Azole fungicides, especially triazole compounds, are widely used in agriculture and as pharmaceuticals. For a considerable number of agricultural azole fungicides, the liver has been identified as the main target organ of toxicity. A number of previous studies points towards an important role of nuclear receptors such as the constitutive androstane receptor (CAR), the pregnane-X-receptor (PXR), or the aryl hydrocarbon receptor (AHR), within the molecular pathways leading to hepatotoxicity of these compounds. Nuclear receptor-mediated hepatic effects may comprise rather adaptive changes such as the induction of drug-metabolizing enzymes, to hepatocellular hypertrophy, histopathologically detectable fatty acid changes, proliferation of hepatocytes, and the promotion of liver tumors. Here, we present a comprehensive review of the current knowledge of the interaction of major agricultural azole-class fungicides with the three nuclear receptors CAR, PXR, and AHR in vivo and in vitro. Nuclear receptor activation profiles of the azoles are presented and related to histopathological findings from classic toxicity studies. Important issues such as species differences and multi-receptor agonism and the consequences for data interpretation and risk assessment are discussed. Azole fungicides, especially triazoles, are widely used in agriculture as antifungal agents in plant protection products . In addiIn rodent toxicity studies, the liver was identified as the main target organ of adverse azole action and activation of nuclear receptors ,6. AccorA number of studies point at the activation of nuclear receptors as the underlying mode of action leading to liver toxicity of triazoles, such as the constitutive androstane receptor (CAR) and/or the pregnane-X-receptor (PXR). According to in vivo studies mainly performed in rodents, activation of CAR and/or PXR is discussed to be involved in the genesis of various adaptive or adverse liver effects, ranging from liver enzyme induction and hepatocellular hypertrophy to hyperplasia and liver enlargement and, as the severest consequences, to hepatic cell death and/or cancer development. While quite some studies have analyzed the links between azole exposure and activity of certain nuclear receptors, a systematic overview of available literature and inter-species comparison is yet lacking. Therefore, nuclear receptor-mediated hepatotoxicity of agricultural azole fungicides is summarized and discussed in the present review.The focus of the literature review was on azole compounds that are or have been in use for agricultural purposes and/or the treatment of other plants. No consideration was given to pharmaceutical azole fungicides, for which, however, also various interactions with xenosensing nuclear receptors and their target genes have been observed, for example in the case of fluconazole ,10,11, oAs detailed in In general, mostly indirect evidence for nuclear receptor interaction  comes from in vivo studies. Mice and rats were the species of choice in most studies , whereasAvailable literature suggests that propiconazole is a weak activator of mouse, rat, and human AHR . Data foSimilarly, in vivo rat and mouse data at the target mRNA and enzyme activity levels indirectly connect propiconazole with the activation of CAR ,36,39,40For PXR activation by propiconazole, in vivo rat and mouse data are only available at the target mRNA level , demonstPropiconazole has been assessed for its toxicity after short- and long-term exposure as well as for its carcinogenic potential in vivo in a number of studies conducted according to harmonized OECD test guidelines within the regulatory approval procedure. Study results are summarized in the assessment report , JMPR 4, as wellCar knockout mice demonstrating the important role of the receptor in the development of hepatotoxicity after propiconazole exposure [The observations made in regulatory studies are in line with published scientific literature also demonstrating increased liver weight and hypertrophy in rats and mice ,6,20,36,Nuclear receptor activation occurs as molecular initiating events of the pathway(s) leading to different adverse effects in the liver. For two important hepatic outcomes frequently observed after exposure to azole fungicides, i.e., hepatocellular hypertrophy and fatty changes/steatosis, schematic drawings of adverse outcome pathways (AOPs) are presented in Hepatocellular hypertrophy after xenobiotic exposure is , similarCar knockout mice underlines the role of this receptor in short-term effects of propiconazole exposure [Thus, several aspects of the adverse hepatic effects of propiconazole observed in vivo can be explained by the activation of the nuclear receptors CAR and PXR: this comprises the findings of hepatocellular hypertrophy resulting in an elevated liver weight cp. , as wellexposure , and it exposure . Compariexposure . Human rexposure , even thexposure . NonetheLimited evidence is available for activation of the AHR by epoxiconazole : weak acCyp2b10 transcription, and also the analysis of a broader CAR-dependent gene expression signature indicate activation of the receptor by epoxiconazole [Data on the effects of epoxiconazole on CAR are mostly based only on indirect findings at the target mRNA and enzyme activity levels obtained from in vivo studies . In miceconazole ,39. Simiconazole ,66. The conazole ,66. Induconazole .A comparable picture emerges when it comes to PXR activation by epoxiconazole : again, Epoxiconazole has been assessed for its toxicity after short- and long-term exposure as well as for its carcinogenic potential in vivo in a number of studies conducted according to harmonized OECD test guidelines within the regulatory approval procedure. Study results are summarized in the respective EFSA conclusion  and in tThe findings are in line with observations published in the scientific literature also describing increased liver weight and hypertrophy upon epoxiconazole exposure in rat and mouse liver ,65,66,69Hepatotoxic effects observed after exposure to epoxiconazole in vivo can be explained by the activation of nuclear receptors as molecular initiating events of toxicity. Even if the majority of data consists of indirect evidence from target gene or protein induction studies, it is possible to conclude that epoxiconazole activates CAR and PXR and thus facilitates the development of hepatocellular hypertrophy cp.  as well Evidence for activation of the AHR by cyproconazole appears inconsistent . ElevateAs with AHR, cyproconazole appears not to activate human CAR to a major extent: even though upregulation of target gene mRNA expression has been reported in human liver cells , reportePXR activation in human liver cells has been clearly shown at the reporter gene, as well as at the target mRNA and protein levels . No in vCyproconazole has been assessed for its toxicity after short- and long-term exposure as well as for its carcinogenic potential in vivo in a number of studies conducted according to harmonized OECD test guidelines within the regulatory approval procedures. Study results are summarized in the respective EFSA conclusion  and in tCar knockout mice, and thus it has been concluded that both, CAR-dependent as well as CAR-independent mechanisms are responsible for liver hypertrophy and liver tumor development in cyproconazole-treated mice [Published data from non-regulatory studies support the above findings: increased liver weight and hypertrophy have been reported for cyproconazole-treated rats and mice ,65,66,69ted mice . Speciested mice .Car knockout mice have demonstrated the importance of the receptor in vivo for liver hypertrophy as well as for fatty acid changes [The activation of nuclear receptors as molecular initiating events may explain most of the hepatotoxic effects of cyproconazole observed in vivo. Mechanistic analyses with  changes ,10,19 . This was interpreted by the authors as proof for a CAR-mediated, not human-relevant mechanism of tumorigenicity. Such a conclusion, however, appears premature: even independent of the discussion of human relevance of CAR-mediated tumor promotion, the mere observation of CAR activation and subsequent transient proliferation in short-term experiments has, if at all, only very limited predictive value with respect to the carcinogenic outcome. If a test compound simultaneously activates another, CAR-independent mechanism of tumor promotion that is linked to suppression of apoptosis in pre-malignant lesions rather than to transient proliferation in normal hepatocytes (see references above).Prochloraz is clearly an activator of the AHR in human and rodent cells, which makes the compound different from the above (tri)azoles which, if at all, activate the AHR only to a very limited degree. In addition, CAR and PXR also appear to be activated to a certain degree. In the absence of mechanistic studies, it is not possible to conclude the individual contributions of the different receptors to the development of hepatotoxicity. Hypertrophic responses cp. , fatty aCYP1A1 transcription was visible [Cyp1a2 mRNA was observed in mice; however, the fact that the effect was diminished in Car-KO mice indicates a substantial contribution of the latter receptor to this finding [Imazalil should be regarded as a moderate activator of AHR in human liver cells . The com visible . Inducti finding .CAR activation by imazalil  has beenReporter gene assays in human cell lines have demonstrated induction of PXR by imazalil ,58 Tabl. ReporteImazalil has been assessed for its toxicity after short- and long-term exposure as well as for its carcinogenic potential in vivo in a number of studies conducted according to harmonized OECD test guidelines within the regulatory approval procedure. Study results are summarized in the respective JMPR evaluation  and EFSAHepatotoxicity of imazalil has also been addressed in other than regulatory studies: a very recent publication reported increase liver weight and hepatocellular hypertrophy in rats . In miceHepatic effects observed after administration of imazalil on the target organ liver in vivo can be explained by the activation of nuclear receptors as molecular initiating events, as for example pictured in Evidence for nuclear receptor activation is also available for a number of additional agricultural azole fungicides. Several compounds, however, have not been extensively studied and thus data are only available for rather few selected endpoints. Results for those compounds are briefly presented in Bitertanol has shown its ability to inhibit an AHR-dependent reporter system in mice . BromucoCollected literature data show that nuclear receptor interaction by azole fungicides is subject to substantial species differences. In particular, the nuclear receptor CAR shows considerable species differences between humans and rodents, whereas the effects observed at AHR or PXR appear much less variable. Allowing for a direct comparison in an otherwise identical system, humanized mice expressing the human version of one or more nuclear receptors are valuable tools for studying species differences . A CAR/PAs already mentioned above, the vast majority of studies have reported an activation of nuclear receptors by different azole fungicides. This is not too surprising as the biological role of these receptors implies their activation upon binding of foreign compounds to induce downstream effects, for example related to the subsequent induction of various enzymes of xenobiotic metabolism capable of metabolizing the respective receptor-activating compound. Receptor activation has often been studied in quite some detail, whereas the molecular basis of the rarer phenomenon of receptor inhibition has not been investigated so much. Nonetheless, evidence is available from the literature suggesting that certain azoles have the potential to inhibit AHR-  or CAR-dIt follows from the published data that most azoles should not be regarded specific activators of a certain receptor. Instead, multi-receptor activation by the compounds is observed frequently. Nuclear receptor activation by agricultural fungicides from the azole family is not confined to the three receptors that are in focus of this work. The impact of azole fungicides on additional nuclear receptors has also been analyzed in various studies, even though the total amount of available data stays considerably behind the amount of experimental results published for AHR, CAR, and PXR. Just to give some examples, it has been shown that propiconazole, besides exerting effects on the abovementioned receptors, also activates human farnesoid-X-receptor, liver-X-receptor (LXR) α, PPARγ, and RARα in human liver cells, while inhibiting PPARα . The samIt is tempting to speculate that the potential to simultaneously act on different nuclear receptors could be an important mechanism underlying the biological effects caused by the respective compound in the liver. For example, hepatic steatosis is a complex process that may involve different nuclear receptors, including AHR, CAR, PXR, PPARα, and others, with the nuclear receptor interaction constituting the molecular initiating events in the adverse outcome pathway for liver steatosis, as for example shown in . InteresThe nuclear receptor-activating and/or -inhibiting profiles of azole fungicides are diverse and mostly do not show pronounced compound selectivity for a specific receptor. Instead, multi-receptor agonism and antagonism is observed with individual compounds, with AHR, CAR, and PXR being induced rather than inhibited by most azoles. The often rather weak-to-moderate effects at the receptor level are subject to pronounced species differences, which have been particularly investigated for CAR. Nuclear receptor activation profiles appear suitable to prognosticate many aspects of hepatic effects of azole class compounds. Nonetheless, in vitro nuclear activation assays do not appear to be appropriate for hepatotoxicity predictions as stand-alone tools. Instead, they may be applied as part of an integrated, step-wise testing strategy and to provide mechanistic information useful for risk assessment and especially for the interpretation of inter-species differences.


In the early 1930s, infectious bronchitis (IB) was first characterized as a respiratory disease in young chickens; later, the disease was also described in older chickens. The etiology of IB was confirmed later as being due to a coronavirus: the infectious bronchitis virus (IBV). Being a coronavirus, IBV is subject to constant genome change due to mutation and recombination, with the consequence of changing clinical and pathological manifestations. The potential use of live attenuated vaccines for the control of IBV infection was demonstrated in the early 1950s, but vaccine breaks occurred due to the emergence of new IBV serotypes. Over the years, various IBV genotypes associated with reproductive, renal, gastrointestinal, muscular and immunosuppressive manifestations have emerged. IBV causes considerable economic impacts on global poultry production due to its pathogenesis involving multiple body systems and immune suppression; hence, there is a need to better understand the pathogenesis of infection and the immune response in order to help developing better management strategies. The evolution of new strains of IBV during the last nine decades against vaccine-induced immune response and changing clinical and pathological manifestations emphasize the necessity of the rational development of intervention strategies based on a thorough understanding of IBV interaction with the host. Coronaviridae and order Nidovirales [Infectious bronchitis virus (IBV) belongs to the family ovirales . IBV infovirales . The infovirales ,4,5,6. Yovirales . In addiovirales . Howeverovirales .The first IB case caused by the Mass serotype was recorded from North Dakota, USA . Since tThe variability of the spike (S)1 amino acid sequence determines the host and tissue tropism of IBV ,27 sinceThe evolution and occurrence of novel strains of IBV is a continuing process . AlthougIBV is typically transmitted to the host by inhalation, whereupon it attaches to the respiratory epithelium and enters by receptor-mediated endocytosis . Once IBIt is well established that, following the initial infection in the respiratory tract, the virus is disseminated to other tissues due to viremia ,57 Figu. HoweverSubsequent clinical manifestations of IBV infection related to the reproductive tract depend on the infecting IBV strain. For example, the M41, Aust T and QX-like strains are known to cause reproductive tract defects in long-lived chickens ,17,25, lHowever, IBV replication in reproductive mucosa has been documented in several studies ,61,62. DHistologically, deciliation of the epithelium and a reduction in the height of the epithelial cells, along with epithelial desquamation and degeneration, are common in infected oviducts between 7 and 21 dpi  with occAlthough the consequences of IBV targeting the reproductive tracts of female chickens is known, little attention has been given to changes corresponding to the reproductive tracts of male chickens, which may cause impacted sperm production, infertility and venereal transmission of IBV ,70. ReceThe nephropathogenic IBV strains include B1648, Aus T, QX-like, 4/91, Holte and Gray ,25,32,50IBV strains that target the kidney have received increased attention due to their higher virulence in young chickens when compared to other IBV strains ,32,73. AAt post-mortem examination, IBV-infected kidneys are pale, discolored and enlarged ,47. UratAlthough IBV has been isolated from cloacal swabs, there is no indication that IBV is transmitted via the fecal–oral route. It is possible that gastrointestinal infection follows respiratory infection, subsequent infection of monocytes and macrophages and the spread of IBV via the blood or lymphatics ,59. IBV In the early 1990s, broiler chickens infected with IBV strain 793/B were found to develop bilateral pectoral myopathy . The disDepending on the IBV strain, the virus can persist in the tissues of chickens for an extended period ,74,78. FThe IBV-induced potential immune-suppressive mechanisms are summarized in One of the immune cell types that bridges innate and adaptive host responses is the macrophages, and the available data show that certain IBV serotypes  target respiratory tract macrophages and replicate within them, thus leading to a productive infection ,88. AlthThe complement system functions as a part of the innate arm of the immune response and also plays a role in adaptive immune functions. The components of the complement pathway aid in the host immune response via complement- and antibody-mediated lysis of viruses ,93,94,95Mycoplasma gallisepticum followed by IBV infection can result in coryza, tracheitis and airsacculitis in the host [Escherichia coli can lead to prominent lesions in respiratory surfaces, pericarditis and death [Haemophilus paragallinarum with IBV could result in severe lesion development and increased mortality rates [IBV replication impacting the respiratory tract brings forth a defective clearance mechanism by the deciliation of the respiratory epithelium, thereby increasing the vulnerability of respiratory surfaces to secondary bacterial infections . The co-the host . In addind death . In addity rates .Protection against IB is mediated by both antibody- and cell-mediated immune responses ,103. AltVaccination is the primary choice for the control of IB in the poultry industry. The chickens receive multiple IB vaccinations, and the frequency of vaccination depends on the expected production life of the chicken. For broilers, day-old vaccination in the hatchery is commonly practiced followed by a booster vaccination at 2–3 weeks of age . MultiplHowever, vaccination of day-old chickens is controversial for three reasons. First, maternal antibodies could be protective against potential IBV infection during the first few days of life while early vaccination could enhance the decay of the maternal antibodies . Second,Since the introduction of vaccination against IB using live attenuated (Mass serotype) vaccines, different vaccine serotypes such as 4/91, Ark, Conn, D274 and D1466 have been developed and made available commercially . Based oAlthough control of IB relies on vaccination , severalGiven the limited efficacy of existing IB vaccination strategies, it is critical to establish an IBV surveillance system that characterizes the different IBV strains circulating in various geographical areas and that we understand the antigenic and/or genetic similarities between the circulating IBVs and the available IB vaccines. These data will lead to the optimization of IB vaccination strategies to prevent vaccine breaks. If the existing vaccines are not useful in optimizing vaccination strategies, it would also worth developing autogenous vaccines (inactivated) using characterized unique IBV isolates prevalent in a given geographical area in order to include in the existing vaccination regimes. Given the available scientific evidence against IB vaccination at the hatchery ,110, it After decades of research into IBV and numerous studies on vaccine efficacy for the control of IB, this disease is still a major economic concern globally. Although many studies have been conducted on IBV pathogenesis, there is little specific information on IBV receptors that determine macrophage tropism and tissue tropism, mechanisms that allow IBV dissemination from the respiratory tract to secondary tissues, IBV persistence in the cecal tonsils and kidney and the immunopathogenesis and immunosuppressive mechanisms of different strains of IBV. Novel and sensitive assays and other necessary tools are now available for in-depth investigations of the mechanisms involved in these pathogenesis events. Given the concern of vaccine breaks and the emergence of heterogeneous IBV strains, investigations leading to an in-depth understanding of the pathogenesis of IBV are necessary.Studies of host–IBV interaction lead to the understanding of tropism of IBV for various body systems, severity of lesions produced in each of these tissues and ways the virus is shed to the environment ,64,134. In addition to secondary bacterial infections, vaccine induced immune response to any pathogen can be impacted by immune suppression induced by IBV. It is necessary to determine if IBV induced immune suppression impact the immune responses intended to be generated by a variety of vaccines used in chickens . Another


Dentistry is a part of the field of medicine which is advocated in this digital revolution. The increasing trend in dentistry digitalization has led to the advancement in computer-derived data processing and manufacturing. This progress has been exponentially supported by the Internet of medical things (IoMT), big data and analytical algorithm, internet and communication technologies (ICT) including digital social media, augmented and virtual reality (AR and VR), and artificial intelligence (AI). The interplay between these sophisticated digital aspects has dramatically changed the healthcare and biomedical sectors, especially for dentistry. This myriad of applications of technologies will not only be able to streamline oral health care, facilitate workflow, increase oral health at a fraction of the current conventional cost, relieve dentist and dental auxiliary staff from routine and laborious tasks, but also ignite participatory in personalized oral health care. This narrative article review highlights recent dentistry digitalization encompassing technological advancement, limitations, challenges, and conceptual theoretical modern approaches in oral health prevention and care, particularly in ensuring the quality, efficiency, and strategic dental care in the modern era of dentistry. Dentistry is a part of the field of medicine that has benefited from the development of modern digital transformation. The utilization of digitalization in dentistry is useful in modern day dentistry especially with numerous challenges involving multiple chronic oral diseases, the complex treatment which is needed by the community with an aging population, and not forgetting continuous rising costs over one’s lifespan ,2. The iAugmented reality (AR) is defined as an interactive development of technology utilizing additional, composite animated information in the user’s real world. AR effectively enhances the user’s real life in the real world through virtual simulation of live imagery and videos. Virtual reality (VR) on the other hand is the total immersion of a user in composite virtual environments in which the user’s feelings, senses, and reactions are virtually simulated by the computer, thus, creating an artificial interaction. Virtual reality systems in the real world normally utilize a device, for example a helmet, with the aim to simulate responses from the user for further exploration based on virtual recreated three and four dimensions . Both syThe key to comprehensive oral healthcare is to be based around patient-centered care. The current challenge in this era is the rapid increase of dental treatment cost, the steady incline of population age, the chronic oral diseases that have affected the quality of life, and the need for dental treatment especially for patients from remote areas with difficult-to-reach geographical locations . TelemedAdditive manufacturing is a rapid production process of any three-dimensional (3D) object using 3D printers. The process allows a complex geometrical design to be produced with additional benefits such as a reduction of unnecessary raw material wastage, mass production of the desired items, and fast production and manufacturing of dental prostheses as compared to subtractive manufacturing . In dentThe conventional implant rehabilitation and therapy usually utilizes multiple gypsum casts for medical record and references, in addition to two-dimensional radiographical imaging  and chairside clinical examination. The inherent disadvantages of this method include far less accuracy in interpretation of the vital anatomical and osseous structures as compared to cone beam computed tomography (CBCT), limited gypsum material properties, potential error-prone manual laboratory procedural, and others . The devThe conventional digital workflow on computer guided surgical guide is as given in the schematic diagram below .The static guided system is a computer-guided derived three-dimensional virtual implant planning that transfers the information into a pre-planned fabricated surgical template. It can be divided into two major types, which are the fully guided implant surgery utilizing full specialized osteotomy kit on guided prefabricated surgical template and partial-guided that utilizes analogue fabrication (non-computer guided) which is pilot-guided and drilling-guided . AnotherStereolithography (SLA) is the most common additive manufacturing technology in fabrication of static surgical guide utilizing computer-aided design and computer-aided manufacturing (CAD-CAM) protocol with specialized resin required as briefly listed in The CAS method is classified as dynamic when real-time computer-assisted programs and tracking devices are used to guide the practitioners placing the implant into the pre-planned insertion pathways intraoperatively . The maiArtificial Intelligence (AI) is the ability of a machine to perform human tasks. It revolves around the ability of a machine, around its own intelligence, to solve problems based on the learning of a specific set of data. The foundation of AI is to increase the ability of machines or its intelligence components to perform tasks with speed, low resources, accuracy, and others ,55. It wThe application of AI in dentistry is huge with enormous potential . In dentThe application of AR/VR in healthcare services, particularly in dentistry, may give rise to issues such as enormous, massive data availability and trusted sharing. The privacy of a patient’s data is handled by a series of systems utilizing software type algorithms intended to represent human cognitive processes in clinical decision-making. The dental practitioner and the auxiliary teams are responsible for data handling with potential risks of data privacy and security breaches. The AI/VR systems are not held accountable for this, though the application is performed either under supervision or not within the legal and jurisprudence context ,67.The emerging wealth disparities among communities widens each year further representing the economic distribution and inequalities. Theoretically, the utilization of AR/VR and AI will streamline the workforce and reduce laborious, repetitive tasks and the need for additional manpower. In the long run, it is predominantly an effective way to reduce the operating cost and increase the revenues for healthcare industries. Nevertheless, the shift of physical, repetitive jobs to a more complex, cognitive driven one as required in the globalized society and industries will effectively reduce the need for human involvement in low-scale, laborious tasks causing depletion of available jobs in the healthcare sector. Hence, there will be issues in a fair, post-labor economy with division of an income-based society in the future .The infrastructure support like computing power and requirements are critical to ensure the smooth processing of data updating, gathering, and interpretation in the delivery of the oral health care system which utilizes AI. The continuous expanding data of patients including demographic, clinical, treatment, and follow up requires consistent upgrading of the computing power which potentially may give rise to health, economic, training, technical logistics, and maintenance issues ,69. The The form of population-derived health records linked at the personalized individual level of information and data is a great model for the health economic policy. The health data can be derived from conventional medical and dental screening, routine check-ups, follow-ups, and hospitalization together with other determinants such as socio-economic  and other social aspects  . AdditioThe conventional impression has played a part in the prosthodontics field in which the main aim of the procedure is to replicate and simulate the functional anatomical parts intraorally. Nevertheless, the challenge lies in producing it due to material disadvantages, namely volumetric shrinkage and expansion of dental stone and silicones, technique sensitivity and critical handling having to be done by the clinician, and others. This procedure is thus prone to error and inadvertently will affect the final prostheses outcome ,75,76.The current development of computer-aided design and computer-aided manufacturing (CAD-CAM) has brought the prosthodontics field to a new frontier. The construction of dental prostheses has been rapidly evolving with the influence of subtractive manufacturing with the example of machinable milling systems and additive manufacturing in 3D printers that have resulted in rapid prosthesis production and shortened manufacturing time. Three-dimensional (3D) dental models are obtained by intraoral scanners, thus, eliminating the need for the conventional impression method. The advantages include less time required for the impression taking procedure, avoiding cross-contamination risks, better communication tools for dental technicians and patients, as well as more simplified procedures for the clinician ,77.Dental prostheses are made available through direct fabrication using a CAD-CAM system after obtaining a digital impression with an intraoral scanner. This will eliminate the need for physical models. However, manual fabrication and the construction of dental prostheses are still required in the construction of lithium disilicate restoration in which manual veneering wax-up must be done and the casting of metal alloy for full or partial coverage for gold restoration . An extrIt is paramount to evaluate the accuracy of these digital approaches, especially the intraoral scanner since it is the first step in adopting the CAD-CAM approach. Multiple studies had evaluated the accuracy of the intraoral scanner; however, they were limited to the production of orthodontic appliances such as retainers and implant prosthodontics ,81,82,83The delivery of modern oral healthcare should be derived based on modern technology driven by a patient-centered outcome. Digitalization in dentistry will facilitate oral healthcare to an optimum level. The pandemic of COVID-19 showed that tele-dentistry with remote consultation and artificial intelligence has a major role to play. It will indefinitely reduce the unnecessary contact between the patients and healthcare providers, shorten the duration of treatment, and be more cost effective in the long run. The field of dentistry is most likely to benefit especially in the utilization of AR/VR and AI systems for the delivery of pedagogy and clinical skills teaching. The research on digitalization in healthcare especially in dentistry should be the main focus in the next few decades with the aim of improving data acquisition and big datasets, safety and security of the “Big Data”, updating the neural networks, machined and deep learning of artificial intelligence, and other relevant fields.


By 3 years of age, diet and gut microbiota closely resemble those of adults. Gut bacteria required for the production of SCFAs and secondary BAs are potential targets for the intervention of microbiome-related diseases.The infant gut microbiota undergoes significant changes in the first two years of life in response to changes in the diet. The discontinuation of the milk-based diet of the first year and the introduction of solid foods in the second year of life results in a decline in  In the first year of life, human milk provides a large quantity and a broad array of complex oligosaccharides (HMO). While humans are unable to digest these complex oligosaccharides, strains of bifidobacterium commonly found in infants readily metabolize them . The larA normal diet in the first year of life consists human milk or cow milk-based infant formula. Both milk preparations contain fats, carbohydrates and proteins, although, the amounts and types of fats, carbohydrates, and proteins vary. For example, human milk contains 100 to 1,000 fold more oligosaccharides than cow milk and more than 250 types of fucosylated, nonfucosylated, and sialylated oligosaccharides. Fucosylated oligosaccharides predominate in human milk at 60%–80% and sialylated oligosaccharides comprise only 10%–15% . In contbifidobacterium colonize 100% of infants and comprise as much as 90% of the gut microbiota in human milk-fed infants; less bifidobacterium and more bacteroides are typical of formula-fed infants   . Of thesoduction .SCFAs consist of five or less carbons. They are products of carbohydrate fermentation and, to a lesser degree, protein metabolism by anaerobic bacteria. In mammals, formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, and isovaleric acid comprise the list of SCFAs. While simple sugars are mostly absorbed or digested by brush border enzymes in the small intestine, the more complex carbohydrates cannot be absorbed or digested by humans; they are, however, metabolized by the aforementioned members of the clostridium class in the colon . The higBacteroides spp. produce acetic and propionic acids as does Akkermansia muciniphila  in cell wall than are Gram positive organisms which lack LPS. It seems reasonable to suggest that reducing the number of Gram negative bacteria reduces the dangers posed by endotoxin leaking through the gut wall. C. difficile.Additional changes to the gut microbiome in response to the introduction of solid foods in year two of life include the appearance of ce birth . They poce birth . Dehydroce birth . The bac disease . The toxHigh levels of secondary bile acids in the gut and in the enterohepatic circulation may be oncogenic and lead to cancer in the colon and liver . FortunaThe effects of bile acids results from stimulation of receptors expressed in multiple tissues. Activation of signaling pathways involve the nuclear receptors Farnesoid X receptor (FXR) and G-coupled receptors TGR5 . Secondaenterobacteria, bifidobacteria, and lactobacilli. Several clinical trials report effectiveness of probiotics treatment for colic , and funds from the University at Buffalo Community of Excellence in Genome, Environment and Microbiome (GEM).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.


According to the research on the influence of resources on mate selection, the amount of financial resources affects an individual’s choice of “luxuries” and “necessities” among mate selection cues, while the amount of time resources affects cue diversity. However, for a long time, researchers only paid attention to the impact of financial resources and ignored the role of time resources. Therefore, this paper draws lessons from the relevant research on the influence of time on decision-making and proposes to study mate selection from the perspective of decision-making. Additionally, current research concerning the influence of resources on the choice of a spouse focuses more on results and neglects to examine the process. Therefore, based on the relevant theories, this paper makes several theoretical assumptions regarding the influence mechanism of resource availability on mate choice decisions, gender differences, and the actor-partner effect. Mate selection is an important link in the continuous development of human society and a complex decision-making problem . Mate seResources, as an important bargaining chip in mate selection, play a decisive role in the process of mate choice decision-making and have attracted the attention of many researchers . NumerouGenerally, the amount of resources influences the dimension and degree of the preference for mate selection cues in the mate selection decision. For example, men with more financial resources have higher requirements regarding women’s physical attractiveness , while wRegarding the impact of resources on mate choice, money is an obvious factor, but resources include not only money but also time . The timTime and money display both similarities and differences. As a resource, time has much in common with financial resources, as both are limited resources that can be saved, spent or utilized . HoweverBased on the preceding discussion, this paper summarizes the relevant theories and studies on the influence of resources on cue preference in mate selection decisions while considering the two aspects of money and time. In addition, it presents a theoretical description of the influence mechanism of resources on mate selection decisions.Researchers have proposed theoretical models of mate selection from several perspectives. In the early stage of this research, mate selection was typically studied from the perspective of evolutionary psychology as a means of reproduction. However, mate selection is both a biological instinct and a result of socialization. For example, positive assortative mating theory, complementarity theory, and social exchange theory elaborate the relationship between resources and mate selection from the perspective of sociology. In recent years, researchers have proposed considering mate selection as a type of decision made in pursuit of optimization. Therefore, a theoretical model that captures the influence of resources on decision-making would represent a valuable reference.Researchers have different views on how resources are integrated to achieve optimal reproduction. Evolutionary psychologists argue that the ultimate goal of human mate selection behavior is to reproduce and that all individual mate selection strategies aim to preserve and optimize the actor’s own genes.According to the theory of parental investment proposed by Reproductive strategy theory, which also focuses on offspring investment, emphasizes the influence of early family life experience on mate selection. Life-history theory focuses on how individuals allocate time, resources, and energy effectively for survival and reproduction ; the proSexual strategies theory divides mate selection strategies into long-term and short-term sexual strategies from the perspective of evolutionary psychology. Long-term sexual strategies refer to mate selection strategies aimed at establishing long-term and stable sexual relationships, while short-term sexual strategies refer to a mate selection strategy aimed at establishing short-term sexual relationships, such as one-night stands , 2016. TComplementarity theory  argues tPositive assortative mating theory  emphasizAccording to social exchange theory, mate selection is a process of seeking resource exchange . This thSocial learning theory  argues tSimilarly, the mate selection gradient theory emphasizes a matching method of “men seeking low and women seeking high,” which reflects the influence of a large social structure on a small family structure. In fact, the mate selection decision behavior of individuals is the result of socialization, and individuals tend to choose the partner who represents the best social match. Specifically, men prefer women who are below them in, e.g., socioeconomic status or education level, to gain the dominant position in the family. In contrast, women are more likely to choose partners who are superior to them in economic ability, educational background, and other aspects . AccordiBased on such gender differences between men and women, Therefore, resources play an important role in mate selection. Different individuals make different trade-offs and resource exchanges when making mate choice decisions and determine whether they improve the quality of future generations or enhance social adaptation. However, although early researchers contributed a substantial number of useful outcomes regarding the influence of resources on mate selection, they limited the studied resources to money, while neglecting the importance of time resources.Mate selection is a complex decision-making process . To achiThe attentional focus model notes that a lack of time resources will affect an individual’s attention to the object and scope in the task environment and limit attention more to task-related factors . The matAccording to the mindset theory, different resources activate different sets of thoughts. The introduction of money will activate the value maximization mindset of individuals, while the introduction of time will lead individuals to assume an emotional mindset . The intThe dual system action model for decision-making  divides Thus, time and financial resources influence mate selection decisions through different action mechanisms, namely, through cognitive channels (money) and through emotional channels (time).The classical economic theory holds that the ideal decision proceeds from the rational evaluation and comparison of various options and that emotional factors can interfere with rational analysis and reduce the efficiency of decision-making; these factors can only play a negative role when we attempt to make optimal decisions. However, modern researchers believe that emotions are as important to decision-making as cognition . TherefoFrom the previous theoretical discussion, we can observe that financial resources affect individuals’ perception of their own resources and self-worth and their cognition of a situation with respect to resource distribution and tradeoffs. That is, the amount of financial resources affects individuals’ self-esteem, mate value, and sense of power. Specifically, the amount of financial resources affects individuals’ cognition of their sense of self-wealth  and affeWe assume that self-esteem plays a mediating role in the influence of financial resources on mate selection decisions. Specifically, the amount of financial resources can make individuals feel subjectively rich or poor . An indiThere are good reasons to suppose that mate value plays a mediating role in the influence of financial resources on mate preference. Self-concept is an individual’s subjective perception and judgment of his or her physiological state, personality, attitude, social role, past experience, and other aspects . Based oOne assumption is that the sense of power plays a mediating role in the relationship between financial resources and mate selection. For consumers, deprivation of financial resources reduces the sense of personal power and resource control , whereasBased on the previous theoretical analysis, time resources primarily influence the mate selection decision through the emotional path. Specifically, a lack of time resources will generate anxiety, fear, and other emotions that affect individuals’ cue preferences in mate selection.According to several empirical physiological studies, a lack of time resources will activate individuals’ anxiety, thereby affecting the outcome of mate selection decisions. When time resources are lacking, an individual’s emotional arousal sensitivity will be improved ; time prRegarding emotion and decision-making, neuroscience studies have found a high degree of overlap between the decision-related brain regions and the neural circuits of emotion, which may reflect the neural basis for emotion’s effect on decision-making . The resA lack of time resources may induce an individual’s fear and affect the mate selection decision. When time resources are scarce, people experience a sense of pressure . In a stIn the field of mate selection, although there is no study that directly measures the influence of individual fear emotions on mate selection decisions, several researchers have experimentally verified that the initiation of the threat of death can significantly affect the life-history strategy and mate selection criteria of individuals . AccordiAccording to the two-system priming model, in the decision-making process, the cold and hot systems generally work together but only because different stimuli will result in situations in which the cold and hot systems play a dominant role. Therefore, we believe that the influence mechanisms of monetary and temporal stimuli are not completely independent of one another. In fact, studies have found that monetary stimuli can affect individuals’ anxiety , while tThis paper reviews and draws lessons from the theoretical models related to the influence of resources on mate selection and finds that a large number of studies have focused on results rather than process. Although achievements have been made, the internal mechanism of this influence remains unclear, and the psychological process requires additional study. Regrettably, the research on resources is too narrowly focused and neglects the investigation of time resources. Therefore, based on the relevant theories, this paper makes several theoretical assumptions regarding the influence mechanism of resource availability on mate choice decisions .We hypothesize that financial resources influence mate choice decisions primarily through the mediation of self-cognition (including self-esteem, mate value, and sense of power; see This paper summarizes previous studies and proposes the cognitive and emotional pathways of resource influence on the mate choice decision and the interaction between the two pathways. However, some areas that have not been elucidated in previous studies are still worth thinking about. For example, do money and time resources have different effects on the outcome of mate choice decisions because of different influencing mechanisms? Previous studies found that money resources can affect individuals’ extent of preference for partners’ economic status and appearance , whereasLife-history theory divides life-history strategies into fast and slow strategies . IndividPrevious research on the influence of resources on mate selection has produced inconsistent conclusions due to the lack of a clear distinction between long-term and short-term mate selection. By reviewing previous studies, it was found that most of the literature on the influence of resources on mate selection begins with long-term mate selection and that the amount of men’s financial resources was not relevant to their requirements regarding the resource acquisition ability and beauty of potential partners . HoweverEvolutionary psychologists believe that culture does not influence mate preferences because of “universal human nature.” In addition, this influence from culture may change as a result of social development. For example, a study of Israelis’ and Americans’ mate preferences found that Israelis value physical appearance more than Americans—a reversal from the study by Buss et al. a decade ago . Some stBased on previous studies, there is a gender difference in the influence of individual resources on mate choice decisions. According to parental investment theory, sexual strategy theory, complementarity theory, social learning theory, and mate selection gradient theory, men and women prefer different characteristics in the process of mate selection decisions, and the amount of resources may have different dimensions of influence on men and women. In the case of fewer financial resources, women attach more importance to the economic status of partners in long-term mate selection, while men attach more importance to the fidelity of women . RegardlThe matching feature of gender is also a topic worth studying. When discussing the influence mechanism of the amount of resources on the decision of choosing a partner, we should pay attention to the particularity of the research object and discuss the mutual influence between men and women, i.e., the actor-partner effect in statistics. More specifically, the actor-partner effect includes the actor effect, which refers to the effect of individuals on their own outcome variables, and the partner effect, which refers to the effect of individuals on the outcome variables of the other party in the paired relationship . AccordiFor example, resources influencing the mate selection decision through cognition and emotion (see JH analyzed and reviewed the literature, revised each draft, and completed the final approval of the version. XF supervised this study, revised each draft, and completed the final approval of the version. TS analyzed and reviewed the literature and revised each draft. All authors contributed to the article and approved the submitted version.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.


Insect chemical ecology (ICE) evolved as a discipline concerned with plant–insect interactions, and also with a strong focus on intraspecific pheromone-mediated communication. Progress in this field has rendered a more complete picture of how insects exploit chemical information in their surroundings in order to survive and navigate their world successfully. Simultaneously, this progress has prompted new research questions about the evolution of insect chemosensation and related ecological adaptations, molecular mechanisms that mediate commonly observed behaviors, and the consequences of chemically mediated interactions in different ecosystems. Themed meetings, workshops, and summer schools are ideal platforms for discussing scientific advancements as well as identifying gaps and challenges within the discipline. From the 11th to the 22nd of June 2018, the 11th annual PhD course in ICE was held at the Swedish University of Agricultural Sciences (SLU) Alnarp, Sweden. The course was made up of 35 student participants from 22 nationalities  as well as 32 lecturers. Lectures and laboratory demonstrations were supported by literature seminars, and four broad research areas were covered: (1) multitrophic interactions and plant defenses, (2) chemical communication focusing on odor sensing, processing, and behavior, (3) disease vectors, and (4) applied aspects of basic ICE research in agriculture. This particular article contains a summary and brief synthesis of these main emergent themes and discussions from the ICE 2018 course. In addition, we also provide suggestions on teaching the next generation of ICE scientists, especially during unprecedented global situations. Since the discovery of insect pheromones and the role of chemicals in plant–insect interactions, insect chemical ecology (ICE) has developed into a distinct research discipline being practiced at universities and other research organizations worldwide. Moreover, basic research in ICE has led to practical applications that contribute significantly to the control of agricultural or blood-feeding pests. High-quality education of PhD students in the field of ICE is of utmost importance for the discipline to grow and advance for future scientific discoveries as well as practical implementation. Recognizing the need for training and international networking of chemical ecologists, Bill Hansson and Ylva Hillbur initiated the first international ICE PhD course in 2005 at the Swedish University of Agriculture (SLU) involving teachers from Alnarp and Lund University, as well as many international lecturers. The interest of students and their positive response led to follow-up courses in 2007 and 2009 at Alnarp. In 2009, it was decided to rotate the location of the ICE courses and increase its frequency  to better accommodate the needs of international PhD students. As a result of this, a 2010 issue of the course was held at the Department of Entomology, Pennsylvania State University (PSU) and a subsequent one in 2012 at Max Planck Institute (MPI) for Chemical Ecology (CE) in Jena, Germany (where Bill Hansson had become the director and head of the Department of Neuroethology), merging resources and competence from three research institutions studying the chemical ecology of insects. With Teun Dekker at SLU , Tom Baker at PSU  and the Neuroethology group members  at MPI, the course continued being arranged in turns by the three host institutions strongly promoting teacher and student exchange across borders. After the 2018 course, which is the subject of the current report, the International Centre of Insect Physiology and Ecology (ICIPE) in Nairobi, Kenya, joined the consortium of organizing institutions and arranged the first ICE PhD course in Africa in 2019, illustrating the establishment and development of the course as an internationally recognized platform for education and exchange of students, junior and senior chemical ecologists.Plants, insects, and microbes are part of terrestrial ecosystems. Trophic interactions, such as the consumption of plant material by herbivorous insects, are key factors that lead to physiological and morphological adaptations in coexisting organisms. For example, plants have evolved multiple defense mechanisms against herbivory, and insects likewise evolve countermeasures against plant defenses  damaged by larvae of the diamondback moth (Plutella xylostella Linnaeus) and cabbage white butterfly (Pieris rapae L. Pieridae)  to the attacking insect(s) Fig. Although these studies demonstrate the potential for the exploitation of volatile compounds from basic to applied research, more studies are needed to decipher in-depth the concept of blends and their meaning for insect behaviors. Furthermore, future research also needs to focus on the effectiveness of the recruited natural enemies  in controlling specific insect pests, as well as the concentrations and active distances of emitted volatile blends.Metschnikowia gruessii, and M. reukaufii, attracts the parasitoid Aphidius ervi (Hymenoptera: Braconidae) via the production of volatile compounds  that associate and interact with different plant species and their organs Vorholt . These iPlants indirectly interact with the beneficial and symbiotic as well as pathogenic microbes that coexist with insects. A diverse community of microbes live within herbivorous insects and enter the plant during insect feeding. It has also been shown that insect-associated microbes can directly induce or suppress plant defenses after an herbivorous attack  levels from soil, alter critical ecological processes and thereby have significant consequences on multitrophic plant-mediated interactions. An increase in temperature can change the direct defenses such as primary and secondary metabolites. For example, in vineyards, an increase in temperature slows down plant defense through reduced production of anthocyanins and amino acids, but an increase in tannins in the grapes, thus making the plants more susceptible to insect damage   resulted in reduced affinity for volatiles produced during fermentation and gained an affinity for short-chain esters found in fresh fruits substrate, which could be considered as an ecological adaptation to a specific niche ) show the development of a well-structured olfactory memory that enables the ant to remember important olfactory landmarks. Further, the ants utilize the acquired knowledge to pinpoint their nest entrance in spatial scale  shows that both extrinsic and intrinsic factors drive host selection and preference. As reviewed by Takken and Verhulst , which could explain the evolution of preference and specialization for human odors  to oviposit. Several factors, including water vapor and VOCs, guide the gravid mosquito in making choices at increasingly fine scales  have been used successfully to disrupt mate location  recruited parasitoids and predators of aphids  plants was found to increase the number of visitations and predation of sentinel eggs by adult lady beetle, adult hoverflies, and predatory mites  was engineered in the laboratory to release Eβf, the alarm pheromone for many pest aphids  and increased the foraging by Aphidius ervi (Ervi), the natural enemy of these aphids  in vineyards  and Chilo partellus Swinhoe (Crambidae), and fall armyworm larvae, Spodoptera frugiperda (J.E. Smith) in maize crops  in pest management strategies against the codling moth in apple orchards and In 2020, the outbreak and rapid spread of novel coronavirus disease (COVID-19) broadly affected almost all aspects of human endeavor, including health, economics, social interactions, and education, among others. Education is a critical sector in modern society and has been primarily achieved best by teaching and training in a face-to-face environment. Following these lines, the ICE course for PhD students in chemical ecology and closely related research had enjoyed a face-to-face format annually for over a decade, while rotating between research facilities spread across three continents. Each year, both students and the selected trainers  would converge at one of the participating research facilities for the course activities. In 2020, the cycle was broken due to the unprecedented Covid-19 pandemic.What options do the ICE organizers and trainers have in responding and teaching the next generation of ICE scientists during a global pandemic, where social distancing is mandatory? In general, the advancement in technology has enabled the shifting of various human interactions from predominantly in-person to predominantly virtual. Such an unprecedented shift from the classical meeting in a host city or laboratory to cyber interactions during the Covid-19 pandemic became a new way to continue scientific exchange in an unprecedented time and has presented an opportunity for accelerated implementation of digital teaching and training technologies, and ‘unprecedented opportunities’ to ensure students do not miss out. Other positive aspects of using these technologies are reduced overall costs  and the inclusion of more students that otherwise could not participate due to either limited course capacity or else limited financial resources. Here, we suggest some ideas on how the ICE course can be successfully conducted during unprecedented situations and going forward even during more normal times.As pandemics such as Covid-19 demand restricted movement and social interactions, the first option to conduct ICE would be virtual-only attendance and teaching. This option offers real-time interactions over the internet. Several platforms for audio, videos, and chatting have been developed to enable interactive online learning experiences including lectures, discussion, and group training. Besides the virtual-only meeting, we suggest embracing the hybrid type of meeting where only students and trainers residing near the participating research facility can be allowed to participate in in-person and laboratory demonstrations. At the same time, those who would need to travel from far can follow the lectures and discussions virtually. The last option is pre-recording lectures and laboratory demonstrations. Here, the trainers can pre-record their lectures and demonstrations and have them streamed or played for the students and followed by a question-and-answer session with the particular lecturers. With this approach, copyright can be an issue. Therefore, we suggest the use of the non-downloadable format of the records or the lectures get played from a central platform and only for a limited time. While ICE courses are not just about teaching only, the students and trainers also get a chance to interact socially and talk about experiences with career progression. In all of the above-proposed methods of organizing and teaching the next ICE courses, we suggest the continued inclusion of social engagement activities even under a virtual setting, where both the trainers and students can interact and exchange from a social perspective, which is critical for students as early career scientists.Insects possess an inimitable capability to generate and recognize chemical cues and interact with a wide range of organisms in their environment. While these processes are only partly understood, the body of studies presented in this article demonstrates steady progress in understanding ICE and closely related fields. Indeed, ICE is a continuously growing and promising field of research where insights gained when studying these natural ecological interactions trigger new questions and sustainable contributions to the field and applications in agriculture and vector-borne disease control. Advancements in methods and instrumentations are accelerating manipulation of the molecular architecture and chemical events underlying signal emission, olfaction, and behavior. This is deepening our knowledge and helping to answer broader chemoecological and evolutionary questions, especially those linked to agriculture and disease vectors. Because ICE is an interdisciplinary field, the collaboration between professionals and early career scientists working in behavioral ecology, electrophysiology, analytical chemistry, molecular biology, data-driven science, medical entomology, and agroecology, among other disciplines, is vital. The ICE PhD course with its yearly organization rotating between SLU Alnarp in Sweden, PSU in the USA, MPI for Chemical ecology in Jena, Germany, and since 2019, ICIPE in Nairobi, Kenya, with the involvement of lecturers from other leading ICE research institutions, is a successful avenue for students to gain insights into the cutting edge of ICE research. Moreover, the course offers an opportunity to build bridges between disciplines, inspire new questions, and establish professional networks between participating students and lecturing scientists. We challenge the early career ICE scientists to follow and develop the present knowledge beyond their known borders.


Chronic wounds often occur in patients with diabetes mellitus due to the impairment of wound healing. This has negative consequences for both the patient and the medical system and considering the growing prevalence of diabetes, it will be a significant medical, social, and economic burden in the near future. Hence, the need for therapeutic alternatives to the current available treatments that, although various, do not guarantee a rapid and definite reparative process, appears necessary. We here analyzed current treatments for wound healing, but mainly focused the attention on few classes of drugs that are already in the market with different indications, but that have shown in preclinical and few clinical trials the potentiality to be used in the treatment of impaired wound healing. In particular, repurposing of the antiglycemic agents dipeptidylpeptidase 4 (DPP4) inhibitors and metformin, but also, statins and phenyotin have been analyzed. All show encouraging results in the treatment of chronic wounds, but additional, well designed studies are needed to allow these drugs access to the clinics in the therapy of impaired wound healing. Diabetes mellitus (DM) is defined as a group of metabolic pathologies characterized by compromised insulin production and/or function, leading to hyperglycemia. DM greatly impacts the quality of life and survival expectation of patients. In fact, as a consequence of hyperglycemia, diabetic patients are at increased risk for comorbid conditions affecting several organs . One of Impaired healing in diabetes is the result of a complex pathophysiology involving vascular, neuropathic, immune, and biochemical components . HyperglDiabetic patients have a 15–25% lifetime risk of developing diabetic foot ulcers, of which 40–80% become so severely infected it involves the bone, leading to osteomyelitis . For thiWound healing is a physiologic, very complex phenomenon that occurs when skin integrity is lost and consequently also the barrier function of the skin is impaired. This may occur quite often since the skin is much exposed to external insults and the need to avoid systemic infections drives a rapid defense mechanism . ThroughThe inflammatory phase is preceded by a coagulation step in which the first response of the injured skin is activation of the clotting cascade with recruitment of platelets and the formation of a fibrin plug. Its significance resides in hemostasis as well as wound coverage and protection . AggregaThese phases are aimed at driving wound closure. In this regard, granulation tissue, together with keratinocyte migration, formation of extracellular matrix (ECM) proteins, and the appearance of myofibroblasts cause contraction, one of the first events leading to wound closure. Fibroblasts are then the main cell type in this phase and, through the release of collagen, they start to rebuild the wounded area. The early phases of wound healing are characterized by hypoxia that plays a role in promoting migration and proliferation of each cell type as well as release of growth factors . HypoxiaWhen the physiologic reparative process fails, a chronic wound condition takes place with the appearance of an ulcer or, alternatively, an excessive repair event with the formation of a hypertrophic scar or a keloid. The appearance of hypertrophic scars usually associates with patient’s predisposition, they are temporary and usually regress within six months. In contrast, keloids cover an area that goes beyond the original skin injury, appear in genetically predisposed patients and are permanent . On the The healing process in diabetes is mainly characterized by chronicization of the inflammatory conditions, disrupted angiogenic process, reduction of endothelial progenitor cells, and an imbalance in extracellular matrix regulation. As observed in physiological wound repair, also in diabetes, neutrophils and macrophages promptly infiltrate the area of the lesion driven by chemotactic chemokines that are particularly elevated in diabetes . InfiltrAdditionally, the maturation phase of wound healing appears impaired in diabetes. The production of factors leading to vascular mature phenotype (including angiopoietin (ANG) 1 and 2, PDGF) is compromised  and topiFinally, an impairment in the regulation of ECM, whose build-up is modulated by metalloproteinase (MMPs) and tissue inhibitors of metalloproteinase (TIMPs) is observed in diabetes. Higher MMPs levels have been reported in diabetic wounds, due to high glucose that may directly induce the production of MMPs and the reduction of TIMPs, thus contributing to disruption of the healing process . MMPs are involved at various stages of wound healing, like cell migration through the degraded ECM, leukocyte invasion, processing of multiple cytokines, and growth factors involved in the healing process . The balThe standard wound-care practice for impaired wound healing includes control of the infection together with debridement, off-loading to relieve pressure, and maintenance of a moist wound bed. One of the first aims in the treatment of chronic wounds is in fact to prevent the occurrence of infection and to clean the area from non-viable tissue material. Infections can easily occur due to the loss of the innate barrier constituted by the skin layer and pathogens accumulating in the wounded area may further interfere with the healing process. Similarly, the removal of debrides and non-viable tissue, or debridement, allows exposure of healthy tissue where cells can migrate and proliferate to repair the wounded area . There aFollowing these initial phases, current treatment of impaired wound healing relies mainly on the use of topical dressings that, by providing the moist environment required for proper healing, facilitate the production of granulation tissue and epithelialization . They alInterestingly, drugs that are commonly used in the therapy of diabetes including insulin, metformin, some sulfonylureas, thiazolidinediones, and DPP-4 inhibitors have shown not only anti-inflammatory properties, but also a broad range of different effects that may be useful in the treatment of chronic wounds. In detail, specific beneficial effects of these medications such as polarization towards a healing-promoting macrophage phenotype, reduction of MMPs, increased keratinocyte and fibroblast proliferation, angiogenesis, and increased formation of granulation tissue have been reported. However, whether this correlates clinically with improved wound healing, in some cases, has to be demonstrated . In seleTreatment of chronic wounds with exogenous growth factors has gone through various and contrasting phases. Several growth factors bear the potential to intervene at various stages of the healing process activating a variety of cellular and molecular responses . They caThe possibility of applying stem cell therapy in the treatment of impaired wound healing appears rather intriguing. Transplanted stem cells can in fact release, in the wounded area, cytokines and growth factors able to promote cell recruitment, angiogenesis and ECM remodeling and exert an immunomodulatory action ,44. AdulFrom that described above, there are several different therapeutic approaches that are available, but all of them carry limitations and none appear adequate to guarantee a successful, conclusive, non-recurrent healing. Hence, the need to develop (or to find) new treatment alternatives is mandatory. Since the sequence of events of impaired wound healing is well characterized, the possibility to identify drugs that are already in the market and that are known to target one or, even better, many of the described molecular events can be taken into account. In this regard, several molecules with different therapeutic indications have shown beneficial effects in promoting wound healing. Sometimes observations have been occasional as in the case of the highest incidence of chronic non-healing wounds in male patients suggesting that the female hormone, estrogen, can be beneficial in the treatment of chronic wounds. Accordingly, topical estrogens accelerate wound healing, favor the formation of capillary-like structures in endothelial cells, stimulate the release of PDGF by macrophages and TGFβ1 by fibroblasts and promote wound contraction, formation of granulation tissue and collagen deposition . More reDespite controversial results are available regarding the use of systemic propranolol in the treatment of chronic wounds, this β-blocker has been tested since activation of β2-adrenergic receptor is known to inhibit keratinocyte migration and delay re-epithelialization. Interesting data were provided by a study in which a 1% propranolol cream was applied to chronic wounds in spontaneously diabetic mice . TopicalThe angiotensin converting enzyme (ACE) inhibitor, captopril, has shown the ability to increase wound healing scores in diabetic rats  and its Besides those mentioned above, there seems to be several other currently used drugs that have shown some activities in the wound repair process. However, we will here selectively focus on few classes of drugs (including some antidiabetic medications) whose potential to be effective in the treatment of wound healing finds support in preclinical and clinical observation and is also substantiated by detailed molecular evidence. They are all small molecules and their chemical formulas and structures are reported in The chemical formula and structure of lovastatin, the first statin to reach the market, is shown. Other available statins include atorvastatin, fluvastatin, pravastatin, simvastatin, rosuvastatin, and pitavastatin. The chemical formula and structure of sitagliptin, the first DPP4 inhibitor to reach the market, is shown. Other available DPP4 inhibitors include vildagliptin, saxagliptin, linagliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, and omarigliptin Statins are 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase competitive inhibitors and represent one of the first line classes among cholesterol-lowering drugs. Inhibition of cholesterol production by statins implies also inhibition of the synthesis of the wound-healing inhibitors farnesyl pyrophosphate (FPP) and cortisol. They both act on glucocorticoid receptors and inhibit epithelization through impairment of keratinocyte migration. Statins are also known to exert cholesterol-independent pleiotropic effects and are endowed with anti-inflammatory, antibacterial, and antioxidant properties, as well as the ability to ameliorate endothelial function and healing outcomes .Simvastatin has been shown to improve tissue repair by promoting neovascularization, mobilization of endothelial precursor cells from bone marrow, and increase of their proliferation, migration, and survival . IncreasGingival fibrous overgrowth is a common side effect of phenytoin when the drug is used as an anticonvulsant and occurs in about 50% of treated patients. The mechanism of action of phenytoin in the control of seizure involves blockade of voltage-dependent Na+ channels but little is known on the molecular process that leads to hypertrophy of the gum. The gingival hypertrophy is so evident that it prompted direct testing of phenytoin first in experimentally induced gingival wounds to move quickly to skin reparative processes, as recently reviewed , with liA topical formulation of phenytoin was then formulated and proved to be efficacious in accelerating wound healing in trophic leprosy ulcers  and postThe biguanide metformin is recognized worldwide as the first-line drug for the treatment of type II DM. It exerts its antihyperglycemic effect at several levels including inhibition of hepatic glucose production, reduction of intestinal glucose absorption, improvement of glucose uptake, and utilization by peripheral tissues . EmerginDPP4, also known as CD26, is a transmembrane serine aminopeptidase cleaving N-terminal dipeptides when proline, hydroxyproline, and alanine are present. Its main recognized function is cleavage of incretins, mainly glucagon-like pepide 1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP), that are released at enteric level and control insulin release. By cleaving in particular the N-terminal dipeptide of GLP-1, DPP4 promptly inactivates the insulin-releasing activity of the peptide . InteresDPP4 is in fact expressed also in epithelial and endothelial cells, keratinocytes, and in subsets of macrophages and hematopoietic progenitor cells . In endoDPP4 is one of the accessory molecules of helper T cells and facilitates T cell activation . It alsoA deeper knowledge of the involvement of DPP4 in reparative processes in wounded skin has prompted studies to investigate the potential for this target in the treatment of diabetic wounds. In excisional wound tissue of diabetic rats, it was shown that activation of GLP1 receptors reduced the formation of superoxide anions, ameliorated wound closure by reducing cytokines and inflammatory cells infiltration , and by Translation to clinical practice is substantiated by few, but significant, studies carried out in diabetic patients with chronic non-healing foot (or leg) ulcers. Inhibition of DPP4 significantly increased wound closure rate compared to placebo, with a good control of the appearance of ulcer-related adverse effects including infection, osteomyelitis, and cellulitis . NotablyThe concept of drug repurposing has grown in recent years, based on the attitude to exploit the knowledge we have on drugs and, at the same time, try to use them to their full potential. This is of course advantageous in terms of research and development of new molecules and the financial burden they imply. Diabetes-related impairment of wound healing and its most serious expression, i.e., the diabetic foot ulcer, offer the great opportunity to occur with a sequence of cellular and molecular events that are now well described and characterized, thus allowing pharmacological intervention in a precise manner. Several drugs have shown the ability to improve skin reparative processes and we have here briefly focused our interest on a few molecules (or classes of drugs) that appear particularly promising in this regard. The availability of clinical data for each drug (or class of drugs) is also reported to provide an idea of the feasibility of practical therapeutic use for each of them . From the large body of evidence found in the literature, several weaknesses emerge as in the case of phenytoin that, although investigated in different clinical trials, provides data that carry a poor methodological approach. Very different is the story with statins. These drugs, when administered systemically, are endowed with adverse events and do not allow significant concentrations at the skin to be achieved. Hence, new formulations for optimized topical delivery are now receiving great attention. Drugs that are already used in the treatment of diabetes could represent the more obvious pharmacological intervention. In this sense, probably the most interesting seem to be DPP4 inhibitors. They have provided good results in preclinical studies, either in vitro and in vivo in animal models of diabetes, and also in clinical trials. If their efficacy in wound healing comes out to be true, data, not only from clinical trials, but more importantly from post-marketing studies should provide us information on whether the prevalence of impaired wound healing and/or the appearance of diabetic foot ulcers is reduced in diabetic populations treated with DPP4 inhibitors. In addition, differently from other drugs examined here, DPP4 inhibitors have been tested only after systemic administration, but not in topical formulations that, if feasible, may reveal even more encouraging results. Probably the effects of DPP4 inhibitors are multifactorial and although GLP1 has been described to exert several properties aimed to repair injured tissue, a main role for SDF1α and HMGB1, other important substrates of DPP4, have also been claimed, very likely all contributing with diverse roles to the improvement of the healing response. Finally, particularly promising appears the possibility to combine all these treatments with non-pharmacological innovative approaches, as already tested with metformin and lovastatin, to achieve improved results on the wound reparative events.


Culicoides imicola), has been reported. Either presented as clinical and/or subclinical infections, the presence of the virus in an extended range of susceptible hosts highlights the cross-species transmission and supports the hypothesis of an endemic circulation of PPRV among susceptible hosts. However, the potential role of large ruminants, camels and unusual hosts for PPRV epidemiology is still obscure. Therefore, there is a need for molecular and epidemiological investigations of the disease among usual and unusual hosts to achieve the goals of disease control and eradication programmes initiated by national and international organisations, such as the FAO and OIE. This review is the first to summarise the scattered data on PPR in large ruminants, camels and unusual hosts to obtain the global scientific communities’ attention for further research on epidemiological aspects, not only in its native hosts, but also in large ruminants, camels and other unusual hosts.Since its first report in 1942, peste-des-petits-ruminants virus (PPRV) has caused several epidemics in a wide range of susceptible hosts around the world. In the last 30 years, the evidence of natural and experimental infections and virus isolation were reported from novel but unusual hosts such as camel, cattle, buffalo, dogs, Asiatic lion and pigs. In addition, PPRV in a potential vector, biting midges ( In the developing world, this virus poses a major threat to sustainable agricultural growth by causing significant economic losses due to high morbidity and mortality in sheep and goats  in India  in Turkey indicate the possibility of virus transmission through vectors (NCBI accession numbers KU325483 & KU175171), although further studies are needed to confirm these results and to investigate whether biting midges are competent or mechanical vectors.Recovery of the PPRV gene segments from biting midges  have significance for host adaptation of PPRV, the conserved PPRV sequences obtained from domestic small ruminants and unusual host origin indicate that this virus has the potential to switch host without necessary mutations , and is most likely due to spill-over from domestic small ruminants , an endangered bovid species of India. During the outbreak, 20 animals died and this was attributed to PPRV lineage IV . A stronger knowledge of animal dynamics, single animal unit production, and management practices and animal movements , will be a critical condition for success. Serological surveys provide crucial information on the possible presence of any disease in unusual hosts, because information on active disease presence may not be available due to poor accessibility to these animals. A new framework, including one that investigates atypical hosts in disease surveillance, is needed by the concerned national and international authorities for a stage-wise progressive control of PPR. Such expansion of disease screening, on the basis of sample availability from all susceptible hosts including atypical hosts, will surely strengthen eradication modelling in the final stages of an eradication programme. A lack of proper awareness on the role of susceptibility of atypical hosts to PPRV in veterinary and para-veterinary personnel, may create a major obstacle towards the progressive control of PPR in disease endemic regions.Indeed, continuous disease surveillance, along with realistic epidemiological modelling , over the coming years and have set the goal of eradicating the disease by 2030. This review article will undeniably assist all scientific communities working on disease eradication and towards sustainable improvement in economy by livestock production. Additionally, these results will strengthen the livelihood resilience of rural societies and benefit food and nutrition security. Taken together, future regional and global programmes for the control of PPR will need to consider and resolve the issues raised here, and wildlife and livestock managers or authorities in PPR endemic countries may need to encourage the protective vaccination of small and large ruminants surrounding wild populations.Disease surveillance programs need to be further extended and strengthened to include usual and unusual hosts. Awareness of disease in large ruminants and unusual hosts should be imparted to farmers, particularly those living in disease-enzootic regions. In this regard, particular attention should be given by national and international authorities (such as the FAO/OIE) under the programme on Global Framework for the Progressive Control of Transboundary Animal Diseases (GF-TADs). This will enable better comprehension coordination among local veterinary authorities and the subsequent implementation of disease control/eradication programmes.Besides usual hosts , PPRV has the potential to infect large ruminants, camels and other unusual hosts. Cross-species transmission, from small to large ruminants/unusual hosts may be prevented by extensive and further-strengthened disease surveillance, coupled with appropriate diagnostics and vaccine constructs. Therefore, for effective disease eradication programmes worldwide (GEP-PPR) under the GF-TADs programme, it is imperative to explore the role of large ruminants and unusual hosts to better elucidate disease epidemiology, particularly in disease-enzootic regions.


Intensive care of patients on left ventricular assist device (LVAD) support is compounded by the peculiar physiological consequences of circulatory assistance.,2. The key principles determining the RV mechanical alterations are series circulatory effects, ventricular interdependence, and ventriculoarterial coupling  function is often encountered post-LVAD implantation, with an incidence of 9.4-44% and is associated with an elevated risk of mortalitycoupling . FirstlyInterestingly, the principle of ventriculoarterial coupling is central to the post-LVAD RV dynamics, with any degree of elevation in pulmonary vascular resistance proving to be detrimental in such scenario. This explains the rationale behind the administration of phosphodiesterase inhibitors and other non-pharmacological and ventilatory manipulations aimed at attenuating an elevated RV afterload.. The coexistent systemic venous congestion compounds the situation furthermore. In the most extreme form, the clinical situation mandates biventricular assistance. Therefore, the echocardiographic predictors of post-LVAD RV failure continue to be actively investigated in order to adequately and consistently define the involved risk. However, the role of serial echocardiography in assessing the degree of septal shift on LVAD support, tricuspid valvular competency, pulmonary arterial pressure, and the concomitant RV function with the titration of inotropic support cannot be overemphasized.The mortality attributable to post-LVAD RV failure is largely a consequence of decreased flow to the LVAD, leading to a significant reduction in pump output, compromising the endorgan perfusion.The aforementioned elucidation of the impact of altered RV mechanics on clinical outcomes post-LVAD insertion highlights the importance of a sound understanding of the underlying pathomechanisms as the basis of echocardiographic surveillance and subsequent therapeutic measures. This discussion is particularly pertinent in the current era of mechanical circulatory assistance, wherein LVAD support continues to evolve as a bridge to transplantation, destination therapy, or as a temporary circulatory support with an expectant recovery of the cardiac function for the ever-growing cohort of patients with advanced heart failure, exceeding the availability of potential organ donors by a considerably wide margin


Inflammatory bowel disease (IBD) includes Crohn’s disease (CD) and ulcerative colitis (UC). These are chronic autoimmune diseases of unknown etiology affecting the gastrointestinal tract. The IBD population includes a heterogeneous group of patients with varying disease courses requiring personalized treatment protocols. The complexity of the disease often delays the diagnosis and the initiation of appropriate treatments. In a subset of patients, IBD leads to colitis-associated cancer (CAC). MicroRNAs are single-stranded regulatory noncoding RNAs of 18 to 22 nucleotides with putative roles in the pathogenesis of IBD and colorectal cancer. They have been explored as biomarkers and therapeutic targets. Both tissue-derived and circulating microRNAs have emerged as promising biomarkers in the differential diagnosis and in the prognosis of disease severity of IBD as well as predictive biomarkers in drug resistance. In addition, knowledge of the cellular localization of differentially expressed microRNAs is a prerequisite for deciphering the biological role of these important epigenetic regulators and the cellular localization may even contribute to an alternative repertoire of biomarkers. In this review, we discuss findings based on RT-qPCR, microarray profiling, next generation sequencing and in situ hybridization of microRNA biomarkers identified in the circulation and in tissue biopsies. Inflammatory bowel disease (IBD) refers to Crohn’s disease (CD) and ulcerative colitis (UC). In UC, inflammation generally includes the rectum and extends towards the coecum and remains confined to the colon. In contrast, in CD, inflammation can involve any part of the gastrointestinal tract (GI) from the oral cavity to the anus. Both CD and UC are associated with multiple pathogenic factors such as environmental changes, the array of susceptibility gene variants, qualitatively and quantitatively abnormal gut microbiota and broadly dysregulated immune response . AlthougIBD starts developing at a younger age, including in infants , and is In this review, we give an overview of microRNAs (miRNAs) as candidate biomarkers in the IBD diagnostic assessment. Changes in miRNA levels are associated with disease development and can be measured both within the diseased tissue and in the circulation by a variety of molecular methods. MiRNAs have been found to be well conserved in archived tissue specimens, enabling retrospective analyses of clinical sample cohorts.MiRNAs play a central role in the regulation of several immune-mediated disorders including IBD ,13,14. MMiRNA expression has been shown to be of importance in a wide variety of human diseases such as cancer, autoimmune, cardiovascular, and neurodegenerative diseases ,22,23,24In IBD, miRNAs have been found to be involved in pathogenesis and have been identified as both diagnostic biomarkers and therapeutic targets . Most ofThere is an increasing interest in exploring epigenetic mechanisms in common diseases, with notable progress in characterizing the contribution of miRNAs . In theiMiRNAs regulate important cellular functions such as cell differentiation and proliferation and signal transduction and apoptosis and exhibit highly specific regulated patterns of gene expression . In autoStudies of circulating miRNAs have shown that miRNAs are potential candidates as biomarkers for diagnosing IBD and various other diseases ,59,60,61To study the pathogenesis and intricacy of IBD, the advancement of a variety of animal models has provided important information. The most extensively used mouse model of colitis utilizes DSS, a so-called chemical colitogen with anticoagulant properties, to stimulate epithelial damage. The DSS colitis model is simple and easy to administer. Acute and persistent colitis is achieved by altering the concentration of DSS and the frequency of administration . A genetThe diagnostic assessment of IBD can be challenging; particularly, discriminating CD from UC can be a diagnostic encounter in cases where the inflammatory lesions are limited to the colon. It is estimated that 10–15% of IBD cases are categorized as IBDU . AlthougChronic inflammation is linked to the development of a variety of cancers such as CRC, pancreatic, breast, and skin cancer ,111 and Patients with extensive IBD or diagnosed with IBD in childhood , have a MiRNAs are believed to take part in the inflammation in IBD and to be implicated in the process from inflammation to CRC . DespiteMiRNAs likely play both oncogenic and tumor-suppressive roles in the carcinogenesis and progression of CRC by regulating the expression of numerous cancer-related genes. The role of the inflammatory burden has also been studied in animal models and indicates that both the initiation and the progression of colonic neoplasia can be aggravated or accelerated by the inflammatory conditions ,129,130.MiR-21 is one of the most prevalent miRNAs in CRC and other cancer types ,132, andMiR-155 is upregulated in both UC and CD patients compared to healthy controls ,140,141 MiR-301a is upregulated in both blood and tissue from IBD and CRC patients ,141,146.The goal of the treatment of IBD patients is to obtain remission and mucosal healing, and thereby lower surgery rates. The classical therapies include corticosteroids, thiopurines, and amino salicylates (5-ASA), which have been in use for decades. 5-ASA has minor side effects ,148 and Currently used therapies in IBD also include Ustekinumab, Vedolizumab and Tofacitinib. Ustekinumab is a monoclonal antibody against IL-12 and IL-23, which is used in patients with moderate to severe CD who are resistant to anti-TNF treatment . ConsideIn general, miRNA-based therapies comprise two fundamental strategies: miRNA antagonism and mimicry ,163,164.It is of importance to determine whether miRNA dysregulation in the circulation reflects similar changes in the lesion. The detection and quantification of circulating miRNAs and the interpretation of their impending role as novel non-invasive biomarkers could be very beneficial in the diagnosis and treatment of IBD. As mentioned above, miRNAs can be detected in distinct body fluids such as saliva, plasma or urine . CurrentAs seen in MiRNAs in IBD research started with the extensive pioneering work by Wu et al. in 2008 , who fou


Nasomaxillary defects may affect patients’ speech, mastication, swallowing, breathing, quality of life, psychology, and social behavior.A combination of surgical reconstruction and prosthetic rehabilitation is frequently required to restore optimal function and esthetics.Of particular concern are the size, weight and contour of the prosthesis, as they can drastically affect comfort, retention, masticatory functionand ease of insertion and removal. This clinical case report describes the prosthodontic rehabilitation of a partially edentulous patient with anasomaxillary defect (Aramany class VI) with a two-component prosthesis joined by magnets. A nasomaxillary defect is the confluence of the oral and nasal cavity as the result of trauma, burns, infection, and surgical removal of tumors or congenital abnormalities - 4. ThA large obturator prosthesis utilizing an attachment system anchored by implants improves the stress distribution, masticatory function, and oral health related qualityof life (OHRQOL)  . HoweveA35-year-old female patient reported to the department of prosthodontics at the A.C.P.M. Dental College, Dhule for replacement of her existing prosthesis.The extraoral exam revealed a midfacial deficiency and loss of nasal prominence . An intrThe patient desired a new prosthesis that would provide optimum function, comfort, and esthetics without surgical intervention. Considering the sizeof the defect, the design necessitated an innovative approach to restore facial harmony, permit nasal breathing, obturate the oronasal communication,replace missing teeth, and restore function. A novel two-component design satisfied the requisites of the prosthesis with a simple path of insertion.Diagnostic and definitive maxillary and mandibular impressions were made in alginate  within prefabricated plastic trays .PatencyAuto polymerizing acrylic resin  was mixed per the manufacturer’s instructions and adapted to the cast’s defectto fabricate a trial nasal obturator . The obtThe maxillary cast with the framework was mounted against the mandibular cast on a semi-adjustable articulator using interocclusal records.Prosthetic teeth were waxed to the framework and evaluated intraorally for phonetics, esthetics, and occlusion. The prosthetic teeth were processedto the framework and the final prosthesis was delivered to the patient. After necessary adjustments, a magnet was attached to the anterior intaglio surface of the processed denture base and its counterpart to the base of the nasal obturator.The patient was pleased with her prosthesis  and 11.Aramany class VI defects are difficult to rehabilitate due to distance of the nasal bulb from the remaining abutment teeth.The anterior segment has the propensity to cantilever into the defect without sufficient support and retention of the prosthesis.However, the path of insertion is dictated by the contours of the remaining abutment teeth.By separating the prosthesis into two components, the nasal bulb can be fabricated for maximum obturation, support and retentionwithout regard to the RDP. Likewise, the RDP can be fabricated for maximum support, stability and function based solely on the contoursof the remaining abutment teeth and oral soft tissue. Therefore, designing each component separately maximizes mechanical design features.The magnets attach the RDP to the nasal bulb upon insertion of the RDP. Magnets allow an undefined path of insertion prior to the finalconnection of the component as well facilitate stability of the nasal bulb. Unfortunately, magnets do lose magnetism over time and aresubject to corrosion without proper concealment. However, the cost and convenience of replacement of a magnet attachment system outweighs its limitations.Optimal rehabilitation of a patient with a nasomaxillary defect can be achieved using a two- component prosthesis attached with magnets.