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.

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.

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.

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.

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.

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.

Revisiting the pathogenic role of insulin resistance in Duchenne muscular dystrophy cardiomyopathy subphenotypes.

INTRODUCTION: Duchenne muscular dystrophy (DMD) is known to impact the subepicardial layer of the myocardium through chronic inflammation. Recent animal studies have shown predominant subendocardial involvement in rats with DMD. The primary outcome parameter was to determine by cardiovascular MRI (CMR) if two differential patterns of myocardial involvements exist in DMD; the secondary outcome parameters were to correlate the observed pattern with metabolic markers such as insulin resistance measures. METHODS: Forty patients with DMD were screened using CMR to determine which of them had predominantly subendocardial dysfunction (SENDO group), or subepicardial/midmyocardial involvement (SEPMI group). Patients were subjected to body mass index measurement, serum creatinine kinase, serum lactate dehydrogenase enzyme, fasting glucose-insulin ratio (FGIR), full lipid profile, left ventricular ejection fraction (LVEF), left ventricle E/E´ ratio (the ratio of early mitral inflow velocity to average early diastolic velocities of the basal septum and mitral annulus) for left ventricle diastolic function, and myocardial layer strain discriminating echocardiography (MLSD-STE). Results: 26 patients displayed SENDO while 34 displayed SEPMI. SENDO group displayed overt insulin resistance; (FGIR (SENDO: 7 ± 1 vs. SEPMI: 5 ± 1, P < 0.001). FGIR was negatively correlated with Subendocardial Global Longitudinal Strain (ENDO-LS) with r = -0.75. CONCLUSION: DMD does not seem to influence the heart uniformly; DMD cardiomyopathy probably has two separate phenotypes with different mechanisms. Insulin resistance might be implicated in its pathogenesis and its reversal may help to slow disease progression.

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.

Single cell sequencing unraveling genetic basis of severe COVID19 in obesity.

COVID-19 has shown a substantial variation in the rate and severity by which it impacts different demographic groups. Specifically, it has shown a predilection towards obese patients as well as well as other vulnerable groups including predilection of males over females, old age over young age and black races over Caucasian ones. Single cell sequencing studies have highlighted the role of cell polarity and the co-expression of proteases, such as Furin, along with ACE2 in the genesis of coronavirus disease rather than exclusively link tissue involvement with ACE2 levels thought previously. It has also forged a connection between the genetic and immune cellular mechanisms underlying COVID infection and the inflammatory state of obese patients, offering a more accurate explanation as to why obese patients are at increased risk of poor COVID outcomes. These commonalities encompass macrophage phenotype switching, genetic expression switching, and overexpression of the pro-inflammatory cytokines, depletion of the regulatory cytokines, in situ T cell proliferation, and T cell exhaustion. These findings demonstrate the necessity of single cell sequencing as a rapid means to identify and treat those who are most likely to need hospital admission and intensive care, in the hopes of precision medicine. Furthermore, this study underlines the use of immune modulators such as Leptin sensitizers, rather than immune suppressors as anti-inflammation therapies to switch the inflammatory response from a drastic immunological type 1 response to a beneficial type 2 effective one.

A multicenter consensus: A role of furin in the endothelial tropism in obese patients with COVID-19 infection.

Furin, a cleavage enzyme, is increasingly recognized in the pathogenesis of metabolic syndrome. Its cleavage action is an essential activation step for the endothelial pathogenicity of several viruses including SARS-CoV-2. This Furin-mediated endothelial tropism seems to underlie the multi-organ system involvement of COVID-19; which is a feature that was not recognized in the older versions of coronaviridae. Obese and diabetic patients, males, and the elderly, have increased serum levels of Furin, with its increased cellular activity; this might explain why these subgroups are at an increased risk of COVID-19 related complications and deaths. In contrast, smoking decreases cellular levels of Furin, this finding may be at the origin of the decreased severity of COVID-19 in smokers. Chinese herbal derived luteolin is suggested to be putative Furin inhibitor, with previous success against Dengue Fever. Additionally, Furin intracellular levels are largely dependent on concentration of intracellular ions, notably sodium, potassium, and magnesium. Consequently, the use of ion channel inhibitors, such as Calcium Channel blockers or Potassium Channel blockers, can prevent cellular transfection early in the course of the illness. Nicotine patches and Colchicine have also been suggested as potential therapies due to Furin mediated inhibition of COVID-19.

Is it infection or rather vascular inflammation? Game-changer insights and recommendations from patterns of multi-organ involvement and affected subgroups in COVID-19.

Coronavirus disease 2019 (COVID-19) is a serious illness that has rapidly spread throughout the globe. The seriousness of complications puts significant pressures on hospital resources, especially the availability of ICU and ventilators. Current evidence suggests that COVID-19 pathogenesis majorly involves microvascular injury induced by hypercytokinemia, namely interleukin 6 (IL-6). We recount the suggested inflammatory pathway for COVID-19 and its effects on various organ systems, including respiratory, cardiac, hematologic, reproductive, and nervous organ systems, as well examine the role of hypercytokinemia in the at-risk geriatric and obesity subgroups with upregulated cytokines' profile. In view of these findings, we strongly encourage the conduction of prospective studies to determine the baseline levels of IL-6 in infected patients, which can predict a negative outcome in COVID-19 cases, with subsequent early administration of IL-6 inhibitors, to decrease the need for ICU admission and the pressure on healthcare systems. Video abstract: http://links.lww.com/CAEN/A24.

Collector Channels: Role and Evaluation in Schlemm's Canal Surgery.

OBJECTIVES: 1) To elucidate the role of collector channels in the aqueous humor outflow pathway 2) To suggest anatomic and functional methods of imaging collector channels in-vitro and in-vivo and 3) To discuss the role of such imaging modalities in the surgical management of glaucoma. METHODS: A thorough literature search was conducted on databases for studies published in English regarding the available methods to determine the role of collecting channels in normal and glaucomatous patients and to assess their patency. RESULTS: Intraocular pressure (IOP) exists as a balance between aqueous humor production and aqueous humor outflow. Collector channels are an essential anatomical constituent of the distal portion of the conventional aqueous humor outflow pathway. There are different surgical options for glaucoma management and with the recent advances in Schlemm's canal-based surgeries, collector channel's patency became a key factor in determining the optimum management for the glaucomatous eye. The advent of anatomic imaging methods has improved the ability to visualize collector channel morphology in-vitro, including swept-source optical coherence tomography (SS-OCT), spectral domain optical coherence tomography (SD-OCT), micro-computed tomography (micro CT), new immunohistochemistry techniques and scanning electron microscopy. The recent advent of real-time assessment of collector channel patency (including evaluation of episcleral venous outflow, observation of episcleral venous fluid wave, and tracer studies utilizing fluorescein, indocyanine green, and trypan blue) has been validated by the aforementioned anatomic imaging modalities. CONCLUSIONS: New modalities of in-vitro and in-vivo studies of collector channels provide promise to aid in the assessment of collector channel patency and individualization of surgical management for glaucoma patients.

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.