Body implants and implantable medical devices have dramatically improved and prolonged the life of countless patients. However, our body repair mechanisms have evolved to isolate, reject, or destroy any object that is recognized as foreign to the organism and inevitably mounts a foreign body reaction (FBR). Depending on its severity and chronicity, the FBR can impair implant performance or create severe clinical complications that will require surgical removal and/or replacement of the faulty device. The number of review articles discussing the FBR seems to be proportional to the number of different implant materials and clinical applications and one wonders, what else is there to tell? We will here take the position of a fibrosis researcher  to elaborate similarities and differences between the FBR, normal wound healing, and chronic healing conditions that result in the development of peri-implant fibrosis. After giving credit to macrophages in the inflammatory phase of the FBR, we will mainly focus on the activation of fibroblastic cells into matrix-producing and highly contractile myofibroblasts. While fibrosis has been discussed to be a consequence of the disturbed and chronic inflammatory milieu in the FBR, direct activation of myofibroblasts at the implant surface is less commonly considered. Thus, we will provide a perspective how physical properties of the implant surface control myofibroblast actions and accumulation of stiff scar tissue. Because formation of scar tissue at the surface and around implant materials is a major reason for device failure and extraction surgeries, providing implant surfaces with myofibroblast-suppressing features is a first step to enhance implant acceptance and functional lifetime. Alternative therapeutic targets are elements of the myofibroblast mechanotransduction and contractile machinery and we will end with a brief overview on such targets that are considered for the treatment of other organ fibroses. Implantable medical devices and body replacement parts have revolutionized modern medicine in supporting and/or replacing malfunctioning human organs and tissues. Clinical applications of implants range from tissue repair and reconstruction, prostheses, neural interfacing, biosensors, controlled drug release and electronic pacing. Despite their undisputable benefits for patients, prolonged presence of objects that are not normally part of the organism often provokes tissue repair responses that are collectively known as the foreign body reaction (FBR). The FBR often starts similar to a physiological healing response to lost tissue homeostasis following implantation surgery ,2 and caIn this review, we will mainly discuss two subsequent FBR stages that differ from the normal wound healing process and occur at implant surfaces: 4) chronic macrophage activation and foreign body giant cell (FBGC) formation, and 5) fibroblastic cell activation into myofibroblasts that form peri-implant scar tissue—a process called implant fibrosis  chronic ,5,6. For fibroblaImplant material allergies, bacterial infections, association with cancer and tissue necrosis are some of the most frequent clinical complications associated with the FBR. For instance, exposure to metal-based materials such as those used for orthopedic, dental, or cardiac (pacemaker leads) implant devices can induce material-induced allergies , and cauSimilarly, mechanical overloading of stainless steel-based orthopedic implants can cause clinical issues by implant loosening, ultimately leading to adverse cell responses and inflammation . HoweverWith our aging population, the demand for implantable devices is also rising to support cardiac and vascular function, such as artificial heart valves, pacemakers, catheters, stents, defibrillators, and prostheses. Cardiac implants can cause local pocket infections and ensuing FBRs that often require device extraction. Pacemakers for instance must be surgically replaced every 10–15 years to function properly and an estimated 10,000–15,000 pacemaker and defibrillators leads are extracted annually in the world ,22,23,24The complications associated with FBR are not limited to implantable devices used for medical or therapeutics purposes, but also in cosmetic or reconstructive surgeries. Placement of reconstructive or esthetic breast implants is one of the most common procedures performed in plastic surgery ,30, withMost if not all animal model and clinical implant placings involve surgical damage to the host tissue which inevitably creates a normal wound healing response, often starting with damage to vascularized connective tissue. Plasma proteins released form damaged vessels include albumin, complement factors, fibrinogen, fibronectin, and vitronectin. Together, these constituents form a fibrin-dominated provisional extracellular matrix (ECM), called thrombus or wound clot that stops bleeding . In the Within hours post implantation, neutrophils are among the first immune cells that appear at the tissue- implant interface and their primary task is to clear bacteria and other debris . DegranuMacrophages, platelets, and other implant-adjacent cells of wounded tissue, such as keratinocytes, endothelial cells, and adipocytes secrete various profibrotic and angiogenic growth factors, including platelet-derived growth factors (PDGF), vascular endothelial growth factors (VEGF), and transforming growth factor-beta (TGF-β) which among other functions attract and activate injury-adjacent fibroblastic cells . During Although the onset of the FBR shares several features with normal wound healing, the nature of the implanted material has a profound impact on the progression of acute immune and repair reactions into chronic conditions . DependiIn addition to having different dimensions, implants are produced of materials with very different surface chemistries . All theSurface charge has been shown to alter the efficacy of host protein adsorption to the implant. For example, the plasma proteins fibronectin and vitronectin possess a higher affinity for positively or negatively charged hydrophobic implant surfaces than to uncharged hydrophobic surfaces ,76,77. MSurface wettability can be changed by physico-chemical treatments and/or by modulating material porosity, which is often used to enhance the stability of implants in the target tissue ,86. LaseInstead of providing implant materials with a rough irregular surface, different patterning approaches have been developed to elicit defined cell responses by controlling cell attachment. Lithography methods can be applied to polymer implant materials that are shaped during the polymerization process such as polyurethanes, silicones, and various hydrogels. Numerous studies demonstrated cell responses to topographies, typically involving cell alignment and shape confinement on top of elevated structures or in the pits of the designed landscapes . When arThese and other studies indicate that perceived stiffness and ‘true’ modulus of the implant surface can be used to control cell responses. Medical implants are carefully designed and fabricated from materials that are compatible with surgical handling but can be orders of magnitude stiffer than the host tissue. Physiologically relevant elastic moduli falling into the mechanosensing range of cells are related to the stiffness of their normal tissue environments. Several studies have used atomic force microscopy to measure the Young’s elastic modulus  of various organs and tissues that typically receive implants, such as skin (0.1–10 kPa) , brain  suppressing the formation of detrimental macrophage phenotypes while stimulating regenerating and resolving activation states ,134,135,Numerous studies investigated how macrophage recruitment, adhesion, spreading, activation, and fusion depend on implant surface chemistry and topography . MacrophSpreading ability and shape directly control macrophage polarization states, i.e., their secretory and remodeling activities in addition to the expression of characteristic polarization markers ,149. ForIn addition to surface topographies and adhesive patterns, the stiffness of surfaces has been shown to be critical for the responses of human and mouse lineage and primary macrophages to implant materials. Stimulating cultured macrophages with LPS and IFN-γ on stiff (elastic modulus ≥47 kPa) but not on softer (≤27 kPa) polyacrylamide hydrogels elicits pro-inflammatory response in a process depending on TLR4, NF-kB, and p65 signal transduction . In geneInflammatory environment, such reactive oxygen species, phagocytosis, and/or proteolysis alone can severely impact certain implant materials that are degradable such as replacement scaffolds or depend in their function on physiological environment, such as glucose sensors. Formation of fibrotic capsules around implantable devices can additionally lead to the physical isolation of the device from the tissue which can disrupt device sensing functions, cause pain and disconnect cell-seeded implants from nutrient support . ImplantThe formation of fibrotic capsules around implants was originally attributed to fibroblasts producing a highly fibrous and acellular ECM which contains collagen I/III, fibronectin, and proteoglycans . HoweverAll these principles are being applied to reduce myofibroblast activation at the surface of implant materials in culture systems and/or animal models of implant fibrosis . In our Organ fibrosis comprises a group of heterogeneous connective tissue diseases that often lead to disruption of soft organ architecture and ultimately organ failure. Fibrosis is characterized by the excessive accumulation of disorganized and stiff ECM that often develops due to impaired wound healing as a result of the repetitive or chronic tissue injury ,189,190.Aberrant ECM mechanosensing by fibroblastic cells and myofibroblast activation are associated with fibroproliferative disease conditions that involve changes in tissue environment and ECM composition ,210,211.Beyond their classical roles in direct mechanosensing, specific αv integrins are also involved in the activation of latent TGF-β1, a key factor in driving myofibroblast activation ,226,227 In addition to driving pro-fibrotic cell programs thorough ‘canonical’ Smad signaling pathways, TGF-β1 also acts through the PI3K/Akt pathway, mitogen activated protein kinases (MAPKs) including Jun N-terminal kinases (JNKs), p38 MAPK (aka MAPK14), extracellular signal-regulated kinases (ERKs), and the Rho/Rho-associated protein kinase (ROCK) pathway ,238,239.Myocardin-related transcription factor (MRTF-A) is another mechanosensitive transcriptional effector that has been implicated in coordinating profibrotic signaling in myofibroblasts . Upon meMacrophage activation and fusion into FBGCs are hallmarks of the FBR and have been studied extensively because of their detrimental effect on medical device functions and surrounding tissue integrity. However, the consequences of chronic inflammation on fibroblastic cell populations in the vicinity of a—usually stiff—foreign body is less well documented. We and others have previously reviewed how macrophage-fibroblast interactions contribute to normal tissue repair and how dysregulation results in fibrosis; similar cross-talk is expected to take place in the environment of an implant ,131. NotStiff materials placed in provisional ECM create boundary conditions that are sensed over long distances by fibroblastic cells ,281,282.


The cardiovascular toxicity of anticancer drugs promotes the development of cardiovascular diseases. Therefore, cardiovascular toxicity is an important safety issue that must be considered when developing medications and therapeutic applications to treat cancer. Among anticancer drugs, members of the anthracycline family, such as doxorubicin, daunorubicin and mitoxantrone, are known to cause cardiotoxicity and even heart failure. Using human-induced pluripotent stem cell-derived cardiomyocytes in combination with “Omic” technologies, we identified several cardiotoxicity mechanisms and signal transduction pathways. Moreover, these drugs acted as cardiovascular toxicants through a syndrome of mechanisms, including epigenetic ones. Herein, we discuss the main cardiovascular toxicity mechanisms, with an emphasis on those associated with reactive oxygen species and mitochondria that contribute to cardiotoxic epigenetic modifications. We also discuss how to mitigate the cardiotoxic effects of anticancer drugs using available pharmaceutical “weapons.” Streptomyces actinobacterial strains. It is the most commonly prescribed chemotherapy drug to treat breast, ovarian and gastrointestinal cancers, sarcomas, leukemia, non-Hodgkin's and Hodgkin's lymphomas, multiple myeloma and various other cancers, because it shows beneficial therapeutic effects  was one of the first anthracyclines isolated from  effects . One of  effects . AnotherDOX acts by producing reactive oxygen species (ROS), causing oxidative stress, damaging cell structures and activating cell death pathways. Patients' responses to this medication are not linear. Indeed, some patients appear to be tolerant to high doses of DOX, while others manifest heart attacks at low-dose . ROS plaper os administration of capecitabine. These mechanisms suggest activation of the protein kinase C signaling pathway, which leads to imbalanced calcium regulation, causing a dramatic reduction in contractility of vascular smooth muscle cells in the vessels. Arterial vasospasm is manifested by endothelial dysfunction related to the toxic effects of 5-FU on endothelial cells. Patients who have pre-existing endothelial dysfunction, such as those with coronary artery diseases, are at greater risk of developing vasospasm from 5-FU than those who do not. In addition, thymidine phosphorylase, which catalyzes the last step in the conversion of capecitabine to 5-FU, is expressed in atherosclerotic plaques. Therefore, its administration can lead to high local concentrations of 5-FU and increased risk (80%) of developing vasospasm. CVDs that usually occur are angina pectoris (45%), followed by myocardial infarction (22%), arrhythmias (23%), ventricular fibrillation, as well as cases of cardiac arrest and sudden cardiac death  and ac death .In contrast, paclitaxel therapy has been associated with acute coronary syndrome. Myocardial infarction and myocardial ischemia have been observed up to 14 days after starting paclitaxel therapy. Increased Rho kinase activity in vascular smooth muscle cells of the coronary artery are thought to be associated with angiospasms caused by paclitaxel. Several alkaloids  have been associated with endothelial toxicity that may cause an acute coronary ischemia. These drugs are usually prescribed in combination, although more than 2/3 of patients develop angina pectoris during chemotherapy. Cisplatin can cause acute thrombosis as well as acute vasoconstriction in cancer patients, with severe effects observed even two decades after its administration. In fact, the probability that these patients will develop coronary artery diseases is seven times higher than expected .The most important epigenetic mechanisms involve pathways leading to DNA methylation, post-translational histone modifications and regulation of gene expression via non-coded RNAs, such as microRNAs  and long non-coding RNAs (lncRNAs) , 2. In aA cell contains ~2 meters of DNA within its nucleus, which is organized into chromatin and further into chromosomes. Each human diploid somatic cell contains 23 pairs of chromosomes, and each chromosome contains several hundreds of thousands of nucleosomes . Each nuEpigenetic modifications occur physiologically, mainly via methylation of the chromatin DNA and via methylation and acetylation of chromatin-histones , 20. DNAHistone acetylation of lysine residues , as well as on arginine residues , is catalyzed via the histone acetyltransferase (HAT) enzymes , which induce the transfer of acetyl residues from acetyl-coenzyme A (CoA) to the ε-amino of lysine residues. Deacetylation of a ε-N-acetyl lysine amino acid from histones occurs via histone deacetylases (HDACs) , 25 Fig. HistonePromising cancer (and cardiovascular) therapeutics that target epigenetics are currently being developed , 29, 30.in vitro and in vivo leukemia models. In terms of cardiotoxicity, there has been a growing interest in sirtuin proteins (SIRTs), a category of NAD+-dependent deacetylases that catalyze the deacetylation of many proteins, including histones. These proteins have been shown to play an important role in cardioprotection against the cardiotoxicity induced by DOX  and cardiac troponin T (cTnT). These elevated levels are well-correlated with myocardial injury and act as important plasma biomarkers for the diagnosis of cardiac damage in clinical and preclinical studies. However, high levels of these biomarkers occur only after heart damage. Unfortunately, these biomarkers can only be detected a few hours after myocardial infarction and after treatment with cardiotoxic drugs. Therefore, identification of novel pharmacogenetic early biomarkers capable of predicting cardiac damage are urgently needed. For example, altered expression of miRNAs was recently found teration .in vitro, human embryonic stem cells and human-induced pluripotent stem cells (hiPSCs) have been used to predict the adverse effects of different compounds on genome and epigenome levels  may be a protective agent against cardio toxicity of anticancer drugs via antioxidant and anti-inflammatory mechanisms. Analysis of the hearts of mice that had undergone cardio toxicity from DOX included inhibition of overactive autophagy and apoptosis mediated by Ak strain transforming activation. Rutin caused a reduction in cardiac fibrosis and morphological changes in the heart linked to treatment with DOX . ResveraThere are some evidence that female animal hearts are protected due to 17-β-estradiol from the doxorubicin-induced cardio toxicity through the increased levels of ROS and apoptosis in male hearts. However, potential clinical cardio-protective benefits of females hearts are controversial discussed .Undoubtedly, anticancer treatments cause a persistent and long-term cardiovascular toxicity, leading to CVDs. Thus, an understanding of the toxicity pathways induced by anticancer therapeutics is a priority and precondition to developing safer and better therapeutic drugs for treatment and to ensure a better quality of life for cancer patients. In the last decade, it was recognized that targeting of epigenetic regulators, such as HDACs, prevents severe cardiovascular toxicity during anticancer treatment. Therefore, promising efforts are ongoing to develop epigenetic drugs, targeting HDACs, to prevent the severe side effects of the anticancer drugs. Classical biomarkers, such as elevated concentrations of troponins in the blood, can only be detected after myocardial infarction and cardio toxicity. Human-relevant test systems based on pluripotent stem cell-derived CMs significantly contributed to the identification of several key cardio toxicity mechanisms, involving both genetic and epigenetic pathways. These studies also lead to identification of genetic and epigenetic markers, such as miRNAs, which may be applied as early biomarkers for predicting and preventing cardiac damage induced by anticancer treatment. Mitochondrial dysfunctions in CMs induced by the anticancer drugs via classical and epigenetic pathways are key cardio toxicity mechanisms. Furthermore, epigenetic remodeling, mediated by anticancer drugs, may disrupt the mitochondrial energy metabolism. We conclude that several genetic and epigenetic targets of anticancer therapeutics have now been identified for preventing or ameliorating cardiovascular toxicity. However, clinical studies still need to confirm the beneficial nature of these so-called epi-drugs.PP, LP, and AS drafted and wrote the manuscript. 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.


Coronavirus disease 2019 (COVID-19) vaccines are being developed and implemented with unprecedented speed. Accordingly, trials considered ethical at their inception may quickly become concerning. We provide recommendations for Data and Safety Monitoring Boards (DSMBs) on monitoring the ethical acceptability of COVID-19 vaccine trials, focusing on placebo-controlled trials in low- and middle-income countries. We provide recommendations for Data and Safety Monitoring Boards (DSMBs) on monitoring the ethical acceptability of coronavirus disease 2019 (COVID-19) vaccine trials, focusing on placebo-controlled trials in low- and middle-income countries. Over 70 vaccine candidates to protect against coronavirus disease 2019 (COVID-19) are currently being tested in humans. At the time of writing, 3 have received emergency use authorization (EUA) in the United States, and 10 vaccines have been approved or authorized in different countries  to exercise its own judgment in such circumstances” . Even inWithout a clearer framework for following or deviating from statistical analysis plans, it is difficult for sponsors, trial steering committees, and others to evaluate the wide range of DSMB recommendations. For example, in the Adaptive COVID-19 Treatment Trial, the DSMB recommended early termination of the placebo arm based on interim data showing that participants treated with remdesivir recovered faster than those receiving placebo . AlthougTo address these challenges in the context of COVID-19 vaccine trials, sponsors, trial steering committees and others with responsibility for constituting DSMBs should select members and draft monitoring plans that will support the independent and value-laden nature of their decision-making. Once DSMBs do make recommendations, sponsors and trial steering committees should be prepared to act on these recommendations  or, in tAs a starting point, including ethicists and experts on the DSMB with strong ties to local communities may help open important channels of communication and sensitize the DSMB to relevant ethical issues and local circumstances. For example, local experts may be best able to determine whether vaccine supply is unjustly allocated in host countries or communities, resulting in a gap between the de jure and de facto standards of care. Although previous capacity building efforts in LMICs have resulted in well-established clinical trial infrastructure and research ethicists at many centers , identifSecond, protocols and statistical analysis plans should expressly recognize the value-laden nature of trial monitoring, including the need to evaluate continued placebo use in light of the de jure standard of care. Stopping boundaries could include potential changes in whether some or all participants should be receiving access to vaccines, alongside safety and efficacy data. Alternatively, factors for deviating from the statistical analysis plan could be explicitly delineated. Second, to allow this assessment, sponsors—ideally in partnership with local health authorities—should provide reports to DSMBs about such availability. Finally, greater clarity is needed on the relationship between the respective roles of DSMBs and RECs. In some cases, rather than merely sharing DSMB reports with RECs, greater collaboration between DSMBs and RECs may be helpful . This co


The aim of the present study was to systematically review studies investigating antibacterial implant abutment surfaces or coatings, which may suppress bacterial growth to prevent plaque-induced peri-implant inflammatory disease. Data were collected after identification of case, assay/laboratory procedure, predicate/reference standard and outcome (CAPO). Seven hundred and twenty (720) records were identified through data base searching. After screening nine publications fulfilled inclusion criteria and were included. The following surfaces/coatings showed antibacterial properties: Electrochemical surface modification of titanium by the anodic spark deposition technique; doxycycline coating by cathodic polarization; silver coating by DC plasma sputter; titanium nitride; zirconium nitride and microwave assistant nano silver coating. Since the current state of the literature is rather descriptive, a meta-analysis was not performed. While several abutment coatings showed to have antibacterial capacity, some of them also influenced the behavior of investigated human cells. None of the studies investigated the long-term effect of surface modifications. Since surface changes are the main contributing factor in the development of antibacterial effects, the biodegradation behavior must be characterized to understand its durability. To date there is no effective structure, material or strategy to avoid peri-implant inflammation used as clinical routine. Furthermore, clinical studies are scarce. With a prevalence of 22%  peri-impThe risks for the development of peri-implant inflammation have been widely studied and were summarized in the Consensus Report of the Sixth European Workshop on Periodontology. Poor oral hygiene, a history of periodontitis and smoking were associated with peri-implant disease . Once peIn general peri-implant inflammation can be divided into mucositis and peri-implantitis. Mucositis describes a bacteria-induced, reversible inflammatory process of the peri-implant soft tissue with reddening, swelling and bleeding on periodontal probing.  In contrThe objectives of the present study are to review and evaluate material, structures or strategies to prevent plaque-induced peri-implant inflammatory disease, i.e., peri-implantitis, by means of antibacterial implant abutment surfaces or coatings for their antibacterial properties suppressing bacterial growth. This systematic review was performed adhering to Transparent Reporting of Systematic Review PRISMA 2020) guidelines 20 guidel was statC (Case): Prevention of peri-implantitis through antibacterial implant-abutment coatingsA (Assay or laboratory procedure): analyzing antibacterial activity and cytotoxicityP (Predicate/reference standard): abutment material without coatingO (Outcome): cell viability, bacterial deathCAPO question:The resulting question was the following:Do abutment coatings suppress bacterial growth or interfere with human cells in comparison to uncoated implant abutments?The following criteria were used to include or exclude published articles.The electronic databases PubMed and Cochrane Central Register of Controlled Trials were searched on 23 April 2021 for studies published until April 2021. The specific search protocol can be seen below: AND (surface)) OR (coating) AND (abutment)).: ti,ab,kw AND (surface): ti,ab,kw OR (coating): ti,ab,kw AND (abutment): ti,ab,kwTwo reviewers  independently screened titles and abstracts of studies according to the predefined search strategy and additional sources. Following this, selected full-text articles were again reviewed and discussed by the two reviewers . The kappa value was calculated as a measure of agreement between the readers after screening the full texts and any disagreements were clarified by discussion with a third reviewer (M.N.). Articles found from additional sources as hand search and grey literature were also screened following the same systematic procedure. The following data were extracted from the included studies by two authors independently : study design, type of coating, control group, test procedure, influence of abutment coating on cell behavior, influence of abutment coating on bacteria, missing or unclear information. EndNote  was used as the software to organize and screen the extracted articles.The included clinical studies were assessed by the revised RoB tool based on the Cochrane RoB assessment method by Higgins et al., (2016) . PreclinFor in vitro studies, also known as mechanistic studies, there are no established RoB tools comparable to the ones for clinical and animal studies. Therefor the Office of Health Assessment and Translation (OHAT) of the U.S. Department of Health and Human Services developed a tool to assess the RoB assessment of in vitro studies. Details can be found in the “Handbook for Conducting a Literature-Based Health Assessment Using OHAT Approach for Systematic Review and Evidence Integration” .k value was calculated and showed a value of k = 1. The extracted data of included studies can be seen in The data extraction process and the study selection can be seen in The results of RoB assessments are included in Two clinical studies ,17 were Finally for the preclinical study of Almohandes et al.,  selectioThe extracted data  of the included studies can be seen in 2 layers of titanium has proven to be difficult due to the low reactivity of this surface, cathodic reduction in acidic solutions can be used to create a hydrogen-rich surface on which biomolecules can bind more efficiently [The included studies investigated the antibacterial properties of different modified implant abutment surfaces. Eight studies modified titanium and one study titanium zirconium samples. Furthermore, eight studies ,15,17,18iciently .Sol-gel treatment is a wet-chemical technique, which is primarily used for the preparation of metal oxides. It is based on a chemical solution that functions as a precursor for an integrated network (or gel) of discrete particles or network polymers . In thisPVD refers to a range of vacuum deposition processes that can be used to create thin films and coatings. It is characterized by a process in which the material passes from a condensed phase to a vapor phase and then back to a condensed thin film phase .The microwave assisted coating for the production of nanoparticles, performed by Odatsu el al., (2020) {Odatsu, 2020 #682}, is a technique that provides better technical control over the separation of nucleation and growth stages in the synthesis of nanoparticles when the reaction is started at room temperature . AnotherWith the exception of one study  all incl2) coating and calcium-treated surfaces did not influence biofilm formation of Streptococcus sanguinis and Actinomyces naeslundii after an incubation period of 2 h and 14 h. [Escherichia coli and showed that DLC has no antimicrobial properties and does not interfere with bacterial adhesion after 3 h and 24 h.Titanium oxide , performed in a calcium phosphate enriched solution, showed statistically significant higher antibacterial activity in ASD samples compared to titanium. Also a statistically significant reduction in bacterial attachment was observed after an incubation period of 3 h and 24 h . Etched operties . Titaniu. oralis . The numof 120 h .Xing et al.,  examinedVisai et al.,  and OdatOdatsu et al.,  includedFurthermore Almohandes et al.,  performeBesides investigating antibacterial properties of implant-abutment coatings Visai et al., , AlmohanThe metabolic activity of MG63 cells was not influenced by electro-chemical surface modification of titanium by ASD, performed in a calcium phosphate enriched solution. Furthermore, the cell number of MG63 cells on ASD treated samples was statistically significantly higher compared to the negative control .In the study of Almohandes et al.,  biopsiesHuman gingival fibroblasts (HGF) incubated directly on sample disks  did not show differences in proliferation. Morphological analysis with scanning electron microscopy, hemolysis test, Ames test, ribonucleic acid (RNA) extraction, first-strand complementary deoxyribonucleic acid (cDNA) synthesis, Real-time polymerase chain reaction (PCR) and indirect immunofluorescence was performed. The genes considered were talin, alpha-actinin, vinculin, zyxin, paxillin, vitronectin, focal adhesion kinase (FAK), and collagen type I, all involved in cell adhesion. Good mRNA relative expression levels were found on all the surfaces examined, but the highest gene expression values were observed on the ZrN-treated disks. HGF adhered on all disks and did not show differences in vinculin expression. None of the samples were hemolytic and no mutagenic activity was revealed for any of the surfaces tested . The infThe objectives of this systematic review were to summarize and evaluate the state of research on antibacterial surfaces or coatings on implant abutments as a primary prevention against mucositis and peri-implantitis. Therefore, a systematic search strategy was applied for the databases PubMed and Cochrane Central Register of Controlled Trials. The search resulted in nine included studies . We found that several abutment coatings investigated in the included studies suppressed bacterial growth or influenced the behavior of investigated human cells, indicating less cell viability or mild cytotoxicity.The PICO question is easily applicable for the evaluation of most therapeutic or interventional studies but can be inappropriate for use in evidence-based laboratory medicine. Therefor the CAPO question was proposed by Christenson . As therAs limitations of this study we can mention that only a few studies were included in the systematic review and none of the studies investigated the long-term effect of implant abutment coatings. All studies investigated antibacterial properties with different bacteria and laboratory methods. Likewise, the cells used differed in the included studies, preventing meta-analysis for outcomes. Furthermore, only two clinical studies and one pre-clinical study in dogs were performed. It is also known that studies presenting significant results are time more likely to be published compared to null results. This so-called publication bias may also have influenced our findings .2 coating by sol gel treatment and did not describe any antibacterial effect. The investigated surface was not irradiated with UV light in this study either. As the antibacterial activity of TiO2 by UV-Light exposure has been confirmed in other studies [2 surfaces without additional photocatalytic activation appears to have no influence on bacterial colonization of implant components.Five of the included studies showed antibacterial properties of investigated implant abutment surfaces/coatings. Electrochemical surface modification of titanium by ASD, performed in a calcium phosphate enriched solution showed statistically significant less bacterial attachment and a lower amount of biofilm formation on the treated than on the non-treated surfaces. During ASD, the titanium oxide film is transformed into the crystal structure of anastasis and thus exhibits photocatalytic activity . However studies ,36,37, tAggregatibacter actinomycetemcomitans, Streptococcus mutans, methicillin-resistant Staphylococcus aureus [Actinomyces naeslundii and Streptococcus sanguinis [Titanium-bismuth-gallium coating did not prevent biofilm formation in a preclinical in-vivo study with dogs. The combination of titanium, bismuth and gallium in terms of bactericidal capacity was to the best of our knowledge not investigated before, although bismuth compounds showed antibacterial properties against s aureus , Actinomanguinis .Despite the investigations of Xing et al., the antibacterial effects of doxycycline abutment coatings have not been described in the literature yet. In general, the antibacterial effect of doxycycline is in accordance with the recent literature and shows, when applied systematically, steady-state levels in gingival crevicular fluid ,41,42. HThe biomedical application of DLC films can promote the growth of cells like fibroblasts, osteoblasts, and macrophages, without signs of inflammation or cytotoxicity . In geneSilver nanoparticles have been shown to be effective biocides against bacteria, fungi and viruses ,53,54,55The antibacterial capacity of titanium nitride and zirconium nitride described in the paper of Brunello et al., has already been reported several times in the literature ,57,58,59When discussing the antibacterial effect of coated surfaces, the duration of the effect should be of particular interest. Early bacterial contamination can lead to bone loss even before incorporating prosthetic restoration, which may finally result in implant loss, i.e., early implant failure. On the other hand, implants with good bone-to-implant contact might show a loss of the marginal bone over the service time of the prosthetic restoration and can thus be assigned to a late implant failure . TherefoPorphyromonas gingivalis, Staphylococcus aureus, Staphylococcus anaerobius, Streptococcus intermedius, Streptococcous mitis, Tanerella forsythia and Treponema socranskii. Bacterial colonization with these bacteria has been shown to be four times higher on peri-implant sites than on healthy implants [2+ appear to be promising [The need for the prevention of peri-implant inflammations is reflected in its prevalence, which was reported to be 43% for mucositis and 22% for peri-implantitis in a recently published systematic review , and in implants . Besidesromising ,65,66,67The CAPO question can be answered as followed: Several abutment coatings investigated in the included studies suppressed bacterial growth . Furthermore, abutment coatings of diamond-like-carbon and silver coating by DC plasma sputter influenced the behavior of investigated human cells, indicating less cell viability or mild cytotoxicity. Since clinical studies are scarce, further clinical investigations need to be conducted.


Precision medicine is a revolutionary new way to deliver cancer treatment by targeting specific genetic changes of the cancer of the individual child with the goal of improving cure rates and reducing toxicity. In this review, we illustrate the evolution of cancer treatment in this groundbreaking new era. We compare characteristics and early results of precision medicine programs in pediatric oncology as well as novel clinical trial initiatives translating these findings into potential clinical benefit for all children and adolescents with cancer.Over the last years, various precision medicine programs have been developed for pediatric patients with high-risk, relapsed, or refractory malignancies, selecting patients for targeted treatment through comprehensive molecular profiling. In this review, we describe characteristics of these initiatives, demonstrating the feasibility and potential of molecular-driven precision medicine. Actionable events are identified in a significant subset of patients, although comparing results is complicated due to the lack of a standardized definition of actionable alterations and the different molecular profiling strategies used. The first biomarker-driven trials for childhood cancer have been initiated, but until now the effect of precision medicine on clinical outcome has only been reported for a small number of patients, demonstrating clinical benefit in some. Future perspectives include the incorporation of novel approaches such as liquid biopsies and immune monitoring as well as innovative collaborative trial design including combination strategies, and the development of agents specifically targeting aberrations in childhood malignancies. Cancer remains the leading cause of death in children and adolescents in high-income countries: about one in five children with cancer will succumb to their disease ,2. DespiIn this review, we summarize the evolution of genomics-informed precision medicine, focused on the results of established pediatric oncology programs worldwide, discussing challenges and opportunities to accelerate the implementation of pediatric precision oncology.http://rayyan.qcri.org; accessed on 2 December 2020) and subsequently assessed on both title and abstract. After inclusion, the reference lists of respective studies and pediatric precision medicine reviews were searched for additional relevant pediatric precision medicine studies. Abstracts and unpublished data were also considered. Studies focused on adult precision medicine that did not separately report results for children and adolescents were excluded. For the independent precision medicine programs, the following data were collected: program name, country, study period, number of patients included, number of patients analyzed, cancer types included, maximum age for inclusion, inclusion criteria , types of molecular analysis performed, percentage of (actionable) somatic and germline events, change in diagnosis or re-classification, target priority score, percentage of targeted therapy applied, and clinical outcome. Before performing the analysis, collected data were sent to their respective authors/project leaders for verification. Data were analyzed using descriptive statistics.To identify pediatric precision medicine studies, a PubMed search was performed with the following search term [”childhood cancers” OR “pediatric oncology” AND “precision medicine” OR “targeted therapy”] up until 1 December 2020. All found studies were uploaded in Rayyan , as published up until December first of 2020 . These sThe following precision medicine programs were developed: the United States initiated BASIC3 , MSKCC PInternationally published and/or presented results demonstrate the feasibility and opportunities of molecular-driven precision medicine and revealing a rate of actionable variants that justify the development of predictive biomarker-driven trials for childhood cancer. In addition to the detection of potentially druggable events, molecular profiling could also be used to identify germline mutations and change or refine diagnosis ,68,69,70Enrollment criteria for patients to enter precision medicine programs are heterogeneous. The majority of precision medicine programs include children, adolescent, and young adults with various tumor subtypes at different time points, although the published cohorts consisted mainly of patients with refractory or relapsed CNS malignancies as well as extracranial solid tumors. Several initiatives aim to inform physicians of clinically actionable targets to promote enrollment in pediatric early clinical phase trials to investigate whether it is effective to treat cancer in children and adolescents by targeting certain genetic changes in their tumors with specific targeted drugs. Other programs aim to increase our understanding of genetic drivers of pediatric cancer and to identify new clinically relevant subtypes.BRAF V600–mutant relapsed and those with refractory low-grade glioma showed a 44% objective response rate [NTRK fusion gene, larotrectinib, a selective TRK inhibitor, had a 93% objective response rate [ALK aberrations by adding ALK-inhibitors to first-line therapy, with molecular profiling transitioning from basic science to validation in the clinic . Finally, there is a subset of patients who do not achieve meaningful responses after induction and therefore harbor a poor prognosis with conventional treatment protocols. Thus, identifying actionable events early in the disease course might provide unique treatment options in a subset of very-high-risk patients.Although most programs included relapsed and/or refractory patients, a debate is ongoing on the timing of inclusion of patients. Several distinct points can be highlighted. First, at diagnosis, patients with standard-risk disease might not benefit from identifying additional treatment options, but refinement of diagnosis as well as disease classification can be crucial for subtypes in CNS tumors as well as sarcoma or tumors of unknown origin ,72. Seconse rate . In non-nse rate ,74. In cDruggable events vary between primary and relapse tumors. Only 37% of primary tumors retained these events upon progression whilst most tumors gained events, as reported in disease-specific reports ,82,83,84Several prospective precision medicine program initiatives have shown feasibility of integrating genomic and epigenomic data in real time to direct treatment decisions for pediatric patients. Applied methods to sequence somatic as well as germline DNA vary, as summarized in https://www.stjude.cloud; accessed on 11 May 2021) [http://r2.amc.nl; accessed on 11 May 2021) [Data sharing thus far is limited and can be challenging due to privacy regulations, but several platforms aim to analyze and publicly visualize genomic data since effective data sharing is key to accelerating research. For example, St. Jude Cloud is an expanding cloud-based data-sharing ecosystem with genomic data from >10,000 pediatric patients (ay 2021) . Anotheray 2021) .To date, no comparisons between precision medicine platforms and strategies have been published and health technology assessment is lacking. Whilst the most optimal approach is still unclear and the optimal molecular profiling approach might vary by disease type and stage, several technologies transition to become the standard of care in developed countries. Institutions will choose NGS approaches based on the quality and quantity of available material, clinical relevance, and research interests as well as sustainable funding opportunities.After sequencing and bioinformatic processing of raw data, molecular data are integrated with (pre)clinical evidence to select clinically relevant alterations. In all programs, an expert review is performed by a molecular tumor board, comprising experts of various disciplines such as molecular biologists, pediatric oncologists, clinical geneticists, pathologists and/or early-phase clinical trial physicians and pharmacists.The percentage of actionable alterations that were reported in the different studies range from 27% to 100% . HoweverAdditionally, prioritization of the detected events differs between precision medicine programs. A common classification system that is used for the recommendation of targeted therapies is the NCI-MATCH tier. Actionable alterations are ranked from high to low level of supporting evidence: Tier 1, clinical evidence in the same cancer; Tier 2, clinical evidence in a different cancer; Tier 3, preclinical evidence in the same cancer; Tier 4, preclinical evidence in a different cancer type . The INFIn conclusion, interpretation and prioritization of actionable event calling is challenging and dynamic in a rapidly evolving landscape of new biomarkers and treatments. Further optimization and standardization of the process of target prioritization will be crucial to allow for the comparison of molecular profiling technologies as well as guide clinical decision making.Most precision medicine studies highlight the importance of germline alterations in cancer-related genes, and cancer predisposition syndromes are recognized as an important cause of pediatric cancer development .Detecting variants differs between programs due to distinct inclusion criteria and various gene panels. The mean percentage of germline mutations detected by molecular profiling is 14% with a minimum of 6% and a maximum of 35% . VariantGermline pathogenic variants can be linked to somatic features of the tumors, identifying potential treatment strategies. High tumor mutational burden is detected in patients with constitutive mismatch repair deficiency based on biallelic germline loss of MSH6 or PMS2. Enrichment in mutational signature 3 (‘BRCAness’) can be found in tumors from patients with germline homologous recombination defects ,51.Therefore, molecular profiling not only has the potential to confirm a mutation in a cancer predisposition gene, but also to guide treatment in cases where germline alterations were not predicted by family history or not clinically evident . MoreoveThere are no structured reports of pharmacogenomic alterations and research on clinical impact of variants on pharmacokinetics, and pharmacodynamics in pediatric oncology is still in its infancy .Next to the identification of somatic alterations that can be targeted by a specific treatment, molecular profiling also has the potential to lead to a clinically relevant change or refinement in diagnosis, for example, through the identification of a specific fusion or DNA methylation-based classification.Tumor re-classification or changing or refinement of diagnosis was possible for a substantial number of patients . These rMolecular tumor boards (MTBs) provide an individual report, summarizing all actionable genomic aberrations and matched treatment and/or clinical trial recommendations. The aim is to help clinicians to translate molecular profiles into clinical benefit, maximizing the impact of precision medicine. Optimal design of these MTBs has not been determined .The time to results varied considerably between the precision medicine programs , dependiThe decision to apply targeted therapy based on the MTB recommendation is made by the treating pediatric oncologist together with the patient and parents. Critical decision-making factors in this process remain to be elucidated. However, patient performance status might be a limiting factor since children are often enrolled with end-stage disease and subsequently deteriorate or die early. In addition, turnaround time between biopsy and molecular tumor board results requires initiating an alternative conventional  treatment protocol, balancing toxicity, and quality of life. Additionally, there might be difficulties accessing targeted therapy drugs, particularly in children. Since only few molecular targeted drugs have pediatric indications, a targeted therapy could either be received through enrolment in a phase I/II clinical trial, by off-label or compassionate approaches . On averFor 5 out of the 18 included precision medicine programs in this study, follow-up after the identification of actionable alterations is not (yet) published, and others reveal contradictory results in a non-randomized setting. Encouraging results have recently been published from large-scale studies in Europe and Australia. Collaborative data from INFORM and iTHER showed increased progression-free survival for the subgroup of patients that followed treatment recommendation for a very-high-priority target . The ZerCurrently, the availability of approved molecular targeted drugs for pediatric patients is still limited compared to adult indications and many new targeted drugs lack dosage guidelines and efficacy data in children . TargeteInnovative strategies in early drug development for children, adolescents and young adults have been proposed by several collaborative groups ,95,96,97Recently, large-scale pediatric trial initiatives have been developed in order to design phase I/II (combination) trials. Basket trials are designed to enroll biomarker-selected patients with many different cancer types who are assigned to one of the biology-matched subprotocols . ExampleIn addition to state-of-the-art molecular profiling, several precision medicine programs are adding functional testing of drug sensitivities in patient-derived models to complement current genomic approaches.Patient-derived xenograft (PDX) models generated from the transplantation of patient tumor cells into immunodeficient mice or zebrafish conserve the original tumor characteristics preserving the heterogeneity ,103. FunPatient-derived organoids resemble in vivo tumors, model treatment response and hold promise to predict drug response in a personalized fashion. They are established with a high success rate and are readily available for drug sensitivity testing ,110,111.Several reports have demonstrated the feasibility of detecting tumor DNA in liquid biopsies using NGS or droplet digital polymerase chain reaction, including for pediatric cancers ,113,114.Immunotherapy has been an exciting new development in systemic cancer treatment in a range of adult cancers such as melanoma and lung cancer. In pediatrics, response rates and outcomes significantly improved in patients with relapsed and refractory hematological malignancies such as B-ALL and lymphoma with antibody-based therapy including blinatumomab and inotuzumab ozogamicin as well as CAR-T therapy . Anti-GDPrecision medicine trials with single-agent small molecules have shown limited success. Studies indicate heterogeneity of molecular mechanisms that can drive tumorigenesis within one tumor type, making it unlikely to improve curation rates with a new single treatment modality ,119,120.Future trial designs will include biologically driven combinations of molecularly targeted therapies as well as targeted treatments combined with chemotherapy or immunotherapy, as initiated by AcSé-ESMART (NCT02813135) ,99 as weIn addition to innovative trial design, global collaboration facilitated by sustainable funding is necessary to identify and enroll eligible patients for each study ,121. A pDespite global collaboration and regulatory changes, several challenges remain. As molecular enrichment in a trial arm does not always take place, it is difficult to determine the clinical outcome for the biomarker-selected patients. Moreover, as basket trials do not have a control group, the potential to assess whether clinical outcome can be improved by molecular selected targeted therapy compared to conventional treatment is limited. Another challenge is caused by tumor complexity and resistance, which makes it unlikely that targeted monotherapy would result in complete remission. More extensive preclinical research is needed to identify the genomic alteration—drug combinations that could be effective. Therefore, in the future, international coordination will be crucial to generate a database to inform rational trial design and to evaluate combination trials, paired with conventional or combined targeted therapy, in enriched cohorts. In addition, little is known about the long-term toxicities of most novel targeted and immunotherapy agents. To address this gap, ACCELERATE has initiated the development of an international long-term follow-up prospective data registry with the aims of supporting the regulatory requirements, labeling information, and providing insight to help guide physicians and families on the appropriateness of a targeted or immune therapy for their child and inform survivorship planning .New methods dedicated to improving data collection, storage, processing, and interpretation continue to be developed. The collection of integrated clinical and molecular results from precision medicine initiatives as well as early phase clinical trials raises a number of challenges with respect to privacy and ethical concerns that need to be addressed to optimize progress in childhood cancer precision oncology ,124.Precision medicine in pediatric oncology has rapidly developed over the last decade. Assessing clinical benefit as well as cost-effectiveness remains challenging due to heterogeneity in patient selection as well as the lack of standardization in data interpretation and treatment recommendations. The development of innovative precision medicine trials incorporating functional model systems and novel techniques is critical to optimizing outcome. Due to global collaborative initiatives, the integration of genomic and (pre)clinical data can be used to direct the development of novel targeted agents more effectively in the future.


Herein, we critically review the available literature on plasma circulating tumor cells (CTCs), cell-free tumors (ctDNAs), circulating cell-free microRNAs (cfmiRNAs), and circulating extracellular vesicles (EVs) for the diagnosis and monitoring of brain tumor. Currently available markers have significant limitations. While much research has been conductedon these markers, there is still a significant amount that we do not yet understand, which may account for some conflicting reports in the literature.Brain tumors are the most common malignant primary intracranial tumors of the central nervous system. They are often recognized too late for successful therapy. Minimally invasive methods are needed to establish a diagnosis or monitor the response to treatment of CNS tumors. Brain tumors release molecular information into the circulation. Liquid biopsies collect and analyze tumor components in body fluids, and there is an increasing interest in the investigation of liquid biopsies as a substitute for tumor tissue. Tumor-derived biomarkers include nucleic acids, proteins, and tumor-derived extracellular vesicles that accumulate in blood or cerebrospinal fluid. In recent years, circulating tumor cells have also been identified in the blood of glioblastoma patients. In this review of the literature, the authors highlight the significance, regulation, and prevalence of molecular biomarkers such as O Central nervous system (CNS) tumor is one of the most malignant tumors in humans. Itaccounts for approximately 1.35% of all malignant neoplasms and 2.95% of cancer-related deaths . These mTumor markers can be categorized into several groups: molecular biomarkers, circulating tumor cells (CTCs), circulating free DNA (cfDNA), circulating cell-free microRNAs (cfmiRNAs), and circulating extracellular vesicles (EVs) , Table 1Although molecular markers are widely used to differentiate particular types of cancer, very few provide reliable and reproducible predictive markers. Due to editorial limitations, we only discuss some of the more well-known molecular markers of brain tumors.The gene encoding O-6 methylguanine-DNA methyltransferase (MGMT) is located on the chromosome at position 10q26. O-6 methylguanine-DNA methyltransferase is involved in DNA repair by reversing DNA alkylation and removing the guanine-alkyl group, which prevents apoptosis . ExpressThe most common method of detecting methylation MGMT in glioblastoma is a polymerase chain reaction (PCR) method or combinatorial PCR with MS technology, SYBR Green, or pyrosequencing in glioblastoma patients .The epidermal growth factor receptor (EGFR) is a major activator of various signaling pathways and physiological responses, including migration, proliferation, survival, and tumor formation. EGFR is a potential glioblastoma biomarker. In healthy cells, it is involved in growth factor signaling, while cancer-related oncogenic changes  often confer ligand-independent oncogenic activity. EGFR is amplified in approximately 40% of glioblastoma patients and is often associated with high-grade tumors. There can be several dozen additional copies of EGFR in tumors . EGFR isIsocitrate dehydrogenase (IDH) is a protein enzyme encoded by genes on chromosome 2, whose main function is to catalyze oxidative decarboxylation in the Krebs cycle. IDH has been grouped into two classes (IDH 1 and IDH 2). These isoenzymes catalyze the reversible oxidation of isocitrate to form α-ketoglutarate while reducing NADP + to NADPH. NADPH provides cell-free protection against intracellular oxidative injury . The mosGlial fibrillary acidic protein (GFAP) is an intermediate fiber protein produced by astrocytes and other cells of the central nervous system. It is detected at a much higher level in tumor tissue compared to normal brain cells . HoweverTelomerase reverse transcriptase (TERT) is an enzyme of the ribonucleoproteinase family involved in replication telomeres at the end of the chromosomes, which contain repetitive DNA sequences. They gradually shorten during successive cell divisions, ultimately leading to a permanent proliferative arrest. Telomerase is the primary enzyme that prevents telomere shortening through cell division and only expressed in stem cells. It is also crucial for cell transformation and immortalization during cancer development . Two speLoss of heterozygosity (LOH) is the loss of genetic material from one of the two alleles of certain genes. LOH is common in malignant neoplastic cells, which mainly affects tumor suppressor genes and then leads to reduced protection of the body’s systems against tumor formation . It is aThe TP53 gene encodes the well-known tumor suppressor protein p53. It is considered the guardian of the genome, and p53 has various roles in inhibiting tumor formation. TP53 point mutations were found much more often in secondary (90%) compared to primary brain tumors (30%), and in some cases, they were not found at all in primary lesions . One of Circulating tumor cells (CTCs) are cells shed from primary or metastatic tumors into the body fluids, including blond, cerebrospinal fluid, and urine. CTC determines the ability of epithelial tumor cells to metastasize. It has not been decided whether CTCs are just central tumor subpopulations or rather randomly selected representing the entire primary tumor. CTCs have been shown to play an important role in the development of metastasis; however, the processes by which CTCs leave the tumor, enter the bloodstream, and attack target organs for metastatic colonization are very complex and have not been fully elucidated . The resCirculating tumor DNA (ctDNA)are DNA fragments released into the bloodstream by the breakdown of cancer tissue. In patients without cancer, blood cfDNA comes mainly from genomic DNA released during the inflammation process or cell apoptosis . GenomicOnce extracted, detection of somatic alterations on ctDNA depends on the quantity of ctDNA and the sensitivity of the sequencing method. The ctDNA proportion among whole cfDNA is correlated with tumor burden in advanced solid tumors. The ctDNA dynamically reflects tumor progression and provides the specific mechanism of primary tumor gene mutation and drug resistance. In addition, ctDNAs show the molecular composition of tumors in patients with CNS tumors, including data on targeted mutations and drug resistance mechanisms in selective therapy. CtDNA analysis can detect tumor progression and drug resistance mutations at an early stage. This information can provide more effective data at an early stage and improve treatment effectiveness .As themean half-life duration of ctDNA is short (~1.5–2 h), plasma must be quickly separated and frozen within 3 h aftercollection . BettegoMicroRNA (miRNA) areshort noncoding RNA molecules (<25 pz) that complete the post-transcriptional level regulation of gene expression by degrading or inhibiting target mRNA . MicroRNMiRNAs are stable in body fluids and could be detected by PCR.miRNA samples are often taken from body fluids  for glioblastoma profiling. The use of miRNAs as biomarkers gives >90% specificity in the detection of glioblastoma. MiRNA is a useful biomarker for cancer detection due to its minimally invasive approach, obtained mainly from body fluids, and also allows for the stratification of patients in terms of the predictive and prognostic capacity of molecular biomarkers .Extracellular vesicles (EVs) are small  lipid-bilayer-enclosed vesicles released by both cancer and noncancer cells into the extracellular space. They carry various cell componentssuch as proteins, lipids, and nucleic acids . They are sometimes referred to as "exosomes" . They meGlioblastomas have been shown to release EVs and interact with endothelial cells to promote angiogenesis and act in an autocrine manner to stimulate tumor cell growth. Skog et al. proved that EVs can be isolated in the serum of patients with brain tumors and that specific genetic changes in the EGFR gene can be detected in EVs derived from the serum of these patients . MoreoveThe most commonly studied categories of extracellular vesiclesare exosomes, which range from 30 to100 nm in size, and microvesicles, which range from 100 to 1000 nm in size . EVs areIn patients with brain tumor, the secretion of proteins may lead to an increase in the level of circulating proteins (CPs) in the blood and urine and/or CSF. Plasma-derived protein markers such as immunosuppressive acidic protein, alpha-1 acidic glycoprotein, and alpha-1 antitrypsin, the glycoprotein fibronectin, and the endothelial cell-derived thrombomodulin-1 were the first proteins to be found elevated in the blood of patients with brain tumor . Then, pThe prognostic CP markers can be divided into two subgroups: tumor-related markers and related markers with endogenous systemic stress responses. The tumor-related plasma markers YKL-40 and the extracellular domain of EGFR and osteopontin were inversely correlated with overall survival ,75. In an = 571). The most extensively studied CP markers are circulating angiogenesis-related proteins. While such proteins may indeed be useful as prognostic and monitoring biomarkers for antiangiogenic therapies, a robust biomarker for the monitoring of bevacizumab treatment has not yet been reported.Circulating protein markers in patients with brain tumors can potentially also be used to monitor the effectiveness of therapy. The individual biological tumor properties and complex tissue changes induced by different cancer therapies are not adequately assessed with current MR imaging protocols. The study included patients treated with bevacizumab and irinotecan. It was found that decreased plasma levels of VEGF protein, appropriately measured, 8 weeks and 15 days after starting the treatment, were associated with an improvement in PFS and OS . UnfortuThe high incidence and mortality rate of brain tumors requires an urgent need to develop minimally invasive methods for the diagnosis and tracking of brain tumors in both primary and metastatic disease. Currently, diagnosis is based on imaging and tumor tissue data; however, there are some limitations. Conventional MRI can help surgery, but it cannot distinguish between the highly advanced tumors and can provide difficult-to-interpret results. Tumor tissue biopsies are invasive and cannot be easily repeated. Despite numerous studies on an effective biomarker for detecting and predicting brain tumors, only a few have produced promising results. High hopes in the near future are associated with the use of liquid biopsies. The liquid biopsies, such as cerebrospinal fluid and blood, can be used as potential tissue biopsy substitutes for the diagnostic and prognostic analysis of biomarkers in brain tumors. As technological advances allow for the further refinement of standardization and improved signal detection, measurement of circulating tumor biomarkers has the potential to be widely used in monitoring tumor burden. Liquid biopsies allow for multiple sampling during treatment in a noninvasive manner. In addition, a liquid biopsy may be able to reveal information about a tumor prior to clinical progression. Each of the biomarkers discussed in this review, including miRNA, ctDNA, CTC, EV, and CP, has great potential for tumor detection and prognosis. There are also other biomarkers such as neudesin, aldehyde dehydrogenase 1, and platelet-derived growth factor alpha receptor (PDGFRA), which, due to editorial restrictions, have not been described in this paper. Because each biomarker has advantages and disadvantages, acombination of markers might be beneficial. The best way seems to be to determine at least two or more markers simultaneously to increase their diagnostic utility.Although much information has been gathered about the molecular changes in brain tumor and glioblastoma stem cells, including the availability of multiple molecular markers, caution should be taken in drawing broad sweeping conclusions regarding their clinical utility. Therefore, further research is needed into new biomarkers for the early detection of brain tumors.


To the Editor,Since removable dentures are a common treatment for optimal improvement in function and esthetics in patients with edentulism , pre-proIn 2000, platelet-rich fibrin (PRF) as the second generation of autologous platelet concentrates (APCs) caught extreme attention for various oral and maxillofacial surgery applications . This naTo reduce the shortcomings of conventional vestibuloplasty procedures, PRF membrane can be employed for covering the exposed area. Therefore, there would be no need for further skin or mucosal graft harvesting; besides, the epithelialization rate of the wound can be accelerated . The eas


Frontiers in Medicine (We read with great interest the article entitled “Heparin Attenuates Histone-Mediated Cytotoxicity in Septic Acute Kidney Injury” by Wang et al. recently published in Medicine . In thisEarlier literatures also showed that heparin and heparinoids could reduce histone-induced endothelial damage, inflammatory responses, coagulation activation, organ dysfunction and improve survival in septic mice –6. HowevIn vivo experiments further showed that these small polyanions could significantly inhibit histone-induced organ dysfunction, thrombocytopenia, anemia, and deep vein thrombosis as effective as heparin. However, at least 50 percent of mice treated by 6.25 mg/kg of heparin had to be euthanized due to bleeding in this study, highlighting the safety concern of heparin use in septic patients with DIC (Recently, non-anticoagulant heparins and small polyanions have been developed for histone neutralization to eliminate the bleeding concern of heparin use , 9. WildYL and YW drafted the manuscript. All authors contributed to reviewing and revising the manuscript. All authors have given approval to the final version of the manuscript.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.


Anopheles mosquitoes usually enter human dwellings. They confer protection by preventing biting indoors and in the peri-domestic outdoor spaces, and also killing a significant proportion of the mosquitoes. Current versions of eave ribbons are made of low-cost hessian fabric infused with candidate insecticides and can be easily fitted onto multiple house types without any additional modifications. This article reviews the evidence for efficacy of the technology, and discusses its potential as affordable and versatile supplementary approach for targeted and efficient control of mosquito-borne diseases, particularly malaria. Given their simplicity and demonstrated potential in previous studies, future research should investigate ways to optimize scalability and effectiveness of the ribbons. It is also important to assess whether the ribbons may constitute a less-cumbersome, but more affordable substitute for other interventions, such as IRS, by judiciously using lower quantities of selected insecticides targeted around eave spaces to deliver equivalent or greater suppression of malaria transmission.Supplementary tools are required to address the limitations of insecticide-treated nets (ITNs) and indoor residual spraying (IRS), which are currently the core vector control methods against malaria in Africa. The eave ribbons technology exploits the natural house-entry behaviours of major malaria vectors to deliver mosquitocidal or repellent actives around eave spaces through which the  Malaria deaths declined by 60% between the year 2000 and 2019 . In addiDespite the observed successes, the protective efficacies of ITNs and IRS are threatened by multiple factors, the most commonly discussed being, widespread pyrethroid resistance –10, incrAnopheles mosquitoes and overall malaria transmission in Africa [As malaria control progresses, the populations most affected increasingly consist of households in rural and peri-urban communities, particularly those living in poorly-constructed houses with gaps on roofs, eaves, walls, windows and doors –18. One n Africa –25. Pastn Africa , 23, 24,Anopheles mosquitoes typically spend significant lengths of time close to the eaves before eventually entering houses [Malaria elimination programmes must seek long-term environmental and health-system resilience to sustain the gains accrued from current commodities, namely drugs, diagnostics, mosquito nets and insecticides. In the meantime, countries may adopt additional methods to effectively complement ITNs and IRS. Examples may include larviciding  and housg houses , there ag houses , 32, insg houses , 34 or cg houses , as wellg houses  and eaveg houses .The eave ribbons approach, recently developed by Ifakara Health Institute, exploits the same mosquito behaviours as other eave-based technologies, notably eave curtains and eave baffles , 36, 38,This article reviews the design features, evidence for efficacy, plausible development pathways and the future potential of eave ribbons as a method to achieve targeted and efficient control of mosquito-borne diseases, notably malaria. The paper focuses primarily on insecticide-treated ribbons used on the outer surfaces of eaves, and is not intended to cover all eave-based technologies.−2 and has varying lengths depending on target house size. The initial studies done in the semi field, the eave ribbons measured 0.15 m wide by 2.5 m long, while tests done in the field used ribbons measuring 0.15 m wide by 25 m long. The eave ribbons present a novel deployment method for a range of products, including vapour-phase and contact insecticides. The hessian material was sourced locally in East Africa, where the material is used for manufacturing a wide range of other products, such as sacks, rope and decorations. The ribbons are fitted onto houses using nails, adhesives or other fasteners, without completely closing eave spaces  be valleys , 46,  valleys , and  protecting low-income households in rural areas and urban slums, including those living in very poorly-constructed houses that cannot be readily screened or modified without being damaged; (ii) protecting people in the peri-domestic spaces, away from homes and indoors at times before bed net use; (iii) for protecting migratory populations such as itinerant farmers, forest workers and campers, pastoralists or fishing communities; (iv) protecting people in temporary shelters such as refugee camps, mining camps, or recreational sites; or (v) as a possible alternative for IRS especially if the ribbons can be safely pre-treated or treated on site and delivered at scale. All these areas need additional field data to validate actual potential and cost-effectiveness.−3) defined by the regulatory authorities of the European Union (EU) [One study by Ogoma et al., which tested concentrations of transfluthrin emanating from the hessian treatments indoors, found that the residual air-borne quantities after 1 h exposure were undetectable using standard instruments for assessing air-quality . Even afion (EU) . Beyond To maximize impact, it is best to treat the ribbons using insecticides or combinations of insecticides with multiple modes of action . This may include vapour-phase insecticides such as transfluthrin which is currently used in most applications, or contact insecticides to ensure that mosquitoes attempting to enter houses via eaves can be directly killed or incapacitated. Using insecticides with toxicant and repellent effects also reduces the likelihood that mosquitoes are diverted to non-users , 45. ThiWhile IRS remains one of the most efficacious vector control tools, its deployment and overall impact are increasingly limited to small geographic areas due to multiple factors, notably high costs and logistical challenges Table . Going fGiven the simplicity and likely scalability of eave ribbons for delivering effective insecticides targeted at the eave space, it is reasonable to also comparatively assess the performance of the eave ribbons and IRS. The outcomes of such comparative evaluations would enable determination of whether the ribbons could constitute a less-cumbersome but more-affordable substitute for IRS by using lower quantities of insecticides near eaves to maximise efficacy.Similar to standard IRS, the eave ribbons can be treated with different insecticides, singly or in combination, which would enable careful selection and deployment for to manage resistance . They maGiven the ease-of-use and affordability (current unsubsidized prototype estimates are ~ $7.00/house/year), eave ribbons may cost-effectively protect entire households both indoors and outdoors , 39), poTo validate this potential, studies should be conducted to directly compare protective efficacy and effectiveness of insecticide-treated eave ribbons relative to standard IRS. While full-scale epidemiological studies  would be desirable, experimental hut studies complemented with small-scale village trials measuring entomological outcomes could already provide reasonable indications of the potential of the ribbons to impact vector densities and transmission intensities Table .The need for stakeholder engagement is increasingly being recognized as an essential component in malaria control efforts , 63. It Eave ribbons offer a practical and affordable intervention suitable for all households, without requiring any major house modifications, electricity and sophisticated skill. There are opportunities to engage local groups at various stages of development, treatment, deployment or maintenance of the ribbons. Involvement of groups such as local tailors, women groups and local entrepreneurs will not only improve ownership, but will also provide direct employment in the communities. Such practices are already being implemented at small scale by Ifakara Health Institute, and could be expanded to support scaled-up distribution campaign.For greater effectiveness, inter-sectoral collaboration is also important in the scale up of the eave ribbons technology. Partnerships between the ministry of health, ministry of housing, chemical providers and local leaders is necessary for scale-up and sustainability of these eave ribbons across the country. It would be important to adapt some approaches such as those proven effective for advocacy, social mobilization and legislative change to improve outcomes in vector control .The WHO has outlined the steps required in evaluation of new vector control interventions . If an iOne plausible pathway would be to present the eave ribbons as possible substitute for IRS, and assume the existing public health value, as supported by the current evidence , 68. ThiWhichever path is taken, additional evaluations with either entomological or clinical outcomes will be necessary to inform adoption in different contexts, and to explore the supply chain factors relevant to the product and its perceived scalability.Anopheles mosquitoes, repel them over wide areas and inhibit blood-feeding) or contact non-pyrethroid insecticides such clothianidin, bendiocarb or pirimiphos methyl, currently approved for IRS. The technology exploits the natural house-entry behaviours of malaria vectors to deliver mosquitocidal or repellent actives around eave spaces, and can prevent mosquito bites indoors and in outdoor spaces. While malaria programmes must seek long-term approaches to sustain the gains accrued from current tools, technologies such as eave ribbons could enable judicious application of available insecticides in ways that maximize transmission control even in the lowest-income communities. Eave ribbons could, therefore, have potential as a supplementary tools to address gaps associated with ITNs and IRS. Given their simplicity and demonstrated potential in previous studies, future research should investigate ways to optimize scalability and effectiveness of the ribbons. It is also important to assess whether the ribbons may constitute a less-cumbersome but more-affordable substitute for other interventions such as IRS; by judiciously using lower quantities of selected insecticides targeted around eave spaces to deliver equivalent or greater suppression of malaria transmission.This article reviewed the evidence for efficacy of eave ribbons and discussed their potential as a supplementary malaria control tool with added advantages of being affordable, locally sustainable, easy-to-target and versatile and effective. The review excludes several other eave-based technologies, and instead focuses primarily on the hessian-based eave ribbons technology conferring protection both indoors and outdoors. The eave ribbons can be treated with vapour-phase pyrethroids such as transfluthrin (which can kill


Similar to nursing homes, COVID-19 has challenged assisted living (AL), given its congregate nature and vulnerable residents. However, COVID-19 recommendations have not consistently recognized differences between nursing homes and AL, and in so doing present implications for the future of AL. This project examined COVID-19 recommendations from six key organizations and compared them across nursing homes and AL. Differences include recommending more flexible visitation and group activities for AL, while similarities suggest that AL may best integrate health care into offered services . Primary points to be discussed are that COVID-19 may accelerate the closer coordination of social work and medical care into AL, because recommendations suggest AL would benefit from the services and expertise of nurses, social workers, and physicians. There seems to be an unmet need to mitigate loneliness in AL, which warrants specific attention moving forward.


Composite tissue injuries (CTI) are common among US Military Service members during combat operations, and carry a high potential of morbidity. Furthermore, CTI are often complicated due to an altered wound healing response, resulting in part from a dysregulation of the innate and adaptive immune responses. Unlike normal wound healing, in CTI, disruptions occur in innate immune responses, altering neutrophil functions, macrophage activation and polarization, further impacting the functions of T regulatory cells. Additionally, the biological underpinnings of these unfavorable wound healing conditions are multifactorial, including various processes, such as: ischemia, hypoxia, low nutrient levels, and altered cell metabolic pathways, among others, all of which are thought to trigger anergy in immune cells and destabilize adaptive immune responses. As a result, impaired wound healing is common in CTI. Herein, we review the altered innate and adaptive immune cells and their metabolic status and responses following CTI, and discuss the role a multi-pronged immunomodulatory approach may play in facilitating improved outcomes for afflicted patients. Composite tissue injuries (CTI) owing to high energy wounding mechanisms  are an unfortunate reality of modern military combat operations. In simple terms, CTI are those injuries that involve significant damage to multiple tissues, including skeletal muscle, nerve, bone, vasculature, and dermal tissues ,2,3,4. WThe immune-inflammatory response to acute injury is a highly complex system comprising multiple soluble  and cellular mediators  that serve to clear pathogens and cellular debris and stimulate tissue repair. Generally speaking, this system is highly redundant with multiple compensatory signaling pathways in place to ensure that the initial inciting stimulus is neutralized and that the injury progresses towards an end-stage wound healing outcome from both a histological and functional perspective. As with any complex system, however, substantial perturbations to the magnitude and/or spatiotemporal kinetics of this process—as is characteristic of CTI—can lead to impaired healing and a chronic pathology, even when wound healing is buttressed by potent exogenous therapeutics.Exogenous therapies have demonstrated a limited benefit towards wound healing in CTI due to knowledge gaps concerning how best to modulate this dysregulated immune response as a means to promote improved wound healing outcomes. Therefore, a deeper understanding of the disrupted immune response following CTI will help to facilitate the development of next-generation, rationally informed therapeutic strategies which aim to facilitate improvements in wound healing with functional recovery. To that end, the disrupted inflammation and immune response resulting from CTI, and the associated interactions within the site of injury, are broadly discussed herein as a means to highlight potential targets for immunomodulation to enhance wound healing.Inflammation is a fundamental physiological response to injury. Acute injury leads to a cascade of inflammation-related events consisting of four overlapping phases: hemostasis, an inflammatory phase (involves resolution), a proliferation phase, and a remodeling phase . During Concurrently, but with slower kinetics, the adaptive immune system is likewise activated. The innate and adaptive immune responses exhibit an interdependent relationship wherein cross-talk is observed to regulate the complex series of events that facilitate wound healing. T lymphocytes are part of the adaptive cell-mediated immune response and play an important role in this cross-talk, both as producers of growth factors and through differentiation into effector cells. T lymphocytes are categorized into subsets based on functionality, with cytotoxic T lymphocytes—identified by the expression of CD8 surface markers—and helper T lymphocytes—identified by the expression of the CD4 surface marker—being the highest-level bifurcation germane to the discussion herein. These cells typically infiltrate into wounds after those of the innate immune response  and play seemingly opposing roles. Cytotoxic T cells are considered the early responders of the adaptive immune system in an injury, and play an important role in enhancing the innate immune responses through expression of interferon (IFN)-γ and transforming growth factor (TGF)-β1 , and by + and CD8+ T cells through the secretion of anti-inflammatory cytokines such as IL-10, TGF-β, and IL-35 [+ T cells and fibrotic collagen deposition within the site of injury [The transition of the inflammatory response is also associated with an increase in recruitment of regulatory T lymphocytes (Tregs). Tregs typically peak in numbers at 3–5 days post-injury, and regulate the repair of injured tissue by modulating the inflammatory response . Tregs and IL-35 . Additiond IL-35  and incrf injury . Thus, i+) satellite cells in skeletal muscle by continuously suppressing excessive inflammatory T cell responses  while concomitantly being permissive to anti-inflammatory  activity [During the later stages of the wound healing process, Tregs regulate the differentiation of a variety of cell populations, such as  and extrinsic (promptly initiated by death ligand and death receptor) apoptotic pathways. It is interesting that the half-lives of pro-apoptotic genes are relatively longer than those of anti-apoptotic genes in these cells. The cellular levels of the anti-apoptotic gene-induced myeloid leukemia cell differentiation protein (Mcl-1) correlate with neutrophil survival and thus the half-life of neutrophils is governed by cellular levels of the anti-apoptotic gene Mcl-1 . Pro-surMacrophages and T cells from different tissues interact to relay required immune responses for enhanced wound healing. Other important innate immune cells that bridge between innate and adaptive immune responses are invariant NKT (iNKT) cells, a specific subtype of T cells, which are often neglected or not studied much in CTI wound healing. Other investigations on iNKT cells also indicate that iNKT cells play a vital role in wound healing ,51. Jo eAs the necessary clearance of DAMPs occurs, neutrophils apoptose and are cleared by macrophages, therefore transmitting a detectable signal for the release of TGFβ1 and IL-10 by macrophages polarized by the cytokines IL-4, IL-13, and IL-10, promptly initiating a proliferative phase in wound healing. As the environment shifts away from a pro-inflammatory profile, fibroblasts proliferate to an active form of myofibroblasts in muscle tissue injuries. Selective TGFβ1 activation initiates the differentiation of myofibroblasts, which contribute positively to collagen synthesis. Fibroblasts play a role in skeletal muscle extracellular matrix formation and modulation in severe injury with potential loss of muscle mass . MalecovhiCD16+, monocytes/macrophages, activated through C-reactive protein [The resolution of inflammation typically favors the production of collagen and the contraction of the lesion. Andermahr et al. made an insightful observation that in polytrauma patients—both with and without concurrent traumatic brain injury—an increase in collagen degradation resulted in decreased osteogenesis and non-union fractures . They re protein . They al protein ,60,61. I protein . TGF-β a protein . Higher  protein . Therefo+ T cells positive for Foxp3+ and CTLA4+ suppressed the proliferation of NKT and CD4 and CD8 T cells through contact inhibition facilitated by CTLA4 and CD36 receptors [T-cell populations are diverse and secrete various cytokines and proteins to carefully regulate the proliferation and repair processes in a wound. Tregs, a specialized subpopulation of T cells which typically contribute towards balancing of Th-1 type pro-inflammation and Th-2 type anti-inflammation during the process of wound healing, are mostly prevalent in high numbers during the proliferative phase. Several published reports suggest that the presence of Tregs could confer faster wound healing  and may eceptors . Tregs meceptors . Tregs aeceptors . Tregs seceptors . This sueceptors . These receptors . Additioeceptors . Very liWound healing involves immune cells, cytokines, growth factors, and progenitor cells, such as FAPs, which are mesenchymal in origin . The phyIn CTI, hypoxic conditions, edema, low nutrient levels, and contributing factors downstream of cell metabolic pathways effectively stimulate immune and vascular endothelial cells to release various cytokines and growth factors that impair angiogenesis and regeneration. If neovascularization is successful, it allows the possible restoration of nutrient delivery and oxygen, and cells use oxidative metabolism for their longer-term functions and contribute positively to restoring the wound. Otherwise, the cells undergo stressful conditions, leading to the release of altered metabolic stressors and sensors. The mammalian target of rapamycin (mTOR), general control nonderepressible 2 (GCN2) kinase, hypoxic conditions, and adenosine, the metabolite of ATP, are known metabolic regulators and sensors that cause anergy in immune cells . These pA second amino acid-sensitive pathway, GCN2 signaling, also affects immune responses under stress conditions. GCN2 signaling can trigger stress response programs causing cell differentiation, suppression, growth arrest, apoptosis, and adaptation to stressful conditions ,82. GCN2Tregs also have shown a complementary immunological arm under unfavorable conditions such as hypoxia. Hypoxia is generally observed in CTI patients due to low oxygen conditions and an inflamed microenvironment. Nanobashvili et al. (2003) reported that 51% of the analyzed patient population showed distal ischemia/low oxygen levels due to mangled injuries associated with damaged vessels . NiteckiIn the above sections, a detailed description of how the immune-inflammatory response interacts throughout both the normative physiologic and CTI-related pathophysiologic wound healing processes was provided as a means to provide a foundation upon which next-generation, rationally informed, multi-pronged immunomodulatory strategies can be developed as a means to facilitate improvements in outcomes following CTI. Furthermore, the spatiotemporal application of these therapies should be conducted in coordination with the known pathophysiology of CTI injury. Thus, a multi-pronged immunomodulatory strategy is an attractive option to complement existing CTI treatment strategies.We previously discussed in detail how uncoordinated interactions between various immune cells at the injury site contribute to a highly unsynchronized microenvironment resulting in impaired wound healing. An example of how immune cells can be modulated to coordinate successful wound healing is provided by macrophages, in which staggered bolus release of IFN-γ and subsequent sustained release of IL-4 promote a shift from a pro-inflammatory to anti-inflammatory phenotype to mediate the scaffold vascularization . Pro-resFurther revelation of the regulatory components involved in the development of inflammatory reaction to CTI holds great potential in the development of effective treatment strategies to maximize immune elements critical for repair, while at the same time suppressing elements of the immune response responsible for further damage to injury progression.Composite tissue injuries remain a major challenge to the US Military and pose the threat of lifelong disability for those affected. Achieving improved clinical outcomes of these injuries will require restoration of normative inflammation and immune cell interactions at the site of injury and redressment of the hallmark inflammatory abnormalities of CTI that disrupt normal wound healing mechanisms. Specifically, a prolonged or heightened inflammatory phase, dysregulation or activation of pro-inflammatory immunological cells/factors, unwanted anti-inflammatory microenvironment at the very early phase of wound healing, and undesired alteration in the cytokine profile at a very initial phase must be addressed to achieve such clinical goals. Additionally, other stress factors such as hypoxic conditions, ischemia, low nutrient levels and altered metabolic processes that influence the immune functions must be managed concurrently. As such, CTI treatment strategies should aim to precisely address the cytokine network dysregulation so as to modulate the secretory profile of various damaged tissues. Ostensibly, this can be achieved by modulating the cytokines themselves  or by precisely controlling the complex spatiotemporal dynamics of different immune cell populations, of which neutrophils and Tregs seem to be promising targets. Practically, however, this is a foreboding task, as very little is known of how the initial inflammation following an injury interacts with local regenerative processes in the context of CTI, and much research is needed to improve our understanding to the point of identifying precise targets for therapeutics which will not have deleterious effects elsewhere in the wound healing process. Specifically, ambiguity still exists as to which phases of immune-inflammatory response are needed to promote successful wound healing outcomes, and the optimal timing for these phases to resolve. These factors are critical, as both insufficient inflammation and chronic inflammation may lead to impaired wound healing and/or scar formation. Therefore, more detailed experimental evidence is needed to help us accurately decide how we could carefully manipulate inflammatory responses towards wound healing and to make informed decisions on the dosing  of immunomodulatory agents following composite musculoskeletal trauma.