Background: The COVID-19 pandemic has positioned fragile healthcare systems in low-income countries under pressure, leading to critical gaps in service delivery. The pandemic response demands the healthcare system to be resilient and continue provision of healthcare services. This review is aimed at describing the healthcare response challenges during the pandemic in Ethiopia. Methodology: Eligible studies dealing with challenges of the healthcare system in response to the COVID-19 pandemic in Ethiopia were included. The six World Health Organization (WHO) healthcare system building blocks were used to categorize healthcare challenges. PubMed ProQuest, databases were searched, and results were summarized using systematic review synthesis. Results: Financial constraints led to a shortage of mechanical ventilators. Furthermore, the pandemic hindered the capacity to avail full packages of personal protective equipment in health facilities and intensive care capacity. The pandemic also affected the delivery of maternal, child and new-born services, prevention, and treatment of childhood illness, including immunization services. Conclusions: The COVID-19 pandemic posed various challenges to the performance of the healthcare system in Ethiopia. It is recommended that policy makers and stakeholders enhance pandemic preparedness and strengthen response capacity by considering the six WHO healthcare system building blocks. The pandemic response demands a healthcare system to be resilient, meaning to be able to bounce back and continue providing services in times of crisis. Nevertheless, the COVID-19 pandemic negatively impacted healthcare systems in low-income countries, highlighting critical gaps. This ultimately affects global health security . In low-As part of the response measures, African health ministers endorsed the Joint Continental Strategy for COVID-19 on the 22 February 2020, whereby countries launched massive mass screening, testing, and containment and mitigation measures . AfricanThe Ethiopian government and Jack Ma Foundation have joined the continental initiatives and distributed medical supplies, including diagnostics and equipment to each of the 55 countries in Africa . From 13 March 2020, until 26 July 2022, a total of 491,917, COVID-19 cases with 7568 deaths were identified in Ethiopia . EthiopiThe Government of Ethiopia established a national COVID-19 response and coordination platforms, and implemented response measures in collaboration with development partners, donors and private sectors . The natThis study is aimed at reviewing the COVID-19 pandemic response challenges of the Ethiopian healthcare system. The six WHO building blocks were used as a conceptual framework to describe the pandemic response challenges in Ethiopia.The Preferred Reporting Items for Systematic Reviews and Meta analyses Statement (PRISMA)  was usedSystematic search was conducted using the electronic databases PubMed andProQuest; manuals, guidelines, and reports from the Ethiopian Federal Ministry of Health were also consulted. Articles focusing on the COVID-19 pandemic in Ethiopia published up to August 2021 and written in English were included. The following key terms ‘pandemic’, ‘challenges’, ‘resilience’, ‘COVID-19’, ‘SAR-COV’, Ethiopia’, ‘Addis Ababa’ were used and combined with Boolean operators ‘OR’ and ‘AND’.Comprehensive screening of titles and abstracts was performed upon downloading articles from the electronic databases. Studies that did not match the research question along with all the duplicates articles were excluded. Inclusion and exclusion criteria  were devAn overview of the studies’ inclusion and exclusion criteria details is reported in Thematic content analysis was used to analyze the narrative account of the data extracted from the included studies based on the six WHO health system building blocks . Data waA total of 4417 eligible studies were identified through a data bases search . After dAn overview of the studies’ details is reported in In the following sections, the main challenges identified in the literature regarding the response to the COVID-19 pandemic from the Ethiopian healthcare system are reported following the frame of the six WHO health system building blocks .Strong leadership and governance are considered vital components for the success of any country’s healthcare system and for health system resilience . In EthiWith the leadership of the ministerial committee, the government of Ethiopia decentralized COVID-19 care. In particular, the government decided to implement COVID-19 care and laboratory services through the involvement of government and private healthcare facilities, both at national and sub-national level as part of policy initiatives. In addition, to generate evidence for decision making, the country conducted the initial COVID-19 readiness assessments and documented priority gaps and, particularly regarding intensive care services . Following a decision of policy makers in Ethiopia, the government did not implement a full-scale pandemic lockdown, but it rather implemented pandemic-preventive measures to reduce the spread of the virus in the country, thus obtaining successful outcomes ,38. NeveWith regard to government financing, in Ethiopia government budget allocation to the health sector has increased, reaching 10% in 2020, with more budget allocated to the health sector following the COVID-19 pandemic . In EkkaThe COVID-19 pandemic has burdened the healthcare system, demanding implementation of measures to build a strong healthcare workforce. In Ethiopia, frontline healthcare workers have a critical role in timely and effectively responding to any health crises and enhancing health system performance ,42. An eOne of the key functions of the healthcare system in any country is ensuring the availability, ensure access to and delivery of health services that meet minimum quality standards. During the COVID-19 pandemic in Ethiopia there was a shortage of supplies and infection prevention and control measures, which ultimately affected the quality of healthcare services delivery ,27. DuriThe pandemic has affected the global medical supply chain. Due to this, the government was struggling to address the critical demand for healthcare facilities for essential medicines and personal protective equipment’s (PPE). With respect to essential medicines, Ethiopia has a supportive national policy of prevention and control of public health threats and of institutions responsible for availing essential medicines, including essential medicine lists and treatment guidelines. However, the pandemic has greatly impacted the pharmaceutical supply chain in Ethiopia. For example, during the early phase of the pandemic the healthcare system was unable to forecast and absorb shocks and unable to ensure continuity of essential medicines in the healthcare system. Accordingly, healthcare facilities were facing shortages of medical supplies, ventilators and medical equipment . ShortagHealth information systems comprise surveillance reporting, healthcare records and other health databases that help to guide policy response decisions . Public This study highlighted the main challenges faced by the Ethiopian healthcare system when responding to the COVID-19 pandemic, paving the way for policy-level recommendations for the health sector that could foster health system resilience in Ethiopia.The weak healthcare system in most African countries hindered the achievement of effective home and facility based-care of COVID-19 cases, as recommended by WHO . OverallA shortage of ventilators and ICU beds affected the pandemic response in Kenya . SimilarStrong leadership and governance is paramount for the success of the healthcare system . In EthiWith regard to healthcare financing, in many African countries government expenditure for the health sector was relatively low  and the Overall, this review shows that multi-sectoral collaboration including private sectors, not-for-profit and faith-based organizations is likely to play a vital role in building healthcare resilience and ensuring provision of uninterrupted essential healthcare services. This collaboration requires the understanding of how the public and private health sectors interact during shocks . The panCreating a resilient health system is one of the key priorities in Africa. In 2016, the WHO endorsed the International Health Regulations (IHR) Joint External Evaluation (JEE) tool designed to measure countries’ capacities to execute and ability to prevent, detect, and respond to public health emergencies of international concern as per the recommendations of the IHR. Accordingly, the country-specific focus should be conducting regular assessment of country preparedness capacity according to the IHR-JEE tools and implementing corrective measures to build pandemic preparedness and resilience capacity . To do t(a)The Ethiopian pandemic response saw good support from policymakers and Ministry of Health authorities;(b)No large-scale lockdown was enforced in Ethiopia, but preventive measures were privileged;(c)Shortage of medical personnel resulted in scarce testing capacity;(d)Ethiopia experienced disruption of routine health services, including MNCH services;(e)The pandemic impacted the pharmaceutical supply chain, leading to a shortage of emergency care supplies;(f)The private sector had an important role in supporting the health system in the response to the COVID-19 pandemic in Ethiopia.This review is not without limitations. Only two scientific databases were screened, and no grey literature was consulted. The lack of consultation of the EMBASE database is a limitation of this study, but no institutional access was granted for it. Given the wide overlap with MEDLINE, the authors are confident that no relevant study was missed. Some strengths of this study are also pointed out. First, this review followed a systematic process for data retrieval and screening. Second, the primary analysis of records was performed by a researcher currently living and working in Ethiopia, thus ensuring deep knowledge of the context and the Ethiopian pandemic management process. Third, the reliance on a well-known framework, namely the six WHO healthcare system building blocks, allows the study to be understood by policymakers and the broader public, as well as it to be compared with similar studies in other contexts. Fourth, the recommendations and key messages elaborated in this study have been tailored to the specific context of Ethiopia, facilitating the translation of knowledge into policy practice.Ethiopia has implemented an abundant pandemic prevention and control measure, with the active participation of policy makers’ leadership. Following the pandemic, healthcare facilities were facing shortages of emergency care medical supplies, ventilators, medical equipment, oxygen supply and well-ventilated isolation rooms. This review shows that strong preparedness and multi-sectoral collaboration play a vital role in building resilience and continued delivery of essential healthcare services. Our finding identified that, in Ethiopia, building healthcare resilience is key and should be taken into account for future pandemic responses to maintain continuity of healthcare services. We recommend policymakers and healthcare system representatives to enhance pandemic preparedness and response capacities by targeting the six WHO health system building blocks. Further studies are warranted on the role of private and non-governmental organizations on pandemic response, resilient healthcare system, and policy level perceptions and barriers for building disaster resilient healthcare system.


Antimicrobial resistance is a major and growing global problem and new approaches to combat infections caused by antibiotic resistant bacterial strains are needed. In recent years, increasing attention has been paid to nanomedicine, which has great potential in the development of controlled systems for delivering drugs to specific sites and targeting specific cells, such as pathogenic microbes. There is continued interest in metallic nanoparticles and nanosystems based on metallic nanoparticles containing antimicrobial agents attached to their surface (core shell nanosystems), which offer unique properties, such as the ability to overcome microbial resistance, enhancing antimicrobial activity against both planktonic and biofilm embedded microorganisms, reducing cell toxicity and the possibility of reducing the dosage of antimicrobials. The current review presents the synergistic interactions within metallic nanoparticles by functionalizing their surface with appropriate agents, defining the core structure of metallic nanoparticles and their use in combination therapy to fight infections. Various approaches to modulate the biocompatibility of metallic nanoparticles to control their toxicity in future medical applications are also discussed, as well as their ability to induce resistance and their effects on the host microbiome. Streptococcus pneumoniae with 900,000 cases, followed by 550,000 infections caused by drug-resistant Neisseria gonorrhoeae, and in third place were 448,400 infections caused by drug-resistant Campylobacter [Antimicrobial resistance (AMR) is a natural phenomenon that occurs when microorganisms are exposed to antimicrobial agents . The spelobacter . Importalobacter . The serlobacter .The problem of increasing resistance is a growing concern as the number of new antibiotics approved since the late 1970s has declined . EvidentNanotechnology is the science of materials/devices defined by size . The term nanotechnology was introduced by American physicist and Nobel Prize winner Richard Feynman in 1959 during a lecture entitled “There’s Plenty of Room at the Bottom”. Dr. Richard Feynman considered some of the consequences of the possibility of manipulating matter on the atomic scale and mentioned the ability to create nanoscale machines . Fifteen2, MnO, ZnO) and semiconductors such as silicon and ceramics [A steadily increasing number of reports indicate that nanomaterials may be also developed as alternative to currently used antibiotics and antifungal drugs . Nanomatceramics . Inorganceramics ,32,33,34ceramics ,36. The ceramics . A key aceramics  and biocceramics ,40. Howeceramics , and theceramics  or poor ceramics . The lasceramics . The advceramics ,46. The ceramics ,48. FromDue to their unique physicochemical properties such as (i) a large surface to the volume ratio, (ii) the ability to functionalize with diagnostic and therapeutic factors, (iii) ease of modification of the method of synthesis, (iv) antibacterial and immunomodulatory properties ,53,54,55The mechanism of action of metallic nanoparticles includes, among others: (i) disruption of the cell walls, thus, increasing their permeability as a result of electrostatic interaction between negatively charged molecules of the cell wall of the microorganism and positively charged nanoparticles resulting in a leakage of cytoplasmic contents ,62 and cHere, we provide a throughfall characterization and discussion of the latest achievements in synthesis and design of metallic nanoparticles and metallic nanoparticle-based nanosystems as potent antimicrobials with the potential to be used for the treatment of drug-resistant bacterial and fungal infections.Over the past few decades, antibiotic-resistant bacteria have become increasingly prevalent; the number of infections caused by multidrug-resistant (MDR) bacteria is increasing and the risk of untreatable infections is rising .3O4) titanium oxide (TiO2) or zinc oxide (ZnO) are commonly used as antimicrobial agents after their strong antimicrobial activity is well known [Among metallic nanoparticles, silver (Ag), gold (Au), copper oxide (CuO), iron oxide  monometallic nanoparticles, (ii) metallic nanoparticles in combination with conventional antibiotics/fungicides or compounds other than antimicrobial agents, (iii) multimetallic nanoparticles alone and (iv) in combination with antibiotics/fungicides, (v) metallic nanoparticles, whose surface has been further functionalized with antibiotics/fungicides or compounds other than antimicrobial agents. The functionalization of metallic NPs surfaces with the desired compound utilizes various types of covalent and non-covalent bonds—these include electrostatic forces, hydrogen bonds and van der Waals interactions, resulting in the integration of a variety of organic and inorganic molecules at the nanoscale . In ordeMonometallic NPs consist of a single metal species, which, depending on the atomic type and properties, may exist in various forms such as metallic, magnetic, transition metal and oxide. Monometallic NPs are the most popular inorganic nanoparticles, which represent a promising solution in the fight against resistance to traditional antibiotics, not only because of their completely different mechanisms of action from commonly used antibiotics, showing activity against bacteria that have developed resistance, but also because they target many biomolecules that impede the development of resistant strains .+/K+ ATPase pump and signal transduction pathways [+ ions , whe of NPs ,110. It e of NPs .Gold nanoparticles (AuNPs) are one of the most important nanoparticles due to their simple and controlled synthesis, inertness, biocompatibility and low toxicity compared with other nanomaterials. Gold nanoparticles, such as silver nanoparticles, disrupt the integrity and structure of the cell membrane, causing leakage of intracellular components ,113,114.Candida by reducing pathogen cell adhesion, resulting in the inhibition of biofilm growth. Interestingly, peanut shaped gold nanoparticles were found to reduce the viscosity of the biofilm formed by Pseudomonas, which may be important in the case of cystic fibrosis where thick mucus are formed, making it difficult for antimicrobial agents to penetrate and subsequently eradicate the pathogens causing infection. , a decrease in the values of the half maximal inhibitory concentration were observed against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Micrococcus luteus strains [The antimicrobial properties of metallic nanoparticles can be improved by increasing the solubility of nanoparticles in aqueous media. By synthesizing silver nanoparticles using an aqueous solution of an extract from the plant  strains . Althoug strains , where s strains .Staphylococcus aureus and Salmonella typhimurium, whereas the functionalized iron oxide nanoparticles showed antimicrobial activity against these strains, as a result of the formation by L-tyrosine functionalization of more stable NPs with different functional groups on the surface, providing a better binding interaction with microorganisms [The activity of metallic nanoparticles can also be governed by modulating their surface to improve their functionality as antimicrobial compounds. By functionalizing the surface of iron oxide nanoparticles with L-tyrosine, a significant difference in antimicrobial activity was observed between nanoparticles whose surface was modified, compared with non-functionalized iron oxide nanoparticles . For therganisms . Nijonshrganisms  comparedrganisms  and coorrganisms . In our rganisms ,119,142.rganisms ,146,147.Lysiloma acapulcensis possessed higher antimicrobial potency than chemically produced Ag NPs. Antimicrobial activity was determined using the disk diffusion method and minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations (MBCs) against four clinical strains: Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Candida albicans. Both a larger zone of inhibition and lower MICs and MBCs of biogenic Ag NPs were observed in comparison with Ag NPs synthesized by the chemical method [Origanum vulgare and Ag NPs synthesized chemically was assessed. Using the disk-diffusion method, their activity against Streptococcus agalactiae, Aeromonas hydrophila, Vibrio alginolyticus, Aspergillus flavus, Fusarium moniliforme, Candida albicans was determined. Against both bacteria and fungi, the zone of growth inhibition and, thus, the antimicrobial activity was higher for biologically synthesized Ag NPs than for chemically synthesized Ag NPs [Pseudomonas aeruginosa and Bacillus subtilis with comparable activity against Staphylococcus aureus [The antimicrobial activity of metallic nanoparticles is influenced by their method of synthesis. In a study by Garibo et al., silver nanoparticles synthesized by green synthesis using an extract from l method . In the d Ag NPs . Mohammad Ag NPs . Also ind Ag NPs . Similard Ag NPs ,153. On s aureus . Recent Due to the antimicrobial activity possessed by metallic nanoparticles, they can overcome resistance mechanisms such as: (i) reduced permeability of bacterial cells, (ii) enzymatic modifications of antimicrobial substance, (iii) modification within target sites/enzymes, (iv) active removal of antimicrobials by overexpression of scavenger pumps to escape the antimicrobial effect of antimicrobials, or (v) overexpression of an enzyme inactivated by an antimicrobial ,164,165.Although broad-spectrum antibiotics and antifungal agents play a very important role in the control of bacterial and fungal infections, they also have a disadvantageous side to their use, namely, the selection and spread of resistance among many bacterial and fungal species and the deleterious effect they can have on the host microbiome ,172,173.Pseudomonas aeruginosa resistant to all commonly used antimicrobial drugs. However, due to the dose-dependent side effects of colistin, the possibility of bacteria treating using colistin and seeking same therapeutic effect, but at a lower dose, is being sought. To achieve these goals, silver nanoparticles have been used in combination with colistin by Khaled et al. [Acinetobacter baumannii. The results obtained indicate a synergistic effect leading to a reduction in the MIC values of colistin, imipenem and silver nanoparticles where a more than fourfold reduction was observed. Due to the synergistic effect of metallic nanoparticles with an antimicrobial agent, it is possible to target not only planktonic cells, but also cells growing within biofilm structure. Our research also confirms the synergism between metallic nanoparticles and antibiotics. As a result of the combination of the classical antibiotics such as vancomycin and colistin, synthetic ceragenins CSA-13 and CSA-131 and the human antimicrobial peptide cathelicidin LL-37 with core-shell magnetic nanoparticles against methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa, an additive or synergistic effect was observed, as well as a strong suppression of biofilm formation. The interaction of magnetic nanoparticles with bacterial cell wall compounds results in increased insertion and/or uptake of membrane-active agents such as colistin or vancomycin, destruction of the membrane and leakage of intracellular contents, as well as induction of oxidative stress by the magnetic nanoparticles, causing damage to bacteria cell’ organelles [Pseudomonas aeruginosa, a strong combinatorial effect of nanoparticles with an antibiotic was achieved, enabling the reduction of biofilm formation and, thus, increasing the effectiveness of antimicrobial therapies [Colistin is considered as an antibiotic of last line of defense for the control of infections of some pathogens such as d et al. . Additioganelles . Also, iherapies .Candida albicans. As a consequence penetration of silver nanoparticles through the cell membrane due to their small size, the integrity of the membrane is disrupted, resulting in easy passage of drugs through the cell membrane leading to their action at the target site [Botrytis cinerea spores at 100 ppm as a result of the increased density of the solution, causing cohesion/sticking of the fungal hyphae [Varthemia iphionoides. The results showed a significant increase in antimicrobial activity of Ag NPs complex with essential oil against multi-drug resistant strains of Enterobacter aerogenes, Pseudomonas aeruginosa, Staphylococcus epidermidis and Staphylococcus aureus. The Ag NPs resulted in an increase in surface area, leading to greater surface contact with the bacteria and, thus, improved bactericidal activity, perforation and lysis of the bacterial cell wall, followed by generation of free radicals and DNA breakdown [Salmonella enteritidis. Synergistically treating bacteria with a sublethal dose of Ag NPs enabled them to be readily lysed by phages even at low concentrations. As a result of the combination of Ag NPs and phages, a new prospect of nanoparticles with greatly improved antibacterial properties and therapeutic efficacy appeared.As a result of the combination of silver nanoparticles with amphotericin B and fluconazole, Ag NPs showed a synergistic effect with amphotericin B and fluconazole against biofilms formed by get site . The metl hyphae . In addireakdown . On the reakdown  evaluateRecent work on the synergistic effect of metallic nanoparticles in combination with antibiotics/fungicides and compounds other than antimicrobial agents is shown in Multimetallic NPs are nanoparticles composed of at least two different metals that form alloy or core-shells nanostructures. Multimetallic nanoparticles are of growing interest due to an increased spectrum of properties compared to monometallic NPs . The bacEscherichia coli, bacterial membranes treated with monometallic NPs had no visible damage. In contrast, the application of bimetallic gold- rhodium (Au-Rh) NPs and gold- ruthenium (Au-Ru) NPs caused significant changes in the cell membrane structure- cell membrane was dramatically ruffled and severely damaged, thus, can induce bacterial cell lysis, leading to leakage of cell substrates and bacterial death. The mechanism of action of the bimetallic nanoparticles also included a decrease in bacterial membrane potential and an increase in ATP and ROS levels. The above results suggest that monometallic nanoparticles  exhibit lower antimicrobial activity under the given experimental conditions (they do not cause noticeable changes in the cell membrane), compared to bi-metallic nanoparticles (Au-Rh and Au-Ru NPs), significant changes in the bacterial cell membrane were observed as a result of synergistic action of their constituent metals. Moreover, the application of bimetallic silver-platinum (Ag-Pt) NPs [Candida auris. Exposure of fungal cells to trimetallic silver-copper-cobalt (Ag-Cu-Co) NPs [By using a combination of metal compounds, it is possible to obtain synergistic antimicrobial properties of the newly synthesized compound compared to the properties of the individual components used alone. The antimicrobial activity of silver nanoparticles involves the anchoring and penetration of NPs in the bacterial cell wall while once inside the cell, they contribute to the formation of free radicals, generating intracellular oxidative stress and ultimately leading to cell death . On the -Pt) NPs  not only-Co) NPs  influencMycobacterium tuberculosis, which is made possible by the rapid export of drugs from the cytosol. One of the targets of the silver and zinc oxide nanoparticles is to weaken the stability of the membrane, resulting in an increase in its permeability to antibiotics [Mycobacterium tuberculosis-infected macrophages in combination with rifampicin resulted in an increase in the potency of the antibiotic by as much as 76%, causing a decrease in the integrity of the Mycobacterium tuberculosis cell envelope due to the interaction of bimetallic nanoparticles with the mycobacterial envelope, which is reflected in an increase in its permeability. Due to this interaction, an increased penetration of rifampicin into the cytosol of the bacteria is possible, which results in an enhanced potency of the drug. The use of multi-metallic nanoparticles proved to be an effective drug delivery vehicle that can be used to transport TB drugs, among others, while increasing the potency of the drug [Some bacterial species have a remarkable ability to adapt to the administration of antibiotics by developing resistance mechanisms such as ibiotics ,201. Theibiotics  of bimetthe drug .Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus. For example, they found that rifampicin activity in the presence of Ag-ZnO NPs increased as much as 15-fold against Staphylococcus aureus, while Ag-ZnO NPs inhibited biofilm against Escherichia coli and Pseudomonas aeruginosa by about 76%. Bimetallic nanoparticles Ag-Au NPs synthesized by the core-shell method [Pseudomonas aeruginosa and Escherichia coli, where the combinatorial effect led to higher drug binding affinity and enhanced antimicrobial efficacy. Synergy of antibiotic with bimetallic nanoparticles may be the current approach with the most promise for the significant improvement of patients treatment with complicated skin infections.Most bacterial infections are associated with biofilm formation, where the microbial cells that make up the biofilm structure have been shown to be 10–1000 times more resistant to antibiotics than planktonic cells . As a rel method  showed sRecent studies on the antimicrobial activity of multi-metallic NPs are summarized in As a result of the generation of reactive oxygen species, the antioxidant defense system is disrupted, which leads to mechanical damage to the cell membrane. A large number of studies on multimetallic nanoparticles describe their mechanism of action as the adhesion of multimetallic NPs to microbial cells and destruction of the cell wall by interaction between the positively charged surface of multimetallic NPs and the negatively charged surfaces of pathogen cells, leading to the generation of ROS, the penetration of multimetallic NPs into the cell, causing damage to proteins and DNA, as well as oxidative stress . ConsideMetallic nanoparticles have great potential in medicine as carriers of small molecules such as drugs, genes, proteins, and enzymes ,216,217.Functionalization of metallic nanoparticles with antimicrobial agents enables strong antimicrobial activity as a result of enhanced ability to penetrate biological membranes. Penetration of hydrophobic antimicrobials is limited by the highly polar environment within bacterial membranes, which impairs their activity . MetalliAnother advantage of the functionalization of metallic nanoparticles is the improved stability of the metallic NPs-antimicrobial agent. Higher stability and antimicrobial activity under conditions such as room temperature, UV exposure or heat stress (increasing temperature up to 90 °C) was reported for the conjugate of Au NPs with ampicillin, streptomycin and kanamycin compared to the free forms of the antibiotics  . MetalliAcinetobacter baumannii was found to be sensitive to conjugated Ag NPs with imipenem [Acinetobacter baumannii, the combination of AgNPs with imipenem is effective antimicrobial agent against carbapenem-resistant strains, showing potent antimicrobial activity [Escherichia coli also proved to be sensitive after exposure to ampicillin-conjugated gold nanoparticles, where an accumulation of Au NPs@ampicillin on the bacterial cell surface was observed, resulting in the formation of pores in the bacterial membrane, allowing the nanoparticles to penetrate the interior of pathogen cells [An important aspect of antimicrobial drug delivery based on metallic nanoparticles is the improvement in the pharmacokinetic properties of the drug in the form of increased solubility of poorly soluble drugs, prolonged drug half-life and systemic circulation time, as well as prolonged and stimulus-controlled drug release, resulting in lower dosage and drug frequency, reducing the toxic effect of the drug . By funcimipenem , where wactivity . Ampicilen cells . The resen cells .Another advantage of functionalizing metallic nanoparticles with antimicrobial agents is the reduction of toxic effects where using nanoparticles as carriers for drug delivery not only improves efficacy, but it also enables a reduction in adverse effects compared to conventional therapy. Functionalization of gold nanoparticles with ciprofloxacin resulted in lower hemolytic activity of Au NPs@ciprofloxacin than the antibiotic in free form thereby reducing the toxicity of the antibiotic . SimilarStaphylococcus aureus peptidoglycan are proving to be a promising treatment method, which can be used alone or in addition to existing conventional antibiotic therapy to achieve complete eradication of the pathogen by means of which extended and selective bacterial death can be achieved [Staphylococcus aureus (MRSA) cells and the ability of the antibody-nanoparticle conjugate to selectively kill pathogens in an animal model [Escherichia coli O157:H7 antibodies were also successfully conjugated on the surface of silver nanoparticles, which effectively bind to the target pathogen [Candida and Gardnerella species, it is possible to correctly identify vaginal infections with very high sensitivity and specificity [By functionalizing metallic nanoparticles with specific antibodies, it is possible to obtain a system that might serve for rapid identification of the pathogens and target treatment to combat infection. Gold and silver nanoparticles conjugated with antibodies specific for achieved ,241,242.al model . Goat anpathogen . An impocificity .Recent studies on the antimicrobial activity of metallic NPs functionalized with antibiotics/fungicides or compounds other than antimicrobial agents are summarized in An important aspect of the biomedical application of various types of nanoparticles is biocompatibility, i.e., the property of a substance determining its correct functioning in a living organism, which should show a lack of toxicity, not affect the body’s immune system and do not induce hemolysis. In order to ensure the effective and safe use of nanomaterials, the interactions between the nanoparticle and the cells of the host must be considered, with particular attention being paid to the environment in which the test compounds act. A great number of information/trends regarding the toxicity of nanoparticles are obtained in cancer research and in studies that are not focused on antimicrobial activity. On the basis of such studies, certain effects can be expected, even their possible therapeutic potential ,255. TheTherefore, different methods are used to assess the biocompatibility of nanoparticles, ranging from quantitative assays using conversion of compounds such as 3--2, 5-diphenyltetrazolium bromide (MTT) , 2, 3-biA very important factor associated with the toxic properties of metallic nanoparticles is their size. Due to their small size, NPs have a much larger surface area per unit mass compared to their bulk counterparts, which translates into higher reactivity, which is associated with a higher risk of cytotoxic effects. As their size decreases, the number of metal atoms per surface area increases exponentially, resulting in higher reactivity of nanoparticles in biological systems . Due to With the help of changing the shape of nanoparticles, it is possible to modulate their cytotoxicity. Nanoparticles can have different shapes and geometries including spheres, ellipsoids, cylinders, stars, octahedral sheets, cubes, spikes, rods, triangles, prisms, which significantly affects their toxicity. The star-shaped AuNPs had the highest anticancer potential but also exhibited the highest cytotoxicity, while the spheres of AuNPs, which were the least cytotoxic, showed weak anticancer activity . Lee et 2 minimized their toxicity as a result of blocking ion release and bacterial and/or cell contact. In addition, the composition of the core can be changed by the addition of other metals, thereby achieving increased chemical stability against degradation of the metallic nanoparticles and consequently against unwanted leakage of metal ions into the body [The toxicity of nanoparticles may also depend on their chemical composition. The degradation of nanoparticles that can occur depends on environmental conditions, such as a change in pH, ionic strength, or ionic valence, resulting in the leakage of metal ions from the core of metallic nanoparticles . The resthe body .Escherichia coli. The positive surface charge of CuO-PVP NPs enhanced antibacterial activity through electrostatic interactions with negatively charged surfaces of Escherichia coli. The authors concluded that the positive surface charge of CuO-PVP NPs resulted in enhanced antibacterial activity through electrostatic interactions with negatively charged Escherichia coli surfaces. It was also observed that the weakly negatively charged CuO-PDA NPs achieved better antibacterial activity, which the authors explain by the presence of lipophilic catecholamine structures on the nanoparticle surfaces, which enabled interaction with the lipid bilayer in the outer membrane of Escherichia coli [The surface charge of nanoparticles plays an important role in their toxicity, as it determines to a large extent the interaction of nanoparticles with biological systems . The relhia coli . In addihia coli .Nigella sativa extract and chemical synthesis against bone-building stem cells of mice. The toxicity of the green synthesized Ag NPs was significantly lower than that of the chemical synthesized Ag NPs after 24, 48 and 72 h. After 72 h exposure of cells to the test compounds at a concentration of 0.2 mg/L, more than an 11-fold decrease in the number of viable cells was observed for chemically synthesized Ag NPs compared to Ag NPs synthesized by the green synthesis method [The biocompatibility of metallic nanoparticles is also influenced by the method of synthesis and its conditions. Using the MTT assay, Amooaghaie et al. determined the toxicity of silver nanoparticles synthesized by two methods: green synthesis using s method . Ghetas s method . Similars method . Slightls method .Staphylococcus aureus after 30 days of exposure [Staphylococcus aureus with cercaptopyrimidine-conjugated gold nanoclusters. The results of our induction of resistance in Candida strains exposed to ceragenin-functionalized gold nanoparticles over 25 passages also confirmed the low potential for resistance development among fungi [Pseudomonas putida and Pseudomonas aeruginosa PAO1, respectively.Due to the rapid spread of resistance among microorganisms , a very exposure . Zheng eng fungi . On the ng fungi ,283. Anong fungi ,284. It ng fungi ,286. Furng fungi . In respng fungi  and Yangng fungi  conclude2 NPs and ZnO NPs, is that they potentially interfere with the intestinal microbiome that can compromise the host health [Another important aspect of metallic nanoparticles including, Ag NPs, TiOt health ,291. At t health . It shout health ,292. Thet health ,291,293.t health . Notablyt health ,291. Whet health . A summa2 NPs and ZnO NPs may affect the intestinal microbiota including the alteration of the F/B ratio , a depletion of Lactobacillus strains and an elevated in the abundance of Proteobacteria. The above consequences can lead to obesity or even CRC  where gut dysbiosis play a significant role [2 NPs and ZnO NPs.Considering all data, it should be highlighted that Ag NPs, TiOant role . What isant role ,291,292.In an era of increasing antimicrobial resistance, metallic nanoparticles appear to hold promise to improve current therapies and to develop new therapeutic agents of nanoscale nature. A possible way to increase the antimicrobial activity of conventional antibiotics is to use them in combination with metallic nanoparticles. This can be done either by synthesizing metallic nanoparticles with a modified surface, functionalization with suitable antimicrobial agents, or by designing a core of synergistically acting metals. It is also possible to select antimicrobial agents and use them in combination therapy . The use of synergism in the nanotechnology context seems to be a very promising approach in the fight against various infections, whether of bacterial or fungal etiology, and against planktonic and biofilm-forming bacteria. Thus, the synergistic combination of metallic NPs with suitable compounds may be a potential source of alternative antimicrobial agents and may play a significant role in the near future. Combining metallic nanoparticles with an antimicrobial agent not only demonstrated synergistic effects, but also improved drug delivery and increased antimicrobial agent efficacy, while reducing the side effects associated with the broad use of these agents. In addition, the synergistic action of metallic nanoparticles with an antimicrobial agent enabled resistance mechanisms to conventional antibiotics/fungicides, thereby providing a more effective use of antibiotics/fungicides available in the clinical practice.2 NPs and ZnO NPs in the development of obesity, IBD, IBS metabolic syndrome or even CRC. Nevertheless, the above mentioned findings raise the need for extended investigation in order to fully explain them, especially in humans.In addition, the activity as well as the toxicity of metallic nanoparticles is influenced by their physical and chemical properties, where the size of nanoparticles has been found to have a significant effect due to the increase in specific surface area at nanoscale sizes, resulting in a higher number of cellular interactions and, consequently, toxicity. Other key factors influencing nanoparticle cytotoxicity include shape, surface charge, method of synthesis, nanoparticle surface modification and metal ion release. Therefore, the control of the physicochemical properties of NPs is crucial in order to obtain safer and more stable NPs. An important aspect of the use of nanotechnologies is the biocompatibility of the design materials. Although metallic nanoparticles in combination with antimicrobial agents have many advantages, they can also have adverse effects, as they have the potential to cross the natural barriers of living cells and tissues, causing toxic and inflammatory responses. The biocompatibility of metallic nanoparticles can be modulated by changing the size of the nanoparticles. It has been found that due to their small size, NPs have a much larger surface area per unit mass compared to their bulk counterparts, resulting in a greater reactivity with a greater risk of cytotoxic effects. By changing factors such as shape, chemical composition, surface charge, and method of synthesis, the biocompatibility of metallic NPs can be influenced. Therefore, it is believed that by controlling the physicochemical properties of nanoparticles, safer and more reliable nanoparticles with high antimicrobial activity can be obtained. Further research is still required to determine how nanoparticles affect the complex human body. In order to reduce the toxic effects of metallic nanoparticles, as well as in combination with other compounds, new methods are needed to reduce the negative effects of NPs while maintaining their activity. Much of the work to date confirms the low potential of metallic nanoparticles due to their divergent mechanisms of action against pathogens. However, there are also reports of the possibility of the development of resistance mechanisms as a result of exposure to nanoparticles, so a highly effective antimicrobial agent such as metallic NPs should be handled rationally to remain effective against various types of infections. Currently, the impact of NPs on intestinal microbiota has caught the increasing attention of researchers. It should be emphasized that there is a compelling amount of evidence indicating the correlation of Ag NPs, TiOFor the safe use of metallic nanoparticles there is a need for future research, which should include the mechanisms of NPs’ translocation, accumulation, long-term and long-lasting effects on the body, their interaction with cells, signaling pathways and receptors, and effects on fundamental processes such as phagocytosis. Understanding the relationship of potentially new nanotechnology-based antimicrobials to biological systems is a key to overcoming the limitations and toxicity barriers of metallic nanoparticles and to their future use in the treatment of bacterial or fungal infections. Although the results presented in this review are promising in the context of fighting infections by combining metallic nanoparticles with antimicrobial agents, at present, no existing product has been approved by the Food and Drug Administration (FDA) for clinical use. Therefore, future research should focus on the elucidation of the interaction of nanotechnology-based antimicrobials with cells, tissues or organs, their metabolism and accumulation in the body, and their effect on the natural flora in order to produce safe and effective means of combating microbial resistance in the next generation of drugs.


At present, there are some problems in underwater low light image, such as low contrast, blurred details, color distortion. In the process of low illumination image enhancement, there are often problems such as artifacts, loss of edge details and noise amplification in the enhanced image. In this paper, we propose an underwater low-light enhancement algorithm based on U-shaped generative adversarial network, combined with bright channel prior and attention mechanism, to address the problems. For the problems of uneven edges and loss of details that occurred in traditional enhanced images, we propose a two-channel fusion technique for the input channel. Aiming at the problems of brightness, texture and color distortion in enhanced images, we propose a feature extraction technique based on the attention mechanism. For the problems of noise in enhanced output images, we propose a multi-loss function to constrain the network. The method has a wide range of applications in underwater scenes with large depth. This method can be used for target detection or biological species identification in underwater low light environment. Through the enhancement experiment of underwater low light image, the proposed method effectively solves the problems of low contrast, blurred details, color distortion, etc. of underwater low light image. Finally, we performed extensive comparison experiments and completed ablation experiments on the proposed method. The experimental results show that the proposed method is optimal in human visual experience and underwater image quality evaluation index. Underwater images are an important carrier and presentation of underwater information. However, due to the influence of many factors such as insufficient irradiance and particles in water, underwater images are characterized by low contrast and unexpected noise. Underwater low-light images can not only cause unpleasant subjective visual experiences, but also affect the implementation of many vision-based technologies, such as underwater target detection and tracking. Therefore underwater image processing is important for ocean exploration and development, underwater rescue, etc. Underwater low-light enhancement, as a subfield of image enhancement, is widely used in the pre-processing of underwater target detection, etc. The enhanced underwater images will significantly improve the detection effect, convey the correct information, and enhance the application of computer vision in underwater.The underwater image low-light enhancement algorithm is based on the research of low-light enhancement algorithm in land scene and color enhancement algorithm for underwater images. Using the imaging model of underwater images, we combine the low-light enhancement algorithm in land scene to study the underwater low-light image enhancement. Low-light image enhancement algorithms and underwater color correction studies mainly divided into two main categories: traditional-based enhancement methods and deep learning-based enhancement methods. Based on the traditional enhancement methods, the low light image is enhanced mainly by using the dehazing physical model, HE, and retinex. For example, Dong et al  proposedIn deep learning-based approaches, the models are usually trained using convolutional blocks using a huge database. Deep learning-based enhancement algorithms are mainly based on two frameworks, namely, convolutional neural networks (CNN) and generative adversarial networks (GAN). For example, the literature –15 propoMost of the above methods are designed for low light enhancement of images in land scenes and color correction of underwater images in shallow water. At present, no research exists on enhancement algorithms for low-light images underwater, when using low-light enhancement algorithms in terrestrial scenes or underwater color enhancement algorithms applied directly to low-light image enhancement in deep water scenes, problems such as enhancement overexposure, halo artifacts, and loss of edge details are likely to occur. In addition, it is difficult to obtain paired images in underwater low-light scenes. Based on these two factors, we propose an enhancement method of dual channel GAN combined with an attention mechanism. First we use the bright channel, and then more features are acquired through dual-channel fusion. Then the attention mechanism is used in the generator to reconstruct the extraction mechanism of features and multiple loss functions are used for constraint training. Specifically, our contributions are mainly as follows:Bright channel prior: It is proposed to extract the bright channel image using the bright channel prior knowledge, then extract the features of the original image and the bright channel image separately, and finally fuse the features of the dual channels to enrich the feature information.Hybrid attention mechanism: A generative adversarial network incorporating an attention module is established, the feature information of color, brightness, texture and other channels in underwater low-light images can be accurately extracted by adding attention mechanism in the feature extraction stage, only the required features of each channel are retained and irrelevant features are discarded, and the feature information is selected effectively.Multiple loss function: The loss function is a combination of self-feature retention loss and color invariant loss. It enables the network to consider the details, color authenticity and texture information of the image at the same time, and solve the problem of distortion and color deviation of underwater low-light enhanced images.This paper is structured as follows: The first part describes the importance of underwater low-light enhancement research and the low-light enhancement research in terrestrial scenes and underwater color correction research related to this research, describing the challenge of underwater low light image enhancement and proposing solutions. The second part presents related works, it mainly includes underwater imaging models, image enhancement methods based on traditional methods and image enhancement methods based on deep learning. The third section illustrates our contributions to underwater low-light image enhancement methods through the design of network models, mainly including bright channel prior, attention mechanism, and multiple loss functions. In the last part, extensive contrast and ablation experiments were conducted. Through qualitative and quantitative experiments, it is proved that the proposed network is superior to several other low-light image enhancement networks. Meanwhile, it is also proved that the designed network methods are effective for image enhancement in underwater low-light image scenes. The underwater low light image will be enhanced from two aspects of visual experience and image quality evaluation index.In this section, the current low light enhancement algorithms and underwater color enhancement algorithms are summarized. The underwater imaging model will be introduced first, and then the image enhancement algorithm based on traditional methods and deep learning will be introduced.Firstly, according to the Jaffe-McGlamery  underwatNormally, the forward scattering component will be ignored due to the small distance between the camera and the target object, so the model of underwater imaging can be simplified as:For the traditional low-light image enhancement methods, they can be mainly divided into the dehazing-based physical model algorithm, the histogram equalization (HE), and the Retinex method. The algorithm based on dehaze physical model is an enhancement algorithm based on atmospheric scattering model. In 2011, Dong et al . HoweverHistogram equalization-based algorithms improve the image contrast by making the uneven histograms evenly distributed by mapping changes. To improve over-enhancement of local image area by HE algorithm, Pizer et al  proposedRetinex-based algorithms are used to enhance low-light images by removing the illumination component from the image to obtain the reflectance component characterizing the image eigenvalue. Retinex is based on color sense consistency (color constancy), which balances dynamic range compression, edge enhancement, and color constancy, therefore, various types of images can be enhanced adaptively. Jobson et al , 6 propoAmong the various traditional low-light image enhancement methods, the physical models designed in most of the methods can better fit the image contrast and saturation changes brought by exposure values in the land scene, but the differences between land scenes and underwater scenes in the imaging process cause frequent image overexposure, color distortion, and poor detail processing when these methods are applied to underwater scenes, which makes it difficult for traditional image enhancement methods to have a better application in image enhancement of underwater low-light scenes.The algorithms of traditional low-light image enhancement methods has strong interpretation, but when faced with different enhancement goals, the model is not robust enough, and it is difficult to achieve good enhancement effect. With the rapid development of deep learning, more and more low-light image enhancement methods based on deep learning are proposed.Deep learning-based image enhancement algorithms are broadly classified into Convolutional Neural Networks (CNN)-based approaches and Generative Adversarial Networks (GAN)-based approaches, which train models from a large database and then process the test images in the input. Hou et al.  proposedBased on the above analysis, the current deep learning-based image enhancement methods applied to underwater low-light scenes have two main defects: first, it is difficult to collect a large number of paired data sets in underwater low-light scenes, which cannot be applied to CNN-based supervised learning networks; second, because underwater scenes are more complex than land scenes, the extraction of various feature information by GAN network-based methods is not accurate enough, this will result in the enhancement not being good enough.In this section, an image enhancement network for underwater low-light scenes is proposed, aiming at the enhancement of underwater low-light images. The overall network structure designed based on the generative adversarial network model, and the most critical proposed bright channel prior knowledge, hybrid attention mechanism, and multi-loss function proposed for underwater low-light scene enhancement tasks will be introduced in detail.As shown in In order to improve the image enhancement effect in underwater low-light environment, it is proposed that the underwater low light images should be subject to a prior processing of bright channels before feature stitching, in order to solve the problem of noise and loss of details of the output image caused by insufficient feature extraction in the current depth learning network. Underwater low-light images often show color distortion and low contrast because the imaging model of underwater low-light images is similar to the hazy model of land scenes, which is composed of direct signal and background scattering signal, and the usual way to solve such morbid problems is to insert priori information. Based on this, a prior method of bright channel is proposed for underwater low light image enhancement. The bright channel prior  is inspiIbright (x) represents the bright channel image and Ic (y) is the underwater low-light image. Underwater low-light images, compared with clear normally illuminated images, have lower bright channel values. On the one hand, it will cause image noise to be amplified and the image details to be lost. On the other hand, it will cause insufficient feature extraction in the learning process of the network. To address these two points, It is proposed for the first time to embed the prior knowledge of bright channel into underwater low light image enhancement. First, obtain bright channel images by using bright channel a priori knowledge, then extracting features of the original image and bright channel images separately. Finally, the two types of features are fused to enrich feature information. The specific process of our proposed bright channel method is shown in Aiming at the problem of color difference and noise of low light enhancement output image, a hybrid attention module is proposed, which can restrain the color deviation and noise of output image. In low-light images, a larger receptive domain is the key to reduce color artifacts , 29, becThe main purpose of adding the hybrid attention module to the generative adversarial network is to model the dependencies among the channels. The flowchart of the feature extraction mechanism of the hybrid attention module is shown in For the problem of distortion and color bias in underwater low-light-enhanced images, the use of self-feature preservation loss  and coloFor unsupervised networks trained with unpaired datasets, due to the lack of strict supervision information, the enhanced images often appear detail distortion, artifacts and other phenomena. To solve this problem, the self-feature preserving loss function  inspiredIL denotes the input low-light image, G(IL) denotes the output after generator enhancement, and ϕi,j denotes the extracted feature map. i denotes the i-th maximum pooling layer, and j denotes the j-th convolutional layer after the i-th maximum pooling layer. Wi,j and Hi,j are the dimensions of the extracted feature map.Self-feature retention loss:Jp is the average intensity value of channel p in the enhanced image, and  is a pair of channels.Color bias is a long-standing problem in image enhancement tasks. In the underwater low light scene, the color deviation of the enhanced image is more prominent due to the extremely low light environment and the complex background scattering signal. Based on this, color constancy loss is proposed to solve the color deviation problem in the underwater low-light scene image enhancement task. It will try its best to maintain the color authenticity of the enhanced image. The color constancy formula can be expressed as follows:Among the above loss functions, the contribution values of different loss functions to the learning ability of the network may be inconsistent. In order to solve this problem, we use the joint loss function to train the whole network. The distortion and color deviation of the enhanced image can be considered at the same time to optimize the color reality and texture details of the output image and the joint loss function is expressed as follows:The self-feature retention loss function adopted by the whole network:Wα, Wβ denote the hyperparameters of the importance of the Lcol loss functions to the overall loss contribution, respectively, which can be adjusted, during training.The joint loss function adopted by the whole network:Our dataset consists of two parts, normal light images and low light images, considering the difficulty in acquiring paired underwater normal light images and low light images, an unsupervised image enhancement network is designed. In the whole network training process, paired normal light and low light image datasets are not required. The low-light images consist of two parts: underwater images taken under ultra-low light environment and some land dark light images selected from the SID dataset , while tTo demonstrate the effectiveness of our proposed network, the designed network was compared with the seven most widely available networks on the same training and test sets, including Retinex , HE, andAnalysis of the enhancement effects of our network and the other seven networks in In addition, in order to evaluate the enhancement effect of various methods more scientifically, we calculate NIQE, UICM and UIQM image quality evaluation indexes before and after enhancement by various methods, as shown in In this section, in order to verify the effectiveness of each part of our proposed methods for underwater low-light image enhancement, ablation experiments on bright channel priors, hybrid attention mechanism and joint loss function were conducted on the basis of GAN, respectively. During each ablation experiment, the hardware equipment was kept constant and the number of epochs trained was 200. After the training was completed, the same test images from the comparison experiments were used, and the test results are shown in According to the results of each index in In this paper, aiming at the problems of enhancement overexposure, halo artifacts, edge detail loss, color distortion and so on which are easy to occur due to harsh environment in the enhancement process, an enhancement method of dual-channel U-type generative adversarial network combined with attention mechanism is proposed. In this method, the proposed bright channel prior solves the problem of feature extraction caused by insufficient brightness, the fused attention mechanism enables the network to extract the feature information of each part, and the joint loss function better solves the problems of color and detail distortion and noise interference that occur during enhancement. In the proposed method, the advantage is that we consider the enhancement task of the whole network from both brightness enhancement and image deblurring simultaneously, in addition to minimizing the distortion in the enhancement process as much as possible. The results of both comparison and ablation experiments demonstrate that our method is effective when applied to image enhancement in underwater low-light scenes, outperforming other methods currently available for low-light enhancement in underwater low-light scenes. However, our method still has shortcomings, a small number of images cannot balance the two tasks of brightness enhancement and deblurring. Refer to


This Special Issue focused on the current understanding of signaling pathways as well as genetic and epigenetic features involved in the pathogenesis of brain tumors and other nervous system tumors, with emphasis on the development of novel therapeutic approaches aimed at improving the current standard of care.Brain tumors and other nervous-system tumors belong to an extremely heterogeneous group of benign and malignant tumors characterized by different aggressiveness and variable clinical outcomes . Among tIn this context, Haase et al. discussed the molecular features, development, and therapeutic perspectives on pediatric high-grade gliomas (pHGGs) arising in cerebral hemispheres . Indeed,The current knowledge regarding the epigenetic mechanisms involved in medulloblastoma (MB) pathogenesis is described by Strejczek et al. MB is one of the most frequent and malignant brain tumors in children. Current therapies, despite being quite effective, unfortunately cause adverse effects that influence the central nervous system’s function, thus lowering the quality of life of patients. Epigenetic-based potential therapies for MB that could ensure a higher survival rate while maintaining a good quality of life are described in this review .Epigenome deregulation plays a crucial role in several tumors besides MB. Notably, bromodomain and extraterminal domain (BET) proteins are epigenome readers of acetylated signals in histones and coactivators for oncogenic transcriptional networks . BET proTwo reviews in the Special Issue are addressed to the analysis of current molecular targeting strategies in gliomas. In detail, Genoud and Migliorini focused their attention on immunotherapeutic approaches in glioblastoma . GlioblaLastly, an interesting and original article was aimed at characterizing the exosomal DNA isolated from plasma of neuroblastoma (NB) patients and its potential use for detection of the mutational status of parental tumor cells . ExosomeDespite their diversity, nervous system tumors share the tendency of being refractory to radical surgical resection, and radio-chemotherapy is often ineffective due to resistance mechanisms. For these reasons, clinical management of these kinds of tumors is frequently challenging and the prognosis is still poor. In this scenario, precision medicine approaches, based on the continuous technological advances, are emerging as promising therapeutic avenues against nervous system tumors and highlight the need to acquire in-depth knowledge about the genetic mutations, signaling pathways, metabolic alterations, and environmental effects involved in tumor biology and resistance to therapies.


Interest in the use of anticholinergics to prevent the development of epilepsy after traumatic brain injury (TBI) has grown since recent basic studies have shown their effectiveness in modifying the epileptogenic process. These studies demonstrated that treatment with anticholinergics, in the acute phase after brain injury, decreases seizure frequency, and severity, and the number of spontaneous recurrent seizures (SRS). Therefore, anticholinergics may reduce the risk of developing posttraumatic epilepsy (PTE). In this brief review, we summarize the role of the cholinergic system in epilepsy and the key findings from using anticholinergic drugs to prevent PTE in animal models and new clinical trial protocols. Furthermore, we discuss why treatment with anticholinergics is more likely to prevent PTE than treatment for other epilepsies. Traumatic brain injury (TBI) is an interruption in normal brain function when a sudden force  damages the brain . TBI hasOne of the main consequences of TBI is posttraumatic epilepsy (PTE), which refers to the development of epilepsy after brain injury. According to the International League Against Epilepsy, epilepsy is considered in the following conditions: one unprovoked seizure and probability of recurrent seizure risk over 60%, a diagnosis of epilepsy syndrome, and two or more seizures occurring more than 24 h apart .Epileptogenesis in PTE is a continuous process in which a normal brain shows hypersynchronous excitability after a head injury  is not completely understood due to its complexity  has been focusing on preventing the occurrence of epilepsy and its progression . TherefoA prospective window of opportunity to prevent, intervene, and stop the development of PTE is the latent period between brain injury and SRS onset; a period that can vary from months to years in humans  and fromTo date, the crucial roles of the glutamatergic and GABAergic systems in the expression and suppression of seizures and the development of epileptic conditions have been widely investigated in preclinical and clinical studies due to the classical mechanism of imbalance between excitation and inhibition. Nonetheless, studies focusing on the involvement of the cholinergic system in epileptic conditions have raised some interest, with recent studies showing the effectiveness of anticholinergics in modifying the epileptogenic process .In this review, we discuss the role of the cholinergic system in epilepsy and the use of anticholinergic drugs to treat PTE in animal models and clinical trials. Additionally, we discuss why PTE is more likely to be prevented than other types of epilepsy. Further, we considered that administering a selective cholinergic antagonist immediately after a brain injury attenuates excitotoxicity and consequently inhibits the development of PTE by interfering with the epileptogenic process at a critical moment. This review aims to provide new insights based on what has been proposed regarding PTE treatment using an anticholinergic strategy.via the acetyltransferase enzyme and subsequently transported into vesicles  is an endogenous neurotransmitter synthesized from choline and acetyl-CoA in the cytoplasm of nerve terminals via the pre-commissural branch of the fimbria-fornix pathway constitute the main cholinergic inputs of the hippocampus, providing direct information to both principal neurons and interneurons , which can lead to status epilepticus (SE) . Howeverin vitro, inducing abnormal sodium influx through mechanically sensitive Na+ channels leading to increased intra-axonal calcium via the opening of voltage-gated calcium channels and reversal of the Na+-Ca2+ exchanger  and controlled cortical impact (CCI) are the most extensively used PTE models. In the FPI model, a precise pressure pulse is distinctly delivered in the animal dura mater using a closed hydraulic system , followeAlong with the PTE models, conventional models, such as pilocarpine, kindling, pentylenetetrazol, and genetics models, have been extensively used to study epilepsy and investigate the prevention of this disease . These aMany anticholinergics have been investigated and proposed as potential treatments for PTE using different animal models of epilepsy. Scopolamine and biperiden are the most well-known of these drugs . Till noIn in vivo study did not demonstrate that the site of action of scopolamine is presynaptic. Thus, muscarinic antagonists may block receptors located on the cell bodies of inhibitory interneurons, leading to increased brain ACh release at late TBI phase , [18F] DPA-714 , allopregnanolone , valproate sodium , and biperiden .According to the Among these, biperiden is the only anticholinergic drug that has been investigated in a PTE clinical trial to evaluates its safety and efficacy. Although presenting dose- and concentration-dependent temporary declines in cognitive functioning , biperidAs mentioned earlier, PTE is likely to develop after a TBI of great severity; however, PTE does not necessarily occur in all cases . FurtherTherefore, considering the predicted risk of epileptogenesis after TBI , preventPosttraumatic epilepsy is a frequent consequence of TBI, depending on the trauma severity and internal and external risk factors. Interest in the cholinergic pathway for preventing PTE has recently grown because of the effectiveness of anticholinergics in modifying the epileptogenic process. Consequently, different anticholinergics have been studied in various laboratories. Scopolamine and biperiden have demonstrated promising results by reducing seizure severity and frequency, decreasing SRS, and increasing hippocampal threshold in different animal models. In particular, biperiden has drawn researchers’ attention and shown exciting results. To date, biperiden is the only anticholinergic drug studied in clinical trials and passed all safety and efficacy tests, raising expectations as the first antiepileptogenic drug. Additionally, considering the need to find effective strategies to prevent epileptic conditions, PTE seems potentially preventable compared to other types of epilepsies, since TBI has a latent period for interventions, thereby increasing the chance of a positive result. Future studies should clarify the anti-epileptogenic properties and overcome the challenge of preventing epileptic conditions caused by TBI.VS wrote the first draft of the manuscript. VS, BL, and MF contributed to the article’s literature search, analysis, and conception. SR, MB, MN-M, and LM contributed to the revision of the manuscript. All authors approved and read the submitted version.


The main feature of body dysmorphic disorder (BDD) is impairing preoccupation with a physical defect that appears slight or non-existent to others.To draw an overview of BDD through a clinical case of a patient with BDD and autolytic ideation, which improved after an adequate diagnosis and an early pharmacological and psychotherapeutic approach.Bibliographic review of the treatment and diagnosis of BDD, from articles published in the last 5 years in Pubmed.18-year-old woman diagnosed with depression and obsessive ideation, which started at the age of 11, after a comment at school. The patient believes that she has intenseunder-eye bags or dark circles, this has caused her to abandon all activity and self-isolate at home. Symptoms included recurring obsessive and intruding thoughts related to the supposed defect, ritualized behaviors of hours of duration aiming toit through makeup, and autolytic ideation. Therapeutic approach combined psychopharmacological and psychotherapeutic treatments, obtaining gradual improvement of symptomatology and disappearance of the autolytic ideation.The disorder is severe, which is reflected in high rates of suicide attempts. Differential diagnosis between obsessive and delirious dysmorphophobia is essential for improving outcomes; the egodystonic nature of the symptom, awareness of illness and obsessive personality traits facilitate the diagnosis. A multidisciplinary approach involving psychiatrists and clinical psychologists is necessary for a correct diagnosis and early treatment of this pathology, as well as recognition by dermatologists, surgeons and medical aesthetic professionals, where these patients go with the aim of finding solutions to their problem.No significant relationships.


Wolf’s isotopic phenomenon occurs when a new dermatosis appears on a site that has already healed from a previous dermatological disease of another etiology. This report describes the case of a 44-year-old female patient undergoing treatment for breast carcinoma who recently had brownish erythematous lesions appearing on the scar region of previous herpes zoster on the right hemithorax. Histopathology and immunohistochemistry examination confirmed skin metastasis of breast cancer. Herpes zoster scars require attention due to the possibility of an isotopic response as a facilitating factor in some dermatoses, sometimes severe ones, such as neoplasms. Wolf’s isotopic response (WIR) is defined as the occurrence of a new cutaneous dermatosis that appears on the site of a previous, healed, dermatological disease. Many skin lesions in the topography of herpes zoster (HZ) have been described as WIR; this viral infection is the most commonly described primary disease predisposing to this response, and the term “postherpetic Wolf’s isotopic response” has been suggested by several authors.2This report describes a 44-year-old woman undergoing treatment for metastatic breast cancer to the lung, pleura and bones, which was submitted to a radical mastectomy, chemotherapy with docetaxel, and previous radiotherapy, and is currently undergoing chemotherapy with fulvestrant and ribociclib. She had a history of HZ on the right hemithorax for two months, with clinical diagnosis attained by the initial classic presentation, good therapeutic response to acyclovir, and complete remission of the condition. She had started one week before with new skin lesions on the same site but with slightly different characteristics, such as slight lesion infiltration and absence of vesicles, erosions or secretion.On physical examination, the right hemithorax showed some macules and an extensive brownish erythematous plaque, with little infiltration and mild desquamation . HistopaIn the present case, in the context of immunosuppression (baseline neoplasm under chemotherapy), the initial diagnosis of another episode of herpes zoster would be possible, but the differential diagnosis with local tumor infiltration would also need to be considered when recalling the presence of WIR, particularly due to the atypical configuration of the disease and the prolonged clinical picture.3WIR is a rare, probably underdiagnosed entity and consists of the development of a dermatosis on the site of a previous skin lesion, of different etiology and already healed. In most cases, the first dermatosis is herpes (zoster or simplex), although other skin lesions can also precede the second lesion. The isotopic response can reveal the existence of several conditions – such as granulomatous diseases, impetigo, psoriasis, and even malignant tumors.The term “Wolf’s isotopic phenomenon” was introduced in 1995. Although the first described clinical case dates from 1929, the understanding of this phenomenon is recent and the number of known cases is relatively scarce.The pathogenesis of WIR remains unclear and includes vascular, immunological, and viral factors. Some authors state that the herpetic infection, by destroying cutaneous nerve fibers, could trigger immune dysregulation phenomena, thus favoring the development of inflammatory reactions or causing local immunosuppression (important in cases of tumor infiltration).3The differential diagnosis between the two dermatoses is extremely important since the treatment differs between them. HZ is a cutaneous manifestation resulting from the reactivation of a previous infection by the Varicela-zoster virus, which remains latent in the sensory ganglia, and typically presents with a prodromal phase of nonspecific symptoms and subsequently with the characteristic erythematous-papulovesicular rash, which follows the path of a dermatome, generally respecting the midline.Histopathological examination shows intraepidermal vesicles or ulceration, as well as epidermal necrosis and ballooning ‒ large, pale keratinocytes with metallic gray nuclei, chromatin margination at the edge of the nucleus, sometimes with pink intranuclear inclusions surrounded by an artefactual cleft , acantholysis, or multinucleated keratinocytes. There may also be extravasated erythrocytes and diffuse perivascular lymphocytes or neutrophils, sometimes with leukocytoclastic vasculitis. Other diagnostic methods available for HZ are cultures, fluorescent antibody smear techniques, or Tzanck preparations.Breast carcinoma is the neoplasm that most often results in cutaneous metastasis in women, usually detected on the trunk as an indurated/infiltrated plaque or nodule, which is commonly an adenocarcinoma. Breast cancer metastasis usually occurs within the first three years after the neoplasm diagnosis and in women aged between 50 and 70 years. Histopathological examination shows tumor nodules with pleomorphic and hyperchromatic nuclei, with increased mitosis in the dermis. In some cases, glandular structures may contain mucin.Most metastatic breast carcinomas express, on immunohistochemistry, CK7 and CK19, estrogen and progesterone receptors, mammaglobin, GCDFP-15, CEA, and E-cadherin, but are negative for CK20, CK5/6, CD10 and TTF-1.In the present clinical case, histopathology showed characteristics of a poorly differentiated carcinoma metastasis, and immunohistochemistry was crucial, confirming the hypothesis of breast carcinoma metastasis, as it expressed the CK-7 and GATA-3 markers, in addition to Ki-67 in 20% of the neoplastic cells.Varicella-Zoster virus infection results in increased chances of developing HZ and WIP. It is very important to pay attention to the possibility of the emergence of different dermatoses in dermatomes that were previously affected by the varicella-zoster virus, including metastatic neoplasms, as in the case described herein. In cases of suspected WIR, histopathological and immunohistochemical studies are extremely relevant.None declared.Bruna Rocha Reolão: Approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.Diego Salomón Mora: Approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.Michele Caroline dos Santos Garcia: Approval of the final version of the manuscript; design and planning of the study; drafting and editing of the manuscript; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.Renan Rangel Bonamigo: Approval of the final version of the manuscript; design and planning of the study; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the manuscript.None declared.


In recent years, respiratory diseases have increasingly become a global concern, largely due to the outbreak of Coronavirus Disease 2019 (COVID-19). This inevitably causes great attention to be given to the development of highly efficient and minimal or non-invasive methods for the diagnosis of respiratory diseases. And electrochemical biosensors based on carbon nanomaterials show great potential in fulfilling the requirement, not only because of the superior performance of electrochemical analysis, but also given the excellent properties of the carbon nanomaterials. In this paper, we review the most recent advances in research, development and applications of electrochemical biosensors based on the use of carbon nanomaterials for diagnosis of human respiratory diseases in the last 10 years. We first briefly introduce the characteristics of several common human respiratory diseases, including influenza, COVID-19, pulmonary fibrosis, tuberculosis and lung cancer. Then, we describe the working principles and fabrication of various electrochemical biosensors based on carbon nanomaterials used for diagnosis of these respiratory diseases. Finally, we summarize the advantages, challenges, and future perspectives for the currently available electrochemical biosensors based on carbon nanomaterials for detecting human respiratory diseases. Respiratory diseases affect the nasal cavity, bronchi, lungs, chest and other parts of the human body, and can be either non-infectious, as in asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis and idiopathic pulmonary fibrosis, or infectious, as in pulmonary infections caused by viruses, bacteria and other microorganisms . With thThe electrochemical biosensor is an important branch of the electrochemical sensor, which uses electrode as energy exchange element . Compare2 and sp3 hybridization . I. I39]. IThese electrochemical biosensors based on carbon nanomaterials for diagnosis of influenza described above have excellent performance, and details are shown in The pandemic of COVID-19 brought on by SARS CoV-2 may become more serious under evolutionary pressure due to the emergence of transmissibility, pathogenicity and pathogenicity or SARS CoV-2 variants  . AdditioSo far, it has been reported that a variety of COVID-19 electrochemical biosensors have been based on carbon nanomaterials . The carThese electrochemical biosensors based on carbon nanomaterials for diagnosis of COVID-19 described above have excellent performance; the details are shown in Pulmonary fibrosis is a severe chronic and progressive interstitial respiratory disease, and it has typical clinical symptoms such as dyspnea and dry cough. At present, high-resolution computed tomography (HRCT) is extensively used for the screening diagnosis of pulmonary fibrosis, which is highly sensitive. However, some patients do not show typical HRCT features and require further diagnostic examinations with surgical lung biopsy. The procedure of surgical lung biopsy is invasive and causes great pain to the patient. Therefore, it is desirable to develop alternative non-/minimal invasive procedures to assist in the diagnosis of pulmonary fibrosis. Electrochemical biosensors based on carbon nanomaterials have appeared to meet this requirement by detecting biomarkers of pulmonary fibrosis. For example, Zuo et al., have proposed an electrochemical biosensor using fullerene (C60) as electrode materials for detecting miR-3675-3p in human serum, which is known as a promising biomarker for pulmonary fibrosis . ElectroThese electrochemical biosensors based on carbon nanomaterials for diagnosis of pulmonary fibrosis described above have excellent performance, and the details are shown in Mycobacterium tuberculosis directly or indirectly . S. S24]. SThese electrochemical biosensors based on carbon nanomaterials for diagnosis of lung cancer described above have excellent performance; details are shown in In addition to the above electrochemical biosensors based on carbon nanomaterials for diagnosis of influenza, COVID-19, pulmonary fibrosis, tuberculosis and lung cancer, there are other reports about electrochemical biosensors based on carbon nanomaterials for diagnosis of other human respiratory diseases such as allergic rhinitis, Middle East respiratory syndrome (MERS), deep vein thrombosis, asthma and pneumonia ,100,101.In this review, we summarize electrochemical biosensors based on carbon nanomaterials for diagnosis of human respiratory diseases. Compared with other biosensors for diagnosis of human respiratory diseases, the biosensors summarized in this review not only show the advantages of carbon nanomaterials, such as stable properties and easy preparation, but also show the advantages of electrochemical strategies such as low detection limit and fast reaction time. Taking COVID-19 as an example, In summary, this article provides a concise overview of recent studies on electrochemical biosensors based on carbon nanomaterials for the diagnosis of several important human respiratory diseases, including influenza, COVID-19, pulmonary fibrosis, tuberculosis and lung cancer. We firstly summarize the electrochemical application of carbon nanomaterials for diagnosis of various respiratory diseases in one review. Compared with other reviews related to human respiratory diseases, this review provides a comprehensive analysis of the unique characteristics of carbon nanomaterials and the advantages of electrochemical assays for diagnosis of human respiratory diseases. Besides, compared with other traditional methods for diagnosis of human respiratory diseases, these electrochemical biosensors based on carbon nanomaterials which are summarized in this review are simple, fast-operating diagnostic procedures for diagnosis of respiratory diseases in the early stage by detection of respiratory viruses, related DNA fragments, proteins or RNA. In addition, these biosensors have shown great potential for both basic research and clinical applications in the field of alerting and preventing the spread of respiratory diseases. There are, however, still many significant challenges that need to be overcome before the research and development of these biosensors successfully translate into clinical practices. The challenges include, but are not limited to (1) the fact that the current electrochemical biosensors based on carbon nanomaterials can detect only a limited number of respiratory viruses, related DNA fragments, proteins and RNAs, (2) carbon nanomaterials as electrode materials in some electrochemical biosensors for the diagnosis of respiratory diseases only play a small role and their excellent properties have not been fully utilized, which is far from the materials’ full potential, and (3) the current range of electrochemical biosensors based on carbon nanomaterials have some restrictions, such as restrictions in terms of the limit of detection and range of linearity, in the diagnosis of respiratory diseases.Thus, in future research and development of electrochemical biosensors based on carbon nanomaterials for diagnosis of respiratory diseases, efforts should be made to exploit not only more biomarkers related to respiratory diseases, but also more functions of the carbon nanomaterials so to develop them into mainstream materials for fabrication of electrochemical biosensors. Further, the detection limit and range of linearity of the electrochemical biosensor based on carbon nanomaterials for diagnosis of respiratory diseases should be optimized. In addition, new synthetic methods of carbon nanomaterials should be exploited to make them possess better optical, electrical and other properties. Finally, due to the excellent application potential of carbon nanomaterials in electrochemical biosensors for diagnosis of human respiratory diseases, carbon nanomaterials should be exploited to be the main electrode materials.


Arterial hypertension (AHT) is the most important risk factor for cardiovascular disease worldwide . As a di2+-handling, as well as cellular factors including activation of myofibroblasts, extracellular matrix, and cardiomyocyte remodeling result in fibrosis, chamber dilatation, especially of the atria, myocardial hypertrophy, systolic and diastolic dysfunction and dyssynchrony [The pathophysiology of HHD has numerous aspects and is not entirely solved today . Though ynchrony . These mynchrony ,6. Even ynchrony . In a clinical context, the definition of HHD remains vague. While the guidelines of the European Society of Cardiology regarding AHT, AF, and HF each highlight certain facets of the disease, neither of them unites all features of HHD ,8,9. MosBut not only is the concept of a global definition of HHD difficult. Identification of HHD and especially its delimitation against other causes of hypertrophy such as hypertrophic cardiomyopathy (HCM) and amyloidosis can be challenging in conventional echocardiography. Modern techniques such as strain imaging or high-frame-rate echocardiography can support the detection of HHD and differential diagnoses when 2D-echocardiography is insufficient to answer such questions ,12. ThisIn addition to echocardiography, cardiac magnetic resonance imaging (cMRI) plays an important role in the detection and classification of HHD. It is particularly useful in the discrimination between HHD and HCM. Recent advancements in cMRI imaging may help in the identification of HHD, for example by analysis of myocardial fibrosis patterns, spatial and temporal mapping in 3D + time models . BuildinRegarding treatment options, the most important question is still the treatment of HFpEF since no treatment has been shown to reduce convincingly especially the mortality in this patient group . HoweverIn this special edition of the Journal of Clinical Medicine, we are hoping to describe diverse phenotypes of HHD and their pathomechanisms. Furthermore, we aim to work towards an improvement of its definition and aid with its classification. Finally, we hope to assess the treatment options and their potential target patients.


Nutrients has thus been devoted to the discussion of the current experimental and clinical evidence regarding the efficacy and the safety of nutraceutical products for managing cardiometabolic diseases, also taking into consideration critical issues such as the quality of nutraceutical products, the related regulatory aspects, and the quality of evidence required to inform guidelines.The effective prevention and treatment of cardiovascular and metabolic diseases is a major task for health systems since these pathological conditions are still major causes of mortality, morbidity, and disability worldwide. To pursue this aim, strategies should be adopted to take advantage of lifestyle changes, including, when appropriate, pharmacological approaches and considering the nutraceutical option, which, according to an increasing research and practical interest, appears to be an additional and effective asset in this biomedical field. This Special Issue of Prunus domestica L. The authors were able to identify the extract’s active components and explore its anti-inflammatory activity and ability to inhibit digestive enzymes involved in some features of the metabolic syndrome [Among papers reporting experimental studies, Ullah et al. approached the potential nutraceutical properties of a hydroethanolic extract of syndrome . Moreovesyndrome .Shifting to clinical studies, Domínguez-López et al. highlighted that the level of urinary tartaric acid, a biomarker of wine intake, correlated with lower total and low-density lipoprotein (LDL) cholesterol in postmenopausal women, suggesting that wine consumption may have a positive effect on the cardiovascular risk profile, thus exhibiting some nutraceutical properties . AnotherNutrients aims to implement a qualified and open evidence-based discussion on the use of nutraceutical products for cardiometabolic health, thus providing an up-to-date set of information useful for readers involved in experimental/clinical research as well as clinical practice in this biomedical area.This Special Issue of