An overview of effects of COVID-19 on mobility and lifestyle: 18 months since the outbreak.

The outbreak of SARS-COV-2 has led to the COVID-19 pandemic in March 2020 and caused over 4.5 million deaths worldwide by September 2021. Besides the public health crisis, COVID-19 affected the global economy and development significantly. It also led to changes in people's mobility and lifestyle during the COVID-19 pandemic. In addition to short-term changes, the drastic transformation of the world may account for the potentially disruptive long-term impacts. Recognizing the adverse effects of the COVID-19 pandemic is crucial in mitigating the negative behavioral changes that directly relate to people's psychological and social well-being. It is important to stress that citizens and governments face an uncertain situation since nobody knows exactly how the viruses and cures will develop. Better understanding uncertainties and evaluating behavioral changes contribute to addressing the future of urban development, public transportation, and behavioral strategies to tackle COVID-19 negative consequences. The major sources of impacts on short-term (route, departure time, mode, teleshopping, and teleworking) and medium and long-term (car ownership, work location, choice of job, and residential location) mobility decisions are mostly reviewed and discussed in this paper.

Association of Ang/Tie2 pathway mediators with endothelial barrier integrity and disease severity in COVID-19.

Endothelial barrier (EB) disruption contributes to acute lung injury in COVID-19, and levels of both VEGF-A and Ang-2, which are mediators of EB integrity, have been associated with COVID-19 severity. Here we explored the participation of additional mediators of barrier integrity in this process, as well as the potential of serum from COVID-19 patients to induce EB disruption in cell monolayers. In a cohort from a clinical trial consisting of thirty patients with COVID-19 that required hospital admission due to hypoxia we demonstrate that i) levels of soluble Tie2 were increase, and of soluble VE-cadherin were decreased when compared to healthy individuals; ii) sera from these patients induce barrier disruption in monolayers of endothelial cells; and iii) that the magnitude of this effect is proportional to disease severity and to circulating levels of VEGF-A and Ang-2. Our study confirms and extends previous findings on the pathogenesis of acute lung injury in COVID-19, reinforcing the concept that EB is a relevant component of this disease. Our results pave the way for future studies that can refine our understanding of the pathogenesis of acute lung injury in viral respiratory disorders, and contribute to the identification of new biomarkers and therapeutic targets for these conditions.

Association of heme-oxygenase 1, hemopexin, and heme levels with markers of disease severity in COVID-19.

Heme-oxygenase 1 (HO-1) is an enzyme with well-known anti-inflammatory and antioxidant properties, whose levels have been previously associated with disease severity in the context of sterile and infectious diseases. Moreover, the heme/HO-1 pathway has been associated with prothrombotic changes in other diseases. Accordingly, the potential of modulating HO-1 levels for the treatment of COVID-19 was extensively speculated during the COVID-19 pandemic, but very few actual data were generated. The aim of our study was to explore the association of HO-1, heme, and hemopexin (HPX) levels with COVID-19 severity and with markers of inflammation and coagulation activation. The study was conducted in 30 consecutive patients with COVID-19 admitted due to hypoxemia, and 30 healthy volunteers matched by sex, age, and geographic region. HO-1 and HPX levels were measured by enzyme immunoassay (ELISA) and heme levels were measured by a colorimetric method. A comprehensive panel of coagulation and fibrinolysis activation was also used. Patients with COVID-19 presented increased levels of HO-1 when compared to controls (5741 ± 2696 vs 1953 ± 612 pg/mL, respectively, P < 0.0001), as well as a trend toward increased levels of HPX (3.724 ± 0.880 vs 3.254 ± 1.022 mg/mL, respectively; P = 0.06). In addition, HO-1 and HPX levels reduced from admission to day + 4. HO-1 levels were associated with duration of intensive care unit stay and with several markers of coagulation activation. In conclusion, modulation of HO-1 could be associated with the prothrombotic state observed in COVID-19, and HO-1 could also represent a relevant biomarker for COVID-19. New independent studies are warranted to explore and expand these findings.

Podoplanin and CLEC-2 levels in patients with COVID-19.

Introduction: Podoplanin (PDPN gene) and CLEC-2 are involved in inflammatory hemostasis and have also been related with the pathogenesis of thrombosis. Emerging evidence also suggest that podoplanin can exert protective effects in sepsis and in acute lung injury. In lungs, podoplanin is co-expressed with ACE2, which is the main entry receptor for SARS-CoV-2. Aim: To explore the role of podoplanin and CLEC-2 in COVID-19. Methods: Circulating levels of podoplanin and CLEC-2 were measured in 30 consecutive COVID-19 patients admitted due to hypoxia, and in 30 age- and sex-matched healthy individuals. Podoplanin expression in lungs from patients who died of COVID-19 was obtained from two independent public databases of single-cell RNAseq from which data from control lungs were also available. Results: Circulating podoplanin levels were lower in COVID-19, while no difference was observed in CLEC-2 levels. Podoplanin levels were significantly inversely correlated with markers of coagulation, fibrinolysis and innate immunity. scRNAseq data confirmed that PDPN is co-expressed with ACE2 in pneumocytes, and showed that PDPN expression is lower in this cell compartment in lungs from patients with COVID-19. Conclusion: Circulating levels of podoplanin are lower in COVID-19, and the magnitude of this reduction is correlated with hemostasis activation. We also demonstrate the downregulation of PDPN at the transcription level in pneumocytes. Together, our exploratory study questions whether an acquired podoplanin deficiency could be involved in the pathogenesis of acute lung injury in COVID-19, and warrant additional studies to confirm and refine these findings.

SARS-CoV-2 uses CD4 to infect T helper lymphocytes.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the agent of a major global outbreak of respiratory tract disease known as Coronavirus Disease 2019 (COVID-19). SARS-CoV-2 infects mainly lungs and may cause several immune-related complications, such as lymphocytopenia and cytokine storm, which are associated with the severity of the disease and predict mortality. The mechanism by which SARS-CoV-2 infection may result in immune system dysfunction is still not fully understood. Here, we show that SARS-CoV-2 infects human CD4+ T helper cells, but not CD8+ T cells, and is present in blood and bronchoalveolar lavage T helper cells of severe COVID-19 patients. We demonstrated that SARS-CoV-2 spike glycoprotein (S) directly binds to the CD4 molecule, which in turn mediates the entry of SARS- CoV-2 in T helper cells. This leads to impaired CD4 T cell function and may cause cell death. SARS-CoV-2-infected T helper cells express higher levels of IL-10, which is associated with viral persistence and disease severity. Thus, CD4-mediated SARS-CoV-2 infection of T helper cells may contribute to a poor immune response in COVID-19 patients.

Plasma Angiotensin II Is Increased in Critical Coronavirus Disease 2019.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) employs angiotensin-converting enzyme 2 (ACE2) as its receptor for cell entrance, and studies have suggested that upon viral binding, ACE2 catalytic activity could be inhibited; therefore, impacting the regulation of the renin-angiotensin-aldosterone system (RAAS). To date, only few studies have evaluated the impact of SARS-CoV-2 infection on the blood levels of the components of the RAAS. The objective of this study was to determine the blood levels of ACE, ACE2, angiotensin-II, angiotensin (1-7), and angiotensin (1-9) at hospital admission and discharge in a group of patients presenting with severe or critical evolution of coronavirus disease 2019 (COVID-19). We showed that ACE, ACE2, angiotensin (1-7), and angiotensin (1-9) were similar in patients with critical and severe COVID-19. However, at admission, angiotensin-II levels were significantly higher in patients presenting as critical, compared to patients presenting with severe COVID-19. We conclude that blood levels of angiotensin-II are increased in hospitalized patients with COVID-19 presenting the critical outcome of the disease. We propose that early measurement of Ang-II could be a useful biomarker for identifying patients at higher risk for extremely severe progression of the disease.

Contact and intrinsic coagulation pathways are activated and associated with adverse clinical outcomes in COVID-19.

Coagulation activation is a prominent feature of severe acute respiratory syndrome coronavirus 2 (COVID-19) infection. Activation of the contact system and intrinsic pathway has increasingly been implicated in the prothrombotic state observed in both sterile and infectious inflammatory conditions. We therefore sought to assess activation of the contact system and intrinsic pathway in individuals with COVID-19 infection. Baseline plasma levels of protease:serpin complexes indicative of activation of the contact and intrinsic pathways were measured in samples from inpatients with COVID-19 and healthy individuals. Cleaved kininogen, a surrogate for bradykinin release, was measured by enzyme-linked immunosorbent assay, and extrinsic pathway activation was assessed by microvesicle tissue factor-mediated factor Xa (FXa; MVTF) generation. Samples were collected within 24 hours of COVID-19 diagnosis. Thirty patients with COVID-19 and 30 age- and sex-matched controls were enrolled. Contact system and intrinsic pathway activation in COVID-19 was demonstrated by increased plasma levels of FXIIa:C1 esterase inhibitor (C1), kallikrein:C1, FXIa:C1, FXIa:α1-antitrypsin, and FIXa:antithrombin (AT). MVTF levels were also increased in patients with COVID-19. Because FIXa:AT levels were associated with both contact/intrinsic pathway complexes and MVTF, activation of FIX likely occurs through both contact/intrinsic and extrinsic pathways. Among the protease:serpin complexes measured, FIXa:AT complexes were uniquely associated with clinical indices of disease severity, specifically total length of hospitalization, length of intensive care unit stay, and extent of lung computed tomography changes. We conclude that the contact/intrinsic pathway may contribute to the pathogenesis of the prothrombotic state in COVID-19. Larger prospective studies are required to confirm whether FIXa:AT complexes are a clinically useful biomarker of adverse clinical outcomes.

The use of live yeast to increase intake and performance of cattle receiving low-quality tropical forages.

The objective was to evaluate the effects of a specific strain of live yeast (LY) on growth performance, fermentation parameters, feed efficiency, and bacterial communities in the rumen of growing cattle fed low-quality hay. In experiment (exp.) 1, 12 Droughtmaster bull calves (270 ± 7.6 kg initial body weight [BW]) were blocked by BW into two groups, allocated individually in pens, and fed ad libitum Rhodes grass hay (8.4% of crude protein [CP]) and 300 g/bull of supplement (52% CP) without (Control) or with LY (8 × 109 colony-forming unit [CFU]/d Saccharomyces cerevisiae CNCM I-1077; Lallemand Inc., Montreal, Canada) for 28 d, followed by 7 d in metabolism crates. Blood and rumen fluid were collected before feeding and 4 h after feeding. In exp. 2, for assessment of growth performance, 48 Charbray steers (329 ± 20.2 kg initial BW) were separated into two blocks by initial BW and randomly allocated into 12 pens. The steers were fed Rhodes grass hay (7.3% CP) and 220 g/steer of supplement (60% CP) without or with LY (8 × 109 CFU/d) for 42 d, after a 2-wk adaptation period. In exp. 1, fiber digestibility was calculated from total fecal collection, and, in exp 2, indigestible neutral detergent fiber (NDF) was used as a marker. Inclusion of LY increased (P = 0.03) NDF intake by 8.3% in exp. 1, without affecting total tract digestibility. No changes were observed in microbial yield or in the efficiency of microbial production. There was a Treatment × Time interaction (P < 0.01) for the molar proportion of short-chain fatty acids, with LY increasing propionate before feeding. Inclusion of LY decreased rumen ammonia 4 h after feeding (P = 0.03). The addition of LY reduced rumen bacterial diversity and the intraday variation in bacterial populations. Relative populations of Firmicutes and Verrucomicrobia varied over time (P < 0.05) only within the Control group. At the genus level, the relative abundance of an unclassified bacterial genus within the order Clostridiales, a group of cellulolytic bacteria, was reduced from 0 to 4 h after feeding in the Control group (P = 0.02) but not in the LY group (P = 1.00). During exp. 2, LY tended to increase average daily gain (ADG) (P = 0.08) and feed efficiency (P = 0.10), with no effect on NDF intake or digestibility. In conclusion, S. cerevisiae CNCM I-1077 reduced the intraday variation of rumen bacteria and increased the amount of NDF digested per day. These observations could be associated with the tendency of increased ADG and feed efficiency in growing cattle fed a low-quality forage.

Inclusion of soybean and linseed oils in the diet of lactating dairy cows makes the milk fatty acid profile nutritionally healthier for the human diet.

Fluid milk and its derivatives are important dietary ingredients that contribute to daily nutrient intake of the modern Homo sapiens. To produce milk that is healthier for human consumption, the present study evaluated the effect of adding soybean oil and linseed oil in the diet of lactating cows. The fatty acid profile of milk, milk composition, and the blood parameters of cows were evaluated. Eighteen Holstein cows were distributed in a replicated Latin square design and distributed according to the following treatments: 1) Control (CC): traditional dairy cow diet, without addition of oil; 2) Soybean oil (SO): 2.5% addition of soybean oil to the traditional diet, as a source of omega-6; 3) Linseed oil (LO): 2.5% addition of linseed oil in the diet as a source of omega-3. Milk production was not affected, but oil supplementation decreased feed intake by 1.93 kg/cow/day. The milk fat percentage was significantly lower when cows were supplemented with vegetable oil (3.37, 2.75 and 2.89% for CC, SO and LO, respectively). However, both soybean and linseed oils decreased the concentration of saturated fatty acids (66.89, 56.52 and 56.60 g/100g for CC, SO and LO respectively), increased the amount of unsaturated fatty acids in milk (33.05, 43.39, and 43.35 g/100g for CC, SO and LO respectively) and decreased the ratio between saturated/unsaturated fatty acids (2.12, 1.34, and 1.36 for CC, SO and LO respectively). Furthermore, SO and LO increased significantly the concentration of monounsaturated fatty acids (29.58, 39.55 and 39.47 g/100g for CC, SO and LO respectively), though it did not significantly alter the level of polyunsaturated fatty acids in milk fat (3.57, 3.93 and 3.98 g/100g for CC, SO and LO respectively). Supplementation with LO enhanced the concentration of omega-3 fatty acids on milk (0.32, 0.36, and 1.02 for CC, SO and LO respectively). Blood variables aspartate aminotransferase, gamma glutamyl transferase, urea, albumin, creatinine and total proteins were not altered. On the other hand, total cholesterol, HDL and LDL were greater in the group supplemented with vegetable oils. Supplementation with vegetable oils reduced the dry matter intake of cows, the fat content of milk, and improved saturated/unsaturated fatty acid ratio of milk fat. Compared to the SO treatment, animals fed LO produced milk with greater content of omega-3, and a more desirable omega-6/omega-3 ratio on a human nutrition perspective. Thus, the inclusion of SO and LO in the diet of lactating dairy cows makes the milk fatty acid profile nutritionally healthier for the human consumption.

Evaluation of the efficacy and safety of icatibant and C1 esterase/kallikrein inhibitor in severe COVID-19: study protocol for a three-armed randomized controlled trial.

BACKGROUND: SARS-CoV-2, the virus that causes COVID-19, enters the cells through a mechanism dependent on its binding to angiotensin-converting enzyme 2 (ACE2), a protein highly expressed in the lungs. The putative viral-induced inhibition of ACE2 could result in the defective degradation of bradykinin, a potent inflammatory substance. We hypothesize that increased bradykinin in the lungs is an important mechanism driving the development of pneumonia and respiratory failure in COVID-19. METHODS: This is a phase II, single-center, three-armed parallel-group, open-label, active control superiority randomized clinical trial. One hundred eighty eligible patients will be randomly assigned in a 1:1:1 ratio to receive either the inhibitor of C1e/kallikrein 20 U/kg intravenously on day 1 and day 4 plus standard care; or icatibant 30 mg subcutaneously, three doses/day for 4 days plus standard care; or standard care alone, as recommended in the clinical trials published to date, which includes supplemental oxygen, non-invasive and invasive ventilation, antibiotic agents, anti-inflammatory agents, prophylactic antithrombotic therapy, vasopressor support, and renal replacement therapy. DISCUSSION: Accumulation of bradykinin in the lungs is a common side effect of ACE inhibitors leading to cough. In animal models, the inactivation of ACE2 leads to severe acute pneumonitis in response to lipopolysaccharide (LPS), and the inhibition of bradykinin almost completely restores the lung structure. We believe that inhibition of bradykinin in severe COVID-19 patients could reduce the lung inflammatory response, impacting positively on the severity of disease and mortality rates. TRIAL REGISTRATION: Brazilian Clinical Trials Registry Universal Trial Number (UTN) U1111-1250-1843. Registered on May/5/2020.

Safety and Outcomes Associated with the Pharmacological Inhibition of the Kinin-Kallikrein System in Severe COVID-19.

Background: Coronavirus disease 19 (COVID-19) can develop into a severe respiratory syndrome that results in up to 40% mortality. Acute lung inflammatory edema is a major pathological finding in autopsies explaining O2 diffusion failure and hypoxemia. Only dexamethasone has been shown to reduce mortality in severe cases, further supporting a role for inflammation in disease severity. SARS-CoV-2 enters cells employing angiotensin-converting enzyme 2 (ACE2) as a receptor, which is highly expressed in lung alveolar cells. ACE2 is one of the components of the cellular machinery that inactivates the potent inflammatory agent bradykinin, and SARS-CoV-2 infection could interfere with the catalytic activity of ACE2, leading to the accumulation of bradykinin. Methods: In this case control study, we tested two pharmacological inhibitors of the kinin-kallikrein system that are currently approved for the treatment of hereditary angioedema, icatibant, and inhibitor of C1 esterase/kallikrein, in a group of 30 patients with severe COVID-19. Results: Neither icatibant nor inhibitor of C1 esterase/kallikrein resulted in changes in time to clinical improvement. However, both compounds were safe and promoted the significant improvement of lung computed tomography scores and increased blood eosinophils, which are indicators of disease recovery. Conclusions: In this small cohort, we found evidence for safety and a beneficial role of pharmacological inhibition of the kinin-kallikrein system in two markers that indicate improved disease recovery.

DISCRETE CHOICE AND RATIONAL INATTENTION: A GENERAL EQUIVALENCE RESULT.

This article establishes a general equivalence between discrete choice and rational inattention models. Matejka and McKay (2015) showed that when information costs are modeled using the Shannon entropy, the choice probabilities in the rational inattention (RI) model take the multinomial logit form. We show that, for one given prior over states, RI choice probabilities may take the form of any additive random utility discrete choice model (ARUM) when the information cost is a Bregman information, a class defined in this article. The prior information of the rationally inattentive agent is summarized in a constant vector of utilities in the corresponding ARUM.

Elevated Glucose Levels Favor SARS-CoV-2 Infection and Monocyte Response through a HIF-1α/Glycolysis-Dependent Axis.

COVID-19 can result in severe lung injury. It remained to be determined why diabetic individuals with uncontrolled glucose levels are more prone to develop the severe form of COVID-19. The molecular mechanism underlying SARS-CoV-2 infection and what determines the onset of the cytokine storm found in severe COVID-19 patients are unknown. Monocytes and macrophages are the most enriched immune cell types in the lungs of COVID-19 patients and appear to have a central role in the pathogenicity of the disease. These cells adapt their metabolism upon infection and become highly glycolytic, which facilitates SARS-CoV-2 replication. The infection triggers mitochondrial ROS production, which induces stabilization of hypoxia-inducible factor-1α (HIF-1α) and consequently promotes glycolysis. HIF-1α-induced changes in monocyte metabolism by SARS-CoV-2 infection directly inhibit T cell response and reduce epithelial cell survival. Targeting HIF-1ɑ may have great therapeutic potential for the development of novel drugs to treat COVID-19.

Canola Oil in Lactating Dairy Cow Diets Reduces Milk Saturated Fatty Acids and Improves Its Omega-3 and Oleic Fatty Acid Content.

To produce milk that is healthier for human consumption, the present study evaluated the effect of including canola oil in the diet of dairy cows on milk production and composition as well as the nutritional quality of this milk fat. Eighteen Holstein cows with an average daily milk yield of 22 (± 4) kg/d in the middle stage of lactation were used. The cows were distributed in 6 contemporary 3x3 Latin squares consisting of 3 periods and 3 treatments: control diet (without oil), 3% inclusion of canola oil in the diet and 6% inclusion of canola oil in the diet (dry matter basis). The inclusion of 6% canola oil in the diet of lactating cows linearly reduced the milk yield by 2.51 kg/d, short-chain fatty acids (FA) by 41.42%, medium chain FA by 27.32%, saturated FA by 20.24%, saturated/unsaturated FA ratio by 39.20%, omega-6/omega-3 ratio by 39.45%, and atherogenicity index by 48.36% compared with the control treatment. Moreover, with the 6% inclusion of canola oil in the diet of cows, there was an increase in the concentration of long chain FA by 45.91%, unsaturated FA by 34.08%, monounsaturated FA by 40.37%, polyunsaturated FA by 17.88%, milk concentration of omega-3 by 115%, rumenic acid (CLA) by 16.50%, oleic acid by 44.87% and h/H milk index by 94.44% compared with the control treatment. Thus, the inclusion of canola oil in the diet of lactating dairy cows makes the milk fatty acid profile nutritionally healthier for the human diet; however, the lactating performance of dairy cows is reduce.