PTSD as an Endothelial Disease: Insights From COVID-19.

SARS-CoV-2 virus, the etiologic agent of COVID-19, has affected almost every aspect of human life, precipitating stress-related pathology in vulnerable individuals. As the prevalence rate of posttraumatic stress disorder in pandemic survivors exceeds that of the general and special populations, the virus may predispose to this disorder by directly interfering with the stress-processing pathways. The SARS-CoV-2 interactome has identified several antigens that may disrupt the blood-brain-barrier by inducing premature senescence in many cell types, including the cerebral endothelial cells. This enables the stress molecules, including angiotensin II, endothelin-1 and plasminogen activator inhibitor 1, to aberrantly activate the amygdala, hippocampus, and medial prefrontal cortex, increasing the vulnerability to stress related disorders. This is supported by observing the beneficial effects of angiotensin receptor blockers and angiotensin converting enzyme inhibitors in both posttraumatic stress disorder and SARS-CoV-2 critical illness. In this narrative review, we take a closer look at the virus-host dialog and its impact on the renin-angiotensin system, mitochondrial fitness, and brain-derived neurotrophic factor. We discuss the role of furin cleaving site, the fibrinolytic system, and Sigma-1 receptor in the pathogenesis of psychological trauma. In other words, learning from the virus, clarify the molecular underpinnings of stress related disorders, and design better therapies for these conditions. In this context, we emphasize new potential treatments, including furin and bromodomains inhibitors.

Endothelial Senescence and Chronic Fatigue Syndrome, a COVID-19 Based Hypothesis.

Myalgic encephalomyelitis/chronic fatigue syndrome is a serious illness of unknown etiology, characterized by debilitating exhaustion, memory impairment, pain and sleep abnormalities. Viral infections are believed to initiate the pathogenesis of this syndrome although the definite proof remains elusive. With the unfolding of COVID-19 pandemic, the interest in this condition has resurfaced as excessive tiredness, a major complaint of patients infected with the SARS-CoV-2 virus, often lingers for a long time, resulting in disability, and poor life quality. In a previous article, we hypothesized that COVID-19-upregulated angiotensin II triggered premature endothelial cell senescence, disrupting the intestinal and blood brain barriers. Here, we hypothesize further that post-viral sequelae, including myalgic encephalomyelitis/chronic fatigue syndrome, are promoted by the gut microbes or toxin translocation from the gastrointestinal tract into other tissues, including the brain. This model is supported by the SARS-CoV-2 interaction with host proteins and bacterial lipopolysaccharide. Conversely, targeting microbial translocation and cellular senescence may ameliorate the symptoms of this disabling illness.

Social distancing and testing as optimal strategies against the spread of COVID-19 in the Rio Grande Valley of Texas.

At the beginning of August 2020, the Rio Grande Valley (RGV) of Texas experienced a rapid increase of coronavirus disease 2019 (abbreviated as COVID-19) cases and deaths. This study aims to determine the optimal levels of effective social distancing and testing to slow the virus spread at the outset of the pandemic. We use an age-stratified eight compartment epidemiological model to depict COVID-19 transmission in the community and within households. With a simulated 120-day outbreak period data we obtain a post 180-days period optimal control strategy solution. Our results show that easing social distancing between adults by the end of the 180-day period requires very strict testing a month later and then daily testing rates of 5% followed by isolation of positive cases. Relaxing social distancing rates in adults from 50% to 25% requires both children and seniors to maintain social distancing rates of 50% for nearly the entire period while maintaining maximum testing rates of children and seniors for 150 of the 180 days considered in this model. Children have higher contact rates which leads to transmission based on our model, emphasizing the need for caution when considering school reopenings.

Modeling the effect of lockdown timing as a COVID-19 control measure in countries with differing social contacts.

The application, timing, and duration of lockdown strategies during a pandemic remain poorly quantified with regards to expected public health outcomes. Previous projection models have reached conflicting conclusions about the effect of complete lockdowns on COVID-19 outcomes. We developed a stochastic continuous-time Markov chain (CTMC) model with eight states including the environment (SEAMHQRD-V), and derived a formula for the basic reproduction number, R0, for that model. Applying the [Formula: see text] formula as a function in previously-published social contact matrices from 152 countries, we produced the distribution and four categories of possible [Formula: see text] for the 152 countries and chose one country from each quarter as a representative for four social contact categories (Canada, China, Mexico, and Niger). The model was then used to predict the effects of lockdown timing in those four categories through the representative countries. The analysis for the effect of a lockdown was performed without the influence of the other control measures, like social distancing and mask wearing, to quantify its absolute effect. Hypothetical lockdown timing was shown to be the critical parameter in ameliorating pandemic peak incidence. More importantly, we found that well-timed lockdowns can split the peak of hospitalizations into two smaller distant peaks while extending the overall pandemic duration. The timing of lockdowns reveals that a "tunneling" effect on incidence can be achieved to bypass the peak and prevent pandemic caseloads from exceeding hospital capacity.

COVID-19, ferrosenescence and neurodegeneration, a mini-review.

Exacerbation of cognitive, motor and nonmotor symptoms have been described in critically ill COVID-19 patients, indicating that, like prior pandemics, neurodegenerative sequelae may mark the aftermath of this viral infection. Moreover, SARS-CoV-2, the causative agent of COVID-19 disease, was associated with hyperferritinemia and unfavorable prognosis in older individuals, suggesting virus-induced ferrosenescence. We have previously defined ferrosenescence as an iron-associated disruption of both the human genome and its repair mechanisms, leading to premature cellular senescence and neurodegeneration. As viruses replicate more efficiently in iron-rich senescent cells, they may have developed the ability to induce this phenotype in host tissues, predisposing to both immune dysfunction and neurodegenerative disorders. In this mini-review, we summarize what is known about the SARS-CoV-2-induced cellular senescence and iron dysmetabolism. We also take a closer look at immunotherapy with natural killer cells, angiotensin II receptor blockers ("sartans"), iron chelators and dipeptidyl peptidase 4 inhibitors ("gliptins") as adjunct treatments for both COVID-19 and its neurodegenerative complications.