Monkeypox: Virology, Pathophysiology, Clinical Characteristics, Epidemiology, Vaccines, Diagnosis, and Treatments.

The World Health Organization, has declared the recent multiregional outbreak of monkeypox, a global public health emergency. Monkeypox is a zoonotic viral infection endemic to the west and central Africa. It belongs to the Poxviridae family, the Chordopoxvirinae subfamily, and the Orthopoxvirus genus. The Poxviridae family generally consists of complex, large, enveloped, and linear double-stranded DNA viruses. The initial clinical symptoms of monkeypox are often fever, severe headache, lymphadenopathy, myalgia, and fatigue. The skin lesions typically erupt within 1-3 days of the onset of fever. The rash tends to be more localized on the face and extremities than on the trunk. Monkeypox is often a self-limiting infection, and symptoms last from 2 to 4 weeks. It is isolated from various species, but the exact natural host is uncertain. Monkeypox is transmitted by close contact with infected humans or animals. Currently, no specific medication is available for monkeypox, and the existing therapeutics are the anti-viral agents approved for smallpox infection, including tecovirimat, cidofovir, and brincidofovir. Additionally, the U.S. Food and Drug Administration has approved Vaccinia Immune Globulin Intravenous for treating vaccination complications. It is diagnosed by PCR. There are currently two vaccines licensed by the U.S. Food and Drug Administration. According to the WHO guidance, the first-generation smallpox vaccines held in national reserves of some countries are not recommended as they do not meet the current safety and manufacturing standards. The interim guidance indicates that new and safer (second- and third generation) vaccines for smallpox, may be beneficial for monkeypox prevention, including JYNNEOS, which has been approved for the prevention of monkeypox. Human monkeypox was first reported in 1970. Since then, it has caused several outbreaks, mainly in central and west Africa. The first monkeypox outbreak outside of Africa occurred in the United States in 2003, linked to contact with infected pet prairie dogs. More recently (2018-2021), monkeypox cases have been reported in travelers from Nigeria to the United Kingdom, Israel, Singapore, and the US. Since May 2022, multiple monkeypox cases have been confirmed in several non-endemic countries, raising the concern of an emerging global pandemic. This review is an updated overview of our current state of knowledge regarding monkeypox virology, pathophysiology, clinical characteristics, epidemiology, vaccines, diagnosis, and treatment options.

The Effect of HIV/AIDS Infection on the Clinical Outcomes of COVID-19: A Meta-Analysis.

PURPOSE: Patients with HIV may be more likely to become severely ill from COVID-19. The present meta-analysis aims to determine the impact of HIV/AIDS infection on the clinical outcomes of COVID-19. METHODS: A comprehensive literature search was performed to identify relevant cohort studies to evaluate the association of HIV/AIDS infection with clinical outcomes of COVID-19. International databases, including PubMed (Medline), Web of Sciences, Scopus, and Embase, were searched from the emergence of the COVID-19 pandemic until January 2022. We utilized the risk ratio (RR) with its 95% confidence interval (95% CI) to quantify the effect of cohort studies. RESULTS: Twelve cohort studies were included in this meta-analysis, which examined a total number of 17,786,384 patients. Among them, 40,386 were identified to be HIV positive, and 17,745,998 were HIV negative. The pooled analyses showed HIV positive patients who were co-infected with SARS-CoV-2 were 58% more likely to develop a fever (RR=1.58; 95% CI: 1.42, 1.75), 24% more likely to have dyspnea (RR=1.24; 95% CI: 1.08, 1.41), 45% more likely to be admitted to ICU (RR=1.45; 95% CI: 1.26, 1.67), and 37% more likely to die from to COVID-19 (RR=1.37; 95% CI: 1.30, 1.45) than HIV negative patients. CONCLUSION: HIV/AIDS coinfection with COVID 19 increased the risk of fever, dyspnea, ICU admission, and mortality.

Anti-Inflammatory Properties of Drugs Used to Control COVID-19 and their Effects on the Renin-Angiotensin System and Angiotensin-Converting Enzyme-2.

COVID-19 infection is associated with systemic inflammation, and sometimes hyperinflammatory responses with cytokine storm. This plays a major role in COVID-19 severity and poor disease prognosis, even death. Higher levels of inflammatory hallmarks including C-reactive protein, ferritin, D-dimers, and cytokines such as interleukin (IL) -6, IL-10 and tumor necrosis factor- α (TNF-α) have been reported. Many anti-viral drugs have been tried, but none were proven fully effective. Supportive care and management of the complications that are caused mainly by inflammation might be the key to greater survival rates and shorter hospitalization (e.g., the use of remdesivir, lopinavir, ritonavir, umifenovir (arbidol), oseltamivir, ganciclovir, favipiravir, darunavir, hydroxychloroquine, chloroquine, colchicine, azithromycin, anakinra, canakinumab, tocilizumab, siltuximab, sarilumab, Type 1 interferon, interferon ß-1a, interferon α- 2b, baricitinib, ruxolitinib, fedratinib, methylprednisolone and dexamethasone). However, the efficacy of these treatments still needs well-planned clinical trials. In such trials, careful attention must be paid to the duration of the treatment, the onset of beneficial effects, and the severity of the disease, otherwise, the outcomes may still remain inconclusive. Herein, we present a review of the current drugs, which are being used in the management of the disease and their anti-inflammatory properties. We also investigated if these drugs directly interact with Angiotensin-Converting Enzyme (ACE 2), which is a crucial component of the virus entry to the cells.

Calcitriol Reverses Induced Expression of Efflux Proteins and Potentiates Cytotoxic Activity of Gemcitabine in Capan-2 Pancreatic Cancer Cells.

PURPOSE: Efflux and influx proteins play a major role in chemo-resistance by affecting the net cellular uptake of anti-cancer drugs. Hence, alteration of the efflux and influx protein expression may result in variations of chemotherapeutics uptake and consequently cell death rate. The present study investigated the effects of pre-treatment of capan-2 pancreatic cancer cells with calcitriol, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA) or silibinin on the induction of three major efflux proteins and the main gemcitabine influx protein. The influence of the pre-treatments on the net cellular uptake of gemcitabine, total ATPase activity, and cell death rate were also evaluated. METHODS: Capan-2 pancreatic cancer cells were pre-treated for 24 h with calcitriol, BHT, BHA, or silibinin, followed by gemcitabine treatment. The concentration of gemcitabine was quantified using ultra-performance liquid chromatography (UPLC). Real-time polymerase chain reaction (RT-PCR) was utilized in order to investigate the expression of the mRNAs. The expression of the proteins was assessed using western blotting. Measurement of the ATPase activity was conducted utilizing a colorimetric method and viability of the cells was determined using a luminescent cell viability assay. RESULTS: Protein expression studies showed that BHT, silibinin, and BHA increased expression of the efflux proteins and decreased the overall uptake of gemcitabine, whereas calcitriol significantly inhibited expression of the efflux proteins and increased gemcitabine uptake. Expression of specific mRNAs correlated reasonably well with the levels of corresponding proteins. Additionally, the expression of efflux proteins and ATPase activity were well correlated, signifying that the induced efflux proteins are functionally active. Moreover, pre-treatment with calcitriol resulted in a significant increase in cell death with gemcitabine treatment, whereas, BHA significantly reduced the cell death rate. On the other hand, pre-treatment with BHT and silibinin had no significant effect on the cell death rate. CONCLUSIONS: Pre-treatment of the pancreatic cancer cells with calcitriol significantly increased gemcitabine cellular uptake and consequently decreased cell viability after treatment with gemcitabine, whereas BHA significantly reduced gemcitabine uptake and decreased cell death rate, which were at least partially attributed to the alteration of expression of efflux and influx proteins. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Synthesis and characterization of a new Peptide prodrug of glucosamine with enhanced gut permeability.

The aim of this study was to synthesize a peptide prodrug of glucosamine (GlcN) with increased gut permeability through the gut peptide transporter 1 (PepT1). Glycine-Valine ester derivative of GlcN (GVG) was synthesised using solid phase synthesis followed by characterization and evaluation of its physicochemical and intestinal stability. In addition, GVG was evaluated for its ability to be biotransformed to GlcN in the liver homogenate. In vitro absorption of the new prodrug through everted rat gut was also assessed. GVG demonstrated significant and meaningful increased gut permeability as compared with GlcN. It showed favorable stability in the gut and a quick cleavage to GlcN after exposure to the liver homogenate. In conclusion, a novel prodrug of glucosamine with superior gut permeability compared to GlcN was developed and successfully tested in vitro.