Glioblastoma (GBM) is the most common primary adult intracranial malignancy and carries a dismal prognosis despite an aggressive multimodal treatment regimen that consists of surgical resection, radiation, and adjuvant chemotherapy. Radiographic evaluation, largely informed by magnetic resonance imaging (MRI), is a critical component of initial diagnosis, surgical planning, and post-treatment monitoring. However, conventional MRI does not provide information regarding tumor microvasculature, necrosis, or neoangiogenesis. In addition, traditional MRI imaging can be further confounded by treatment-related effects such as pseudoprogression, radiation necrosis, and/or pseudoresponse(s) that preclude clinicians from making fully informed decisions when structuring a therapeutic approach. A myriad of novel imaging modalities have been developed to address these deficits. Herein, we provide a clinically oriented review of standard techniques for imaging GBM and highlight emerging technologies utilized in disease characterization and therapeutic development. Treatment shortcomings can be attributed to intratumoral heterogeneity, inability to completely resect infiltrating tumor edges, rapid development of treatment-resistant pathways, and pharmacokinetic limitations due to poor blood-brain-barrier (BBB) permeability.Gliomas are primary brain tumors that arise from glial cells or neuroglial progenitors and account for approximately 80% of adult central nervous system malignancies.6 Tumors invariably recur after treatment, with no standardized protocol for managing recurrence. Efforts to better understand the molecular pathogenesis of GBM and to extend lifespan have translated into only three FDA approved treatments—temozolomide, bevacizumab, and TTFields—all of which have minimal impact on overall survival.7–9 Recent research strategies have shifted to targeting GBM with immunotherapy-based approaches, though a number of phase III trial failures have left the field fairly stagnant.8–21The current standard of care for GBM is treatment with maximal safe surgical resection, post-operative radiation, and chemotherapy, followed by adjuvant temozolomide chemotherapy.22Radiographic evaluation plays a crucial role in managing patients with GBM, both during initial diagnosis and following treatment. Magnetic resonance imaging (MRI) is the modality of choice for diagnosis and assessment of treatment response due to its wide availability, and superior soft tissue visualization over computed tomography (CT). The interpretation of imaging studies after treatment of GBM is challenging because treatment-related changes frequently mimic tumor progression (termed “pseudoprogression”). Similarly, some biologically directed therapies can mask the presence of persistent lesions (termed “pseudoresponse”).It is important to understand what imaging can offer in diagnosis and management of GBM so that the right imaging techniques can be employed. Herein, we review the prospects and limitations of various imaging techniques with data in the evaluation of GBM available in most academic medical centers.23 GBM characteristically presents on imaging as a heterogeneous enhancing mass with a central necrotic core and peritumoral edema.21 Associated features such as tumor volume, peritumoral edema, necrosis, degree of enhancement, and presence of cysts are additional parameters that can be used to predict outcomes and survival in patients with GBM24 27 and high ITSS score is more common in larger GBMs and GBMs arising from or in close proximity to the subventricular zone.28T2-weighted, fluid attenuated inversion recovery (FLAIR) and pre- and post-gadolinium T1-weighted MRI are routinely used for diagnosis, pre-operative surgical planning, and evaluation of treatment response in patients with GBM.th GBM24 , 1B, 1C.th GBM24 . Intratu2 an MRI sequence that assesses cellular architecture by measuring the Brownian motion of water in tissue, has shown promise in predicting tumor grade, peritumoral infiltration, and treatment-related effects in GBM. The apparent diffusion coefficient (ADC) represents the average magnitude of diffusion at the voxel or region of interest level and has been shown to negatively correlate with the cellularity of brain tumors29–31  can differentiate high grade gliomas from low grade gliomas with high sensitivity and specificity.33 ADC values may also be used to predict the genetic architecture of a GBM. IDH mutated tumors have significantly higher ADC values compared to the IDH wild-type tumors.34 Additionally, some studies have used ADC to predict prognosis, whereas low tumor ADC is associated with shorter survival times.36Diffusion weighted imaging (DWI),ors29–31 . ADC val37–39 Moreover, ADC is a scalar quantity that measures isotropic diffusion of water and therefore lacks information regarding anisotropy, precluding ADC from accurately differentiating areas of tumor infiltration from peritumoral edema and healthy nervous tissue.Evaluation of GBM with qualitative DWI has become standard, however, the significance of DWI images should be interpreted carefully. The accuracy of DWI can be significantly affected by hemorrhage, which is frequently present in GBMs. In addition, high-grade gliomas have been shown to upregulate aquaporin channels, notably AQP4 and AQP1, limiting the ability of ADC to truly capture restricted diffusion in a hypercellular environment.41 On the other hand, high ITSS score on SWI is associated with IDH wildtype and MGMT unmethylated GBMs.42Recently, many conventional imaging features have been identified that may serve as unique features in certain biomarkers of GBM. T2-FLAIR mismatch sign , homogenAs previously alluded to, diagnosis of GBM using conventional imaging alone is not always straightforward. Many other brain pathologies  can mimic GBM on conventional imaging sequences and can be difficult to differentiate from GBM. As such, conventional imaging in combination with other advanced imaging techniques have better diagnostic performance and have been developed for this reason.Advanced MRI techniques, when available, should be routinely used for evaluation of GBM, both at diagnosis and during follow-up. Diffusion imaging, perfusion imaging, and MR spectroscopy (MRS) provide more detailed information about the tumor physiology and metabolism that is essential to make an informed decision about tumor management . Additio43 Multiple studies have demonstrated increased progression-free survival and retention of functionality using DTI tractography to guide tumor resections.45 The concurrent use of DTI with other methods such as functional-MRI (fMRI) and direct electrical stimulation to assess brain function when constructing a surgical plan permits more robust analysis of white matter integrity.Diffusion tensor imaging (DTI) is another powerful diffusion imaging tool that can detect more intricate tissue microarchitecture by tensor modeling of diffusion data to provide anisotropy and diffusivity measurements. DTI is often obtained pre-operatively to reconstruct white matter tracts in peritumoral regions, enabling surgeons to assess tumor infiltration and viability of peritumoral nervous tissue.46–51 resulting in a decreased fractional anisotropy, which may be modeled as an abrupt termination of the tract53 and lead surgeons to incorrectly conclude that healthy nervous tissue is unsalvageable. Furthermore, DTI tractography is unable to model the geometric complexity of the microscopic nervous architecture such as crossing fibers, which may result in incorrect or incomplete reconstructions. Like all imaging obtained preoperatively, the use of DTI for intraoperative guidance is complicated by intraoperative brain shift. This may result in significant discrepancies between neuronavigation and the intraoperative anatomy.54–56 Finally, significant disagreement can be encountered between DTI and the intraoperative gold standard for identifying functional white matter tracts, direct electrical stimulation. Novel diffusion MRI techniques are being developed to overcome DTI’s limitations and have shown promise in characterizing tumoral vs. healthy white matter and correlating diffusion metrics to tumor histology in both adult and pediatric brain tumor specimens.57–59 Nevertheless, DTI currently serves as a valuable adjunct imaging method, with its limitations understood in light of other more accurate intraoperative adjuncts such as direct electrical stimulation.55Its benefits notwithstanding, DTI tractography faces several limitations due to the complex pathology and microinfiltrative nature of GBM. The tendency of gliomas to invade adjacent white matter disrupts the diffusion of water in affected tracts,60  is used to scan the brain before, during and after injection of contrast. The dynamic signal intensity of each voxel is plotted against time, thereby generating a signal intensity vs. time curve. Using mono-compartmental modelling, this curve is then utilized to compute multiple perfusion parameters with or without incorporating the ∆R2* function. As disruption of the blood brain barrier is almost universal in GBMs, these parameters need to be corrected to account for contrast leakage. Of the many parameters, cerebral blood volume (CBV) is most widely used, which correlates with vascular endothelial proliferation, vascular density, and neoangiogenesis and has been shown to reliably correlate with histopathologic grading and survival outcomes in glioma patients60 .62DSC-MRI is an attractive option given its short acquisition time and simple postprocessing but is nevertheless subject to several limitations. Most notably, the fundamental basis of this technique is based on a single compartment vascular model , which is rarely the case in GBMs. Indeed, disruption of the BBB is routinely seen in GBMs, so rCBV measurements should be performed with proper leakage correction techniques.Ktrans), which is a measure of microvascular permeability. Ktrans has diagnostic power in determining glioma grade, with increased Ktrans values reflecting a higher degree of BBB damage and vascular compromise.63 DCE-MRI is not subject to susceptibility artifacts and has therefore been used to differentiate pseudoprogression from recurrent GBM with 85% sensitivity and 79% specificity.64 The major drawback of this method, as compared to the DSC referenced above is the sparse literature confirming imaging via histopathologic validation and a notable lack of FDA-approved/validated post-processing software.DCE-MR perfusion is a technique that estimates cerebral perfusion parameters by evaluating T1 shortening induced by a contrast bolus passing through tissue. The most common parameter used in tumor imaging is the volume transfer constant . ASL has proven utility as a noninvasive method of determining glioma grade and distinguishing between treatment effects and tumor recurrence in postoperative gliomas.solution .70 The main principle underlying MRS is that the distribution of electrons within an atom will cause small variations in the magnetic field experienced by different molecules, shifting the detected resonance frequency. Common neurobiological substrates include lactate, alanine, N-acetylaspartate (NAA), creatinine (Cr), choline (Cho), 2-hydroxyglutarate (2-HG), and glutamine/glutamate, and brain tumors demonstrate markedly different spectra than healthy brain tissue .MRS is a non-invasive imaging modality used to interrogate the tissue metabolic environment.n tissue , 2G. Hig78 Gray matter is relatively well-vascularized, enabling fMRI to assess function and preservation of underlying neurons in cortical areas. Due to fMRI’s dependence on activity-induced changes in adjacent vasculature and not the neurons themselves, direct assessments of structural information, e.g., neuronal integrity and microstructural architecture, are impossible using BOLD fMRI alone.Functional magnetic resonance imaging (fMRI) indirectly measures neuronal activity via the blood oxygen level dependent (BOLD) signal, a measure of the ratio of oxyhemoglobin to deoxyhemoglobin.79–83 As stated above, DTI tractography may incorrectly reconstruct tracts in the presence of glioma-induced changes in diffusion of peritumoral white matter tracts, as well as shifting of tissue after resection.84 In addition, DTI’s modelling of the diffusion tensor currently limits identification of crossing fibers, leading to potential tractography errors in highly complex subcortical areas. The addition of fMRI as a seeding tool for DTI tractography and as a confirmatory tool to assess functionally sensitive areas serves to minimize DTI’s shortcomings.Its limitations notwithstanding, fMRI is a valuable tool for surgical planning and in particular, when deciding on awake vs. asleep procedures. It can help direct cortical mapping to decrease the case length and time under anesthesia, and aid in cortical preservation when awake surgeries are impossible or fail. The combination of fMRI and DTI increases the accuracy of the preoperative planning across modalities.86 Resting-state fMRI (rs-fMRI) records fluctuations in brain activity as a result of spontaneous metabolic changes and has been shown to correlate with underlying anatomic networks in the somatomotor cortices87 and language areas.88 Rs-fMRI has several advantages over fMRI in the setting of GBM. First, rs-fMRI does not depend on motor and cognitive activity, which may be affected in patients with GBM. Second, rs-fMRI can be used in combination with anesthesia to assess neural function in patients who may not comply with motion restrictions inside of a scanner . Finally, rs-fMRI simultaneously records activity from multiple areas of the brain that fire spontaneously, eliminating the necessity to perform multiple tasks to assess multiple areas of the brain.The utility of fMRI for preoperative planning of brain tumor resection has recently expanded to include assessment of resting-state (non-task-based) activity of neural networks.55 Guisanni et al89 found that fMRI had specificities and sensitivities ranging from 0% to 97% and 59% to 100%, respectively, when compared to direct electrical stimulation for language mapping. Further, fMRI does not always inform the surgeon of areas of the brain that can be safely resected due to the brain’s limited ability to compensate without them . Therefore, pre- and intraoperative decision making based solely on fMRI can lead to patient under selection as well as increased likelihood for limited tumor resection leaving significant amounts of tumor infiltrated tissue behind.55Despite the aforementioned, direct electrical stimulation remains the gold standard in identifying functional gray and white matter tissue, highlighting significant limitations with fMRI.Positron emission tomography is an imaging technique that involves intravenous injection of a positron-emitting radioisotope followed by detection of radioactivity to analyze patterns of accumulation and distribution throughout the body. In the oncology setting, PET provides valuable physiologic information not obtainable by conventional MR and CT imaging methods, and PET has utility in tumor grading, spatial reconstruction, surgical planning, post-treatment monitoring, and prognostication.18F-2-fluoro-2-deoxy-D-glucose (18F-FDG) is the most widely studied and commonly used radiotracer.18F-FDG is a glucose analog and its uptake into cells is dependent upon both transport across the BBB and metabolism within tumor cells, which provides information on differentiation and specificity. In line with other malignant tumors, GBM is highly18F-FDG avid due to its increased glycolytic metabolism and cellular proliferation. However, normal brain tissue has a relatively high rate of physiologic glucose metabolism, leading to regional variation that may confound accurate radiographic interpretation. Contrast-enhanced MR imaging is often performed in tandem with FDG-PET and the resulting images are fused to allow for tumor co-localization90. FDG-PET shows high sensitivity in differentiating high grade gliomas from other types of brain tumors and has also been shown to correlate with survival and time to tumor progression91–94. However, due in part to poor distinguishability of tumor from normal brain, FDG-PET alone is rarely used in routine clinical practice for evaluation of intrinsic brain tumors.95 These compounds demonstrate high uptake in glioma cells and low uptake in inflammatory and normal cerebral tissue. They are therefore more useful in delineating tumoral boundaries, which are classically underestimated by conventional MRI and obscure with FDG PET due to high background metabolic activity97  PET tracers are an alternative class of radiotracers commonly used for clinical studies in glioblastoma and include 11C-MET, 11C-AMT, 18F-FET, and 18F-FDOPA.tivity97 .92 and prognosis.98 Pharmacokinetic analysis yields physiologic data regarding uptake mechanisms and tumoral heterogeneity that allows for further differentiation and superior tumor grading prediction as compared to static scanning.92 This method can detect high-grade transformation in lesions otherwise presenting as suspected LGGs, and can be used to predict methylation status 100. As such, dynamic FET scanning has immense potential and may ultimately be employed to assess IDH1/2 mutational and 1p/19q co-deletion status 101.Dynamic FET PET is a powerful imaging tool that relies upon sequential scans to provide information on glioma grading102–104. While iMRI was associated with increased EOR and gross total resection in a multicenter retrospective study of 640 adult patients with newly diagnosed glioblastoma, it was not a predictor of overall survival 105. Therefore, further research is needed to determine the full benefit of iMRI. Despite its successes in increasing EOR and gross total resection, iMRI faces several limitations, as reviewed by Kubben et al.106 and has not been widely implemented outside of a limited number of high-volume centers. Namely, iMRI is extremely cost prohibitive, with an individual machine in the range of several million dollars with additional costs incurred from ancillary equipment and specialized training required for operating room personnel. Further, iMRI provides only a one time (per imaging scan) immediate feedback of the surgical field of view, but similar to pre-operative MRI, once surgery resumes, any intraoperative brain shift that occurs can lead to significant discordance between the iMRI images and the intraoperative reality due to registration errors. To combat this, hybrid iMRI and 3D ultrasound techniques are being evaluated to compensate for brain shift in intraoperative navigation 107. Finally, iMRI has been shown to be time consuming with a significant increase in the surgical time, limiting the number of scans obtained during the same surgical setting to one or two scans in most centers. It does not, however, appear to increase perioperative risk with respect to infection or complications arising from prolonged time under anesthesia 109.Gross total resection is the mainstay of GBM surgical management, with the extent of resection (EOR) correlating to symptomatic improvement and to significant improvement in both progression free survival and overall survival. EOR is largely dependent upon tumor proximity to, and infiltration of, eloquent brain regions with a high risk of neurologic comorbidities conferred by a necessarily aggressive surgical approach. Innovative technological developments have better enabled surgeons to balance maximizing EOR and preserving function. In particular, the advent of intraoperative MRI (iMRI) has led to enhanced safety and noninvasive visualization of tumor location and adjacent structures with immediate radiographic feedback prior to closure. iMRI is associated with a greater extent of gross total resection and a quantitative increase in EOR as compared to conventional neuronavigation methods 111 Woydt et al. identified solid tumor tissue in 89% (47 of 53) of biopsies taken from central areas of high grade and low grade gliomas, 72% (34 of 53) of which were inconspicuous on microscopic assessment. Furthermore, iUS enabled detection of histologically validated residual tumor in 22 of 25 cases in which gross total removal was suspected. Collectively, these findings suggested potential efficacy of iUS to delineate central areas of tumors compared to tumor rims, as well as to detect residual tumor that is indistinct by initial microscopic evaluation. However, iUS detection of hyperechoic rims was not specific to tumor tissue, as 44% (11 of 25) of biopsies were histologically assessed as normal brain tissue. Results from a more recent study demonstrate inferiority of iUS to detect tumor remnants after resection compared to iMRI.112 Additionally, interuser variability, low signal-to-noise ratio, and low resolution have limited further applications of iUS. To address these limitations, different approaches have been created to improve iUS. One of the more detailed approaches was performed by Liang et al. who overlayed contrast-enhanced iUS images with preoperative MRI images, which improved gross total resection rate from 31.58% (6 of 19 cases) to 84.62% (22 of 26 cases) and improved post-operative morbidity.113 As reviewed by Del Bene et al.,114 numerous other studies have attempted to use contrast-enhanced iUS, Doppler iUS, and multimodal imaging overlays with iUS. No randomized controlled trials have been completed to definitively determine whether any iUS method provides significant benefit for delineating gliomas, detecting residual tumor tissue, or improving overall survival or morbidity compared to other intraoperative imaging techniques, thereby limiting confidence for which iUS can be used clinically. iUS is therefore used as an adjunct imaging modality to supplement iMRI and other intraoperative methods and to repeatedly image resections after brain shift.Intraoperative ultrasound (iUS) is a cheap, rapid, and repeatable imaging technique used since the 1980s to maximize EOR and functional protection postoperatively. In addition, iUS is appealing because it can be implemented several times to correct for brain shift throughout resection, but the literature is unclear on whether it is efficacious for detecting and grading glioma and tumor remnants during/after surgery as compared to other imaging methods. Standard gray-scale (B mode) iUS has been the most widely implemented iUS method and has been shown to reveal tumor areas as hyperechogenic and cystic tumoral areas as hypoechogenic compared to adjacent parenchyma, enabling visibility of low and high grade gliomas.115–117 The main advantage of FGS over conventional iMRI or image-guided technologies is the ability to provide immediate, intraoperative feedback regarding the surgical field of view while the neurosurgeon continues to actively perform surgery. As such, FGS does not encounter intraoperative accuracy problems due to brain shift, which is a major problem with image-guided technologies using pre-operative MRI, or the delayed, one-time feedback from iMRI.56Fluorescence-guided surgery (FGS) is an intraoperative imaging modality that has become a mainstay of treatment world-wide for GBM, as it has been shown to significantly increase the EOR.118 The three most used drugs are 5-aminolevulinic acid (5-ALA), indocyanine green (ICG), and fluorescein.120 5-ALA leads to endogenous formation of protoporphyrin IX (PpIX), which is a fluorescent tumor biomarker that emits a red-pink fluorescence in the visible range of the spectrum of light (620–710 nm). Fluorescein emits a green-yellow fluorescence with a maximum fluorescence at 521 nm. ICG is a near-infrared agent, and as such is invisible to the human eye, emitting a maximum fluorescence at 835 nm.122 During surgery, neurosurgeons use a surgical microscope modified with light sources for exciting the fluorophores, appropriate filters to selectively collect the emitted fluorescent light, and sensors such as color cameras or near-infrared enabled cameras. These fluorescence-enabled microscopes allow the surgeon to visualize the fluorescence light emitted from tumor infiltrated tissue either with their eyes, using surgical oculars, or digitally by means of camera detection.120 Tumor infiltrated tissue will then display a distinct color that enables the surgeon to differentiate it from adjacent, normal brain. In FGS, patients are administered a drug prior to surgery, which leads to significant accumulation of a fluorescent biomarker in tumor tissues.117 5-ALA is the most widely used agent for FGS in GBM, with approval in the USA and Europe. However, the first FGS studies in neurosurgery date back to 1948 with the use of fluorescein, which accumulates in extracellular spaces and in areas of a broken blood brain barrier.123 ICG, which historically has served as a fluorescence agent for cerebrovascular imaging in neurosurgery, has seen an increase in research studies applied to GBM. Recent studies use what is known as second window ICG imaging, which entails administration of ICG 24 h prior to surgery. Then, likely due to biological processes dependent on the enhanced permeability and retention effect, ICG significantly accumulates in GBM, allowing for strong tumor-to-background signal and differentiation of tumor tissue from normal brain.121 In addition, several neurosurgical trials are evaluating novel FGS agents, adding to the already existing armamentarium of 5-ALA, ICG, and fluorescein, which includes endothelial growth factor receptor (EGFR) targeting antibodies, EGFR-targeting affibodies, protease activated fluorescent agents, and fluorophore labeled peptides.115A pivotal phase III clinical trial comparing standard of care resection using conventional white light guided resection versus FGS with 5-ALA, showed that FGS almost doubled the EOR (65% vs. 36%) and significantly increased the overall 6-month progression free survival of patients (41% vs. 21.1%).122 Second, each fluorescent biomarker may have a differing tumor-targeting profile that is dependent on the biology of the tumor tissue.122 Third, assessment of tissue fluorescence to date are all based on subjective, non-quantitative assessments of the raw, visible fluorescence observed by the naked eye or detected by a digital camera. These technologies do not take into account the heterogeneous effects of how light interacts with different tissues, which can lead to assessments of tissue fluorescence which are inaccurate . These inaccurate assessments do not detect diagnostic levels of fluorescent tumor biomarker and may ultimately leave significant amounts of residual tumor tissue unresected.125 Finally, fluorescence agents to date provide the surgeon only with immediate structural feedback, but not with immediate functional feedback to differentiate functional from non-functional brain parenchyma . As such, surgical resection based purely on FGS can lead to undesirable functional deficits if not properly used.126FGS has been shown to be a useful adjunct for maximizing the EOR in GBM surgery, though still has its limitations. First, current approaches using 5-ALA are limited to just surface assessments of tissue fluorescence. Near-infrared approaches such as ICG are also limited to depth assessments of tissue fluorescence of approximately 1 cm in depth.To summarize, FGS has become a useful adjunct for improving the EOR in GBM. FGS provides the neurosurgeon with immediate feedback of the surgical field, distinguishing tumor infiltrated tissue from normal tissue, meanwhile the surgeon continues to actively perform surgery. However, like any surgical adjunct, the neurosurgeon needs to clearly understand its limitations to perform the most extensive tumor resection, meanwhile ensuring preservation of functional brain.127 It is important to diagnose infarct at the surgical margin at this early stage because subacute infarct can mimic progressive tumor on imaging. Immediate post-operative MRI is often used for planning of radiation therapy  complete response: disappearance of all enhancing lesions on consecutive MRIs at least one month apart, patient off steroids with stable or improved neurological exam; (b) partial response: >50% reduction in the size of the enhancing lesions on consecutive MRIs at least one month apart, patient on stable or reduced steroid dose with stable or improved neurological exam; (c) progressive disease: >25% increase in size of the enhancing lesions or appearance of new lesion, patient on stable or increased steroid dose with worsened neurological exam; or (d) stable disease encompassing all remaining radiographic and clinical scenarios.90 Using these criteria, clinicians are more accurately able to distinguish between responses to therapies and progression of disease. By detailing timeframes with which to discuss treatment effects or failures, it allows time for the therapeutic agent, and in particular trial agents, to develop a more robust response before determining whether or not there is disease progression.131The response assessment in neuro-oncology group has proposed standardized imaging practices for use in both clinical management and translational therapeutic protocols. In response to the failure of existing classification systems to account for (a) changes in enhancement secondary to corticosteroid use, antiangiogenic agents, postsurgical changes, radiation effects, and other inflammatory processes and (b) changes in the non-enhancing T2-hyperintense components secondary to use of antiangiogenic agents, Wen et al. introduced modified RANO guidelines for high-grade gliomas. These criteria measure enhancing lesions and additionally incorporate abnormalities in T2/FLAIR signaling to better differentiate between true tumor response and pseudoprogression or pseudoresponse in the setting of concomitant temozolomide and antiangiogenic therapy.132 These criteria are better than RANO and have limited the premature withdrawal of subjects from clinical trials. However, given the complexity of immunotherapy centered approaches, it is remains difficult to use one set of criteria for all therapies/clinical trials. Results from recent clinical trails continue to shed light on how imaging can be used for assessment of novel immunotherapies.133As described above, conventional therapies have done little to improve the survival of patients with GBM. As such, novel therapies are increasingly being investigated; immunotherapies are at the forefront of such approaches. Critically, patterns of imaging response to immunotherapies are quite unique from those of conventional therapies thereby necessitating the development of a response criteria capable of accounting for such differences. In line with this Okada et al. published the immunotherapy response assessment in neuro-oncology (iRANO) predominantly based on the experience of immunotherapies in non-CNS tumors.134Since the inception of the RANO criteria, it has been used almost exclusively for assessment of GBM, including pediatric GBM. However, it is prudent to note that the biology of high-grade gliomas in children is different from that in adults, and children frequently require different management. To mitigate these discrepancies, the Response Assessment in Pediatric Neuro-Oncology working group has recently published recommendations for response assessment for pediatric patients with high-grade gliomas.135; similarly, residual contrast-enhancing tumor following surgery is also negatively associated with survival in patients with newly diagnosed GBM.136 Pretreatment ADC histogram and CBV-based thresholding values have been shown to predict response in recurrent GBM treated with antiangiogenic therapies.138 Early reduction of CBV following bevacizumab treatment in recurrent glioblastomas can predict survival as well.139Prediction of treatment response in GBM is immensely challenging. The enhancing components of GBM at presentation are inversely associated with survival141 The mechanism of pseudoprogression remains poorly understood, but it is thought to represent edema and increased vascular permeability secondary to chemoradiotherapy-induced tumor and endothelial cell death. Notably, O6-methyl guanine-DNA methyl transferase (MGMT) methylated tumors have a higher incidence of pseudoprogression due to their increased sensitivity to temozolomide.141–145 Pseudoprogression is also expected with targeted therapy and/or immunotherapy.146 Pseudoprogression carries significant clinical impact as studies have shown this subgroup of patients experience improved median survival if correctly identified.148 Pseudoprogression typically stabilizes or resolves without a corresponding change in treatment. The apparent enlargement of the tumor on MRI due to pseudoprogression can be difficult to reliably distinguish from true tumor progression although patients with pseudoprogression are less likely to experience worsening of neurological symptoms. Critically, the ability to distinguish pseudoprogression has become ever more relevant in the era of immunotherapy.Pseudoprogression is a well-documented phenomenon observed in 20–30% of patients in which new tissue enhancement is detected within three months of completion of radiation with concurrent temozolomide therapy in the absence of true tumor growth, as determined by the presence of necrosis or gliosis on biopsy.MRI is essential in assessing response to treatment and tumor progression during the disease course. The ability to identify surrogate imaging biomarkers allows for a noninvasive way to risk-stratify patients and to refine individual therapeutic approaches. An overview of the techniques currently in use along with their specific advantages and limitations is provided below.150  compared with pseudoprogression (>1.3 µm2/ms).152 In the presence of extremely heterogeneous tumor microenvironments, the presence of therapy-related hemorrhage confounds the ADC measurement. Similarly, bevacizumab therapy is associated with a distinct persistent diffusion restriction  calculation is a technique of histogram-based thresholding that can be an excellent tool to quantitatively differentiate pseudoprogression from true tumor progression and predict survival.156 A simple dichotomous “true progression” and “pseudoprogression” approach is challenging in clinical practice because enlarging enhancement, most of the time, is contributed to by both tumor tissue and tissue with treatment related effects. Unfortunately, if a voxel contains both tumor tissue and tissues with pseudoprogression, the sensitivity and specificity of perfusion imaging in differentiating pseudoprogression from true tumor progression decline. Additionally, there is wide variability in DSC-MRI acquisition, and post processing approaches can contribute to variation in results. Standardized acquisition techniques and post processing techniques have been recently recommended for consistency and inter-institutional comparability.158Perfusion MRI has also been successfully used to differentiate pseudoprogression from true tumor progression with estimated sensitivity and specificity approaching 90%.159 This method generates a tumor density profile comprising voxel intensities corresponding to specific regions within the tumor. Probability density functions applied in a Fisher–Rao Riemannian framework are used for metric-based clustering of patients. The outputted patient clusters demonstrate significant associations with tumor morphology, driver gene mutations, and prognostic clinical outcomes and additionally map with known GBM subtypes .160 Whereas most methods employ scalar summary measures to analyze tumor heterogeneity, DEMARCATE gains predictive and correlative power by using the entire density of an individual tumor density profile to capture highly refined information that can be used to detect small-scale and sensitive changes in the tumor due to treatment effects.DEMARCATE is a novel MRI-based technology used to analyze tumor heterogeneity.161MR spectroscopy has been used to identify tumor progression as well. Chuang et al. have also shown that Cho/Cr and Cho/NAA ratios are significantly higher in tumor recurrence compared with radiation injury.162Itakura et al. identified three distinct phenotypic GBM subtypes utilizing a quantitative MR imaging analysis of lesion shape, texture, and edge sharpness with subsequent consensus clustering. The three clusters, pre-multifocal, spherical, and rim-enhancing, mapped to distinct sets of molecular signaling pathways  using molecular activity estimates from The Cancer Genome Atlas and notably demonstrated differential probabilities of survival.163–165 The European Association of Nuclear Medicine (EANM), the Society of Nuclear Medicine and Molecular Imaging (SNMMI), the European Association of Neurooncology (EANO), and the working group for Response Assessment in Neurooncology with PET (PET-RANO) have jointly published guidelines for appropriate use of PET imaging in evaluation of gliomas.166PET imaging is increasingly used in situations when MRI inadequately differentiates pseudoprogression from true progression. Although 18FDG PET has been used in this setting, LNAA PET can reliably distinguish tumor progression from treatment-related effects and can in turn identify responders to antiangiogenic therapy with near complete diagnostic accuracy.167 This is likely the result of reduced mass effect and vasogenic edema. Of note, patients requiring a drug holiday due to toxicities have been shown to demonstrate rebound enhancement and edema with a subsequent “re-response” after restart.169Pseudoresponse describes the rapid reduction in tumor enhancement and surrounding vasogenic edema following the administration of an anti-angiogenic agent that is not representative of a true anti-tumor response. Treatment with bevacizumab, an anti-VEGF monoclonal antibody approved for use in GBM refractory to first line radiation, temozolomide, and lomustine, commonly causes pseudoresponse as it decreases microvascular proliferation and BBB permeability . Though 171The differentiation between clinically distinct radiographic phenomena from a true tumor response has critical implications for patient care as failure to correctly identify tumor progression or regression may result in inappropriate modification or cessation of effective treatment.173 Radiographically, radiation necrosis presents as a heterogeneously enhancing lesion with a characteristic “soap-bubble” or “Swiss cheese” appearance and surrounding vasogenic edema. MR findings are useful in differentiation from both pseudoprogression and tumor progression. For example, development of a lesion in an area of radiation-induced leukoencephalopathy or in the bed of a previously non-enhancing tumor with minimal to no mass effect and associated hemosiderin and calcifications is suggestive of radionecrosis. In addition, an elevated lipid-lactate peak on spectroscopy and a low normalized cerebral blood volume (CBV) ratio, a biomarker for angiogenesis, also carry diagnostic value.Radiation necrosis is a delayed manifestation of tissue injury that typically occurs three months to one year following radiotherapy. Radiation necrosis occurs as a result of disruption of the BBB with consequent occlusive vasculopathy, thrombosis, and ischemia. Histologic examination shows extensive glial and white matter damage, fibrinoid necrosis of small vessels, and vessel wall hyalinization.ex vivo mass spectrometry imaging (MSI) a feasible and valuable tool in guiding intraoperative decision-making during tumor resection.175 MSI is an imaging modality that analyzes the molecular composition of thin tissue sections based on the mass-to-charge ratios of the ionized compounds that constitute the surface. Unlike traditional liquid chromatography methods, MSI does not require chromatographic purification and thus preserves spatial information and tissue architecture. The two most common ionization techniques for surface analysis of biological tissue are matrix-assisted laser desorption ionization (MALDI) and desorption electrospray ionization (DESI).Technological ingenuity over the past several decades has rendered 176 which may provide novel genomic targets for antibody-mediated therapy. DESI-MSI has also been used to analyze the ganglioside composition of healthy and malignant nervous tissue and could reliably distinguish between tumor, grey matter, and white matter, while also identifying ganglioside forms present exclusively in GBM tissue.177 Looking forward, a multicenter effort to investigate GBM tissue protein composition using liquid chromatography-tandem mass spectrometry could be used to construct a GBM proteome and identify actionable serum GBM biomarkers.179 MSI has additional functionality in determining tissue penetration and efficacy of various therapeutic agents, e.g. boron neutron capture therapy relies on fission reactions to selectively kill tumor cells that have reached a sufficient intracellular density of boron, a measure that can be reliably studied using secondary ion MSI.180 In addition, the efficacy of oncolytic viral therapy in GBM treatment is highly dependent upon the selective targeting of tumorigenic cells, which can be assessed with MALDI-MSI.181MALDI and DESI-MSI have numerous applications in GBM research. MALDI-MSI has been used to detect in situ, spatial histone variation in patient-derived xenograft models,182 In short, supervised and unsupervised machine learning and different neural network techniques can be used to train algorithms via a series of known values  thereby facilitating the prediction outcomes based on initial training datasets.In recent years, there has been great interest in applying artificial intelligence (AI) within multiple medical fields, including imaging. Sotoudeh et al. have recently reviewed AI techniques in the context of brain tumor imaging.183 Importantly, these methods are able to be employed in even the most complex of tumoral environments. Convolutional neural networks are among the most powerful machine learning techniques applied to imaging interpretation in GBM. They are able to operate without any human training. By eliminating human error, deep convolutional neural networks have been used to differentiate glioblastoma subcompartments based on MR imaging by generating rapid and accurate three-dimensional segmentations of the tumor. Radiomic features have been identified that accurately predict survival in patients with GBM.184 Radiomic features derived from these segmentations are particularly useful in helping to predict genetic biomarkers.186 For example, artificial intelligence has been used to predict IDH, ATRX, and CDKN2 family mutations in addition to chromosome 7/10 aneuploidies with astonishing sensitivity and specificity.187 Another promising application of artificial intelligence was demonstrated with stimulated Raman imaging, a form of optical imaging, where clinicians showed that a convolutional neural network driven stimulated Raman imaging technology had a noninferior performance compared to pathologist interpretation of histologic images for tissue diagnosis during brain tumor surgery (94.6 % vs. 93.9% accuracy).188 While still in its infancy, AI represents a promising future direction for imaging analysis in patients with GBM and may ultimately prove helpful in multiple aspects of brain tumor management, including tumor diagnosis/grading, the prediction of genomic and histopathologic architecture, and/or operative/radiation planning.Interestingly, AI has been employed as a method to automate complex imaging analyses in an unbiased and reproducible manner. Machine learning is a subfield of AI where machines can perform pattern recognition without any explicit instruction. In this way, patterns and models may be generated based on datasets without the influence or unconscious bias of human input. Given sufficiently large datasets, machines are able to determine the optimal combination of relevant features to explain a given phenomenon. For example, machine learning can determine radiomic parameters that may be present in histopathologically and molecularly distinct subgroups of glioma in any given imaging modality. This abstraction becomes especially powerful given our relative inability to process a near infinite volume of voxel data.In the last two decades, there have been significant changes in the way GBM is imaged. Advanced imaging techniques now play a significant role in the current diagnostic and treatment paradigms. Diffusion and perfusion MRI are now routinely used for diagnosis of brain tumors. DTI and fMRI in combination are now part of current standard(s) of care for brain mapping prior to surgical resection. Intra-operative MRI, ultrasound, and fluorescent techniques are increasingly being adopted for more precise tumor surgery with significantly better operative outcomes. Advanced MRI techniques are also routinely used for assessment of treatment responses which is critical in the era of biologic/immune centered therapies. Such advanced imaging modalities are critical and physicians, surgeons and scientists look to advance treatments and improve clinical outcomes for patients in dire need.


Existing research has seldom examined patient safety problems experienced by service users accessing community mental healthcare, with the growing evidence base focusing largely on safety in psychiatric inpatient settings. Accordingly, there is poor understanding of safety issues in community-based mental health services as perceived by service users, carers, and healthcare professionals.This study aims to explore safety problems in adult community-based mental health services, their causation, and priority areas for improving the safety of care provided in these services.In-depth, semi-structured interviews and focus groups were conducted with users of community-based mental health services, carers, and healthcare professionals employed within these settings. Interview topic guides were designed jointly with stakeholders from these groups (N=7) and piloted (N=3). Interviews and focus groups will be transcribed, coded, and analysed using an inductive thematic analysis approach. Illustrative quotes will be extracted and used to describe the key themes that emerge from the analysis and their inter-relationships.This presentation will provide an outline of patient safety as understood and experienced by key stakeholder groups. Study findings will explicate safety issues, healthcare system factors underpinning their causation, as well as practices which could improve safety in this context.This research will help to advance understanding of the nature of patient safety problems in community-based mental healthcare services for adults, based on the experiences of service users, carers, and healthcare professionals within these services. The research will address key evidence gaps and represents an important step towards identifying areas which warrant intervention to improve patient safety.NS is the director of London Safety and Training Solutions Ltd, which offers training in patient safety, implementation solutions and human factors to healthcare organisations and the pharmaceutical industry. The other authors have no competing interests.


Chromosomal abnormalities are now considered a common cause of intellectual disability.With increased genetic testing, phenotyping and technological advancements, many newsyndromes have been identified. This review sought to explore parental stress andadjustment in the context of rare genetic syndromes to evaluate their clinical impact. Asystematic review of English peer-reviewed literature across three databases  was completed and 69 articles were included. Parents of children withrare genetic syndromes experienced greater distress relative to other disabilities.Differences in parental wellbeing were syndrome-specific relative to ASD thusdemonstrating the need to consider the contribution of syndrome-specific phenotypes. Childemotional and behavioural difficulties were the most consistent predictor of parentaldistress. Research reflecting other factors such as physical health, syndrome-specificbehaviours, benefit finding and, parental appraisal in the context of a rare geneticaetiology is required in order to support parental adjustment in these conditions. Rare conditions are characterised by their relatively low prevalence of less than 200,000people total in the United States and 1 in 2,000 people in the European Union . A recenWhile this technology brought a surge in research attempting to elucidate behaviouralphenotypes associated with rare intellectual disability syndromes , familieResearch has predominantly focused on challenges or adverse outcomes such as stress,burden, strain and mental health difficulties experienced by parents of children with adisability. Parents reported greater stress and psychological difficulties such as anxietyand depression with having a child with a disability relative to those without adevelopmental disability or relative to the general population . StudiesThere is a growing body of research that highlights the possibility of positivepsychological change or growth as a result of adversity . ResearcThe current review was primarily informed by two theoretical models; a Model of Stress inFamilies of Children with Developmental Disabilities  and the The receipt of a genetic diagnosis is an experience unique to parents of children withgenetic syndromes and the journey to diagnosis is often challenging and complex . ParentsScoping reviews use transparent and rigorous methods to synthesise research in order toclarify concepts, evidence and identify gaps in the literature . WhereasA comprehensive review of three databases  was completed toidentify relevant articles. The search extended from the origin date of each database toMarch 2020. Peer-reviewed quantitative, qualitative and mixed methods articles written inEnglish were included. All searches included a combination of keywords relevant to parents, stress/adjustment, rare geneticsyndromes  limited to the abstractsearch field and intellectual disability  in the full text field. Search terms were truncated where appropriate tomaximise the search outcomes. A follow up search was conducted with specific geneticsyndromes identified in the first search . All searches were performed betweenJanuary and March 2020.Articles were selected based on the following inclusion criteria: (a) studies presentedoriginal research published in a peer-reviewed English-language journal, (b) studyparticipants included parents of individuals with a rare genetic syndrome , and (c) the topic of study incorporated the general stress or adjustmentof parents of individuals with a rare genetic syndrome. The exclusion criteria were asfollows: (a) studies that pooled parents with other family members or groups, (b) studiesthat did not distinguish rare genetic syndromes from common syndromes , syndromes not commonly associated with intellectual disability or fromother physical disabilities, (c) review articles and, (d) articles that specificallyfocused on parenting programmes or interventions. The presence or absence of theintellectual disability phenotype as well as syndrome prevalence was checked against raredisease online resources  .Data extracted from full texts consisted of, the author(s), year of publication, title ofthe study, country of origin, demographics, methodology, and key findings .A deductive analysis of relevant findings from each full text was performed. Resultspertinent to the research question were then coded and grouped by their codes. Keyfindings were subsequently categorised into five key areas: (a) parental outcomes (b)child-related factors, (c) parent-related factors, (d) family-related factors and, (e)contextual factors.The electronic search yielded 2,924 articles; an additional 14 articles were identifiedthrough references from selected articles. After duplicates were removed, 1,511 articlesremained. Following screening of titles and abstracts, 1,398 articles were excluded. 113full text articles were assessed for eligibility and 44 were excluded (n = 4 excluded forno access). 69 full text articles were included in the final review . QuantitThe majority of quantitative studies used measures of stress , mental health  and/or caregiverburden/strain  toreflect adverse parental outcomes. Direct measures of positive affect or positive aspectsof having a child with a genetic syndrome , quality of life , or wellbeing, life satisfaction and, psychological adaptation were used less frequently. As such, many studies imply that the absence of negativeoutcomes such as stress, mental health difficulties or burden is equivalent to wellbeing.Multiple measures were used to represent parental outcomes in several studies thus thetotal number of measures used is not equivalent to the number of studies explored in thisreview. Qualitative studies (n = 13) were also included to provide a deeper understandingof factors associated with parental stress and adjustment in the context of having a childwith a rare genetic syndrome.Studies explored the prevalence of clinically significant parental outcomes relative topopulation norms, parents of typically developing children, Down syndrome and otherdisabilities. Within rare genetic syndromes, prevalence was also reported. Relative topopulation norms or typically developing populations, parental stress, psychologicaldifficulties was significantly higher across several syndromes including Prader-Willi,Cornelia de Lange, Angelman, Cri du Chat, Williams and Fragile X syndromes . Lower pGiven its prevalence, Down syndrome was used as a comparative group in a number ofstudies and different profiles of stress were observed across syndromes. Greater parentalstress was reported in Smith-Magenis, Williams, Prader-Willi and Fragile X syndromesrelative to Down syndrome . Stress Exploration of parental stress and wellbeing in rare genetic syndromes was contextualisedin relation to other disabilities including physical disability, intellectual disabilityand Autism Spectrum Disorder (ASD). Hodapp and colleagues reported high levels of parentalstress in Smith-Magenis and Prader-Willi syndromes relative to intellectual disabilities,particularly in parents of children under 11 years , 1998. HSyndrome-specific studies and comparative studies of rare genetic syndromes demonstratevariable prevalence rates of parent outcomes across syndromes. Rates of clinical stressranged from over 50%  to less than 30% , 2010. AIn order to explore the factors associated with parental adversity and wellbeing in raregenetic syndromes, the findings across these syndromes are pooled and discussed in foursub-sections: (a) child-related factors, (b) parent-related factors, (c) family-relatedfactors and, (d) contextual factors.A number of studies indicated that child age was not associated with parental stress, lifesaIn terms of child gender, the majority of studies demonstrated no effect of gender onparental outcomes . Two stuSeveral studies indicated no impact of level of intellectual disability on parentaloutcomes in rare genetic syndromes . WhileKStudies exploring the impact of child adaptive functioning on parental outcome haveproduced mixed results. Adaptive functioning typically refers to abilities in four keyareas: communication, daily living skills, socialisation, and motor skills. Parentingstress was associated with lower adaptive functioning in several studies wheredeficits in communication and socialisation were most commonly reported . SeveralSeveral instruments were used across studies to assess general behaviours  relative to parental outcomes. Subscales onparental measures of stress  also reflect child behaviours. Maladaptivebehaviours were consistently associated with parental outcome measures. Bothexternalising behaviour, i.e. aggression, challenging behaviour , and intParental wellbeing was also associated with reduced syndrome-specific behaviours suchas idiosyncratic face movements in Rett syndrome  and hypePhysical health and syndrome-specific features (e.g. Rett Syndrome BehaviourQuestionnaire) were explored and reported less frequently. Parental outcomes wereassociated with sleep disturbance , seizureMaternal uniparental disomy  has been found to be associated with poorer parental outcomes inPrader-Willi and Angelman syndromes  relativeVariable patterns of association between parental demographics  and parental outcomes were demonstrated across studies. Some studiesindicated that parental age was not associated with parental outcomes .HoweverRespondents were primarily mothers thus there was an imbalanced representation ofparental gender. The majority of studies that included both mothers and fathershighlighted no significant difference between maternal and paternal outcomes with theThe influence of education on parental outcomes was mixed. In some studies, a higherlevel of education was associated with greater parental wellbeing , howeverA number of studies demonstrated that parental outcomes measures were correlated. Forexample, psychological distress including anxiety and depression was associated withparental stress , strain Parental perspectives with regard to their role as a parent and with regard to havinga child with a rare genetic condition also influenced parental adjustment. Perceivedparental self-efficacy, benefit finding, parenting knowledge and satisfaction in thecaregiver role were associated with better outcomes . BenefitParent use of coping strategies was associated with stress , strainMarital status was not associated with maternal life satisfaction or physical qualityof life , howeverA number of measures of family functioning, support, coping and cohesion  assessed theinfluence of family factors. Parental wellbeing was promoted by greater family support and mariPositive parental outcomes were related to non-familial support from friends or otherparents  andhealContextual factors such as employment, financial and residential status and theirassociation with parental wellbeing were also explored. Due to caregiving demands,parents reported challenges with employment . ParentsThe aim of this review was to explore parental stress and adjustment in the context of raregenetic syndromes and examine factors associated with parental outcomes in order tohighlight gaps in knowledge, to promote parent adjustment and improve the provision offamily-centred care. The first key finding demonstrated that a significant proportion ofparents with children diagnosed with a rare genetic syndrome experienced clinicallysignificant levels of stress, strain and mental health difficulties relative to populationnorms, parents of typically developing children, parents of children with Down syndrome andparents of children with a physical disability or an intellectual disability of unknownaetiology. However, relative to ASD, the findings were more variable dependent on thesyndrome. The prevalence of ASD has been estimated at approximately 1 in 68  thusoccFurthermore, significant variation on parental outcome measures was observed across raregenetic syndromes. Syndromes such as Angelman, Cornelia de Lange and Smith-Magenis syndromereported higher prevalence of parental adversity relative to norms and relative to othersyndromes. This suggests that syndrome-specific phenotypes likely contribute to parentstress and adjustment. The importance of understanding the behavioural phenotypes of geneticsyndromes associated with intellectual disability has previously been argued . WaitehA number of factors were shown to influence parental stress in the context of their child’sgenetic condition. The findings demonstrated that both child maladaptive behaviour and childemotional difficulties consistently predicted poorer parental outcomes across rare geneticsyndromes. This association is consistent with existing disability literature . SignifiInterestingly, late childhood into early adulthood emerged as a potential risk period forparental adversity. Quality of life studies indicate that physical rather than emotionalparental wellbeing declines with both child and parental age at this time. This suggeststhat the physical demands of caregiving are a significant factor. This is supported by theassociation between lack of time resources, higher caregiving hours and poorer parentaloutcomes identified in this review. It is likely that a number of child and contextualfactors contribute to a greater burden of stress during this period. It has been highlightedthat maladaptive behaviours increased during adolescence in both disability and neurotypicalpopulations . FurtherTo date, much of the research has predominantly focused on how child-related factors impactparental stress and adjustment. Parental, family and contextual related factors have beenexplored in the research to a lesser extent. Parental stress or caregiver burden measureswere correlated with mental health measures, thus illustrating a reciprocal relationshipbetween these factors in genetic syndromes. This review also demonstrated differentialrelationships between parental coping strategies and measures of parental stress or mentalhealth difficulties suggesting that certain coping styles may have better outcomes dependingon type of burden experienced by parents. Both adaptive and maladaptive coping strategiesare evidenced highlighting that parents vary in their ability to cope and manage theirchild’s care needs in these syndromes. Self-efficacy and cognitive appraisal have previouslybeen shown to mediate the effect of child behavioural difficulties on parent stress in bothASD and developmental difficulties . This reThis review highlighted a number of gaps in the literature and considerations for futureresearch. Genetic syndromes are often reported to bring specific physical needs or complexmedical conditions however, the impact of such conditions have not been routinely exploredin rare genetic syndrome literature. Rett syndrome is a possible exception due thedevelopment of a Rett specific behaviour-related questionnaire. While some studiesdemonstrated an association between health conditions and poor parental outcomes, a numberof studies excluded any measure of health or physical limitations. In addition, despitethe likely contribution of syndrome-specific phenotype and behaviour to parental distress,few studies specifically explored behaviours directly associated with the studiedsyndrome, e.g. hyperphagia in Prader-Willi syndrome. This review highlights the need todevelop and incorporate syndrome-specific measures into future research in order tounderstand how syndrome-associated behaviour and health conditions contribute to parentaldistress. While it is apparent that some aspects of the impact of having a child with arare genetic syndrome are similar, there are also likely to be syndrome-specific aspectsthat are more pertinent for particular syndromes.Furthermore, findings in this review preliminarily suggest that the factors associatedwith parental stress and adjustment may be differentially associated between mothers andfathers. However, even in mixed parent gender studies, the respondents were predominantlymothers. Thus, future studies should purposefully seek out fathers as respondents in orderto explore any relational differences in parental wellbeing. A greater depth of researchis required to evaluate parental appraisal, coping and adjustment in rare geneticconditions. In particular, benefit finding in the parental experience as well as the roleof uncertainty and sense of agency or self-efficacy in the context of a genetic aetiologyshould be explored further. Few studies included measures of positive aspects or wellbeingand all, with the exception of one study, explored them in the context of mitigatingstress rather than as outcome measures. Thus, in the current literature, parentaladjustment is implied by the absence of negative outcomes rather than by the presence offactors associated with wellbeing such as autonomy, self-acceptance, purpose in life,environmental mastery, positive relationships, personal growth that interact andcontribute to psychological wellbeing .The current review has significant clinical relevance in the context of disabilityservices and family wellbeing. Firstly, it demonstrates the need to look beyond the levelof intellectual functioning when determining allocation of family resources in theseconditions and consider other child factors such as internalising and externalisingdifficulties, adaptive behaviour, physical health as well as syndrome-specific features.A strength of this study is the systematic and broad search that likely captured allrelevant articles published in academic journals. The search did not address greymaterial, a factor that may have resulted in missing relevant information. In addition,the absence of a quality assessment prior to study inclusion must also be acknowledged. Assuch, some of the conclusions drawn may be considered tentative. However, qualityevaluation of studies is not typically conducted in scoping reviews  due to tThis review aimed to explore parental stress and adjustment in rare genetic syndromes tohighlight the current gaps in knowledge, to promote parent adjustment and improve theprovision of family-centred care. Findings highlighted that parents of children with raregenetic syndromes experience greater distress relative to parents of children with Downsyndrome or with intellectual disabilities of unknown aetiology. Differences in parentalwellbeing were syndrome-specific relative to ASD thus demonstrating the need to considersyndrome-specific phenotypes. The relationship between parental outcomes and child emotionaland behavioural difficulties was the most consistent finding across studies. Researchreflecting other factors such as physical health, syndrome-specific behaviours, benefitfinding and, parental appraisal and coping in the context of a rare genetic aetiology isrequired in order to support parental adjustment in these conditions.Click here for additional data file.Supplemental Material, sj-docx-1-jld-10.1177_1744629521995378 for Parental stress andadjustment in the context of rare genetic syndromes: A scoping review by JacquelineFitzgerald and Louise Gallagher in Journal of Intellectual Disabilities


Cardiomyopathies are a heterogeneous group of structural, mechanical, and electrical heart muscle disorders which often correlate with life-threatening arrhythmias and progressive heart failure accounting for significant cardiovascular morbidity and mortality. Currently, cardiomyopathies still represent a leading reason for heart transplantation worldwide. The last years have brought remarkable advances in the field of cardiomyopathies especially in terms of understanding the molecular basis as well as the diagnostic evaluation and management. Although most cardiomyopathy treatments had long focused on symptom management, much of the current research efforts aim to identify and act on the disease-driving mechanisms. Regarding risk assessment and primary prevention of sudden cardiac death, additional data are still pending in order to pave the way for a more refined and early patient selection for defibrillator implantation. This review summarizes the current knowledge of hypertrophic, dilated and arrhythmogenic cardiomyopathy with a particular emphasis on their pathophysiology, clinical features, and diagnostic approach. Furthermore, the relevant ongoing studies investigating novel management approaches and main gaps in knowledge are highlighted. Cardiomyopathies encompass a diverse group of diseases characterized by structural and functional disorders of the heart in the absence of coronary artery disease, hypertension, valvular disease, and congenital heart disease sufficient to cause the observed myocardial abnormality. They can be either inherited and/or acquired and represent a leading cause of heart failure-related morbidity and mortality. Cardiomyopathies can present with heterogeneous clinical courses, ranging from an asymptomatic to a severely symptomatic phenotype which can present with heart failure, malignant arrhythmias, or sudden cardiac death . During HCM is the most common inherited cardiomyopathy. It involves mutations in numerous genes encoding sarcomeric proteins and is transmitted in an autosomal dominant manner with variable penetrance. Historically, HCM was first defined in 1868 by Vulpian et al. as an idiopathic hypertrophic subaortic stenosis . In the HCM is defined as the presence of an increase in wall thickness (greater than 14 mm) in one or more LV segments, as measured by an imaging technique, which cannot be justified by abnormal loading conditions. The estimated prevalence according to epidemiological studies ranges from 1:200 to 1:500 with an annual mortality rate of approximately 1.4% . Di. Di32]. Septal reduction therapy at experienced centers is indicated in patients with a resting or provoked obstructive disease who remain symptomatic despite optimal medical therapy (Class I-recommendation)  33]. Co. Co33]. According to the latest European guidelines, a 5-year-SCD assessment is recommended (Class I-recommendation) in all HCM patients in order to identify candidates who will benefit from primary prevention using an implantable cardioverter-defibrillator (ICD) . To thisAdvances in understanding the genetic mechanisms of HCM has led to an increasing interest to develop targeted molecular therapies which improve symptoms and positively influence the disease course .Recently, mavacamten (MYK-461) has emerged as a novel allosteric inhibitor of cardiac myosin adenosine) triphosphatase (ATPase) sarcomere level, causing a reduction of the cardiomyocyte hypercontractility and promoting cardiac muscle relaxation. Its beneficial effects on HCM patients were first shown in the phase 2 PIONEER-HCM trial. The results were promising since mavacamten was associated with improvement of post-exercise LVOT-gradient and exercise capacity in patients with obstructive HCM . FollowiHCM cardiomyocytes are characterized by an enhanced late sodium current activity, leading to increased levels of intracellular calcium which ultimately contribute to arrhythmic propensity. Moreover, the intracellular sodium overload promotes the cardiomyocyte diastolic dysfunction and impaired myocardial perfusion ,45. RanoThe inefficient phosphate metabolism observed in HCM patients is another target of novel therapies. Perhexiline  was initially utilized as an antianginal treatment because of its coronary dilatator effects. Successively, this agent had demonstrated positive effects on the myocardial energetic status by shifting the myocardial metabolism from fatty acid to glucose utilization and consequently ameliorating the myocardial efficiency by increasing ATP production . This obDCM is defined as dilatation of the left or both ventricles and systolic dysfunction in the absence of abnormal loading conditions  or significant coronary artery disease sufficient to explain a global systolic impairment . DCM repThe causes of DCM are heterogeneous and can be broadly classified into genetic and nongenetic. Gene mutations occur in up to 40% of DCM cases and usually involve genes encoding for cytoskeletal, sarcomere and nuclear envelope proteins . InteresMore than 50 DCM-related genes have been shown to be implicated in the pathogenesis of DCM. Most of these genetic alterations have an autosomal dominant inheritance pattern; however, other patterns have been reported including autosomal recessive, x-linked, mitochondrial and polygenic . MutatioAbout 5% of DCM cases are linked to mutations in the Lamin A/C (LMNA) gene encoding to lamin proteins A and C involved in the stabilization of the inner nuclear lamina in cardiomyocytes. Notably, LMNA mutations have been shown to be associated with malignant ventricular arrhythmias and a high incidence of SCD. Moreover, LMNA mutations have been described in patients with muscular dystrophy Emery-Dreyfus (EDMD), limb-girdle-dystrophy, axonal neuropathy type 2 Charcot- Marie-Tooth, and familiar partial lipodystrophy . Other mTo date, mutations in metabolic genes as a direct cause of DCM have not yet been reported in humans. However, recent findings from an animal model showed that suppression of cardiac low-density lipoprotein receptor-related protein 6 (LRP6) expression is associated with altered cardiac fatty acid utilization and lethal DCM. Subsequently, further human studies to determine the extent of contribution of fatty acids metabolism in the pathogenesis of DCM could help to elucidate disease pathogenic events .Although myocarditis usually heals completely, it is reported that up to 6–30% of cases may shift in DCM with worsening of cardiac function . MyocardIn the western countries, excessive alcohol intake has been shown to be associated with up to 36% of DCM cases . The posPeripartum cardiomyopathy (PPCM) is a rare, often dilated, cardiomyopathy with heart failure secondary to LV systolic dysfunction affecting childbearing women in late pregnancy or up to 5 months postpartum. Potential risk factors for PPCM include race (mainly Afro-Caribbean descent), multiparity, advanced maternal age and presence of hypertension with or without pre-eclampsia. Although the exact pathogenesis of PPCM is still not fully established, the proposed etiology is multifactorial. A main proposed mechanism suggests an unbalanced peripartum oxidative stress that triggers the cleavage of the nursing hormone prolactin into a potent antiangiogenic and proinflammatory fragment leading to endothelial and cardiomyocyte dysfunction . Recent Usually, DCM presents typical signs and symptoms of congestive heart failure as progressive dyspnea, ankle swelling and orthopnea. Other forms of initial presentation include arrhythmias , thromboembolic events and SCD. In fewer cases, asymptomatic cardiomegaly may be the first presenting sign .Echocardiography has crucial importance in the diagnosis, follow-up and family screening of DCM. The main echocardiographic diagnostic feature is characterized by presence of LVEF < 45% and LV end-diastolic diameter (LVEDD) or volume greater than two standard deviations according to nomograms corrected by age, gender and body surface area . These fThe presence of right ventricular dilatation and dysfunction correlates usually with a worse functional status and more advanced stages of heart failure . Recent CMR offers a highly sensitive assessment of global biventricular size and function. Moreover, CMR enables through LGE assessment detection of myocardial fibrosis and oedema, which allows a differentiation among various causes of DCM . In thisIschemic cardiomyopathy can be differentiated from DCM by echocardiography in the vast majority of cases. However, ischemic cardiomyopathy may present as global hypokinesis mimicking DCM. In these situations, coronary angiography should be considered to exclude ischemic cause, especially in the presence of risk factors for coronary artery disease . In patiCurrently, the American and European Heart Rhythm Societies recommend genetic testing for DCM patients and their first-degree relatives in the presence of significant conduction disease and/or a family history of SCD. Relatives who do not carry a pathogenic variant are reassured and discharged from ongoing cardiac follow-up. On the other hand, carriers of a familial variant should undergo close clinical surveillance ,77.The management of DCM is focused on reducing congestive heart failure symptoms as well as early surveillance and treatment of arrhythmia.The pharmacological treatment of heart failure in DCM patients with reduced LVEF follows the current guideline-directed therapies which includes angiotensin-converting enzyme (ACE) inhibitors (or Angiotensin receptor blockers (ARBs)), in association with beta-blockers, and mineralocorticoid antagonists . Incremep = 0.002) ..113].An International Task Force Consensus Statement proposed a risk stratification algorithm for preventive implantation of ICD, based on a review of observational cohort studies in patients with right ventricular variants of ACM . AccordiCurrent management in ACM patients is limited to symptom relief and prevention of SCD. However, novel therapeutic approaches targeting the underlying genetic and molecular mechanisms are on the horizon.In preclinical ACM models, application of adeno-associated virus (AAV) gene therapy targeting PLN-gene mutation by delivering antisense ribonucleic acid (RNA) has been shown to restore normal calcium handling .Recent promising findings from a translational study highlighted an involvement of extra-cardiac bone marrow (BM)-mesenchymal stem cells (MSCs) in the pathogenesis of ACM. The examination of both cardiac- and BM- MSCs isolated from DSG2-mutant mice showed profound alterations in cytoskeletal organization, which are directly caused by DSG2 downregulation. Interestingly, the mutant circulating BM-MSCs have shown an increased propensity to migrate to the injured region of the heart . This fiIn recent years, we have witnessed growing improvements in cardiovascular imaging modalities as well as a deeper knowledge of genotype–phenotype correlations in the field of cardiomyopathies, which in return brought significant advances in the diagnostic and therapeutic decision-making. On the other hand, there are still a number of unanswered questions due to knowledge gaps.In HCM, SCD remains the most devastating and challenging presentation since it may occur without preceding symptoms. Indeed, the developed risk stratification models adopted by the American and European societies are still imperfect since they are primarily based on registries, retrospective, or prospective small-scale studies.Another issue is related to the assessment of myocardial fibrosis by CMR through LGE. In fact, there is still no universal standardized technique for the quantification of LGE  technique) . FurtherConcerning familial cases of DCM, recommendations for familial cascade screening to identify relatives at risk of developing the disease have been well established by current guidelines. However, there is still no specific evidence for early pharmacological treatment in phenotype-negative carriers of pathogenic genetic variants to prevent LV remodeling or cardiovascular mortality.Although the fact that around one-third of patients with DCM experience a relapse in chronic disease after an initial recovery of LVEF, current guideline recommendations for DCM treatment still do not vary from general heart failure management . TherefoAnother remarkable challenge emerged from the refinement of primary ICD indication in non-ischemic DCM by respective guidelines which well delineated the limitation of relying mainly on LVEF . New insLastly, a growing body of evidence based on pathological and clinical studies in patients with right-sided phenotypic variants of ACM has provided significant insights into the clinical manifestations, risk stratification, and indications for primary SCD-prevention. However, prospective data on clinical outcome and predictors of arrhythmic burden in patients with biventricular or left-dominant ACM are still lacking in the current guidelines’ recommendations. Another issue to overcome concerns the effectiveness and safety of applying catheter ablation techniques in the management of atrial arrhythmias in ACM. Further, psychosocial stress has been recently suggested as an independent risk factor involved in the pathogenesis of ACM by promoting disease penetration . In the


Maintaining spontaneous breathing has both potentially beneficial and deleterious consequences in patients with acute respiratory failure, depending on the balance that can be obtained between the protecting and damaging effects on the lungs and the diaphragm. Neurally adjusted ventilatory assist (NAVA) is an assist mode, which supplies the respiratory system with a pressure proportional to the integral of the electrical activity of the diaphragm. This proportional mode of ventilation has the theoretical potential to deliver lung- and respiratory-muscle-protective ventilation by preserving the physiologic defense mechanisms against both lung overdistention and ventilator overassistance, as well as reducing the incidence of diaphragm disuse atrophy while maintaining patient–ventilator synchrony. This narrative review presents an overview of NAVA technology, its basic principles, the different methods to set the assist level and the findings of experimental and clinical studies which focused on lung and diaphragm protection, machine–patient interaction and preservation of breathing pattern variability. A summary of the findings of the available clinical trials which investigate the use of NAVA in acute respiratory failure will also be presented and discussed. Competing evidence has suggested both beneficial and deleterious consequences of spontaneous breathing during assisted ventilation when compared to controlled mechanical ventilation, in patients with acute respiratory failure . In factFurthermore, spontaneous breathing during mechanical ventilation, when improperly applied, may itself aggravate lung injury . PathwayProportional modes of ventilation, such as proportional assist ventilation with load-adjustable gain factors (PAV+) and neurally adjusted ventilatory assist (NAVA), have the potential to deliver lung and respiratory muscle protective ventilation by preserving the physiologic defense mechanisms against both lung overdistention and ventilator overassistance, as well as reducing the incidence of diaphragm disuse atrophy, while optimizing patient–ventilator synchrony . In thisTwo main mechanisms contribute to the occurrence of lung injury: volutrauma or barotrauma (overdistension) and atelectrauma  . It is iPatient–ventilator dyssynchrony is the uncoupling of the ventilator  delivered breath and patient  respiratory effort. Such mismatch can be classified into timing and flow assist asynchrony: the former relates to a discrepancy between the timing of the patient neural respiratory cycle and that of the ventilator and can potentially happen during triggering, insufflation and cycling off, with extremes such as auto-triggering and ineffective efforts . Flow asDuring assisted ventilation, desynchronization of patient effort and ventilator support occurs commonly and is related with ICU and hospital length of stay and duration of mechanical ventilation ,22,23. IAn inadequate titration of mechanical support can also injure the respiratory muscles, leading to myotrauma and the so-called ventilator-induced diaphragm dysfunction (VIDD) ,31. BothIntegration of lung-protective ventilation principles and the growing concept of diaphragm-protective ventilation is the key to a new approach: targeting an effort level that can protect the respiratory system from both hazards ,40.Proportional ventilatory modes are designed to optimize patient–ventilator interaction and deliver lung and respiratory-muscle protective ventilation . These mWhile under mechanical assistance, both the patient and the ventilator participate to generate the pressure needed to overcome elastic and resistive forces, as outlined by the equation of motion of the respiratory system :(1)Ptot=2, tidal volume increases approximately in a linear fashion with inspiratory effort during unassisted ventilation . Th. Th59]. Brender implemented the information derived from transoesophageal electrocardiogram interpretation, considering the relative position of right atrium and diaphragm . In the A simplified approach is based on the formula including measurement from Nose to Ear lobe to Xiphoid process of the sternum  , modifieData on normal EAdi reference values are limited : differe2O/μV), so that at every time, the pressure delivered to the respiratory system is:Under neutrally adjusted ventilator assist, the EAdi signal, measured in microvolts, is multiplied by a user-controlled gain factor, the NAVA level  above the baseline and cycling off depends on reduction of the signal at a fixed (preset 70%) percentage of the peak value. The use of electrical trigger and cycling-off criteria allows for preservation of the physiological variability of respiratory drive, improved patient–ventilator synchrony and unloading of respiratory muscles while avoiding overassistance. Moroever, EAdi is independent from pressure and flow generated in the respiratory system, therefore, assisted ventilation is guaranteed even in presence of high PEEP or air leaks .NVE describes the capacity of the respiratory muscles to generate pressure and ventilatory volume. It can be calculated as the ratio between tidal volume and EAdi during an unassisted respiratory act  . This inTo quantify the relative contribution of the patient versus the ventilator to the inspiratory tidal volume, Grasselli and colleagues proposed the PVBC, calculated as the ratio of NVE during assisted and unassisted breaths .Bellani et al. developed an index that relates the electrical activity of the diaphragm during NAVA (EAdi) to the pressure generated by the respiratory muscles (Pmusc)  NME quanSeveral strategies have been proposed to adjust the NAVA level gain factor, each with its principles, advantages and drawbacks. The main methods are reported in The first method proposed is based on a “pressure matching” setting with the NAVA preview option. A curve is displayed on the ventilator in a different color, which shows an appraisal of the airway pressure that would be delivered if NAVA mode were applied. The NAVA preview (Paw) curve profile is proportional to diaphragm electrical activity and the amount of assist depends on EAdi amplitude and NAVA level setting.Notably, the mechanical energy supplied to the lung, even when the peak pressures are similar, is lower in NAVA than PSV because proportionality implies a smaller area under the Paw curve. Hence, it is possible to set an inspiratory assist to obtain peak or mean airway pressure values similar to the ones previously reached during PSV (Paw matching). However, the application of this principle entails the risk of frustrating the full-range of potential advantages of NAVA ventilation itself , as the Another NAVA level setting requires targeting the same minute ventilation obtained in PSV with protective volume at a fixed respiratory rate (ventilation matching) . HoweverMore recent methods have been developed to make the best use of EAdi potentials. NAVA level titration can be performed by systematically rising the gain factor to identify an ideal level of respiratory muscle unloading . BranderAnother EAdi-guided method was proposed by Rozé and colleagues: the authors arbitrarily titrated NAVA level targeting an EAdi equivalent to 60% of the amplitude peak produced in a daily spontaneous breathing trial (SBT), and applied for the first time a method which was based directly on the observation of diaphragm activation . SystemaCampoccia et al. assessed the feasibility of titrating the NAVA assist on different levels of muscle unloading via the application of the neuro-ventilatory efficiency index . ModeratAs described earlier, NAVA allows physiological ventilation protective mechanisms to operate unhampered. Since during proportional ventilation, the mechanical inflation strictly pursues patient ventilatory demand, if inspiratory time is reduced because of Hering–Brauer reflex activation, then the tidal volume delivered will be proportionally lower. Moreover, as the airway pressure-time curve has a triangular-shaped profile, yielding lower mean Paw and transpulmonary pressures compared to PSV, this may prevent VILI occurrence. NAVA has a beneficial effect on the ventilation of the dependent regions in patients with injured lungs ; data obBrander and colleagues indicated that VILI  and non-pulmonary organ damage were significantly lower in NAVA and conventional low Vt controlled ventilation strategy compared to high tidal volume-controlled ventilation in 27 rabbits with induced ARDS .2 than with PSV, while the ventilator modes did not affect patients’ dyspnea, limb fatigue, distance, hemodynamics and breathing pattern, suggesting a possible enhancement of the training effect and facilitation of rehabilitation [During assisted ventilation, a reliable measure of respiratory system mechanics is necessary to protect the patient from the risk of self-inflicted lung injury ,86. Graslitation .Proportional ventilation may also facilitate a diaphragm-protective ventilation, avoiding both over- and underassistance. The effects of NAVA and PEEP on breathing pattern during experimentally induced acute lung injury have been studied in a small animal model . The autShimatani et al. suggested that maintaining spontaneous breathing, both with NAVA and PSV, could be beneficial on preventing diaphragm atrophy . The autRecently, Scharffenberg and colleagues conducted a randomized study to assess lung and diaphragmatic function in a ARDS-induced porcine model . Twenty-Clinical data suggest that NAVA may facilitate weaning —from a p2 values; moreover, ventilatory rate and tidal volumes are adjusted to optimize work of breathing and lung stress and strain. The electromyographic signal of diaphragm activity integrates information provided by feedback systems from respiratory system mechanoceptors, vagal afferences and central respiratory centers [2 [NAVA ensures greater variability and therefore a more physiologic breathing pattern, which is one of the cofactors determining gas exchange improvement. EAdi reflects natural adaptation targeting the preservation of PaCO centers ,99. NAVA centers ; consistnters [2 ,100. Indnters [2 .NAVA has the potential benefit of optimizing neuromechanical coupling, reducing the likelihood of asynchrony during mechanical ventilation. As outlined above, proportional modes, by their very definition, supply a ventilatory assist as close as possible to the patient’s physiological needs. The use of EAdi as the criteria to trigger (even in patients with high intrinsic PEEP) and cycle-off the ventilatory support is the finest approach developed so far to achieve human–machine harmonization .Beck et al. considered the different patterns of interaction and muscle unloading in response to two different modes of assist: ARDS was induced in 12 rabbits and various levels of PSV and NAVA assistance were compared on synchrony, breathing pattern variability, mechanical work of breathing (expressed as transdiaphragmatic pressure time product-PdiTP) and electrical energy consumption (as EAdi time product-EAdiTP) . The incThe same authors also assessed whether NAVA could supply ventilatory assistance employing non-invasive interface in rabbits . Even ifA prospective interventional study in 22 spontaneously breathing patients intubated for acute respiratory failure found that NAVA, as compared with PSV, reduced trigger delay and total asynchrony events from an average of 3 to 1 event/minute; no ineffective effort or late cycling was observed, and premature cycling was significantly reduced with NAVA .As opposed to PSV, this ventilatory mode led to patient–ventilator interaction improvement in observational studies . SchmidtIn the only physiologic study comparing NAVA and PAV+ in adult patients, Akoumianaki et al. found that PAV+ performed better than NAVA when elastic load increased: the authors found that the linear correlation between tidal volume and the inspiratory integral of transdiaphragmatic pressure was weaker with NAVA than with PAV+ and PSV on account of a weaker inspiratory integral of the electrical activity of the diaphragm–transdiaphragmatic pressure linear correlation during NAVA. The authors questioned whether such a weak EAdi-PTPdi integral linear relationship during NAVA might limit its effectiveness to assist the inspiratory effort .Neurally adjusted ventilation has not yet, to our knowledge, conclusively demonstrated improved patient-centered outcomes in any clinical trial, nor has it been extensively adopted into clinical practice. As an example, Hadfield et al. could not find a superiority of NAVA compared with PSV in terms of ICU or hospital stay, duration of MV or mortality .Several technological aspects may relate to this limitation. During NAVA an EAdi increase >0.5 μV above baseline triggers inspiratory assist and cycling is determined by a fall at a pre-set percentage of its peak value. In the absence of a quality EAdi signal, assisted breaths can be initiated either by variations in Paw or flow, depending on which trigger happens first. Indeed, the electromyographic signal is independent from pressure and flow, thus, triggering is not affected by the presence of air-leaks or autoPEEP . NonetheIn the end, the exact reasons for the differences between the theoretical advantages and the practical use of NAVA remain to be investigated. Even though ‘technical issues’ was most commonly selected as the most important single disadvantage in a recent clinical survey, ‘low experience, skills or confidence’ were pointed out as a major barrier to acceptance and implementation of NAVA . ContextAutomated (computerized) weaning from mechanical ventilation has recently been suggested as an attractive alternative to usual physician-driven weaning, for its potentially beneficial effects in terms of reduction of the duration of mechanical ventilation. Such modes were originally developed to overcome the clinicians’ underrecognition of patients’ ability to breathe without assistance, prolonging mechanical ventilation and increasing the incidence of its complications ,114,115.Optimizing ventilator machine–patient interaction, minimizing ventilator-related and self-inflicted lung injury, reducing myotrauma are the main strategies to improve the outcome in patients with acute respiratory failure. Most clinical trials advocating the use of NAVA in patients with acute respiratory failure considered pressure support ventilation as the comparator, established treatment mode . In geneColombo and colleagues performed the first study of NAVA in critically ill patients, evaluating the response to different levels of ventilatory assistance . They inDemoule et al. conducted a randomized multicenter study which enrolled patients who received mechanical ventilation for more than 24 h for acute respiratory failure with a respiratory cause . Sixty-t2O. When compared to PSV, NAVA reduced patient–ventilator asynchrony index, by reducing triggering and cycling delay, and generated, during an SBT, a similar breathing pattern.Ferreira and colleagues designed a crossover trial on 20 mechanically ventilated patients who underwent an SBT in PSV or NAVA . This isLiu et al. performed a randomized monocentric trial to investigate whether NAVA was more effective in difficult-to-wean patients when compared to PSV . Ninety-Hadfield and colleagues compared NAVA and PSV in patients at risk of prolonged mechanical ventilation  in a feasibility RCT . NAVA leDiniz-Silva and colleagues compared NAVA and PSV in providing protective ventilation in ARDS patients . ARDS paKacmarek et al. carried out a multicenter, randomized controlled trial under the hypothesis that NAVA, compared to conventional lung-protective mechanical ventilation, may determine benefits on ventilator-free days and mortality in patients with acute respiratory failure . The stuSome recent systematic reviews and meta-analyses compared either NAVA alone or proportional modes (NAVA and PAV+) with conventional assist ventilation: Yuan et al. included 7 studies suggesting that NAVA might be superior to PSV in difficult-to-wean patients ; Chen etNeurally adjusted ventilation assist provides the potential for lung and diaphragm protective ventilation. This ventilatory mode allows physiological mechanisms to minimize the probability of volutrauma and atelectrauma, patient–ventilator asynchrony and myotrauma, while optimizing breathing pattern variability and patient–machine interaction. Indeed, the same beneficial effects of NAVA on lung and diaphragm protection and patient–ventilator interaction might apply to PAV+ as well, since both proportional modes share the same operational principles.Setting NAVA level may be challenging in everyday clinical practice: inspiratory assist, respiratory muscle effort and unloading all need to be tailored to each patient and clinical situation. During NAVA, an optimal inspiratory assist level titration can be achieved by different means. Different approaches, based on various physiological assumptions, have been explored so far and this represents an interesting field for further investigation.In conclusion, various clinical trials concluded that NAVA mitigate the risk of overassistance, reduced patient–ventilator asynchrony and improved patient–ventilator interaction, leading to a reduced duration of mechanical ventilation. These results seem to be even more promising in specific conditions and setting. While we wait for more conclusive evidence regarding the impact of neurally adjusted ventilatory assist on patient-centred outcomes, we suggest that the application of NAVA in acute respiratory failure patients might lead to clinically relevant results, especially if the whole range of advantages of proportional ventilation are considered with a careful titration of the inspiratory assist.