Bombyx mori larvae, has been primarily used in the textile industry and in clinical settings as a main component of sutures for tissue repairing and wound ligation. The biocompatibility, remarkable mechanical performance, controllable degradation, and the possibility of producing silk-based materials in several formats, have laid the basic principles that have triggered and extended the use of this material in regenerative medicine. The field of neural soft tissue engineering is not an exception, as it has taken advantage of the properties of silk to promote neuronal growth and nerve guidance. In addition, silk has notable intrinsic properties and the by-products derived from its degradation show anti-inflammatory and antioxidant properties. Finally, this material can be employed for the controlled release of factors and drugs, as well as for the encapsulation and implantation of exogenous stem and progenitor cells with therapeutic capacity. In this article, we review the state of the art on manufacturing methodologies and properties of fiber-based and non-fiber-based formats, as well as the application of silk-based biomaterials to neuroprotect and regenerate the damaged nervous system. We review previous studies that strategically have used silk to enhance therapeutics dealing with highly prevalent central and peripheral disorders such as stroke, Alzheimer’s disease, Parkinson’s disease, and peripheral trauma. Finally, we discuss previous research focused on the modification of this biomaterial, through biofunctionalization techniques and/or the creation of novel composite formulations, that aim to transform silk, beyond its natural performance, into more efficient silk-based-polymers towards the clinical arena of neuroprotection and regeneration in nervous system diseases.Silk refers to a family of natural fibers spun by several species of invertebrates such as spiders and silkworms. In particular, silkworm silk, the silk spun by  The nervous system is composed of specialized cells organized in complex networks with the ability to integrate and adopt signals from different tissues and organs. The nervous system receives sensorial inputs from the outside environment and sends signals to the periphery cells and muscles to execute simple and complex motor commands . In the However, cell therapy is faced with the strong decline in survival observed for the majority of transplanted cells. This fact is even more accentuated in the nervous tissue, a very hostile environment for donor cells, independently of their germinal origin. For example, MSC show poor survival after brain transplantation into the brain as soon as one week post-transplantation . MSC viaMatrices for tissue engineering have a diverse origin . NaturalIn an attempt to combine the advantages of natural and synthetic sources ECM-derived matrices have been proposed ,25. ECM-Alternatively, electrospun matrices have been widely applied to tissue engineering for several decades. However, cellular penetration and limitations associated with the toxicity of undesirable by-products and chemical molecules from electrospinning dopes are a serious concern.Independently of its origin, the properties of a biomaterial can be further improved if the matrix shows the ability to adapt to the cellular environmental and physiological signals. This concept can be turned into reality by the addition of informational domains, by cross-linking the biomaterial and by making natural/synthetic composites ,30. In pIn this context, silk-based biomaterials stand out for its versatility and natural biocompatibility. Although silk is regarded as a natural polymer it shows strong potential as a tunable biomechanical and biochemical material in various formats. Silk biomaterials have been applied, e.g., in bone, cartilage, muscular, vascular, and skin tissue engineering . In receIn this article, we present and discuss previous reports and current trends in the field of using silk biomaterials applied for neural tissue engineering in neurodegenerative diseases and different trauma conditions.Silk is probably one of the oldest known natural materials that have accompanied the history of humanity. It was already used in the early Neolithic Age, more than 8500 years ago  and nowaBombyx mori) silk have attracted most of the attention due to their large availability from controlled and non-expensive sources. Natural silkworm silk is composed of two families of proteins: silk fibroin (SF) and silk sericin (SS). As a result, in this article it is intended to use the word “silk” only as long as the combined presence of SS and SF is implied. SF shows negligible immunogenicity and forms fibers insoluble in water. By contrast, SS is a water-soluble biocompatible protein. Both SS and SF are reported to exhibit various neuroprotective, anti-inflammatory, and anti-oxidant properties. For reasons that are still unclear, the combined use of fibroin and sericin in an organism tends to induce a proinflammatory reaction [Although silk is naturally spun by various species of insects and spiders, studies about silkworm  ,44. SpidExtraction of the proteins from the natural source (mainly from the silkworm). This extraction can be done directly from the silk glands of the animal ,47 or byProduction of recombinant silk proteins by cloning the gene expressing the silk fibroin in a host organism ,50,51. TSilk fibers are originally produced in the glands of the silkworm  Figure  from an B. mori cocoons, this amount of decrease in the net weight is expected after completing the degumming process [The resulting silk fiber (bave) is composed of two fibroin monofilaments (brins) surrounded by a sticky sericin layer  that flu process . A SF so process   used the solution prepared by mechanically stirring the silkworm cocoon in an alcoholic solution . HoweverAs indicated above, the secondary structure and the molecular assembly of SF are important features not only for the formation of the native fibers, but also with regard to the fabrication of the 2D and 3D scaffolds for tissue engineering. In this respect, the presence of β-sheet crystalline structures that lead to water insolubility is most relevant. Shimizu (1941) reported for the first time that silk proteins are found in two forms, which later were called Silk I (soluble) and Silk II (insoluble) ,72. A fuSilk II appears as a consequence of the tendency of the Gly-Ala-Gly-Ala-Gly-Ser motifs to arrange into a stable anti-parallel β-sheet conformation . The preIn this review, we have divided the strategies for the fabrication of silk-based biomaterials into fiber and non-fiber-based formats as illustrated in Silk regeneration from silk dopes is the process that induces the production of highly arranged and stable Silk II structures in the biomaterial, making the biomaterial insoluble in water and with appropriate stiffness and strength . The regSilk fibroin sponges a are proSilk hydrogels can be produced from the solution containing the regenerated silk as a consequence of its meta-stability. Changes in temperature, mechanical shear stresses, ultrasound waves, variations in composition, such as modifying pH or extracting/adding salts can lead to the gelation as the result of the self-assembly process of silk fibroin. Strategies such as using vortex agitation , sonicatSilk films c are fabCollectively, non-fiber-based SF biomaterial fabrication methods can produce 2D and 3D biomaterials that can be used as biocompatible grafts to treat neuronal damages. However, these biomaterial configurations normally lack direction and polarity. After SF regeneration, the formed β-sheet does not show any orientation, and the biomaterial itself is not orientated, so it cannot guide cells to a specific path, which is especially important, for example, for rewiring damaged axonal tracts. This limitation might be compensated by surface modification, considering chemical and physical alterations that could enhance or provide patterns for cell growth, which is discussed in the following sections ,93. It iSolid Free Form Fabrication (SFF) techniques, also known as Rapid Prototyping techniques, groups a number of processing techniques, that include 3D printing, that create shapes by the addition of subsequent layers of material. SFF techniques and, in particular, 3D printing, allow fabricating silk structures with detailed custom shapes and geometries based on necessity d. There Fiber-based SF formats e–g can bSF fibers e can be ®, Heerbrugg, Switzerland) technique to fabricate fibers with tunable mechanical properties. This technique is inspired on the natural spinning process of spiders and silkworms [To address this problem, our group has developed the biomimetic Straining Flow Spinning , which comprises neurons and glial cells in brain and spinal cord, and the peripheral nervous system (PNS), mainly formed by nerve bundles that extend in many parts of the body including limbs and organs. Because of the highly specialized function and inter-connected wiring between CNS and PNS, a central or peripheral injury might have dramatic consequences in sensorial, motor, or cognition capacities.In humans, the most prevalent neurological pathology is ischemic stroke, which is caused by a deficiency in the provision of sufficient blood and oxygen to the brain. Brain stroke might produce vision impairment, loss of cognition, and body limb deficits. The symptoms are variable depending on the affected area.Stroke produces a core or irreversible injury surrounded by an ischemic penumbra that can be salvable . InflammTo revert this pathological condition, main neuroprotective strategies are orientated to reduce inflammation, excitotoxicity and/or oxidative stress. Later, once the damage is established (chronic phase), the replacement of neural damaged circuitry and/or the stimulation of endogenous repairing mechanisms are usually targeted with specific cell therapy approaches.Although the implantation of cells has been associated with a significant enhancement in cognition, memory, and restoration of plasticity, the regeneration of neural tissue can be strongly stimulated by different biomaterials that help to connect the implanted cells with the host for further maturation into pre-existing circuitry . The mecThe features of SF for the healing of various stages of neuronal damage can possibly be split into two categories. The first one is defined by the properties related to the amino acid sequence and the by-products generated after SF degradation, which show antioxidant and anti-inflammatory properties. The latter is related to the biomaterial properties by itself  to interact with the target tissue providing tissue and cellular anchorage, stem cells, and/or drug delivery.The in vitro evaluation of SF with primary culture of hippocampal neurons demonstrated the biocompatibility of SF fibers without cytotoxic effects . The in The provision of stem cells alongside a biomaterial has been suggested as a regenerative medicine-based method that can lead to functional recovery. Although the invasiveness of intracerebral implantation of stem cells seeded with biomaterials for the usage in patients has been questioned, several clinical trials have reported positive outcomes after intracerebral implantation of stem cells, showing the feasibility of this approach to treat neural diseases ,114,115.In the context of stroke, our group designed an injectable silk hydrogel and assessed the quality and tolerability of the hydrogel after injection in the caudate putamen. It was demonstrated that the injection of silk hydrogels in the healthy mouse brain did not cause changes in the animal’s behavior in terms of sensorimotor skills, learning ability, or sleep–wake regulation . FollowiNeurodegenerative diseases are conditions that cause progressive degeneration of neural networks. Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and multiple sclerosis (MS) frequently affect the elderly, and due to demographic changes, the social impact of these disorders is increasing. Such diseases can place people at risk of a wide range of disabilities or death . NeurodeAlzheimer’s disease causes progressive neurodegeneration and dementia mainly affecting those over 65 years old. Alzheimer’s disease was regarded as the sixth leading cause of mortality in the United States in 2019 . The cauNeural network disruption produces a wide variety of clinical signs, which profoundly affect cognitive abilities, especially the capacity to memorize sensory experiences, including verbal and or visual learning. However, neuronal damage and impaired neural circuitry can be reduced or healed by antioxidant agents and regeneration strategies. Anti-inflammatory agents, modulators of amyloid-β and tau pathways, stem cells, and biomaterials have been considered promising therapies.ChaT gene, increasing the expression of choline acetyltransferase, an enzyme required for ACh synthesis [The intrinsic properties of SF arising from the amino acid sequence can be used not only in the treatment of cerebral ischemia, but also in the context of Alzheimer’s therapeutics. For example, the hydrolysate of silk fibroin can be achieved by enzymatic , chemicaynthesis .Furthermore, the neuroprotective effect of SS protein was demonstrated in an Alzheimer-induced rat model, where a significant increase in the amount of ACh receptors ran in parallel to an improvement of cognition ,128,129.Parkinson’s disease (PD) is a neurodegenerative central disorder caused by the progressive death of dopaminergic neuronal cells, mostly in the substantia nigra, which translates into a reduction of dopamine content. In patients, PD causes motor symptoms such as tremor, rigidity, bradykinesia, muscle cramps, and dystonia or speech dysfunction, alongside non-motor symptoms such as sleep disruption, pain, impaired memory, and dementia . The degThe usage of L-DOPA, with the commercial name of Levodopa, as the precursor of dopamine, is the most common approach to increase the concentration of dopamine in PD patients . L-DOPA N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a precursor of the neurotoxin 1-methyl-4-phenylpyridinium, which is involved in the destruction of dopaminergic receptors within the substantia nigra [SS has been found as an inhibitor of tyrosinases , while tia nigra . TyrosinSF has shown competing results for the delivery of tyrosine in PD rat models ,139. In Based on the biocompatibility of the SF biomaterials in vitro and in vivo and the properties of this material that drive neuronal migration and axonal guidance , it woulA main cause of localized PNS traumatic injuries is severing of one or more nerves produced by an external force or trauma. In this case, neurons lost their connections and will need a pattern for regeneration. In general terms, and depending on location and extension of damage, PNS injury is more salvable than CNS damage. Although the regenerative capacity of peripheral nerves is potentially plausible, many patients show permanent motor and sensorial deficits.Following Seddon and Sunderland’s works, PNS damage can be divided into five categories based on the extension and severity of the injury ,143,144 Silk fibers might address these two limitations . The bioNon-functionalized electrospun tubular silk mats have been used as a conduit to regenerate PNS in a sciatic nerve-damaged rat model . The stuFollowing the successful results with SF fibers, the regeneration properties of the 30 mm gap filler silk fibroin scaffolds have been assessed by Xue et al. in the sciatic nerve damage inside of the dog. This model resulted in a similar quality of post-damage regeneration than in autologous nerve grafts .The natural properties of silk can be also further modified to improve the quality of cell adhesion, induce polarity to the biomaterial, and further tune the bulk and the surface properties. Some of such improvements in the biomaterial have been also applied in the context of drug delivery. In this section, we describe such strategies in the arena of SF usage.Through different sets of studies in various formats of SF, it has been confirmed that SF can offer minimal requirements for cell adhesion, which is essential for cell integration and regeneration ,88,90,91Coating SF biomaterials with positive-charge-based polymers is a good strategy to modify the partial charge of SF, enhancing the adhesion of stem cells and neuronal progenitors promoting neuronal outgrowth by interaction with the negatively charged surface of the cells. Polymers such as polylysine, propylenemeine, and polyethyleneimine (PEI) have been conventionally used for neuronal cell attachment . PerhapsCoating the biomaterial with ECM proteins might result in the provision of binding domains for adhesion receptors on the cell membrane, thus increasing cell adhesion and performance of the local biomechanical forces to cells . MoleculOther commonly used ECM-based proteins for coating silk fibroin are laminins. Laminins are composed of various α, β, and γ chains and are strongly bioactive molecules found in the basal lamina with an important role in cellular adhesion and differentiation. In silk fibers, the treatment with laminin has been found to promote cell migration, proliferation, nerve regeneration, and neurite outgrowth with considerable axonal extensions . The lamAntheraea yamamai and Antheraea pernyi has various RGD sites with the ability to improve cell adhesion, while the RGD content in the B. mori (silkworm) is lower [B. mori [The ECM proteins contain one or several short peptide motifs involved in several cellular processes such as cell adhesion, migration, and proliferation. The natural SF from various species of insects such as is lower . Consequ[B. mori . Further[B. mori . This stGrowth factors (GFs) are included in the family of trophic factors and are naturally occurring molecules capable of binding the cells to regulate many aspects of cellular function. Several GFs such as nerve growth factor (NGF) and fibroblast growth factor (FGF) are normally secreted from glia and neuronal cells in response to trauma conditions in a bell-shaped trend with the highest amount in the early phases of the injury and the reduction within one month of the damage ,164. TheGFs are heat-sensible proteins subject to proteolytic degradation with a short half-life. In the context of nervous system disorders, the integration of neural GFs with silk-based biomaterials has been associated with positive outcomes mostly due to the capacity of SF, like other biomaterials, to provide a continuous and controllable source of GFs as a result of the progressive biodegradability of the biomaterial . AdditioBased on the biodegradation properties of SF, it is possible to direct the delivery of GFs by integrating them within the bulk or the surface of the biomaterial. For example, the Vascular Endothelial Growth Factor (VEGF) and Brain-Derived Neurotrophic Factor (BDNF) have been integrated respectively within the surface or the core of the silk fibers. It was shown that, while the coating of VEGF on the surface and BDNF in the core has been linked with vascularization and neuronal regeneration of cavernous nerve, the integration of BDNF in the surface and VEGF in the center stimulated Schwann cell proliferation .By several techniques of coating and particle modification, SF can be loaded with small drugs to target specific areas. This will increase the bioavailability and will reduce the effective dose of the required drug. However, in the context of CNS disorders, an important challenge is the presence of the BBB, which limits the passage of substances administrated systemically. The delivery of drugs to the brain becomes even further challenging in injured brains, e.g., due to a traumatic injury or brain edema, as the result of damage limits the drug diffusion significantly . AlthougTo overcome these challenges, different silk formats such as films and micro- and nanoparticles can be applied. For example, SF films have been used to bypass the BBB to deliver small molecules that reached deep brain structures . The parThe potential of SF microparticles as a biocompatible regenerative construct has been discussed and assessed by Moisenovich et al. (2019). They found that the delivery of SF and SF/gelatin microparticles did not cause any toxicity or activation of microglia and astrocytes. Similarly, liposomes have been reported as efficient nanoparticles to bypass the BBB. Additionally, liposomes have been found to improve the therapeutic index, increasing the drug half-life and reducing side effects , and SF Drug delivery with silk fibroin and their promising results in non-neuronal tissues has been reviewed by Pham et al. . The conThe application of silk nanoparticles to bypass the BBB might constitute an attractive paradigm to neuroprotect and regenerate the damaged brain after trauma or neurodegeneration. An interesting example of silk for drug delivery can be considered for the treatment of epileptic seizures. Adenosine augmentation therapies have been found as an effective approach to suppress epileptic seizures based on the anti-convulsion effects of this nucleotide ,183. SysBy creating composites of SF and other materials, it is possible to tune the mechanical and bulk properties of the material and enhance the attachment of cells to the fibers. For example, the mixture of cellulose fibers and SF sponges were linked with extensive cell attachment potential. The cellulose fibers have a partial solubility upon the addition of lithium bromide solution so the SF/cellulose composite can be created by mixing these solutions in 9.2 M LiBr . It was Composites of PLA/SF have been spun by electrospinning with an integrated growth factor (NGF) that was able to sustain the attachment and growth of neural cell lines . In thisProviding a polar pathway is important for guiding neuronal cells, further maturation, and differentiation. Composites of polar spun and non-polar biomaterial can provide an arrangement in non-polar 3D silk biomaterials and scaffolds such as sponges and hydrogels . As a rePerformance of the physical surface modifications to the biomaterial and the alteration of the topology by patterns or molecules can introduce polarity and arrangement of the biomaterial to guide proliferation and cellular migration. Techniques such as photolithography, pattern stamping and lyophilization have been utilized to provide polarity and patterns for cells guiding ,191. TheAnother strategy to guide cells is to establish topological patterns by coating them with bioactive molecules. One of the first studies in this regard was done by Kang et al. (2004); where the gradient dispensing with RGD molecules caused a significant arrangement of fibroblast cells . This stRecently, we have identified that SF fibers obtained through SFS seem to have a natural compatibility for axonal guidance . ApplicaThe application of mechanotransduction and intermittent mechanical stress regimes in neuronal outgrowth and maturation was found to be important in neural engineering , but extIt is only recently that we have realized the opportunities that silk affords in treating a variety of neurological disorders such as Alzheimer’s disease, Parkinson’s disease, stroke, and peripheral nerve injury. This natural material shows innate anti-inflammatory and neuroprotective properties.It is relatively easy to structure silk proteins in various 2D and 3D formats including hydrogels, films, sponges, and fibers. The ultimate biocompatibility, biodegradability, and the ease of SF handling allow for a loading of stem cells, bioactive molecules, and other drugs to boost bioactivity and nervous tissue regeneration.Despite the recognized advantages of silk fibroin in vitro and in vivo, the transition of the silk application from the scientific research to the large-scale industrial purpose is dependent on the further research to increase the reproducibility of the inter and intra batch utilization to produce a standard strategy that is resource-efficient, environment friendly, time efficient and cheap. At the same time the processing procedure should be endowed with the ability of automation and production of high-quality silk-based biomaterials. In this regard, the industrial production line of silk sutures  reflect the range of properties offered by this material and how they can be combined with an industrial production ,204,205.Another important point to focus, is the need for further experimentation to prove the usability of SF in the clinical area and the context of regulatory agencies. In this sense, it is essential to test the safety, tolerability, and effectiveness of different therapeutic SF-based products before their translation into clinics .Addressing this problem, our group has performed a set of studies for the assessment of the safety and tolerability of SF in a hydrogel format in the mouse brain , which s


Hospital logistics staff comprise a crucial, albeit easily overlooked, group in the prevention and control of hospital nosocomial infections, especially during the COVID-19 pandemic. From the perspective of hospital safety improvement, this paper describes the current situation and challenges in the prevention and control of nosocomial infections among hospital logistics staff. We also provide the following suggestions to improve nosocomial infections: (1) updating the learning system of nosocomial infections, (2) reinforcing the training of infections prevention, (3) properly arranging manpower and resources, and (4) improving the supervision and management system. Nosocomial infections, also known as hospital-acquired/associated infections, refer to infections occurring within 48 hours of hospital admission, 3 days of discharge, or 30 days of an operation , 2. NosoWhile medical staff, such as doctors and nurses, have received extensive training on nosocomial infections awareness and prevention, other staff, especially logistics staff, in the hospital received far less attention in the management of nosocomial infections prevention. Hospital logistic staff are a crucial part of the hospital and play essential roles in maintaining the normal operation and management of hospital routine activities. Logistics staff account for more than 10% of the total hospital staff and are highly involved with multiple daily duties including cleaning, sanitizing, collecting and transporting the medical waste, and cleaning contaminated materials, etc. Due to their diverse and extensive daily duties, logistics staff are in close contact with patients, which may expose the patients in a potential risk of nosocomial infections –7.The global pandemic of the COVID-19 further aggravates the severity of nosocomial infections, especially after several outbreaks being reported in China. According to the current policy and guideline on COVID-19 management, all outpatient clinics of a hospital will be closed once a hospital staff was suspected to be infected with COVID-19. Such a strict lockdown policy not only negatively affects the normal operation of hospitals, but more importantly, may cause great inconvenience in patients' visits to hospitals to get timely and proper treatment for their own diseases. Therefore, hospital logistics staff, as a key chain in maintaining hospital normal operation, cannot be ignored in the prevention and control of nosocomial infections. This paper describes the current situation and challenges in the prevention and control of nosocomial infections among hospital logistics staff using a provincial hospital as an example, based on which we further propose several strategies to control nosocomial infections.Hospital logistics staff are characterized by low education levels and have a poor understanding of nosocomial infections; they also lack the professional knowledge in appropriate prevention and control of nosocomial infections . Among tHospital logistics staff often undertake multiple tasks such as cleaning, sanitizing, delivering medicines, and maintaining elevator operation, leading to a heavy workload on these staff. However, most logistics staff are hired through an outsourcing company, which usually cuts down the number of workers to reduce labor costs and increase company benefits. As a result, the few limited logistics staff working in the hospital are overloaded with extensive logistics work and are at high risk of burnout. In addition, the wages of logistics staff are very low and do not increase with an increased workload, further discouraging staff's enthusiasm in work. This situation is even worsened by the COVID-19 pandemic that is characterized by its sudden outbreak, destructiveness, and uncertainty, leading to a large number of logistics staff resigning due to excessive fear . All theHospital logistics staff's primary duties include cleaning and disinfecting the hospital environment and medical products for the cleanliness and safety of the hospital. Multiple pathogens may exist in patients' body fluids such as blood, urine, and secretions, as well as medical wastes, object surfaces, and the surrounding air, making it imperative to strictly implement standard protective measures among logistics staff . HoweverMost of the hospitals only focus on the training and monitoring of nosocomial infection among clinical medical staff such as doctors and nurses but ignore the training and monitoring among logistics staff. There is a lack of comprehensive training requirements and plans on nosocomial infections among newly employed logistics staff . WithoutThe prevention and control measures of nosocomial infections may vary according to the various positions the logistics staff hold in various time periods. This requires targeted training to be implemented among logistics staff based on their requirements for various positions in various time periods . The “BaOnce the learning system on nosocomial infections is updated, logistics staff will be immediately organized to receive standardized training. The training is mainly led by the head nurse and the nurses in charge of nosocomial infections and is composed of two major parts: theoretical training and skills training. Theoretical training includes the following parts: (1) knowledge on infectious diseases, such as the etiology, transmission routes, and basic protective measures of COVID-19; (2) knowledge on nosocomial infections, such as various disinfection requirements in various regions, specimen transfer, and medical waste disposal; (3) knowledge on self-protection, such as face-masks wearing, hand hygiene procedures, temperature monitoring, and reporting. Skills training includes appropriate hand hygiene procedures, face-masks wearing, and protective clothing wearing and takeoff. Considering the general low literacy level of the logistics staff, the training will take diverse forms such as live demonstrations and video shows to improve the training effect . After aThe COVID-19 pandemic has led to a widespread shortage of staff and medical resources at various positions in all hospitals. Hospitals should actively mobilize resources from all over the country to meet various position requirements and ensure normal resources supply. The logistics management department of the hospital should negotiate with the outsourcing company to protect the rights and well-being of logistics staff including increasing the number of staff workers, decreasing their workloads, and enhancing effective communications. In addition, the hospital should also provide encouragement and support to alleviate psychological distress such as panic, depression, and anxiety caused by work overload and fear of infections. Negative emotions among logistics staff during the COVID-19 may lead to the ignorance of and inadequate implementation of nosocomial infections prevention and control measures, thus increasing the risk of nosocomial infections. In addition, the hospital should distribute protective resources based on the actual needs of each post in each department and strengthen the management of these protective resources. The logistics staff should be instructed to take appropriate protective measures according to their exposure risk while avoiding resources waster caused by overprotection .Hospitals should attach more importance to their logistics staff and understand the essential roles they play in the prevention and control of nosocomial infections. Hospitals should strengthen cooperation with outsourcing companies to establish a complete, orderly, and feasible management model that connects the hospital logistics management department, hospital nosocomial infections control department, hospital clinical departments, and outsourcing companies. This multiparty comanagement model establishes a joint inspection team to conduct on-site inspections and enables each department to implement its own function, as well as strengthens communications among departments . In addiSince the outbreak of COVID-19 in 2020, the National Epidemic Prevention and Control Department has issued multiple policy documents on infections prevention, emphasizing the importance of nosocomial infections prevention and control. Whether for daily medical management or for the fight against the COVID-19 pandemic, the prevention and control of nosocomial infections in medical institutions have always been a priority. Logistics staff are a crucial part of the hospital and their important roles in maintaining the hospital's normal operation can never be ignored. Logistics staff are characterized by heavy workloads, high personnel mobility, and low education levels, making it difficult to implement standard protection and constituting a weak link in the prevention and control of nosocomial infections. In recent years, there have been reported cases of nosocomial infections among logistics staff in the fight against major infectious diseases. Based on the past experiences and challenges in the prevention and control of nosocomial infections, the establishment of a comprehensive training and monitoring system for nosocomial infection prevention and control among logistics staff carries significant implications and may be extended to other countries.


The development of CFTR modulator therapies significantly changed the treatment scheme of people with cystic fibrosis. However, CFTR modulator therapy is still a life-long treatment, which is not able to correct the genetic defect and cure the disease. Therefore, it becomes crucial to understand the effects of such modulation of CFTR function on the airway physiology, especially on airway infections and inflammation that are currently the major life-limiting factors in people with cystic fibrosis. In this context, understanding the dynamics of airway microbiome changes in response to modulator therapy plays an essential role in developing strategies for managing airway infections. Whether and how the newly available therapies affect the airway microbiome is still at the beginning of being deciphered. We present here a brief review summarizing the latest information about microbiome alterations in light of modern cystic fibrosis modulator therapy. CFTR (cystic fibrosis transmembrane regulator) gene that encodes a cAMP-dependent chloride and bicarbonate channel (Cystic fibrosis (CF) is the most common genetic disorder among Caucasian populations . It is p channel . Over 21 channel , which c channel . Althoug channel . The hyp channel . CF path channel .Pseudomonas aeruginosa or Staphylococcus aureus.Since infection plays a critical role in CF pathology, many studies have been performed to investigate the airway microbial community structure in people with CF. In the past few years, the cost-reduction of next-generation-sequencing (NGS) has made it possible to apply culture-independent methods to investigate the CF airway microbiome. Multiple studies have revealed diverse polymicrobial communities in CF respiratory samples , and idePseudomonas, Staphylococcus, Stenotrophomonas, or Burkholderia) were associated with decreased microbial diversity and positively correlated to worsened lung functions, higher inflammation, and increase in antibiotic exposure   .P. aeruginosa relative abundance and an increase in alpha diversity. However, the underlying mechanisms of how the correction of CFTR function may alter the airway microbiome remain elusive. Improved mucociliary clearance, changes in the biophysical properties of the microenvironment, the antimicrobial and anti-inflammatory properties of CF modulators, or disruption of a vicious cycle may all possibly contribute to changes in the airway microbiome.It appears that CFTR function and airway microbiome are interrelated, and correction of the CFTR function defect results in improvement of airway bacterial community structure towards a decrease in The studies we reviewed here only included subjects age 6 years and older, many of whom had already established infections when the modulator therapy started. It is known that the rise of typical CF pathogens with more advanced disease starts at 3-5 years of age, whereas in 1-2 years old individuals, the airway microbiome is usually polymicrobial with a high relative abundance of oral commensals . Based oCFTR mutations, up to now, the focus of the studies is the effects of ivacaftor therapy on airway microbiome in patients with at least one allele G551D. For the most frequent CF mutation F508del, the patients can be treated with several other modulator therapies, e.g. lumacaftor-ivacaftor therapy, tezacaftor-ivacaftor therapy, and elexacaftor-tezacaftor-ivacaftor therapy. However, only one study of the effects of lumacaftor-ivacaftor on airway microbiome in F508del-homozygous individuals has been reported, and the effects of other modulator therapies on the airway microbiome have not been reported yet. The relevant investigations need to be performed in patients with diverse genetic backgrounds. From the experimental design aspect, it would be informative to investigate the correlations between airway microbiome parameters and clinical (or inflammatory) parameters, the result of which may provide important information for optimizing personal and precision medicine in CF treatment.Although multiple modulator therapies are now available for the treatment of patients with a wide range of Regarding the NGS methods for analyzing the microbiome, up until now only 16s rRNA targeted approaches have been used in the studies investigating the effects of CFTR modulator therapies on airway microbiome, whereas the shotgun metagenomics approach has not been utilized yet. In addition to the advantage of achieving information about gene repertoire of the microbiome, with the shotgun metagenomics approach, it is possible to identify the frequency and abundance of each component in the community at the species or even strain level , which cP. aeruginosa? Understanding the dynamics of the airway microbiome in response to different therapies and unraveling the interaction between pathogens and commensals might be able to provide answers to this important question.In summary, the results of most prior studies indicate that airway bacterial community structure can be regulated by CFTR modulator therapies, at least to a certain extent. Owing to the highly limited number of studies investigating this topic, this topic is just at the beginning of being deciphered. To reach a more comprehensive understanding, more investigations should be carried out to study the effects of lumacaftor-ivacaftor therapy, tezacaftor-ivacaftor therapy, and elexacaftor-tezacaftor-ivacaftor therapy in patients with diverse genetic backgrounds. Several other aspects need to be addressed as well including the effects of modulator therapy on the airway microbiota in individuals < 6 years old, the correlations between airway microbiome changes and clinical (or inflammatory) parameter alterations, or the inter-microbial interactions within the CF microbial community. Controlling chronic CF airway infections is one of the most important tasks for physicians in the healthcare management of people with CF. In addition to utilizing antibiotics, is it possible to apply other strategies to fight pathogens in the lung, especially BY, AD, and SB performed literature research and wrote the manuscript together. All authors contributed to the article and approved the submitted version.This work was supported in part by the German Ministry for Education and Research (82DZL004A1 to SB) and from the German Cystic Fibrosis Association Mukoviszidose e. V. (Project number 1805 to AD and SB).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Calcifying aponeurotic fibromas (CAFs) are rare benign tumors that typically develop in the soft tissue of the extremities. We report a case of 64-year-old woman with a CAF in the soft tissue surrounding her left clavicle. A plain radiograph showed an asymmetrical increase in opacity of the left internal clavicular region. Computed tomography and magnetic resonance imaging confirmed the presence of a heterogeneous lesion of the periclavicular soft tissue, with peripheral calcifications, and remodeling of the adjacent clavicular bone. Following ultrasound-guided biopsy and surgical resection of the mass, the final histological diagnosis was made. To the best of our knowledge, this is the first case of a CAF described in the soft tissue adjacent to the clavicle. It is essential to use all the diagnostic methods available  to obtain the final diagnosis of this rare disease. In 1953, Keasbey first described a soft tissue lesion located in the hands and feet of four children; he classified the lesion as "juvenile aponeurotic fibroma." In 1964, Lichtenstein and Goldman termed it "fibromatosis cartilage analog." In 1973, Iwasaki and Enjoji termed the same lesion “calcifying aponeurotic fibroma” (CAF) after it was found that it was present not only in children but also in adolescents and adults ,7,11,15.A 64-year-old female patient was referred to our hospital with a history of long-term polyarthralgia and myalgia. She also presented with swelling of the left clavicular region that had been present for 3 years and had progressively increased in size and become more painful. On physical examination, there were no motor or sensory function abnormalities in the left upper limb. Routine laboratory tests showed no significant alterations. A standard chest radiograph revealed clear asymmetry and increased opacification at the left medial clavicular region A. Plain No-contrast computed tomography (CT) revealed the presence of a soft tissue lesion with chondroid calcifications located under the left pectoral muscles: between the first rib, its chondrocostal joint, and the clavicle . It was Because of these findings, the initial diagnostic consideration was synovial osteochondromatosis, although it was not possible to completely rule out a primary cartilaginous tumor of the soft tissue, such as chondroma, periosteal chondroma, or chondrosarcoma. Following an ultrasound B-Mode evaluation , an ultrMicroscopic examination revealed a multinodular, lobulated, architectural pattern with extensive areas of calcified cartilaginous tissue, adjacent non-calcified cartilage remnants, and an outer fibroblastic component without atypia, necrosis, or mitoses . Most ofCAFs are benign fibroblastic tumors located in the subcutaneous tissue Enzinger and Weiss suggested that CAFs develop biphasically, with initial and late phases. In the initial phase, seen more frequently in young patients, the tumor has an infiltrative and destructive growth and often lacks calcification; while in the late phase the tumor is more compact and nodular and exhibits a more prominent degree of calcification and cartilage formation ,8,13,18.MRI and CT are the imaging modalities of choice for CAFs The final diagnosis was reached after percutaneous and surgical biopsy, and subsequent cyto-histological analysis.In conclusion, we present a rare case of a CAF with the lesion located in the soft tissue around the clavicle, an unusual location for this lesion. A thorough clinical evaluation is vital for accurate diagnoses; advanced radiographic and imaging evaluation can aid in preoperative planning, and a definitive diagnosis is obtained by histopathology. Surgical treatment and excision of the tumor produce favorable results; however, recurrence rates are high due to its multinodular characteristics, which may result in seeding or hourglass remnant tumor nests. Although it is a well-known entity, CAFs can be a diagnostic challenge, particularly when they occur at unusual ages and in atypical locations, as in our case. The characteristic images of CAFs may mimic those of malignant lesions and this should be considered in the differential diagnosis when chondroid and sarcomatous soft tissue lesions are suspected.Publication approval was received from Netcare research operations committee. A copy of the approval is available for review by the Editor-in-Chief of this journal.No funding.Written informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the editor-in-chief of this journal.Salvatore Marsico MD.None declared.


The classical debate between nativism  and empiricism  originated in ancient Greece and developed in the Renaissance, including analogies of Aristotle and metaphors of Gottfried Wilhelm Leibniz about the contents of the mind, persists to our days in neurobiology. The subject of this Research Topic is an example of this controversy. From a methodological perspective, an obesogenic environment is an experimental approach in which environmental manipulations, such as exposure to hypercaloric diets, drinking sugar-sweetened beverages , and reduced physical activity, separately or in combination, may lead to metabolic imbalances, weight gain, and finally to adiposity. The scientific field continues making strides to determine the contribution of the myriad of obesogenic factors modulating energy homeostasis.Flores-Dorantes et al. provide an integrative view on the relationship between obesogenic environments and obesity, with both neurodegenerative and neurodevelopmental diseases. The authors emphasize the involvement of genes traditionally associated with food intake regulation, such as those that code for the leptin-melanocortin pathway proteins and their incidence on neurodegenerative and neurodevelopmental diseases. They call our attention to the gene-environment interaction that promotes an imbalance between caloric intake and energy expenditure. They provide further evidence for common neurobiological pathways between obesity and neurodegenerative diseases, suggesting that metabolic syndrome and obesity are risk factors for Parkinson's disease and Alzheimer's disease (AD).In this Research Topic, six original papers, two reviews, and one mini-review summarize the impact of several obesogenic factors upon food intake regulation, obesity-associated biomarkers, and describe several behavioral and molecular approaches that enhance our understanding of obesity. In the context of the sedentary lifestyle and the constant availability of junk food that has dramatically increased in the last 30 years all over the world, Bello-Medina et al. demonstrate evidence for spatial memory deficits, differences in beta diversity, and lower relative abundances of Actinobacteria and TM7 in the gut microbiota of 3 months-old 3xTg-AD mice, one of the most used transgenic models of AD, compared to non-transgenic mice. Their results suggest that microbiota alterations could be related causally to cognitive decline and may be employed as non-invasive biomarkers of AD, even at a presymptomatic stage.Whereas a relationship between obesity and the development of neurodegenerative diseases is widely accepted, we are just beginning to understand how environmental factors and the microbiome contribute to these conditions. Peleg-Raibstein focuses on the impact of maternal overnutrition by highly palatable diets, high-fat diets, a combination of high-fat-high-sugar diets, or cafeteria diets on the development of obesity and cardio-metabolic dysfunction and cognitive aging in the progeny. The article emphasizes the risk of unhealthy food environments provided by parents and the consequent exposure of their children. The author points to difficulties to discern between genetic and environmental risk factors to develop obesity and brain pathologies in the offspring. Related to these concepts, Cruz-Carrillo et al. employed a 9-week maternal overnutrition protocol. The authors report that the offspring from cafeteria diet-fed mothers exhibit an increased motivation to obtain pellets in operant tasks and reinforce their orexigenic response following subcutaneous injection of ghrelin. This behavior was associated with a higher global methylation in the shell region of the nucleus accumbens (NAcSh) and correlated with changes in the expression of pro-inflammatory cytokines. These results propose that high caloric nutritional intake during pregnancy and lactation increases the susceptibility to develop addictive-like behavior patterns in the progeny.Tsan et al. review literature in which overconsumption of highly palatable and dense foods leads to long-lasting multiple neurocognitive impairments in diverse rodent models. They conclude that overconsumption of Western diets during critical neurodevelopment stages is associated with detrimental cognitive performance across the lifespan. An example of this intricated relationship is given by Vega-Torres et al. In their study, the consumption of a Western-like high-saturated diet by adolescent rats for only 1 week is sufficient to impair emotional reactivity and anxiety. Cued fear extinction memory and neuronal activation of the basomedial amygdala attenuated, and corticosterone mRNA levels in the medial prefrontal cortex increased, altogether reveal the harmful impact of short-term exposure to obesogenic environments on the corticolimbic circuitry and emotional regulation during specific stages of neurodevelopment. Another study provided by Han et al. investigated the effect of a much more chronic exposure of young C57BL/6J mice to a high-fat diet. In their study, body weight, anxiety-like behavior, and, at the molecular level, the midbrain content of dopamine and D2 dopamine receptors increased after chronic diet exposure. From the pharmacological perspective and in line with food intake-associated dopaminergic activity, Kalyanasundar et al. evaluated the effect of D-norpseudoephedrine , an amphetamine-like sympathomimetic and anorexigenic drug, on food intake, body weight loss, and locomotion. Their results suggest that NPE-induced anorexia and body weight loss modulates neuronal spiking activity in the NAcSh. Though NPE is an African lifestyle drug with addiction risk, as an experimental tool, it elucidates feeding regulation associated with NAcSh neurons' activity in part controlled by midbrain dopaminergic neurons. Regarding the genetic aspects of metabolic diseases, Amaya et al. performed a translational study in AdKO2.0 transgenic mice, an animal model of Cushing's syndrome (CS), which is characterized by hypercorticosteronemia and metabolic abnormalities predisposing for obesity and metabolic syndrome, due to an inactivation of the gene encoding the regulatory subunit 1 alpha of the PKA, targeted to the adrenal cortex. Long-term exposure to high plasma glucocorticoids is strongly related to the gain of visceral tissue and stimulation of lipogenic pathways triggered by chronic stress. Their study shows overall parallels between imaging data from CS patients and AdKO2.0 transgenic mice as there is volume reduction in several brain areas and lower astrocytic and microglial markers, providing the opportunity to study the molecular basis and consequences of hypercorticosteronemia in a preclinical model.Apart from influencing obesity and metabolic dysfunction, The articles included in this Research Topic contribute to a more profound view of the complex relationship and potential causality between various obesogenic environmental conditions with the etiology of relevant neurodevelopmental and neurodegenerative diseases. The editors of this topic want to thank all the authors for their important contributions.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Tumor heterogeneity in liver cancer is a major contributor to the high lethality rate found in patients suffering from this disease. The therapeutic outcomes are drastically affected by this heterogeneity, which complicates patient stratification and response prediction. Better understanding of all the factors that can contribute to this heterogeneity will be critical to improve our understanding of liver cancer, in order to optimize the outcome of patients.Hepatocellular carcinoma (HCC) represents a global health problem. The incidence keeps increasing and current therapeutic options confer limited benefits to the patients. Tumor heterogeneity plays a central role in this context, limiting the availability of predictive biomarkers and complicating the criteria used to choose the most suitable therapeutic option. HCC heterogeneity occurs at different levels: within the population (inter-patient heterogeneity) and within tumors from the same patient (intra-patient and intra-tumor heterogeneity). Experts in the field have made many efforts to classify the patients based on clinicopathological characteristics and molecular signatures; however, there is still much work ahead to be able to integrate the extra-tumor heterogeneity that emerges from the complexity of the tumor microenvironment, which plays a critical role in the pathogenesis of the disease and therapy responses. In this review, we summarize tumor intrinsic and extrinsic sources of heterogeneity of the most common etiologies of HCC and summarize the most recent discoveries regarding the evolutionary trajectory of liver cancer cells and the influence of tumor-extrinsic factors such as the microbiome and the host immune system. We further highlight the potential of novel high-throughput methodologies to contribute to a better understanding of this devastating disease and to the improvement of the clinical management of patients. Liver cancer represents a major health problem, causing more than 800,000 deaths annually worldwide . The mosIn addition to the vast inter-patient heterogeneity, HCCs are characterized by high levels of intra-tumor heterogeneity, which entail that tumor cells within a tumor are phenotypically different ,15. MoreThe high inter-patient heterogeneity in HCC limits the availability of predictive biomarkers, complicates the development and clinical implantation of targeted therapies, and contributes to the poor outcome of the patients. The dissection of the contribution of each tumor-extrinsic and tumor-intrinsic factor in the process of hepatocarcinogenesis may help in the future to discover novel biomarkers and better define prognosis in patients.HCC is a complex malignancy that can be triggered by many different factors including hepatic viral infections, alcohol abuse, and diet-induced metabolic disorders. The different etiologies can promote various oncogenic pathways and most liver tumors (up to 90%) develop in the context of underlying chronic liver disease (CLD) that is characterized by the accumulation of extracellular matrix (fibrosis), scar formation (fibrosis and cirrhosis), and chronic inflammation, which together constitute the perfect pro-oncogenic niche for tumor initiation and progression ,20,21. More importantly, the surrounding microenvironment greatly affects the phenotypic output of liver tumors, even of those presenting activation of the same oncogenic pathways, contributing to HCC heterogeneity and highlighting the relevance of all the factors involved in the malignant transformation of hepatocytes . MicroenAmong the different tumor-extrinsic factors, demography is a very relevant epidemiologic aspect to consider. Viral infections caused by hepatitis B virus (HBV) and environmental exposure to aflatoxin B1, for example, are the most frequent risk factors in Asia and Africa, whereas hepatitis C virus (HCV) infection, chronic alcohol intake, and metabolic syndrome are frequently related to HCC in Western countries ,25. AmonThe exposure to environmental carcinogens has also been linked to the emergence of specific genetic alterations. The best known example, aflatoxin B1 (AFB1), is a mycotoxin that has been found in contaminated food, mainly in Asia and Africa, and is associated with a specific genetic signature of HCC characterized by a high rate of C > A mutations and the R249S specific mutation in the tumor suppressor TP53 ,34. In aMore prevalent in Western and developed countries are HCC cases associated with alcohol abuse and metabolic syndrome, although these etiologies are found globally. The incidence of alcoholic liver disease (ALD) and, specially, non-alcoholic fatty liver disease (NAFLD), have greatly increased across most developed countries during the last decades . NAFLD iExcessive alcohol intake can lead to alcoholic liver disease (ALD), and this is another prevalent diet-derived risk factor for HCC. The carcinogenic process in these patients, similar to that in NAFLD patients, has been linked to increased production of reactive oxygen species (ROS), changes in metabolic pathways, increased inflammation, and cell death along with impaired immune response . Those pRelated to diet-derived risk factors, there is a growing number of studies suggesting a strong contribution from host microbiome dysbiosis. Dysbiosis refers to changes in microbiota and, therefore, changes in microbial metabolites, that commonly co-occur with defects in the gastrointestinal barrier that facilitate the translocation of microbial products into the portal circulation. Patients with NASH ,43 or ciFinally, another relevant tumor-extrinsic factor to be mentioned in this review is the immune system, which is patient-specific with a unique genome and expression patterns, plays a pivotal role in tumor growth, and therefore contributes to inter-patient heterogeneity. Special attention has been paid to the study of the tumor immune microenvironment in the last years due to the emergence of immune-based therapies as effective first-line systemic treatment options against HCC. Moreover, the availability of high-resolution comprehensive analyses has enabled the immune profiling of HCC tumors despite their diversity and complexity. Studies of the interactions between tumor cells, immune cells, and non-immune stromal cells have shown different patterns across the different tumor subtypes, demonstrating clinicopathological significance and inter-patient, but also intra-tumoral, heterogeneity ,49,50,51During hepatocarcinogenesis, as well as during the carcinogenic process of other solid tumors, numerous genetic alterations emerge and accumulate during the different stages of the disease, resulting in unique cancer genomes. An accurate landscape of the genetic alterations in HCC has been established thanks to the cumulative data from high-throughput sequencing efforts for large numbers of samples from patients. In order to improve the understanding of the molecular basis of HCC, several molecular subclasses presenting distinct oncogene signaling pathways and recurrent mutations have been established ,62,63,64Unlike other tumor types, HCC rarely appears as a consequence of monogenic syndromes. Exceptionally, HCC has been seen in patients with APC germ-line mutations or presenting rare monogenic metabolic diseases such as hemochromatosis , Wilson disease , tyrosinemia type I , cutanea tarda , a1 antitrypsin disease , von Gierke disease , or diabetes of the young type 3  ,65. In aMost of the polymorphisms associated with HCC development are related to specific etiologies in the context of CLD, highlighting the close relation between the different environmental factors and the genetic background in the liver . AlthougThe so-called “genomic landscape of HCC” has been rigorously characterized in the work published in 2015 by Schulze and colleagues , which iIn addition to genetic alterations, aberrations in the epigenetic machinery are commonly observed in HCC ,78. EpigSummarizing this section, it can be clearly concluded that, contrary to other solid tumors, HCC development is not determined by the dysregulation of one specific molecular pathway but of many. Prediction of patients’ outcome or prognosis and therapeutic decisions based on the molecular features of the disease cannot be limited to the unique presence of specific genetic or epigenetic alterations, but to the combination of all the altered pathways that usually emerge along the chronic process until tumor development and that can be subjected to changes during the tumor progression.As explained above, genetic alterations in HCC are found in a variety of cancer driver pathways with a highly heterogeneous pattern of alteration among patients ,73,88. TSome groups of patients present HCC derived from the malignant transformation of hepatocellular adenoma, which is a rare benign hyperproliferation of hepatocytes ,102. HCAIn 2007, Boyault and colleagues  further Despite the advances in the stratification of HCC patients, above summarized and supported by the implementation of high-throughput analysis , the intIntra-tumor heterogeneity is a feature frequently found in many solid tumors ,106. HCCAbout 70% of the patients with HCC under curative treatment options develop recurrence, considered early-recurrence within two years of treatment or late-recurrence when it occurs after more than two years ,111,112.From a clinical perspective, it would be expected that high intra-tumoral heterogeneity and clonal diversity in HCC correlates with worse patient prognosis and limited therapeutic options, as this enhanced heterogeneity in the tumors would trigger worse therapeutic responses in addition to more susceptibility to developing targeted therapy resistance. In fact, it has been observed that those HCC patients with higher heterogeneity correlate with a worse prognosis and poor survival ,116; howReferences to the clinical implications of liver tumor heterogeneity have been mentioned along the different aspects addressed in this revision. The devastating concerns associated with the inefficient therapeutic responses against liver cancer reaffirm the imperative need to study in detail the mechanisms driving heterogeneity, to standardize a better subclassification of the patients for clinical management. Regarding decisions about the treatment of patients with HCC, physicians commonly rely on the stage of the disease rather than its molecular singularities. However, as it has been extensively explained here, the phenotypic differences at the molecular level between patients within the same stage are abysmal. Characterization of molecular subtypes and/or oncogenic signatures have generally improved the patient outcome for several types of cancer. However, the molecular classification of HCC has not been implemented for managing patients. Due to this complexity, there are not clear inter-patient biomarkers that can predict the response to a specific therapy (with the exception of ramucirumab and high AFP levels), whereas the high incidence of intra-tumor heterogeneity can induce a positive selection in the tumor subclones that is hard to foretell. In this sense, the widespread implementation of transcriptomic profiling of tumors at single-cell resolution by performing single-cell RNA and DNA sequencing along with single-cell proteomic studies might provide a comprehensive view of the tumor microenvironment and tumor cell trajectories to more accurately provide stratification strategies for HCC patients. The implementation of this novel methodology along with the use of experimental systems to properly model and understand HCC heterogeneity will enable better therapeutic approaches, based on the identification of molecular signatures that foster the choice of one therapy over another see . MoreoveAltogether, from a clinical point of view, the introduction of standardized methods to assess tumor heterogeneity in liver cancer would most likely enable better therapeutic outcomes and improve survival prognosis. Finally, it would be ideal to implement novel tools to monitor, in real-time, the molecular changes and cancer clonal evolution in patients with HCC. The technical advances in the next decade will be critical to reduce costs and show feasibility.


In this comprehensive review, we focused on the neurosurgical treatment as an integrative part of the challenging multidisciplinary management of cerebral metastases, a neuro-oncologic entity, which has been observed to have an increased incidence over the last years. In selected cases, the surgical removal of the space-occupying mass reduces the intracranial pressure, normalizes the metabolic environment, reduces the symptom burden, and allows for the intensification of local and systemic adjuvant treatment. In detail, we discuss the incidence of brain metastases, the role of surgical resection, as well as the evolution of current neurosurgical techniques, the surgical morbidity and mortality of single and multiple lesions, and we enlighten the role of surgery for recurrent tumors.The multidisciplinary management of patients with brain metastases (BM) consists of surgical resection, different radiation treatment modalities, cytotoxic chemotherapy, and targeted molecular treatment. This review presents the current state of neurosurgical technology applied to achieve maximal resection with minimal morbidity as a treatment paradigm in patients with BM. In addition, we discuss the contribution of neurosurgical resection on functional outcome, advanced systemic treatment strategies, and enhanced understanding of the tumor biology. Cancer is the second most prevalent cause of death worldwide , with luAlthough it is challenging to define the exact frequency of BM occurring in cancer patients due to the different data sources ranging from autopsy series ,17 throuThe BM location is an essential factor defining the clinical symptoms, management strategies, and prognosis of the affected patients . Althoug(1)The primary cause of CNS failure-related death in BM patients is the intracranial mass lesion that results in elevated intracranial pressure and increasing brain stem compression . The res(2)The brain as a host organ is highly susceptible to functional impairment due to local pressure and changed local biochemical environment in the context of metastatic tumor growth . Consequ(3)As shown in Patchell`s landmark paper, even in patients that were diagnosed with metastatic cancer, an intraaxial lesion is not a metastatic tumor in 11% of the affected patients . One mig(4)Finally, increasing evidence has indicated significant differences in the biology of primary cancers and the corresponding BMs, possibly resulting in additional therapeutic options . In a prTraditionally, the prognosis of patients with BM has been considered to be extremely poor , with a When analyzing the frequency of surgical complications, there appears to be a positive trend along the time axis . After aBased on clinical studies, between 30–50% of all BM patients present with multiple lesions, depending on the primary cancer type ,91,92,93Metastatic tumors of the brain were traditionally considered to be well-delineated with very limited infiltration of the surrounding tissue . CarefulBasically, the neurosurgical treatment modalities’ refinements were achieved by the implementation of various technologic advances, resulting in a better anatomical and physiological understanding of the affected brain. The identification of eloquent cortical areas is now routinely performed by functional magnetic resonance imaging (fMRI) in clinical practice ,120, whiSignificant efforts have been put forward to maximize tumor resection, as recent reports have shown a correlation between median overall survival in BM patients and the extent of resection as indicated by early postoperative MRI ,122,123.A rather clear-cut border zone between the tumor and unaffected brain was easily identified under the filtered light, and tumor resection was continued under the YELLOW illumination. The fluorescence-guided technique in removing BM has been evaluated repeatedly concerning safety, feasibility, specificity, and radiographic outcome ,132,133.Finally, the modern era’s neurosurgeons may be called in to foster the understanding of BM infiltration by a more sophisticated tissue sampling out of the infiltration areas, which will allow the more precise analysis of biologically relevant signal pathways responsible for BM infiltration. Image-based identification of areas that are critical for this question , transfeDespite the significant development of surgical technology reviewed in this article, the majority of BM patients are not considered to be adequate candidates for microsurgical resection, due to general condition, the level of comorbidities, as well as number and location of the metastatic lesions . Therefo3) treated by LITT may be associated with a higher likeliness of clinically relevant LITT-induced cerebral edema [LITT implies the minimally invasive, stereotactically guided application of photons by a fiberoptic laser to eradicate lesions within the brain ,154. Mosal edema ,166. In al edema . One stual edema . With real edema ,166; ceral edema ,166; andal edema ,166,169.Being introduced by Lars Leksell in the 1950s , stereotThe surgical resection of a metastatic tumor reduces mass effects and the intracranial pressure, leading to prolonged overall survival. Besides, the decompression of eloquent areas of the brain and normalization of the metabolic microenvironment causes a reduction of symptom burden and improvement of focal neurological deficits, which is associated with intensified adjuvant local and systemic treatment contributing to enhanced survival. Finally, the acquisition of tissue during surgical resection allows for the confirmation of the histological diagnosis of a metastatic tumor and the detection of brain-specific molecular alterations, which may lead to additional therapeutic options in the multimodal treatment of BM patients.


Dentists and dental staff have an increased risk of airborne infection with pathogens such as SARS-CoV-2 since they are exposed to high levels of droplets and aerosols produced during specific dental procedures. Hence, new guidelines such as patient screening and temperature control, air purification, space, surface and hand sanitizing and the use of protective equipment and physical barriers have been successfully implemented. In addition, the use of teledentistry has expanded considerably in pediatric dentistry, orthodontics, oral medicine and periodontics in order to address oral and dental health issues during the COVID-19 pandemic while minimizing virus transmission. Thus, teleconsultation, telediagnosis, teletriage, teletreatment and telemonitoring have emerged as valuable tools not only in the delivery of care, but also in the academic and research training of dental health professionals. This narrative review summarizes the current literature on the impact of the pandemic on dental care, dental staff and dental education, with an emphasis on how newly emerging protocols and technologies can be successfully utilized as integral parts of various branches of the dental practice and their future implications without compromising patient care. According to data provided by the World Health Organization (WHO), the new coronavirus, SARS-CoV-2, had caused 5,493,846 deaths globally by 10 January 2022, of which approximately 20% were recorded in the USA. Multiple factors are responsible for differences in contamination and mortality due to SARS-CoV-2 between countries. These include the implementation of domestic policies to control the spread of infection, vaccination, population density, comorbidities and the proportion of the ageing population, to name a few [Among medical practitioners, dentists and dental staff have an increased risk of being infected with airborne pathogens such as SARS-CoV-2 because they are always exposed to droplets and aerosols produced during specific treatment procedures. Transmission may occur due to the inhalation of droplets and aerosols from an infected individual or by direct contact with mucous membranes, oral fluids and contaminated instruments or surfaces. To evaluate the effects of intraoral and extraoral aspiration on the spread of infection during dental treatments, the bacterial colonization of droplets and aerosols was evaluated following simulations of scaling by the dentist and dental hygienist in three healthy volunteers. Extraoral aspiration has been shown to reduce the production of droplets and aerosols, and since it is restricted to the left and back of the dental chair, right-handed operators could perform treatment with relatively low contact with the pathogens. This study suggests that both aspiration methods were effective; however, extraoral aspiration was more effective in reducing the number of droplets and aerosols compared to intraoral aspiration or a lack of aspiration . FurtherSince COVID-19 is primarily spread through droplets and aerosols, it could reasonably be assumed that dentistry might be among the professions with the highest mortality rate . For exaThis qualitative, narrative review summarizes the most recent literature on the effects of the COVID-19 pandemic on dental practice and dental education, as well as the use of teledentistry in the delivery of oral and dental care to avoid virus contamination. Research and review papers were identified and selected using Scopus, PubMed and Web of Science scientific databases. Commentaries, letters and in vitro studies were excluded from the analysis. The paper describes in a comprehensive and critical manner, the effects of COVID-19 pandemic on the delivery of oral and dental care and dental education and its impact on current and future dental practice. Teledentistry has been defined as “the remote practice of dentistry by oral health professionals, within the limits of their practices, via the use of information and communication technology” . Its objFurthermore, 89% of dentists recommended oral rinses with solutions based on hydrogen peroxide and chlorhexidine before commencing therapeutic procedures. The combination of hydrogen peroxide with chlorhexidine solutions has been shown in vitro to be more effective than either solution alone in preventing transmission of SARS-CoV-2 . Other sAlthough SARS-CoV-2 has a predominantly airborne transmission, salivary contamination can be controlled much easier in dental offices. For example, recent studies that examined increasing suction capacity by using a large volume of air (150 mm Hg or 325 L/min) suggest that this measure may be sufficient to eliminate viral contamination . To furtA recent study conducted in Italy showed a state of normalcy in dental practices after the initial wave of COVID-19 pandemic. Since its onset, Italian dentists have experienced high levels of anxiety and stress, mainly due to the rapid spread of SARS-CoV-2 at the national level and the need for rapid adaptation to the new health standards in dental offices . ApproxiA recent study highlighted the changes in the spectrum of procedures performed before and during the pandemic. For example, during the COVID-19 pandemic, the number of conservative procedures, such as coronal restorations or root canal fillings, decreased significantly, while the percentage of surgical procedures increased significantly. In the following months, the decrease in the number of patients was offset by an increased number of procedures per visit ,13. LikeTelemedicine has proven to be an effective tool in mitigating some of the effects caused by the imposition of restrictive measures during the COVID-19 pandemic. Several authors have suggested that the lack of coherence in the implementation of telemedicine as a solution for continuous medical education is one reason for the absence of uniform protocols for aerosol-generating procedures . For exa® have emerged since 2019 and are dedicated to the prevention and management of oral malignant disorders in addition to improvement of oral health, in order to reduce unnecessary travel and loss of productivity [Teledentistry has been increasingly used by dental schools during the pandemic. Although there are regional differences in isolation policies, the severity of the outbreak and the availability of resources have greatly impacted the functioning of dental schools during the pandemic, although the responses of dental institutions to the COVID-19 pandemic show some similarities. For example, distance learning was the only alternative to theoretical dental education in many institutions. While e-learning already existed, it evolved and expanded as a result of the COVID-19 pandemic, with the use of synchronous online teaching methods when interacting with participants . In Italuctivity . Likewisuctivity .Telemedicine was further used in cases that would normally require clinical examination in order to distinguish between potentially malignant lesions from those that were truly malignant and necessitated immediate attention. This allowed dentists to keep patients with precancerous lesions, osteonecrosis of the jaw associated with medication and autoimmune diseases under control by comparing recently received photos with the last photos taken at the dental clinic. For these pathologies, clinical changes were evaluated to determine the risk of malignant processes and manage possible recurrences, infections, pain and stability of lesions . For exaNotwithstanding, teledentistry appears to be a promising tool in the remote management of patients requiring non-surgical or surgical treatment, especially by reducing costs and waiting times . To thisIn addition to the various devices that can be used in telemedicine, instant messaging applications have become increasingly popular for better communication between doctor and the patient. For example, WhatsApp-based teleradiology consultation proved to be an effective tool for interpreting X-rays with different dental pathologies . FurtherIt is well established that COVID-19 had a significant impact on nurses working in the field of dentistry, which affected the quality of medical services. Chronic diseases, immunodeficiencies, the risk of SARS-CoV-2 infection, working in a private environment and family responsibilities associated with financial risks caused by the pandemic have all contributed to significant increases in anxiety, burn-outs and other mental health disorders . This neAcademics working in the field of dentistry have been subjected to a high level of stress during the COVID-19 pandemic, not only related to teaching and research activities but also to concerns related to the possibility of contaminating their family members . This trThe COVID-19 pandemic has led to an increase in negative emotional states among students. Students were the population group most affected by the pandemic, showing an increased prevalence of stress, anxiety and insecurity . Female The COVID-19 pandemic has considerably affected the quality of dental students’ training. Dentistry is a scientific–educational field which combines theoretical concepts and principles with the acquisition of practical skills. In the absence of a mandatory residency program, basic dental education requires sufficient preclinical and clinical training to ensure an adequate level of competence for future professionals in the field . While dThe COVID-19 pandemic has greatly impacted research in the dental field. In some cases, having limited access to patients delayed and even compromised the results of clinical trials and restricted the implementation of new ones. For example, saliva and crevicular fluids are valuable diagnostic tools in dental medicine ,35. DiagThe COVID-19 pandemic has affected and still continues to significantly impact the delivery of dental healthcare due to changing clinical protocols and adapting them in order to minimize contamination risks. Teledentistry has expanded its initial scope and, when correctly implemented, could be an effective tool, but should be considered as a complementary means rather than an alternative to on-site, conventional treatments that are based on the principle of personalized medicine. Teledentistry can offer tremendous benefits in the delivery of some applications, while it can be limited in others. For example, pre- and post-operative counselling, education and care, nutrition advice and quick access to images of oral cavities through user-friendly imaging devices accessible to patients can all be performed via teledentistry. On the other hand, there are many challenges associated with teledentistry. These are primarily related to the lack of guidelines, standardization and scientific validation of teledentistry procedures and tools used in addition to issues related to data security and privacy. Other constraints are related to the inability to perform a clinical tactile exam, lack of direct contact with the patients, risk of misdiagnosis, lack of technological infrastructure, poor access to the Internet, lack of hardware, low information technology literacy, resistance to new technologies, and a lack of training and consumer awareness. There is no “one-fit-all” solution to overcome these challenges, and as the field evolves, new creative models will be developed in order to fit particular scenarios. Irrespective of the model used, the patient should be provided with the same quality of dental care as performed in the clinic. As a minimum, it should meet the following criteria: provide easy access to all populations, including the underserved, provide oral health delivery, including specialty care in a timely manner, and be sustainable, affordable and time effective. There are several limitations of this narrative review that include the inherent lack of quantitative analyses of published studies and being prone to biases. Notwithstanding, teledentistry proved to be useful in enhancing communication with, and treatment of, various categories of patients, such as those from nursing homes and prisons, and it is cost and time efficient. It is readily accessible, user friendly, and will no doubt continue to be expanded to new areas of dentistry and remote dental services, even after the COVID-19 pandemic. Moving forward, teledentistry will play a significant role in dental education and curriculum delivery by using technological advances in offering the skills required to maintain the quality of care while minimizing disease transmission. Finally, there is a need for more long-term comprehensive studies evaluating the impact of teledentistry in prevention, clinical outcomes and delivery of treatment across all branches of dentistry, as well as in developing distant training protocols in order to provide dental education in a safe environment.Dental staff, academic personnel, dental students and dental researchers were severely affected by the COVID-19 pandemic, which led to a decrease in the quality of care, clinical work and practical training. Despite its limitations, teledentistry has become a critically important tool during the COVID-19 pandemic in mitigating the risks of virus contamination and transmission. Overcoming challenges in adopting teledentistry by improving patient and management tools via new technologies coupled with innovations in dental engineering and equipment to minimize aerosol-transmitted pathogens will, no doubt, find the dentistry world better prepared to withstand the negative impact of a potential future pandemic. Thus, future research should focus on improving the quality and reliability of teledentistry in order to eliminate current technological errors and further integrating it as a complementary option in dental healthcare systems worldwide.


Depression is one of the most common mental disorders in the general population, and multiple mechanisms are involved in the etiology of this disease, including myelination. According to the Developmental Origins of Health and Disease (DOHaD) hypothesis, maternal diet affects the lifetime of the individual during adulthood and may contribute to the development of neuropsychiatric disorders. Additionally, the intensive processes of myelination contribute to the development of the central nervous system in the perinatal period, while any alterations during this crucial process providing the physiological functioning of neurons may lead to neuropsychiatric disorders in the next generation. The present review summarizes the current knowledge on the role of the myelin-related changes in depression, as well as the crosstalk among maternal malnutrition, myelination, and depression in preclinical and clinical settings. Depression is one of the most common mental disorders in the general population and affects all aspects of human life; it is characterized by sadness, guilt, loneliness, low self-worth, disturbed sleep or appetite, and loss of pleasure or concentration. Multiple potential mechanisms are involved in the etiology of depression, indicating the large heterogeneity of this disease . It is nMaternal nutrition, stress, physical activity, substance use disorder, and food preferences seem to be crucial during the fetal period. The Developmental Origins of Health and Disease (DOHaD) hypothesis posits that the in utero and early postnatal experience of the maternal diet affects the lifetime of the individual during adulthood and may contribute to the development of neuropsychiatric disorders . In the Over the past decade, several studies have suggested that diet could play an important role in the treatment and prevention of depression, as well as the potential effect of maternal nutritional imbalance during gestation on the risk of depressive-like behavior in offspring ,9,10,11.The present review summarizes the current knowledge on the role of the myelin-related changes in depression, as well as the crosslink among maternal malnutrition, myelination, and depression, and it discusses new directions in studies of depression based on a more comprehensive understanding of molecular determinants related to the myelination that participates in this brain disorder.v) channels required for the genesis of the action potential and subsequent repolarization using paranodal fast potassium (K+) channels [Myelin is a lipid-rich membrane structure produced by myelinating glial cells, the oligodendrocytes in the CNS, and Schwann cells in the peripheral nervous system. The myelin sheets are composed of (i) tightly packed spiraling layers of the membrane of mature oligodendrocytes that lack a cytoplasm, called compact myelin, and (ii) cytoplasmic noncompact regions connecting the oligodendrocyte cell body to the axonal side of the wraps and the nodes of Ranvier . Unlike channels . Then, tchannels  from botchannels  and inhichannels  neurons,channels ,21, reguchannels , neuronachannels , and synchannels .Oligodendrocytes derive from highly migratory and proliferative neonatal progenitors, which appear in the developing nervous system starting from approximate midgestation. During development, oligodendrocytes undergo a multistep process of maturation to obtain the capacity for myelination. The majority of neonatal oligodendrocyte progenitors differentiate into mature oligodendrocytes, but a small number of neonatal progenitors remain and transform into adult oligodendrocyte progenitors ,26,27,28+) with branched cell processes may remain in their undifferentiated state with a high proliferative potential in the CNS [The maturation of oligodendrocytes is characterized by several overlapping markers, whose expression is specific to the maturation steps  Figure . The cap the CNS . Differe the CNS . After t the CNS . Mature  the CNS  , a lower volume of white matter  and the v1.1) in the corpus callosum, and decreased activity in white matter, suggesting the association of morphological changes in oligodendrocytes with an inhibition of axonal activity [A similar myelin-related structural effect of chronic stress was seen in the medial prefrontal cortex of mice  and rat activity  Table 1v1.1 in tactivity .In a very recent study by Kurokawa and coworkers (2020), major myelin proteins and mature oligodendrocytes were decreased in the hippocampus of stress-maladaptive but not stress-adaptive mice following chronic exposure to restraint stress . On the Reductions in myelin thickness, length of internodes, and myelinated segments in the medial prefrontal cortex were specific to mice that displayed social avoidance behavior (“susceptible” mice) during chronic social defeat stress, while decreased MBP labeling was observed in mice both susceptible and resilient to stress in the nucleus accumbens . Additio+) in the medial prefrontal cortex of rats [According to these observations, in which the myelination is damped during depression (above), antidepressant drugs should reverse and/or normalize this alteration. In fact, it was shown that fluoxetine, a selective serotonin reuptake inhibitor, administered chronically reversed the suppressive effect of chronic unpredictable mild stress (CUMS) on myelin-related gene expression in the amygdala ,59 and c of rats . Moreove of rats . Further of rats  Table 1+ in the Myelin-related changes in depression were also documented in human studies. In fact, in patients with major depressive disorder (MDD), myelin levels were reduced in the whole brain and nucleus accumbens, whereas, in the lateral prefrontal cortex, myelin levels were decreased in depressed patients with a greater number of depressive episodes . DepressPostmortem studies on the brains of depressed patients confirmed the lower intensity of myelin staining in the dorsolateral prefrontal cortex regions in MDD individuals  and unipThe molecular data from human depressed brains show that reduced levels of oligodendroglial cells correlate with downregulation of myelin-related genes and proteins related to transcription factors ,97,99, oCompared to the preclinical study in which genetic ablation of oligodendrocyte precursor cells provoked the depressive-like behavior in mice , human sFrom the preclinical point of view, a modified maternal diet during pregnancy and lactation seems to play a critical role in producing a depression-like phenotype in offspring ,7,8,9,10l-ferritin) and disruption of iron regulation in pups born to high-fat diet-fed dams, which is a crucial component in the progression of myelination in developing neurons. Next, maternal-obesity-induced hepcidin dysregulation was associated with neuroinflammation and oxidative stress in pups at the critical period from birth through 21 days, when active brain growth, extension of neuronal processes, migrating oligodendrocytes, and myelination were the most extensive. Furthermore, an iron-deficient diet during gestation and lactation in female rats evoked a decrease in the diameter of myelinated axons and peak amplitudes of compound action potentials specific to these axons in the corpus callosum of offspring at PND 40, whereas a reduction in the dendritic length of pyramidal neurons in the hippocampus and a decrease in branching complexity in the cortex were observed at PND 21 [A maternal high-fat diet 5 weeks before mating and during pregnancy and lactation reduced the level of oligodendrocyte precursors in the lateral cortex of offspring at PND 7 . At the t PND 21 . Parallet PND 21 . Anothert PND 21 . These dt PND 21 . Reductit PND 21 . The abot PND 21 . Additiot PND 21 . On the t PND 21 . On the t PND 21  and decrt PND 21 , suggestt PND 21 . Cotreatt PND 21 . Similart PND 21 .In the latest study by Trujillo-Villarreal and coworkers (2021), it was shown that a cafeteria diet in mothers for 9 weeks  might prime depression-like behavior in the offspring, observed as a deficient motivation for natural rewards . StructuInterestingly, chronic nutritional stress using a low-calorie protein diet in mothers during pregnancy and lactation produced long-term changes in network parameters in offspring brain  and in tIn summary, since most brain development occurs prenatally and during lactation, maternal nutrition has been identified as a key factor for brain growth and maturation in offspring. According to preclinical research, a modified maternal diet provokes different myelin-related changes in rodents including gene and/or protein expression related to myelin, maturation of oligodendrocytes, and myelin structure changes, as a cellular mechanism that may contribute to behavioral alterations in offspring. Moreover, further research is needed to elucidate the molecular mechanisms related to myelin responsible for the development of depressive-like behavior in offspring exposed to a modified maternal diet, as well as search for contributory factors in the development of mental brain disorders.In humans, there are several lines of evidence that maternal malnutrition is implicated in myelin-related alterations. A case study on a 9-month-old girl with vitamin B12 deficiency, whose mother was a strict vegetarian with a low socioeconomic status, showed psychomotor regression, hypotonia, and lethargy with cerebral atrophy and delayed myelination . A similThe behavioral changes observed in early childhood may be associated with morphological, molecular, and functional alterations in the brain after a modified maternal diet. Importantly, several mechanisms including epigenetic , inflammatory, and hormonal may contribute to individual differences in predisposition to depression; however, further investigations are needed. In this regard, the maternal diet during gestation and lactation can lead to long-lasting alterations in the epigenome, which may induce long-term neurobiological modifications affecting synaptic function and structural plasticity.This review can raise awareness regarding the higher risk of developing problems during delivery of children (including the transmission of disorders), thus allowing for a better understanding of the mechanisms of such transmission and ultimately preventing it. In fact, the diet is one of the main sources of developmental brain damage with possible long-life neurodevelopmental disabilities; thus, understanding the effects of maternal diet on the developing brain as well as on depression is an important public health concern worldwide. Poor antenatal and postnatal nutrition further prevents infants from attaining their full developmental potential and developing affective cognition and increases their susceptibility to psychiatric disorders. As presented in this review, preclinical and clinical studies show that depression is associated with myelin-related changes. Additionally, maternal malnutrition during pregnancy and lactation is associated with specific alterations in the myelination processes in offspring, which seem to contribute to neurobehavioral changes in adolescence and adulthood, including a depression-like phenotype. However, more studies are required to determine the exact outcome of this problem to break new ground in our understanding of the impact of a maternal high-fat diet during gestation and lactation on myelination in brain offspring and to provide novel mechanistic strategies underlying myelin modulation in the pathogenesis of depression.