The global patent landscape of emerging infectious disease monkeypox.

BACKGROUND: Monkeypox is an emerging infectious disease with confirmed cases and deaths in several parts of the world. In light of this crisis, this study aims to analyze the global knowledge pattern of monkeypox-related patents and explore current trends and future technical directions in the medical development of monkeypox to inform research and policy. METHODS: A comprehensive study of 1,791 monkeypox-related patents worldwide was conducted using the Derwent patent database by descriptive statistics, social network method and linear regression analysis. RESULTS: Since the 21st century, the number of monkeypox-related patents has increased rapidly, accompanied by increases in collaboration between commercial and academic patentees. Enterprises contributed the most in patent quantity, whereas the initial milestone patent was filed by academia. The core developments of technology related to the monkeypox include biological and chemical medicine. The innovations of vaccines and virus testing lack sufficient patent support in portfolios. CONCLUSIONS: Monkeypox-related therapeutic innovation is geographically limited with strong international intellectual property right barriers though it has increased rapidly in recent years. The transparent licensing of patent knowledge is driven by the merger and acquisition model, and the venture capital, intellectual property and contract research organization model. Currently, the patent thicket phenomenon in the monkeypox field may slow the progress of efforts to combat monkeypox. Enterprises should pay more attention to the sharing of technical knowledge, make full use of drug repurposing strategies, and promote innovation of monkeypox-related technology in hotspots of antivirals (such as tecovirimat, cidofovir, brincidofovir), vaccines (JYNNEOS, ACAM2000), herbal medicine and gene therapy.

Rapid and highly potent humoral responses to mpox nanovaccine candidates adjuvanted by thermostable scaffolds.

Monkeypox (mpox) is a zoonotic disease caused by monkeypox virus (MPXV) of the orthopoxvirus genus. The emergence and global spread of mpox in 2022 was declared as a public health emergency by World Health Organization. This mpox pandemic alarmed us that mpox still threaten global public health. Live vaccines could be used for immunization for this disease with side effects. New alternative vaccines are urgently needed for this re-emerging disease. Specific antibody responses play key roles for protection against MPXV, therefore, vaccines that induce high humoral immunity will be ideal candidates. In the present study, we developed thermostable nanovaccine candidates for mpox by conjugating MPXV antigens with thermostable nanoscafolds. Three MPXV protective antigens, L1, A29, and A33, and the thermostable Aquafex aeolicus lumazine synthase (AaLS), were expressed in E. coli and purified by Ni-NTA methods. The nanovaccines were generated by conjugation of the antigens with AaLS. Thermal stability test results showed that the nanovaccines remained unchanged after one week storage under 37℃ and only partial degradation under 60℃, indicating high thermostability. Very interesting, one dose immunization with the nanovaccine could induce high potent antibody responses, and two dose induced 2-month high titers of antibodes. In vitro virus neutralization test showed that nanovaccine candidates induced significantly higher levels of neutralization antibodies than monomers. These results indicated that the AaLS conjugation nanovaccines of MPXV antigens are highly thermostable in terms of storage and antigenic, being good alternative vaccine candidates for this re-emerging disease.

Mpox Management: A Holistic Local Response to a Global Threat.

Newly formed local public health units in Victoria have been established to support a place-based approach that tailors and delivers public health initiatives and responds to public health incidents and issues. Initially, post-establishment of these units, public health activities focused on the prevention and control of communicable diseases. In 2022, mpox emerged as a global public health threat. As case numbers rose across Australia, local public health units in Victoria were engaged by the Department of Health to support a localized response to this new threat. The South East Public Health Unit, Monash Health, developed a number of targeted initiatives to control the local spread of mpox, ranging from capacity building of health professionals to increase early diagnosis, contact tracing, facilitating vaccine delivery, and community engagement. This contributed to effective local elimination within 6 months, demonstrating how LPHUs are well placed to engage with local communities and health care providers to respond rapidly to newly emerging public health threats.

Comprehensive overview of 2022 human monkeypox outbreak and its pathology, prevention, and treatment: A strategy for disease control.

The 2022 Monkeypox virus, an evolved DNA strain originating in Africa, exhibits heightened human-to-human transmissibility and potential animal transmission. Its host remains unidentified. While its initial slow transmission rate restrained global impact, 2022 saw a surge in cases, causing widespread concern in over 103 countries by September. This virus's distinctive human-to-human transmission marks a crucial shift, demanding a prompt revaluation of containment strategies. However, the host source for this shift requires urgent research attention. Regrettably, no universal preventive or curative methods have emerged for this evolved virus. Repurposed from smallpox vaccines, only some vaccinations offer a partial defense. Solely one therapeutic drug is available. The article's essence is to provide a comprehensive grasp of the virus's epidemiology, morphology, immune invasion mechanisms, and existing preventive and treatment measures. This knowledge equips researchers to devise strategies against its spread and potential public health implications.

Screening potential treatments for mpox from Traditional Chinese Medicine by using a data-driven approach.

Mpox (MPX) has escalated into a public health emergency of international concern, necessitating urgent prophylactic and therapeutic measures. The primary goal of this investigation was to systematically extract Wan Quan's expertise in treating smallpox, as documented in Exclusive Methods for Treating Pox (Dou Zhen Xin Fa in Chinese), with the aim of identifying potential prescriptions, herbs, and components for alternative MPX therapies or drugs. This research utilized data mining to identify high-frequency Chinese Medicines (CMs), high-frequency CM-pairs, and CM compatibility rules. Network pharmacology, molecular docking, and molecular dynamic simulation were employed to reveal the potential molecular mechanisms of the core CM-pair. 119 prescriptions were extracted from Exclusive Methods for Treating Pox. We identified 25 high-frequency CMs and 23 high-frequency CM pairs among these prescriptions. Combined association rule mining analysis, Gancao (Glycyrrhiza uralensis Fisch.), Renshen (Panax ginseng C. A. Mey.), Danggui (Angelica sinensis (Oliv.) Diels), Shengma (Cimicifuga foetida L.), and Zicao (Lithospermum erythrorhizon Siebold & Zucc.) were selected as the core CM-pair for further investigation. Network pharmacology analysis yielded 131 active components and 348 candidate targets for the core CM-pair. Quercetin and celabenzine were chosen as ligands for molecular docking. GO and KEGG enrichment analyses revealed that the core CM-pair could interact with targets involved in immune, inflammatory, and infectious diseases. Moreover, key mpox virus targets, F8-A22-E4 DNA polymerase holoenzyme and profilin-like protein A42R, were docked well with the selected core components. And molecular dynamic simulation indicated that the component (quercetin) could stably bind to the target (profilin-like protein A42R). Our findings identified potential prescriptions, herbs, and components that can offer potential therapies or drugs for addressing the MPX epidemic.

Adjuvant Topical Interferon Alpha 2b for the Treatment of Monkeypox Ocular Manifestations.

PURPOSE: The aim of this study was to report a case of ocular Mpox that responded favorably to treatment with topical interferon and oral doxycycline. METHODS: This is a case report of a previously healthy 24-year-old woman who developed a pustular rash, headache, fever, arthralgia, sore throat, and asthenia 3 weeks before attending to our clinic. Her main complaint at the moment of the visit was pain, photophobia, foreign body sensation, blurred vision, red eye, and discharge on the left eye. The slit-lamp examination of the left eye showed severe conjunctival hyperemia associated with tarsal follicles, 360 degrees ciliary injection, diffuse corneal epithelial edema with white linear epithelial infiltrates, pigmented and nonpigmented keratic precipitates, and two 1-mm peripheral corneal ulcers with white infiltrates, associated with positive fluorescein staining. Anterior chamber cellularity and flare were mildly present. RESULTS: Mpox with ocular manifestations diagnosis was confirmed by real-time quantitative reverse transcription polymerase chain reaction assay (qRT-PCR) testing; samples were taken from corneal, conjunctival, and nasopharynx swab as well as a skin scab. Topical interferon alpha 2b 1 MIU/mL every 6 hours for 1 month and oral doxycycline 100 mg BID were administered along with other medications with consequent decrease of inflammation and malaise symptoms 1 week later, associated with uncorrected visual acuity improvement. CONCLUSIONS: Alternative and efficacious treatment options for Mpox ocular manifestations are needed to prevent further disease progression and sequelae in countries with no access to the gold-standard therapy. Topical interferon alpha 2b and oral doxycycline have shown adequate response as shown with this patient.

Human skin-on-a-chip for mpox pathogenesis studies and preclinical drug evaluation.

Timely intervention of preventative and therapeutic measures abated a 2022 mpox global outbreak. However, the high transmissibility and unique pathological characteristics of mpox demand further investigation. Here, we discuss the potentials of human skin-on-a-chip as a valuable model for mpox disease evaluation, to achieve in-depth physiological understanding and desirable therapeutic predictive capabilities.

Natural photosensitizers potentiate the targeted antimicrobial photodynamic therapy as the Monkeypox virus entry inhibitors: An in silico approach.

BACKGROUND: Monkeypox is a viral zoonotic disease that has emerged as a threat to public health. Currently, there is no treatment approved specifically targeting Monkeypox disease. Hence, it is essential to identify and develop therapeutic approaches to the Monkeypox virus. In the current in silico paper, we comprehensively involve using computer simulations and modeling to insights and predict hypotheses on the potential of natural photosensitizers-mediated targeted antimicrobial photodynamic therapy (aPDT) against D8L as a Monkeypox virus protein involved in viral cell entry. MATERIALS AND METHODS: In the current study, computational techniques such as molecular docking were combined with in silico ADMET predictions to examine how Curcumin (Cur), Quercetin (Qct), and Riboflavin (Rib) as the natural photosensitizers bind to the D8L protein in Monkeypox virus, as well as to determine pharmacokinetic properties of these photosensitizers. RESULTS: The three-dimensional structure of the D8L protein in the Monkeypox virus was constructed using homology modeling (PDB ID: 4E9O). According to the physicochemical properties and functional characterization, 4E9O was a stable protein with the nature of a hydrophilic structure. The docking studies employing a three-dimensional model of 4E9O with natural photosensitizers exhibited good binding affinity. D8L protein illustrated the best docking score (-7.6 kcal/mol) in relation to the Rib and displayed good docking scores in relation to the Cur (-7.0 kcal/mol) and Qct (-7.5 kcal/mol). CONCLUSIONS: The findings revealed that all three photosensitizers were found to obey the criteria of Lipinski's rule of five and displayed drug-likeness. Moreover, all the tested photosensitizers were found to be non-hepatotoxic and non-cytotoxic. In summary, our investigation identified Cur, Qct, and Rib could efficiently interact with D8L protein with a strong binding affinity. It can be concluded that aPDT using these natural photosensitizers may be considered an adjuvant treatment against Monkeypox disease.

Network pharmacology and bioinformatics to identify molecular mechanisms and therapeutic targets of Ruyi Jinhuang Powder in the treatment of monkeypox.

Monkeypox outbreaks across the globe has aroused widespread concern. Ruyi Jinhuang Powder (RJP), a common formula in Chinese medicine, is used to treat pox-like illnesses. This study aimed to identify the molecular mechanisms and therapeutic targets of RJP for the treatment of monkeypox using network pharmacology and bioinformatics techniques. The bioactive substances and potential targets of each component of RJP were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). The differentially expressed genes (DEGs) of the monkeypox virus (MPXV) were identified from the GSE24125 by GEO2R. Key signaling pathways, bioactive components, and potential targets were obtained by bioinformatics analysis, including gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), disease ontology (DO), and protein-protein interactions (PPI) analyses. Finally, molecular docking was used to predict the interaction between active compounds and core targets. A total of 158 active ingredients and 17 drug-disease-shared targets of RJP were screened. Bioinformatics indicated that wogonin and quercetin might be potential drug candidates. Potential therapeutic targets were identified. Immune-related mechanisms that exerted antiviral effects included signaling pathways like TNF, age-rage, and c-type lectin receptor pathways. Our results illustrated the good therapeutic effect of RJP on monkeypox in terms of biological activity, potential targets, and molecular mechanism. This also offered a promising strategy to reveal the scientific basis and therapeutic mechanism of herbal formulas used to treat the disease.

Comparison of human monkeypox, chickenpox and smallpox: a comprehensive review of pathology and dermatological manifestations.

Variola virus, the causing agent of smallpox, was eradicated in 1980s and today no new cases are reported. The first human infectious illness to be eliminated globally is variola. On the contrary to Variola, monkeypox, which is a zoonotic and variola-like disease, has nowadays turned to be a major health problem worldwide. VZV is a neurotropic virus and the cause of varicella (chickenpox) and herpes zoster (shingles), which is also a highly infectious disease, especially prevalent in children. These three skin diseases-monkeypox, smallpox, and chickenpox-are frequently mistaken with one another due to similar manifestations including fever, rash, myalgia, chills and headache, but they can all be distinguished by their distinctive symptoms. Although these rash-causing disorders might present different skin lesions; diagnostic tests can be extremely useful in their differentiation. We searched for these concepts on a search engine like Google Scholar, scanning the results for alternative words and phrases, and examined relevant abstracts or articles for alternative words. The clinical diagnosis of monkeypox infection is commonly made based on the occurrence pattern of its skin rash. It is possible in varicella to concurrently identify lesions in their various stages including macular, papular, vesicular, pustular, and crusts; however, monkeypox lesions are all in the same stage and evolve with the same rate. In this review, we have tried to provide a holistic and comprehensive comparison between these three skin infections with a focus on the newly epidemic monkeypox, bringing about the most recent knowledge about its features and its diagnosis.

An overview on monkeypox virus: Pathogenesis, transmission, host interaction and therapeutics.

Orthopoxvirus is one of the most notorious genus amongst the Poxviridae family. Monkeypox (MP) is a zoonotic disease that has been spreading throughout Africa. The spread is global, and incidence rates are increasing daily. The spread of the virus is rapid due to human-to-human and animals-to-human transmission. World Health Organization (WHO) has declared monkeypox virus (MPV) as a global health emergency. Since treatment options are limited, it is essential to know the modes of transmission and symptoms to stop disease spread. The information from host-virus interactions revealed significantly expressed genes that are important for the progression of the MP infection. In this review, we highlighted the MP virus structure, transmission modes, and available therapeutic options. Furthermore, this review provides insights for the scientific community to extend their research work in this field.

Virtual screening and computational simulation analysis of antimicrobial photodynamic therapy using propolis-benzofuran A to control of Monkeypox.

BACKGROUND: Monkeypox is a viral zoonotic disease and there are no available treatments that specifically target the monkeypox virus. Antimicrobial photodynamic therapy (aPDT) is a non-invasive approach that has been introduced as a targeted adjuvant treatment against various microbial infections. In this study, we used a computational strategy to investigate the potential of aPDT using propolis-benzofuran A against the Monkeypox virus. METHODS: In this in silico study, the evaluation of drug-likeness, molecular properties, and bioactivity of propolis-benzofuran A was carried out using SwissADME. Pro-Tox II and OSIRIS servers were used to identify the organ toxicities and toxicological endpoints of propolis-benzofuran A. Molecular docking approach was employed to screen the potential binding modes of propolis-benzofuran A ligand with the Monkeypox virus A48R protein (PDB ID: 2V54). RESULTS: The results of the computational investigation revealed that propolis-benzofuran A obeyed all the criteria of Lipinski's rule of five and exhibited drug-likeness. The photosensitizing agent tested was categorized as toxicity class-5 and was found to be non-hepatotoxic, non-carcinogenic, non-mutagenic, and non-cytotoxic. The docking studies employing a predicted three-dimensional model of Monkeypox virus A48R protein with propolis-benzofuran A ligand exhibited good binding affinity (-7.84 kcal/mol). DISCUSSION: The computational simulation revealed that propolis-benzofuran A had a strong binding affinity with the Monkeypox virus A48R protein. Hence, aPDT based on this natural photosensitizer can be proposed as an adjuvant treatment against the Monkeypox virus.

Addressing the Silent Spread of Monkeypox Disease with Advanced Analytical Tools.

Monkeypox disease is caused by a virus which belongs to the orthopoxvirus genus of the poxviridae family. This disease has recently spread out to several non-endemic countries. While some cases have been linked to travel from endemic regions, more recent infections are thought to have spread in the community without any travel links, raising the risks of a wider outbreak. This state of public health represents a highly unusual event which requires urgent surveillance. In this context, the opportunities and technological challenges of current bio/chemical sensors, nanomaterials, nanomaterial characterization instruments, and artificially intelligent biosystems collectively called "advanced analytical tools" are reviewed here, which will allow early detection, characterization, and inhibition of the monkeypox virus (MPXV) in the community and limit its expansion from endemic to pandemic. A summary of background information is also provided from biological and epidemiological perspective of monkeypox to support the scientific case for its holistic management using advanced analytical tools.

Situação epidemiológica do Monkeypox (MPX) no Brasil, até outubro de 2022: Casos notificados, confirmados, suspeitos e mortalidade / Epidemiological situation of Monkeypox (MPX) in Brazil, until October 2022: Notified, confirmed, suspected cases and mortality / Situación epidemiológica de la Viruela del Simio (MPX) en Brasil, hasta octubre de 2022: Casos notificados, confirmados, sospechosos y mortalidade

Objetivo: Analisar a frequência de registros de Monkeypox (MPX) no recorte histórico formado pelos meses de "janeiro a outubro de 2022" no recorte geográfico formado pelo "Brasil". Método: Pesquisa exploratória, descritiva, comparativa e quantitativa. Os dados foram adquiridos junto ao Centro de Informações Estratégicas em Vigilância em Saúde (CIEVS), do Centro de Operações em Emergências (COE) do Ministério da Saúde (MS). Resultados: Foram notificados o universo de 13.915 registros de MPX, sendo que 65% (n=9.045) eram de casos confirmados e 35% (n=4.870) eram de casos suspeitos. A região Sudeste (SE) computou a maior preponderância, tanto de casos confirmados com 65,1% (n=5.886) quanto de casos suspeitos com 33,6% (n=1.635). O estado de São Paulo (SP) obteve maior preponderância com 44,4%(n=4.012) casos confirmados e 23,2% (n=1.131) casos suspeitos. Conclusão: Foi identificado aumento na frequência de registros de casos confirmados e suspeitos no recorte geográfico e histórico analisados.

Objective: To analyze the frequency of Monkeypox (MPX) records in the historical period formed by the months from "January to October 2022" in the geographic region formed by "Brazil". Method: Exploratory, descriptive, comparative and quantitative research. Data were acquired from the Center for Strategic Information on Health Surveillance (CIEVS), from the Emergency Operations Center (COE) of the Ministry of Health (MS). Results: A total of 13,915 MPX records were reported, of which 65% (n=9,045) were confirmed cases and 35% (n=4,870) were suspected cases. The Southeast (SE) region accounted for the highest preponderance, both of confirmed cases with 65.1% (n=5,886) and of suspected cases with 33.6% (n=1,635). The state of São Paulo (SP) had the highest prevalence with 44.4% (n=4,012) confirmed cases and 23.2% (n=1,131) suspected cases. Conclusion: An increase in the frequency of records of confirmed and suspected cases was identified in the geographical and historical scope analyzed

Objetivo: Analizar la mortalidad por infarto agudo de miocardio (IAM) en Brasil de 1996 a 2017. Método: Estudio epidemiológico, exploratorio, descriptivo y cuantitativo. Los datos fueron extraídos del Servicio de Información de Mortalidad (SIM) del Ministerio de Salud (MS). Se realizó análisis estadístico descriptivo. Resultados: Se identificó un universo de 1.592.197 registros, con media y desviación estándar de (72.373±12.999,9). El año 2016 registró la mayor preponderancia con 5,9% (n=94.148) y 1996 la menor con 3,5% (n=55.900). La mayor preponderancia estuvo constituida por 59,1% (n=940.552) del sexo masculino, 25,6% (n=407.340) tenían entre 70 y 79 años, 54,7% (n=871.319) eran blancos, 45,5% (n=725.234) casados, 20,7 El % (n=328.981) tenía de 1 a 3 años de escolaridad, el 55,6% (n=885.368) tenían sus defunciones registradas en el hospital. Conclusión: Se identificó un aumento en la frecuencia de registros de defunción por IAM en el área geográfica e histórica analizada.

Mpox (monkeypox) causing penile lesions and acute urinary retention.

This is the first ever reported case of mpox (monkeypox) causing penile lesions and acute urinary retention (AUR) in a homosexual man, who had intercourse with his confirmed positive mpox (monkeypox) partner. The patient did not have any significant comorbidities and was managed conservatively with an urgent urethral catheter and co-amoxiclav as per the microbiologist's advice to cover for his skin soft tissue infection (SSI). His blood parameters, urine and blood cultures were all normal. He was successfully trialled without a catheter (TWOCd) in a few days and was discharged home with an outpatient follow-up plan in Andrology Clinic with a flow rate, postvoid residual (PVR), International Prostate Symptoms Score (IPSS) and pain score. He was also planned to be contacted by the sexual health team to ensure a holistic follow-up.

Integrated Analgesic Care in the Current Human Monkeypox Outbreak: Perspectives on an Integrated and Holistic Approach Combining Old Allies with Innovative Technologies.

Monkeypox (MPX) is a zoonotic infection caused by an orthopoxvirus that is endemic to Central and Western Africa. The MPX virus is a part of the same family of viruses as the variola virus, which causes smallpox. Since May 2022, there has been a global increase in the incidence of MPX infections in multiple countries where the illness is not usually prevalent. A growing number of publications have emphasized on the need for increased awareness among all health professionals for the rapid recognition and diagnosis of this disease and for proper public health measures. However, atypical presentations and occurrence of uncommon symptoms receive less than the desired attention. More specifically, MPX infection related nociceptive symptoms are currently underexposed. Nevertheless, reports from the current outbreak have revealed that (severe) pain is one of the major causes for distress and even hospitalization in these patients. As for all serious pain conditions, an integrated, multidisciplinary, and holistic approach is indicated. This approach should be multimodal and include non-pharmacological therapies alongside pharmacological approaches. Health care professionals should be aware of available alternatives when first choice analgesic therapies fail. Protocols for identification of pain type and prolonged monitoring of clinical status should be implemented to improve patient well-being during acute infection, but also prevent chronic nociceptive syndromes.

Development and implementation of a clinical decision support system tool for the evaluation of suspected monkeypox infection.

Monkeypox virus was historically rare outside of West and Central Africa until the current 2022 global outbreak, which has required clinicians to be alert to identify individuals with possible monkeypox, institute isolation, and take appropriate next steps in evaluation and management. Clinical decision support systems (CDSS), which have been shown to improve adherence to clinical guidelines, can support frontline clinicians in applying the most current evaluation and management guidance in the setting of an emerging infectious disease outbreak when those guidelines are evolving over time. Here, we describe the rapid development and implementation of a CDSS tool embedded in the electronic health record to guide frontline clinicians in the diagnostic evaluation of monkeypox infection and triage patients with potential monkeypox infection to individualized infectious disease physician review. We also present data on the initial performance of this tool in a large integrated healthcare system.

Coadministration of cidofovir and smallpox vaccine reduced vaccination side effects but interfered with vaccine-elicited immune responses and immunity to monkeypox.

While the smallpox vaccine, Dryvax or Dryvax-derived ACAM2000, holds potential for public immunization against the spread of smallpox by bioterror, there is serious concern about Dryvax-mediated side effects. Here, we report that a single-dose vaccination regimen comprised of Dryvax and an antiviral agent, cidofovir, could reduce vaccinia viral loads after vaccination and significantly control Dryvax vaccination side effects. However, coadministration of cidofovir and Dryvax also reduced vaccine-elicited immune responses of antibody and T effector cells despite the fact that the reduced priming could be boosted as a recall response after monkeypox virus challenge. Evaluations of four different aspects of vaccine efficacy showed that coadministration of cidofovir and Dryvax compromised the Dryvax-induced immunity against monkeypox, although the covaccinated monkeys exhibited measurable protection against monkeypox compared to that of naïve controls. Thus, the single-dose coadministration of cidofovir and Dryvax effectively controlled vaccination side effects but significantly compromised vaccine-elicited immune responses and vaccine-induced immunity to monkeypox.