Low iron mitigates viral survival: insights from evolution, genetics, and pandemics-a review of current hypothesis.

Background: Upon re-examination of our human history, evolutionary perspectives, and genetics, a prevailing iron deficiency phenotype appears to have evolved to protect the human race from extinction. Body: In this review, we summarize the evolutionary and genetic perspectives pointing towards the hypothesis that low iron mitigates infection. The presence of infection promotes the generation of resistance alleles, and there are some evolutionary and genetic clues that suggest the presence of an iron deficiency phenotype that may have developed to protect against infection. Examples include the relative paucity of iron overload genes given the essential role of iron, as well as the persistence of iron deficiency among populations in spite of public health efforts to treat it. Additional examination of geographic areas with severe iron deficiency in the setting of pandemics including H1N1, SARS, and COVID-19 reveals that areas with higher prevalence of iron deficiency are less affected. RNA viruses have several evolutionary adaptations which suggest their absolute need for iron, and this dependency may be exploited during treatment. Conclusion: RNA viruses pose a unique challenge to modern healthcare, with an average of 2-3 new pathogens being discovered yearly. Their overarching requirements for iron, along with human evolutionary and genetic adaptations which favored an iron deficiency phenotype, ultimately suggest the potential need for iron control in these infections.

More than meets the eye: a scoping review on the non-medical uses of THZ eye drops.

Tetrahydrozoline is an alpha agonist imidazole derivative found in over-the-counter decongestive eye and nasal drops. The drug was patented in 1954 and was available for medical use in 1959. This drug recently gained the attention of law enforcement as it has been utilized in criminal activity such as homicide and drug-facilitated sexual assault. The aim of this scoping review is to scope the literature for all mentions of tetrahydrozoline eye/nasal drops use in a non-medical context to delineate areas of future research and development. We used Google Scholar and PUBMED/Medline databases to search for non-medicinal and criminal uses of THZ. The search word used was "tetrahydrozoline." A total of 15 articles matched our criteria. Among the case reports, two (11.1%) cases reported on drug-facilitated sexual assault, and two (11.1%) cases used THZ eyedrops to attempt suicide. Incidental ingestion of THZ eyedrops was reported in eight (44.4%) cases, three (16.7%) cases of attempted murder were reported, two (11.1%) cases of intentional ingestion were reported, and one (5.5%) case was a combination of drug-facilitated sexual assault and attempted murder. The most common clinical presentation was unexplained and resistant bradycardia and hypotension. THZ eye drops can be used to produce false negative results on drug tests. This study recognizes that THZ can be used in non-medicinal and criminal uses. There is room for future research and development. More studies should be conducted to better understand the mechanism of action, therapeutic window, and toxicity levels among various age groups at different methods of intake and to find an effective treatment in case of overdose. Eyedrop and nasal decongestant bottles should be designed with child proofing to prevent incidental ingestion and should contain warning labels. A fast and alternative test to GC/MS can be developed to ease the diagnosis of THZ toxicity. Purchases of this medication may need to be monitored.

Brave Clarice-healthcare serial killers, patterns, motives, and solutions.

Healthcare serial killing involves the intentional killing of multiple patients by a healthcare professional. It is a formidable challenge to identify in the medical context, and a daunting legal task to prove beyond reasonable doubt. What can be done or remains to be done to intercept these serial killing events and help serve justice, while at the same time not risk dismantling public trust in the healthcare system? In light of several recent modern charges of murder against healthcare practitioners across the world, this review aims to report the themes, patterns, and motives of medical serial killers as well as highlight areas of work on both medical and legal fronts to help identify these events, and to most importantly protect the vulnerable patient community.

The role of miRNAs in viral myocarditis, and its possible implication in induction of mRNA-based COVID-19 vaccines-induced myocarditis.

Background: Several reports of unheeded complications secondary to the current mass international rollout of SARS-COV-2 vaccines, one of which is myocarditis occurring with the FDA fully approved vaccine, Pfizer, and others. Main body of the abstract: Certain miRNAs (non-coding RNA sequences) are involved in the pathogenesis in viral myocarditis, and those miRNAs are interestingly upregulated in severe COVID-19. We hypothesize that the use of mRNA-based vaccines may be triggering the release of host miRNAs or that trigger the occurrence of myocarditis. This is based on the finding of altered host miRNA expression promoting virus-induced myocarditis. Short conclusion: In conclusion, miRNAs are likely implicated in myocarditis associated with mRNA vaccines. Our hypothesis suggests the use of miRNA as a biomarker for the diagnosis of mRNA vaccine-induced myocarditis. Additionally, the interplay between viral miRNA and the host immune system could alter inflammatory profiles, hence suggesting the use of therapeutic inhibition to prevent such complications.

Contemporary approach to understand and manage COVID-19-related arrhythmia.

Arrhythmia, one of the most common complications of COVID-19, was reported in nearly one-third of diagnosed COVID-19 patients, with higher prevalence rate among ICU admitted patients. The underlying etiology for arrhythmia in these cases are mostly multifactorial as those patients may suffer from one or more of the following predisposing mechanisms; catecholamine surge, hypoxia, myocarditis, cytokine storm, QTc prolongation, electrolyte disturbance, and pro-arrhythmic drugs usage. Obviously, the risk for arrhythmia and the associated lethal outcome would rise dramatically among patients with preexisting cardiac disease such as myocardial ischemia, heart failure, cardiomyopathy, and hereditary arrhythmias. Considering all of these variables, the management strategy of COVID-19 patients should expand from managing a viral infection and related host immune response to include the prevention of predictable causes for arrhythmia. This may necessitate the need to investigate the role of some drugs that modulate the pathway of arrhythmia generation. Of these drugs, we discuss the potential role of adrenergic antagonists, trimetazidine, ranolazine, and the debatable angiotensin converting enzyme inhibitors drugs. We also recommend monitoring the level of: unbound free fatty acids, serum electrolytes, troponin, and QTc (even in the absence of apparent pro-arrhythmic drug use) as these may be the only indicators for patients at risk for arrhythmic complications.

Salivary markers and coronavirus disease 2019: insights from cross-talk between the oral microbiome and pulmonary and systemic low-grade inflammation and implications for vascular complications.

To date, coronavirus disease 2019 (COVID-19) has affected over 6.2 million individuals worldwide, including 1.46 million deaths. COVID-19 complications are mainly induced by low-grade inflammation-causing vascular degeneration. There is an increasing body of evidence that suggests that oral dysbiotic taxa are associated with worse prognosis in COVID-19 patients, especially the Prevotella genus, which was retrieved from nasopharyngeal and bronchoalveolar lavage samples in affected patients. Oral dysbiosis may act by increasing the likelihood of vascular complications through low-grade inflammation, as well as impairing respiratory mucosal barrier mechanisms against SARS-CoV-2. Salivary markers can be used to reflect this oral dysbiosis and its subsequent damaging effects on and the lungs and vasculature. Salivary sampling can be self-collected, and is less costly and less invasive, and thus may be a superior option to serum markers in risk stratification of COVID-19 patients. Prospective studies are needed to confirm such hypothesis. Video Abstract: http://links.lww.com/CAEN/A28.

Shedding light on vitamin D: the shared mechanistic and pathophysiological role between hypovitaminosis D and COVID-19 risk factors and complications.

Severe acute respiratory syndrome coronavirus (SARS-COV-2) is the culprit of the Coronavirus Disease (COVID-19), which has infected approximately 173 million people and killed more than 3.73 million. At risk groups including diabetic and obese patients are more vulnerable to COVID-19-related complications and poor outcomes. Substantial evidence points to hypovitaminosis D as a risk factor for severe disease, the need for ICU, and mortality. 1,25(OH)D, a key regulator of calcium homeostasis, is believed to have various immune-regulatory roles including; promoting anti-inflammatory cytokines, down regulating pro-inflammatory cytokines, dampening entry and replication of SARS-COV-2, and the production of antimicrobial peptides. In addition, there are strong connections which suggest that dysregulated 1,25(OH)D levels play a mechanistic and pathophysiologic role in several disease processes that are shared with COVID-19 including: diabetes, obesity, acute respiratory distress syndrome (ARDS), cytokine storm, and even hypercoagulable states. With evidence continuing to grow for the case that low vitamin D status is a risk factor for COVID-19 disease and poor outcomes, there is a need now to address the public health efforts set in place to minimize infection, such as lock down orders, which may have inadvertently increased hypovitaminosis D in the general population and those already at risk (elderly, obese, and disabled). Moreover, there is a need to address the implications of this evidence and how we may apply the use of cheaply available supplementation, which has yet to overcome the near global concern of hypovitaminosis D. In our review, we exhaustively scope these shared pathophysiologic connections between COVID-19 and hypovitaminosis D.

Blalock-Taussig Shunt versus Ductal Stent in the Palliation of Duct Dependent Pulmonary Circulation; A Systematic Review and Metanalysis.

In infants with ductal dependent pulmonary blood flow, Blalock-Taussig (BT) shunt and Patent Ductus Arteriosus (PDA) stent, are two palliative procedures aimed to restore circulation. A systematic review and metanalysis was performed on studies comparing PDA stents and BT shunts, in accordance with PRISMA guidelines. Meta-analysis revealed the following; (1) a reduced risk of mortality [RR = 0.585 [0.399-0.859], (P = 0.006)], (2) a reduced risk of complications [RR = 0.523 [0.318-0.860], (P = 0.011), and (3) a reduced risk of ECMO use [R = 0.267 [0.101-0.706] (P = 0.008)], all in the stent group. Additionally, stent group showed higher post procedure oxygen saturation [SMD = 1.307 [95% CI 1.065-1.550], (P < 0.001)], and Nakata index [SMD = 0.679 95% CI [0.513 to 0.845], (P < 0.001)]. PDA stenting presents a viable alternative to BT shunt procedure with better post procedure stability.

JAK out of the Box; The Rationale behind Janus Kinase Inhibitors in the COVID-19 setting, and their potential in obese and diabetic populations.

The adaptive use of Janus kinase (JAK)-inhibitors has been suggested by rheumatology experts in the management of COVID-19. We recount the rationale behind their use in this setting, and the current evidence for and against their use in this review. JAK-inhibitors role in COVID-19 infection appears to be multifaceted, including preventing viral endocytosis and dampening the effect of excessive chemokines. This drug class may be able to achieve these effects at already preapproved dosages. Concerns arise regarding reactivation of latent viral infections and the feasibility of their use in those with severe disease. Most interestingly, JAK-Inhibitors may also have an additional advantage for diabetic and obese populations, where the dysregulation of JAK-signal transducer and activator of transcription pathway may be responsible for their increased risk of poor outcomes. Targeting this pathway may provide a therapeutic advantage for these patient groups.

PPAR agonists as effective adjuvants for COVID-19 vaccines, by modifying immunogenetics: a review of literature.

BACKGROUND: Several coronavirus vaccine have been fast-tracked to halt the pandemic, the usage of immune adjuvants that can boost immunological memory has come up to the surface. This is particularly of importance in view of the rates of failure of seroconversion and re-infection after COVID-19 infection, which could make the vaccine role and response debatable. Peroxisome proliferator-activated receptors (PPARs) have an established immune-modulatory role, but their effects as adjuvants to vaccination have not been explored to date. It is increasingly recognized that PPAR agonists can upregulate the levels of anti-apoptotic factors such as MCL-1. Such effect can improve the results of vaccination by enhancing the longevity of long-lived plasma cells (LLPCs). The interaction between PPAR agonists and the immune system does not halt here, as T cell memory is also stimulated through enhanced T regulatory cells, antagonizing PD-L1 and switching the metabolism of T cells to fatty acid oxidation, which has a remarkable effect on the persistence of T memory cells. What is even of a more significant value is the effect of PPAR gamma on ensuring a profound secretion of antibodies upon re-exposure to the offending antigen through upregulating lipoxin B4, therefore potentially assisting the vaccine response and deterring re-infection. SHORT CONCLUSION: In view of the above, we suggest the use of PPAR as adjuvants to vaccines in general especially the emerging COVID-19 vaccine due to their role in enhancing immunologic memory through DNA-dependent mechanisms.

The potential use of lactate blockers for the prevention of COVID-19 worst outcome, insights from exercise immunology.

Following the decline in Physical Activity (PA) due to COVID-19 restrictions in the form of government mandated lockdowns and closures of public spaces, the modulatory effect of physical exercise on immunity is being heavily revisited. In an attempt to comprehend the wide discrepancy in patient response to COVID-19 and the factors that potentially modulate it, we summarize the findings relating PA to inflammation and immunity. A distinction is drawn between moderate intensity and high intensity physical exercise based on the high lactate production observed in the latter. We hypothesize that, the lactate production associated with high intensity anaerobic exercise is implicated in the modulation of several components of the innate and adaptive immunity. In this review, we also summarize these immunomodulatory effects of lactate. These include increasing serum IL-6 levels, the main mediator of cytokine storms, as well as affecting NK cells, Macrophages, Dendritic cells and cytotoxic T-lymphocytes. The implications of high lactate levels in athletic performance are highlighted where athletes should undergo endurance training to increase VO2 max and minimize lactate production. Tumor models of hypoxia were also reported where lactate levels are elevated leading to increased invasiveness and angiogenesis. Accordingly, the novel lactate blocking strategy employed in cancer treatment is evaluated for its potential benefit in COVID-19 in addition to the readily available beta-blockers as an antagonist to lactate. Finally, we suggest the diagnostic/prognostic purpose of the elevated lactate levels that can be determined through sweat lactate testing. It is the detrimental effect of lactate on immunity and its presence in sweat that qualify it to be used as a potential non-invasive marker of poor COVID-19 outcome.

The potential use of ABO blood group system for risk stratification of COVID-19.

ABO blood groups is a cheap and affordable test that can be immediately retrieved from COVID-19 patients at the diagnosis. There is increasing evidence that non-O blood groups have both higher susceptibility and higher severity of COVID-19 infections. The reason behind such relationship seems elusive. Regarding susceptibility, Non-O individuals have Anti-A antibodies which can prevent viral entry across ACE-2 receptors, moreover, Non-O individuals are at higher risk of autoimmunity, hypercoagulable state, and dysbiosis resulting in an augmented tendency for vascular inflammatory sequelae of COVID-19. We can conclude, on the diagnostic level, that ABO blood groups can be potentially used for risk stratification of affected COVID-19 patients, to anticipate the deterioration of patients at higher risk for complications. On a therapeutic level, plasma from normal O blood group individuals might potentially replace the use of convalescent serum for the treatment of COVID-19.

Obese communities among the best predictors of COVID-19-related deaths.

Coronavirus disease 2019 (COVID-19) is the largest outbreak to strike the world since the Spanish flu in 1918. Visual examination of the world map shows a wide variation of death tolls between countries. The main goal of our series is to determine the best predictors of such discrepancy. METHODS: This is a retrospective study in which the rate of COVID-19 deaths was correlated with each of the following independent variables: total tests per 1 million population, gross domestic product (GDP), average temperatures per country, ultraviolet index, median age, average BMI per country, food supply, Bacille Calmette-Guerin compulsory status, and passenger traffic. RESULTS: BMI per country proved to be the second best predictor of death rate with an R value of 0.43, and GDP being the best predictor with R = 0.65. CONCLUSION: This article shows a tight correlation between average BMI, food supply per country, and COVID-19-related deaths. Such predisposing factors might operate by upregulating the inflammation pathway in heavily struck countries, leading to easier triggering of the infamous cytokine storm syndrome. Obesity also increases cardiovascular and respiratory morbidities, which are coupled to increased ICU demand and deaths among infected cases.Video abstract: http://links.lww.com/CAEN/A25.