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BackgroundHealth disparities in underserved communities, such as inadequate healthcare access, impact COVID-19 disease outcomes. These disparities are evident in Hispanic populations nationwide, with disproportionately high infection and mortality rates. Furthermore, infected individuals can develop long COVID with sustained impacts on quality of life. The goal of this study was to identify immune and endothelial factors that are associated with COVID-19 outcomes in Riverside County, a high-risk and predominantly Hispanic community, and investigate the long-term impacts of COVID-19 infection.Methods112 participants in Riverside County, California, were recruited according to the following criteria: healthy control (n = 23), outpatients with moderate infection (outpatient, n = 33), ICU patients with severe infection (hospitalized, n = 33), and individuals recovered from moderate infection (n = 23). Differences in outcomes between Hispanic and non-Hispanic individuals and presence/absence of co-morbidities were evaluated. Circulating immune and vascular biomarkers were measured by ELISA, multiplex analyte assays, and flow cytometry. Follow-up assessments for long COVID, lung health, and immune and vascular changes were conducted after recovery (n = 23) including paired analyses of the same participants.ResultsCompared to uninfected controls, the severe infection group had a higher proportion of Hispanic individuals (n = 23, p = 0.012) than moderate infection (n = 8, p = 0.550). Disease severity was associated with changes in innate monocytes and neutrophils, lymphopenia, disrupted cytokine production (increased IL-8 and IP-10/CXCL10 but reduced IFNλ2/3 and IFNγ), and increased endothelial injury (myoglobin, VCAM-1). In the severe infection group, a machine learning model identified LCN2/NGAL, IL-6, and monocyte activation as parameters associated with fatality while anti-coagulant therapy was associated with survival. Recovery from moderate COVID infection resulted in long-term immune changes including increased monocytes/lymphocytes and decreased neutrophils and endothelial markers. This group had a lower proportion of co-morbidities (n = 8, p = 1.0) but still reported symptoms associated with long COVID despite recovered pulmonary function.ConclusionThis study indicates increased severity of COVID-19 infection in Hispanic individuals of Riverside County, California. Infection resulted in immunological and vascular changes and long COVID symptoms that were sustained for up to 11 months, however, lung volume and airflow resistance was recovered. Given the immune and behavioral impacts of long COVID, the potential for increased susceptibility to infections and decreased quality of life in high-risk populations warrants further investigation.

Abstract Background Health disparities in underserved communities, such as inadequate healthcare access, impact COVID-19 disease outcomes. These disparities are evident in Hispanic populations nationwide, with disproportionately high infection and mortality rates. Furthermore, infected individuals can develop long COVID with sustained impacts on quality of life. The goal of this study was to identify immune and endothelial factors that are associated with COVID-19 outcomes in Riverside County, a high-risk and predominantly Hispanic community, and investigate the long-term impacts of COVID-19 infection. Methods 112 participants in Riverside County, California, were recruited according to the following criteria: healthy control (n = 23), outpatients with moderate infection (outpatient, n = 33), ICU patients with severe infection (hospitalized, n = 33), and individuals recovered from moderate infection (n = 23). Differences in outcomes between Hispanic and non-Hispanic individuals and presence/absence of co-morbidities were evaluated. Circulating immune and vascular biomarkers were measured by ELISA, multiplex analyte assays, and flow cytometry. Follow-up assessments for long COVID, lung health, and immune and vascular changes were conducted after recovery (n = 23) including paired analyses of the same participants. Results Compared to uninfected controls, the severe infection group had a higher proportion of Hispanic individuals (n = 23, p = 0.012) than moderate infection (n = 8, p = 0.550). Disease severity was associated with changes in innate monocytes and neutrophils, lymphopenia, disrupted cytokine production (increased IL-8 and IP-10/CXCL10 but reduced IFNλ2/3 and IFNγ), and increased endothelial injury (myoglobin, VCAM-1). In the severe infection group, a machine learning model identified LCN2/NGAL, IL-6, and monocyte activation as parameters associated with fatality while anti-coagulant therapy was associated with survival. Recovery from moderate COVID infection resulted in long-term immune changes including increased monocytes/lymphocytes and decreased neutrophils and endothelial markers. This group had a lower proportion of co-morbidities (n = 8, p = 1.0) but still reported symptoms associated with long COVID despite recovered pulmonary function. Conclusion This study indicates increased severity of COVID-19 infection in Hispanic individuals of Riverside County, California. Infection resulted in immunological and vascular changes and long COVID symptoms that were sustained for up to 11 months, however, lung volume and airflow resistance was recovered. Given the immune and behavioral impacts of long COVID, the potential for increased susceptibility to infections and decreased quality of life in high-risk populations warrants further investigation.

People living with HIV (PLWH) continue to develop HIV-associated neurocognitive disorders despite combination anti-retroviral therapy. Lipocalin-2 (LCN2) is an acute phase protein that has been implicated in neurodegeneration and is upregulated in a transgenic mouse model of HIV-associated brain injury. Here we show that LCN2 is significantly upregulated in neocortex of a subset of HIV-infected individuals with brain pathology and correlates with viral load in CSF and pro-viral DNA in neocortex. However, the question if LCN2 contributes to HIV-associated neurotoxicity or is part of a protective host response required further investigation. We found that the knockout of LCN2 in transgenic mice expressing HIVgp120 in the brain (HIVgp120tg) abrogates behavioral impairment, ameliorates neuronal damage, and reduces microglial activation in association with an increase of the neuroprotective CCR5 ligand CCL4. In vitro experiments show that LCN2 neurotoxicity also depends on microglia and p38 MAPK activity. Genetic ablation of CCR5 in LCN2-deficient HIVgp120tg mice restores neuropathology, suggesting that LCN2 overrides neuroprotection mediated by CCR5 and its chemokine ligands. RNA expression of 168 genes involved in neurotransmission reveals that neuronal injury and protection are each associated with genotype- and sex-specific patterns affecting common neural gene networks. In conclusion, our study identifies LCN2 as a novel factor in HIV-associated brain injury involving CCR5, p38 MAPK and microglia. Furthermore, the mechanistic interaction between LCN2 and CCR5 may serve as a diagnostic and therapeutic target in HIV patients at risk of developing brain pathology and neurocognitive impairment.

The DNA vaccine, AV-1959D, targeting N-terminal epitope of Aβ peptide, has been proven immunogenic in mice, rabbits, and non-human primates, while its therapeutic efficacy has been shown in mouse models of Alzheimer's disease (AD). Here we report for the first time on IND-enabling biodistribution and safety/toxicology studies of cGMP-grade AV-1959D vaccine in the Tg2576 mouse model of AD. We also tested acute neuropathology safety profiles of AV-1959D in another AD disease model, Tg-SwDI mice with established vascular and parenchymal Aβ pathology in a pre-clinical translational study. Biodistribution studies two days after the injection demonstrated high copy numbers of AV-1959D plasmid after single immunization of Tg2576 mice at the injection sites but not in the tissues of distant organs. Plasmids persisted at the injection sites of some mice 60 days after vaccination. In Tg2576 mice with established amyloid pathology, we did not observe short- or long-term toxicities after multiple immunizations with three doses of AV-1959D. Assessment of the repeated dose acute safety of AV-1959D in cerebral amyloid angiopathy (CAA) prone Tg-SwDI mice did not reveal any immunotherapy-induced vasogenic edema detected by magnetic resonance imaging (MRI) or increased microhemorrhages. Multiple immunizations of Tg-SwDI mice with AV-1959D did not induce T and B cell infiltration, glial activation, vascular deposition of Aβ, or neuronal degeneration (necrosis and apoptosis) greater than that in the control group determined by immunohistochemistry of brain tissues. Taken together, the safety data from two different mouse models of AD substantiate a favorable safety profile of the cGMP grade AV-1959D vaccine supporting its progression to first-in-human clinical trials.

In the last decades, the notion that leadership comprises responsible leadership has gained support and the academic debate has shed some light on the antecedents, processes, and multi-level outcomes of responsible leadership. Being at the intersection of the leadership and sustainability discourses, responsible leadership has benefitted from the increasing interests that both fields of study have received. Nevertheless, the debate has left several questions around the nature and development of responsible leadership unanswered. Among these questions we reckon an understanding of "responsible" in the definition of "responsible leadership," the width of leaders' responsibility and the depth of their impact including the role of personal alongside formal leadership, and the distinction between "responsible" and "non responsible" leaders. The aim of this theoretical paper is to further the academic discussion on leadership in the context of sustainability and its integration in higher education settings. We review the literature and explore the academic debate while step-by-step building a description of responsible leadership that could form the basis for leadership programmes in higher education. Then, borrowing insights from pro-environmental psychology, we share a tripartite description of responsible leadership, which centres around identity, behaviour and responsiveness. As a final step, we share our experience in building an undergraduate programme based on this tripartite description of responsible leadership. Here, we illustrate how the leadership description can be visualised in a figure and used to develop an undergraduate Liberal Arts and Sciences curriculum centred on the UN Sustainable Development Goals.

In this study, 23 African American broadcast journalists, who graduated from college between 1994 and 2014, were interviewed about their experiences working in network television news, specifically the role their mentor played to help their professional success. Mentors largely provided both vocational and psychosocial support, but were overwhelmingly not seen as role models. The majority of mentees also believed race was a factor in their careers. The findings led to recommendations on how mentors can guide their mentees toward career progression, such as verbal encouragement, guiding mentees to position themselves so "Others" see the value they bring to the newsroom, and networking opportunities.

Introduction: The disruption of the functional state of the vascular endothelium is among the main causes of preeclampsia, which is one of the most common causes of maternal and perinatal mortality. It can be enhanced by the humoral factors secreted by the activated platelets. The use of acetylsalicylic acid is an effective way to prevent preeclampsia. However, its ability to activate eNOS is a prerequisite for researching its ability to correct the disorders in developing preeclampsia, including by reducing the platelet activity. In this case its effect can be enhanced through increasing the bioavailability of L-arginine by using a selective arginase II inhibitor KUD 975. These facts were the prerequisite for conducting this study. Materials and methods: The study was conducted on 180 female Wistar rats weighing 250–300 g. Acetylsalicylic acid was used at a dose of 7 mg/kg/day and 10 mg/kg/day, KUD 975 – at a dose of 1 mg/kg/day and 3 mg/kg/day. Adenosine diphosphate (ADP, 6.5 microns), arachidonic acid (ASPI, 0.5 mM), and collagen (3.2 mcg/ml) were used as aggregation inducers. Results and discussion: ADMA-like preeclampsia simulation led to an increase in platelet aggregation ability when using all aggregation inducers. This is evidenced by an increase in a degree, rate of aggregation, and a shortened time of thrombus formation. The use of acetylsalicylic acid and a selective arginase II inhibitor KUD 975 led to a decrease in the aggregation ability of platelets and an increase in thrombosis time, while the combined administration of the studied agents showed a more pronounced effect. Conclusion: The data obtained while performing a series of experiments strongly indicate a promising outlook for using acetylsalicylic acid and a selective arginase II inhibitor KUD 975 in order to correct emerging disorders in preeclampsia.

Introduction: In this review, the analysis of technologies for obtaining biologically active proteins from various sources is carried out, and the comparative analysis of technologies for creating producers of biologically active proteins is presented. Special attention is paid to genetically modified animals as bioreactors for the pharmaceutical industry of a new type. The necessity of improving the technology of development transgenic rabbit producers and creating a platform solution for the production of biological products is substantiated. The advantages of using TrB for the production of recombinant proteins: The main advantages of using TrB are the low cost of obtaining valuable complex therapeutic human proteins in readily accessible fluids, their greater safety relative to proteins isolated directly from human blood, and the greater safety of the activity of the native protein. The advantages of the mammary gland as a system for the expression of recombinant proteins: The mammary gland is the organ of choice for the expression of valuable recombinant proteins because milk is easy to collect in large volumes. Methods for obtaining transgenic animals: The modern understanding of the regulation of gene expression and the discovery of new tools for gene editing can increase the efficiency of creating bioreactors for animals and help to obtain high concentrations of the target protein. The advantages of using rabbits as bioreactors producing recombinant proteins in milk: The rabbit is a relatively small animal with a short duration of gestation, puberty and optimal size, capable of producing up to 5 liters of milk per year per female, receiving up to 300 grams of the target protein.

Relevance: Cardiovascular diseases continue to be the leading cause of premature adult death. Lipid profile and atherogenesis: Dislipidaemia leads to subsequent lipid accumulation and migration of immunocompetent cells into the vessel intima. Macrophages accumulate cholesterol forming foam cells – the morphological substrate of atherosclerosis in its initial stage. Inflammation and atherogenesis: Pro-inflammatory factors provoke oxidative stress, vascular wall damage and foam cells formation. Endothelial and mitochondrial dysfunction in the development of atherosclerosis: Endothelial mitochondria are some of the organelles most sensitive to oxidative stress. Damaged mitochondria produce excess superoxide and H2O2, which are the main factors of intracellular damage, further increasing endothelial dysfunction. Short non-hematopoietic erythropoietin-based peptides as innovative atheroprotectors: Research in recent decades has shown that erythropoietin has a high cytoprotective activity, which is mainly associated with exposure to the mitochondrial link and has been confirmed in various experimental models. There is also a short-chain derivative, the 11-amino acid pyroglutamate helix B surface peptide (PHBSP), which selectively binds to the erythropoietin heterodymic receptor and reproduces its cytoprotective properties. This indicates the promising use of short-chain derivatives of erythropoietin for the treatment and prevention of atherosclerotic vascular injury. In the future, it is planned to study the PHBSP derivatives, the modification of which consists in adding RGD and PGP tripeptides with antiaggregant properties to the original 11-member peptide.

The aim of the present work was to study the pharmacological activity of a low-molecular arginase II selective inhibitor (low-molecular compound with laboratory code ZB49) with the chemical formula 2-{1-[3-(3-[chloroisoxazole-5-yl) propyl] piperidin-4-yl}-6-(digibroxyboryl) norleucine dihydrochloride) using a model of monocrotaline-induced pulmonary hypertensionMaterials and methods. The work was performed on 40 adult male Wistar rats weighing 180– 220 g. The simulation of monocrotaline pulmonary hypertension was performed on 20 animals using a subcutaneous injection of an alcohol-aqueous solution of monocrotaline (MCT) at a dose of 60 mg/kg in a volume of 0.5 ml per animal. 7 days after the MCT injection, the administration of the studied pharmaceutical substance (PS) (laboratory code ZB49) was started at a dose of 5 mg/kg. ZB49 was administered intragastrically, once a day with the administration duration of 21 days.Results. Under the intragastric FS ZB49 administration at a dose of 5 mg/kg, a statistically significant decrease in the coefficient of endothelial dysfunction, systolic right ventricle pressure (SRVP), average the right ventricle pressure (ARVP), diastolic right ventricle pressure (DRVP), maximum contraction rate (dP/dt max) and minimum contraction rate (dP/dt min) was established at the background of the simulation of monocrotaline-induced pulmonary hypertension. At the same time, a statistically significant positive effect of ZB49 on the blood gas composition was established.Conclusion. The study has confirmed the possibility of using arginase inhibitors to prevent the development of endothelial dysfunction and the disorders of nitric oxide metabolism in pulmonary arterial hypertension. Among the substances of this group, arginase II selective inhibitors should be considered as the most promising.Conflict of interest: the authors declare no conflict of interest.

Abstract Background Bioethicists argue that inclusion of pregnant women in clinical research should be more routine to increase the evidence-base for pregnant women and foetuses. Yet, it is unknown whether pregnant women and others directly involved are willing to be routinely included. Therefore, we first need to establish what these stakeholders think about research participation in regular pregnancy-related research. However, studies on their views are scarce. In our study, we piggy-backed on a relatively conventional RCT, the APOSTEL VI study, to identify the views of stakeholders on inclusion of pregnant women in this study. Methods We conducted a prospective qualitative study using 35 in-depth semi-structured interviews and one focus group. We interviewed pregnant women (n = 14) recruited for the APOSTEL VI study, in addition to healthcare professionals (n = 14), Research Ethics Committee members (RECs) (n = 5) and regulators (n = 7) involved in clinical research in pregnant women. Results Three themes characterise stakeholders’ views on inclusion of pregnant women in the APOSTEL VI study. Additionally, one theme characterises stakeholders’ interest in inclusion of pregnant women in clinical research in general. First, pregnant women participate in the APOSTEL VI study for potential individual benefit and secondarily for altruistic motives, contrary to hypothetical studies. Second, a gatekeeping tendency hampers recruitment of pregnant women who might be eligible and willing, and questions about pregnant women’s decisional capacities surface. Third, healthcare professionals sometimes use the counselling conversation to steer pregnant women in a direction. Fourth, all stakeholders are hesitant about inclusion of pregnant women in clinical research in general due to a protective sentiment. Conclusions Pregnant women are willing to participate in the APOSTEL VI study for potential individual benefit and altruistic motives. However, an underlying protective sentiment, resulting in gatekeeping and directive counselling, sometimes hampers recruitment in the APOSTEL VI study as well as in clinical research in general. While bioethicists claim that inclusion of pregnant women should be customary, our study indicates that healthcare professionals, regulators, RECs and pregnant women themselves are not necessarily interested in inclusion. Advancing the situation and increasing the evidence-base for pregnant women and foetuses may require additional measures such as investing in the recruitment and feasibility of RCTs and stimulating pregnant women’s decisional capacities.

Abstract Evidence-based treatment for pregnant women will ultimately require research conducted in the population of pregnant women. Currently, few scholars have addressed the issue of responsible inclusion of pregnant women in drug research. Because of additional risks associated with including pregnant women in drug research and the altered ways in which drugs are processed by the pregnant body, pregnant women cannot be treated as an ordinary subgroup in the various phases of drug development. Instead, responsible inclusion of pregnant women requires careful design and planning of research for pregnant women specifically. Knowledge about these aspects is virtually nonexistent. In this article, we present a practical framework for the responsible inclusion of pregnant women in drug development. We suggest that the framework consists of using a question-based approach with five key questions in combination with three prerequisites which should be addressed when considering inclusion of pregnant women in drug research. The five questions are:A. Can we consider the drug safe (enough) for first exposure in pregnant women and fetuses? B. In which dose range (potentially depending on gestational age) can the drug be considered to remain safe in pregnant women? C. At what dose (regimen, within the range considered safe) can we expect efficacy in pregnant women? D. Can efficacy be confirmed at the target dose, either similar to the initial population or different? E. Can clinical safety be confirmed at a sufficiently acceptable level at the target dose for pregnant women and fetuses, so as to conclude a positive benefit–risk ratio? Combining questions and prerequisites leads to a scheme for appropriate timing of responsible inclusion of pregnant women in drug research. Accordingly, we explore several research design options for including pregnant women in drug trials that are feasible within the framework. Ultimately, the framework may lead to (i) earlier inclusion of pregnant women in drug development, (ii) ensuring that key prerequisites, such as proper dosing, are addressed before more substantial numbers of pregnant women are included in trials, and (iii) optimal use of safety and efficacy data from the initial (nonpregnant) population throughout the drug development process.

Abstract Background Since pregnant women are severely underrepresented in clinical research, many take the position that the exclusion of pregnant women from research must be justified unless there are compelling “scientific reasons” for their exclusion. However, it is questionable whether this approach renders research with pregnant women fair. This paper analyzes and evaluates when research with pregnant women can be considered as fair and what constitutes scientific reasons for exclusion. Methods Conceptual ethical and methodological analysis and evaluation of fair inclusion. Results Fair inclusion of pregnant women means (1) that pregnant women who are eligible are not excluded solely for being pregnant and (2) that the research interests of pregnant women are prioritized, meaning that they ought to receive substantially more attention. Fairness does not imply that pregnant women should be included in virtually every research project, as including only a few pregnant women in a population consisting only of women will not help to determine the effectiveness and safety of a treatment in pregnant women. Separate trials in pregnant women may be preferable once we assume, or know, that effects of interventions in pregnant women differ from the effects in other subpopulations, or when we assume, or know, that there are no differences. In the latter case, it may be preferable to conduct post-marketing studies or establish registries. If there is no conclusive evidence indicating either differences or equivalence of effects between pregnant and non-pregnant women, yet it seems unlikely that major differences or exact equivalence exist, the inclusion of pregnant women should be sufficient. Depending on the research question, this boils down to representativeness in terms of the proportion of pregnant and non-pregnant women, or to oversampling pregnant women. Conclusions Fair inclusion of pregnant women in research implies that separate trials in pregnant women should be promoted. Inclusion of pregnant women has to be realized at the earliest phases of the research process. In addition to researchers and research ethics committees, scientific advisory councils, funders, drug regulatory agencies, pharmaceutical companies, journal editors and others have a joint responsibility to further develop the evidence base for drug use in pregnant women.

Abstract Background There is ambiguity with regard to what counts as an acceptable level of risk in clinical research in pregnant women and there is no input from stakeholders relative to such research risks. The aim of our paper was to explore what stakeholders who are actively involved in the conduct of clinical research in pregnant women deem an acceptable level of risk for pregnant women in clinical research. Accordingly, we used the APOSTEL VI study, a low-risk obstetrical randomised controlled trial, as a case-study. Methods We conducted a prospective qualitative study using 35 in-depth semi-structured interviews and one focus group. We interviewed healthcare professionals, Research Ethics Committee members (RECs) and regulators who are actively involved in the conduct of clinical research in pregnant women, in addition to pregnant women recruited for the APOSTEL VI case-study in the Netherlands. Results Three themes characterise the way stakeholders view risks in clinical research in pregnant women in general. Additionally, one theme characterises the way healthcare professionals and pregnant women view risks with respect to the case-study specifically. First, ideas on what constitutes an acceptable level of risk in general ranged from a preference for zero risk for the foetus up to minimal risk. Second, the desirability of clinical research in pregnant women in general was questioned altogether. Third, stakeholders proposed to establish an upper limit of risk in potentially beneficial clinical research in pregnant women in order to protect the foetus and the pregnant woman from harm. Fourth and finally, the case-study illustrates that healthcare professionals’ individual perception of risk may influence recruitment. Conclusions Healthcare professionals, RECs, regulators and pregnant women are all risk adverse in practice, possibly explaining the continuing underrepresentation of pregnant women in clinical research. Determining the acceptable levels of risk on a universal level alone is insufficient, because the individual perception of risk also influences behaviour towards pregnant women in clinical research. Therefore, bioethicists and researchers might be interested in changing the perception of risk, which could be achieved by education and awareness about the actual benefits and harms of inclusion and exclusion of pregnant women.

Vaccines against dengue virus (DV) are commercially nonexistent. A subunit vaccination strategy may be of value, especially if a safe viral vector acts as biologically active adjuvant. In this paper, we focus on an immunoglobulin-like, independently folded domain III (DIII) from DV 2 envelope protein (E), which contains epitopes that elicits highly specific neutralizing antibodies. We modified the hepatitis B small surface antigen (HBsAg, S) in order to display DV 2 DIII on a virus-like particle (VLP), thus generating the hybrid antigen DIII-S. Two varieties of measles virus (MV) vectors were developed to express DIII-S. The first expresses the hybrid antigen from an additional transcription unit (ATU) and the second additionally expresses HBsAg from a separate ATU. We found that this second MV vectoring the hybrid VLPs displaying DIII-S on an unmodified HBsAg scaffold were immunogenic in MV-susceptible mice (HuCD46Ge-IFNarko), eliciting robust neutralizing responses (averages) against MV (1:1280 NT90), hepatitis B virus (787 mIU/mL), and DV2 (1:160 NT50) in all of the tested animals. Conversely, the MV vector expressing only DIII-S induced immunity against MV alone. In summary, DV2 neutralizing responses can be generated by displaying E DIII on a scaffold of HBsAg-based VLPs, vectored by MV.