HIGH-RESOLUTION MAPPING OF T-CELL HYBRID IMMUNITY TO THE ENTIRE SARS-CoV-2 PROTEOME

Background: To understand T-cell responses to SARS-CoV-2, it is essential to define the contribution of infection versus immunization to virus-specific hybrid immunity. Here, we characterized the breadth and magnitude of T-cell responses to the entire SARS-CoV2 proteome over a 2-year follow-up period in infected and vaccinated (CoV2+Vac+) and vaccinated and infected (Vac+CoV2+) individuals. Method(s): We selected samples from 38 (19 CoV2+ and 19 CoV2-, time1, T1) ProHEpiC-19 cohort participants, a prospective, longitudinal study starting in March 2020 involving 7,776 healthcare workers in Spain. Longitudinal samples were available from 10 of them after a 3-dose mRNA vaccination, including 5 CoV2+Vac+ and 5 Vac+CoV2+, at 824.5 and 250.5 days from symptoms onset (DfSO, time 2, T2). We measured the breadth and magnitude of IFN-y T-cell responses by ELISpot assay in cryopreserved PBMCs, using a 15-mer overlapping peptide (OLP) library of 2,790 SARS-CoV-2 peptides in 100 pools. Result(s): We identified immunodominant T-cell responses in S1, S2, nsp3, Env, NC, and M proteins across the SARS-CoV2 proteome. We observed an increased breadth of T-cell responses (responding pools over the entire region) to S1 (44 - 30%) and S2 (31 - 40%) in CoV2+Vac+ and Vac+CoV2+, respectively. In addition, CoV2+Vac+ had an exclusive and sustained response to M. We found significantly stronger responses in CoV2+Vac+ (P=0.0313). Particularly the total magnitude was greater in CoV2+Vac+ vs. Vac+CoV2+ in S1 (4476.88 vs. 1498.53), Env (457.34 vs. 250.50), and M (455.13 vs. 0.00) but not in S2 and nsp3. The total number of peptides for deconvolution was higher in CoV2+Vac+ (32 peptides) than in Vac+CoV2+ (3 peptides) during the follow-up. Seventy-five percent of the responses targeted S, and 25% M, ORF1a, and Env. Conclusion(s): These results profile immunodominant T-cell responses in S1, S2, nsp3, Env, NC, and M proteins across the entire SARS-CoV2 proteome. The data delineate differences in the number of T-cell responses primed hybrid immunity by infection previous to vaccination (CoV2+Vac+), being broader and of higher magnitude and underlining an exclusive T-cell response to the M region. Overall, these findings identify differences in long-term T-cell hybrid immunity primed by infection or vaccination, which may have implications in protection from re-infection and vaccine design.

Project-based learning for an online course of simulation engineering: From bioreactor to epidemiological modeling

Before the pandemic, distance learning was not a widely adopted option for science and engineering programs where in some courses, such as chemistry, electromagnetism, or fluid mechanics, etc., attending to laboratories and workshops was in most cases mandatory. The lockdown forced us to innovate, searching alternative ways to teach experimental phenomena, suddenly replaced with simulation science and technology, subjects that although rely on computers, also suffered changes from the transition. In this contribution, we propose an undergraduate course on simulation for chemical engineering, departing from the fact that modeling, and simulation are multipurpose and multidisciplinary tools. The course aims to reinforce the concepts of dynamical systems by using analogies between process engineering examples and other disciplines, particularly, epidemiology. For this purpose, a final project on modeling the dynamics of the COVID 19 pandemic in Mexico was designed and validated with a public database from the Mexican Secretariat of Health. By doing this, the students got in touch with the evolution of the dynamics outside of school hours, since it was common to see weekly updates and extrapolation trends of the pandemic, thus applying their skills to the final project. It was found that success factors were the use of official data, the use of Graphical User Interfaces to explore diverse simulation scenarios and the final project. The transition to the Distance Learning faced several challenges that were partially coped with the redesign of the course. © 2023 Institution of Chemical Engineers

Does the COVID-19 Pandemic have Implications for Machine Ethics?

Algorithms have advanced in status from supporting human decision-making to making decisions for themselves. The fundamental issue here is the relationship between Big Data and algorithms, or how algorithms empower data with direction and purpose. In this paper, I provide a conceptual framework for analyzing and improving ethical decision-making in Human-AI interaction. On the one hand, I examine the challenges and the limitations facing the field of Machine Ethics and Explainability in its aim to provide and justify ethical decisions. On the other hand, I propose connecting counterfactual explanations with the emotion of regret, as requirements for improving ethical decision-making in novel situations and under uncertainty. To test whether this conceptual framework has empirical value, I analyze the COVID-19 epidemic in terms of "what might have been” to answer the following question: could some of the unintended consequences of this health crisis have been avoided if the available data had been used differently before the crisis happened and as it unfolded? © 2022, The Author(s), under exclusive license to Springer Nature Switzerland AG.

Project-Based Learning for an Online Course of Simulation Engineering: From Bioreactor to Epidemiological Modeling

Before the pandemic, distance learning was not a widely adopted option for science and engineering programs where in some courses, such as chemistry, electromagnetism, or fluid mechanics, etc., attending to laboratories and workshops was in most cases mandatory. The lockdown forced us to innovate, searching alternative ways to teach experimental phenomena, suddenly replaced with simulation science and technology, subjects that although rely on computers, also suffered changes from the transition. In this contribution, we propose an undergraduate course on simulation for chemical engineering, departing from the fact that modeling, and simulation are multipurpose and multidisciplinary tools. The course aims to reinforce the concepts of dynamical systems by using analogies between process engineering examples and other disciplines, particularly, epidemiology. For this purpose, a final project on modeling the dynamics of the COVID 19 pandemic in Mexico was designed and validated with a public database from the Mexican Secretariat of Health. By doing this, the students got in touch with the evolution of the dynamics outside of school hours, since it was common to see weekly updates and extrapolation trends of the pandemic, thus applying their skills to the final project. It was found that success factors were the use of official data, the use of Graphical User Interfaces to explore diverse simulation scenarios and the final project. The transition to the Distance Learning faced several challenges that were partially coped with the redesign of the course.

WE WANT TO HELP: INTEGRATING PRECLINICAL MEDICAL STUDENTS INTO THE HEALTH SYSTEM TO PROACTIVELY CONNECT PATIENTS TO RESOURCES

STATEMENT OF PROBLEM/QUESTION: How can preclinical medical students be leveraged to address racial and geographic disparities in COVID19 vaccination rates? DESCRIPTION OF PROGRAM/INTERVENTION: As vaccine rollout began in Chicago, communities most affected by the pandemic had the lowest vaccination rates. At our urban academic medical center, eligible patients received vaccine invitations via the patient portal or text message;however, this approach did not effectively reach many elderly patients who were not technologically connected or who had circumstance-specific questions. Due to clinical demands, staff were unable to reach out to individual patients. Preclinical medical students, with more flexible schedules, volunteered to address this gap in access. Targeting patients who lived in high-risk ZIP Codes (per the The COVID-19 Community Vulnerability Index), we aimed to leverage preclinical students to expand the capacity of our vaccine outreach and tackle vaccine hesitancy. MEASURES OF SUCCESS: 1. How many patients were contacted to inform them of their eligibility? 2. How many patients were scheduled for a vaccination? FINDINGS TO DATE: Overall, 34 students contacted 820 patients. Most patients were Black or African American (91.0%). Of the patients that were reached (n=489), 84 (17.2%) were scheduled for vaccine appointments. Additionally, 79 (16.2%) of the patients that were reached were not immediately scheduled but agreed to vaccination, 52 (10.6%) said they were considering vaccination, 193 (39.6%) reached patients had already scheduled or received vaccination elsewhere, and 89 (18.2%) declined the vaccine after some discussion. KEY LESSONS FOR DISSEMINATION: We showed that integrating preclinical medical students into the health system can extend existing outreach efforts and thus is a model that is generalizable across many health-related issues. Beyond the tangible impacts of connecting patients with vaccine information and appointments, we learned several lessons. 1) Trainees' outreach increased healthcare accessibility for many patients. Many patients did not have a primary care physician and/or had previously only been seen in the Emergency Department, which created an opportunity to connect these patients to the healthcare system. 2) Many patients had difficulty independently making an appointment or held misinformed beliefs. As such, direct outreach gave us the opportunity to assist with patient-specific issues. 3) This intervention also benefited clinicians, who have limited time to proactively reach out to thousands of patients. 4) Further, our initiative benefited medical education: preclinical medical students gained experience and confidence speaking to patients, delivering patient education, and using the electronic medical record. Models like ours can address gaps in care beyond COVID-19, this model can be applied effectively to address inequities in healthcare access while leveraging the time, motivation, and skills of preclinical trainees.

Non-hybrid glycemic control of type 1 diabetes ambulatory patients

In this work, we present the experience of our research group with the glucose regulation in people with Type 1 Diabetes (insulin-dependent), known as artificial pancreas. Our research group has carried out three clinical trials in Argentina, which were the first ones in Latin America. The first two studies took place in 2016 and 2017, both in the Hospital Italiano de Buenos Aires (HIBA) with five adult subjects and a duration of 36 hours. The second trial evaluated the performance of a novel closed-loop control algorithm (without meal insulin boluses), called ARG (Automatic Regulation of Glucose) and based on switched LQG control and a safety layer called SAFE (Safery Auxiliary Feedback Element), developed by researchers of our team. More recently and during COVID-19 pandemic, the first ambulatory trials took place, which were carried out in 2021 in a hotel with 5 subjects during 6 days. Additionally, for this third trial, the use of the artificial pancreas platform developed by the UNLP, called InsuMate, was incorporated. This platform connects a smartphone with the insulin pump and glucose monitor, houses the control algorithm, and allows the remote monitoring of multiple users. The results suggest that the ambulatory use of the ARG algorithm is feasible, safe and effective, compared to the usual treatment. In addition, the InsuMate platform was intuitive and easy to use for both healthcare staff and participants of the trial, achieving an over 95 % of time in closed-loop.

LAST ADVANCES OF THE ARG ARTIFICIAL PANCREAS PROJECT

Background and Aims: After the artificial pancreas (AP) trials performed in 2016-7 with DiAs system, during the COVID-19 pandemic the first outpatient clinical trial was carried out in Argentina. The main objective was to evaluate the feasibility of running full closed-loop (FCL) algorithms in an own and free platform developed from open-source resources. Methods: The ARG project (Automatic Regulation of Glucose) aims at developing a robust AP algorithm prioritizing patient autonomy. The evolution of the project phases is summarized in the figure. The last step towards this objective was the implementation of a FCL algorithm in our InsuMate platform and its evaluation in an outpatient setting. Five adults with DMT1 completed one week of study, consisting in 3 days of open-loop (OL) followed by 3 days of FCL (i.e., without CHO counting and without delivering meal priming insulin boluses). Accu-Chek pumps and Dexcom G6 CGMs were used. Results: When analyzing the full duration of the trial, the time in range increased in FCL control vs. OL, while the time above range decreased, as did the mean BG. On the other hand, the time below range and the time in severe hypoglycemia remain similar across methods, both achieving the ADA recommended values. The FCL showed greater improvement by the end of the trial, particularly for daytime metrics. InsuMate properly operated in FCL for an average of 95.4% of time. Conclusions: It can be concluded from this experience that the outpatient automatic regulation of glucose levels using the ARG algorithm and Insumate platform is feasible, safe, and effective. (Figure Presented).

Outpatient Full Closed-Loop Trial Using an Open-Source Remote Monitoring and Artificial Pancreas Platform

Objective: The first artificial pancreas (AP) ambulatory clinical trial in Argentina conducted in March 2021 in the COVID-19 pandemic context is reported. The main objective of this trial was to evaluate the feasibility of running advanced full closed-loop (FCL) algorithms for glycemic control in an own and free platform developed by the team at UNLP from open-source resources (www.insumate.com.ar). Method: The ARG algorithm, a FCL algorithm previously evaluated in-vivo [1], was implemented in InsuMate-AP. This platform was then connected to Dexcom G6 CGMs and Accu-Chek Spirit Combo insulin pumps. After configuring conventional open-loop (OL) treatment in the pumps, five adults with Type 1 Diabetes Mellitus completed one week of an ambulatory clinical trial, consisting in 3 days of OL treatment followed by 3 days of FCL glycemic control (i.e., without delivering meal priming insulin boluses). The participants performed regular activities in a hotel, including networking, eating without carbohydrates counting and extensive walking (3-5 km) around the neighborhood. Result: The last 24 hours of each phase were compared, finding a 25,3% increase in time in range (TIR, 70 mg/dl<G<180mg/dl), a 24,5% reduction of the time below range (TBR, G<70 mg/dl) and a 21,1% decrease in time above range (TAR, G>180 mg/dl) during FCL vs OL treatment. The InsuMate system performed reliably and showed good connectivity performance with both the multiple remote monitoring interface and the peripheral devices, achieving adequate FCL operation for 95.4% of time. Conclusion: The InsuMate system and the ARG algorithm were evaluated under challenging and patient-relaxed conditions showing safe and effective behaviour.

The Political Repercussions of a Pandemic

This essay looks at data that account for the impact of the pandemic on the conditions of democracy around the world. The source of the information is the Varieties of Democracy (V-Dem) project, which for 2021 includes, in addition to its monitoring of the situation of democracy in over two hundred countries, a compilation of state responses to the pandemic and its impact on the validity of democratic standards. In this regard, throughout the last decade there has been a decline in democracy, and although the effects of the pandemic are still limited, it is to be feared that in the long term its consequences will be worse than those perceived today. And given the evident relationship between the autocratic character of the regimes and the propensity to violate democratic standards with exaggerated or non-consensual measures to combat the pandemic, a deepening of the gap between countries where democracy prevails and those with autocratic forms of exercising power is to be expected.

China, the T-MEC and the uncertainty against COVID-19

China's trade relations with the rest of the world, affected by the COVID-19 pandemic, and particularly with the economies of North America, are the central aspects of this work. In it, we propose to review China's economic ties with the three North American countries. The analysis will be carried out keeping the historical perspective, analyzing chronologically and reasonably first the immediate antecedents and then those that occur before the threat of the spread of the lethal virus. It highlights how the economic ties of the Asian giant's relationship with this region have been upset, integrated into an integration mechanism that succeeded NAFTA in a context of uncertainty. It is reviewed case by case and in a comprehensive way, how, in the face of this global health threat, the links between the power of the eastern Pacific and the western bloc of said ocean behave.

Outcomes After Vascular Surgery Procedures in Patients with COVID-19 Infection: A National Multicenter Cohort Study (COVID-VAS).

OBJECTIVES: To analyze the outcome of vascular procedures performed in patients with COVID-19 infection during the 2020 pandemic. METHODS: This is a multicenter, prospective observational cohort study. We analyzed data from 75 patients with COVID-19 infection undergoing vascular surgery procedures in 17 hospitals across Spain and Andorra between March and May 2020. The primary end point was 30-day mortality. Clinical Trials registry number NCT04333693. RESULTS: The mean age was 70.9 (45-94) and 58 (77.0%) patients were male. Around 70.7% had postoperative complications, 36.0% of patients experienced respiratory failure, 22.7% acute renal failure, and 22.7% acute respiratory distress syndrome (ARDS). All-cause 30-days mortality rate was 37.3%. Multivariate analysis identified age >65 years (P = 0.009), American Society of Anesthesiologists (ASA) classification IV (P = 0.004), preoperative lymphocyte count <0.6 (×109/L) (P = 0.001) and lactate dehydrogenase (LDH) >500 (UI/L) (P = 0.004), need for invasive ventilation (P = 0.043), postoperative acute renal failure (P = 0.001), ARDS (P = 0.003) and major amputation (P = 0.009) as independent variables associated with mortality. Preoperative coma (P = 0.001), quick Sepsis Related Organ Failure Assessment (qSOFA) score ≥2 (P = 0.043), lymphocytes <0.6 (×109/L) (P = 0.019) leucocytes >11.5 (×109/L) (P = 0.007) and serum ferritin >1800 mg/dL (P = 0.004), bilateral lung infiltrates on thorax computed tomography (P = 0.025), and postoperative acute renal failure (P = 0.009) increased the risk of postoperative ARDS. qSOFA score ≥2 was the only risk factor associated with postoperative sepsis (P = 0.041). CONCLUSIONS: Patients with COVID-19 infection undergoing vascular surgery procedures showed poor 30-days survival. Age >65 years, preoperative lymphocytes <0.6 (x109/L) and LDH >500 (UI/L), and postoperative acute renal failure, ARDS and need for major amputation were identified as prognostic factors of 30-days mortality.

Early core signature of soluble factors in mild to moderate SARSCOV-2 infection

Background: Understanding the kinetics of early immune responses to SARSCoV-2 infection is critical to identify potentials biomarkers of disease outcome. A myriad of soluble mediators including, pro-inflammatory, immune-suppressors and growth factors, play a relevant role in the disease progression. However, to date, limited data is available about the role of soluble factors and most studies focus only in severe cases with limited follow-up. Here, we studied with high resolution the kinetics of soluble mediators in mild to moderate cases of SARSCoV-2 infection 1-90 days from symptom onset (DfSO). Methods: We selected individuals from the ProHEpiC-19 cohort study that included mainly healthcare workers with a PCR+ and mild or moderate disease within 1-14 DfSO. IgG and IgM levels were determined by ELISA. We selected plasma samples (n=30) in the range of 1-90 DfSO, and performed a Luminex multiplex assay including 45 soluble human factors. Results: We identified a core signature including 19 highly correlated soluble factors at 1-14 DfSO, based on clustering analysis. The core signature contained three sub-clusters: #1 (RANTES, IL13, TGFa, PDGF-AB, PDGF-AA, EGF, MIP1b, CD40L and GROb), #2 (G-CSF, PDL1-B7, Fractalkine, IL8, IFNg, Granzyme B and IL10) and #3 (IL7, IL6, and VEGF). We found major changes in #2 and #3 cluster composition between 1-14 and 30-45 DfSO, due to the loss of PDL1-B7, Fractalkine, IL8, IL7, IL6, and VEGF association. Moreover, by 60-75 DfSO, the soluble factor association in #2 and #3 disappeared from the core signature. In addition, we observed a negative correlation between IgG and IgM levels with IL4 production at 1-14 DfSO (IgG: ρ =-0.82, p=0.012;IgM ρ=-0.83, p=0.011). Similarly, a negative correlation was observed between Igs and Mip3a at 30-45 DfSO (IgG: ρ=-0.78, p=0.023;IgM: ρ =-0.81, p=0.022). Conclusion: We delineated a core signature of soluble factors in mild to moderate SARS-CoV-2 infection, including growth factors, chemokines and pro-inflammatory cytokines. The longitudinal follow-up of this signature revealed significant changes during the 1-90 DfSO. This information can provide new insights for the definition of biomarkers for patient stratification in mild or moderate SARS-Cov-2 infection. Further data is needed to understand the association between IL4 and Mip3a with low Igs levels.

SARS-CoV-2 non-seroconvertors present t-cell responses with decreased activation

Background: Many immune studies of SARS-CoV-2 (CoV-2) infection have focused on the generation of virus-specific as a means of protection. However, a small group of CoV-2 infected individuals called Non-seroconverters (NSC), do not generate antibodies but experience a mild or moderate disease course. Identifying mechanism of CoV-2 control in NSC may inform the development of novel therapeutics and vaccines approaches. Methods: We identified eleven CoV-2 NSC (3.6%) from the King-cohort study (PI-20-217). NSC were defined by a positive CoV-2 PCR at the time of diagnosis in the absence of IgG, IgA and IgM in serum and plasma measured by two independent ELISA techniques. For comparison, we identify groups of CoV-2 convalescent (n=15) and low-neutralizers (n=15). We measured T-cell responses to the CoV-2 Spike (S) and Nucleocapsid (NP) recombinant proteins in PBMCs by ELISPOT and flow cytometry. We combined T-cell surface and lineage markers together with PD-1, functional (TNF, IFN-y, and IL-2) and activation induced markers (AIM: CD25, CD137 and OX40). Results: We identified CoV-2 specific CD4+ and CD8+ T-cells against the S and the NP in NSC individuals. All NSC responded to S by production of one or more cytokine in either CD4+ or CD8+ T-cells, and 57% responded to NP. Specific-CD8+ T cells against S in NSC were characterized by IFN-y, and TNF production, and we observed higher levels of TNF production as compared to low neutralizers (p=0.02). No differences were found in IFN-y, IL-2 and TNF production in S-specific CD4+ T cells between groups, nor in NP CD8+ or CD4+ T-cell responses. The levels of CD137/OX40 in CD8+ and CD4+ T cells were significantly lower in NSC in response to S (p=0.006, and p=0.012). Also, lower levels of PD-1 were observed in CD8+ T cells in response to NP in NSC (p=0.017). Conclusion: We provide evidence of SARS-CoV2 cellular immunity in NSC individuals despite the absence of humoral neutralizing responses. CD8+ and CD4+ T cells against the S and NP were present in NSC and characterized by TNF production in CD8+ T-cells in responses to S when compared to low neutralizers. Decreased levels of activation markers were observed in NSCs following S and NP stimulation. We propose a protective role of cellular immunity in NSC potentially driven by preexisting cellular responses.

Epidemiology of COVID-19 cases diagnosed at quarantine facilities in Paraguay

Aims: This study aimed to describe the epidemiological characteristics of COVID-19 cases diagnosed in quarantine facilities in Paraguay. Methods: This was a descriptive, cross-sectional, temporarily retrospective study. The time scope was from April 1 to September 30 2020. The variables were sex, age and administrative departments. The open access data available on the website of the Ministry of Public Health and Social Welfare was used. Frequencies expressed in percentages and the Chi square value were calculated to observe the statistically significant differences between cases and age and sex. Results: from April 4 to September 30 2020, 1.581 cases were diagnosed in COVID-19. The fewest number of positive cases were reported in April (50) and the highest number was reported in May (628). From the total, 69.6% (1.101) were male, (male / female ratio 2.3), 42.1% (666) were aged between 20-29 years, the average age was 30.23 years (range 0 to 87, standard deviation 14.66. 95% CI 1.5 - 58.95). The departments with the highest number of cases were Caaguazu 21.7 % (343), Alto Parana 17.3 % (274), Central 13.3% (210) and Asuncion 11.4% (180). The least number of cases of COVID-10 in women were registered in the Departments of Amambay, Pdte. Hayes, Neembucu and Boqueron, and in men the Departments of Neembucu and Boqueron. The largest number of male cases were registered in Caaguazu 70.8% (243), Alto Parana 66.1% (181), Central 69.5% (146) and Asuncion 68.9% (124). The number of Covid-19 infected people in quarantine facilities presented statistically significant differences between the variables sex and age. Conclusion: the quarantine facilities are one of the measures that the Paraguayan government needed to avoid the rapid spread and dispersion of the virus. The epidemiology of the cases diagnosed in them corresponds to what was expected according to the characteristics of the country.

Labor Rights and COVID-19. The Experience of Cuba

COVID-19 has generated an unprecedented economic and social crisis. For the ILO, the employment crisis numerically exceeds that left after the second World War, hence the need implement labor protection mechanisms to protect workers and their main sources of satisfaction of needs. Wages. Cuba has implemented social protection measures aimed at protecting workers' job stability. Likewise, it has meant adapting the work organization and its legal rules to the new normal and to equitable protection for all economic actors. On the transformations carried out in these times, and the remains that the Cuban State assumes in pursuit of a country of "social justice" the following article of scientific reflection refers to.