To date, genome-wide association studies (GWASs) have successfully identified thousands of associations between genetic polymorphisms and human traits. However, the pathways between the associated genotype and phenotype are often poorly understood. The transcriptome, proteome, and metabolome, the omics, are positioned along the pathway and can provide useful information to translate from genotype to phenotype. This review shows useful data resources for connecting each omics and describes how they are combined into a cohesive analysis. Quantitative trait loci (QTL) are useful information for connecting the genome and other omics. QTL represent how much genetic variants have effects on other omics and give us clues to how GWAS risk SNPs affect biological mechanisms. Integration of each omics provides a robust analytical framework for estimating disease causality, discovering drug targets, and identifying disease-associated tissues. Technological advances and the rise of consortia and biobanks have facilitated the analyses of unprecedented data, improving both the quality and quantity of research. Proficient management of these valuable datasets allows discovering novel insights into the genetic background and etiology of complex human diseases and contributing to personalized medicine. Genome-wide association studies (GWASs) are study designs for evaluating associations between genetic variants and phenotypic traits across the genomes, revealing the genetic impacts on a variety of phenotypes since its first success in 2002 –3. In reIdeally, researchers prefer to use identical samples with data across each omics. However, few datasets contain all the omics data in individuals. While it would be ideal for defining a new sample and collecting all of the omics, genetic and phenotypic data, that undertaking has enormous cost and time required. While individual raw data is often restricted in its use due to ethical issues, de-identified or anonymized analysis results are available in many biological databases. We can perform comprehensive analyses for various phenotypes by integrating the accumulated data with our own data. In particular, the quantitative trait loci (QTL), or loci associated with a variation of a quantitative trait Fig. b, play aThis review introduces several useful resources that can be applied to trans-layer omics analysis and describes how the data can be utilized, mainly focusing on QTL.More than 90% of the risk variants identified by GWASs have been found in non-coding regions , 5, and The Genotype-Tissue Expression (GTEx) Project has built a large-scale database of organ-specific eQTL data. The latest GTEx database is version 8, deployed in 2020, which includes curated data on as many as 15,201 RNA sequencing samples from 49 tissues of 838 donors [Several eQTL analyses for individual blood cell types have been successfully performed due to easy access to the sample and the cell diversity , 19–21. + T memory cell types) and two activated cell types isolated from 106 leukapheresis samples provided by 91 healthy subjects in the San Diego area. They identified a total of 12,254 genes with cis-eQTL and a large fraction (41%) of these genes showed a strong cis-association with genotype only in a single cell type. Furthermore, they confirmed several cases in which the cell types with eQTL corresponding to GWAS risk SNPs related to the well-known pathogenesis.The DICE  and epigenomics) project was established to define the transcriptional and epigenomic landscape of many human immune cell types in relation to genetic variation . As the As for the eQTL analysis of non-Europeans, Ishigaki et al. conducted the eQTL analysis on five immune cell types  and unfractionated peripheral blood from 105 healthy Japanese volunteers . In thisAssociation analyses for genome-wide gene expression, as was done in this study, are called transcriptome-wide association studies (TWASs). TWASs use penalized regression techniques, such as LASSO, Ridge, or Elastic net, which incorporate eQTL reference data as training data and evaluate associations between predicted gene expression levels and a target trait. TWAS can also be performed with only GWAS summary statistics and external eQTL reference data , 23. HowMost transcriptome studies focus on coding genes because many non-coding genes have unknown functions, and the analysis results can be challenging to interpret. Sakaue et al. developed a method for estimating GWAS-target miRNAs and GWAS-related tissues by integrating GWAS summary statistics and miRNA expression data . AnalyseSingle-cell RNA sequencing makes it possible to evaluate gene expression at an unprecedentedly fine resolution in individual cell types and identify rare populations without assumptions. The previous classification of cells by surface markers could only identify existing cell types and had difficulty identifying heterogeneity in captured cell types . Single-In general, eQTL analyses that handle RNA data have a limit in that they capture a snapshot at a single point in time, not reflective of transcriptome fluctuations. Therefore, many eQTL are conditional, and some can only be identified through cell activation or cell differentiation , 31. Dav+HLA-DRAhi sublining fibroblasts), were increased in RA synovium. This study showed that the integration of multiple experimental modalities helps us select trait-specific cells by increasing the individual cells’ information. QTL analyses of these cells central to the etiology should provide more evident and profound insights into genetic impacts on various diseases.Mass cytometry is another single-cell modality and provides different cell-type-specific profiles. Mass cytometry measures a limited number (~ 40) of pre-selected markers, but these markers are supported by decades of experimental evidence that they are useful for defining cellular heterogeneity . Zhang eThe proteome comprises the entire protein complement produced in an organism or system. Sun et al. investigated the associations between genetic variants and 2994 proteins in 3301 Europeans . They idPlasma proteins play essential roles through biological processes and represent a significant resource for drug targets . MendeliThe metabolome consists of small molecules that are intermediates or products of metabolism, ranging from peptides and lipids to drugs and pollutants. Several studies that tested the associations between genetic variants and serum metabolites have reported hundreds of loci changing serum metabolite amount, or metabolite quantitative trait loci (mQTL), which were often mapped to genes encoding for enzymes or transporters –42. The Furthermore, they used the colocalization method to confirm whether a GWAS risk variant was also responsible for mQTL signals in the locus. GWAS and QTL signals can overlap for three reasons: two independent causal variants in linkage disequilibrium (linkage), a single causal variant affecting the GWAS trait via gene expression modulation , or a single causal variant affecting both traits independently (pleiotropy) . ColocalThe epigenome describes a biological phenomenon where chemical compounds can modify or mark the genome to affect gene expressions. DNA methylation at CpG dinucleotides plays an important role in gene regulation by altering DNA affinity with TF or chromatin-binding proteins. DNA methylation can occur for various reasons: normal development such as genomic imprinting, aging, environmental factors, or genetic factors. In these, genetic factors can be inherited and diversify the innate methylation status among individuals. Gaunt et al. evaluated the genetic influences on DNA methylation, or methylation quantitative trait loci (meQTL), in the human blood at five different life stages: children at birth, childhood, adolescence, and their mothers during pregnancy and at middle age . They idWhile QTL are beneficial information in evaluating the effects of GWAS risk SNPs, most QTL analyses do not cover all tissues and probably have insufficient power in some tissues due to a lack of adequate sample size. It is useful to consider what functional annotations target variants are located in Table . ENCODE The FANTOM Consortium has used a unique technique called cap analysis of gene expression (CAGE) to identify promoters and enhancers across hundreds of cells and tissues . Hirabayχ2 association statistic for a given SNP in GWASs includes the effects of all SNPs tagged by this SNP [r2 measures of the target variant and the surrounding variants . The regression of the χ2 statistics by the LD score in a genome-wide manner provides an estimate of heritability. The modified form, or stratified LDSC regression, partitions SNP heritability by functional genomic annotations and tests whether the GWAS statistics is enriched in the annotations [Linkage disequilibrium score regression (LDSC regression) is an effective tool for combining GWAS summary statistics with these genome annotations. In the polygenic traits, the this SNP . The LD otations . For strotations .Ishigaki et al. estimated TF enrichment in various diseases using the annotation of TF binding sites defined by 2868 publicly available chromatin immunoprecipitation sequencing datasets for 410 unique TFs . They idThe available omics data has improved in both quantity and quality. State-of-the-art technology, such as whole-genome sequencing, long lead sequencing, mass cytometry, and single-cell RNA sequencing, should illuminate currently unreachable areas. Furthermore, trans-layer omics analysis empowers the information from the individual omics. If the relationship between the genome and each omics is revealed, various living organisms’ phenomena could be predicted from genome data. The tools introduced in this review are not limited to one type of omics pair but can be applied to various omics data combinations . The trans-layer omics analyses using these sophisticated methods and a vast amount of data provide novel insights into the genetic background, etiology of complex diseases, and drug discovery, which should contribute to the implementation of personalized medicine.


Transcatheter aortic valve implantation (TAVI) is an increasingly widespread percutaneous intervention of aortic valve replacement (AVR). The target population for TAVI is mainly composed of elderly, frail patients with severe aortic stenosis (AS), multiple comorbidities, and high perioperative mortality risk for surgical AVR (sAVR). These vulnerable patients could benefit from cardiac rehabilitation (CR) programs after percutaneous intervention. To date, no major guidelines currently recommend CR after TAVI. However, emerging scientific evidence shows that CR in patients undergoing TAVI is safe, and improves exercise tolerance and quality of life. Moreover, preliminary data prove that a CR program after TAVI has the potential to reduce mortality during follow-up, even if randomized clinical trials are needed for confirmation. The present review article provides an overview of all scientific evidence concerning the potential beneficial effects of CR after TAVI, and suggests possible fields of research to improve cardiac care after TAVI. Transcatheter aortic valve implantation (TAVI) is a percutaneous intervention of aortic valve replacement (AVR), primarily indicated for elderly, vulnerable patients with severe aortic stenosis (AS). The benefit of cardiac rehabilitation (CR) in post-TAVI populations is still unclear, and CR is not currently recommended by the major guidelines for the management of patients after TAVI ,2. The pCR is a set of measures aimed at providing patients with cardiovascular disease with the optimum psychological and physical conditions to prevent the disease from progressing or potentially reversing its course . The thrIn physiopathological terms, the benefits achieved by exercise-based CR can be attributed to various mechanisms: reduction in major risk factors, such as smoking, obesity, and arterial hypertension; improvement in lipid profile; improved medication adherence; depression identification and treatment; reduction in inflammation; ischemic preconditioning; improved endothelial function; improved insulin sensitivity and glucose levels; and more favorable fibrinolytic balance. CR also seems to favor a reverse cardiac remodeling with a reduction in left ventricular (LV) volumes, an increase in LV ejection fraction, and an improvement in LF and left atrial mechanics .Although CR is strongly recommended after cardiac surgery, little is known about the impact of CR in patients with AS following TAVI.Degenerative AS is the most common valvular heart disease in developed countries, with a growing prevalence due to the ageing of the general population . Its proSurgical AVR (sAVR) has been the gold standard treatment for a long time, but with an ageing and increasingly multimorbid population, the need for less invasive treatments has emerged. TAVI is recommended as the therapy of choice among inoperable patients by the current European guidelines on the management of valvular heart disease . MoreoveRecently, the results of two randomized clinical trials (RCTs) comparing TAVI and sAVR  showed that the risk of death, disabling stroke, and rehospitalization for heart failure was lower in the TAVI group compared to the sAVR group, even among patients at low surgical risk ,13. In aThe increasing TAVI indications led to a growing interest in CR programs aimed at improving cardiac care after TAVI. Observational data from different geographical areas show variability in the participation to rehabilitation programs among post-TAVI patients ,16.The Working Groups on Valvular Heart Disease, Thrombosis, and Cardiac Rehabilitation and Exercise Physiology of the European Society of Cardiology (ESC) recommend exercise-based CR after sAVR . No recoOver the years, various studies have investigated the safety and effectiveness of different CR programs in patients undergoing sAVR, whereas only a few studies have specifically addressed patients undergoing TAVI ,19.Apart from age and comorbidities, severe AS represents per se a contraindication to physical activity; consequently, patients usually undergo TAVI in a very deconditioned state. Moreover, hospital-acquired functional decline, defined as new or worsened functional decline during hospitalization, develops in at least 30% of hospitalized elderly patients. This functional decline has been observed to be independent of functional status and pre-operative frailty, and might be explained by a susceptibility to hospital-induced stresses. It is also independently associated with worse clinical outcomes . As hospAn exercise-based CR program after TAVI has been demonstrated to be safe without detrimental effects on prosthesis hemodynamics ,19,21.CR programs following TAVI show a gain in exercise tolerance, mainly assessed by the 6 min walking test distance (6MWD), and in some studies by the exercise test ,23,24,25In their meta-analysis, Ribeiro et al. reported that the average increase in 6MWD was three times greater than the minimum clinically important difference in 6MWD observed in coronary artery disease patients who participated in a CR program after percutaneous coronary revascularization. The gain in exercise tolerance was similar after TAVI and SAVR .In a study carried out by Tarro Genta et al., TAVI patients compared with sAVR patients exhibited a higher disability profile and a reduced exercise capacity, both in absolute terms and as improvement induced by CR . TAVI paThe effect of a structured exercise program versus usual care after TAVI was evaluated in a small randomized pilot trial . Both grAn important goal of TAVI in elderly patients is to enhance their functional status. CR programs are associated with gains in functional independence, mainly assessed by the Bathel Index (BI), and in health-related quality of life ,21. SupeIt should not be forgotten that psychological endpoints, such as anxiety reduction, are part of quality of life, and they improve due to multicomponent rehabilitation programs ,22.Rehabilitation was shown to provide benefit in terms of 6 month survival after TAVI . In partA trend toward better survival was also observed in the follow-up analysis of the randomized Safety, applicability and outcome of regular exercise training after transcatheter aortic valve implantation [SPORT: TAVI] pilot trial, with a non-significant difference presumably due to the small number of patients .Though patients referred to rehabilitation are older and at higher risk , a recenConfirmation of the effects of rehabilitation on hard outcomes is needed with further RCTs.Predictors of mid- and long-term adverse outcomes in patients who undergo TAVI are usually based on an assessment conducted before or at the time of percutaneous procedure. Some parameters deriving from CR programs can predict long-term outcomes. In particular, low exercise tolerance and severe residual disability at discharge from a residential CR program were shown to predict a 3 year follow-up . HoweverThe lack of improvement in physical performance at 6 months after TAVI, evaluated through the 6MWD, was found to be an independent predictor of mortality and adverse cardiovascular outcomes during the ensuing 4 years . CR progIntensified follow-up programs of multidisciplinary rehabilitation improve the clinical outcome of patients affected by cardiac disease, and should be offered whenever possible .2AT), but not in oxygen uptake at peak workload (VO2peak), muscular strength, and quality of life compared to usual care. VO2AT is considered a more comprehensive marker of aerobic efficiency, while VO2peak describes the net limitation in exercise capacity. Both of them are strong predictors of all-cause mortality in heart failure patients. Although this has not specifically been investigated in TAVI populations, persisting improvements in submaximal exercise performance are thus very likely to facilitate activities of daily living, as these activities usually do not require maximal effort.Acute exercise effects of rehabilitation after TAVI were mostly non-sustained over time in the follow-up of the SPORT: TAVI trial, indicating that once the intervention had stopped, patients were not willing or able to participate in regular home-based exercise . In partIt is likely that adherence to regular exercise declines over time, resulting in a loss of initial clinical benefits. Strategies to promote the access to regular exercise programs may improve long-term outcomes after TAVI.Traditionally, the offered CR programs are center-based, with activities performed in hospitals, gymnasiums, or sports centers. Home-based CR programs have been introduced to increase participation given their easier access and lower costs.In patients with cardiac disease, home- and center-based CR are similarly effective in improving clinical status and health-related quality of life, and were shown to be safe . AdherenScarce evidence is presently available for home-based CR in high-risk populations, such is the majority of TAVI patients. It is reasonable to assume that even this subset of patients shows better adherence to home-based than center-based CR programs.Evidence is accumulating that high-risk and frail cardiac patients might benefit from a preventive enrolment in rehabilitation strategies before cardiac and thoracic surgery: the prehabilitation (prehab) ,38. At pSince patients undergoing TAVI at present time are, by definition, at higher risk than patients undergoing surgery, the possible role of a cardiac prehab is of rising interest. Two RCTs are ongoing to evaluate the benefit of multicomponent cardiac prehab in patients at higher risk for clinical events before TAVI: The Protein and Exercise to Reverse Frailty in Older Men and women undergoing Transcatheter Aortic Valve Replacement , and the Prehabilitation for Patients Undergoing Transcatheter Aortic Valve Replacement .Identifying patients at increased risk of poor post-procedural outcome and adverse long-term prognosis is of pivotal importance to optimize their clinical status before TAVI , to minimize peri-procedural risks , and, poFrailty is a geriatric syndrome that diminishes the potential for functional recovery after TAVI. Different tools have been proposed to evaluate it, and the Essential Frailty Toolset (EFT) has been found to be the most robust predictor of outcomes, among other frailty scales, in older patients undergoing SAVR and TAVR ,43. In tOn the spectrum of possibilities to improve clinical status before TAVI, a role for balloon aortic valvuloplasty (BAV) has been proposed. It could serve as a bridge-to-decision in patients with relative contraindications to TAVI, since improvement in mobility, New York heart association (NYHA) functional class, frailty, and left ventricular function have been described after BAV, allowing for definitive aortic treatment in up to 75% of high-risk cases ,46,47.CR is not currently recommended by the major American and European guidelines for patients undergoing TAVI. However, studies carried out over the last few years have proven that CR programs following TAVI are safe, improve patients’ exercise tolerance, functional independence, and quality of life. Moreover, preliminary data show a benefit on mid-term survival when CR is performed after TAVI, even if further and larger RCTs are needed for confirmation. Based on the existing literature, CR programs after TAVI (perhaps home-based), and intensified follow-up characterized by a multidisciplinary approach including medical care, exercise training, lifestyle advice, and psychological support, may be recommended.


Imaging serves a key role in the diagnosis of patients suspected of having idiopathic pulmonary fibrosis (IPF). Accurate pattern classification at thin-section chest CT is a key step in multidisciplinary discussions, guiding the need for surgical lung biopsy and determining available pharmacologic therapies. The recent approval of new treatments for fibrosing lung disease has made it more critical than ever for radiologists to facilitate accurate and early diagnosis of IPF. This document was developed by the Radiology Working Group of the Pulmonary Fibrosis Foundation with the goal of providing a practical guide for radiologists. In this review, the critical imaging patterns of IPF, pitfalls in imaging classifications, confounding imaging findings with other fibrotic lung diseases, and reporting standards for cases of lung fibrosis will be discussed.Published under a CC BY 4.0 license.White and Galvin in this issue.See also the commentary by  Understanding the imaging findings and patterns associated with idiopathic pulmonary fibrosis and other fibrotic lung diseases is a key task of radiologists that can substantially impact patient care.■ Thin-section CT including inspiratory, expiratory, and prone sequences is the most important imaging tool for the evaluation of pulmonary fibrosis.■ Categorizing the imaging pattern of fibrosis according to the Fleischner Society guidelines and/or American Thoracic Society guidelines is a critical role for the radiologist.■ Radiology reports should use recognized standard terminology and include supporting language to justify the fibrosis pattern diagnosed.■ Multidisciplinary discussion is the reference standard for diagnosis of diffuse fibrotic lung disease, and imaging plays a key role in these discussions.Interstitial lung disease (ILD) consists of several hundred separate diseases, each with sometimes unique, but frequently overlapping, patterns of lung injury at thin-section CT. This guide focuses on the key imaging findings and differentiators necessary to evaluate a patient for idiopathic pulmonary fibrosis (IPF). IPF is a progressive chronic interstitial fibrotic lung disease of unknown etiology . Risk faThe Pulmonary Fibrosis Foundation has developed a network of care centers to promote excellence in the management of IPF and other fibrotic lung conditions. As the field of pulmonary fibrosis continues to grow, this foundation has established working groups to provide views on topics important to the diagnosis and treatment of pulmonary fibrosis using published data and expert opinion. The Pulmonary Fibrosis Foundation formed a Radiology Working Group to provide a practical guide for radiologic diagnosis of fibrotic lung disease, based on recent evidence-based recommendations ,6.Chest radiography is frequently an initial screening test for ILD due to its wide availability and low radiation exposure to the patient. However, ILD, if mild or early in the disease course, is difficult to identify on chest radiographs. Normal radiographs were described in older literature (1970s) in 10%–15% of patients with ILD, and this number is probably higher in clinical practice today given advances in cross-sectional imaging to detect very mild or early disease . Chest rThin-section CT, in which images are reconstructed with thin sections and high-spatial-frequency algorithms, is recommended to optimally image the lung interstitium and to characterize parenchymal abnormalities. Technical factors used for the thin-section CT scanning protocol are important and can help prevent diagnostic errors when properly set ,3,6. WhiBecause the fine detail of the lung parenchyma is of paramount importance in thin-section CT scans, technologists should review scans immediately after acquisition and consider repeat scanning for any portions of the study that are compromised by patient or respiratory motion or inadequate inspiration ,3. RespiIn addition to inspiratory acquisitions, two additional scans—expiratory and prone acquisitions—are considered part of a “complete” thin-section CT. Unlike the inspiratory examination, the expiratory and prone images may be acquired with noncontiguous parameters to minimize radiation dose  .Expiratory sequences are specifically included to evaluate the presence of small airways disease. Air trapping at expiratory thin-section CT has been shown to correlate with obstructive deficits at pulmonary function testing, and the presence of small airways disease can substantially change the differential diagnosis (see discussion on mosaic attenuation). Ensuring that an adequate expiratory examination was performed is important to avoid false-negative findings. Proper CT technologist training and patient preparation can facilitate good expiratory scans. Expected CT findings on expiratory sequence include increased lung attenuation and decreased overall lung cross-sectional area. Additionally, anterior bowing of the posterior tracheal wall (the noncartilaginous portion) is frequently one of the easiest and most reliable signs of expiratory effort . If the Prone imaging is necessary in some patients to detect early or mild ILD. Dependent lung atelectasis is often present at supine inspiratory scanning, which can mimic mild subpleural reticular abnormality and ground-glass opacities ,3. Pronedata-driven textural analysis, linking machine learning techniques  with textural analysis to identify healthy and fibrotic lung at thin-section CT  or objective (quantitative) assessment method. In the subjective method, radiologists use a visual scoring system to grade the extent of the pulmonary fibrosis, which can then be correlated to clinical risk factors, including age, pretest probability, and pulmonary function tests, to assign a mortality risk assessment . While tction CT . The resMRI has limited value in the evaluation of ILD. MRI provides inadequate imaging of the lungs due to the relative lack of protons within the aerated lungs and air-induced artifacts. Additionally, the interstitium itself is at too small of a resolution to be visualized by available MRI techniques. Currently, thoracic MRI for evaluation of diffuse lung disease is limited to very specific pathologies for research purposes, such as cystic fibrosis and sarcoidosis ,16.(a) the airways , (b) lung parenchyma , (c) pleura, (d) mediastinum, (e) upper abdomen, and (e) musculoskeletal system. As the primary concern of this guide is IPF, the majority of this review will focus on the lung parenchyma. However, the extra pulmonary findings can sometimes provide key diagnostic clues or prognostic information for the patient’s underlying disease, especially in the setting of connective tissue disease (CTD)  .As already discussed, thin-section CT is the most sensitive radiologic examination to evaluate the lung parenchyma for evidence of ILD. The key anatomic components of the lung parenchyma that are evaluated for in IPF are the interstitium and secondary pulmonary lobule. The interstitium provides structural support to the lobule itself, and as such, diseases that distort the pulmonary interstitium result in distortion of the secondary pulmonary lobule. Although the axial interstitium surrounding the bronchovascular bundles is generally less important when evaluating for IPF, it may be important in other causes of pulmonary fibrosis. However, the peripheral interstitium and the intralobular interstitium are important in IPF. As such, when evaluating the lung parenchyma for IPF, abnormalities which predominantly affect these components lead to several key findings to evaluate . Their nreticulation, consists of a fine network or mesh of overlapping linear lines within the secondary pulmonary lobule  being more lower lung–predominant. This is the most common pattern observed in IPF. Other frequently used descriptors for disease distribution in the lungs include upper lung–predominant, mid lung–predominant, and diffuse  in which the increased opacity does not obscure the underlying bronchial and vascular structures (ructures  17). As. AsGrounConsolidation refers to an area of increased lung opacity (a process which completely fills the airspaces) in which the increased opacity does obscure the underlying vascular and bronchial structures (ructures  17). Co. CoConsoMicronodules are small rounded opacities, less than 3 mm in size, that can follow variable distributions within the lung parenchyma. A full distribution of nodular patterns is outside the scope of this work, but the presence of micronodules is important to note when classifying cases of possible IPF . Common Mosaic attenuation refers to a pattern of heterogeneous attenuation of the lung parenchyma at thin-section CT with generally well-defined geographic borders corresponding to the outlines of pulmonary lobules  suggest a diagnosis other than IPF. Cyst appearance and distribution can be quite useful for narrowing the differential diagnosis for diffuse lung diseases; however, this is beyond the scope of this guide . Lung cyOn thin-section CT scans, honeycombing appears as subpleural cystic air spaces, usually 5 mm or less in diameter, though sometimes as large as 1–2 cm, with well-defined walls. Honeycomb cysts typically share walls and occur in multiple layers, though early honeycombing may manifest as a single layer of subpleural cysts .Paraseptal emphysema appears as subpleural cysts or lucencies that can mimic honeycombing. However, paraseptal emphysema usually occurs in a single subpleural layer, with cyst size usually larger than 1 cm, and is often associated with centrilobular emphysema. Additionally, paraseptal emphysema generally has thinner walls than honeycomb cysts and also lacks the architectural distortion and reticular abnormality seen in association with pulmonary fibrosis and honeycomb cyst formation  18)..18).Traction bronchiectasis and bronchiolectasis can generally be separated from honeycombing by carefully examining contiguous thin-section CT sections and observing continuity and branching of bronchi and bronchioles rather than discrete honeycomb cysts . In someTraction bronchiectasis and bronchiectasis due to chronic inflammation and intrinsic airways disease should be distinguished. Traction bronchiectasis refers to airway dilatation caused by an underlying pulmonary fibrotic parenchymal abnormality that causes the bronchiectasis rather than an airway-centered process, such as chronic bronchitis, that leads to airway dilatation. Traction bronchiectasis generally lacks clinically significant wall thickening or mucoid impaction, and it is always adjacent to other findings of fibrosis, such as irregular reticular opacities, subtle ground-glass opacities, honeycombing, architectural distortion, and volume loss, which result in a “tethering” effect that causes the bronchiectasis  18)..18).familial fibrosis (fibrosis that has a genetic component including short telomeres and/or tends to run in families) which can manifest with a UIP pattern  with traction bronchiectasis or bronchiolectasis.2. Honeycomb cyst formation.3. Absence of features to suggest an alternative diagnosis.This is the classic pattern and has a predictive value of greater than 90% for histologic UIP  with traction bronchiectasis and bronchiolectasis.2. Absence of features to suggest an alternative diagnosis.This pattern was previously known as 1. Distribution of reticular abnormality not predominantly subpleural or not predominantly basal.2. May have some inconspicuous or minor findings that suggest an alternative, non-IPF diagnosis (as defined below). This would include a small amount of ground-glass opacity or a minor degree of air trapping seen in several lobules.In this pattern, the CT features are not sufficient for a firm diagnosis of UIP. About 50% of cases with this pattern have UIP .1. Upper- or midlung-predominant disease distribution (suggests HP).2. Areas of subpleural sparing with a peribronchovascular distribution .3. Significant findings typically found with non-IPF diagnosis .With this pattern, an alternative diagnosis should be strongly suggested. However, about 50% of cases with this pattern ultimately have UIP on histologic examination findings and a clinical diagnosis of IPF (example shown in ”).In radiologic reports, the specific alternative diagnosis  should be provided   ,6.Both the ATS/ERS/JRS/ALAT guidelines and Fleischner statement ,6 are evThe thin-section CT abnormalities of NSIP can overlap with UIP but are frequently visually distinct. The predominant abnormalities feature more ground-glass opacities with frequent underlying reticular abnormality and traction bronchiectasis . HoneycoAlthough classically thought of as upper lung predominant, the thin-section CT abnormalities of fibrotic HP can mimic UIP (including lower lung predominance) in upwards of 50% of cases . HoweverAll four stages of sarcoidosis tend to demonstrate an upper lung predominance at thin-section CT. Additionally, the fibrosis tends to demonstrate a more central or peribronchovascular distribution and radiate outward from the superiorly retracted hila with substantial upper lung volume loss, all features that should point toward a non-IPF diagnosis . One shoUpper lung–predominant fibrosis with substantial associated apical pleural thickening characterizes the rare condition of idiopathic pleuroparenchymal fibroelastosis . There iAccelerated deterioration or acute exacerbation of UIP and IPF typically manifests with a short prodrome of 1 to 2 months with progressive dyspnea or cough. Histopathologically, it represents diffuse alveolar damage and/or organizing pneumonia superimposed on UIP. As such, thin-section CT demonstrates bilateral ground-glass opacities and/or consolidations that mimic heart failure or opportunistic infection superimposed on the preexisting underlying fibrosis pattern . Understinterstitial pneumonia with autoimmune features to describe patients who have idiopathic interstitial pneumonia with findings from defined clinical, serologic, and morphologic domains that indicate an underlying systemic autoimmune process but who do not meet diagnostic criteria of a specific CTD. Suggestive radiologic patterns include the following: NSIP, organizing pneumonia, and lymphoid interstitial pneumonia , biopsy is necessary.CT pattern indeterminate for UIP or CT features most consistent with an alternative diagnosis.—Biopsy should be considered regardless of clinical scenario.(a) there is a progressive fibrosing interstitial pneumonia, and (b) there is no viable alternative diagnosis. Any such working diagnosis of IPF should be reviewed regularly.Biopsy is unavailable.—A working diagnosis of IPF can be established if When considering biopsy, it is important to remember that open lung biopsy is not without patient risk. Although some patients may need biopsy to confirm a confidence diagnosis, biopsy may not be appropriate on the basis of their risk profile. Also, biopsy may not be of benefit unless there are identifiable treatment changes that would be affected by confirming a diagnosis.1. Emphysema, which can be a confounding factor in patients with a UIP pattern at CT. The extent and relative severity should be reported, as it influences patient treatment and prognosis .2. Pleural effusion, esophageal dilatation, or pericardial abnormality, which regardless of confidence of UIP pattern should raise the possibility of underlying CTD.3. Hiatal hernia along with esophageal thickening or dilatation, which are important findings, as chronic aspiration is an underreported but common cause of fibrosis involving the basilar lungs and can also contribute to worsening fibrosis.4. Cardiac chamber and pulmonary arterial size, as the presence of pulmonary hypertension can be an important prognostic factor.5. Lymphadenopathy and pulmonary nodules, which are common findings with underlying ILD; however, a new or enlarging pulmonary nodule or enlarging lymph nodes should be critically considered, as the risk of developing malignancy (particularly lung cancer and lymphoma) is elevated in this patient population.Taking the above information into consideration, each report for evaluation of lung fibrosis should include the presence or absence of the features defined in the previous text, with the ultimate goal of identifying whether a UIP pattern is present and the interpreter’s confidence level . It is important to comment on the presence of new ground-glass opacities as well as to evaluate for disease progression, not only comparing with the most recent prior examination, but also with older studies (if available). Other commonly observed findings associated with IPF and other diffuse lung diseases should also be reported as they may frequently guide toward an alternative diagnosis such as the following:Please see In patients suspected of having pulmonary fibrosis, the initial steps in clinical work are to assess for any potential known causes of pulmonary fibrosis. As such, integration of this clinical information into the diagnostic process is key and when combined with the thin-section CT pattern present, frequently alleviates the need for invasive lung biopsies. Both the Fleischner Society guidelines and the ATS/ERS/JRS/ALAT IPF guidelines provide algorithms for approaching a diagnosis ,6. Thin-It is recommended that multidisciplinary diagnosis groups should consist of clinicians, radiologists, and pathologists with experience in ILD and be conducted in a face-to-face public forum format, with a teleconference format a reasonable alternative if an in-person conference format is impractical. These groups have been shown to improve patient outcomes on a case-by-case basis by reviewing hard-to-categorize clinical, radiologic, and histologic findings, especially important when there is discordant clinical, pathologic, and/or radiologic findings ,6. It haThin-section CT is the primary diagnostic imaging tool for initial categorization and follow-up imaging of IPF. As such, radiologists evaluating these cases should be familiar with the diagnostic criteria of the UIP pattern as well as the findings seen in other causes of pulmonary fibrosis. Understanding these imaging patterns greatly facilitates multidisciplinary discussions that serve as the reference standard for diagnosis and management of IPF.


An implant-supported crown represents an established and validated option for single-tooth replacement; however, a restorative solution should be selected according to a wide number of factors including patient's desire, expectations, specific clinical conditions, and financial possibilities. The aim of this case report is to describe a conservative rehabilitation strategy for the replacement of a periodontally compromised mandibular incisor: the extracted natural tooth was used as a pontic bonded to adjacent elements with polyethylene fiber and resin composite. This way, a chairside fabrication of a resin-bonded fiber-reinforced prosthesis is possible, using the patient's own tooth. After showing a satisfactory functional and esthetic result, advantages and pitfalls of this technique along with available data on the literature regarding the natural tooth pontic are addressed. Both patients and clinicians should be aware of minimally invasive, successful solutions for single-tooth replacement; whether indicated or necessary, the natural tooth pontic technique leaves open other treatment options for the future. The replacement of a single missing or failing tooth presents one of the greatest challenges in restorative dentistry, especially when the esthetic zone is considered . NowadayResin-bonded fixed partial dentures (RBFPDs) were first introduced into dentistry in the 1970s : their pHistorically, cast RBFPDs were produced exclusively using noble metals like high-gold alloys ; nowadayFiber-reinforced resin composites (FRC) have been widely adopted in dentistry , as direThe immediate bonding of a natural tooth to adjacent elements presents a low-cost alternative for direct tooth replacement , 17–19; The aim of this study is to describe a conservative rehabilitation strategy for the replacement of a periodontally compromised mandibular incisor: the extracted natural tooth was used as pontic, precisely repositioned with a customized index, and finally bonded to adjacent elements with polyethylene ribbon and resin composite. After case illustration, an analysis of available data in the literature related to NTP and associated outcomes will be addressed.A male, 55-year-old Caucasian patient presented at our private practice seeking treatment for increased tooth mobility at the lower right central incisor (tooth number 4.1). The medical history revealed a longstanding, drug-controlled type II diabetes mellitus and single-episode acute pancreatitis. The patient was a nonsmoker and had received some previous treatments in our office in the past; however, he demonstrated poor adherence to follow-up visits and maintenance care. Two panoramic radiographs Figures  were avaClinically, tooth 4.1 exhibited a deep probing pocket depth (PPD > 10 mm) on both mesial and distal sides, in association with class 2 mobility according to Miller's index  . GingivaDuring consultation, clinical problems related to the tooth and side effects associated to extraction without replacement were explained to the patient; his main desire was to preserve function and receiving at the same time a cost-effective treatment. In addition, the immediate prosthetic replacement at the stage of surgery was not a priority for the patient: an agreement for a delayed approach was reached (see next). Due to systemic and dental local conditions, a surgical plan based on implant-supported prosthesis (either immediate or delayed) was discarded; adjacent teeth were not affordable abutments for a traditional, fixed, definitive dental bridge.Despite a poor periodontal prognosis, the color, shape, and position of the lower central incisor were considered acceptable . According to the above considerations, a chairside fiber-reinforced composite bridge using the patient's own natural tooth as pontic was the selected therapeutic approach; informed consent was obtained.A preliminary prophylaxis for supra- and subgingival calculus debridement was scheduled: a single session, full-mouth disinfection with mechanical scaling and root planing was carried out one week before extraction. The spatial relationship of the hopeless tooth with adjacent incisors was recorded: a silicone-based, medium-consistency bite registration material  was directly applied on the lower anterior teeth (from canine to canine) and allowed to set . A transUnder local anesthesia, the lower central incisor was atraumatically extracted with forceps; the alveolar socket was carefully debrided/degranulated (with the aid of hand excavators) and finally rinsed with saline solution. 4-0 silk crossed sutures were used for gingival and clot stabilization; a postextraction radiograph was exposed Figures . After sA traditional endodontic access cavity was prepared; coronal pulp tissue was mechanically removed and chemically dissolved from the chamber to avoid later discoloration through decomposing of organic remnants. The root canal was instrumented using stainless steel manual K-files (up to ISO size #25), along with 5.25% NaOCL and EDTA irrigations. To prevent dehydration, the tooth was kept in saline solution until any further manipulation.Seven weeks after the extraction procedure, an uneventful healing of soft tissues was confirmed . The rooProper seating and proximal contacts of the natural tooth pontic were checked, along with the correct shade and texture integration before rubber dam application. The length of the polyethylene fiber  required for splinting was measured (with the aid of the previously fabricated silicone index) and cut: all four lower incisors were included. A relative coronal insertion of the fiber was selected to ensure adequate interdental cleaning  of periodontally compromised teeth. Following rubber dam isolation, a superficial groove was prepared on the lingual surfaces of the incisors  to inlay the splint (Ribbond™ Ultra thickness: 0.12 mm); a corresponding slot preparation was carried out on the natural tooth pontic at the same level of adjacent teeth. The lingual and proximal surfaces were conditioned with 35% phosphoric acid, rinsed, and dried thoroughly; a single-bottle, multipurpose, light-curing universal adhesive resin  was applied to etched preparations according to manufacturer instructions and light cured for 40 seconds. A thin layer of flowable composite resin  was applied to the grooves and proximal surfaces of adjacent teeth. Just before placement, the fiber was impregnated with the adhesive bonding agent; then, it was precisely adapted to the preparations with hand instrument—in order to obtain an excellent fit into the slots—and light cured from multiple directions (20 s per surface). The polyethylene fiber is adapted easily to dental contours and can be manipulated during the bonding process; a passive application prevented unintentional orthodontic movement of involved teeth. During flow and fiber placement, the pontic was maintained in a correct spatial relationship with adjacent teeth using the silicone index. A direct composite resin was finally placed and photopolymerized to completely cover the fiber and restore the lingual anatomy of the incisors . All marThe patient was recalled six months later; no fractures of the splint or pontic failure  were recorded during this period. A satisfactory esthetic integration with adjacent lower incisors is shown .When facing a lost mandibular anterior tooth, alveolar defects of the edentulous area, and/or periodontal disease of adjacent teeth might be present, making implant-supported or traditional FPD restorations more difficult. Our case report demonstrated the chairside fabrication of an FRC-prosthesis, using a natural tooth as pontic, that solution represents a minimally invasive approach for tooth replacement. In addition, the glass fiber composite splint was simultaneously used for stabilization of adjacent teeth with reduced periodontal support . AccordiLi et al. evaluated indirect (lab fabricated) glass fiber-reinforced RBFPD as periodontal splints to replace lost anterior teeth: a survival rate of 89% at the fourth year was found; the bleeding index scores and probing depths (mm) of adjacent teeth significantly improved from 1 year after the restoration to the end of the observation period . A chairFew data is available for the long-term survival/success of natural tooth pontic prosthesis. The mean follow-up period of published case reports on that topic is 1 year , 20; howA single-retainer, cantilever design has been suggested for traditional and all-ceramic anterior RBFPDs ; in factThe natural tooth pontic might be seated in a number of ways: flow or restorative composite without any additional reinforcement , metal wKnown limitations of resin-bonded prosthesis  are related to fractures of the framework/splint, exposures of the fiber, and partial/full debonding of the attached tooth; long-term wear, discoloration, microleakage, or secondary caries at the tooth-restorative interface are also possible. Despite common adhesive techniques can be used for intraoral repairings or reluting, these complications imply additional interventions (repairings or substitution), costs, and sometimes unscheduled appointments at the office. According to Graetz et al., 75.3% of splinted teeth in periodontitis patients required repair (from zero up to three repairs/splint/year), highlighting potential frequent interventions in the long term . Next stDespite the limitations of our study, an excellent functional, esthetic, mid-term result has been achieved adopting a minimally invasive restorative solution for single-tooth replacement; whether indicated or necessary, the natural tooth pontic technique leaves open other treatment options for the future.


Postprandial plasma glucose and triglyceride concentrations are predictive of relative cardiovascular disease (CVD) risk, and the pathogenesis of both insulin resistance and atherosclerosis has been attributed to acute states of hyperglycemia and hypertriglyceridemia. Postprandial lipemia and hyperglycemia suppress vascular reactivity and induce endothelial dysfunction. Epidemiological studies suggest that chronically-high consumption of milk and milk products is associated with a reduced risk of type 2 diabetes, metabolic syndrome, and CVD. The addition of dairy products to meals high in carbohydrates and fat may lessen these risks through reductions in postprandial glucose and triglyceride responses. Purported mechanisms include dairy proteins and bioactive compounds, which may explain the inverse relationship between dairy consumption and cardiometabolic diseases. The current review evaluates the available literature describing the relationships between metabolic dysfunction, postprandial metabolism, and vascular dysfunction and discusses the potential role of milk and dairy products in attenuating these impairments. Traditionally, fasting plasma glucose and triglyceride concentrations have been used as clinical determinants of CVD (cardiovascular disease). However, as most individuals spend the majority of their awake and ambulatory time in a postprandial state, acute responses in plasma glucose and triglycerides following a meal have been shown to be better predictors of relative CVD risk than fasting measures ,2,3. EpiThe pathogenesis of both insulin resistance and atherosclerosis has been attributed to acute states of hyperglycemia and hypertriglyceridemia. Indeed, postprandial hyperglycemia and hypertriglyceridemia are associated with increased risk of CVD and mortality ,6,7,8. EEpidemiological studies suggest that chronically-high consumption of milk and milk products is associated with a reduced risk of type 2 diabetes ,15,16, mIn the past, clinical evaluation of hyperglycemia and hypertriglyceridemia as a predictor of CVD and mortality has utilized fasting measures. In more recent years, it is becoming increasingly well accepted that atherosclerosis is a postprandial phenomenon . Most huPrecise matching of glucose utilization with endogenous glucose production and dietary glucose delivery is required for maintenance of normal plasma glucose concentrations. In a fasting state, plasma glucose concentration is maintained relatively stable as a tightly-regulated physiological variable . After aAn intervention study using participants with impaired glucose tolerance determined whether an intervention to limit postprandial hyperglycemia would reduce the risk of CVD . AcarbosThe response of insulin following a meal is highly variable and depends on a number of factors, including timing, quantity, and composition of the meal, as well as the rate and degree of glucose absorption. The postprandial insulin response is also attributed to the secretion of insulinotropic amino acids as well as enterogastric incretin hormones . GLP-1 and GIP are secreted from enteroendocrine cells in a nutrient-dependent manner and their release stimulates glucose-dependent insulin secretion via binding to their distinct receptors on the pancreatic β-cells to stimulate insulin secretion. Both incretins promote expansion of β cell mass by stimulating β cell proliferation and inhibiting apoptosis . GIP andAcute hyperglycemia, independent of insulin levels, significantly attenuates forearm endothelium-dependent, but not independent, vasodilation in healthy humans . In bothThere are a number of other ways that hyperglycemia could influence vasculature. Thrombin is a molecule involved in the coagulation cascade, alterations of which are linked to thrombosis . PostpraLipoprotein lipase (LPL), present on the luminal side of endothelial cells, is responsible for the hydrolysis of triglycerides into glycerol and free fatty acids. After consumption of a high-fat meal, chylomicrons carry triglyceride through the vasculature where fatty acids are liberated by lipoprotein lipase and taken up by surrounding adipose and muscle cells . TriglycThe magnitude of postprandial plasma lipid increase is directly proportional to the fat content in meals ,52,53. AEndothelial dysfunction is present in states of hypertriglyceridemia and hypercholesterolemia and is attributed in large part to reduced bioavailability of NO . Though Acute hypertriglyceridemia induced by a high-fat meal correlates positively with changes in leukocyte production of reactive oxygen species. These changes are not seen with a low-fat meal, indicating that acute hypertriglyceridemia causes endothelial dysfunction via enhanced oxidative stress that reduces NO bioavailability . HyperchConsidering that for most individuals in modern society, a majority of time is spent in a postprandial state, identification of treatments that moderate or attenuate postprandial hyperglycemia and hypertriglyceridemia is critically needed. Lifestyle modifications, including dietary interventions, offer an affordable and easily implemented alternative to pharmacological interventions.Bovine milk is comprised of approximately 87% water, 4–5% lactose, 3% protein, 3–4% fat and less than 1% of vitamins and minerals combined. Milk supplies 32 g of protein per liter. Of the milk protein fraction, 20% is whey, a soluble protein, and 80% is casein, an insoluble protein. Both are considered high-quality proteins because they provide essential amino acids, are readily digested, and have high bioavailability. These two protein fractions differ in their amino acid profile. Whey protein is rich in branched chain amino acids whereas casein is higher in histidine and phenylalanine. The fat fraction of milk, present as globules, is dependent on animal origin, stage of lactation, and feed-related factors. Typically, the fat found in milk is comprised of 98% triglycerides, of which 70% is saturated fatty acids  and 30% is unsaturated fatty acids . Lactose, the carbohydrate found in milk, is a disaccharide sugar comprised of galactose and glucose. The glycemic index of lactose is 45 compared with the reference 100 for glucose. In addition to the primary macronutrient composition, dairy products have a specific micronutrient composition including calcium, magnesium, and vitamin D .Both epidemiological and prospective studies indicate that chronic consumption of dairy exhibits a protective effect in preclinical populations. A diet including high consumption of dairy products show lower chances of having prediabetes, undetected diabetes, or prevalent diabetes, compared with a Western diet . For indBeyond preclinical states, chronic dairy consumption is associated with a reduced risk of type 2 diabetes and CVD ,15,16,74Dietary intervention studies investigating the effects of milk or dairy products and glucose response indicate a wide range of effects, likely due to the different types of dairy utilized. In a six-week randomized cross-over trial, participants replaced 13% of their daily energy intake with either butter or cheese of equivalent fat content . CompareThe effects of dairy on postprandial metabolism indicate that milk elicits favorable effects on glucose metabolism both alone or with a meal. In a well-designed randomized cross-over study , whole mThe majority of intervention studies examining postprandial metabolism and dairy employed milk-derived proteins, specifically whey protein. The incremental AUC for glucose decreased in a dose-dependent manner with the highest dose of whey protein supplement having a significantly greater effect than lower doses on postprandial hyperglycemia from a glucose drink . SimilarDairy products appear to have favorable effects on post-consumption glycemia independent of insulin . Milk prThe effects of regular dairy consumption on lipid profiles has been examined in the literature ,92,93. WIn a 10-year longitudinal study, a higher intake of dairy saturated fatty acids was associated with a lower CVD risk compared with a higher intake of saturated fat from meat products . InteresThe available studies show conflicting results regarding milk protein’s effects on lipid profiles. Whey protein isolate supplementation over 3 months reduced fasting triglycerides, total cholesterol, and LDL cholesterol concentrations in overweight and obese adults . A similPostprandial triglyceridemia is strongly influenced by the composition of the meal, including the quality and quantity of fat. To date, there are few studies examining the role of complete dairy products on postprandial metabolism ,21,100. In general, intervention studies examining the effects of dairy intake suggest favorable effects on vascular function. A recent scoping review reported that proteins derived from milk are common interventions for prediabetes and that significant improvements in brachial artery flow-mediated dilation and oxidative stress markers are observed without any evidence to support the benefit of milk proteins on insulin or lipid profiles . In the In a two-month study examining the effects of lactotripeptide supplementation (isolated from sour milk) with or without exercise on vascular functions in postmenopausal women, lactotripeptide supplementation, alone and with concomitant aerobic exercise, reduced arterial blood pressure, improved a measure of endothelium-dependent vasodilation, and reduced central artery stiffness ,109. A oSolitary addition of conventional non-fat dairy products to the routine diet reduces blood pressure and improves vascular function in middle-aged and older adults with elevated blood pressure ,112. HowDespite the beneficial effects of the bioactive peptides derived from milk proteins, only a limited number of research studies have been conducted investigating vascular effects during the postprandial state with milk or milk proteins. Previous studies in adults with prediabetes reported that dairy milk, presumably mediated by its protein content, attenuates postprandial hyperglycemia-induced impairments in vascular endothelial function by limiting oxidative stress . These eThe acute vascular effects of dairy in a postprandial setting have been minimally investigated, but the overall findings suggest a favorable response. The potential for dairy to limit postprandial impairments in FMD indicates significant therapeutic applications for at-risk individuals. However, the investigations into the vascular effects of dairy are still in an early stage and mechanisms of action have yet to be fully determined.Of the milk protein fraction, 20% is whey and 80% is casein. Whey and casein differ in their amino acid profile and while both are readily digestible, casein is digested more slowly. Whey protein is a soluble protein whereas casein, an insoluble protein, clots in the stomach causing a delay in gastric emptying and results in the slower release of amino acids through the gastrointestinal tract . Whey anThe beneficial effects of milk, as seen in cross-sectional and epidemiological studies ,92,93,94The suggested mechanisms for improved glucose regulation include a protein-induced increase in insulin concentration when milk products are added to a meal high in carbohydrates. The high amino content, in particular branched chain amino acids (BCAA), may modulate glucose levels by increasing postprandial insulin secretion. Interestingly, whey hydrolysate elicits higher insulin responses compared with whole milk  and intaThe available studies investigating dairy-derived proteins suggest a cardioprotective effect in preclinical populations. For instance, proteins derived from milk are common interventions for prediabetes since significant improvements have been observed in oxidative stress markers and glucose metabolism, especially postprandial glucose and glycated hemoglobin A1c (HbA1c), without any improvements of insulin profiles . A proprWhey protein reduces acute postprandial glucose response in healthy adults and those with type 2 diabetes ,127,128.The effect of casein on glucose metabolism is not as well studied as the effects of whey protein. While both whey and casein exhibit insulinotropic properties in healthy participants, whey is a more potent insulin secretagogue than casein . In indiPostprandial triglyceridemia is a characteristic of type 2 diabetes. But dairy proteins can modify these metabolic responses. For instance, compared with 20 g whey protein consumed with a high-fat meal, pre-meal protein intake (20 g whey protein) before a fat-rich meal increases hormone secretion  and delays gastric emptying, but does not influence lipid or glucose responses, in individuals with and without type 2 diabetes . CompareA recent controlled, randomized clinical trial made an attempt to discern the role of milk protein in regulating postprandial hyperglycemia . In indiWhile the protein content of dairy is typically the primary constituent associated with reductions in glycemia, evidence is emerging that points to dairy’s fat content as a potential contributor. In a cross-sectional study of Brazilian adults, the intake of total dairy was inversely associated with fasting glucose and postprandial glucose concentrations after adjusting for covariates. Interestingly, myristic acid (14:0), a long chain saturated fatty acid found in dairy foods, was the only apparent nutrient to mediate the association between dairy intake and glycemia, indicating that this saturated fatty acid may play an important role in improving glucose homeostasis . This fiIn addition to the aforementioned potential mechanisms of protein and fat in altering metabolism, dairy also contains a number of bioactive compounds with functional properties. The combined vitamin and mineral contents comprise less than 1% of milk, but this rather small volume is capable of eliciting significant metabolic effects. A systematic review and meta-analysis found that vitamin D status, calcium, and dairy intake are all inversely associated with type 2 diabetes and metabolic syndrome . This meThe leading food source of vitamin D in the American diet is fortified cow milk, which contains ~100 IU/8 oz . EvidencThe high calcium content and lipid fractions in dairy may benefit the serum lipid profile. Nearly half of the calcium in the American diet is from dairy . SeveralMagnesium has also been proposed as a significant mediator in postprandial metabolism. Upwards of 10% of the magnesium in the American diet comes from dairy . Data frDairy’s micronutrient profile offers significant potential for favorable effects on the cardiometabolic profile. As with the insulinotropic effects of milk proteins, evidence suggests that these micronutrients offer their greatest benefits to individuals who are either deficient in the respective vitamin or mineral or who are farther along the spectrum of disease progression. However, their mechanisms of action have yet to be fully described as no study is yet to determine the role of dairy’s micronutrients in a controlled intervention trial.The available literature describing the relationships between metabolic dysfunction, postprandial metabolism, and vascular dysfunction recognizes the role of milk, specifically milk proteins, in reducing these clinical risk factors. Milk and milk products are associated with a reduced risk of cardiometabolic diseases, and the addition of dairy products, in particular dairy proteins, to meals high in carbohydrates and fat may potentially lessen these risks through reductions in postprandial glucose and triglycerides. The mechanisms of these effects are attributed in part to the functional properties of several bioactive compounds found in dairy as well as the insulinotrophic properties of dairy proteins. Increased insulin production stimulates vasodilation which may serve to increase limb blood flow and capillary recruitment for nutrient disposal thereby facilitating the clearance and storage of glucose and triglycerides after a meal. The resultant clearance of glucose and triglycerides may lead to an attenuated impairment of postprandial vascular dysfunction and reduced risk of cardiometabolic diseases. The available literature suggests that the addition of milk may be an easily implemented means of reducing elevations in postprandial hyperglycemia and hypertriglyceridemia and resultant metabolic dysfunction from consuming a high-fat or high-carbohydrate meal.


Continued expansion of the chemical biology toolbox presents many new and diverse opportunities to interrogate the fundamental molecular mechanisms driving complex plant–microbe interactions. This review will examine metabolic labeling with click chemistry reagents and activity-based probes for investigating the impacts of plant-associated microbes on plant growth, metabolism, and immune responses. While the majority of the studies reviewed here used chemical biology approaches to examine the effects of pathogens on plants, chemical biology will also be invaluable in future efforts to investigate mutualistic associations between beneficial microbes and their plant hosts. A diverse array of chemical biology tools and approaches has been developed for investigating biological questions in a wide variety of systems, spanning single-cell organisms to plant and animal models, as well as humans. Increasingly, researchers are delving into systems of higher and higher complexity, including microbiomes containing hundreds to thousands of different species, many of which have not yet been identified. Given this ongoing exploration, the flexible and versatile chemical biology toolbox offers unique opportunities to elucidate biological processes even in poorly characterized systems, such as gut and soil microbiomes ,2,3.The critical role that the plant microbiome plays in plant health is well-recognized, but we frequently lack a fundamental understanding of plant–microbe interactions at the molecular level. Microbes can be found in all regions of the plant, including the roots, stems, leaves, and seeds. Microbes may colonize tissue surfaces (epiphytes), but may also be present within plant tissues (endophytes) ,5. The sAt the heart of plant–microbe interactions are chemical and biochemical signals, ranging from nutrient sensing and acquisition, to growth and development, to defense and immune responses ,11. As aThis review will survey click chemistry reagents for metabolic labeling and activity-based probes (ABPs) that have been used for interrogating plant-microbe interactions . The exaChemical biology has relied upon bioorthogonal reagents and reactions to investigate a diverse range of systems, with ongoing exploration of new strategies and chemistries that are compatible with the biological milieu ,17,18. AMetabolic labeling of plants and microbes using bioorthogonal click chemistry reagents has led to the development of a broad range of tools, including synthetic analogs of monolignols ,21,22,23Arabidopsis seedlings followed by click chemistry to attach fluorophores for fluorescence imaging, time-dependent distribution of the labeling in root cells was observed. Anderson and coworkers determined that a significant amount of the FucAl was incorporated into pectic rhamnogalacturonan-I (RG-I). This labeled RG-I first localized to punctae in cell walls  with subsequent copper-catalyzed alkyne-azide cycloaddition (CuAAC) to attach a fluorophore to the alkyne label. Simon and coworkers used this technique to achieve labeling of flax stems and roots, noting that the fluorescent labeling was most intense in the outermost layers of the secondary xylem actively undergoing lignification H 23]. A. A23]. AMetabolic labeling of proteins using bioorthogonal noncanonical amino acid tagging (BONCAT) has been applied in both plant tissues and soil microbial communities to investigate protein synthesis under various conditions and identify metabolically active community members from complex microbiome samples ,28. AzidArabidopsis thaliana by Paper et al. . Fa. Fa30]. Arabidopsis thaliana, only ~77% of the protein-coding sequences have been assigned structured annotation [The growing application and potential of activity-based probes (ABPs) in plant sciences has been well reviewed by Morimoto and van der Hoorn . Since Anotation , while fnotation ,40,41. IABPs have been developed for diverse enzymatic activities and protein targets . ABPs foNicotiana benthamiana infected with bacterial pathogen Pseudomonas syringae. ABPP of apoplastic fluids showed a ~19-fold decrease in JJB70 labeling of BGAL1 in infected plants compared to controls  involved in plant immune response, by the subtilisin class of serine proteases . DCG-04,Candidatus Liberibacter asiaticus (CLas), which causes Huanglongbing, also known as citrus greening disease [Heterodera schachtii in Arabidopsis [Ralstonia solanacearum [Cladosporium fulvum [A number of other studies have demonstrated the utility of protease ABPs in diverse systems, highlighting the broad applicability of these chemical tools for investigating plant–microbe interactions. A recent study by Franco et al. demonstrated the use of the FP-TAMRA probe for visualizing changes in serine protease activities in citrus infected with the bacterium  disease . Previou disease . Anotherbidopsis . Vacuolabidopsis  and seribidopsis . Similarnacearum . ABPs hanacearum  and enzym fulvum ,53. AlthAlthough chemical biology is making significant strides forward into systems of increasing complexity, challenges remain ahead for researchers applying these chemical tools to plant-microbe systems.One of the greatest challenges in the future study of plant–microbe interactions is the increasing need to connect laboratory studies to the field. Many of the studies highlighted in this review were performed on aerial plant tissues or in plants grown in artificial substrates. Unsurprisingly, there are far fewer examples of chemical biology investigations of plant roots in natural soils, despite the abundance of biological activity occurring in the rhizosphere. Soil is incredibly complex in both its physical and chemical properties; it is notoriously difficult to sterilize , and it Models for plant–microbe interaction studies often rely on artificial growth substrates, including hydroponic, semihydroponic, and gel-based growth media that can be sterilized, making axenic plant and microbe cultures possible. Separation of delicate plant roots from these substrates during sampling is often easier than isolating roots that have been grown in natural soils. However, artificial substrates often dramatically alter root morphology in plants ; althougContinued progress in soil microbiome research will also contribute to improved models for studying plants and their associated microbiomes, including expansion of single strain models to microbial consortia to communities . UltimatUniform application of chemical tools to plant tissues remains a significant complication. Given the intricate spatial organization of specific cellular types in plant tissues, in vivo labeling would be ideal, but the robust barriers presented by plant cells and tissues makes it difficult to predict passive or active uptake of a probe compound. Syringe infiltration or simple bath application can be used for introducing probes to live, intact plant tissues, although achieving equal exposure of all cells to the probe during in vivo labeling is challenging . When apDelivery of chemical probes in aqueous solution may also pose a challenge for investigating drought-related changes in plants. Buffers containing polyethylene glycol (PEG) or mannitol have been used previously to trigger osmotic stress in plants to simulate drought stress; this strategy was used by Glenn and colleagues to examine changes in protein synthesis via BONCAT .Exploration of new delivery methods for probes targeted to above and below ground tissues may provide additional opportunities for probing intact tissues. Fichman, Miller, and Mittler have developed a fumigation approach wherein fluorescent indicators for reactive oxygen species were nebulized and taken up by plant leaves and stems . This teThe technologies and approaches summarized in this review are only a small selection of the chemical biology tools available for probing complex interkingdom interactions. In conjunction with genetic and biochemical analyses, these tools will continue to improve our understanding of plant-microbe systems. While much of the work in this review has focused on pathogenic bacterial and fungal interactions with plants, future efforts to understand plant growth-promoting microbes may also benefit from the use of these and other chemical biology tools.Additional development of chemical probes for key signaling molecules and phytohormones is still needed to better understand plant–microbe interactions, particularly beneficial interkingdom relationships. Already, applications of clickable N-acyl-homoserine lactone (AHL) analogs , auxin a


Research should also integrate novel knowledge on the mechanisms and constraints guiding the impact of electrical and magnetic fields on cerebral tissues and brain activity, and incorporate the principles of information-based neurostimulation.Low birth rates and increasing life expectancy experienced by developed societies have placed an unprecedented pressure on governments and the health system to deal effectively with the human, social and financial burden associated to aging-related diseases. At present, ∼24 million people worldwide suffer from cognitive neurodegenerative diseases, a prevalence that doubles every five years. Pharmacological therapies and cognitive training/rehabilitation have generated temporary hope and, occasionally, proof of mild relief. Nonetheless, these approaches are yet to demonstrate a meaningful therapeutic impact and changes in prognosis. We here review evidence gathered for nearly a decade on non-invasive brain stimulation (NIBS), a less known therapeutic strategy aiming to limit cognitive decline associated with neurodegenerative conditions. Transcranial Magnetic Stimulation and Transcranial Direct Current Stimulation, two of the most popular NIBS technologies, use electrical fields generated non-invasively in the brain to long-lastingly enhance the excitability/activity of key brain regions contributing to relevant cognitive processes. The current comprehensive critical review presents proof-of-concept evidence and meaningful cognitive outcomes of NIBS in eight of the most prevalent neurodegenerative pathologies affecting cognition: Alzheimer’s Disease, Parkinson’s Disease, Dementia with Lewy Bodies, Primary Progressive Aphasias (PPA), behavioral variant of Frontotemporal Dementia, Corticobasal Syndrome, Progressive Supranuclear Palsy, and Posterior Cortical Atrophy. We analyzed a total of 70 internationally published studies: 33 focusing on Alzheimer’s disease, 19 on PPA and 18 on the remaining neurodegenerative pathologies. The therapeutic benefit and clinical significance of NIBS remains inconclusive, in particular given the lack of a sufficient number of double-blind placebo-controlled randomized clinical trials using multiday stimulation regimes, the heterogeneity of the protocols, and adequate behavioral and neuroimaging response biomarkers, able to show lasting effects and an impact on prognosis. The field remains promising but, to make further progress, research efforts need to take in account the latest evidence of the anatomical and neurophysiological features underlying cognitive deficits in these patient populations. Moreover, as the development of  Due to low birth rates and increasing life expectancy, developed societies are facing rapid population aging. Consequently, health systems have to deal with dramatic increases of the incidence and prevalence of cognitive decline and aging-related diseases mainly due to neurodegenerative pathologies, which significantly impact daily life .It has been estimated that about 24 million people worldwide suffer from cognitive neurodegenerative diseases , and thegamified mind training software  based on Transcranial Magnetic Stimulation (TMS) or transcranial Direct Current Stimulation (tDCS) have been shown to enable plastic reorganization processes. On that basis, they have been extensively used for more than a decade on healthy participants to explore the modulation of various cognitive processes. Moreover, NIBS has been applied therapeutically to improve abnormal brain function in several conditions, including neuropsychiatric disorders such as depression . We will then present the main clinical, anatomical and physiological features of seven relevant neurodegenerative diseases affecting cognition, which have been explored or treated with NIBS approaches: AD, Parkinson’s Disease (PD), Dementia with Lewy Bodies (DLB), Primary Progressive Aphasias (PPA), behavioral variant of Frontotemporal Dementia (bv-FTD), Corticobasal Syndrome (CBS), Progressive Supranuclear Palsy (PSP), and Posterior Cortical Atrophy (PCA). For each of these diseases, we will present the state of art on exploratory or therapeutic TMS/tDCS investigations aiming at modulating cognitive impairments, and discuss the consistency and relevance of such evidence. Finally, using the framework of so-called mulation , we willThe two most commonly employed noninvasive technologies to modulate cortical activity in neurodegeneration are TMS and tDCS.Transcranial Magnetic Stimulation is a focal brain stimulation technology, using brief-lasting magnetic field to painlessly convey electrical current into a brain cortical area. Such current has a sufficient intensity to trigger action potentials in the stimulated region. Developed by Anthony Barker in the mid-eighties, it was initially used to estimate pathway integrity and measure central conduction times in the cortico-spinal tract . Since tonline and offline Electroencephalography  recordings  to localize or map cortical function representations, double (or paired) pulse TMS (dTMS) to study intracortical local or distant modulatory mechanisms or repetitive TMS (rTMS) patterns to lastingly modulate activity beyond the duration of stimulation  tend to remain active for at least half of the stimulation time, and their duration depends strongly on the temporal organization of the TMS pulses, the targeted cortical site, and also the behavioral measure chosen to evaluate the impact (Depending on pulse frequency and following long-term potentiation (LTP) or long-term depression (LTD)-like phenomena , rTMS hae impact . Importae impact , openingThe relevance of TMS in research, diagnostic or therapeutic applications is based on its excellent focality, particularly for well-identified cortical targets see . It is aSham approaches are generally used in basic and clinical research to ensure that the observed effects are caused by the intended neural activity manipulation and not by other potental side, or placebo, effects. Sham conditions in TMS refer to any approach that aims at mimicking the auditory and/or somatosensory effects of active stimulation without delivering active stimulation to the brain . The delactive (anode or cathode) and a return electrode placed on distant regions of the skull . This recent approach has shown an ability to entrain oscillatory activity and promote frequency-dependent synchrony effects across large brain networks, favoring frequency specific synchrony . Both tA2). Nonetheless, individual anatomical features such as skull shape, cortical thickness, cerebrospinal fluid volume, and cortical surface topography can influence tDCS spatial distribution patterns even more largely , with wide current dispersion . Nonethe largely .The strongest assets of tDCS compared to TMS are its low cost, an outstanding safety profile [side-effects are limited to local tinkling and/or an itching sensation under the active electrode ], its poThe use of rTMS or tDCS for improving brain function is currently developing around two main strategies: (1) to enable increases of cortical excitability within areas of interest hosting specific cognitive operations ; and/or (2) to suppress networks (likely via LTD-like processes) in damage-spared brain areas that under normal conditions interfere performance . The lattranscranial direct current stimulation in Alzheimer’s disease,” with the terms in italics  AND “neurodegenerative disease” or “dementia” or “cognitive functions” or “cognition” or “Alzheimer’s disease” or “Parkinson’s disease” or “Levy body dementia” or “primary progressive aphasia” or “semantic dementia” or “frontotemporal dementia” or “posterior cortical atrophia”. Search queries were as follows: “1.Articles published in English.2.Articles that appeared in peer-reviewed journals or in conference publications.3.Articles published until September 23, 2020 (last search date).We excluded studies which did not present original research, did not specify statistic analysis for each specific population when mixed populations were included or did not include the analysis of NIBS impact on cognitive deficits or cognitive functions, either as thir primary or secondary outcome.1 was used. Information about the published studies is reported in After review of all studies we extracted (i) population and sample size, (ii) stimulation type and parameters, (iii) stimulated brain regions, (iv) presence/absence of a sham condition, (v) study design vi) presence/absence of tasks during the stimulation period and vii) outcome measures and results. To rate the relative strength of the results obtained by each study and their therapeutic evidence, the Classification of Evidence Schemes- Criteria for Rating Therapeutic StudiesIn the following subsections, we will briefly present the most frequent neurodegenerative diseases affecting cognition which have been the object of exploratory or therapeutic NIBS, and we will provide a synthesis of the results/effects of NIBS in these diseases. It is important to acknowledge that each of the neurodegenerative diseases covered by this review could be impacted by cerebrovascular damage, a pathological process which operates as a “disease-modifier,” impacting the evolution of the neurodegenerative disease , that maWith prevalence levels estimated around 3.9% after 60 years of age  AD is thEvidence supporting brain plasticity in individuals at risk for developing AD has steered the evaluation of NIBS (TMS and tDCS) aiming to promote plasticity on specific neural systems in AD populations . Small cAnodal stimulation delivered over right  and leftInterestingly, seven TMS/tDCS studies in AD associated neurophysiological biomarkers for stimulation impact (EMG responses to TMS or EEG recordings) to cognitive assessments with diverse outcomes. n = 129), showed stronger improvements in mild AD patients (ADAS-Cog < 30) compared to more severely affected patients (Adas-Cog > 30). However, as the authors note, only 15% of the whole cohort belonged to the more severily impacted group and so these results should be taken carefully . They suggested efficacy of rTMS/tDCS within a limited window of clinical severity, with high clinical response in mild to intermediate rather than severe levels of impairment. For example, whereashigh frequency rTMS improved significantly MMSE and IADL scores in patients with mild to moderate AD, identically treated patients with severe AD did not respond to stimulation . Severitarefully .Alzheimer’s disease is the neurodegenerative disase in which NIBS has been most widely evaluated, with a total of 31 published studies  . Five reConsidering evidence collected for the last 10 years, high frequency rTMS and anodal tDCS delivered for at least 2 weeks have the potential to improve cognitive function in patients with AD, maximizing performance and containing the progression of cognitive decline. However, no solid evidence supports the ability of these approaches to tackle the physiopathological basis of this condition and eventually stop its course. The rapid progression combined with the broad distribution of cortical damage in AD poses a difficult scenario for these techniques. NIBS might prove either too focal (TMS) or not sufficiently intense (tDCS), and difficult to combine actively with rehabilitation, given the poor level of compliance of these clinical populations. Awaiting additional studies particularly at prodromal or early AD stages, the field has focused towards testing NIBS approaches in early onset and more focal forms of neurodegenerative diseases, in which they might prove more successful.substantia nigra (pars compacta)  . Additioompacta) .The large majority of rTMS studies in PD patients have focused on treating motor disabilities. Despite a focus on motor symptoms, a growing body of evidence has shown the benefit of NIBS to treat cognitive dysfunction in PD. Five other independent tDCS studies tested the impact of: (a) 10 consecutive sessions of anodal stimulation over the right and the left DLPFC ; (b) 4 wTwo additional tDCS studies in PD patients reported working memory improvements lasting for at least one month  or 2 monThe only study that applied rTMS and measured its impact on cognitive outcomes suggests that this technique might impact cognitive abilities in PD. The outcomes of the seven studies that have applied tDCS to improve cognition in PD indicate that tDCS may induce changes in working memory, attention and verbal fluency, whereasthe most relevant effects appear to be generated with left DLPFC stimulation. All of these studies showed positive outcomes, a result that should encourage further research in this condition if possible combined with neuroimaging or physiological measures.substantia nigra and brainstem nuclei combined this time with cortical and limbic system damage , logopenic (lv-PPA), and nonfluent/agrammatic PPA (nfv-PPA). Sv-PPA is linked to damage to the anterior tempoal lobes (ATL) with a left hemisphere predominance   , 2016. Tulation)  and the ulation) . Taken tulation) , naming ulation) , grammarulation) , auditorulation) . For somulation) . InteresIn sv-PPA, a recent double-blind cross-over pre-therapeutical trial compared the impact of single sessions of anodal or cathodal tDCS over the left and right ATL, respectively, with sham tDCS. It showed beneficial effects on a verbal semantic association paradigm after both active  tDCS strategies . NeuronaTogether with AD, the three PPA variants are among the neurodegenerative diseases accruing the highest number of reports with 19 studies . Eleven of these studies used either very small cohorts (less than 10 patients) and/or explored non-homogenous cohorts of patients mixing several PPA variants. Surprisingly, only two studies employed supportive neuroimaging   and anotThe bv-FTD is an early onset neurodegenerative disease, characterized by apathy, diminution of social convenience, impulsivity and disinhibition . PatientOnly 4 studies have thus far addressed the impact of NIBS on cognitive symptoms in bv-FTD. A decade old pilot study failed to detect effects on verbal fluency task of active anodal versus sham tDCS over the left prefrontal area delivered during 20 minutes . In contDue to the lack of significant effects of the first tDCS study in a cohort of bv-FTD patients , the useThis syndrome is part of the Frontotemporal Lobar Degeneration spectrum . With anDespite promising resultsfrom a single study, indications for non-invasive stimulation in CBS remain to be further tested and developed.Progressive Supranuclear Palsy affects relatively young patients often before 65 years . Its mosTo date only three studies have been carried out to rehabilitate cognitive dysfunction via NIBS. A pre-clinical study evaluated the effects of left anodal DLPFC tDCS and right cathodal DLPFC tDCS, compared to sham stimulation on language impairments. Stimulation enabled significant improvements in a category judgment task with cathodal tDCS and a verbal fluency task with anodal tDCS . AnotherIn view of rTMS or tDCS preliminary evidencecoming from other neurodegenerative diseases and from only two tDCS studies, these techniques may have the potential to improve motor symptoms and also language impairments in PSP patients. Nonetheless further studies using periodical stimulation regimes combined with behavioral and physiological measures are now necessary to confirm such promise.Posterior Cortical Atrophy impacts relatively young patients in their mid-50s or early 60s. Its most frequent deficits are visuospatial and visuo-perceptual impairments , and it Only one study explored the effects of NIBS in a single case of PCA . After 3Patients with PCA are rare, hence hard to study in large numbers. However, the early age of onset, the atrophy impacting focally parietal and occipital lobes, their spatially-specific gradient of clinical progression, and the rich evidence on rTMS/tDCS effects in perception and spatial attention, make them suited for NIBS interventions.The current review of NIBS studies shows that rTMS and tDCS have been evaluated quite extensively for the improvement of cognitive impairments in neurodegenerative diseases. Yet the large variety of stimulation strategies, parameters and patterns used to evaluate efficacy, the diversity of cognitive tasks, and the scarcity of adequately controlled double-blind sham-controlled studies in homogenous patient populations preclude at this time a reliable meta-analysis of therapeutic applications.The field of NIBS research has shown during the last decade an outstanding degree of dynamism and innovation. Basis science, pre-therapeutic and therapeutic TMS/tDCS studies have expanded our knowledge on how NIBS may operate, and opened new avenues for the characterization and development of cognitive rehabilitation treatments in neurology and psychiatry. Nonetheless, an effective use of NIBS requires the neurostimulation community to move beyond classical approaches and fully integrate growing neurophysiological and neuroanatomical evidence subtending cognitive function and dysfunction.Information-based neurostimulation  could be employed prior, during or even following TMS/tDCS to maximize the effects driven by excitatory stimulation patterns. Similarly, sensory, motor or cognitive priming tasks shall be applied to increase ongoing levels of activity, during or even following stimulation to facilitate the suppressive effect of inhibitory TMS/tDCS patterns and render such populations less sensitive to stimulation  has shown to induce impairments of memory consolidation in inferior prefrontal frontal regions  and reported for example decreases in network efficiency in the gamma band for AD and PCA, whereas alterations in bv-FTD, PSP and nfv-PPA impacted lower frequencies  .Finally, a very recent study in bv-FTD used a hypothesis driven single network analyses of MEG data during the generation and inhibition of responses using a Go-NoGo motor task and explored alterations of cross-frequency coupling phenomena . AuthorsIn sum, electrophysiological evidence suggests a disorganization of functional circuits and alterations of neural synchrony at early stages of neurodegenerative diseases preceding structural atrophy changes . MoreoveThe use of oscillation-based rhythmic neuromodulation principles in the rehabilitation of cognitive deficits in neurodegenerative patients remains to be developed. Nonetheless, successful application of anti-phasic tACS individually tailored for tremor in PD patients may show an interesting path to follow to improve cognitive impairments . Indeed,23A myriad of variables  will determine effective current intensity received by a brain region. In absence of direct physiological evidence, finite element methods (FEM) biophyisical computational models can be employed to estimate the spread and intensity of current fields based on individual structural MRI, and individually tailor stimulation settings . Such moThe field of NIBS technologies is continuously developing novel stimulation technologies to be used in human clinical settings. In an attempt to overcome some of the limitations of TMS and tDCS, particularly noteworthy has been the search for devices capable of inducing electrical fields of higher magnitude, in a more focal and steerable manner, and when possible directly into subcortical brain structures without having to influence all layers of non-neural and neural tissue before reaching a cortical target.via focused ultrasound (FUS) sources  initially explored in rodent models eventually will be transferred to human patients with the ambition to expand the array of neuromodulation technologies at the service of neurology  concentrations of the amyloid-β 1-42 peptide, high CSF concentrations in total tau and phospho-tau; mesial temporal lobe atrophy on MRI, and/or temporoparietal/precuneus hypometabolism or hypoperfusion on PET  to allow critical and open-minded vigilance needs to be alloted to the emergence of new brain stimulation technologies, which might overcome some of the critical limitations of either TMS or tDCS such as lack of intensity, focality or steerability.However, we here suggest that attaining full potential for therapeutic success will require the consideration of information-based neurostimulation principles put forward recently, i.e., cutting-edge knowledge on anatomical (sites and networks subtending function) and neurophysiological features  characterizing each specific neurodegenerative condition, and their dynamic changes across disease stages. To such end, it is essential (1) to consider the network-distribution of neurostimulation effects when planning strategies and interpreting outcomes; (2) to monitor and manipulate through specific tasks the level of brain activity prior, during or following stimulation to boost outcomes; (3) to integrate This framework will help build innovative therapeuticrationales on the basis of an accurate characterization of a dynamically evolving anatomical and neurophysiological features  of each neurodegenerative disease. Finally, to establish therapeutic value of NIBS and better understand its mechanisms of action it is essential to integrate in studies brain neuroimaging and neurophysiological recordings and use such to monitor brain activity state and characterize network connectivity and their changes with treatment.RM and AV-C were responsible for the coordination of the manuscript. CSa, RM, and AV-C devised the manuscript project and contributed to manuscript redaction. JM, CSt, and JG contributed to the redaction of specific sections of the manuscript. Csa and JG were responsible for the process of literature search. MT contributed to the revision of 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.