The aim of this study was to quantify and visualize the degenerative patterns of the talus in ankle osteoarthritis (OA). The differences in talar morphology between sides of patients with unilateral varus ankle OA  were compared. Computed tomography images of both feet of 35 patients  were analyzed. Each surface model of the right and left tali was registered to the opposite talus via a mirror-image technique and an iterative closest point algorithm. The surface deviation between the two models was quantified and visualized by deviation color maps. The results quantitatively demonstrated that osteophytes are generated in the area under the antero-medial margin of the trochlea in OA tali. In severe OA tali, bone resorption of more than 2 mm in the medial portion of the trochlea, as well as a similar degree of osteophyte formation on the lateral surface, was also seen. Stereotypical patterns of degeneration occurring in OA tali were successfully visualized and quantified by left-right comparison of patients with unilateral ankle OA. Such information would contribute to better understanding of the development of ankle OA and preoperative planning of total ankle arthroplasty and arthrodesis. In the majority of such ankle OA patients, not only bony degeneration of the talus, but also tibiotalar varus alignment is observed, regardless of underlying etiology2. Such bony degeneration and joint alignment have been clinically assessed based on a plain weight-bearing radiograph4. However, morphological assessment of ankle OA based on a two-dimensional radiograph is generally difficult due to the fact that the talus is overlapped with the tibia, fibula, navicular, and calcaneus; thus, the talar bony degeneration is not clearly visible on a plain radiograph.Ankle osteoarthritis (OA) is one of the most important progressive diseases causing pain and chronic disability in the ankle joint6. In these previous studies, the shape of the OA talus was compared with that of subjects without OA. However, owing to the marked inter-individual variations in the size and shape of the talus, detailed analysis of the morphological degeneration of the talus due to ankle OA has been challenging. Therefore, the patterns of morphological degeneration of the talus due to ankle OA have not been quantified previously.Recently, computed tomography (CT) examinations have been used to observe the three-dimensional bony degeneration of talar bodies in patients with ankle OA7. Therefore, an excessive left-right difference in the morphology of the talus observed in such patients could possibly be attributed to osteophyte formation and bone resorption due to ankle OA. Quantitative understanding of the three-dimensional degeneration of the talus in patients with ankle OA is important for foot and ankle orthopedic surgeons for correct preoperative planning and achieving successful clinical outcomes of total ankle arthroplasty8 and arthrodesis9.If we analyze the left-right differences in talar morphology of patients with unilateral varus ankle OA, however, the effect of the large inter-individual variabilities of the talar morphology can be eliminated, and the pattern of morphological degeneration of the talar morphology in patients with ankle OA can be extracted. Therefore, the present study investigated the left-right differences in talar morphology of patients with unilateral varus ankle OA based on CT imaging, with the aim of extracting the pattern of bony degeneration of the talus in patients with ankle OA. Specifically, the left and mirror-reflected right talar surface models were generated and registered to each other to quantify the bony differences of the OA talus with respect to the opposite talus without OA (non-OA). It has been demonstrated that left and right tali of healthy human ankle joints show a strong degree of symmetry10. The numbers of patients classified into each stage were five, eleven, and six, respectively. Thirteen patients of the control group were not diagnosed as having ankle OA on plain radiographs. There were no significant differences between the two groups in age and the sex ratio.Based on the plain radiographs, 22 patients of the OA group were found to be in stage 3a, 3b, or 4 on the OA side and in stage 1 or less on the opposite non-OA side, according to the Takakura classificationThe deviation color maps of the control group indicated that the tali were essentially bilaterally symmetrical in the control group Fig. . On the Figure 6. However, the human talus generally shows marked inter-individual variations in size and shape7. Therefore, talar morphological differences extracted in these studies were the result of not only degeneration due to ankle OA, but also to possible differences in the pattern of congenital inter-individual variations. On the other hand, the present study compared the right and left tali of the same individual in patients with unilateral varus ankle OA to extract pure morphological differences of the talus due to ankle OA, while eliminating the effects of inter-individual variations. To the best of our knowledge, this is the first study to visualize and quantify the pattern of osteophyte formation and bone resorption of tali in ankle OA. This information would be very useful for the operative technique of bone recession for the talus component in total ankle arthroplasty and arthrodesis.The present study successfully extracted and visualized the morphological differences of talar articular morphology in patients with unilateral varus ankle OA. The previous three-dimensional morphological analyses of ankle OA compared differences in talar morphology between OA patients and healthy subjects7. In particular, the talar spur was found to protrude medially off the medial edge of the talar neck even in the early stage of ankle OA  onto a standard template talus using a deformation function. It has been proposed that intra-individual variability of human talar shape is quite smallIn conclusion, the morphological bony degeneration of the talus due to OA was characterized visually as osteophyte formation and surface resorption around the talar trochlea using a method to compare the left and the right tali in patients with unilateral varus ankle OA. These findings may be due to a stereotypical pathological loading condition of the talus in varus ankle OA and may contribute to better understanding of the development of varus ankle OA. Furthermore, this morphological information will be useful for developing better techniques and designs for total ankle arthroplasty and arthrodesis.18, and stage > 3a according to the Takakura classification. Patients with ankle OA following fractures of the tibia, ankle, or talus or inflammatory diseases such as rheumatoid and infectious arthritis were excluded. Both secondary ankle OA patients following repetitive ligamentous injuries and primary ankle OA patients with unknown sprain histories were included in the analysis. The Takakura classification10 of the recruited ankle OA patients was independently evaluated by two of the authors, who are foot and ankle orthopedic surgeons with more than 10 years of experience (H.S. and T.K.), and the classification results were completely identical. The control group included 13 patients  with fresh trauma without involvement of the talus, such as fractures of the tibia, calcaneus, or forefoot. The diagnostic process with interviews confirmed all patients to be free of any foot and ankle pathologies except for the above fresh trauma. The present study was approved by the Institutional Review Board of Tachikawa Hospital , and informed consent was obtained from all patients. The methods were carried out in accordance with the approved guidelines.Thirty-five patients , consisting of an ankle OA group and a control group, were recruited in this study. The ankle OA group included 22 patients  diagnosed with unilateral varus ankle OA. Varus ankle OA was judged based on a talar medial tilt angle > 4° measured on weight-bearing anterior-posterior radiographset al.31 and Kanamoto et al.32 . CT scans of both feet of each participant were performed. All scan data had an in-plane resolution of 512 × 512, with slice thickness of 0.5 mm. CT images were reconstructed at 0.5-mm intervals with pixel size ≤0.682 mm. The left and right tali were then reconstructed in a virtual three-dimensional space using specialized software . Mirror image models were created for the right-side specimens, so that all specimens could be treated as left-side specimens. To facilitate visual comparisons, a body-fixed coordinate system of the talus  was defined based on Lisowski ® XOS . The ICP algorithm iteratively transforms the OA talus model to match the non-OA talus model so as to minimize the distance between the two sets of vertices constituting the two models. The surface deviation was calculated as the distance between the two surfaces along the surface normal direction of the OA talus. The light green color indicated that the deviation was less than 0.6 mm, whereas the red and blue colors were deviations of the OA talus outside and inside of the non-OA talus. The gray color indicated the area where the surface deviation could not be calculated because there was no corresponding surface on the non-OA talus due to large deformation.To extract possible left-right differences in the talar morphology of each participant, the OA talus model was registered to the opposite non-OA talus model via an iterative closest point (ICP) algorithm Fig. , using G33. The sign of the distance was determined based on the direction of the vertex normal vector . The mean deviations were calculated for each region to quantify and statistically evaluate the degrees of surface growth or resorption observed on the OA talus with respect to the non-OA talus. The color maps of the mean deviations were also provided for each of the three stages  was used for statistical analyses. A post hoc power analysis was conducted using G*Power 334.A normal distribution was ensured using the Shapiro-Wilk tests. Comparisons between the control and OA groups were performed using the independent


Determining aetiology of genetic disorders caused by damaging mutations in protein-coding genes is well established. However, understanding how mutations in the vast stretches of the noncoding genome contribute to genetic abnormalities remains a huge challenge. Cis-regulatory elements (CREs) or enhancers are an important class of noncoding elements. CREs function as the primary determinants of precise spatial and temporal regulation of their target genes during development by serving as docking sites for tissue-specific transcription factors. Although a large number of potential disease-associated CRE mutations are being identified in patients, lack of robust methods for mechanistically linking these mutations to disease phenotype is currently hampering the understanding of their roles in disease aetiology. Here, we have described the various systems available for testing the CRE potential of stretches of noncoding regions harbouring mutations implicated in human disease. We highlight advances in the field leading to the establishment of zebrafish as a powerful system for robust and cost-effective functional assays of CRE activity, enabling rapid identification of causal variants in regulatory regions and the validation of their role in disruption of appropriate gene expression. Human genetic diseases affect a wide range of tissues and are caused by numerous types of mutations. Understanding the cause and progression of these diseases relies heavily on the use of animals, including mouse, rat and zebrafish, to generate models mimicking the human condition. The use of these approaches for determining the aetiology of genetic disorders caused by damaging mutations in protein-coding genes is well established. However, functional analysis of mutations in the noncoding regions remains a huge challenge. Rapid technological advances have enabled the widespread application of whole-genome sequencing (WGS) for the identification of putative pathogenic mutations in patient cohorts. It has been firmly established that many of these mutations reside in the noncoding regions of the human genome, most of which are likely to harbour cis-regulatory elements (CREs) ,2. CRE sAdvances in genomic sequencing technologies have enabled widespread application of whole genome sequencing technology to patient DNA samples. These studies have led to the identification of clinically-relevant mutations in the noncoding regions of the human genome, most of which are likely disrupting CRE function of these sequences by altering the sequences of transcription factor binding sites . The nexThese predictions are further substantiated by looking for enrichments of hallmarks of enhancer function on the predicted CREs. Transcription factor profiling of the CRE sequences helps discern the possible effects of disease-associated mutations in CREs. These profiles can be predicted both computationally  and experimentally  ,8. EnricThese assays have been performed on a large number of in vitro cultured cell lines, whole embryos and tissues derived from human, mouse and zebrafish . The infThe putative CREs harbouring the disease-associated mutations are tested in CRE-reporter assays to determine their function and how this is affected by the presence of disease-associated mutations. The most widely used assays, along with their merits and de-merits, are described in Although WGS has the power to identify variants in noncoding regions, the pathogenicity of these variants is much more difficult to assess compared to variants in coding regions. The use of in vivo reporter transgenic assays in mouse or zebrafish for determining their functional potential is indispensable.Zebrafish is an excellent in vivo system for characterising putative tissue-specific CREs ,20. LargThe functional output from each CRE version (wild type or SNP/mutation bearing) is visualised simultaneously as eGFP or mCherry signal within a live developing embryo bearing both transgenes. This enables unambiguous comparison of the activity of both wild type and mutant CREs in a developmental context, simultaneous assessment of multiple separate elements for subtle differences in spatio-temporal overlap, and the validation of putative TFs by analysing the effect of morpholino-mediated depletion of the putative TF on CRE activity. We established proof of principle for the robustness of the assay using known mutations associated with holoprosencephaly, identified in a CRE from the SHH locus . This apThe approaches described in this review enable rapid and confident identification of the stretches of noncoding DNA harbouring CREs, likely to be crucial for regulating the expression of target genes implicated in the particular disease cohort. However, since all the methods described here study the function of CREs in isolation and outside the genomic context of their native locus, these predictions would need further validation . Confide


Drosophila melanogaster, usually in the face of a threatening visual stimulus. Two branches of the circuit promote the response by stimulating an escape jump followed by flight initiation. A recent work demonstrated an age-associated decline in the speed of signal propagation through the circuit, measured as the stimulus-to-muscle depolarization response latency. The decline is likely due to the diminishing number of inter-neuronal gap junctions in the GFS of ageing flies. In this work, we presented a realistic conductance-based, computational model of the GFS that recapitulates the experimental results and identifies some of the critical anatomical and physiological components governing the circuit’s response latency. According to our model, anatomical properties of the GFS neurons have a stronger impact on the transmission than neuronal membrane conductance densities. The model provides testable predictions for the effect of experimental interventions on the circuit’s performance in young and ageing flies.The giant fiber system (GFS) is a multi-component neuronal pathway mediating rapid escape response in the adult fruit-fly  Drosophila melanogaster, the escape response system mediates quick propagation of signals from the brain to the muscles, instructing flight initiation following a threatening visual stimulus. It was previously shown that this circuit shows a marked decline in the speed of signal propagation with age, likely due to loss of synaptic gap junctions. Here, we generated a computational model of the system and uncovered novel anatomic and physiologic parameters that govern the circuit’s function in young and old animals. These predictions can be tested experimentally and have significance for other fast circuits in flies and other species.Finding potential targets for preventing functional decline of neuronal circuits is important from both biological and clinical perspective. In the nervous system of Drosophila melanogaster executes a stereotyped sequence of events that results in an escape jump followed by flight initiation  instructs the formation of heterotypic, unidirectional (rectifying) electrical synapses  is comprised of four cells: The GF neuron, the TTM motoneuron (TTMn), a peripherally synapsing interneuron (PSI), and a DLM motoneuron  of the PSI and the medial passive section (dendrite) of the TTMn. The TTMn contains two dendrites  were largely modeled according to an existing model of a toneuron  and basetoneuron . They coTo test the TTM and DLM response latency in the model, we stimulated the proximal end of the GF with a current step duration of 0.03 ms  of all model electrical synapses to 135 μS resulted in the voltage recordings shown in gap will therefore be used to model the response latency in young flies. When using this value, the latency in the PSI and TTMn cells is similar, owing to their equivalent position in the circuit .To examine how the electrical coupling in the fly’s GFS contributes to the transmission latency, we stimulated the model circuit with a 120-nA pulse at the proximal end of the GF A and recgap to 34.5 μS results in longer membrane charging time to firing threshold due to weaker current across the gap junction, and thus to increased latency for both TTM and DLM, up to the values recorded in old (45–50 d old) flies . Scanning a range of conductance values reveals the expected monotonic decrease of the response latency as ggap increases , along with either the maximal transient voltage-gated sodium conductance for all axons  is compensated by an increase in ḡNat (moving toward the right). The plots below the contour maps show the change in latency for young (blue) and old (orange) flies as a function of the conductance in question, thus they represent horizontal cross sections through the contour maps. While the directionalities of the effects on response latency were expected from basic biophysical principles, this approach enabled us to assess the relative efficacies of these changes. As expected, increased transient voltage-gated sodium conductance reduced the response latencies  shortened the response latency, with the increase in potassium and leak currents having the expected, opposite, effect (+ conductance is likely due to lowered AP threshold. However, when manipulated within a physiologically relevant range, sodium conductances were unable to revert the latencies from old flies to youthful levels (Secondly, our model demonstrated the degree to which manipulations of principal membrane ionic conductances can influence the GFS response latencies. Augmentation of the transient voltage-gated sodium conductance in our model (equivalent to an overexpression or hyperactivation of voltage-gated sodium channels , effect , 5A. Con, effect , the effl levels A,D.in vivo; it does, however, make it possible to determine, for example, whether the effect of various physiologic and morphologic parameters is continuous or whether there is a threshold beyond which an effect occurs.Thirdly, we showed that anatomic features of the GFS neurons can have a stronger effect on the speed of signal propagation via the circuit , 5C compDrosophila motoneuron simulations and several literature-based physiologic constraints, our model is likely to faithfully reproduce salient anatomic and physiologic features of the GFS.Since the bulk of the signal propagation in the circuit is done via long axons and with minimal convergence of inputs, we could use simple, reduced geometry to represent the circuit components. With the addition of ion channel parameters previously characterized in Drosophila genetic toolbox allows for time-controlled modulation of relevant membrane conductances in individual GFS neurons and in the whole circuit (The versatile  circuit . Genetic circuit , althoug


A systematic quantitative evaluation of the available evidence of the treatment for caries lesions in primary teeth that considers how different caries progressions lead to the need for distinct interventions might provide additional useful information for clinical evidence-based decision making. The aim of this systematic review and network meta-analysis was to verify the effect of the treatments on caries lesion arrestment (CLA) or the success rate (SR) of dentin caries lesion treatments in the primary teeth.A search was conducted using the MEDLINE/PubMed, Web of Science and Scopus databases through December 2017. The primary search terms used in combination were primary teeth, caries lesion and restoration. The grey literature was also screened, as were the reference lists of eligible studies. A search of prospective studies with at least 12 months of follow up that compared different techniques was performed. The exclusion criteria were the absence of a comparison group; no evaluation of different restorative techniques; the evaluation of other outcomes unrelated to this review; and the recruitment of specific patient. The risk of bias was evaluated by the tools: the Cochrane Handbook for Systematic Reviews of Interventions and ROBINS-I. A network meta-analyses and meta-analyses were conducted considering CLA or SR as outcomes according to the surface involved and the depth of progression.Of the 1671 potentially eligible studies, 15 were included. For occlusal surfaces, only two studies presented data regarding the outer half of the dentin, with conventional restorative treatment (CRT) using composite resin showing superior results; five studies presented data regarding the depth of caries lesions, and CRT with compomer resulted in the best results. Seven studies considered occlusoproximal surfaces, and the Hall technique showed the best SR among the evaluated treatments. Finally, two annual applications of silver diamine fluoride showed the best nonrestorative approach to arrest caries lesions on occlusal and smooth surfaces.The treatments for dentin caries lesions in primary teeth depend on the depth of progression and the surface involved. However, few of the included studies provided evidence to strongly recommend the best treatment option.Funding: FAPESP; Systematic review registration number—PROSPERO CRD42016037784. The current scenario in dentistry indicates a high prevalence of dental caries across different age groups and populations , despiteDespite the knowledge and scientific evidence regarding the prevention of dental caries ,6, inforPrevious systematic reviews that evaluated the preferred treatment for dentin caries lesions in primary teeth have focused on comparing only two types of treatments or the same treatment with different restorative materials, considering only the type of surface involved  –9 or eveThus, a systematic quantitative evaluation of the available evidence on the treatment for caries lesions in primary teeth that considers how different caries progressions lead to the need for distinct interventions might provide more useful information for clinical evidence-based decision making. Therefore, this systematic review and network meta-analysis compared the performance of the available treatments for dentin caries lesions, regardless of nearness to pulp or pulp involvement in primary teeth, on caries lesion arrestment (CLA) or the success rate (SR) and considered the different progression depths and surfaces involved.http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42016037784).This systematic review and network meta-analysis was reported according to the PRISMA-NMA extension  S1 Tabl and was A systematic search of the available studies in the literature was conducted using the following electronic databases: MEDLINE/PubMed, Web of Science and Scopus. The grey literature (OpenSigle/Opengrey) and the reference lists of identified full texts were also screened to retrieve additional relevant studies that might fulfill the inclusion criteria. No restriction was placed on the language or year of publication. The last search was performed on December 14, 2017.A search strategy was developed for the MEDLINE/PubMed database and then adapted for the others based on the following PICO question: "Which is the best treatment for CLA or SR of the dentin caries lesions of primary teeth?" The results of the different databases were cross-checked manually to locate and eliminate duplicate studies. The complete search strategy is shown below:  AND  AND  AND .Initially, the titles and abstracts of the potentially eligible studies identified using the databases were evaluated by two independent reviewers (TKT and TG), who were previously trained and calibrated for study selection (Kappa = 0.8). The studies were considered eligible if they were prospective clinical studies with at least 12 months of follow up evaluating treatments for dentin caries lesions without a possible nearness to a pulp or pulp involvement in primary teeth. Studies without listed available abstracts were fully assessed for full copy inclusion/evaluation.After the first evaluation, the studies that meet the inclusion criteria had their full texts independently reviewed; then, those with at least one exclusion criterion were considered as ineligible. The exclusion criteria were the absence of a comparison group; no evaluation of different restorative techniques; the evaluation of other outcomes unrelated to this review; and the recruitment of specific patient groups . When more than one study included the same sample, the one that presented more complete data was considered. For data synthesis, we only included the data from manuscripts that presented separate data based on surface involved, depth of progression, or both.All available approaches to treat dentin caries lesion of primary teeth was considered in this systematic review. Atraumatic restorative treatment (ART) was considered as a restorative procedure that included caries removal using only hand instruments  and restoration with high-viscous glass ionomer cement (HV) without the use of a rubber dam. Alternatively, conventional restorative technique (CRT) was considered as including caries removal using rotary instruments and restoration with any restorative material, including the use of a rubber dam. Thus, studies reporting treatment procedures that differed from those definitions were not included in the present review.All discrepancies regarding the eligibility criteria were resolved in consultation with a third reviewer (DPR), and consensus was reached.Studies that fulfilled the eligibility criteria were considered for further assessment of risk of bias and data extraction. Data were extracted from the full texts of the included articles using a standardized form. The authors categorized similar information into groups according to the main outcomes of interest. One of the reviewers (TKT) collected the required information from full-text eligible studies, and a second reviewer (TG) independently checked all of the collected data using those standardized outlines.For each included study, the following data were systematically extracted: publication details (authors and year), sample characteristics , study methodology  and outcome information (follow-up time and success rate). The success rate was considered as the survival of treatment (no need of repair) or the success of treatment .For studies that did not report this precise and required information, the authors of these studies were contacted via email to provide missing data or more information. Only the data of interest within the selected studies were extracted for analysis.After data collection, two independent reviewers (TKT and IF) assessed the potential risk of bias of the included studies. A specific protocol developed to analyze intervention studies was used to assess the randomized clinical trials included: the Cochrane Handbook for Systematic Reviews of Interventions 5.0.1 . This toThe risk of bias assessment of observational study was evaluated according to The Risk of bias in non-randomized studies of interventions (ROBINS-I). This tool is based on seven domains that included bias due to confounding, selection of participants, classification of interventions, deviations from intended interventions, missing data, measurement of outcomes and selection of the reported result .Both risk of bias assessment tools require that researchers rank the item as "yes" (low risk of bias), "no" (high risk of bias) or "unclear"  for each included study. For the final risk of bias classification, disagreements between the reviewers were resolved via consensus.The GRADE tool was used to evaluate the certainty of the evidence as a strategy to consider the confidence in the results from a meta-analysis or network meta-analysis. For this procedure, the adaptation of Salanti  was usedConfidence is scored as very low, low, moderate and high, and the reason for downgrading is reported.2 test.Direct evidence was computed using a random-effects model meta-analysis in which two treatments  were evaluated for the same level of caries lesion progression. Heterogeneity was evaluated using the IOtherwise, when more than two treatments were considered across different studies with regard to the same depth or surface involved, a network meta-analysis was conducted that synthesized direct and indirect comparisons to strengthen the evidence. Indirect comparisons were performed according to the method proposed by Bucher et al. . To simuFor each included study, the risk ratio and 95% confidence intervals were calculated. Studies with multiple arms need specific care to avoid double counting, one of the possibilities of approach is to perform a mixed treatment comparison (MTC), allowing each two groups to be compared indirectly through comparisons with the third , as we dThe systematic literature search identified 2142 potentially relevant manuscripts, and four additional were retrieved from a manual search of the reference lists of eligible manuscripts. A total of 471 titles were considered as duplicates and were therefore excluded. No eligible manuscripts were found in the grey literature. After the title and abstract screening, 1521 manuscripts were considered ineligible, mainly for not being related to the scope of this review (81%). A total of 150 remaining studies were retrieved as full-text manuscripts for more detailed information, and 135 articles excluded. The main reason for exclusion was that these studies evaluate the same restorative technique 61%; . FinallyThe major characteristics of the included studies are summarized in Tables Details of the assessment of the risk of bias for the clinical trials and practice-based research are displayed in Tables unclear using at least two questions because of the lack of information in the manuscripts. On the other hand, all reported the method of random sequence generation, whereas only three studies discussed allocation concealment [free of incomplete outcome data item. Regarding the question about free baseline imbalance, two studies reported this information and were indicated as having a low risk of bias [For clinical trials, all studies were classified as cealment ,32,33. Icealment ,26,27,29yes and were considered as having a low risk of bias. However, the items about the bias due to missing data, in measurement of outcomes and in the selection of the reported were categorized as unclear because of our inability to identify this information in the manuscript. A high risk of bias was identified only with regard to the item addressing statistical analysis . The primary outcome of this comparison was the success rate. Considering the overall analysis of the included clinical trials with regard to the success rate outcome, resin composite (RC) showed a higher success rate than sealing with a resin sealant   .However, when caries arrestment was considered as the primary outcome, no difference was observed between the restorative treatments  .For the studies that considered only the occlusal surface without information about the depth of progression, a network meta-analysis was conducted, and five studies that considered five treatment options were included. Heterogeneity was not observed among the included studies. The primary outcome of this comparison was the success rate . The resSeven studies were considered for the analysis that considered dentin caries lesions on occlusoproximal surfaces, without information about the depth of progression, and eight possible treatments were evaluated. One manuscript evaluated restorative techniques that were not addressed in the others studies; thus, the data from this observational study were not included in the network meta-analyses.Thus, a network meta-analysis was conducted. The primary outcome of this comparison was the success rate . The resFinally, three studies evaluated the caries arrestment assessment of the occlusal and smooth surfaces, considering five possible treatment options. Thus, a network meta-analysis was performed. The primary outcome of this comparison was caries arrestment . The resThe lack of strong scientific support regarding treatments of dentin caries lesions in the primary teeth makes recommending the best available treatment challenging. Therefore, the present systematic review sought to verify the effect of the available treatments on caries lesion arrestment and the success rate for dentin caries lesions in the primary teeth, considering different depths of progression and the surface involved.In general, we observed that the treatment efficacy to control caries lesions depends on the surfaces involved and the depth of progression. Two manuscripts considered only treatments for caries lesions on the outer half of the dentin of the occlusal surface, and a meta-analysis identified a similar performance with regard to caries arrestment for both treatment options . This finding seems to occur in response to the blockade of the cavity from the biofilm formation by resin sealant; thus, even if the infected dentin has not been removed, there is no nutritional supply to the caries lesion progression ,33. HoweThe results regarding caries lesions on the outer half of the dentin of the occlusal surface must be considered with caution because the inclusion criteria of these studies differed. Hesse et al.  considerLikewise, without information about the depth of progression, the best results on the occlusal surfaces were verified for CRT with compomer, followed by ART. The difference between these techniques is specifically related to the use of rotary instruments and, in the current situation, the restorative material. Previous studies have observed better compomer mechanical properties that might explain this trend in performance ,37. OnlyThe network meta-analysis of the studies that treated occlusoproximal cavities resulted in a higher success rate when using the Hall technique. This phenomenon occurred because of the use of stainless-steel crowns, which can isolate the dentinal lesion from biofilm deposition and dietary challenges, leading to caries lesion arrestment . CorroboSurprisingly, in opposition to this theory, the nonrestorative treatment was ranked as the second management possibility for occlusoproximal cavities. This technique enables biofilm removal via toothbrushing to arrest the caries lesion through the opening of the lesion with a high-speed bur and the removal of overhanging enamel . ParticiIn relation to nonrestorative approaches to controlling caries on occlusal and smooth surfaces, two annual applications of 38% SDF showed a higher proportion of arresting active dentin caries lesions. The other silver diamine fluoride applications did not demonstrate similar performances. The positive effect of application every 6 months is in line with the recommended frequency of recall visits for children at high risk for caries ,40. AlthTo obtain an overview of the effects of the treatments for dentin caries lesions in the primary teeth, different follow-up times were considered in the same analysis; this decision might be considered as a limitation of this systematic review. However, the small number of studies in this topic precludes subgroups analyses that consider the effect of follow-up time on the outcomes assessed. Importantly, the longevity of primary teeth is biologically brief. Thus, the follow-up time depends on the degree of tooth rhizolysis, which is correlated with patient age. The range of participants’ ages from the included studies is wide (3 to 10 years old); the longevity of the teeth and the survival rate of the treatments differ greatly across both situations.The risk of bias analysis performed on the clinical trials showed that all studies received more unclear scores because of the uncertainty regarding potential bias in the questions, especially those related to allocation concealment, incomplete outcome data and baseline imbalances given that we were unable to identify this information. This finding shows that several authors fail to provide required methodological information even with guidelines for reporting clinical trials. On the other hand, because the observational study met the eligibility criteria, it was possible to include it in our systematic review. However, since the evaluated restorative techniques were not addressed in the others studies, the data from observational study were not included in the network meta-analyses. This study was designed as practice-based research and was evaluated by a tool for non-randomized studies of interventions. Most of the parameters were labeled as “yes”. Because of the low risk of bias in this study, we believe that this decision did not introduce an extra source of bias in our systematic review.Another point to be highlighted is related to the evaluation of the quality of evidence, which showed low confidence in the results from the network meta-analysis regarding most of the analyses due to the risk of bias from the included studies. Furthermore, two studies included in the quantitative analysis presented greater than 30% dropout rates ,28, whicThe treatment of dentin caries lesions in primary teeth depends on the progression depth and surface involved. However, few studies exist, and most have a high risk of bias to provide enough evidence to strongly recommend the best treatment option.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S5 Table(DOCX)Click here for additional data file.S1 Fig(DOCX)Click here for additional data file.S2 Fig(DOCX)Click here for additional data file.S3 Fig(DOCX)Click here for additional data file.S4 Fig(DOCX)Click here for additional data file.S5 Fig(DOCX)Click here for additional data file.S6 Fig(DOCX)Click here for additional data file.


Pipelines are widely used for the transportation of hydrocarbon fluids over millions of miles all over the world. The structures of the pipelines are designed to withstand several environmental loading conditions to ensure safe and reliable distribution from point of production to the shore or distribution depot. However, leaks in pipeline networks are one of the major causes of innumerable losses in pipeline operators and nature. Incidents of pipeline failure can result in serious ecological disasters, human casualties and financial loss. In order to avoid such menace and maintain safe and reliable pipeline infrastructure, substantial research efforts have been devoted to implementing pipeline leak detection and localisation using different approaches. This paper discusses pipeline leakage detection technologies and summarises the state-of-the-art achievements. Different leakage detection and localisation in pipeline systems are reviewed and their strengths and weaknesses are highlighted. Comparative performance analysis is performed to provide a guide in determining which leak detection method is appropriate for particular operating settings. In addition, research gaps and open issues for development of reliable pipeline leakage detection systems are discussed. The use of pipeline is considered as a major means of conveying petroleum products such as fossil fuels, gases, chemicals and other essential hydrocarbon fluids that serve as assets to the economy of the nation . It has The average economic loss due to incidents of pipeline leakages is enormous . Over thBased on these statistics, incidents of pipeline leakage are hard to entirely avoid as the sources of failures are diverse. However, in order to reduce the impacts of oil spillage on society it is very important to monitor pipelines for the timely detection of leakage or even leak prediction, as early detection of leaks will allow quick responses to stop oil discharge and proper pipeline maintenance. Hence, it is possible to reduce the loss rate, injuries and other serious societal and environmental consequences due to the pipeline failures.Several pipeline leak detection methods have been proposed during the last decades using different working principles and approaches. Existing leakage detection methods are: acoustic emission ,14,15, fThis paper aims to examine the state-of-the-art achievements in pipeline leakage detection technologies and to discuss research gaps and open issues that required attention in the field of pipelines leakage detection technology. The rest of the paper is organised as follows: Exterior methods mainly involve the use of specific sensing devices to monitor the external part of the pipelines. These methods can be used to determine abnormalities in the pipeline surrounding and also detect the occurrence of leakages. Irrespective of the working principles these sensing methods are based on, they require some form of physical contact between the sensor probes and the infrastructure under monitoring. Examples of these devices include acoustic sensing, fibre optic sensing, vapour sampling, infrared thermography and ground penetration radar. The operational principle, strengths and weaknesses of these methods are discussed in the subsequent sections.Acoustic emission, according to American Society of Mechanical Engineering (ASME) 316 standard , is defis 20 μPa . As SPL ocedures . The acoocedures ,49. The use of acoustic emission methods for pipeline leaks detection have been reported in several studies ,51,52. Aposed in . The stuposed in , a combiJia et al. conducted a gas leakage detection experiment on a gas pipeline length of 3.13 km using measured acoustic waves with the sensors positioned at different locations along the gas pipeline . During The use of a cross-correlation method for detecting multiple leaks points in buried pipelines was investigated in . The stuApart from the abovementioned studies that are totally based on acoustic emission, accelerometers are another type of vibro-acoustic measuring device that are also useful to monitor low-frequency pipe-shell vibrations . SeveralThis method involves installation of fibre optic sensors along the exterior of the pipeline. The sensors can be installed as a distributed or point sensor to extensively detect the variety of physical and chemical properties of hydrocarbon spillage along the pipelines. The operation principle of this method is that cable temperature will change when pipeline leakage occurs and hydrocarbon fluid engross into the coating cable. By measuring the temperature variations in fibre optic cable anomalies along the pipeline can be detected . DistribThe manifestation of Brillouin scattering takes place as a result of the interaction between acoustic waves and propagated optical signals. This leads to a shift in frequency components in the received light, but in the case of Raman scattering approach changes in temperature only result in backscattered light intensity fluctuations. The frequency shift mechanisms in Raman backscattered light consists of two components, namely, Stoke and anti-Stoke components . The varSeveral pipeline leakage detection systems based on fibre optic approaches have been proposed in literature ,68,69,70Water ingress which commonly occurs in a low-pressure gas pipeline distribution network is a major challenge in subsea pipeline systems . This ocVapour sampling is generally used to determine the degree of hydrocarbon vapour in the pipeline environment. Though, it is applicable in gas storage tank systems, it is also suitable to determine gas discharges into the environment surrounding the pipeline. The tube is pressure dependent and filled with air at atmospheric pressure. Oil spillage can be determined by measuring the recorded gas concentration as a function of the pumping time for thus the degree of absorption . In the Different types of vapour sampling-based pipeline leak monitoring systems have been proposed in the literature ,74. The The advantages of vapour sampling systems include the capability of detecting small leaks, independent of the pressure or flow balance and superlative performance for detecting leaks in multiphase flow applications . BesidesPipeline leakage detection systems based on the infrared thermography (IRT) mechanism are also applicable for the detection of pipelines leakages. IRT is an infrared image-based technique that can detect temperature changes in the pipeline environment using infrared cameras which shows the infrared range of 900–1400 nm . The imaThermal cameras are effective devices for sensing objects of various shapes with different material properties from any perspective. The object acquired using a thermal camera can be processed to recognise anomalies in the pipeline environment through the warm and cooler areas displayed in the thermal image with a different colour in that particular environment. Improvements of IRT have been ongoing for several decades. Details of the origin and theory of IRT have been presented in . IRT hasThe use of IRT systems for pipeline condition monitoring enables timely detection of anomalies in the pipeline network thereby, reduced loss associated with gas wastage. Besides, the complexity of IRT system integration is not high. The major components to set up the system are a camera stand, an infrared camera and a display unit for visualisation of the acquired infrared thermal images. Moreover, the benefits of the IRT system include efficient transmission of the scan objects into a visualisation form , fast re2, 3, In an attempt to address these shortcomings, a leakage quantification mechanism using a combination of infrared thermography and ultrasound methods was proposed . The repThe emergence of ground penetration radar (GPR) is considered as an environmental tool which is valuable to detect and identify physical structures such as buried pipelines, water concentrations and landfill debris in the ground . The uses follow :(6)Vm=c-based techniques a variation in structural mechanical impedance instigated by the incidence of pipeline damage is monitored to detect the occurrence of pipeline failure. EMI transducers are made up of small piezoelectric patches that is usually less than etection . In the etection . Zuo et etection  proposedetection  a new meetection . In ordeetection . The obtThis section briefly presents less popular methods for pipeline leaks detection techniques based on information provided by the Joint Industry Project (JIP) offshore leak detection industry , equipmeVisual/biological methods of detecting leakages refer to the traditional process of detecting oil spillage in pipeline surroundings using trained dogs, experienced personnel, smart pigging or helicopters/drones . This meThe emergence of autonomous underwater vehicles (AUVs) in subsea pipeline inspection and monitoring has reduced the extent of human operator involvement in unmanned vehicles through the implementation of intelligent control machinery and thus drastically lower the chance of human casualties. Though, the operation principle of AUVs is similar to the teleoperation of ROVs, only limited skilled operators are required in supervisory control of AUVs . There aAs bolt connections are widely utilised in the assembly of different sections of petroleum pipeline systems, effective technique for monitoring bolted flange connections is essential. Several vision-based assessment methods for real-time bolt looseness detection have been proposed ,123,124.Interior or computational methods utilise internal fluid measurement instruments to monitor parameters associated with fluid flow in pipelines. These systems are used to continuously monitor the status of petroleum products inside the pipeline such as pressure, flow rate, temperature, density, volume and other parameters which quantitatively characterise the released products. By fusing the information conveyed from internal pipeline states, the discrepancy between two different sections of the pipeline can be used to determine the occurrence of leakage based on various methods, namely mass-volume balance, negative pressure waves, pressure point analysis, digital signal processing and dynamic modelling. Details of each of these techniques are discussed in the subsequent sections.The mass-volume balance approach for leak detection is straightforward . Its opeSimilarly, according to , assuminThe imbalance This method has been commercialised and is widely adopted in the oil and gas industry . Some ofLeak detection techniques using negative pressure waves (NPWs) are based on the principle that when a leakage occurs, it causes a pressure alteration as well as a decrease in flow speed which results in an instantaneous pressure drop and speed variation along the pipeline. As the instantaneous pressure drop occurs, it generates a negative pressure wave at the leak position and propagates the wave with a certain speed towards the upstream and downstream ends of the pipe. The wave contains leakage information which can be estimated through visual inspection and signal analysis to determine the leakage location by virtue of the time difference with which the waves reach the pipeline ends . A NPW-bThis method has been widely employed in pipeline monitoring due to its fast response time and leak localisation ability . HoweverThe pressure wave signal created by small leakage can be easily mixed with noise and background interference. This makes accurate signal detection and thus the oil spillage detection process challenging. An effective method of identifying small leakage signals using an improved harmonic wavelet was proposed in . The proAn alternative method of detecting small leakages using a specially designed morphological filter has been presented in . The morThe location of a unknown leakage along the pipeline between stations (sensors) A and B shown in The pressure point analysis (PPA) method is a leak detection technique based upon the statistical properties of measured pressures at different points along the pipeline. The leakage is determined through the comparison of the measured values against the running statistical trend of the previous measurements . If the The PPA method has been successfully applied in underwater environments, cold climates and functions adequately under diverse flow conditions. Small leakages which cannot be easily detected by other methods can be detected using PPA. However, it is difficult to determine leak location using this method . The easIn digital signal processing approaches, the extracted information such as amplitudes, wavelet transform coefficients and others frequency response is employed to determine leakage events. Generally, pipeline leak detection using digital signal processing involves five steps as illustrated in Different signal processing techniques have been employed in this research domain. Some of the existing method includes wavelet transform ,150, impThe authors of  proposedA recent study by Liu et al. proposed a new method of leak localisation for the gas pipeline using acoustic signals . Two metDynamic modelling-based pipeline leak systems are gaining considerable attention as they appear to be a promising technique for the detection of anomalies in both surface and subsea pipeline networks. In this approach, mathematical models are formulated to represent the operation of a pipeline system based on physics principles. The detection of leakages using this method is performed from two different points of views: (1) a statistical point of view and (2) a transient point of view. From the statistical point of view, the system utilises decision theory based on the assumption that parameters associated with fluid flowing remain constant except in the presence of anomalies along the pipeline . HypotheAccording to the technical report of the Alaska Department of Environmental Conservation , the mosYang et al. proposed a characterisation of hydraulic transient modelling using the equations of state of the fluid . PartialState estimator or observer is a method that is based on dynamical modelling of flow process in the pipeline to estimate or observe variations in the variables associated with the fluid flow and indicate the occurrence of fault as a result of pipe damage . This teA leak detection and isolation algorithm that is based on state estimation observer was proposed in . The obsTorres et al.  investigThis section presents a qualitative performance analysis of various pipeline leak detection approaches based on the literature cited above and American Petroleum Institute (API) performance requirement guidelines ,91. VariThe performances of various pipeline leakage detection methods are next compared using two-level performance analysis. System accuracy, system mode of operation, leak localisation, leak size estimation, ease of usage and ease of retrofitting are the criteria employed to evaluate the performance of the reviewed methods using a yes or no, high or low, and steady or transient state or not applicable (indicated by “—”) scale. As mentioned in the previous sections, there are various methods and mechanisms for pipeline leak detection and localisation. However, the applicability of each method varies considerably depending on pipeline operating conditions, pipeline characteristics and the medium to be detected. For instance, detection of leakages in surface, underground or subsea environments can be attained through the use of the approaches such as fiber optic cable, fluorescence and interior methods. While GPR can only be applied to underground pipeline networks. Some methods are applicable for all types of hydrocarbon fluid—including oil and gas—and water. However, only specific types of hydrocarbon fluid can be detected by some methods. In order to provide guidelines for selecting a method appropriate for a particular scenario, Based on the various reviewed pipeline leak detection methods, research gaps and future research directions are identified in this section. The performance of pipeline leakage detection methods generally varies depending on the approaches, operational conditions and pipeline networks. However, guidelines set by American Petroleum Institute (API 1555) such as sensitivity, accuracy, reliability and adaptability  must be Remote monitoring of oil and gas pipeline networks using wireless communications technology provide benefits of low cost, fast response and the ability to track the locations where leakages occur. However, to attain benchmark performance in monitoring pipelines remotely some of the design issues that require research attention include sensing modality, sensing coverage and leak localisation. As mentioned in the previous sections, several sensors are designed for monitoring pipeline leakages using different sensing modalities. Usually, sensors are deployed for monitoring steady-state conditions where the physical pipeline context is expected to remain stable over time. Variations in physical parameters of the pipeline operation such as vibration, temperature, pressure etc. are expected to be detectable and communicated to reveal the incidences of anomalies. Leaks can only be accurately detected if the incident is within the vicinity of the monitoring sensor and thus the accuracy of leak detection systems becomes questionable if the leaks are not within the receptive fields of the sensors. Sensors deployed for remote monitoring of pipelines are employed to perform both sensing and communication functions, however, the challenge of how to cover a monitoring region efficiently and relay the obtained measurements to their neighbouring nodes is also challenging in wireless sensor networks (WSNs), which impact on the network performance can be severe. There are many issues in designing optimal WSNs, particularly for pipeline monitoring. These issues include: (i) self-organisation, (ii) fault-tolerance, (iii) optimal sensor node placement, (iv) sensor coverage, (v) energy saving routing, (vi) energy harvesting and so on. During the lifetime of the sensor network some of the deployed sensor nodes are expected to experience hardware failure and the network may not be able to cope with this failure. This will limit the effectiveness of the whole network. The operation and performance of WSNs is largely dependent on optimal node placement as communication among the sensor node is required to transmit the acquired data. Besides, sensor placement also influences the resources management such as energy consumption in WSNs , while tLeak localisation is very essential in pipeline monitoring as it will speed up the repair process. Different methods of defect localisation in pipelines have been proposed ,199,200.The subsea industry activity has been continuously growing, which has made the sector a truly global industry with the industry operations amounting to billions of NOK in turnover . HoweverIn general, the aim of future pipeline monitoring is to design a real-time intelligent pipeline leak detection and localisation system for subsea pipeline networks. The effect of environmental factors, in particular, hydrodynamic forces due to oblique wave and current loading on subsea pipelines still require further research study. Extensive simulation and laboratory experiments are being conducted to study the effects of leakage parameters, like size and shape, on the flow mechanism and validate different models. Numerical simulations of fluid flow in pipeline using computational fluid dynamics (CFD) have been proved to provide a better understanding of pipeline internal flow and the conditions of pipeline leaks on various scales, thereby reducing the cost in experimental studies. However, high computational complexity remains one of the major drawbacks of CFD. Further research efforts are still required to optimise and/or parallelise CFD solution algorithms in terms of computation and memory resource constraints.This survey paper provides a rudimentary reference to guide readers in selecting an appropriate leak detection technology for a particular setting. In this paper, a comprehensive survey of various available pipeline leakage detection and localisation methods was carried out. A summary of what has been demonstrated to date is presented, along with research gaps and open issues that require attention in this research domain. A wide variety of pipeline leak detection approaches was reviewed and grouped into three different categories. The first category is the exterior methods which involve the use of specially designed sensing systems to monitor the external parts of pipelines. The methods considered in this category includes acoustic emission sensors, fibre optic sensors, vapour sampling, infrared thermography and ground penetration radar. In the second category, the visual methods of detecting leakages in the pipeline which include trained dogs, experienced personnel, smart pigging or helicopters/drones/ROVs/AUVs were discussed. The interior method of detecting leakage using parameters associated with hydrocarbon fluid such as mass-volume balance, negative pressure waves, pressure point analysis, digital signal processing and dynamic modelling were presented in the third category. We then performed a comparative analysis using various performance requirements based on the American Petroleum Institute (API) guidelines ,92. Base


The endothelium is a thin monolayer of specialized cells that lines the luminal wall of blood vessels and constitutes the critical innermost portion of the physical barrier between the blood and the brain termed the blood-brain barrier (BBB). Aberrant changes in the endothelium occur in many neuropathological states, including those with high morbidity and mortality that lack targeted therapeutic interventions, such as traumatic brain injury (TBI). Utilizing ligands of surface determinants expressed on brain endothelium to target and combat injury mechanisms at damaged endothelium offers a new approach to the study of TBI and new avenues for clinical advancement. Many factors influence the targets that are expressed on endothelium. Therefore, the optimization of binding sites and ideal design features of nanocarriers are controllable factors that permit the engineering of nanotherapeutic agents with applicability that is specific to a known disease state. Following TBI, damaged endothelial cells upregulate cell adhesion molecules, including ICAM-1, and are key sites of reactive oxygen species (ROS) generation, including hydrogen peroxide. Reactive oxygen species along with pro-inflammatory mediators are known to contribute to endothelial damage and loss of BBB integrity. The use of targeted endothelial nanomedicine, with conjugates of the antioxidant enzyme catalase linked to anti-ICAM-1 antibodies, has recently been demonstrated to minimize oxidative stress at the BBB and reduce neuropathological outcomes following TBI. Here, we discuss targeted endothelial nanomedicine and its potential to provide benefits in TBI outcomes and future directions of this approach. Traumatic brain injury is a growing healthcare concern with 2.5 million TBI-related emergency department visits, hospitalizations, and deaths occurring in the United States in 2013 , 5. ConsFew treatment options exist to facilitate functional recovery following TBI –8. CurreThe pathophysiology of TBI has been described to occur in two sequential, interconnected phases . First, in vivo approach to ROS detection  approved all procedures detailed under ad libitum. Eight-week-old male C57BL/6J were obtained from The Jackson Laboratory .The Institutional Animal Care and Use Committee (IACUC) at Temple University  approved all procedures detailed in studies presented herein that required the use of vertebrate animals prior to initiating any experimental objectives. Additionally, all methods were performed in full compliance with Temple University's IACUC policies and the National Institutes of Health (NIH) ethical guidelines. Animals were housed and allowed to acclimate for 1–2 weeks in the Temple University Central Animal Facility. The animals were provided standard environmental enrichment conditions and were fed with a commercial pellet diet and water All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Dental implant failure in the anterior maxilla can be caused by the range of the features. One of them is neighboring neurovascular structure damage, such as the canalis sinuosus (CS), that carries the superior anterior alveolar nerve. The aim of the report is to demonstrate clinical symptomatology and radiographic signs of CS damage in a 45-year-old female patient who underwent upper left lateral incisor extraction and immediate implant placement and implant removal in 16 days secondary to pain and paresthesia in the maxillary left region. Immediate implant placement has been considered as an effective treatment for partially edentulous patients with a high implant survival rate . Howevercanalis sinuosus (CS) [The anterior superior alveolar nerve (ASAN) is a branch of infraorbital nerve that enters in the infraorbital canal, which has a side intrabony branch called the sus (CS) , 6. The sus (CS) , residinsus (CS) –12. CS nsus (CS) .The proximity to the neurovascular bundle of the CS can compromise dental implant treatment , 14, 15 When planning dental implants, carrying out radiographic examinations, alongside clinical examinations, has become necessary to reduce the risk of implant procedure failure and complications. The cone-beam computed tomography (CBCT) imaging is a valuable tool to determine the anatomic structures before any surgery, including implant surgery . The recAlso, it was shown that the terminal portion of CS is more prevalent in the anterior region of the maxilla, more specifically in the incisor and canine regions near the palate . On the The aim of this article is to report a case with clinical and radiographic signs of CS damage after immediate dental implant placement in the maxillary left lateral incisor region.A 45-year-old female patient underwent maxillary left lateral incisor extraction secondary to severe horizontal tooth fracture below the cementoenamel junction (CEJ). Preoperative CBCT examination was provided and evaluated before the procedure.The CBCT scan was obtained with a 3D eXam  with standard exposure settings  and was analyzed with the I-CAT viewer software .The patient gave written consent before all procedures. Extraction was provided atraumatically with the luxators. The flap was reflected. Immediate implant placement was performed with the simultaneous guided bone regeneration (GBR) without corticotomy and soft tissue grafting . ThIn a few hours after the procedure, the patient started complaining about the pain and paresthesia in the left maxilla. First week pain was insignificant, and 400 mg of ibuprofen was prescribed twice a day and it relieved the pain. In one week, the pain started increasing and became so strong and continuous that none of the painkillers could relieve it.The pain generally was located in the area of the maxillary left canine. All sensitive disorders were not located in the area of implant site—they spread out around the maxillary left canine, the palate, and the nasal region. Also, the patient complained about burning in the back of the head in the occipital region. Painkillers, tranquilizers, and neurotropic agents were ineffective at this moment. However, no significant findings were noted during extraoral and intraoral clinical examinations.After the clinical examinations, it was suspected to be a neurological disorder, so differential diagnostic procedures were held. During these procedures, different types of the nerve blocks were performed on the patient. Palatal, incisive, and infraorbital nerve blocks were used one by one; however, only the infraorbital block relieved the pain.No other symptoms of inflammation were found such as pain, fever, exudation, or excessive bleeding in the area of implant placement and GBR. Neither the patient nor her relatives presented neurological disease in the medical history.New CBCT evaluation was performed after the surgery with the same equipment. During precise examination of the CBCT scans before and after the implant placement, CS was found with the diameter 2.3 mm in size with two small branches. One of them was found close to the palatal side with the diameter 1.9 mm in size; the other was found close to the buccal side in the maxillary left lateral incisor/implant region Figures  with theThe implant was extracted in two weeks and two days. Then, the pain and paresthesia started slowing down. However, an area of necrosis was found by the end of the third week on the palatal mucosa  even thoThe bony defect after implant removal healed under a blood clot as an alveolar socket after tooth extraction. The patient was prescribed antiseptics for local application. Further treatment and follow-ups of the patient were impossible, because the patient decided to change the clinical practice.The CS, first described by Jones , carriesSeveral studies and clinical cases showed that CBCT is the best radiographic technique for CS visualization . The CBCThough CBCT provides accurate three-dimensional images of dentomaxillofacial hard tissues , its limDuring the preoperative CBCT evaluation and dental implant planning, none of the nerve structures around left lateral incisor were noticed. This demonstrates the necessity of knowing the existence of CS and its characteristics, which may influence treatment outcomes.There are several case reports with dental implants placed in the anterior maxilla and CS damage, presenting the same neurological symptomatology , 17; howAs the damage of the greater palatal and nasopalatine nerve and blood supply was excluded, the palatal mucosa necrosis that appeared after implant extraction could be explained by the contraction of smooth muscle within the arterial wall during the neurovascular bundle constriction that leads to transient ischemia of structures and tissue necrosis . HoweverTo avoid sensory disturbance in the anterior maxilla in the case of CS detection, Shelley et al.  in theirThis clinical report of immediate implant placement showed the importance of anatomical structure knowledge and accurate and precise preoperative CBCT scan estimation, especially in the esthetic zone. The damage of CS can lead to neurological symptomatology and implant extraction.We suggest that single-tooth defects with the risk of CS damage in the region should be restored without implant treatment or with the use of surgical guides designed for fully guided implant placement.


ClinicalTrial.gov database results in about 300 recruiting clinical trials, stating the actuality of this topic [The 21st century has finally seen the full achievement of targeted therapy to treat cancer with the promise of lower side effects and improved efficacy with respect to cytotoxic chemotherapeutics. Today, in oncological practice, we have numerous antitumoral “bullets” with 114 approved drugs that target 128 different cancer-associated proteins [1-Patient selection: Preclinical studies have often shown that TKs play an important role in sustaining basic functions in cancer biology. This evidence encouraged oncologists to design clinical trials that did not consider the actual expression of TKs in the patient. On the contrary, results from clinical trials have clearly demonstrated that the assessment of the expression and activity of the target is fundamental in order to predict the efficacy of the drug. If a therapeutic prediction based on the oncogenic activation of the target is easily achievable for certain hematological tumors with few genetic alterations , unfortunately, it is not equally practicable in high heterogeneous solid tumors. A striking example of the real use of this approach in solid tumors is the analysis of HER2 overexpression that is propaedeutic for the use of trastuzumab in the treatment of breast carcinoma. In fact, although all members of ERBB family could play a promotion role in cancer, important therapeutic benefits have been described only targeting overexpressed family member or in presence of an oncogenic variant form. It is the case of ERBB4 variant that Donoghue et al. individuated as an independent prognostic marker for glioblastoma subpopulations with poorer prognosis [Although a precision definition of gene expression profile in single patient is important in determining therapeutic cohorts, an effective strategy of patient selection needs more solid evidence about predictive markers. Kozaki et al. utilized a wide panel of hematopoietic cell lines in order to investigate the response to BTK inhibitor, and then they explored the most effective combination therapy in order to avoid BTKi resistance . This ty2-Selectivity for the target: Single target therapies have shown activity for only few cancer types. The current data support the hypothesis that in the majority of cancers agents targeting multiple signalling pathways are more effective than single targeted therapy. Among 32 TKi small molecules approved for therapy only about 30% could be considered single targeted. The median number for these drugs is 3 targeted TKs. However, it is questionable if multi-TK inhibition should be achieved by a single multitarget inhibitor or by different selective inhibitors. Currently the most accredited answer is the use of combination therapy. In fact, the high number of deregulated pathways and the inter-patient heterogeneity in TK profiles render less feasible the use of a single multi-targeted TKi. Another problem for the utilization of a single multi-kinase inhibitor is that it should preferentially have the same high activity against different targets. Simiczyjew et al. demonstrated that the combination of two, relatively target-restricted TKis, could be effective in very aggressive breast cancer subtype, where HER2 cannot be used as single target . These s3-mutations: Despite the increase in overall survival allowed by TKis in many cancers, drug resistance onset based upon aminoacidic substitution may generate a challenging therapeutic hurdle. Investigation of structural mechanism of action and the evaluation of TKi activity against the most frequent mutant forms of the target is fundamental to overcome this type of resistance. Ponatinib, third-generation BCR-ABL TKi, represents a model for the effective development of new small molecules for targeted therapy. Wei et al. well describe in their review the scientific effort in the development of TKi able to overcome resistance to crizotinib in ALK positive tumors . Preclin4-one ring to rule them all: The broad spectrum importance of TKs in carcinogenesis determines that the same signaling pathway could be over-activated in different tumors. This is why some anti-TK families have been approved for different cancers. In addition, the use of a drug already approved in a different cancer offers the opportunity to speed up the approval process. KIT, PGF, LCK, FLT4 are among the most frequent targets in cancers . HoweverThe path toward the cure of cancer with TKis has just started, and its building is dependent on the achievement of two goals in the close future: (1) more solid preclinical models able to recapitulate cancer heterogeneity in genetic background and expression profiles and (2) the definition of predictive markers for the effective design of multitarget therapy.


The aim of this article is to review the clinical and imaging features of symptomatic hypertrophic (TP) in a cohort of symptomatic patients.Twenty-three patients with chronic lateral ankle pain were retrospectively included in our study group. Patients underwent ultrasound (US), (cone beam) computed tomography (CB)CT or magnetic resonance (MR) examination or a combination of these examinations with a standardized protocol. Patients with an underlying fracture were excluded. The following parameters were recorded: clinical history, size of the TP on different imaging modalities, presence and grade of peroneus brevis/longus tenosynovitis and the presence of bone marrow edema at the os calcaneus on magnetic resonance imaging (MRI).The mean width of the hypertrophic TP was 5.6 mm. Combined tenosynovitis of the peroneus longus (PL) and brevis tendon (PB) was most common, followed by isolated PL and finally PB tenosynovitis. Grade 1 tenosynovitis was most common. BME was present in 53% of the cases.The width of the TP is may be evaluated on the (oblique) coronal US, (CB)CT or non-fat suppressed MR images. Both US and MRI may detect and grade involvement of the peroneal tendons. By the use of fluid sensitive sequences, MRI may be of additional value to detect bone marrow edema as result of repetitive friction. Ankle pain may result from a variety of diseases. An underestimated cause of chronic lateral ankle pain is the presence of a hypertrophic tuberculum peroneum (TP) . As the The TP is located on the lateral surface of the calcaneus, anteriorly to the eminentia retrotrochlearis Figure . AnatomiIts size is defined by width, height and length. Because conventional radiography (CR) is usually not accurate for precise evaluation of the size of the TP, measurements are far better performed on ultrasound (US), (CB)CT or MRI  The widtHypertrophy of the TP will cause friction and mechanical irritation which may lead to peroneal tenosynovitis causing lateral ankle pain. Anatomically, the peroneus longus tendon is most at risk for tenosynovitis because of its long excursion and changing direction. The peroneus brevis tendon is less prone to be involved 5.Despite multiple previous case reports and small studies, a uniform definition of a hypertrophic tuberculum peroneum is still debated. Based on those small reports a width exceeding 5 mm is considered as being hypertrophic predisposing to tenosynovitis .The aim of this article is to review the clinical and imaging features of symptomatic hypertrophic (TP) in a cohort of symptomatic patients.Our study is a monocentric, retrospective cohort study of 23 patients. Inclusion criteria included referral for imaging  CT or MRI; Table Conventional radiography was performed on the Luminos dRF MAX . AP, lateral and Mortise view are the three standard images performed of the ankle. Additional axial image to visualize the hypertrophic tuberculum was performed. US images using EPIQ5G  Figure . Cone BeThe following parameters were retrospectively reviewed by two observers in consensus: history of previous ankle sprain or trauma, width of the TP on all available imaging modalities, the presence and grade (I–III)  of tenosTwenty-three patients were included in our study, 10 men and 13 women. Eleven patients presented with right-sided chronic ankle pain while the left ankle was affected in 12 cases.Nine patients had a history of previous ankle distortion, ranging between several months to years previous to presentation. In four patients the request form for imaging mentioned overuse. One patient had planovalgus foot deformity.The mean width of the TP in these symptomatic patients was 5.6 mm range 3.6–8.6 mm). Isolated tenosynovitis of the peroneus longus Figure  was seen.6–8.6 mmHypertrophy of the tuberculum peroneum is an underdiagnosed cause of chronic lateral ankle pain. Detailed anatomy of the calcaneus and the TP was previously described by Laidlaw  and EdwaThe pathogenesis of a hypertrophic TP is variable and controversial. Some authors consider a hypertrophic tuberculum peroneum as a pre-existing congenital abnormality , whereasSymptomatic patients complain of pain at the lateral side of the ankle. In acute posttraumatic setting local swelling may be present. There may be concomitant painful palpation and inversion as well.Friction with the peroneal tendons cause local attrition and tendon degeneration. The grade of tenosynovitis varies from focal thickening of the tendon and local effusion to a partial thickness tear or even complete rupture . Because44Only a few cases of tenosynovitis of the peroneus brevis have been described in the literature . HoweverAlthough there is currently no standardization on the measurement of TP on different imaging techniques, we recommend ultrasound as the initial imaging modality in case of suspicion of a symptomatic TP and MRI for more precise locoregional evaluation, demonstration of associated BME at the calcaneum and especially for differential diagnosis Figure  for otheDue to its complex anatomy and superposition of osseous structures, plain radiography is inaccurate for evaluation of a TP.(CB)CT allows more precise measurement compared to plain radiography, but there is a concern about radiation exposure. Moreover, if CBCT is used, there is insufficient visualisation of surrounding soft tissues.Ultrasound allows precise correlation with the location of the pain of the patient. Evaluation of the width of the TP is readily done on oblique coronal images. The dynamic capability of this modality is a major advantage to evaluate real time peroneal tendon impingement or clicking. Ultrasound allows also accurate staging of the grade of tenosynovitis with a very high spatial resolution.Whilst MRI lacks the dynamic aspect of ultrasound, it allows visualization of BME at the calcaneum caused by repetitive friction of the peroneal tendons against the adjacent bone.The best sequences to document BME are fluid-sensitive sequences, such as STIR or fat suppressed T2-WI. In our series, BME was seen in 53% of symptomatic patients. For evaluation of the width of the TP, non-fatsuppressed coronal or axial PD or T1-WI are preferred, because they allow better visualisation of the cortical margins of the TP.A significant limitation of our study is the retrospective design, which may result in selection bias, as a hypertrophic tuberculum peroneum may have been present in other asymptomatic individuals not seeking medical assistance. Furthermore, due to its retrospective design, every single patient was not examined by every imaging modality, which renders strict correlation of the imaging modalities impossible. Note also that the routine MR protocol in our institution includes strict coronal, axial and sagittal 3 mm slices, which are not corrected for the oblique anatomical orientation of the TP, which may be the origin of subtle mismatch of measurements on ultrasound compared to MRI. The second limitation is the limited number of patients. However, in comparison to the previously published literature, this is one of the largest series in symptomatic patients. The fact that the measurements were performed by 2 observers in consensus and not independently is another limitation of the study.Therefore, further studies are needed to define the size of the TP in a large cohort of asymptomatic individuals and to correlate those measurements on different imaging modalities and slice orientations. Calculation of inter- and intra-observer variability will be useful to find out whether imaging techniques are reliable in assessment of the size of TP and for further refinement of the diagnostic algorithm of chronic lateral foot pain.Hypertrophy of TP should be considered as a potential origin of chronic lateral ankle pain.Ultrasound may be used as screening modality in the diagnosis by measurement of the width on coronal oblique images and evaluation of the peroneal tendons. Associated BME is best detected on the fatsuppressed T2-WI MR or STIR images, in combination with T1-WI or PD images for evaluation of the size of the TP.