Usefulness of Unstimulated and Stimulated Whole Saliva, Accuracy of Minor Labial Salivary Gland Biopsy in the Diagnosis of Primary Sjögren's Disease: A Croatian Single-Center, Cross-Sectional Study

The aim of this cross-sectional study was to determine the accuracy of minor labial salivary gland (MLSG) biopsy in the diagnosis of primary Sjögren' s disease (pSD); to study the correlation between the focus score (FS) and anti-SSA/Ro, anti-SSB/La, anti-SSA and -SSB antibodies, unstimulated whole saliva (UWS) and stimulated whole saliva (SWS); to determine the role of UWS and SWS in the clinical evaluation of pSD patients and patients with sicca symptoms. Methods. A total of 37 subjects were enrolled in the study and divided into two groups: the test group consisted of 15 patients diagnosed with pSD; the control group consisted of 22 patients who had sicca symptoms but did not meet the 2016 American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) diagnostic criteria. Clinical and laboratory tests, including saliva collection, MLSG biopsy, autoantibody titers, were performed in all patients. Results. The median of the FS was 1.00 [IQR=1.00-1.50] in the test group, whereas in the control group, it was 0.00 [IQR=0.00-0.00] (p< 0.001). The sensitivity, specificity, and accuracy of MLSG biopsy were 86.7%, 100.0%, and 94.6%, respectively. The results showed a correlation between the FS and antinuclear antibodies (ANA) (p=0.002). In addition, Pearson’s correlation showed a weak negative correlation between UWS (r=-0.058, p=0.73) and SWS (r=-0.022, p=0.90) and the FS. In the test group, 73.3% of patients had abnormal UWS values, while 86.7% had abnormal SWS values; among them, values of 0.00 ml/min for UWS and SWS were found in 60.0% and 26.7% of patients, respectively. Conclusions. Although MLSG biopsy has great diagnostic value and accuracy in diagnosing pSD, it is not always definitive. Our study found a statistically significant association between the FS and ANA, and the greater utility of SWS in diagnosing pSS

Effect of Low Selenium Diet on Glutathione Peroxidase 3 Concentration in Male Sprague-Dawley Rats’ Serum

Aim: Determination of antioxidative enzyme glutathione peroxidase 3 (GPx3) serum concentrations after consumption of food which contains different concentrations of selenium (Se). Research subjects and methods: Four-week-old Sprague Dawley rats consumed food containing different concentrations of Se (food Divan) over a period of 10 weeks. The animals were divided into two groups: 1) normal Se (0.363 mg/kg Se) and 2) low Se (0.030 mg/kg Se). Each animal was weighed at the end of protocol, and serum samples were collected for determining GPx3 concentrations. All experimental procedures were in compliance with the European Convention for the Protection of Vertebrate Animals used for Experimental and other Scientific Purposes and approved by the Ethics Committee of the Faculty of Medicine in Osijek and the Ministry of Agriculture of the Republic of Croatia. Results: Different concentrations of Se in food did not cause a change in body weight. Food containing the recommended intake of Se according to the guidelines of the World Health Organization significantly increased GPx3 enzyme concentration (13.96±0.42 mg/ml) when compared to low selective Se (12.04 ± 0.33 mg/ml, p = 0.002). Conclusion: Serum concentration of the antioxidant enzyme GPx3 depends on the concentration of Se in food. It is shown that, in comparison with food with low Se levels, food containing a normal concentration of Se is enriched with the antioxidant GPx3 which, according to numerous studies, has a protective role in the human body

Conformational occlusion of blockade antibody epitopes, a novel mechanism of GII.4 human norovirus immune evasion

Extensive antigenic diversity within the GII.4 genotype of human norovirus is a major driver of pandemic emergence and a significant obstacle to development of cross- protective immunity after natural infection and vaccination. However, human and mouse monoclonal antibody studies indicate that, although rare, antibodies to conserved GII.4 blockade epitopes are generated. The mechanisms by which these epitopes evade immune surveillance are uncertain. Here, we developed a new approach for identifying conserved GII.4 norovirus epitopes. Utilizing a unique set of virus-like particles (VLPs) representing the in vivo-evolved sequence diversity within an immunocompromised person, we identify key residues within epitope F, a conserved GII.4 blockade antibody epitope. The residues critical for antibody binding are proximal to evolving blockade epitope E. Like epitope F, antibody blockade of epitope E was temperature sensitive, indicating that particle conformation regulates antibody access not only to the conserved GII.4 blockade epitope F but also to the evolving epitope E. These data highlight novel GII.4 mechanisms to protect blockade antibody epitopes, map essential residues of a GII.4 conserved epitope, and expand our understanding of how viral particle dynamics may drive antigenicity and antibody-mediated protection by effectively shielding blockade epitopes. Our data support the notion that GII.4 particle breathing may well represent a major mechanism of humoral immune evasion supporting cyclic pandemic virus persistence and spread in human populations

Incentivizing the Dynamic Workforce: Learning Contracts in the Gig-Economy

In principal-agent models, a principal offers a contract to an agent to perform a certain task. The agent exerts a level of effort that maximizes her utility. The principal is oblivious to the agent's chosen level of effort, and conditions her wage only on possible outcomes. In this work, we consider a model in which the principal is unaware of the agent's utility and action space. She sequentially offers contracts to identical agents, and observes the resulting outcomes. We present an algorithm for learning the optimal contract under mild assumptions. We bound the number of samples needed for the principal obtain a contract that is within $\epsilon$ of her optimal net profit for every $\epsilon>0$

Animal models for COVID-19

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the aetiological agent of coronavirus disease 2019 (COVID-19), an emerging respiratory infection caused by the introduction of a novel coronavirus into humans late in 2019 (frst detected in Hubei province, China). As of 18 September 2020, SARS-CoV-2 has spread to 215 countries, has infected more than 30 million people and has caused more than 950,000 deaths. As humans do not have pre-existing immunity to SARS-CoV-2, there is an urgent need to develop therapeutic agents and vaccines to mitigate the current pandemic and to prevent the re-emergence of COVID-19. In February 2020, the World Health Organization (WHO) assembled an international panel to develop animal models for COVID-19 to accelerate the testing of vaccines and therapeutic agents. Here we summarize the fndings to date and provides relevant information for preclinical testing of vaccine candidates and therapeutic agents for COVID-19.info:eu-repo/semantics/acceptedVersio

Histo-Blood Group Antigens Act as Attachment Factors of Rabbit Hemorrhagic Disease Virus Infection in a Virus Strain-Dependent Manner

Rabbit Hemorrhagic disease virus (RHDV), a calicivirus of the Lagovirus genus, and responsible for rabbit hemorrhagic disease (RHD), kills rabbits between 48 to 72 hours post infection with mortality rates as high as 50–90%. Caliciviruses, including noroviruses and RHDV, have been shown to bind histo-blood group antigens (HBGA) and human non-secretor individuals lacking ABH antigens in epithelia have been found to be resistant to norovirus infection. RHDV virus-like particles have previously been shown to bind the H type 2 and A antigens. In this study we present a comprehensive assessment of the strain-specific binding patterns of different RHDV isolates to HBGAs. We characterized the HBGA expression in the duodenum of wild and domestic rabbits by mass spectrometry and relative quantification of A, B and H type 2 expression. A detailed binding analysis of a range of RHDV strains, to synthetic sugars and human red blood cells, as well as to rabbit duodenum, a likely gastrointestinal site for viral entrance was performed. Enzymatic cleavage of HBGA epitopes confirmed binding specificity. Binding was observed to blood group B, A and H type 2 epitopes in a strain-dependent manner with slight differences in specificity for A, B or H epitopes allowing RHDV strains to preferentially recognize different subgroups of animals. Strains related to the earliest described RHDV outbreak were not able to bind A, whereas all other genotypes have acquired A binding. In an experimental infection study, rabbits lacking the correct HBGA ligands were resistant to lethal RHDV infection at low challenge doses. Similarly, survivors of outbreaks in wild populations showed increased frequency of weak binding phenotypes, indicating selection for host resistance depending on the strain circulating in the population. HBGAs thus act as attachment factors facilitating infection, while their polymorphism of expression could contribute to generate genetic resistance to RHDV at the population level

Repurposing the Ebola and Marburg Virus Inhibitors Tilorone, Quinacrine, and Pyronaridine: In Vitro Activity against SARS-CoV-2 and Potential Mechanisms

Severe acute respiratory coronavirus 2 (SARS-CoV-2) is a newly identified virus that has resulted in over 2.5 million deaths globally and over 116 million cases globally in March, 2021. Small-molecule inhibitors that reverse disease severity have proven difficult to discover. One of the key approaches that has been widely applied in an effort to speed up the translation of drugs is drug repurposing. A few drugs have shown in vitro activity against Ebola viruses and demonstrated activity against SARS-CoV-2 in vivo. Most notably, the RNA polymerase targeting remdesivir demonstrated activity in vitro and efficacy in the early stage of the disease in humans. Testing other small-molecule drugs that are active against Ebola viruses (EBOVs) would appear a reasonable strategy to evaluate their potential for SARS-CoV-2. We have previously repurposed pyronaridine, tilorone, and quinacrine (from malaria, influenza, and antiprotozoal uses, respectively) as inhibitors of Ebola and Marburg viruses in vitro in HeLa cells and mouse-adapted EBOV in mice in vivo. We have now tested these three drugs in various cell lines (VeroE6, Vero76, Caco-2, Calu-3, A549-ACE2, HUH-7, and monocytes) infected with SARS-CoV-2 as well as other viruses (including MHV and HCoV 229E). The compilation of these results indicated considerable variability in antiviral activity observed across cell lines. We found that tilorone and pyronaridine inhibited the virus replication in A549-ACE2 cells with IC50 values of 180 nM and IC50 198 nM, respectively. We used microscale thermophoresis to test the binding of these molecules to the spike protein, and tilorone and pyronaridine bind to the spike receptor binding domain protein with Kd values of 339 and 647 nM, respectively. Human Cmax for pyronaridine and quinacrine is greater than the IC50 observed in A549-ACE2 cells. We also provide novel insights into the mechanism of these compounds which is likely lysosomotropic

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Beyond prompt brittleness:Evaluating the reliability and consistency of political worldviews in LLMs

Due to the widespread use of large language models (LLMs) in ubiquitous systems, we need to understand whether they embed a specific “worldview” and what these views reflect. Recent studies report that, prompted with political questionnaires, LLMs show left-liberal leanings (Feng et al., 2023; Motoki et al., 2024). However, it is as yet unclear whether these leanings are reliable (robust to prompt variations) and whether the leaning is consistent across policies and political leaning. We propose a series of tests which assess the reliability and consistency of LLMs’ stances on political statements based on a dataset of voting-advice questionnaires collected from seven EU countries and annotated for policy domains. We study LLMs ranging in size from 7B to 70B parameters and find that their reliability increases with parameter count. Larger models show overall stronger alignment with left-leaning parties but differ among policy programs: They evince a (left-wing) positive stance towards environment protection, social welfare state and liberal society but also (right-wing) law and order, with no consistent preferences in foreign policy and migration