Advances in three-dimensional (3D) printing techniques and the development of tailored biomaterials have facilitated the precise fabrication of biological components and complex 3D geometrics over the past few decades. Moreover, the notable growth of 3D printing has facilitated pharmaceutical applications, enabling the development of customized drug screening and drug delivery systems for individual patients, breaking away from conventional approaches that primarily rely on transgenic animal experiments and mass production. This review provides an extensive overview of 3D printing research applied to drug screening and drug delivery systems that represent pharmaceutical applications. We classify several elements required by each application for advanced pharmaceutical techniques and briefly describe state-of-the-art 3D printing technology consisting of cells, bioinks, and printing strategies that satisfy requirements. Furthermore, we discuss the limitations of traditional approaches by providing concrete examples of drug screening  and drug delivery systems , followed by the introduction of recent pharmaceutical investigations using 3D printing-based strategies to overcome these challenges. Since its introduction in the 1980s, three-dimensional 3D) printing has become a representative adjunct manufacturing technology. This technology was first developed for rapid prototyping and is widely applied in various industrial fields, including automotive, home appliances, space, and consumer goods . Since tD printinThe development of new drugs is a high-cost and time-consuming endeavor, with high risks involved due to preclinical validation and clinical trials. Reportedly, an estimated 12–15 years are required for a single new drug candidate to undergo a series of evaluations before market availability B 4]. Fo. Fo4]. FOver the past few decades, drug screening has conventionally depended on transgenic animals as disease models. However, the use of animal models raises serious ethical concerns, as well as confer inevitable limitations in precisely representing human tissue in the context of pathophysiology owing to genetic discrepancies . StatistIn addition to drug screening, the development of printable materials with various biodegradation profiles has facilitated the manufacture of drug delivery systems with individually controlled doses and customized medical devices that closely match the patient anatomical features . A key oThis review provides a summary and brief classification of pharmaceutical applications applied to 3D printing technology. We first discuss the requirements of drug screening and drug delivery systems for advanced pharmaceuticals, which could be met by 3D printing. Furthermore, we describe the current methodological approaches of 3D printing applicable to the pharmaceutical field. Lastly, based on the strategy of 3D printing for more advanced drug screening and drug delivery systems, we introduce the recent pharmaceutical applications of 3D printing.Pharmaceutical applications can be broadly divided into drug screening and delivery methods. The following sections classify and describe the elements required for advanced pharmaceutical technologies in each field of application.Drug screening is employed to identify and optimize potential drugs prior to clinical trials to achieve an approved drug candidate. Drug screening allows the reduction of unnecessary time and costs by rapidly excluding unsuitable drug candidates from the initial stage of the validation. Moreover, the importance of screening for distinguishing drugs that can be effectively administered for therapeutic purposes is gradually gaining momentum. We discuss the essential elements of drug screening in the following sections.Establishing a disease model that more accurately recapitulates pathophysiological behaviors and responses to a potential drug markedly improves the reliability of validation studies. Accordingly, the formulation of a 3D microenvironment reflecting actual tissues offers several advantages in drug screening, which can be achieved by encapsulating cells within the extracellular matrix (ECM). A 3D culture system enables physicochemical reactions that occur in native tissues to be executed by reproducing familiar in vivo conditions through cell–ECM interactions, as well as cell–cell interactions . Li et aCollectively, while 2D culture systems have limitations in representing complex tissue-level physiology, 3D culture conditions enable a more precise reproduction of tissue maturation by providing a native environment, enhancing cellular function, and promoting innate phenotypes. Accordingly, the development of 3D disease models that precisely simulate in vivo responses to potential drugs has gained considerable interest as a promising alternative to conventional disease models.Pharmaceutical development requires various considerations, including clear screening criteria for quantification, comparisons via counter screening, precise sequencing, drug metabolism processes, and response to false positives and negative outcomes . These rConventional experimental samples are manually prepared by distributing small volumes of cell-containing suspensions into a 96-well or greater array using a multi-channel pipette . HoweverSignificant advances in precision engineering have confirmed the possibility of establishing customized tissue/organ models. In particular, precision medicine has served as a tool to help identify effective treatments based on patient-specific data, such as genetics, through ex vivo disease research . Cells oGenetic information closely related to multiple symptoms and disease pathologies contains vital information on disease behavior, enabling pharmacological studies of disease progression and drug treatment response ,33. For Drug delivery systems are engineered devices or formulations that allow therapeutic agents to selectively reach the site of action. The development of an effective drug delivery system has the advantage of reducing potential off-target side effects, thereby maximizing efficacy. In the following sections, we discuss the requirements of drug delivery systems for pharmaceutical applications.Controlled drug release improves tolerability and reduces the incidence of side effects. Miller et al. demonstrated that the conversion of antiepileptic drugs from an immediate to a sustained-release formulation stabilized variabilities in absorption and improved tolerance to high doses exceeding 1200 mg per day . The autAdministered drugs are exposed to diverse environments depending on their location, method, and metabolic pathway. Accordingly, 3D printing strategies for controlled drug release involve the regulation of drug release profiles by printing a drug carrier composed of a material that degrades in response to specific stimuli to protect the drug until it is delivered to the region of interest. For example, Okwuosa et al. and Goyanes et al. developed 3D printed oral drugs for intestinal illness by using enteric polymers such as methacrylic acid  and hyprIn order to overcome the limitations of conventional mass production, targeted drug delivery is attracting attention as a personalized therapy to tailor disease prevention and treatment by accounting for differences in each patient or lesion site. Recently, advances in biomedical technology have enabled the on-demand manufacture of individual geometrics through the rapid optimization of multiple parameters. Robinson et al. introduced a fabrication approach for the rapid prototyping of a customized implant to treat bronchomalacia in newborns . The autAlthough prescribing each active pharmaceutical ingredient separately to treat a combination of diseases remains a commonly employed strategy, this inconvenient approach might lead to medication errors and serious patient compliance problems ,42. To a3D printing is an additive manufacturing process for creating three-dimensional objects from a digital file. 3D bioprinting has been recognized as a promising technology for creating tissue-based platforms with high reproducibility and versatility by accurately positioning biomaterials together with cells and biomolecules. These features of 3D bioprinting are directly associated with requirements of drug screening and drug delivery systems, enabling the design of more advanced pharmaceutical applications. To meticulously design a physiologically functioning model/device, researchers should consider various aspects of 3D bioprinting, such as suitable biomaterials, cell sources, and printing strategies.The appropriate choice of printable biomaterials, commonly referred to as bioinks, is essential for building tissue architectures with desired biophysical and biochemical properties. Biomaterials currently employed as bioinks are predominantly natural or synthetic-based polymers, which should possess features of biocompatibility and printability. In selecting an appropriate bioink, the major features of each bioink should be considered.Naturally derived biomaterials offer greater similarity to biophysical and biochemical constituents in native tissues, thereby closely recapitulating biological responses when compared with synthetic biomaterials. Numerous natural polymers isolated from animal or human tissues have been developed as bioinks and have revealed superior cell affinity to promote cellular functions such as migration, proliferation, and differentiation . HoweverSelecting a proper bioink depends on various factors, such as the characteristics of the target tissue, printing strategy, and biological process. To effectively build a drug screening platform and drug delivery device, it is necessary to continue developing and optimizing physically and chemically tunable biomaterials.Although most drug delivery devices are acellular, appropriate cell selection is a paramount factor in designing a drug screening platform to represent the physiological state and pathological process of the tissue of interest more precisely. Three types of cell sources  are commonly used to create a 3D bioprinted cellular model. To narrow the gap in biological responses due to genetic discrepancies between animals and humans, most in vitro platforms for disease modeling prefer utilizing cells derived from human tissue ,60,61. ARegardless of the nature of the cell source, there is a high possibility of variations between batches, attributed to various causes such as technical skills of users, differences in culture conditions , and incThe 3D printing strategy for biomaterial deposition includes inkjet-based, extrusion-based, and laser-assisted printing. These approaches possess different features, including the printing mechanism, resolution, speed, and applicable biomaterials. Herein, we provide a brief overview of the respective printing strategies.Inkjet-based 3D printing is a non-contact approach that allows controlled volumes of liquid bioink to be precisely dispensed onto a planar substrate A. InkjetInkjet printing can regulate the amount of bioink ejected with a high resolution of up to 20 μm ,72. UsinAlthough inkjet bioprinting has gained momentum in recent decades owing to its versatile potential, there remain limitations that need to be solved in the near future. As only bioinks with low viscosity (~0.1 Pa∙s) can be applied in inkjet printers, the narrow range of printable bioinks has often been challenging in inkjet-based bioprinting . In addi4 Pa∙s), including dECM, gelatin, alginate solution, and thermally or chemically molten synthetic polymers . T. T97]. TLight-assisted 3D printing has a significant advantage in constructing complex structures rapidly, but it remains challenging to build a heterogeneous construct consisting of multiple materials. Thus, the selection of an appropriate printing strategy should be considered based on the characteristics of each printing technology.To evaluate the pharmaceutical safety and therapeutic efficacy of drug candidates, in vitro analytical platforms should precisely recapitulate the anatomical characteristics and critical functions of target tissues/organs. Owing to the advantage of flexibly positioning cells, biomolecules, and biomaterials, 3D bioprinting techniques enable the establishment of advanced 3D cell culture devices that can be typically divided into three typical subjects: organoid, organ-on-a-chip (OOC), and tissue/organ equivalent . This seOrganoids, defined as miniature organs, are derived from the 3D culture of mammalian tissue-resident stem/progenitor cells or embryonic stem cells in the presence of necessary physiological cues and matrices. Organotypic constructs rely on cell proliferation, self-organization, and differentiation into specific cell lineages, and multiple types of cells resembling both the microarchitecture and functional characteristics of the target organ can be generated. Bissell et al. reported the first organoid structure in 1982, which was derived from both normal and tumor murine mammary glands by cell self-assembly in the presence of laminin and collagen IV . SubsequAlthough the traditional 3D culture of stem cells has been widely used to produce organoids due to its simplicity, this methodology has several critical limitations limiting the application of organoids. In particular, the random configuration of traditional 3D culture lacks precise control of organoids in terms of dimension and complexity. Challenges in reproducibility significantly limit the standardization and industrial production of organoids. In addition, it is difficult to incorporate complex and dynamic microenvironments  found in organ morphogenesis as instructive cues during organoid assembly. Therefore, to increase the complexity of organoids, challenges concerning the reproduction of 3D cellular structure and recruitment of perfusion networks need to be addressed. Owing to the ability to precisely position cells and biomaterials in a specific environment to create living constructs that closely imitate natural tissue and organs, 3D bioprinting techniques demonstrate unparalleled potential for overcoming the current challenges of organoid fabrication.Although 3D bioprinting of organoids is still in its infancy, undifferentiated pluripotent stem cells or differentiated stem cells have been biofabricated using extrusion and light-based bioprinting techniques to generate organoids in vitro. Gu et al. extruded human iPSCs within a hybrid bioink composed of alginate, carboxymethyl-chitosan, and agarose, differentiated in situ to self-assemble 3D embryoid bodies expressing three germ markers . In a reIn addition to the biofabrication technique, accumulating evidence has demonstrated that the composition of the applied bioink plays a vital role in ensuring long-term cell viability while offering stem cell niches for guiding cell differentiation. For example, Nguyen et al. compared the performances of human iPSCs co-cultured with chondrocytes in bioinks consisting of nanofibrillated cellulose (NFC) with alginate and hyaluronic acid . CompareExcept for the living cell-embedded bioink, cell aggregates or even organoids can be used as biomaterials for 3D bioprinting. For instance, a recent study developed a new bioprinting approach to transfer pre-cultured cellular spheroids into self-healing support hydrogels at high resolution, which enabled their patterning and fusion into high-cell density microtissues of a predetermined spatial organization C 121]. . 121]. IBy incorporating the 3D bioprinting technique, various organoids have been developed for regenerative medicine, disease modeling, and drug screening. The liver and kidney are critical organs for detoxification and systematic metabolism, attracting considerable interest in organoid construction to assess drug toxicity and metabolic processes. Yang et al. utilized extruded HepaRG cells encapsulated in a bioink composed of alginate and gelatin to construct 3D bioprinted hepatorganoids in vitro and demonstrated the detoxification function D 123]. . 123]. MNotably, 3D bioprinted organoids could address the limitations of 2D cell culture and animal models for in vitro disease modeling, given their ability to reproduce both cell–cell and cell–ECM interactions. Various bacteria/virus-induced intestinal organoid models have been developed. During the coronavirus disease (COVID-19) pandemic, human organoids have been employed to elucidate the pathology and develop effective treatments. Pioneering works evaluated how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects and damages human organs by using organoids of the human eye , airway Organoids created from patient-derived stem cells possess unique merits for understanding hereditary diseases and investigating optimal therapies for individual patients. Patient-derived liver organoids have enabled the modeling and study of disease pathology of genetic liver diseases, including α1-antitrypsin deficiency and Alagille syndrome . UndoubtFor drug discovery, equipped with a 3D bioprinting technique, it is possible to construct massive and reproducible organoids. This advantage allows modulating the microenvironment with high freedom. Reid et al. demonstrated the precise generation of tumoroid arrays and positioned cancer cells within chimeric structures using a 3D bioprinter, facilitating the study of tumorigenesis and microenvironmental redirection of breast cancer cells E 130]. . 130]. IIn contrast to organoids generated by morphogenesis following population and differentiation of self-renewal stem cell colonies, the tissue/organ in vitro equivalent was directly constructed to mimic the anatomical and physiological characteristics of their natural counterparts. The tissue/organ equivalent has emerged as a promising tool for drug toxicity assays and disease modeling, given the advantages of reproducing complex key human physiological aspects. Although conventional tissue engineering techniques can combine scaffolds and cells to generate living tissues for medical applications, traditional methods are limited to constructing structures with precise architectural features and spatial localization of multiple types of cells, hindering the generation of tissue/organ equivalents. As an additive fabrication technique, 3D bioprinting can produce a construct with complex structures and heterogeneous compositions, which emulates native tissues and organs. These constructs are valuable for drug discovery, precise drug application, and personalized drug screening.Although organotypic bioprinting could pave the road ahead for fabricating biomimetic tissues/organs in vitro, several critical challenges should be overcome before achieving applicable tissue/organ equivalents. First, the tissue/organ equivalent should replicate the anatomical and structural complexity of natural targets, such as spatial localization of different tissues, as well as their interfaces, vital for executing regular tissue/organ functions. For example, human skin is composed of dermal and epidermal layers. The signal crosstalk between resident fibroblasts and keratinocytes is critical for epidermal differentiation and maturation . SimilarSecondly, the vasculature, i.e., the circulatory system in the human body, is closely related during a large group of diseases  and is the site of action of several drug candidates . In addition, a hypoxic microenvironment may develop in the fabricated tissue analogs owing to the limited diffusion of nutrients. Reportedly, cells located distant from blood vessels (>200 μm) showed significantly decreased viability . TherefoThird, the human body is a complex environment entailing various physiological stimulations, such as chemical, physical, mechanical, and electrical signals. In order to better recapitulate the function and model disorders of tissues and organs, these microenvironmental elements should be considered. For instance, a regular laminal bloodstream maintains the quiescent phenotype and stable function of endothelial cells in blood vessels, while turbulent flow induces endothelial dysfunction that leads to the initiation of atherosclerosis . Gao et To date, these innovative strategies have encouraged researchers to successfully construct a variety of tissue/organ equivalents that resemble the complex anatomical and pathological features of the simulated targets, including the heart , kidney OOC is broadly defined as a microfluidic cell culture device that models the functional units of human organs. Microchannels allow not only the control of nutrient supply but also the flexible manipulation of biomechanical microenvironments  and biochemical features . Moreover, the microfluidic technique can achieve the effective spatiotemporal delivery of pharmaceuticals/biomolecules and in situ monitoring of cellular responses, facilitating the implementation of versatile and real-time drug screening. Furthermore, as a goal of OOC, combining multiple chips representing different organs can reconstitute a body-on-a-chip to mimic organ–organ interactions that regulate the drug delivery process, such as drug metabolism and absorption at the systemic level. Given these merits over 2D cell culture models, OOC is considered a potential analytic tool for pathological studies and drug screening.The construction of a viable OOC relies on understanding the anatomy of the target organ and simplifying it to fundamental elements that are essential for physiological functions. A representative example is a lung-on-a-chip device, which includes two adjacent microchannels separated by a thin and flexible porous membrane . While tHowever, the conventional construction of OOC usually relies on the precise processing and manufacture of polydimethylsiloxane (PDMS) , followed by selective cell-seeding, which remains complicated, time-consuming, and expensive. However, PDMS can only be used as an element for building the reaction device rather than simulating ECM for encapsulating cells; therefore, it is difficult to establish a 3D heterogeneous construct. Although PDMS is a nontoxic and biochemically inert material, its active absorbance of small molecules (less than 500 Da) can largely affect the test results of relevant drugs . In contOne essential goal of OOC 3D bioprinting is the incorporation of microfluidic channels with patterned living constructs to dynamically provide metabolic supplies and biochemical/mechanical stimulations simulating natural microenvironments in the human body. Pioneering investigations have explored various fabrication strategies for building microchannels, including (1) direct fabrication of fluidic chambers, (2) micro-molding, and (3) coaxial printing of hollow tubes.Extrusion- and lithography-based bioprinting were applied to directly create microchannels using printable polymeric materials. Lee et al. reported a one-step construction process that deposits multiple types of living cells within a prefabricated chamber by 3D extrusion of poly(ε-caprolactone) (PCL) A 91]. T. T91]. T3D bioprinting of fugitive templates with sacrificial materials ) is an effective approach for defining channels with complicated patterns and networks within hydrogel constructs. Upon seeding endothelial cells, microchannels that exhibit vascular functions can be acquired. Based on this methodology, Wu et al. developed perfusable vascular networks of 200–600 μm in diameter by printing PF127 within a PF127 diacrylate (PF127-DA) reservoir . By empl2+ ions . . 184]. Teuticals .Transdermal drug delivery is a method for delivering medications by applying a formulation to intact skin. This route affords the advantage of bypassing metabolic processes, reducing the burden of pill administration, and improving patient compliance . In partSurgical implants require a customized design that satisfies various considerations, such as anatomical differences according to patients, age, sex, and disease state. In this context, commercially available surgical devices generally lack a technological approach for creating drug-eluting implants that outline the patient’s anatomy. However, recent advances in 3D printing have allowed the fabrication of various types of patient-specific implantable devices containing drugs, providing opportunities for customized dosing in a narrow therapeutic window.Traditional drug delivery systems have relied on the mass production of average-sized therapeutic devices for a typical patient through implantation or attachment to the lesion. This mass production-based system remains a challenge for implementing various treatment regimens due to individual differences, resulting in low drug efficacy and several side effects in some patients. The introduction of flexible technology that allows the creation of customized devices that reflect the anatomical, pathological, and physical characteristics of a patient is of great interest in the pharmaceutical development of drug system.A recent strategy using 3D printing technology to manufacture patient-specific pharmaceuticals established complex freeform shapes with a high resolution based on clinical information obtained from CT or MRI scans of the patient. The printing of implants reflecting the patient’s anatomical characteristics through CAD further enhances the competitiveness of narrow therapeutic window drugs. Muwaffak et al. successfully printed a patch-shaped structure that accurately reflected the patient’s nose contour through STL technology based on facial data obtained from a 3D scanner . AnotherIn conclusion, the current strategy in 3D printing utilizing CAD-based biomedical information and printable biodegradable materials offers a straightforward and less expensive solution to create customized devices for transdermal and surgical drug delivery.Multiple attempts have been made to introduce 3D printing into pharmaceutical studies for establishing topically applicable drug delivery systems . The skiMicroneedle transdermal patches are microscopic applicators that create microscopic pores in the skin to allow drugs such as vaccines and macromolecules to be topically administered and offer an attractive alternative to oral non-steroidal anti-inflammatory drugs. The needle length is approximately 25–2500 µm, which can reach the depth of the skin capillary, and the diameter is designed to prevent nerve damage when attached . These mSurgical patches are one of the most widely employed medical tools, as they are relatively simple in terms of fabrication and can provide direct treatment to internal organs. As illustrated by Yi et al., 3D printed biodegradable patches consisting of an anticancer drug, 5-fluorouracil, demonstrated dramatically decreased tumor size in a mouse tumor model with few side effects B 203]. . 203]. TAdvances in 3D printing technology for transdermal and surgical drug delivery systems have accelerated the development of innovative personalized drug delivery systems that accommodate various patient cases.3D printing is broadly defined as the process via which a 3D model is used to generate a physical object, and it has recently garnered considerable attention due to growing applications. In recent years, the development of numerous biomaterials has resulted in advances in 3D printing, thus, making it a novel engineering tool that can build 3D objects to be applied in the pharmaceutical industry. Furthermore, 3D bioprinting has been widely introduced as a method of constructing living tissues or organs by employing biological components such as cells and biomolecules.In traditional pharmaceutical approaches for drug screening, 2D-based cell cultures and animal models have been used to elucidate biological mechanisms of test drugs and uncover disease states. However, these screening models have often failed to comprehensively represent the actual human body due to different microenvironments and genetic discrepancies. The ability of 3D bioprinting to recapitulate living tissues that are substantially similar to natural structures can overcome the limitations of existing preclinical models. Although current pioneering drug screening research has proven the obvious benefits of 3D bioprinting technology, research into patient-specific drug development is still in its infancy. Studies on various characteristics that may appear when using patient cells should be conducted more actively.Furthermore, the manufacture of drug formulations utilizing 3D printing is expected to play a vital role in the development and innovation of various drug delivery systems. Unlike traditional pharmaceuticals that rely on mass manufacturing, 3D printing approaches can potentially provide individualized treatments to patients, improving efficacy and side effects for individual patients. The study of the 3D printed drug delivery systems currently under investigation are focused on the design depending on the drug release behavior and drug delivery mechanism; thus, 3D printing technology is an effective approach to the formulation of patient-specific drug delivery systems.Taken together, as a growing number of patients demand customized therapeutics, 3D printing technology is well suited to offer tailored drug screening platforms and drug delivery systems that fulfill a set of individualized needs. Given its potential applications in several medical domains, 3D printing is uniquely suited to assist biologists and pharmacologists at different stages of drug development and patient treatment.


Chronic neurodegenerative diseases are complex, and their pathogenesis is uncertain. Alzheimer’s disease (AD) is a neurodegenerative brain alteration that is responsible for most dementia cases in the elderly. AD etiology is still uncertain; however, chronic neuroinflammation is a constant component of brain pathology. Infections have been associated with several neurological diseases and viruses of the Herpes family appear to be a probable cause of AD neurodegenerative alterations. Several different factors may contribute to the AD clinical progression. Exogeneous viruses or other microbes and environmental pollutants may directly induce neurodegeneration by activating brain inflammation. In this paper, we suggest that exogeneous brain insults may also activate retrotransposons and silent human endogenous retroviruses (HERVs). The initial inflammation of small brain areas induced by virus infections or other brain insults may activate HERV dis-regulation that contributes to neurodegenerative mechanisms. Chronic HERV activation in turn may cause progressive neurodegeneration that thereafter merges in cognitive impairment and dementia in genetically susceptible people. Specific treatment for exogenous end endogenous pathogens and decreasing pollutant exposure may show beneficial effect in early intervention protocol to prevent the progression of cognitive deterioration in the elderly. Retrotransposons constitute approximately 40% of the human genome and are major drivers of genomic evolution ,2,3. ThrIt has been reported that approximately 0.1% of spontaneous mutations are caused by retrotransposon insertion and ∼95% these mutations are induced by SINE or LINE ,5.A classification of transposable elements in human genome is reported in For instance, syncytin is encoded by HERV-WE1, a full-length provirus at locus 7q21.2 on chromosome 7 and is involved in placental development . HERV elThe mammalian genome has evolved molecular mechanisms  to contrFor instance, DNA methylation ,19,20,21Few mutations associated with human retrotransposon activation have been implicated in familial neurodegenerative syndromes and some autoimmune disorders ,30,31,32An abnormal activity of HERV has also been described in human brain diseases. For instance, levels of HERV-K have been found elevated in patients with amyotrophic lateral sclerosis ,32,33,34The above data are suggestive that ERV activation might represent a mechanistic and pathogenetic link of inflammation and neurodegeneration with some human disease and brain aging and pathology. However, our knowledge regarding the inducers of retrotransposon and ERV activation is still limited.In this paper, we illustrate and discuss a new notion suggesting that limited and chronic insults of central nervous system (CNS) such as infections by microorganisms or insults by pollutants may activate previously silent endogenous retrovirus which in turn may induce chronic inflammation, amyloid production, and neuro degenerative pathology associated with AD.An increasing burden of neurological disorders has been reported in the USA, with stroke, Alzheimer disease (AD), and other dementias being prevalent neurological diseases .AD is a chronic neurodegenerative disease and the prevalent form of dementia in the elderly. Declining immunity during ageing is often associated with peripheral chronic inflammation  and chroSeveral alleles in immunoregulatory genes have been shown to modify the AD risk and most of these gene are also involved in immune defenses against viruses and other microbes .Pathogens, such as viruses of the Herpes family, through frequent cycles of reactivation and latency, constantly trigger the immune system; however, immune responses cannot completely eradicate these microbes. Therefore, we suggested that these persistent neurotropic pathogens might play a role in microglia activation in the brain of genetically susceptible elderly and promote neurodegenerative processes .The amyloid-β (Aβ) peptide is associated with AD neurodegenerative processes and show antimicrobial activity against eight common and clinically relevant microorganisms . MoreoveThe Aβ peptide has also been shown to play a protective function against in vitro infection by Herpes Simplex virus-1 (HSV-1) . This obRecent findings have confirmed a causative role of viruses of the Herpes family in AD  and a reOur recent data showed that antimicrobial defense mechanisms of innate immunity appeared to be impaired in AD brains and we suggested that these immune alterations might contribute to neurodegeneration .However, findings regarding the presence of viruses or other pathogens in human normal and AD brains are conflicting and a pathogenetic role of infectious agents in AD pathogenesis remains controversial.Tau intra neuronal deposition is a neurodegenerative hallmark of AD and tau pathology is also found in a heterogeneous group of neurodegenerative syndromes, the tauopathies, causing cognitive and/or motor impairment.Chromosomal instability is frequently found in ageing and neurodegenerative diseases and AD brain pathology is accompanied by genomic instability in affected neurons .In a drosophila model, tau induces global nuclear chromatin relaxation , abnormaRecently, differential expression for several retrotransposons in association with neurofibrillary tangle burden was observed in serial RNA sequencing from human AD brains . These rMoreover, another investigation provided evidence that the tau protein promoted neuronal death in tauopathies by dysregulating TE .Recently, a study showed that the plasma levels of a phosphorylated form of tau (p-tau217) increased over time in preclinical AD, e.g., cognitively unimpaired subjects with brain amyloid deposits, and prodromal stages of AD or MCI patients with brain amyloid deposits. Moreover, the plasma levels of p-tau217 increased with longitudinal worsening of cognitive performances and brain atrophy .These results might reinforce the notion of a pathogenetic role of tau in AD. However, we previously discussed that tau may induce HERV activation and neurodegenerative related mechanisms. Therefore, elevated p-tau217 appears to be a useful marker of cognitive impairment and might also be associated with TE dysfunction in AD. This topic deserves further studies.Retroviridae family contain two copies of single-stranded RNA (ssRNA) genome at their core and are encapsulated by host-derived lipid membrane inserted with the surface gp120 and the transmembrane gp41 proteins [Currently, two exogenous retroviruses are known to induce human diseases: human immunodeficiency virus (HIV) and human T lymphotropic virus (HTLV). While HTLV is a “classical” oncovirus, causing T cell leukemia, HIV infection causes acquired immunodeficiency syndrome (AIDS), which is accompanied by several comorbidities, including an increased incidence of some cancers . Virusesproteins . In geneproteins .On the other hand, ERVs are considered molecular remnants of ancient exogenous retroviruses which integrated their genomes in vertebrate ancestors during evolution .Here, we suggest that neuro infection agents such as exogenous neurotropic virus, other human pathogens with neuro damage potential, and chemical environmental insults might cause ERV activation by inducing brain temporary immune responses and inflammation. For instance, cyclic endogenous re-infections by virus of the Herpes family and chronic insults by environmental pollutants might be particularly relevant in inducing retrotransposon mutations and ERV induction. Virus–virus interactions have been reported in the pathogenesis of several human diseases. Examples are coinfection of hepatitis C virus (HCV) with HIV  or otherResults regarding HHV-6A and EBV interaction with HERVs, as a pathogenic mechanism in multiple sclerosis (MS), have also been reported . Those dFinally, data are on record showing that the HIV Rev protein can functionally interact with many repetitive elements (RcREs) present in the human genome, depending on the RcRE sequence, as well as the Rev sequence. This interaction may lead to the export of some of the HERV-K pro-viral mRNAs, changing the expression of non-viral genes .HERVs’ expression depends on several factors, and is epigenetically regulated by stimuli such as inflammation, viral and microbial infections. Increased expression of HERVs occurs in physiological and pathological conditions and several diseases have been attributed to one or more HERVs, particularly neurological diseases.We suggest that microbes’ infections of human CNS not only may directly induce inflammation and neurodegeneration, but they may also activate brain HERV which in turn by acting as continuous abnormal stimulation of inflammatory responses may contribute to neurodegenerative hallmarks associated with AD.Our hypothesis is supported by data regarding abnormal retrotransposon activation in AD which are indeed on record. For instance, a quantitative bisulfite-PCR pyrosequencing method was used to evaluate the methylation of Alu, LINE-1 and SAT-α sequences in 43 AD patients and 38 healthy donors and LINE-1 methylation resulted increased in AD patients .Moreover, Guo et coworkers  leveragiThe above results were confirmed and extended, since TE dysregulation was identified as a key mediator of neuronal death in tauopathies, and a significant increase in HERVs transcripts was found in AD and in progressive supranuclear palsy, suggesting that TE dysregulation might be a hallmark in human tauopathy .Recently, the increased brain expression of ERV has been shown in a drosophila model of human frontotemporal dementia (FTD) which is the second most prevalent form of human pre-senile dementia after AD. It was found than neuronal expression of CHMP2BIntron5 causes an increased activity of the endogenous drosophila RV, called gypsy, in the nervous system. Genetically blocking Drosophila gypsy activation or pharmacologically inhibiting viral reverse transcriptase activity stopped degenerative phenotypes observed in fly and rat neurons .Since FTD appears to overlap genetically and pathologically with amyotrophic lateral sclerosis (ALS), the authors  claimed Whether microorganism infections might induce the activation of ERV and whether such an activation might play any role in the pathogenesis of human diseases deserve more investigations. However, results are on record suggesting that immune cells activation by microbes induced increased expression levels of endogenous ERV . The autInfection with virus of the Herpes family can also induce an increased expression of ERV, as showed in a mouse model after infection with EBV. In this animal model lymphocytes from infected animals showed increased transcription of the env gene of HERV-K18. This protein is known to possesses a super antigen activity  and may It of interest that EBV, even during the latent phase of the infection, appears to be able to induce ERV activation in men. In fact, it has been reported that activation of MSRV-type of ERV was detectable during both human infectious mononucleosis and EBV latency .env in blood cells and astrocytes, and these mechanisms might contribute to the onset of MS [In this context, EBV glycoprotein 350 (EBVgp350) was found to trigger the expression of HERV-W et of MS . Similaret of MS ,70,71,72An important activator of HERV expression is the nuclear factor kappa-light-chain-enhancer of the activated B-cells (NF-kB) signaling pathway. These data are based on an earlier report demonstrating that the pro-inflammatory cytokine tumor necrosis factor (TNF) can stimulate the HERV-W promoter, at that time known as ERVWE1/syncytin, via the induction of NF-kB .A summary of the concomitant presence of exogenous virus and HERV activation in human neurological disease is presented in Therefore, an initial inflammation of small brain areas induced by Herpes virus invasion may induce a dysregulation of HERV activation and expression which in turn may contribute to neurodegenerative mechanisms. Subsequent virus cycles of activation and latency may induce not only limited brain damages and neurodegenerative mechanisms, but also persistent HERV activation which in turn may cause further neurodegeneration. These vicious and damaging cycles thereafter merge in cognitive impairment and dementia in genetically susceptible people.Amyloid deposition and the accumulation of iper-phosphorylated Tau (p-Tau) are two classical hallmarks of AD neuropathology. However, accumulating evidence have shown that these two compounds are also induced by infection with exogenous virus both in vivo and in vitro models. For instance, it was shown that infection of cultured neuronal and glial cells with HSV-1 leads to a dramatic increase in the intracellular levels of A-β peptides 1–40 and 1–42, .The observation was then confirmed in a in mouse model where the HSV-1 repeated cycles of activation, latency, and reactivation were induced by thermal stress. In this animal model, the accumulation of AD hallmarks including amyloid-β protein, tau hyperphosphorylation, and neuroinflammation markers such as astrogliosis, IL-1β, and IL-6 were induced. Moreover, repeated virus reactivations correlated with increasing cognitive deficits which become irreversible after seven cycles of infection . It of iDifferent viruses of the herpes family, such as HHV-6 and 7, were also able to seed A-beta deposition in a mutant mouse model of AD (5xFAD) or in a 3D model of human neural cell cultures. The author suggested that amyloid deposition leads to protective virus entrapment .Recent data showed that p-tau was transiently induced in mouse adult hippocampal neuron cultures infected by HSV-1, whereas A-beta was constantly produced during infection and colocalized with HSV-1 latency-associated transcript (LAT). The authors concluded that p-Tau may act as acute phase response factor, while A-beta aggregation may represent a long-term response to infection. .However, discordant results are on record suggesting that amyloid may not be protective against virus infection in the 5xFAD animal model of AD. .A relationship between brain infection and amyloid and Tau protein is not limited to viruses of the Herpes family. HIV, a human exogenous retrovirus, also show the ability to induce amyloid production and deposition in the brain of patients with HIV-associated neurocognitive disorder (HAND) . RecentlThe above results support the notion that infection by exogenous viruses may indeed induce brain A-β peptide production, amyloid deposition, and increased p-tau as counteracting antimicrobial mechanisms.Data regarding the role of amyloid or tau proteins in HERV activation and control are scarce. However, when HERVs are activated, they act as infectious virus and induce cell invasion and inflammatory response. Therefore, HERVs may contribute to neurodegeneration by chronic inflammatory pathway activation in human brain.Recently, it was reported that amyloid deposition in mouse hippocampus induced increased SINE B2 non-coding RNA processing. . On the Recent data showed that increased HERV transcripts were detectable in the brains of patients with different tauopathies . These dOn the other hand, the inappropriate activation of HERVs might interfere with brain immune response against exogenous virus and other microbes and increase the invasive behavior of these pathogens.In conclusion, a non-casual relation appears to link amyloid and tau proteins to infection by exogenous virus and abnormal expression of transposons and HERV in brain affected by neurodegenerative processes.Pathogens are not the only insults able to induce neurodegenerative lesions in the human brain. In fact, pollutants can induce many neuro-pathological alterations and affect brain functioning. A recent report indicates that in a cross-sectional study of 18,178 individuals with cognitive impairment, people living in areas with worse air quality were more likely to have positive amyloid positron emission tomography scan results .2.5) air levels appeared to be associated with brain amyloid-β plaques, one neuropathological hallmark of AD [Moreover, higher particulate  and concomitant presence of cardiovascular disease on the risk of developing dementia in a selected population from Sweden. The study found that air pollution exposure was associated with a higher risk of dementia. Patients suffering heart failure and ischemic heart disease and exposed to air pollutants showed increased risk of dementia, whereas stroke seemed to be an important intermediate condition between the association of air pollution exposure with dementia. [An interesting longitudinal investigation assessed the relationship of long-term exposure (2001–2004) to air pollutants  to PMdementia . All tog2.5 showed that brains from these animals had increased levels of amyloid plaque deposition, astrogliosis and inflammation [An experimental investigation using an AD mouse model (APP/PS1 transgenic mice) exposed for three months to PMammation . TherefoChemical pollutants are also involved in brain damage. In fact, another study using APP/PS1 transgenic mice exposed to benzo(a)pyrene for two months showed that brains from these animals suffered increased neuronal loss, A-β peptide burden and amyloid deposition .Chronic insults from air and chemical pollutants reaching the brain may also interfere with transposons and ERV activation and control.Preliminary results are on record suggesting that another environmental chemical pollutant such as bisphenol A (BPA) activates HERV . MoreoveResults reported above suggest that chronic insults such as air and chemical pollutants induce brain damages, promote AD associated neurodegenerative hallmarks and in some instance may activate HERVs and induce dysregulation of RE which might have pathogenetic consequences on neurodegenerative mechanisms.Alternatively, we cannot exclude that environmental pollutants may induce neurodegenerative processes by activating latent human neurotropic virus such as those of the Herpes family which in turn are able to induce AD related neuropathology directly or after the activation of HERV.Another emerging human virus with brain lesion potential is the pandemic SARS-Cov-2 or COVID-19 virus. This virus infects nasal mucosa and the respiratory tract causing in several instances severe respiratory distress and death in frail patients.COVID-19 virus along with other neurotrophic virus, such as those of the Herpes family, can enter the brain by olfactory fibers of the nasal mucosa and the olfactory nerve, thereafter reaching by axonal retrograde transportation the human brain. Therefore, neurotropic virus may access the brain by olfactory mucosa and its nerve terminations. On the other hand, air pollutants might use the same way to enter human brains. Here, these insults may directly induce inflammation and neurodegenerative mechanisms and/or indirectly promote neuronal damages by activating HERVs which may induce chronic brain inflammation and neurodegeneration.COVID-19 is indeed a neurotropic virus and can induce cognitive impairment and brain alterations during the acute clinical phase. It is of note that COVID-19 infection accelerates cognitive deterioration in persons with preexistent cognitive impairment and conversion of patients with mild cognitive impairment to AD . This neThe spike protein of COVID-19 has been shown to bind amyloid peptide and tau protein and increase deposition of these molecules . MoreoveWhether this virus might induce a dysregulation of HERV in the brain and long-term alterations of brain metabolism also remain open questions.Olfaction is an animal ancient sense. Across different species, it modulates the interactions between an organism and the surrounding environment. In different neurological pathologies, like Parkinson’s and Alzheimer’s disease, dysosmia is exacerbated compared to the physiological decrease associated with ageing and occurs before motor and cognitive disabilities .Many studies claim that the alteration of the olfactory system may be used as an early predictor for detecting AD, because several brain olfactory regions are impaired in the asymptomatic prodromal phase of this disease due to the deposition of pathological hallmarks .We have already discussed that acute virus infections, such as COVID-19, as well as air pollutants are able to damage olfactory mucosa and its nerve terminations. Therefore, it not surprising that the decline in smell acuity and sensitivity is also an early sign of acute COVID-19 virus infection and possibly of chronic persistent infection by some viruses of the Herpes family.It remains to be determined whether smell impairment may correlate with recently reported blood markers of impaired cognition such as p-tau217 and used in tandem to clinical screening of cognitive impairment in pre-clinical phases of dementia.As presented here, environmental insults, such as persistent virus infection and pollutants, may reach the brain via anterograde transportation along the olfactory nerve and induce neuron damages which in turn may activate HERV and TE disfunction.This hypothesis is compatible with our recent data showing impaired mRNA expression of IFN pathway in AD brains, since both exogeneous viruses and HERV induce IFN defensive mechanisms .The activation of HERV may induce neuronal infection and intraneuronal damages amplifying neurodegenerative alterations and activation of persistent neuroinflammation with further neuronal damages.Inappropriate chronic activation of HERV induced by infections or other environmental insults may represent the driving force able to induce continuous neurodegenerative processes that after several years may merge as clinical manifestation of dementia and other neuro-degenerative diseases. An inappropriate activation of HERV may induce neurodegenerative processes by different mechanisms. First, these ancient retroviruses can induce inflammation and immune responses mediated by Toll-like recognition receptors and type I-IFN production. Therefore, HERV by inducing neuroinflammation contribute to neuronal and synaptic loss. Second, HERV activation or their induced inflammatory response may activate other transposable elements which in turn may induce neuronal loss by increasing chromatin instability.Therefore, HERV activation might be the missing link between exogenous brain insults and internal damaging mechanisms such as A-β peptide and Tau expression and deposition. Other factors such as age, gender, genetic makeup, smoke, exercise, and diet also contribute to neurodegenerative processes.The notions presented here have relevant implications for the prevention and treatment of prodromal and early phase AD.In fact, it is possible to diagnose the presence of Herpes virus infection and reinfection by detecting plasma levels of IgM and IgG virus specific antibodies. In subject with high level of these antibodies anti-viral treatment would be advisable. Following up these persons and monitoring their cognitive performances during and after anti-viral treatment would be also advisable and would provide valuable information.It is of interest that a randomized clinical double blind clinical trial of AD patients with valacyclovir, an anti-herpetic drug, is in progress .Moreover, infections by exogeneous viruses can induce activation on HERV and we discussed the potential serious consequences of HERV reactivation on cognitive decline and dementia risk.Several laboratory analyses are available to detect HERV activation and infection and some antiretroviral drugs have been proposed for specific treatment of these new potential infectious agents . AntiretWe also suggest the relevance of detecting the possible presence of other pathogen infections in prodromal and early clinical phase AD and treating these patients accordingly the specific infectious agent. For instance, periodontitis is a common condition in aging population, and it is associated with an increased AD risk. Therefore, this chronic inflammatory disease should be treated appropriately.In conclusion, infections by exogeneous pathogens, insults by pollutants, and HERV activation appear to play a relevant role in the clinical history of AD. The specific treatment of these pathogens and decreasing environmental risk exposure may show beneficial effect in early intervention protocol to prevent the progression of cognitive deterioration in the elderly.


Surgical liver resection is a treatment option in patients with resectable colorectal liver metastases. We present two cases of focal nodular hyperplasia (FNH) development after treatment with oxaliplatin during follow-up of colon carcinoma. The first case was a 40-year-old male patient who developed multiple liver lesions suspect for metastatic disease four years after he had undergone laparoscopic right-sided hemicolectomy and adjuvant chemotherapy . He underwent a metastasectomy of segments three and four and microwave ablation (MWA) of the lesion in segment one. Pathological analysis demonstrated FNH. The second patient was a 21-year-old woman who presented with multiple liver lesions during follow-up for colon carcinoma. She underwent a laparoscopic right-sided hemicolectomy and was adjuvantly treated with capecitabine and oxaliplatin three years ago. Magnetic resonance imaging (MRI) was performed, and the lesions showed no signs of metastatic disease but were classified as FNH. Therefore, the decision was made to follow up the patient. In conclusion, the development of benign liver lesions could occur during follow-up of colon carcinoma and might be caused by oxaliplatin-induced changes to the liver parenchyma. Hence, it is important to distinguish these from metastatic liver disease. Colon carcinoma is one of the most common cancers in the world. About 18-25% of patients are diagnosed with liver metastasis in less than five years of the primary diagnosis . In addiμg/L). Subsequently, contrast-enhanced MRI of the liver was performed which showed seven lesions suspect for metastatic disease  and was subsequently treated with eight courses of capecitabine and oxaliplatin regimen as adjuvant chemotherapy, was referred to our hospital's specialised liver surgery unit because of multiple focal liver lesions suspicious for metastatic disease. During routine follow-up in 2019, two small liver lesions were discovered on ultrasound. At that time, the concentration of carcinoembryonic antigen (CEA) was low . Postoperative MRI after three months did not demonstrate any new lesions.μg/L), but a thoracoabdominal CT scan demonstrated multiple focal liver lesions suspicious for metastatic disease  was 54% and 24.5%, respectively. In contrast, there were no lesions described in the group of patients treated with surgery alone (n = 111). Therefore, it must be noted that benign liver alterations can occur after treatment with chemotherapy.The development of FNH mimicking metastatic disease after colon surgery with adjuvant chemotherapy is rare. A quick survey under specialised liver surgeons in the Netherlands did not show any other patients who developed FNH after oxaliplatin-based chemotherapy during follow-up after colon surgery. Only a few published case studies describe the development of FNH after colon surgery and adjuvant treatment with oxaliplatin –14. An iIn conclusion, these two cases illustrate the development of FNH during the follow-up of colon carcinoma after treatment with oxaliplatin. Although rare, it is important for physicians to be aware of the onset of benign lesions that mimic metastatic disease possibly caused by the hepatotoxic effect of oxaliplatin in order to prevent unnecessary invasive procedures.


Our aim was to identify clinical and sociodemographic factors associated with oral pain and oral health-related productivity loss among US adults.We included adults aged ≥30 years who completed the dental examination, had at least one natural tooth, and provided an answer about their oral pain experience or oral health-related productivity loss in the 2015–2018 National Health and Nutrition and Examination Survey (NHANES). We performed descriptive analyses and multivariable binary logistic regression analyses on weighted data.One out of four adults had oral pain and 4% reported oral health-related productivity loss occasionally or often within the last year of the survey. The odds of oral pain were higher among non-Hispanic black  and non-Hispanic Asian individuals  compared to non-Hispanic white individuals, and individuals with untreated dental caries . The odds for oral health-related productivity loss were 13.85 times higher among individuals who reported oral pain (95%CI = 8.07–23.77), and 2.18 times higher among individuals with untreated dental caries (95%CI = 1.65–2.89). The odds of oral pain and reported oral health-related productivity loss decreased as family income increased.Factors including non-Hispanic black race/ethnicity, lower socio-economic status, and untreated dental caries are associated with oral pain experience, which increases the odds of oral health-related productivity losses. Identifying factors associated with oral pain and productivity loss will enable clinicians, policymakers, and employers to proactively target and prioritize the higher-risk groups in early interventions and policies. Chronic oral diseases constitute a range of preventable conditions, primarily dental caries and periodontal disease, which affect more than 3.5 billion people worldwide, especially those living in low- and middle-income countries . Oral diOral pain is a common clinical symptom of oral disease and has a major influence on vital oral functions, self-esteem, quality of life, and overall health and well-being . Oral paOral problems account for 9–27% of sickness-related absences and 28–50% of presenteeism (reduction of productive capacity in the workplace) among adults, with oral pain being one of the most common reasons . SimilarIn the United States, approximately 2.1 million Emergency Department (ED) visits each year are related to oral pain . DespiteOral pain has been associated with a variety of factors which may lead to adverse psychosocial consequences . HoweverWe used data from the 2015–2016 and 2017–2018 cycles of the NHANES. This cross-sectional annual survey is conducted by the National Center for Health Statistics (NCHS), a part of the Centers for Disease Control and Prevention (CDC), and examines a representative sample of the non-institutionalized US population, with aggregate findings published every two years. The NHANES collects comprehensive data through self-reported questionnaires, physical examinations, and laboratory investigations. NHANES is one of the main sources of information on oral health status in the US, and includes questions related to oral pain experience and productivity loss ,15. We iAll data were fully anonymized before we accessed it.Oral pain and productivity loss were self-reported by participants aged 30 years or older. We categorized oral pain based on responses to the question, “How often during the last year have you had painful aching anywhere in mouth?” Individuals who reported feeling pain “very often,” “fairly often,” or “occasionally” were grouped into one category, while those who answered “hardly ever” or “never” formed another group. To assess productivity loss, we used the same criteria to categorize participants based on responses to the question, “How often during the last year have you had difficulty doing usual jobs or attending school because of problems with teeth, mouth, or dentures?” This question is one of the three questions adopted from original OHIP-49 and used at these NHANNES surveys .Dentists who performed the clinical oral health examinations were trained and calibrated to ensure reliable measurements among examiners and throughout cycles. We measured the presence of untreated dental caries and restored teeth among dentate individuals. Untreated dental caries was defined as any untreated dental decay involving the crown or root. Filled teeth were defined as teeth with coronal or root restorations for a carious lesion. We also included non-carious root lesions (erosions/abrasions) and restorations of non-carious root lesions in the assessment.The self-reported sociodemographic risk factors included age , sex , race/ethnicity , education level , and family income ratio to the federal poverty line (FPL) . We also included the individual’s daily average of total sugar consumption in grams (gm) using the first 24-h dietary recall data collected in-person. The average total sugar consumption was calculated if participants reported the second dietary interview 3–10 days later by telephone.Descriptive statistics for oral pain experience were obtained for all risk factors, including sociodemographic factors, teeth with untreated dental caries, and teeth with fillings. We recalibrated the weights to report a nationally representative prevalence and population counts of the pooled NHANES data across two cycles by dividing the sample weights by 2. Taylor linearization methods in the survey procedures were used to estimate the standard error (SE) using the supplied masked variance pseudo-stratum and masked variance pseudo-primary sampling units.Next, we obtained logistic regression models using the survey commands to estimate the socio-demographic and dental factors associated with the outcomes: oral pain experience and oral health-related productivity loss within the last 12 months. We calculated and reported the crude and adjusted odds ratios (OR) of the outcomes, with the corresponding 95% confidence interval (95% CI). After adjusting for all risk factors in multivariable logistic regression for oral pain, we included oral pain as a predictor in the full model for oral health-related productivity loss. We performed a sensitivity analyses by including edentulous individuals, as well as assessing the association for each survey cycle. Multicollinearity was checked by the variation inflation factor (VIF). Cook’s distances were calculated to assess residuals. Hosmer & Lemeshow tests evaluated the goodness-of-fit of the final models. Our estimates were deemed statistically significant at <0.05, and Stata/MP 16 (StataCorp) was used for all the statistical analyses.One out of 4 adults aged 30 years or older in the US reported experiencing oral pain occasionally or often within the last 12 months, representing approximately 41.3 million individuals . The higThe unadjusted OR indicates that oral pain generally decreases with age, is more prevalent among minorities than non-Hispanic white individuals, and has an inverse relationship with education level and family income . After aThe national prevalence of productivity loss due to oral health-related factors was estimated to be 4% among adults aged 30 years and older, which represents 7.0 million individuals who occasionally or often experienced difficulty in performing their jobs or attending school within the last year . IndividAfter adjusting for demographic and dental confounders, the logistic regression demonstrated that individuals with oral pain had 13.85-fold higher odds of experiencing difficulty in performing their work or attending school due to oral health-related factors (95% CI = 8.07–23.77) . FurtherAll the associations identified in the final models for both outcomes were maintained in the sensitivity analysis. Analyzing each NHANES cycle separately, some estimates of the smaller samples were slightly different than the overall average  Tables. This study evaluated the socio-demographic and dental factors associated with oral pain and oral health-related productivity loss among adults in the US using the NHANES dataset. Nearly one out of four adults in the US experienced oral pain occasionally or often within a year, and 4% reported oral health-related productivity loss. Non-Hispanic blacks, non-Hispanic Asian and disadvantaged populations had higher odds of oral pain or related productivity loss. We also found that oral pain was the strongest factor associated with productivity loss, among other dental and socioeconomic factors.The prevalence of oral pain was similar to the range identified in a 2001 review of the literature  and to fThe role of socioeconomic status in oral pain has already been demonstrated in different contexts –19. SociIn the US, non-Hispanic black adults have the highest odds of untreated dental caries, in contrast to non-Hispanic white adults . This stBehavioral factors, such as sugar consumption, increase the risk of developing dental caries, and as consequence, oral pain . ElderlyIn the present study, 7.0 million adults 4%) reported productivity loss due to oral problems within the last year, with oral pain and untreated caries being the strongest factors. The prevalence of absenteeism from work or school due to dental disease varies in the literature, ranging from 9% in an Australian study to 35.1% in a Canadian study . However% reporteThe literature describes the importance of oral health for quality of life, as well as the impact of oral pain on daily activities, especially at work and at school –7. In ad7 found that higher education level and income were associated with greater work absenteeism due to dental diseases and attempts to seek dental treatment [Considering the significant association between oral pain and oral health-related productivity loss, we found common socioeconomic factors associated with both outcomes. Although we found that less education and lower income were related to productivity loss, a study by Hayes et al.reatment .To tackle the challenges imposed by unmet dental needs, one of the national Healthy People 2030 objectives is to “reduce the proportion of people who can’t get the dental care they need when they need it” . With coAlthough the sampling and measurement methods, including clinical examinations, used to obtain the data used for this analysis are sufficiently valid and rigorous enough to represent the oral health of the US population, the study had some limitations. The cross-sectional survey design of NHANES made it impossible to evaluate temporality. Thus, we cannot validate the assumption that education, income, and dental diseases preceded our outcomes. In addition, the measurements of oral pain experience and oral health-related productivity loss were not quantifiable, and the timeframes for the questions could potentially introduce a recall bias. The recall bias could also lead to differential misclassification of the outcomes among individuals with severe dental diseases and those with mild dental disease. Lastly, the outcomes were measured among individuals aged 30 years or older, which limits our ability to make inferences about younger groups. Another limitation of this study is the findings obtained may not be generalized to other population or settings outside of US. Nevertheless, this is the first study to evaluate oral pain, productivity loss, and associated factors among adults in the US using the NHANES dataset.Oral health is an integral part of overall well-being; thus, oral pain can hinder the ability to achieve an optimal quality of life. Identifying factors associated with oral pain and productivity loss will enable clinicians, policymakers, and employers to proactively target and prioritize the higher-risk groups in early interventions and policies. Dental students and dentists should aim to identify the social determinants of oral pain and productivity loss, so they can gain more social competence in recognizing health disparities.S1 Table(TIF)Click here for additional data file.S2 Table(TIF)Click here for additional data file.S3 Table(TIF)Click here for additional data file.S4 Table(TIF)Click here for additional data file.


It is generally required in the case of moderate to severe atrophy of bone in the oral cavity due to tooth loss, trauma, or surgical resection. Currently utilized surgical techniques, such as autologous bone blocks, distraction osteogenesis, and Guided Bone Regeneration (GBR), have various limitations, including morbidity, compromised dimensional stability due to suboptimal resorption rates, poor structural integrity, challenging handling properties, and/or high failure rates. Additive manufacturing (3D printing) facilitates the creation of highly porous, interconnected 3-dimensional scaffolds that promote vascularization and subsequent osteogenesis, while providing excellent handling and space maintaining properties. This review describes and critically assesses the recent progress in additive manufacturing technologies for scaffold, membrane or mesh fabrication directed at vertical bone augmentation and Guided Bone Regeneration and their  Bone resorption is a phenomenon characterized by the volumetric reduction in viable bone tissue. Whilst osteoclast-mediated bone remodeling is an essential part of healthy bone metabolism, irreversible bone resorption can occur due to trauma or pathology within bone tissues . This isSeveral existing techniques aimed at vertical bone augmentation, such as autologous block grafts, distraction osteogenesis, and guided bone regeneration combined with particulate grafts (GBR), have shown varying levels of success and are generally considered to be technique sensitive and clinically unpredictable . Indeed,In vivo application of such scaffolds has yielded some success in pre-clinical trials and generated strong interest within the field (he field . This reSignificant progress in additive manufacturing technology (3D printing) has been achieved over the past twenty years. Multiple techniques ranging from powder ceramic to polymer fabrication have been developed and optimized, bringing the field to a level of technological competency whereby a diverse range of geometries can be fabricated relatively quickly, and with a high degree of dimensional accuracy and patient customization . UtiliziSynthetic scaffolds can be fabricated by a broad range of techniques, and the following For vertical bone augmentation, scaffolds must fulfill several essential criteria. The scaffold must be biocompatible and should not induce cytotoxicity, acute inflammation or any form of rejection or fibrous encapsulation . The matAs mentioned, whilst bone grafting techniques result in desirable clinical success rates, the method is still prone to post-surgical complications, and handling can be difficult for large bone deficiencies . This haBio-ceramics characteristically exhibit excellent osteoconductive and sometimes osteoinductive properties . This isin-vivo in an intramuscular rodent model. Surprisingly, the monetite scaffold underwent a more rapid degradation than the brushite. While brushite is a highly soluble phase and hence should have degraded first, a phase transition towards hydroxyapatite occurred via a dissolution/precipitation mechanism, thus rendering a proportion of the bio-ceramic block insoluble.Several research endeavors have advocated a shift away from particulate grafting to programmable 3D fabricated bio-ceramics blocks . GbureckThe versatility of this 3D-powder printing method was further demonstrated by manufacturing anatomically accurate scaffolds for potential craniofacial implantation  Klammer. The stuin vivo setting. The 3D-printed bio-ceramic scaffolds were trialed as an onlay graft and a 9 mm diameter and 2 mm thick monetite disc was compared to the performance of an autologous bone block of similar dimensions. Both structures were secured using a titanium osteosynthesis self-drilling screw placed at the center of the block. The samples were retrieved 8 weeks post-implantation and displayed no obvious signs of inflammation and were well integrated with the calvarium. However, the bone block demonstrated some resorption and histology analysis revealed intense osteoclastic activity at both the outer and inner regions of the autologous bone graft. The monetite scaffolds performed moderately well, resulting in bone formation preferentially on the lateral portions and in the area of the 3D-printed scaffold in direct contact with the calvarial bone. The bio-ceramic also displayed signs of extensive degradation and there was no significant difference in bone height when compared to the autologous bone block  in the scaffold is a potent means of increasing osteogenesis due to its ability to trigger osteoblastic differentiation in a wide range of cell types . This stThe development of more flexible polymeric scaffolds has been advocated as an alternative for circumventing the brittleness of bioceramic scaffolds and their poor fixation ability. The following sections describe the most recent advances in the use of additively manufactured polymeric structures for vertical bone regeneration.Polymer printing is capable of building a refined interconnected porous network which facilitates neo-vascularization and a provide an environment suitable for osteogenesis to occur. In addition, the utilization of flexible and ductile polymers enables adaption of the defect shape and allows usage of titanium screws for biomechanical fixation. Several proof-of-concept clinical reports using 3D-printed scaffolds for oro-dental tissue regeneration in socket preservation  and peri3) was implanted in the mandible of dogs  scaffold  and functionalized with BMP-2 in a rabbit model . This stIn a follow up study performed in an extraskeletal ovine calvarium model, the regenerative potential of the PCL 3D-printed/melt electrowritten biphasic scaffold was further explored for the formation and maintenance of vertically augmented bone . A 2-staAlthough not directly related to vertical bone augmentation, Goh et al. demonstrated in both an preclinical and a pilot clinical study that a 3D-printed PCL scaffold was capable of providing space maintenance in fresh extraction sockets . The stuOther approaches have utilized additive manufacturing as a tool for fabricating guided bone regeneration membranes in conjunction with particulate materials for vertical bone augmentation. These are discussed further in the following sections.in vivo was around 9 weeks as previously reported for a porous sponge . As anticipated, no material resorption was observed within the titanium mesh, and this is consistent with this structure requiring additional surgery for removal in the clinical setting. Whilst Shim et al. recorded no signs of inflammation at 8 weeks post-implantation , the rap3 was generated in six mandibular locations, in three different animals. The membranes were fastened by titanium pins, with bovine graft particulate placed underneath each membrane and healing occurred over 8 weeks.Shim et al. therefore explored two further refined versions of the polymer membranes ; PCL onlInterestingly, and despite the difference in initial pore size between the collagen and the 3D-printed membranes, both performed similarly, and no significant differences were found between the respective amount of bone formed . The maig centrifugation of blood and proven to increase soft tissue healing (A recent development has seen the emergence of a patient-specific 3D-printed titanium mesh for vertical bone augmentation . This sy healing . As a re healing .This review has described the major 3D-printing strategies for achieving extraskeletal bone formation: 3D-powder printing of bio-ceramic, bio-ceramic extrusion 3D-printing, fused deposition modelling using polymer or a mixture of polymer and inorganic filler, and metal 3D-printing. While each strategy is respectively limited by brittleness, the lack of bioactivity, and the requirement of removing non-degradable devices, it is clear that the future of the field lies with the manufacturing of patient specific geometries. The ideal anatomically accurate construct will promote extraskeletal bone formation and provide long-term space maintenance in order to allow for multiple cycles of bone remodelling, towards preventing bone resorption upon implant placement, thus ensuring implant longevity.


Mycosis fungoides (MF) is a cutaneous T-cell lymphoma that disproportionately affects people with skin of color and is difficult to diagnose.This study characterized the dermoscopic features of MF and its subtypes in patients with skin of color.Dermoscopic images of patients with skin of color seen at the cutaneous T-cell lymphoma clinic at Michigan Medicine Dermatology between 2018 and 2019 were reviewed. Specific dermoscopic features were identified and summarized for each subtype of MF.A total of 33 dermoscopic images from 11 patients with skin of color were reviewed. Four patients had classic MF (18 dermoscopic images), 4 had hypopigmented MF (9 dermoscopic images), 1 had folliculotropic MF (4 dermoscopic images), and 2 had verrucous MF (2 dermoscopic images). Classic MF was characterized by striking pigmentary change, thick black lines, white rosettes, and geometric white lines. Hypopigmented MF was characterized by the loss of the patient’s natural pigment network. In folliculotropic MF, follicular plugging and hyperpigmented to violaceous perifollicular halos were observed. In verrucous MF, large, yellow-gray amorphous structures with yellow-gray ridges and comedo-like openings were observed within hyperkeratotic areas. Overall, vessel morphology was difficult to discern on dermoscopy.Dermoscopic features of MF in patients with skin of color are predominantly characterized by striking pigmentary alteration. Vessel morphology is not a reliable diagnostic feature. As patients with MF and skin of color have a worse prognosis than light-skinned individuals, a better understanding of dermoscopic features may aid in early diagnosis and improve outcomes in this group. Mycosis fungoides (MF) is the most prevalent type of cutaneous T-cell lymphoma (CTCL) . It dispIn this study, we characterized the dermoscopic features of MF and its subtypes in SOC patients. We hypothesized that the dermoscopic features of MF in SOC patients are unique due to the greater presence of the chromophore melanin. In SOC, melanosomes are larger, more abundant throughout the epidermis, and singly dispersed from melanocytes to keratinocytes. The keratinocyte layers are also thicker in SOC than in lighter skin. These differences pose a challenge to appreciating vessel patterns in skin lesions of SOC patients.This was a single-center, retrospective review of dermoscopic images obtained from patients presenting to the CTCL Clinic at Michigan Medicine Dermatology between 2018 and 2019. Images of all patients with SOC (Fitzpatrick skin type IV-VI) who gave verbal consent to have dermoscopic images obtained were included. Each dermoscopic image was retrospectively and independently reviewed by four of the authors , and specific dermoscopic features were identified. Any discrepancies were resolved by discussion. Skin biopsy slides for histopathologic correlation were reviewed for selected cases. This study was deemed exempt from the need to obtain the patients’ informed consent by the University of Michigan Institutional Review Board (HUM00155110).The study included a total of 33 dermoscopic images from 11 SOC patients. Four patients had classic MF (18 dermoscopic images), 4 had hypopigmented MF (9 dermoscopic images), 1 had folliculotropic MF (4 dermoscopic images), and 2 had verrucous MF (2 dermoscopic images).Classic MF  was charHypopigmented MF  was charIn folliculotropic MF, dermoscopy showed follicular plugging, perifollicular scale, and hyperpigmented to violaceous perifollicular halos . On histIn verrucous MF, large, multicolored amorphous structures with yellow-gray ridges and comedo-like openings mimicking seborrheic keratosis were observed within hyperkeratotic areas . HistoloMF, especially early stage MF, can be difficult to diagnose; the median time from symptom onset to diagnosis is 4–6 years –13. AlthAlthough only a few, small-scale studies have tested dermoscopy in the diagnosis of MF, it seems that dermoscopy can improve the diagnostic accuracy of classic MF . Vessel In classic MF, a pigment pseudonetwork consisting of brown-gray clods and dots was present. Thick black lines surrounding structureless areas with rosettes and geometric white lines were also prominent. Superposition of these changes resulted in foci reminiscent of the blue-white veil often described in dermoscopy of melanoma. These features should help one differentiate MF from other papulosquamous disorders. Psoriasis in SOC exhibits dotted vessels under dermoscopy, perhaps due to a thinning of the suprapapillary plates . IrregulHypopigmented MF is characterized by loss of the patient’s natural pigment network. Although the cause of hypopigmentation is not known, it is thought to be due to the infiltration of CD8+ cytotoxic T-cells, which damage the melanocytes; this phenomenon has also been described in inflammatory vitiligo . The hypFolliculotropic MF was characterized by follicular plugging along with perifollicular hyperpigmentation; the latter feature has not been described in light-skinned individuals. This study also highlights the first dermoscopic description of verrucous MF in SOC: Multicolored amorphous structures with yellow-gray ridges and comedo-like openings mimicking seborrheic keratoses were observed within hyperkeratotic areas.This study is limited by its single-center, retrospective nature and small sample size. Larger studies are needed to better delineate dermoscopic features of MF in SOC patients. However, this is the first report to date to describe dermoscopic features of MF and its variants in SOC.MF in SOC patients is distinct from MF in patients with light skin, and it is characterized by striking pigmentary changes. Dermoscopic features such as rosettes and geometric white lines are unique to MF in SOC patients, while vessel morphology is not a reliable diagnostic feature. Given that SOC patients with MF have worse prognosis than light-skinned individuals, a better understanding of the dermoscopic features may aid in early diagnosis and potentially improve outcomes in this group.