahrain, and Morocco â are autocracies. And their citizens were not as eager to go along with a new Middle East. In response, the governments of these countries censored criticism of the deals in the press and stifled public protests. âActivists who were involved in pro-Palestine activism â either through local organizations or through the Gulf Coalition Against Normalization â also reported worsening online harassment, forcing many to take a step back from their activities,â Dana El Kurd, a political scientist at the University of Richmond, writes. +
++Surveys show how unpopular those accords were. Recent polls show their Arab support has dropped significantly since 2020, with just 27 percent of Emiratis and 20 percent of Bahrainis in favor of the accords. +
++âIf you had democracy in the Arab world, you wouldnât have any normalization,â historian Rashid Khalidi of Columbia University told me. âPublic opinion is overwhelmingly against normalization with Israel. Overwhelmingly, in every poll in every country.â +
++The past few days have seen renewed calls for boycotting of Israeli-linked businesses in Bahrain and Qatar, and a resurgence of anti-normalization activism in Gulf countries, El Kurd told me. Far from being relegated to the backburner, the Palestinian cause is now front and center in the Arab world. And that is something American policymakers canât afford to ignore. +
++Palestine is so central to the Arab Middle East that even US military leaders historically understood the peril of ignoring the Palestinian cause. +
++When David Petraeus, then the top US military commander in the Middle East, went before the Senate in 2010, he warned that the unresolved Israel-Palestinian conflict was endangering American lives. +
++âThe enduring hostilities between Israel and some of its neighbors present distinct challenges to our ability to advance our interests,â he testified. âThe conflict foments anti-American sentiment, due to a perception of US favoritism for Israel. Arab anger over the Palestinian question limits the strength and depth of US partnerships with governments and peoples in the AOR [area of responsibility] and weakens the legitimacy of moderate regimes in the Arab world.â +
++But President Bidenâs policies have not recognized the centrality of Palestine in the region. Instead, Biden spent last year repairing relations with Saudi Crown Prince Mohammed bin Salman, and prioritized a diplomatic deal between Saudi Arabia and Israel that now appears dead on arrival. +
++Biden told the United Nations last month that his team is working âtirelessly to support a just and lasting peace between the Israelis and Palestinians â two states for two people.â But in reality, the administrationâs empty commitment to the two-state solution has precluded the development of actual policies that would lead to peace. +
++Where does that leave a US policy focused on normalization in a region that largely cares more about Palestinians? +
++The governments of Bahrain, Morocco, and the United Arab Emirates are balancing their relations with Israel and their peopleâs solidarity with Palestine. The Bahraini foreign ministry âstressed the need to immediately stop the ongoing fighting between the Palestinian Hamas movement and the Israeli forces.â Moroccan Foreign Minister Nasser Bourita, in remarks to a session of the Arab League, acknowledged the âbloody and horrifying events that erupted on Saturday, October 7, 2023â and an Arab League resolution urged restraint, warning of âcatastrophic repercussions, both human and security, of the continuation and expansion of the escalation.â The Emirati Ministry of Foreign Affairs said in a statement that it âdeeply mourns the loss of Israeli and Palestinian livesâ and âstressed that attacks by Hamas against Israeli towns and villages near the Gaza Strip, including the firing of thousands of rockets at population centers, are a serious and grave escalation.â +
++It would seem unlikely that those countries would break off or downgrade their diplomatic relations with Israel. What seems certain is that more Arab countries are not likely to normalize with Israel. The ongoing bombardment of Gaza, and a ground assault if one goes ahead, will undermine those prospects further. +
++âIn the short term, the normalization deal with Saudi Arabia is going to be delayed or face some level of obstacle,â El Kurd told me. âBecause the whole point of them engaging on this topic is to say, âOh, weâre going to meaningfully change Palestinian living conditions.â I donât think thatâs within their ability to change, even marginally, at this point.â +
++Now, one hopes that Bidenâs advisers are watching protests in Arab capitals with a new understanding of the significance of Palestine to any Middle East policy. An approach to the region that does not take into account the mass, popular support for Palestinian rights â as has been on display since Biden took office â is not suited to reckon with realities on the ground. By focusing on solidifying Israelâs ties to Arab leaders, Biden has neglected to listen to Arab people. +
++
++
+The high stakes of Polandâs elections, explained. +
++WARSAW, Poland â âWe have been talking that these are the most important elections since 1989, which was the first partly free elections since the fall of communism,â Jakub Kocjan, a rule of law campaigner for Akcja Demokracja, a Polish pro-democracy organization, told me from his apartment in Warsaw, less than a week before parliamentary elections that may determine the democratic future of Poland. +
++Behind him, a map of the European Union spans the wall. Another map, this one of Poland, hangs on the other side of the room. Kocjan sits in a desk chair, one leg extended and propped up on a bed. His foot is in a plastic boot, an old injury flaring up. +
++âThere is some point,â Kocjan says, âwhere there is no possibility to go back to democracy.â +
++For Kocjan, and for many other civic and pro-democracy activists, opposition party members, and some observers, this October 15 election is that point. +
++Polandâs democracy is wounded, the consequence of eight years of rule by the right-wing populist Law and Justice Party (PiS). The party has captured state institutions and resources, dismantled the judicial system and constitutional courts, consolidated control over public media. The party has mainstreamed nationalism, which has put Poland at odds with the European Union and its members, like Germany and with other partners, most recently, Ukraine. +
++The stakes of the election are undeniable: If PiS wins again and returns to power, it will keep Poland on this illiberal path: more undermining of the rule of law and the judiciary; more domination over the media and the state resources; more tension with European partners. Which is why these elections feel to many like the most important vote in more than 30 years. +
++âThis time, many people are expecting the same â but more. Stronger, with the Hungarian path actually becoming a reality,â said Piotr Ćukasiewicz, a former Polish diplomat and analyst for security and international affairs with Polityka Insight, referring to Viktor OrbĂĄnâs authoritarian consolidation in Hungary. +
++Yet Poland is divided, and right now the elections are a bit too close to call â and that means, despite the odds, the democratic opposition has a chance to unseat PiS. PiSâs control of the media and state resources has skewed competition, but it has not eliminated it. Broad public frustration over the high cost of living has eaten away at PiSâs support, along with the rise of a more radical far-right party, the Confederation that has questioned Polandâs support for Ukraine, and is appealing to younger voters, especially men. +
++The opposition centrist Civic Coalition, led by former Prime Minister Donald Tusk, is promising to restore Polandâs democracy and improve relations with Europe. Civic and an array of other opposition coalitions on the left, center, and center-right, are pulling close in polls. It is a catch-all, diverse group, but together they may be able to get PiS out of power and try to begin unraveling the illiberal regime it created. +
++None of this is a guarantee. PiS seems unlikely to win an outright majority, but it very much could still garner the most votes, enough to form a government, even if they have to seek the help of the more right-wing Confederation. Even if the opposition coalitions win enough seats to potentially form a government, it is likely to be a slim edge, under a very broad tent, and reliant on cooperation from many disparate groups, which may weaken its effectiveness. No matter who emerges, this parliamentary election could make Polish politics a lot more unstable. That may dislodge PiS for now, but make unpredictable what could replace it. +
++These election results also matter for more than just Poland. They will reverberate across Europe and the North Atlantic Treaty Alliance (NATO). Poland is Europeâs front line in Russiaâs invasion of Ukraine, a critical transfer point for arms, and a host of more than 1 million Ukrainian refugees. The future of Polandâs democracy may influence regional stability and its future support of Ukraine; PiS has picked fights with Kyiv, in part, to fend off the rise of the far right, and if PiS retains power, those tensions may persist, another nick in an increasingly fragile Western coalition as the war moves closer to its third year. +
++Poland is not alone in being framed as a last-chance election: Recent votes in Brazil, Turkey, and soon the United States and India, all carry similar stakes. One election isnât enough to unmake polarization or fully fix a faltering democracy, but it may be the first step to healing the break. This is Polandâs test: not just whether it can save its own democracy, but whether it can be a model for Europe and the world that itâs even possible. +
++âThere are two feelings that everyone has,â Kocjan told Vox. âFirst is a lot of hope because we really know that we have this chance, and we cannot waste it. Because it will be too late.â +
++The other, he said, was anxiety that even if the opposition won enough votes, it would be able to take control. âIt is really hard to imagine,â he said, referring to PiS, âthat they will simply give the power to the other party.â +
++Warsaw, Polandâs capital and biggest city, is largely an opposition town. The campaign signs at bus stops or on street signs skew toward the opposition, Koalicja Obywatelska (KO), or the Civic Coalition. On Nowy Ćwiat, a main thoroughfare in Warsawâs Old Town â the part of the city reconstructed after World War II to look like it did before it was destroyed â many voters criticized the direction of the country, the state of education, health care, and democracy. âI really want to change whatâs been there so far,â one Warsaw resident told Vox. âMy whole heart is with the Civic Coalition, with the opposition party.â +
++Elsewhere, near the WileĆski (Vilnius) metro station in the North Praga, an area by the Warsaw district that had the most PiS support in the last parliamentary election in 2019, not everyone seemed eager to vote for PiS again. A woman sitting at a stand selling socks said sheâd had enough and would definitely not vote for JarosĆaw KaczyĆski, the deputy prime minister and leader of the PiS party. She recently had to buy medicine. It cost too much for her, and yet, she saw plenty of people getting benefits who didnât work for them. +
+ ++It reflected some of the fatigue around PiS. The right-wing party is socially conservative, but a lot of its popularity was built on its populist economic policies, which included generous welfare benefits like a child subsidy. PiS oversaw a period of growth, which they canât take exclusive credit for, but their policies did benefit lower-income households, and so PiS became the party most trusted on economic issues. +
++But the economic aftershocks of Covid-19 and the war in Ukraine have raised Polandâs inflation to some of the highest in Europe and that has refracted onto PiS. PiS was popular as long as Poles felt things were improving, but now with the costs rising, support for PiS is flagging. +
++That did not necessarily translate to support for the Civic Coalition in this neighborhood though; one man said heâd take the current government over the opposition, but heâd prefer to clear them all out. Another woman said she wouldnât vote because she didnât like anyone. +
++Some of this disillusionment is because, as high as the stakes of the election, voters are mostly dealing with the same cast of characters (if that sounds familiar). Civicâs leader, Tusk, was the Polish prime minister from 2007 and 2014 and is the former president of the European Council â that is, a guy whoâs been around for a long time. âThe Civic Coalition doesnât look like a new offer,â explained Edwin Bendyk, chairman of the Fundacja im. Stefana Batorego, a pro-democracy organization, of some of the publicâs hesitation around the party. Plus, media propaganda doesnât help. Polandâs public media has relentlessly attacked Tusk, framing him as a European bureaucrat who is an agent of Germany, but also an appeaser of Russia. On Warsawâs streets, residents repeated some of these attacks. +
++Still, it all felt fairly typical for a week ahead of a major election: the motivated, the undecided, the disillusioned, the indifferent. This is the trickiness of an illiberal democracy. It isnât a fully authoritarian state where elections are a farce. The PiS has chipped away at the rule of law and democracy but not destroyed it entirely, and the beats of the electoral system are intact. The outcome of the vote is still uncertain, though exactly how uncertain is hard to know because itâs difficult to quantify exactly how far the scales have been tipped. +
++âThe election will be free. Itâs not fair because of the advantages that the government has. But itâs still more or less a functioning democracy,â said Adam Traczyk, director of More in Common Polska, a pro-democracy think tank. +
++The PiS party was legitimately elected in 2015, and since then has used the levers of power to capture the state and its institutions. PiS has subverted the constitutional and judicial system. PiS painted judges as post-communist holdovers, acting against the peopleâs interests â in part because they had previously thwarted some of PiSâs legislation and agenda, and they, after all, PiS had a democratic mandate. Polandâs Constitutional Tribunal is stacked with PiS loyalists and is now neutered to the point of dysfunction. +
+ ++In this, and other ways, PiS has fully captured the state, subverting it to its own political interests. This election has shown just how tilted things are. PiS has turned public media into state propaganda that relentlessly attacks the opposition. In this campaign, PiS has raised funds from state-controlled entities and its employees. A state-controlled oil and gas company owns a press company that publishes almost 20 regional newspapers and hundreds of weeklies and online sites; they refused to publish ads for certain candidates because of their âleft-wingâ values. The PiS party has approved benefit and pension hikes ahead of this campaign. +
++As a nationalistic party, PiS has also tried to hype up its base by fear-mongering around immigration, especially from the Middle East and Africa (though PiS itself was embroiled in a cash-for-visa scheme), and a meddlesome Europe that is trying to interfere in Poland. To motivate their supporters, PiS is staging a referendum it has little power to implement, with loaded questions like: Do you support âthe admission of thousands of illegal immigrants from the Middle East and Africa, according to the forced relocation mechanism imposed by the European bureaucracy?â +
++PiS has also tweaked electoral rules, increasing polling stations in rural areas, places most likely to benefit PiS. It is likely PiS strongholds are already overrepresented since the country hasnât updated its parliamentary count to adjust for potential population changes, and some estimates suggest cities â where the opposition tends to do well â are underrepresented. Right now, a record number of Poles â some 600,000 â have registered to vote abroad. Those will most likely favor the opposition, but they must be counted within 24 hours or they are disqualified, a rule PiS passed in January that notably does not apply to the rest of Polandâs votes. +
++These baked-in disadvantages are why the opposition faces steep odds, and it explains some of the desperation they feel. âFor the opposition, this is seen pretty widely as an election that if they donât win this one they might not be able to win another one, that the systemic advantage of the government would be so strong,â said Michal Baranowski, managing director for the German Marshall Fund East, in Warsaw. +
++Tusk and the opposition have framed this election as the last chance to save Polandâs democracy. Jakub (Kuba) KaryĆ, chair of Komitet Obrony Demokracji (Committee to Protect Democracy), said he believed if the opposition did not win these elections, they would be the last ones. +
++âHaving this government for the third time would be a disaster because they will continue to close up this authoritarian system,â Bendyk said. Poland was not authoritarian yet; there was still a free press, strong civil society, and thriving local democracy which Bendyk described as the immune system in the democratic resistance. But one by one, PiS would target these. âItâs quite easy to lay down rules to demand you can be penalized for different actions,â Bendyk said. âIt can be difficult to do what we are doing now.â +
+ ++In her office in Warsaw, Marta Lempart, leader of Strajk Kobiet, or Womenâs Strike, a womenâs rights and pro-abortion-rights group, was preparing to film videos to respond to different election outcomes. She has campaigned against PiSâs strict abortion laws. I asked how the organizationâs work would change if PiS won again. âWhen they close the system,â Lempart replied, âour operations will be different because I will be in jail, obviously.â +
++The opposition has an incentive to hype the stakes and make this election existential. But most experts and other observers Vox spoke to agreed that Poland would continue on this anti-democratic path if PiS captured power again. +
++And, right now, the opposition does have a real, if tenuous, opening. +
++The cost of living concerns of the electorate are real. Beyond that, PiS is facing a challenge from its right, the radical, anti-establishment party Konfederancja, or Confederation. The group doesnât really fit into neat boxes; itâs a wild mess of libertarians, conspiracy theorists, anti-vaxxers, antisemites, and incels. Confederation also has a strong anti-Ukraine strain, reviving historical grievances, criticizing the war and Polandâs support for it, and Warsawâs welcome of Ukrainian refugees. +
+ ++Broadly, Poles are still supportive of Ukraine and of Warsawâs political and humanitarian response to Russiaâs invasion, and Russia is too big of a security threat for a real pro-Russia party to thrive. But Confederationâs anti-establishment message is peeling off some disillusioned voters, especially from younger demographics. That has freaked out PiS enough that it has hardened its stance on Ukraine, an uncomfortable development for the Western alliance given Polandâs position on NATOâs eastern flank. +
++Together, though, PiS looks somewhat vulnerable. So the pro-democracy opposition is mobilizing. In early October, hundreds of thousands of opposition supporters attended a massive rally in Warsaw. KaryĆ, of the Committee to Protect Democracy, said his group has registered more than 27,000 volunteers so far to observe the polls. +
++The democratic opposition â both parties running and pro-democracy activists and civil society leaders â is a diverse group. They are unified to dislodge PiS, which gives the vote a bit of the feel of the 2020 US election: anti-Trump more than pro-Biden; anti-PiS more than pro-Tusk and pro-Civic. Kocjan, the rule of law campaigner, said people are trying to vote strategically; that is, if they live in a more conservative district, voting for the opposition party most likely to win, not necessarily the one they favor the most. +
+ ++In 2020, PiS oversaw a near-total ban on legal abortion, one of the most extreme in Europe. Lempart, leader of Strajk Kobiet, is trying to motivate voters on the abortion issue, especially younger voters, ages 18 to 25, to convince them they can get enough pro-abortion MPs elected, they can dismantle these restrictions. +
++She noted that many young voters are disillusioned with the current political establishment â something backed up by surveys â but the opposition wasnât offering a positive message, just criticizing young people, telling them to vote and save the country or else. +
++Her organizationâs approach was to give voters a clear deliverable. âWeâre saying âitâs absolutely okay if you donât feel anything, when you see the flag, when you hear the anthem, if you donât care what happens, [if] the call to save the country just doesnât appeal to you,â she said. But the Parliament needs 50 percent plus one to change the abortion laws. âIf you go and vote for abortion, believe that then we can deliver,â Lempart said. +
++The radical far-right Confederation may end up the decider on Polandâs democratic future. PiS is still likely to win the most seats in parliament, though it seems unlikely to secure an outright majority. It may have to look to its rivals in the Confederation. The Confederation hates PiS because of its welfare spending; going into government with them would probably destroy their anti-establishment credentials. Still, PiS might just need to persuade a few opportunistic politicians to switch sides. +
++And even if the opposition can pull it out, the path forward is likely turbulent and tricky. One wild and risky possibility is the far-right Confederation tolerating a minority government led by the Civic Coalition. And no matter what, PiS is unlikely to go quietly. Their allies are in the courts, including the ones that deal with elections. Their allies control the business interests. Their allies control the messages on public media. +
++âIf the opposition really manages to win or has enough votes to form a coalition, itâs not that on the 16th of October, we will all be sitting and singing Kumbaya and everything will be fine,â said Maria SkĂłra, a researcher at the Institute for European Politics (IEP), in Berlin. âThe thing is that Law and Justice will not give up their powers too easily.â +
++Which is why many activists, experts, and observers in Warsaw seemed to think the most likely outcome of this election is one of instability: a fragile, messy government that might not last very long. That instability still offers the chance of evicting PiS from some of the centers of power, but the consequences of that are just as uncertain. It might make it far more difficult to undertake any meaningful reforms, and the opposition in disarray could be replaced by an emboldened PiS or a radical right, maybe in snap elections next year. +
++Even if the opposition does take control, it is a prospect â but not a guarantee â of change. âWe also realize that the democratic opposition parties are not angels,â Bendyk said. But, he added, âAt least open the window for opportunity for changes.â +
++What that window looks like is hard to say because reversing an illiberal democracy hasnât really been done. âYou donât have an example of a country where you had an illiberal regime, established over years, and then rolled back by a democratic, liberal government,â said Piotr Buras, head of the Warsaw office for the European Council on Foreign Relations. Because Poland isnât a full-on authoritarian system, you canât just start from scratch. If the opposition gets into power, it will be because it won an election, after all. âAn illiberal regime, this is a different animal,â he added. +
++Experts and activists suggested the opposition might find some tasks easier than others: replacing people at the public media station, or disentangling some of the state-controlled businesses from the state. But for the judiciary and the courts, even experts are perplexed by some of the changes there. How to unravel that and restore rule of law will be a complicated, and maybe even doomed process. On top of that, Polandâs PiS-aligned president, Andrzej Duda, will be in power until at least 2025. He can veto legislation, which a divided Parliament probably wonât have the votes to override. +
++âItâs the question,â Tracyzk said. âDo you want to do it quickly? Or create possibly even more chaos risking that every four years there will be chaos once again? Or do you want to try to do it kind of in a more democratic stable manner, knowing that it will take more time, knowing that you will not be able to fix all the things that quickly?â +
++Yet Poland, if it has the chance, has to try. These elections are critical for global democracy but also for Europe and the rest of the world. The PiS party has challenged Europe and the supremacy of its rule of law, a perpetual and persistent problem from the bloc. PiS is picking fights with its neighbors, like Germany, at a time when Europe is trying to figure out its own future â on foreign policy, governance, and security. Tusk, a former European official, will almost certainly reset Polish relations with the EU, although heâll be dealing with a long list at home. +
++But the war in Ukraine looms over all of it. After Russiaâs full-scale invasion, Poland emerged as Ukraineâs ironclad supporter. Poland used this position to rally other EU countries, putting pressure on its partners, like Germany, to deliver tanks. It won some goodwill, including from the EU, and some saw it as a sign that Warsaw might become the new power center in Europe and of NATO. +
++That has since shifted. The Polish public remains broadly supportive of Ukraine and of hosting Ukrainian refugees, but inflation and inflammatory rhetoric, especially by the Confederation, has eroded some of that enthusiasm. As a result, the PiS party has turned Ukraine into an electoral issue, most notably with its dispute over Ukrainian grain. +
++Poland has said the transit of Ukranian grain into Europe is hurting undermining Polish farmers (who also happen to be an important voting bloc for PiS), and so it (along with some others) would defy a EU rule and continue banning Ukrainian grain imports. The spat culminated with Polish Prime Minister Mateusz Morawiecki saying last month that Poland was no longer giving weapons to Ukraine. This was a bit misleading; Poland continues to be a transfer point for international aid and weapons, but Poland itself is not sending more weapons, mostly because it has already given everything it has to give. But the damage was done. +
++âHow can this Polish government go back and become an advocate again, and actually name and shame our bigger allies â Europeans, Americans, as well, to some extent â on sending more, or sending more advanced weapons?â Baranowski, of GMF, said. âWe, as a country, just gave away a huge chunk of credibility that could have been used and was used successfully.â +
+ ++As experts said, Ukraine is not about to break with the Western alliance; it still sees Russia as too big of a threat and the war as critical to its security. But as the war enters something of a standstill, Polandâs domestic politics could spill over and further strain the Western alliance, which is already under pressure, especially as the United States now struggles to approve Ukraine aid. And if the PiS party must work with the Confederation to stay in power, Polandâs tensions with Ukraine may only grow deeper. +
++Although the PiS party has sold itself as the real protectors of Poland, if opposition wins they will continue support for Ukraine, and potentially offer a little relations reset. Beyond that, so much of the rhetoric around Ukraine support revolves around defending democracy â even as some of its supporters, like Poland, are not exactly living up to those values. +
++With Sundayâs election, Poland has the chance to rebuild its democracy, as it also defends the one next door. âPoland is the final buffer between the West and the East,â said KaryĆ. âItâs incredibly important for Europe and the world for it to be there.â +
+California wants to find out. +
++If you order a company to reveal how much it pollutes, would it clean up its act? And if a business has to chalk out all the ways extreme weather and rising sea levels hurt its bottom line, will that force it to better prepare? +
++California certainly thinks so. The Golden State recently enacted two climate laws. One would make billion-dollar businesses in the state â the likes of Apple, Google, Walmart, and Chevron, more than 5,300 companies in total â disclose their greenhouse gas emissions publicly. The second requires companies making more than $500 million a year, applying to more than 10,000 companies, to report their climate-related financial risks. +
++To limit climate change, simply getting a handle on where heat-trapping gasses are coming from is a critical step. And figuring out how rising average temperatures will hurt businesses could make the cost-benefit case for investing in more action on climate change right now. +
++Thatâs why several states, the US federal government, and some other countries have been exploring forms of climate change disclosure rules, reporting their tallies to independent monitoring groups. And many companies have already started publishing their numbers. +
++âAlready today, issuers are making climate risk disclosures, and investors are making investment decisions based on those disclosures,â Gary Gensler, the chair of the Securities and Exchange Commission, said at a Treasury Department meeting in July. âFurther, investors representing tens of trillions of dollars in assets are making decisions relying on those disclosures.â +
++However, Californiaâs latest laws go further than most other climate reporting requirements on the books in the US. In particular, the new greenhouse gas accounting law requires big companies to measure their scope 3 greenhouse gas emissions. These are the indirect emissions from an organization, including things like the carbon dioxide output from employees commuting to work, pollution from shipping, or the energy needed to power their products. A companyâs scope 3 emissions can be more than 11 times greater than its direct emissions. +
+ ++By including this category, it expands the spotlight beyond major manufacturers and fossil fuel companies to envelop businesses that donât often face scrutiny for their impact on the climate. Tech companies, financial firms, and retailers may not have smokestacks coming out of their data centers, office towers, and stores, but it can still take a lot of greenhouse gasses to keep their supply chains moving. +
++âIt has changed the conversation for people who are sitting on the fence who are not the Exxons or the Chevrons â people who havenât been pressured as much â to start thinking about these issues,â said Shivaram Rajgopal, a professor of accounting and auditing at the Columbia Business School. +
++For companies whose raw materials, warehouses, and operations sprawl across the world, calculating these numbers can quickly turn into an expensive ordeal. Accounting for the business impact of rising average temperatures is also tricky and costly since it requires an accurate estimate of where things stand and then simulating the knock-on effects of different climate change scenarios, like higher insurance premiums due to wildfire risk. In signing statements for both bills, California Gov. Gavin Newsom expressed concern about the financial pain the new rules could inflict and directed state regulators to monitor compliance costs. +
++But some major corporations have backed these measures, including REI, Adobe, Microsoft, and IKEA, companies that are already voluntarily reporting their emissions and climate risks. In an August letter, these companies said Californiaâs new rules will help spur laggards to act and âensure economy-wide accountability and action.â +
++The question, then, is how big an impact this will have. +
++California is one state out of 50, but it is the largest one and has the biggest economy so its rules can change the game across the country and the world. However, policies are fragmented across the states. While California is pushing businesses to do more on climate change, states like Texas and Florida are penalizing companies that are cutting back on investments in fossil fuels. +
++The new rules in California may also be too hasty, even for California. Gov. Newsom wrote that âthe implementation deadlines in this [emissions disclosure] bill are likely infeasible, and the reporting protocol specified could result in inconsistent reporting across businesses subject to the measure.â The legislature and state regulators will therefore have to go back to revise their timelines and hammer out more details. +
++The SEC is now proposing to harmonize emissions reporting and risk disclosure rules across the country. But it has triggered a vast right-wing campaign against this initiative, with some business groups arguing that making companies publish their climate data violates the First Amendment. âGroups like the US Chamber of Commerce, the National Association of Manufacturers, Americans for Prosperity, and the Competitive Enterprise Institute have flooded the SEC with comments that argue company free speech would be violated,â wrote Voxâs Rebecca Leber. +
+++I recently co-lead a letter with @RepAdamSchiff and 24 members of the California Delegation urging @GaryGensler to ensure that large corporations must keep informing investors and the public about their environmental impact.
+â Rep. Juan Vargas (@RepJuanVargas) October 12, 2023 +
Learn more: https://t.co/qz63BHINZs +
+The US Federal Reserve has also asked major banks to launch an experiment on how they will cope with climate change-related shocks to the economy, as well as examine what will happen to their portfolios as more businesses switch away from fossil fuels toward cleaner energy. +
++Meanwhile, the European Union has implemented its own climate reporting rules for big businesses. The EUâs rules go even further, requiring companies to also publish their impacts on communities, biodiversity, and human rights. And it applies to all but the tiniest of companies, so upward of 50,000 businesses could be subject to the EUâs disclosure checklist. +
++So, even if disclosure regulations in the US get watered down or blocked in the courts, companies that do business in multiple countries will likely face some kind of reporting requirement; it would behoove them to start tallying up their emissions and risks. +
++And while monitoring and disclosure is an important fist step for addressing climate change, itâs only a step. A paper published in the journal Science in August noted that disclosure rules could help policymakers craft further, more targeted regulations that lead to direct emissions reductions. Exactly how much of an impact this will have on investments and climate pollution is not clear. Environmental activists argue that these measures need further backing with regulations that ratchet down fossil fuel production and consumption overall. +
++The SEC is expected to publish its climate disclosure rules in the coming months. Itâs not certain how strict the final rules will be, but it shows that regulators are paying attention, which in turn could change how everyone does business. And California will be an important laboratory for how these rules play out. According to Newsom, the regulations demonstrate âCaliforniaâs continued leadership with bold responses to the climate crisis, turning information transparency into climate action.â +
+A hard-fought win against a formidable Australian outfit will enthuse India -
Well-rounded India has the edge in battle of equals -
Shamrock, Aldgate, Champions Way, Knight In Hooves, Blue God and Bruce Almighty excel -
Baby Bazooka and Northern Lights catch the eye -
India-Pak WC clash: Man arrested for posing as GCA official, cheating ticket seeker of âč2.68 lakh - Mr. Kandoria contacted Shah on the mobile number mentioned on the social media platform and sought 41 tickets for friends and kin
Woman ends life in Arasikere, complaint filed against her husband, relatives -
City gears up for Dasara, a slew of events to be inaugurated on Sunday -
Sitharaman pitches for strong, quota-based and adequately resourced IMF - The 16th General Review of Quotas is expected to provide greater say to developing economies in the International Monetary Fund
Bronze medal winner in Asian Games felicitated in Ballari -
Patients seek Centreâs intervention for shorter regimen in Indiaâs TB control programme - The BPaL regimen uses only three drugs over 26 weeks, in contrast to up to 5,000 tablets for as many as 21 months in the conventional treatment for DR-TB
France raises security level after school knife attack - France is put on its highest counter-terrorism alert, following the death of a teacher stabbed at a high school.
Poland election: Poles prepare to vote as rivals end acrimonious campaign - Poland elects a new parliament on Sunday with the right-wing ruling party seeking a third term.
Germany migrants: Seven dead after vehicle crashes in Bavaria - Authorities said the driver of a âsuspected smuggling vehicleâ attempted to evade police before losing control.
Putin denies Russia behind Finland gas pipeline damage - Finnish officials say they cannot rule out a state actor being responsible for the rupture.
French police break up pro-Palestinian demo after ban - Tear gas is used after pro-Palestinian rallies are banned as a possible threat to public order.
Plant-based cheese may be getting more appetizing - Can we skip the dairy and still get a cheese that doesnât taste like plants? - link
This exoplanet might literally be the most metal planet out there - Itâs likely that something stripped the outer layers off a once-rocky exoplanet. - link
CEO Bobby Kotick will leave Activision Blizzard on January 1, 2024 - Schreier: Kotick will depart after 33 years, employees are âvery excited.â - link
Hydro dams are struggling to handle the worldâs intensifying weather - Climate change is robbing some hydro dams of water while oversupplying others. - link
Raw milk outbreak sickens 14 in Utahâa state with loose laws, bad track record - The people sickened range in age from 2 to 73. - link
A 95 year old man and his 94 year old wife see a lawyer about a divorce. -
++The lawyer asks them when they got married. +
++âI was 19â says the man. +
++âThat means youâve been married for 75 years at leastâ the lawyer points out +
++âYes. And all of it miseryâ says the woman. +
++âReally? When did you start to regret the marriage?â +
++âAlmost immediately,â says the man. âI hated her after about two years, and every year it gets worse. Everything about her is obnoxious and irritating.â +
++âOh lord,â says the woman, âI lasted three years but after that tolerating him in any way has been a huge problem. He has awful habits and treats me like trash.â +
++The lawyer thinks for a moment. +
++âWell I can help you to get divorced, but why did you wait so long to apply for one if youâve hated each other the whole time?â +
++She says: âWe were waiting for the children to dieâ +
+ submitted by /u/slbain9000
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A poor farmer has two sons; a smart one and a dumb one. -
++One day he goes to his smart son and he tell him âBring this duck to the market and sell it for 5 dollars. If you sell for any extra go ahead and take that to the whorehouse on your way back home.â +
++So the son goes to the market with the duck, manages to sell it for 7 dollars and promptly goes to the whorehouse and spends the extra 2 dollars he had earned and gets home by the end of the day. +
++About a month later the farmer needs a few extra bucks so he decides to use the same plan with his sons. For some reason this time he canât find his smart son so he goes to the dumb son and says again âtake this duck to the market and sell it for 5 dollars. Any extra you earn you can go spend at the whorehouse on the way home.â +
++The dumb son leaves carrying the duck but after getting a couple miles out he gets horny and forgets what he was sent to do so he turns the truck straight to the whorehouse. Upon arrival the lady running the place asks him how he expects to pay and he says âwell I got this duck.â The lady thinks it over and decides thereâs no harm in getting paid a duck for a couple minutes. So she takes him into the next room and they have wild amazing sex. After they finish she says to him âWow that was fantastic. Can we please do this again? Iâll even let you keep the duck.â And he happily agrees. +
++Now tired he goes to drive back home. On the drive the duck gets spooked and flies out the window, directly into the path of a semi. The semi driver immediately pulls over and so does the son. The driver says âOh my god Iâm so sorry I killed your duck, it all happened in a flash. Please take 15 dollars for your troubles.â And the son happily agrees and goes on his way. +
++Once he arrives home his father asks him how much money he got. The son proudly empties his pocket and shows his father the 15 big ones. The farmer is stunned and asks him exactly what happened that day. The son says âWell, I got a fuck for a duck, a duck for a fuck, and 15 bucks for a fucked up duck!â +
+ submitted by /u/Buddy2269
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A man is shocked to find his buddy wears a bra. He asks âHow long have you been wearing that?â -
++The friend replies, âEver since my wife found it in the glove compartment.â +
+ submitted by /u/Major_Independence82
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a man buys a parrot -
++A man buys a parrot. The bird is beautiful, but swears in the most foul manner all day long. +
++The man tries everything to silence the parrot: he covers the cage, he turns on loud music, he threatens to hit the parrot⊠but itâs all of no use. +
++After a few days of incessant ranting, he becomes so unnerved that he grabs the parrot and puts it in the freezer. The parrot is rioting around at first, but then suddenly everything in the freezer becomes dead quiet. +
++The man feels guilty and is afraid that the parrot may have died of fear. So he opens the chest again. The parrot climbs out, climbs up the manâs arm, sits on the shoulder and says, âI would like to apologize profusely for my unbecoming behavior. I assure you that this will never happen again.â +
++The man is completely flabbergasted, but before he can say anything himself, the parrot clears his throat and says: âIf you allow me to ask⊠what did the chicken do?â +
+ submitted by /u/bohogirl1
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Top Oâ The Morninâ -
++Father Flanahan is having a rough morning in the confessional booth. During a brief pause in a seemingly endless parade of sinners, he flags down Dooley the church janitor, says âBe a good lad, and cover far me whoile I take me eleven oâ clock dump!âand shoves him into the booth in his place. +
++Dooley isnât in there half a minute when here comes Mrs. Conroy, the local sexpot. She sits down and wails: " Forgive me, father, I just canât stop suckinâ cock! I blow me hoosband every marninâ bafore he leaves fer work. Then I spend the rest âo the day blowinâ the milkman, the mailman, the Maytag repair man, and the nayborâs dog!! Can ya grant a poor sinner absolution??" +
++Dooley, at a loss, stamners âOne moment, my childâ, then leans out and desperately flags down a passing altar boy. âPatrick , me boy,â he whispers, âwhat does Father Flanahan usually give fer blowjobs?!â +
++Patrick eyes Dooley with suspicion, and intones: âWell,he usually gives ya a Snickers bar and a pat on the head afterwardsâbut fer you, Dooley itâll be five bucks up front!!â +
+ submitted by /u/DonkeyPunchDelicious
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