Post-exposure Treatment Research Articles

A stem-loop RNA RIG-I agonist protects against acute and chronic SARS-CoV-2 infection in mice.

As SARS-CoV-2 continues to cause morbidity and mortality around the world, there is an urgent need for the development of effective medical countermeasures. Here, we assessed the antiviral capacity of a minimal RIG-I agonist, stem-loop RNA 14 (SLR14), in viral control, disease prevention, post-infection therapy, and cross-variant protection in mouse models of SARS-CoV-2 infection. A single dose of SLR14 prevented viral infection in the lower respiratory tract and development of severe disease in a type I interferon (IFN-I)-dependent manner. SLR14 demonstrated remarkable prophylactic protective capacity against lethal SARS-CoV-2 infection and retained considerable efficacy as a therapeutic agent. In immunodeficient mice carrying chronic SARS-CoV-2 infection, SLR14 elicited near-sterilizing innate immunity in the absence of the adaptive immune system. In the context of infection with variants of concern (VOCs), SLR14 conferred broad protection against emerging VOCs. These findings demonstrate the therapeutic potential of SLR14 as a host-directed, broad-spectrum antiviral for early post-exposure treatment and treatment of chronically infected immunosuppressed patients.

HeberNasvac, a Therapeutic Vaccine for Chronic Hepatitis B, Stimulates Local and Systemic Markers of Innate Immunity: Potential Use in SARS-CoV-2 Postexposure Prophylaxis.

IntroductionMore than 180 million people have been infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and more than 4 million coronavirus disease-2019 (COVID-19) patients have died in 1.5 years of the pandemic. A novel therapeutic vaccine (NASVAC) has shown to be safe and to have immunomodulating and antiviral properties against chronic hepatitis B (CHB).Materials and methodsA phase I/II, open-label controlled and randomized clinical trial of NASVAC as a postexposure prophylaxis treatment was designed with the primary aim of assessing the local and systemic immunomodulatory effect of NASVAC in a cohort of suspected and SARS-CoV-2 risk-contact patients. A total of 46 patients, of both sexes, 60 years or older, presenting with symptoms of COVID-19 were enrolled in the study. Patients received NASVAC (100 μg per Ag per dose) via intranasal at days 1, 7, and 14 and sublingual, daily for 14 days.Results and discussionThe present study detected an increased expression of toll-like receptors (TLR)-related genes in nasopharyngeal tonsils, a relevant property considering these are surrogate markers of SARS protection in the mice model of lethal infection. The HLA-class II increased their expression in peripheral blood mononuclear cell's (PBMC's) monocytes and lymphocytes, which is an attractive property taking into account the functional impairment of innate immune cells from the periphery of COVID-19-infected subjects. NASVAC was safe and well tolerated by the patients with acute respiratory infections and evidenced a preliminary reduction in the number of days with symptoms that needs to be confirmed in larger studies.ConclusionsOur data justify the use of NASVAC as preemptive therapy or pre-/postexposure prophylaxis of SARS-CoV-2 and acute respiratory infections in general. The use of NASVAC or their active principles has potential as immunomodulatory prophylactic therapies in other antiviral settings like dengue as well as in malignancies like hepatocellular carcinoma where these markers have shown relation to disease progression.How to cite this articleFleites YA, Aguiar J, Cinza Z, et al. HeberNasvac, a Therapeutic Vaccine for Chronic Hepatitis B, Stimulates Local and Systemic Markers of Innate Immunity: Potential Use in SARS-CoV-2 Postexposure Prophylaxis. Euroasian J Hepato-Gastroenterol 2021;11(2):59–70.

Factors Influencing Hospital Cleaners’ Knowledge and Practices toward Hepatitis B prevention in Northern Province of Rwanda

This study aimed to assess factors influencing knowledge and practices of hospital cleaners towards hepatitis B prevention. This was a hospital-based cross-sectional study conducted at in Northern Province of Rwanda. A pretested self-administered questionnaire was used to gather data from study participants. A total of 134 cleaners were recruited in the study. Data were entered using Kobo collect toolbox and exported to Microsoft office excel for data cleaning and to entered in SPSS version 21 for analysis. Descriptive and logistic regression analysis was done and the significance level was 5%. More than a half of respondents were female (51.5%), and had primary level of education (54.5%). Results showed that only 9.7% of respondents had a high level of knowledge about HBV and only 2.2% had good practices on HBV practices. The odds of having high level of knowledge towards HBV prevention was 2.3 times (AOR=2.3, 95%CI: (1.1-27.3); p=0.045) among respondents with high school compared to those with no educational level. Respondents with work experience of 5-7 years were 1.5 times to have high level of knowledge towards HBV prevention than those with work experience of less than one year. Being aged between 20-30 years was associated with 2.5 times more likely to have good practices on HBV prevention than respondents aged less than 20 years. The odds of having good practice towards HBV had found to increase with work experience (AOR=2.3; 95%CI: (1.29-4.3); p=0.014). Considerable proportion of participants lacks the requisite knowledge of post-exposure treatment and prevention of HBV. Training programs on HBV infection, including PEP are highly recommended.

Application of a caprylate/chromatography purification process for production of a high potency rabies immune globulin from pooled human plasma

BackgroundHuman rabies immunoglobulin (RIG) is an integral part of post-exposure prophylactic treatment of rabies (along with rabies vaccination). Infiltration of most, if not all, of the RIG dose at the wound site is recommended. RIG produced by a caprylate/chromatography manufacturing process (RIG-C; HyperRAB) increased the potency and purity of this product over the existing licensed RIG from a solvent/detergent process (RIG-S/D; HyperRAB-S/D). MethodsA series of studies were conducted to characterize the content and purity of RIG-C. A single-dose pharmacokinetic study in rabbits was performed to compare intramuscular (IM) immunoglobulin products manufactured by two different purification processes, solvent/detergent (IGIM-S/D) and caprylate/chromatography (IGIM-C). ResultsRIG-C was found to be a highly purified IgG formulation with high monomer content and formulated with twice the anti-rabies potency of RIG-S/D while maintaining the same overall protein concentration. RIG-C facilitates IM administration at the wound site by halving the injection volume. The new caprylate/chromatography process eliminated detectible levels of pro-coagulant impurities and IgA that were carried through in the prior S/D process. These impurities have been associated with thrombotic complications and allergic reactions in susceptible patients. After single dose administration, IGIM-C was pharmacokinetically equivalent to IGIM-S/D in rabbits. ConclusionRIG-C is a more potent RIG formulation with less impurities yielding a safer and more convenient product with similar pharmacokinetic profile.

A Rabbit Model for the Evaluation of Drugs for Treating the Chronic Phase of Botulism.

Antitoxin, the only licensed drug therapy for botulism, neutralizes circulating botulinum neurotoxin (BoNT). However, antitoxin is no longer effective when a critical amount of BoNT has already entered its target nerve cells. The outcome is a chronic phase of botulism that is characterized by prolonged paralysis. In this stage, blocking toxin activity within cells by next-generation intraneuronal anti-botulinum drugs (INABDs) may shorten the chronic phase of the disease and accelerate recovery. However, there is a lack of adequate animal models that simulate the chronic phase of botulism for evaluating the efficacy of INABDs. Herein, we report the development of a rabbit model for the chronic phase of botulism, induced by intoxication with a sublethal dose of BoNT. Spirometry monitoring enabled us to detect deviations from normal respiration and to quantitatively define the time to symptom onset and disease duration. A 0.85 rabbit intramuscular median lethal dose of BoNT/A elicited the most consistent and prolonged disease duration (mean = 11.8 days, relative standard deviation = 27.9%) that still enabled spontaneous recovery. Post-exposure treatment with antitoxin at various time points significantly shortened the disease duration, providing a proof of concept that the new model is adequate for evaluating novel therapeutics for botulism.

Small-molecule polymerase inhibitor protects non-human primates from measles and reduces shedding

Measles virus (MeV) is a highly contagious pathogen that enters the human host via the respiratory route. Besides acute pathologies including fever, cough and the characteristic measles rash, the infection of lymphocytes leads to substantial immunosuppression that can exacerbate the outcome of infections with additional pathogens. Despite the availability of effective vaccine prophylaxis, measles outbreaks continue to occur worldwide. We demonstrate that prophylactic and post-exposure therapeutic treatment with an orally bioavailable small-molecule polymerase inhibitor, ERDRP-0519, prevents measles disease in squirrel monkeys (Saimiri sciureus). Treatment initiation at the onset of clinical signs reduced virus shedding, which may support outbreak control. Results show that this clinical candidate has the potential to alleviate clinical measles and augment measles virus eradication.

Polyclonal alpaca antibodies protect against hantavirus pulmonary syndrome in a lethal Syrian hamster model

The use of antibody-based therapies for the treatment of high consequence viral pathogens has gained interest over the last fifteen years. Here, we sought to evaluate the use of unique camelid-based IgG antibodies to prevent lethal hantavirus pulmonary syndrome (HPS) in Syrian hamsters. Using purified, polyclonal IgG antibodies generated in DNA-immunized alpacas, we demonstrate that post-exposure treatments reduced viral burdens and organ-specific pathology associated with lethal HPS. Antibody treated animals did not exhibit signs of disease and were completely protected. The unique structures and properties, particularly the reduced size, distinct paratope formation and increased solubility of camelid antibodies, in combination with this study support further pre-clinical evaluation of heavy-chain only antibodies for treatment of severe respiratory diseases, including HPS.

Efficacy and safety of hydroxychloroquine as pre-and post-exposure prophylaxis and treatment of COVID-19: A systematic review and meta-analysis of blinded, placebo-controlled, randomized clinical trials.

BackgroundHydroxychloroquine (HCQ) is an anti-malarial and immunomodulatory drug considered a potential candidate for drug repurposing in COVID-19 due to their in vitro antiviral activity against SARS-CoV-2. Despite the potential antiviral effects and anti-inflammatory profile, the results based on clinical studies are contradictory. Therefore, the quality of the decision-making process from meta-analyses summarizing the available evidence selecting studies with different designs and unblinded trials is limited. The aim of this study was to synthesize the best evidence on the efficacy and safety of HCQ as pre-and post-exposure prophylaxis and treatment of non-hospitalized and hospitalized patients with COVID-19.MethodsSearches were performed in PubMed, Web of Science, Embase, Lilacs, the website ClinicalTrials.gov and the preprint server medRxiv from January 1, 2020 to May 17, 2021. The following elements were used to define eligibility criteria: (1) Population: individuals at high-risk of exposure to SARS-CoV-2 (pre-exposure), individuals who had close contact with a positive or probable case of COVID-19 (post-exposure), non-hospitalized patients with COVID-19 and hospitalized patients with COVID-19; (2) Intervention: HCQ; (3) Comparison: placebo; (4) Outcomes: incidence of SARS-CoV-2 infection, need for hospitalization, length of hospital stay, need for invasive mechanical ventilation (MV), death, and adverse events; and (5) Study type: blinded, placebo-controlled, randomized clinical trials (RCTs). Risk of bias was judged according to the Cochrane guidelines for RCTs. Treatment effects were reported as relative risk (RR) for dichotomous variables and mean difference (MD) for continuous variables with 95% confidence intervals (CI). We used either a fixed or random-effects model to pool the results of individual studies depending on the presence of heterogeneity. The GRADE system was used to evaluate the strength of evidence between use of HCQ and the outcomes of interest.FindingsFourteen blinded, placebo-controlled RCTs were included in this meta-analysis. Four trials (1942 patients: HCQ = 1271; placebo = 671) used HCQ as a prophylactic medication pre-exposure to COVID-19, two (1650 patients: HCQ = 821; placebo = 829) as a prophylactic medication post-exposure to COVID-19, three (1018 patients: HCQ = 497; placebo = 521) as treatment for non-hospitalized patients, and five (1138 patients: HCQ = 572; placebo = 566) as treatment for hospitalized patients with COVID-19. We found no decreased risk of SARS-CoV-2 infection among individuals receiving HCQ as pre-exposure (RR = 0.90; 95% CI 0.46 to 1.77) or post-exposure (RR = 0.96; 95% CI 0.72 to 1.29) prophylaxis to prevent COVID-19. There was no significant decreased risk of hospitalization for outpatients with SARS-CoV-2 infection (RR = 0.64; 95% CI 0.33 to 1.23) and no decreased risk of MV (RR = 0.81; 95% CI 0.49 to 1.34) and death (RR = 1.05; 95% CI 0.62 to 1.78) among hospitalized patients with COVID-19 receiving HCQ. The certainty of the results on the lack of clinical benefit for HCQ was rated as moderate. Moreover, our results demonstrated an increased risk for any adverse events and gastrointestinal symptoms among those using HCQ.InterpretationAvailable evidence based on the results of blinded, placebo-controlled RCTs showed no clinical benefits of HCQ as pre-and post-exposure prophylaxis and treatment of non-hospitalized and hospitalized patients with COVID-19.FundingThere was no funding source.

Preventing hepatitis B virus infection among healthcare professionals: potential impact of a 2-dose versus 3-dose vaccine

ABSTRACT The exposure risk to the highly infectious hepatitis B virus (HBV) is an established and recognizable hazard to healthcare professionals (HCPs). In the United States, implementing preemptive vaccination programs and safety procedures resulted in drastic reductions in HBV infections among HCPs; however, many HCPs remain unprotected and risk of exposure persists, especially among those first entering a healthcare system and undergoing professional training. First-generation HBV vaccines require completion of a 3-dose schedule over a 6-month interval for maximum immunogenicity. By comparison, HepB-CpG (HEPLISAV-B®) is a 2-dose HBV vaccine licensed in the United States in 2017, inducing rapid seroprotection over a 1-month interval and may represent a more effective strategy for combating HBV infection in US healthcare systems. In this modeling study, the health and economic impact of implementing an HBV vaccination strategy with HepB-CpG versus the 3-dose HBV vaccine (Engerix-B®) was evaluated among HCPs newly entering a healthcare system. The model used effective seroprotection rate, a real-world metric accounting for HCP vaccine compliance and seroprotection rates for different dosing regimens and considered current pricing for postexposure prophylaxis treatment. Compared with the 3-dose vaccine, HepB-CpG was anticipated to provide faster, increased protection against HBV infection among newly entered HCPs. In protecting a greater percentage of HCPs, HepB-CpG was also projected to substantially reduce the risk of HBV exposure. Accordingly, an economic analysis showed HepB-CpG vaccination would reduce costs of postexposure prophylaxis treatment compared with the 3-dose vaccine. Overall, HepB-CpG represents an effective therapeutic strategy against HBV infection for US healthcare systems.

Epitope diversity of SARS-CoV-2 hyperimmune intravenous human immunoglobulins and neutralization of variants of concern

SummaryHyperimmune immunoglobulin (hCoV-2IG) generated from SARS-CoV-2 convalescent plasma (CP) are under evaluation in clinical trials. Here we explored the antibody epitope repertoire, and virus neutralizing capacity of six hCoV-2IG batches as well as nine CP against SARS-CoV-2 and emerging variants of concern (VOCs). Epitope-mapping by gene-fragment phage display library spanning the SARS-CoV-2 spike demonstrated broad recognition of multiple antigenic sites spanning the entire spike that was higher for hCoV-2IG than CP, with predominant binding to the fusion peptide. In the pseudovirus neutralization assay and in the wild-type SARS-CoV-2 PRNT assay, hCoV-2IG lots showed higher titers against the WA-1 strain compared with CP. Neutralization of VOCs were reduced to different extent by hCoV-2IG lots but were higher than CP. Significant reduction of hCoV-2IG binding was observed to RBD-E484K followed by RBD-N501Y (but not RBD-K417N). This study suggests that post-exposure treatment with hCoV-2IG could be preferable to CP.

Convalescent plasma therapy: A promising solution for SARS-CoV-2 outbreak

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has caused more than 18 million confirmed cases and 700000 deaths worldwide after the outbreak in November 2019 (COVID-19). It has been considered as most pathogenic infection under this category. Till date none of the therapeutics or prophylaxis measures have been claimed by any researcher which could cure the patient suffering from the SARS-CoV-2 infection. There is an urgent need for any alternative and effective way of disease management for COVID-19. However, convalescent plasma therapy (CPT) has gain attention of researchers with significant improvement of patient survival rate. Interestingly, there are numerous examples where CPT has proven its potential upon post-exposure prophylaxis and/or treatment in various diseases including COVID-19. This review summarizes the essential elements related to CPT, its past clinical evidences and application of CPT for the management of SARS-CoV-2 infection during COVID-19. We used the published literatures from PubMed, EMBASE and Medline databases until 31st May 2020.

SARS-CoV-2 Spike Protein Extrapolation for COVID Diagnosis and Vaccine Development.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) led to coronavirus disease 2019 (COVID-19) pandemic affecting nearly 71.2 million humans in more than 191 countries, with more than 1.6 million mortalities as of 12 December, 2020. The spike glycoprotein (S-protein), anchored onto the virus envelope, is the trimer of S-protein comprised of S1 and S2 domains which interacts with host cell receptors and facilitates virus-cell membrane fusion. The S1 domain comprises of a receptor binding domain (RBD) possessing an N-terminal domain and two subdomains (SD1 and SD2). Certain regions of S-protein of SARS-CoV-2 such as S2 domain and fragment of the RBD remain conserved despite the high selection pressure. These conserved regions of the S-protein are extrapolated as the potential target for developing molecular diagnostic techniques. Further, the S-protein acts as an antigenic target for different serological assay platforms for the diagnosis of COVID-19. Virus-specific IgM and IgG antibodies can be used to detect viral proteins in ELISA and lateral flow immunoassays. The S-protein of SARS-CoV-2 has very high sequence similarity to SARS-CoV-1, and the monoclonal antibodies (mAbs) against SARS-CoV-1 cross-react with S-protein of SARS-CoV-2 and neutralize its activity. Furthermore, in vitro studies have demonstrated that polyclonal antibodies targeted against the RBD of S-protein of SARS-CoV-1 can neutralize SARS-CoV-2 thus inhibiting its infectivity in permissive cell lines. Research on coronaviral S-proteins paves the way for the development of vaccines that may prevent SARS-CoV-2 infection and alleviate the current global coronavirus pandemic. However, specific neutralizing mAbs against SARS-CoV-2 are in clinical development. Therefore, neutralizing antibodies targeting SARS-CoV-2 S-protein are promising specific antiviral therapeutics for pre-and post-exposure prophylaxis and treatment of SARS-CoV-2 infection. We hereby review the approaches taken by researchers across the world to use spike gene and S-glycoprotein for the development of effective diagnostics, vaccines and therapeutics against SARA-CoV-2 infection the COVID-19 pandemic.

Memantine and Its Combination with Acetylcholinesterase Inhibitors in Pharmacological Pretreatment of Soman Poisoning in Mice.

Nerve agents pose a real threat to both the military and civil populations, but the current treatment of the poisoning is unsatisfactory. Thus, we studied the efficacy of prophylactic use of memantine alone or in combination with clinically used reversible acetylcholinesterase inhibitors (pyridostigmine, donepezil, rivastigmine) against soman. In addition, we tested their influence on post-exposure therapy consisting of atropine and asoxime. Pyridostigmine alone failed to decrease the acute toxicity of soman. But all clinically used acetylcholinesterase inhibitors administered alone reduced the acute toxicity, with donepezil showing the best efficacy. The combination of memantine with reversible acetylcholinesterase inhibitors attenuated soman acute toxicity significantly. The pretreatment administered alone or in combinations influenced the efficacy of post-exposure treatment in a similar fashion: (i) pyridostigmine or memantine alone did not affect the antidotal treatment, (ii) centrally acting reversible acetylcholinesterase inhibitors alone increased the antidotal treatment slightly, (iii) combination of memantine with reversible acetylcholinesterase inhibitors increased the antidotal treatment more markedly. In conclusion, memantine alone failed to decrease the acute toxicity of soman or increase post-exposure antidotal treatment efficacy. The combination of memantine with donepezil significantly increased post-exposure effectiveness (together 5.12, pretreatment alone 1.72). Both drugs, when applied together, mitigate soman toxicity and boost post-exposure treatment.

Beating the Bio-Terror Threat with Rapid Antimicrobial Susceptibility Testing.

A bioterror event using an infectious bacterium may lead to catastrophic outcomes involving morbidity and mortality as well as social and psychological stress. Moreover, a bioterror event using an antibiotic resistance engineered bacterial agent may raise additional concerns. Thus, preparedness is essential to preclude and control the dissemination of the bacterial agent as well as to appropriately and promptly treat potentially exposed individuals or patients. Rates of morbidity, death, and social anxiety can be drastically reduced if the rapid delivery of antimicrobial agents for post-exposure prophylaxis and treatment is initiated as soon as possible. Availability of rapid antibiotic susceptibility tests that may provide key recommendations to targeted antibiotic treatment is mandatory, yet, such tests are only at the development stage. In this review, we describe the recently published rapid antibiotic susceptibility tests implemented on bioterror bacterial agents and discuss their assimilation in clinical and environmental samples.

Epitope Diversity and SARS-CoV-2 Variants Neutralizing Capacity of SARS-CoV-2 Hyperimmune Intravenous Immunoglobulins for Treatment of COVID-19

Hyperimmune immunoglobulin (hCoV-2IG) preparations generated from SARS-CoV-2 convalescent plasma (CP) are under evaluation in several clinical trials of hospitalized COVID-19 patients. Here we explored the antibody epitope repertoire, antibody binding and virus neutralizing capacity of six hCoV-2IG batches as well as nine convalescent plasma (CP) lots against SARS-CoV-2 and emerging variants of concern (VOC). The Gene-Fragment Phage display library spanning the SARS-CoV-2 spike-based epitope-mapping demonstrated broad recognition of multiple antigenic sites spanning the entire spike including NTD, RBD, S1/S2 cleavage site, S2-fusion peptide and S2-heptad repeat regions. Antibody binding to the immunodominant epitopes was higher for hCoV-2IG than CP, with predominant binding to the fusion peptide. In the pseudovirus neutralization assay (PsVNA) and in the wild-type SARS-CoV-2 PRNT assay, hCoV-2IG lots showed higher titers against the WA-1 strain compared with CP. Neutralization of SARS-CoV-2 VOCs from around the globe were reduced to a different extent by hCoV-2IG lots. The most significant loss of neutralizing activity was seen against the B.1.351 (9-fold) followed by P.1 (3.5-fold), with minimal loss of activity against the B.1.17 and B.1.429 ( Funding: The research work described in this manuscript was supported by FDA Medical Countermeasures Initiative (MCMi) grant # OCET 2021-1565 and NIH-NIAID IAA #AAI20040. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Declaration of Interest: The authors declare no competing interests.Ethical Approval: This study was approved by Food and Drug Administration’s Research Involving Human Subjects Committee (RIHSC #2020-04-02). This study complied with all relevant ethical regulations for work with human participants, and informed consent was obtained. Samples were collected from patients who provided informed consent to participate in the study.

Pattern of Animal Bites and Post Exposure Prophylaxis for Rabies: An One Year Study in Bangladesh Institute of Tropical Infectious Disease (BITID) Chattogram

Background: Rabies is a global disease occurring in more then 150 countries including Bangladesh. It was neglected in Bangladesh before 2010 with more than 2000 annual rabies case. Number of rabies patients are declining in whole world due to more availability of resources needed for rabies prevention. In this background here our objective is to study the Post Exposure Prophylaxis (PEP) in rabies & to observe the pattern of animal bites in Bangladesh Institute of Tropical and Infectious Disease (BITID) which is a national institute dealing Tropical & Infectious disease of Bangladesh.
 Materials and methods: It was a retrospective study carried out among bite patients coming to BITID (Both outdoor & indoor) from 01.01.2017 to 31.12.2017 where a registry of all post exposure treatment was maintained. Total 1863 cases of animal bite patients came to BITID over the study period. The data were analyzed finally.
 Results: Among 1836 cases, 1185(63.66%) were male and 678 (34.44%) were female. 1155 cases (62%) belonged to >12 years of age and 708 (38%) cases belonged £12 years of age 815(43.74%) cases were category III bite. 1386 (74.4%) cases were bitten by dog & bites in 1110 (59.6%) cases occurred in lower limbs. Most patients 1138 cases (61.1%) came from rural areas & maximum bites occurred from March 2017 to September 2017.
 Conclusion: Animal bite is a great burden for Bangladesh. To prevent it we need public awareness, mass dog vaccination, street dog control and complete post exposure prophylaxis as per schedule given by national rabies elimination program of Bangladesh government.
 Chatt Maa Shi Hosp Med Coll J; Vol.20 (1); January 2021; Page 51-54

Trend and epidemiological patterns of animal bites in Golestan province (Northern Iran) between 2017 and 2020.

Rabies is one of the oldest zoonosis viral diseases, which still remains as one of the most important threats to public health in the 21st century. This cross-sectional study examined epidemiologic features of all 33,996 cases of persons bitten by animals and referred to the rabies prophylaxis centers in Golestan province between March 2017 and March 2020. Factors included demographic information of the victim (age, gender, and occupation), type of invasive animals (dog, cat, and other types), time of bite (year, month, and hour), place of residence (urban or rural), and injury and treatment statuses. We also obtained national and provincial animal bite incidence data for all of Iran and for Golestan province for the longer interval 2013-2020 to examine broader time trends. We used SPSS version 19, QGIS version 3.1, and Excel 2013 to generate frequency distributions and descriptive statistics. The incidence rates of animal bites in Golestan province and Iran as a whole both increased smoothly. The latest incidence rate of animal bites in Golestan was 652 per 100,000 people, almost three times the overall national figure for 2020. Most cases of animal bites (67.6%) occurred in rural areas, and 36% of the victims aged under 19 years old. Dog and cat bites accounted for the great majority of cases (89% and 8%, respectively). The highest rate of animal bites was reported in the spring (30.8%). The lower limb was the most commonly bitten area in these individuals (64.6%). Of note, 87% of the cases received incomplete prophylactic post-exposure treatment, and 18% received immunoglobulin. The increasing rates of animal bites in the study area as well as the higher rate compared to the national average indicates the need for further review of animal bite control programs.

Cell-Type Apoptosis in Lung during SARS-CoV-2 Infection.

The SARS-CoV-2 pandemic has inspired renewed interest in understanding the fundamental pathology of acute respiratory distress syndrome (ARDS) following infection. However, the pathogenesis of ARDS following SRAS-CoV-2 infection remains largely unknown. In the present study, we examined apoptosis in postmortem lung sections from COVID-19 patients and in lung tissues from a non-human primate model of SARS-CoV-2 infection, in a cell-type manner, including type 1 and 2 alveolar cells and vascular endothelial cells (ECs), macrophages, and T cells. Multiple-target immunofluorescence assays and Western blotting suggest both intrinsic and extrinsic apoptotic pathways are activated during SARS-CoV-2 infection. Furthermore, we observed that SARS-CoV-2 fails to induce apoptosis in human bronchial epithelial cells (i.e., BEAS2B cells) and primary human umbilical vein endothelial cells (HUVECs), which are refractory to SARS-CoV-2 infection. However, infection of co-cultured Vero cells and HUVECs or Vero cells and BEAS2B cells with SARS-CoV-2 induced apoptosis in both Vero cells and HUVECs/BEAS2B cells but did not alter the permissiveness of HUVECs or BEAS2B cells to the virus. Post-exposure treatment of the co-culture of Vero cells and HUVECs with a novel non-cyclic nucleotide small molecule EPAC1-specific activator reduced apoptosis in HUVECs. These findings may help to delineate a novel insight into the pathogenesis of ARDS following SARS-CoV-2 infection.

Toxicology of Blister Agents: Is Melatonin a Potential Therapeutic Option?

Blister or vesicant chemical warfare agents (CWAs) have been widely used in different military conflicts, including World War I and the Iran-Iraq War. However, their mechanism of action is not fully understood. Sulfur and nitrogen mustard exert toxic effects not only through the alkylation of thiol-bearing macromolecules, such as DNA and proteins, but also produce free radicals that can develop direct toxic effects in target organs such as the eyes, skin, and respiratory system. The lack of effective treatments against vesicant CWAs-induced injury makes us consider, in this complex scenario, the use and development of melatonin-based therapeutic strategies. This multifunctional indoleamine could facilitate neutralization of the oxidative stress, modulate the inflammatory response, and prevent the DNA damage, as well as the long-term health consequences mediated by vesicant CWAs-induced epigenetic mechanisms. In this context, it would be essential to develop new galenic formulations for the use of orally and/or topically applied melatonin for the prophylaxis against vesicant CWAs, as well as the development of post-exposure treatments in the near future.

The need to prioritise childhood tuberculosis case detection

The need to prioritise childhood tuberculosis case detection