As one of the most common neurological diseases in children, epilepsy affects 0.9–2% of children. Complex interactions among the etiologies of epilepsy, interictal discharges, seizures, and antiepileptic drugs lead to cognitive impairments in children with epilepsy. Since epilepsy is considered as a network disorder, in which seizures have a widespread impact on many parts of the brain, childhood epilepsy can even affect the normal development of language. About 25% of children with epilepsy do not respond to medications; therefore, brain surgery is considered as a treatment option for some of them. Presurgical neuropsychological evaluations including language mapping are recommended to preserve cognitive and language abilities of patients after surgery. Functional magnetic resonance imaging as a non-invasive technique for presurgical language mapping has been widely recommended in many epileptic centers. The present study reviewed language representation and presurgical language mapping in children with epilepsy. Mapping language in children with epilepsy helps to localize the epileptogenic zone, and also, to predict the cognitive outcome of epilepsy surgery and possible cognitive rehabilitation. This review collected information about language representation and language mapping in pediatric epilepsy settings.  As a neurological disease, recurrent and unprovoked seizures are the main symptoms of epilepsy . EpilepsCognition and language in pediatric epilepsyComplex interactions among the etiologies of epilepsy, interictal discharges, seizures, and antiepileptic drugs lead to cognitive impairments in epilepsy  . Frequent focal interictal discharges affecting the perisylvian regions, without any significant brain lesion or neurologic history, are the main characteristics of benign epilepsy of childhood with centrotemporal spikes (BECTS), which is a localization-related seizure disorder . About 1Children’s language development studies started in the 1960s . It has Since epilepsy is considered as a network disorder, and seizures have a widespread impact on many parts of the brain, childhood epilepsy can affect the normal development of language. It is not known how childhood-onset epilepsy affects functional language networks . LanguagIt is claimed that a genetic mutation or a structural lesion causes both seizures and language disorders, because even after seizure control, language problems are reported in children with new onset seizures, and are not always resolved . Speech Overvliet et al.  stated tSome recent studies have proposed that there are dorsal and ventral processing streams connecting Broca’s area with the temporal and parietal language cortex . The venIt appears that the ventral stream tracts mature early in infancy, while the tracts of the dorsal stream (arcuate fasciculus) continues to develop into adolescence . Croft eLanguage laterality  is the phenomenon, in which one hemisphere shows greater involvement in language functions than the other . To deteSome researchers have reported that developmental aspects of language laterality in typically developing children are not fully characterized . Some otThere are contradictory findings about age-related language lateralization. Some studies have reported that lateralization continues to increase with age . On the Weiss-Croft and Baldeweg  conducteBerl et al.  investigShtyrov et al.  carried Imaging studies have shown atypical language laterality and the asymmetry of cortical activity during linguistic tasks in patients with epilepsy . AtypicaOther fMRI studies also showed atypical language lateralization in children with epilepsy , 40. RigGaillard et al.  investigSome studies have also reported different findings about types of epilepsy with a larger effect on language. Other studies have also found that children with absence epilepsy have worse language performance than children with focal epilepsy .Ojemann et al.  reportedPatients with epilepsy-aphasia spectrum, including LKS and benign epilepsy, share features of sleep-potentiated EEG abnormalities, rare or even absent clinical seizures, and cognitive problems .Children with LKS, as the canonical example of the epilepsy-aphasia spectrum with previously normal development, face a progressive language regression. They may lose the ability to understand speech, and speech production diminishes in the end . Presurgical evaluationin children with intractable epilepsy It has been reported that about 25% of children with epilepsy do not respond to medications . Brain sEpilepsy surgery is considered as highly successful if children with intractable focal epilepsy are selected carefully based on presurgical evaluations . It has Téllez-Zenteno et al.  conductePresurgical assessment including data from video electroencephalographic (video EEG) recordings, structural and functional imaging as well as neuropsychological and clinical assessments are considered necessary for presurgical structural and functional mapping to preserve cognitive and language abilities after surgery.It has been claimed that brain anatomy alone cannot show language areas and may cause risk of injury in epilepsy surgery , 51. To fMRI is based on the observation that increased neuronal activity is associated with tightly-regulated and regionally-specific increases in the cerebral blood flow . DetectiConsidering the challenges of fMRI language mapping in clinical settings, the procedure has been recommended to be applied in children with epilepsy, even as young as 5–7 years of age . The most commonly used tasks for presurgical language mapping with fMRI are based on verbal fluency to identify expressive language functions in the dominant hemisphere . Verbal Language mapping with the same or developmentally-adapted paradigms leads to similar results in children as in adults . Althoug.To the best of our knowledge, there is no documented report on pediatric language mapping in Iran. There are some studies on the assessment of normal language development as well as developmental language impairments in Iranian children. Nilipour et al.  comparedIt is not still clear which language and memory paradigms produce optimal activation for children and how these should be quantified in a statistically robust manner . HoweverIn Conclusion, Precise presurgical language mapping as a non-invasive method has been proven to be helpful for children with intractable epilepsy to preserve their language abilities after surgery. Moreover, it has been indicated that epilepsy may affect normal language development and laterality in some children. Since possible language impairments can affect social interaction and academic achievements in epileptic children, it is highly essential to know how language is processed and represented in children with epilepsy and possible language disorders in epileptic children in both presurgical and postsurgical stages. Further, as the results of studies in clinical settings on pediatric epilepsy in other cultural settings indicated, it is not still clear which language and memory paradigms produce optimal activation for children and how these should be quantified in a statistically robust manner (t manner . Linguistic and culturally standardized presurgical language mapping paradigms are recommended for Persian speaking children with intractable epilepsy to preserve their language abilities after surgery. Finally, the results of fMRI language mapping as a non-invasive method based on culturally and linguistically standardized paradigms can help us to specify the laterality index and regions of interests to promote quality of life in the affected children, even in the post-surgery stage.Mahdieh Karami: prepared the first draft of the paper Reza Nilipour, was the corresponding author of the manuscript and revised the article Majid Barekatain: Reviewed the related literature and contributed to the discussion William D. Gaillard: supported the preparation and writing of the manuscript, made substantial contribution in developing and eviewing the related literature and discussion.


Classification is taxonomic nomenclature system established for the purposes of statistical analysis of the phenomena and in order to facilitate and uniform the language of professionals in different countries. Classification systems in medicine, hence in psychiatry are composed of nosological units. The latter as well as the relevant methods for their exploration are characterized with the criteria of validity, reliability, specificity, and sensitivity.it is intended to capture. In other words, when we introduce a term like “depression” or “depressiveness” as a symptom and develop relevant instruments to measure it , we are supposed to ascertain that it measures specifically depression and not some other related, phenomenon, e.g. delusions. When two different assessment tools for depression happen to coincide in their score/interpretation, it is regarded as convergent validity, and whenever their results are discrepant it is considered as divergent or discriminative validity. Divergent validity should generally characterize phenomena which differ each from other and in this respect is supposed to assist differential diagnosis between them. In this context, a valid measure (e.g. test) for depression should have convergent validity with other test, established to assess depression and discriminative validity with tests, designed for assessment of paranoid delusions. In other fields of medicine, external criteria for validity are introduced, such as biological measures. No such criteria have been introduced so far in clinical psychiatry.Whenever we introduce some term, method or assessment system, we should inquire whether it can capture the exact phenomenon relatively high level of reliability  and problematic validity .Psychiatric diagnosis is characterized with Over the past two decades there have been established mainly post-hoc correlations between the different types of clinical tools  on one hand and imaging neuroscience. This far different kinds of measures represent mere statistical correlations with limited or no reference to the mechanism of disorder and therefore cannot be effectively translated and embodied into normative criteria, diagnostic standards, and clinical evaluation procedures . This unsubject of reification that procedures of translation may address? Is it the clinical assessment inventory/test that is reified by means of functional MRI for example or the opposite?There has been raised a conceptual issue: What is the Squarcina et al.) and PVSAT/PASAT .This Research Topic has particular focus on whether and to what extent it is feasible to translate data from multimodal neuroimaging in terms of cross-validation against different trait and state measures, such as the Temperament and Character Inventory or Paranoid-Depressive Scale , the most powerful functional MRI pattern which allows discriminative validation of schizophrenia from affective disorders is comprised of BOLD signal corresponding to negative signature on depressive items response and positive signature to neutral items response from interest scale along with the signal associated with paranoid items. Essentially this means that neutral items are not neutral for patients with schizophrenia, but incorporated into their psychotic disturbance system.In one of the presented papers in this Research Topic  instability of the default mode network (DMN) and impaired cognitive control when patients experience auditory verbal hallucinations (AVH), and 2‑3) preliminary possibility to disentangle brain activation due to paranoia in schizophrenia and depression by using a self-evaluation scale. Three investigations explored mood disorders, reporting 1) mismatch between cerebral blood supply and oxygen metabolism in bipolar disorder, being a potential brain sign of energy homeostasis inefficiency, 2) no effect of the BDNF genotype on encoding-related neural activity in bipolar patients, with a superior memory performance in Met carriers, and 3) symptom improvement after 3-weeks of repeated transcranial magnetic stimulation (rTMS) therapy on the left dorsolateral prefrontal cortex (5 consecutive weekdays every week) in patients with unipolar depression. Three other reports detected fascinating results in different pathologies suggesting: 1) reduced interhemispheric functional connectivity in patients with obsessive-compulsive disorder (OCD), 2) activation in left Brodmann area (BA) 40  as a possible mechanism for diminishing fatigue impact on cognitive functioning in cognitively preserved patients with multiple sclerosis (MS), and 3) brain reorganization due to pre-/perinatal damage in left hemisphere .Interestingly, in healthy subjects the biochemical brain basis  of specific personality traits during adolescence were here presented with particular regards to self-directedness and self-transcendence along with the functional brain activations during memory paradigm performance after intensive learning particularly in both occipital and temporal regions.Three single cases reported intriguing perspectives on delirious mania , schizophrenia , and Alzheimer’s disease (PSEN-1 gene mutation in an early-onset patient). Finally, five reviews described the state of the art of cognitive and neuroimaging correlates in PTSD, depression, substance abuse and eating disorders, debating their translational and clinical implications, and future directions whereas.In conclusion, we believe this is a comprehensive and well composed Research Topic of Frontiers in Psychiatry pointing out key topics for translational psychiatric neurosciences and neuroimaging. In particular, this Research Topic corroborated the fact that nowadays, we need further research on the genetic, neurobiological, and cognitive bases of major psychiatric disorders in order to better delineate different domains charactering commonalities and dissimilarities across different spectrum and continuum diagnostic prototypes . This wiBoth authors have contributed on equal basis to this paper.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Innovations in medical technology have revolutionised both medical and surgical practice. Indeed, with such innovations, training for specific specialties has become more advanced and streamlined. However, despite these novel approaches to train students and specialist trainees, training for interventional radiology (IR) is lagging. While the reason for this lag remains contentious, one of the primary reasons for this issue may be the lack of standardisation for IR training due to a scarcity of specific guidelines for the delivery of IR procedural training. Interventional radiologists manage a vast array of conditions and perform various procedures. However, training for each procedure is largely dependent on the centre and access to a range of cases. Recently, the use of simulation technology has allowed this issue to be addressed. Simulation technology allows trainees to participate in a range of procedures regardless of their centre and availability of cases. Specialties such as cardiology and vascular surgery have already adopted simulation-based technology for trainees and have commented positively on this approach. However, simulation-based training is still lacking in the IR training pathway. Here, we evaluate why IR training can benefit from a more simulation-based approach. We further consider the cost-effectiveness of implementing simulation-based training nationally. Finally, we outline the potential pitfalls that may arise of introducing simulation-based training for IR trainees. We conclude that despite its disadvantages, simulation training will prove to be more cost-efficient and allow standardisation of IR training. Simulation training has the potential to help trainees learn practical skills outside the cath lab, reducing the learning curve during real cases, facilitating the learning process. However, many of the simulators that have been developed are expensive and have been criticised for low fidelity. Here, we present our viewpoint on the use of simulation for better training and finding the balance between effective simulation training and being cost-effective.Interventional radiology procedures have revolutionised the field of medicine. Interventional radiologists now perform a huge range of procedures for many conditions, including haemorrhage, cancer, and vascular disease. Interventional radiology services are essential for both emergency and elective treatment, and with the development of mechanical thrombectomy, these skills will become increasingly important in the treatment of stroke. The development of minimally invasive treatments using image guidance has allowed quicker patient recovery and reduced mortality, and there is a growing need for interventional radiology procedures in the United Kingdom. Interventional radiology procedural training largely follows the traditional apprenticeship model, where a trainee scrubs with a senior on a patient case and learns by doing. However, training via this model heavily relies on the trainer and risks variation in teaching standards, as well as potentially affecting patient safety if a trainee has minimal experience before performing procedures on a real patient. Other specialties that perform image-guided interventional procedures, particularly interventional cardiology, have embraced simulation as a way of developing technique outside of the cath lab, and the curriculum for interventional cardiology lists simulation as a learning method for learning catheter skills outside of the cath lab.4 compared outcomes among trainee cardiologists in gaining femoral access during cardiac catheterisation. The group found that those who had undertaken simulation training had reduced patient complications and reduced time in achieving 5 successful unassisted femoral artery access than those who had undertaken the standard, non-simulation-based training. Moreover, studies6 have also reported reduced procedural times in cardiac angiography in those who have undertaken simulation-based training. Reduction in procedural time minimises risk of intraoperative complications and also demonstrates the trainees’ procedural skills. These findings are further supported by Bagai and colleagues7 who evaluated whether simulation training affects trainees’ ability to perform cardiac catheterisation in real patients. The authors randomised 27 cardiology trainees into 2 groups: one group underwent simulation-based training and the control group took standard apprenticeship alone. The study showed that those trainees who undertook simulation-based training demonstrated a significantly improved technical ability than the control group.Other medical specialties have shifted towards simulation-based training and have reported successful outcomes in educating their trainees. In cardiology, gaining arterial access is a key procedure required for cardiac catheterisation. Gurm et al8 In 2017, Robinson et al9 investigated the impact of a vascular surgical skills and simulation course on the procedural knowledge and self-rated competence of vascular surgery trainees. In this study, candidates took a 1.5-day course entailing open and endovascular procedures on high-fidelity simulators and cadavers. The group reported that this simulation-based workshop significantly increased the self-rated competence among the trainees. Furthermore, in a nationwide study10 across the United States conducted by The Association of Program Directors in Vascular Surgery Committee on Education and Simulation reported that operative experience and confidence is increased among those trainees who have access to simulation-based training.In the United Kingdom, simulation-based training is regarded as an important training tool among vascular surgery programme directors.11 developed an endovascular course to assess the outcomes among neurosurgery trainees who underwent simulation training. In this study, 37 participants were assessed on their ability to perform diagnostic angiogram using simulators. The study found these participants showed significant improvements in their overall performance following simulation training. In 2013, Choudhury and colleagues12 developed a conceptual training framework for use on virtual reality neurosurgical simulator. The authors identified appropriate skills from the neurosurgical oncology curricula including ventriculostomy, endoscopic nasal navigation, tumour debulking, haemostasis, and microdissection. These tasks were elaborated onto training modules and were deemed as useful for neurosurgical skills training by subject matter experts. Following the development of similar conceptual training frameworks, engineers partnered with neurosurgeons of the National Research Council of Canada to establish the NeuroTouch neurosurgical simulator. This simulator offers trainees several scenarios based on real-life cases including endonasal pituitary surgery and transsphenoidal surgery.13 Taken together, it is evident that several medical and surgical specialties have trialled incorporating simulation-based training in their curricula and have shown positive outcomes in improving trainees’ competency and skill as well as improving patient safety and care. A summary of simulator use in other specialties is provided in Endovascular procedures have become a critical technique for neurosurgeons, especially when performing cerebral angiography, thrombolytic therapy, endovascular coiling carotid artery stenting, and angioplasty. This discipline is heavily dependent on imaging. Indeed, in 2010, the Congress of Neurological Surgeons (CNS) established a committee termed ‘CNS Simulation Committee’. The aim of this committee was to maximise resident education and improve patient outcome by creating simulation-based training. Fargen et al,30 Using simulators, trainees can learn the basic catheter skills outside the cath lab, which allows them to focus their attention on the more advanced aspects of the procedure in a real case. This would overall reduce the number of procedures required to achieve proficiency. This would provide large benefits for patient safety, as trainees would have had the chance to hone the basics when first performing the procedure, resulting in reduced radiation doses and sedation times. In addition, by reducing the number of procedures required, trainees would be able to get exposure to procedures that do not have a high caseload at their institution. This allows standardisation of training across the country and ensures that all trainees are able to learn certain procedures. Simulators are also accessible at any time, which gives the trainee more flexibility as opposed to learning whenever cases occur. Another advantage of simulators is that it can provide early exposure to IR procedures. This is particularly important for a recruitment perspective, and early exposure has shown to increase interest in IR for medical students. In 2011, a meta-analysis31 examined studies over 20 years regarding the skill acquisition from simulation-based training compared with traditional training. In this analysis, the authors identified 3742 articles, of which 14 met the inclusion criteria. The studied showed that the overall effect size for the 14 studies comparing the effectiveness of simulation-based training compared with traditional clinical training was 0.71 . Although the sample size of the 14 studies was relatively small, the duration over which these studies were analysed shows that there is a consistent positive impact on education following simulation training. However, it can be argued that the cost-effectiveness and other logistics were not factored when comparing the 2 interventions.The use of simulators as an adjunct to training offers a huge number of potential benefits. The main benefit is that trainees reduce the learning curve for new procedures.Simulators exist in multiple forms, but the most common forms are virtual reality simulators and phantom simulators. Simulation training in its current form is not without its problems. The biggest issue with the current simulators is fidelity. Many of the current simulators do not accurately reflect the actual procedure, which limits its effectiveness. This makes purchasing a simulator a large financial commitment that may not achieve the desired result. A specific challenge for IR is the issue of simulating many different procedures in different body systems. The range of procedures is much greater in IR compared with other specialties that use simulation, and a simulator that truly acts as an adjunct to IR training would ideally be able to offer simulation for a wide range of procedures. Financial barriers exist to the widespread use of simulators. IR residency programmes should work with local cardiology, vascular surgery, and neurosurgery programmes to share the financial burden of purchasing simulators and provide benefits to all trainees. A solution could be to hold a common endovascular skills course for all trainees in these 4 specialties at the start of training. In addition, there is currently not enough objective evidence for simulation training specifically in IR. Further evidence is required to demonstrate that simulation training is beneficial for trainee-focused outcomes, procedure-based variables, and patient outcomes.32 Given the range of procedures required in IR residency, we recommend that there should be a required simulation training curriculum at the beginning of residency to reduce the learning curve during residency and facilitate acquisition of catheter-based skills. Further simulation should be recommended throughout residency as an adjunct to improve specific aspects of a particular procedure that an individual trainee may require further practice on.The question of when simulation training should be offered still remains. Specialty recommendations in the United Kingdom currently vary. Vascular surgery includes mandatory simulation training at induction, as well as recommending continued use of simulation throughout training. However, neurosurgery and interventional cardiology recommend supplementing skills with simulation throughout training without a formal requirement. Evidence suggests that there is a benefit of simulation training for both newcomers and advanced practitioners.The length of an ideal simulation training programme is yet to be determined. Previous studies have varied, and this ranges from a single 30-minute session to a 2-day intensive course. Although simulation has shown benefits for both novice and experienced practitioners, there is evidence of diminishing returns as a trainee gains proficiency in the procedure. Therefore, there needs to be a balance of offering the highest benefit for trainees vs increasing time demands on an already busy residency schedule. Outcome measures of simulation training are also an important issue. Previous studies have used 3 main metrics – simulator metrics, evaluation by an experienced physician, and questionnaire responses from subjects. However, future work should evaluate the success of training on patient-based outcomes and assess the impact of simulation on patient outcomes.The expanding range of procedures in IR has meant a high degree of technical ability is critical to a successful resident. With this in mind, the dilemma of whether we should use performance metrics in selection for residency has raised. We would recommend against using simulator-based assessment for residency selection. The evidence shows that inexperienced practitioners improve with time. Therefore, pre-residency success on such a test would largely be determined by whether a student has had exposure to the simulator or not.Interventional radiology is a rapidly expanding specialty. Indeed, simulation-based training has become a novel and exciting technique to educate trainees in interventional procedures. While other medical and surgical specialties have adopted simulation training to teach catheter-based interventions, interventional radiology still lacks such innovative methods for training. We envisage that simulation-based training can help shape the interventional radiology training pathway to become more standardised. Simulation training can provide access to a range of real-life cases which may not be as easily accessible across all centres. This method of training can better equip trainees with the correct skill set and self-confidence when performing procedures which can ultimately lead to better and safer patient care.


The bioavailability of an orally administered small molecule is often dictated by drug-specific physicochemical characteristics and is influenced by many biological processes. For example, in fed or fasted conditions, the transit time within the gastrointestinal tract can vary, confounding the ability to predict the oral absorption. As such, the effects of food on the pharmacokinetics of compounds in the various biopharmaceutics classification system (BCS) classes need to be assessed. The consumption of food leads to physiological changes, including fluctuations in the gastric and intestinal pH, a delay in gastric emptying, an increased bile secretion, and an increased splanchnic and hepatic blood flow. Despite the significant impact of a drug’s absorption and dissolution, food effects have not been fully studied and are often overlooked. Physiologically-based pharmacokinetic (PBPK) models can be used to mechanistically simulate a compound’s pharmacokinetics under fed or fasted conditions, while integrating drug properties such as solubility and permeability. This review discusses the PBPK models published in the literature predicting the food effects, the models’ strengths and shortcomings, as well as future steps to mitigate the current knowledge gap. We observed gaps in knowledge which limits the ability of PBPK models to predict the negative food effects and food effects in the pediatric population. Overall, the further development of PBPK models to predict food effects will provide a mechanistic basis to understand a drug’s behavior in fed and fasted conditions, and will help enable the drug development process. Oral administration is the most common route of drug delivery because of the convenience, relative cost-effectiveness, and ease of administration. These combined factors promote patient compliance. Despite its many advantages, it is often difficult to predict the drug’s oral pharmacokinetic profile in vivo. Specifically, there exists intra- and interindividual variabilities in oral drug absorption which affects bioavailability and impacts the therapeutic outcome. Drug-specific physicochemical characteristics  dictate the drug’s ability to travel across or through the intestinal wall into the hepatic portal vein and offers an initial understanding of its oral pharmacokinetics. Furthermore, complex biological processes including fluctuations in pH, gastric and intestinal movement, rate of blood flow, and bile salt secretion can impact the orally administered drug’s rate of absorption.The gastrointestinal tract’s physiology influences drug absorption and it is therefore imperative to ensure that any situations deterring the digestive system from homeostasis are explored. Food ingestion is known to alter the gastrointestinal environment, and individuals typically consume three meals a day. This could affect the frequency at which drugs can be administered and when they can be taken. According to the Food and Drug Administration (FDA), drug administration in the fasted condition occurs when there is an overnight fast lasting for a minimum of 10 h and no food is consumed until after at least 4 h of drug dosing  for the ratio of population geometric means between fed to fasted treatments, based on log-transformed data, is not contained in the equivalence limits of 80–125% for AUC0-inf (AUC0-t when appropriate) or Cmax” [There is an abundance of novel small molecules that exhibit clinically relevant biological activity, and their physicochemical properties  indicate a need to determine the food effects to avoid dosing in the subtherapeutic or supratherapeutic range. Relevant pharmacokinetic parameters, such as the total drug exposure  is dependent on the compound-specific effective permeability (effP), which is calculated based on an equation derived from Fick’s law of diffusion.ak is the absorption rate constant, and R represents the small intestine’s radius.The drug can then permeate the gastrointestinal wall into the hepatic portal vein. Similar to dissolution, permeation follows first-order kinetics (Equations (2) and (3)). The rate at which the drug permeates the intestinal wall , time (t), transit rate constant (tk), and the number of compartments (N) [The CAT model, proposed by Yu et al. , separatents (N) ,21.(4)dThere are several model assumptions: (i) linear transfer kinetics from one compartment to the next, (ii) instantaneous mixing allowing for uniform concentrations, (iii) minimal absorption in the stomach or large intestine. Similar to the major disadvantage of the mixing tank model, the CAT model does not account for the pre-systemic (gut and hepatic) metabolism and cannot be used to explain the absorption of non-degradable drugs.The inception of the CAT model established an introductory framework for others to advance models to mechanistically quantify oral drug absorption.®, a commercially available software  mimics the intestinal mucosa in vitro and this model is useful in exploring a drug candidate’s transport from the intestinal lumen to systemic circulation . PermeabIn the past couple of decades, there has been a shift towards using simulated intestinal fluids (SIFs) because of its resemblance to in vivo physiological conditions. Fasted state simulated intestinal fluids (FaSSIF) and fed state simulated intestinal fluids (FeSSIF) contain bile salts , phospholipids , and/or fatty acids. Gastric fluids have also been simulated for the fasted (FaSSGF) and fed (FeSSGF) states. Over the years, the compositions of these simulated fluids have been optimized several times to more closely resemble the characteristics of the human in vivo environment, creating new ‘versions’ such as FaSSIF-V2 and FeSSIF-V2 ,30,31. TMultiple in vitro studies were performed with FaSSGF, FeSSGF, FaSSIF, and FeSSIF to measure the initial dissolution rate and the overall dissolution profile. Transfer models using a scaled-down USP paddle apparatus are often the method of choice to assess a drug’s solubility and precipitation in both fed and fasted states . This inAlthough in vitro studies provide useful information, there are limitations to their reliability in translation into humans. The transfer model does not describe the absorption of a drug from the lumen, impacting the equilibrium that dictates the drug precipitation which is particularly significant when predicting the food effect of BCS class II weak bases . DespiteFood effect studies are commonly conducted in the canine model since they can be fed a solid formulation with food composition akin to the human diet, and their luminal characteristics show similarities with humans. Nevertheless, there is a lack of confidence in using canine models because they often overpredict the food effects in humans ,37. SpecMathematical models can be used to describe the anatomy and physiology of the animal model and it has been previously suggested that they provide more accurate forecasts than allometric scaling . An adapmax, as a result of slower gastric emptying rates, was observed after food consumption. In a subsequent study, a more complex mechanism-based pharmacokinetic model with four physiological and one central compartment was developed to evaluate the changes in the gastrointestinal system from the pre- to post-prandial state, and the ensuing fenofibrate absorption [max and AUC, the latter could mechanistically quantify the effects of each physiological parameter in the fasted and fed  states. PBPK models serve as an expansion of mechanism-based pharmacokinetic models and provide an even deeper understanding of specific mechanisms influencing the food effect and oral drug absorption in general.Some of the first mathematical models used to assess the effects of the concomitant intake of food on pharmacokinetics were one- , two- 4, and thrsorption . The sto® and SimCYP® have often been used to evaluate the food effects on compounds from all BCS classes. These softwares have subtle differences in the physiological parameters used to describe the prandial states including the gastric emptying time, gastric volume, and bile salt concentrations throughout the gastrointestinal tract [® and SimCYP® provide the encoded ACAT and ADAM models, many values describing the physiological differences between the fasted and fed states are not reported in published literature since these parameter values may not be easily accessible. In contrast, there exist platforms that allow researchers to custom-build PBPK models with compartments representative of the gastrointestinal tract linked by differential equations that describe important oral absorption processes.Numerous biological processes are initiated following food consumption, as outlined in the earlier section, and these physiological changes can be captured in mechanistic PBPK models by adjusting the model parameters. Commercially available software such as GastroPlusal tract . Since GVarious changes in the physiological parameters in PBPK models that influence drug absorption following food consumption have been identified. Specifically, the gastric emptying time, gastric pH, and increase in bile salt concentrations throughout the intestinal tract are physiological processes that can enhance drug solubility and are important to consider when describing the food effects for poorly soluble compounds . These pThe physiochemical characteristics of BCS class IV compounds significantly impact rate-limiting processes governing oral absorption, and thereby present the greatest obstacle when predicting food effects. Typically, positive food effects are correlated with drugs displaying a solubility-limited absorption, whereas it is largely hypothesized that low permeability compounds can exhibit a decrease in bioavailability under fed conditions . Since tp > 5) significantly through an increased lymphatic uptake [p of 8. Predictions of the observed positive food effect of a high-fat meal on venetoclax likely require the incorporation of the lymphatic uptake process into the mechanistic PBPK model [The food effects on BCS class IV compounds have been predicted using PBPK models with some success. For example, the predicted vs. observed clinical pharmacokinetic parameters of venetoclax given with a low-fat meal was within the 0.8- to 1.25-fold range criteria, indicating that the model could accurately predict the observed food effects . Howeverc uptake . LymphatPK model .The food effects on a second compound, NVS113, were not accurately predicted using PBPK models. The human PBPK model predicted an insignificant food effect, whereas clinical data showed an approximate 30% decrease in the AUC following food consumption . InteresA majority of the compounds that have been studied for food effects fall under the BCS class II category . There imax and increased Tmax value, corresponding with a decreased bioavailability following food consumption [The predictive power of mathematical models is a direct translation of the information inputted into the model. There is no clear consensus on which parameters hold the greatest significance when predicting food effects. The majority of physiological parameters see  that havsumption ,54. Howesumption . These rmax and AUC of this BCS class III drug decreases significantly following food consumption. Heimbach et al. [In addition to viscosity, potential food–drug interactions, the induction of pre-systemic metabolism, drug degradation, and inhibition of transporters need to be further investigated to determine whether these phenomena need to be accounted for when modeling negative food effects ,40. FoodA majority of the PBPK models published in the literature simply indicate that their simulations are “predictive” or “not predictive”, without including their criteria. PBPK model performance is typically evaluated through goodness-of-fit plots and visual predictive checks. Recently, Li et al.  assessedRelative to the adult population, there are a limited number of studies investigating the food effects on oral drug absorption in the pediatric population. Oftentimes, the outcomes observed in adults are scaled according to body surface area to make dosing recommendations for neonates, infants, and children. Food effects in the pediatric population cannot be fully disregarded when no clinically significant outcomes are observed in adults . Currentmax. Neonates and infants also consume meals at a greater frequency and are rarely truly fasted compared to adult standards [The food composition and frequency of consumption vary significantly among the pediatric population and between the adult population. Neonates and young infants are likely fed milk as their primary source of nutrients, whereas there is a shift towards carbohydrate consumption in children . Gastrictandards . Food actandards . Moreovemax, Tmax, and AUC, and identify the potential consequences of dosing in a fed and fasted state. These models are typically created to predict pharmacokinetics in the adult population and then adapted to perform pediatric simulations [There remain challenges in designing efficient processes to adequately assess the risk of food effects in the pediatric population. Clinical trials with neonates, infants, and children exploring the impact of food on drug absorption are not always feasible. Furthermore, there is an added complexity with the rapid developmental changes in both physiology and biochemistry of the gastrointestinal tract, resulting in a large variability in parameters cited in literature when describing the pediatric population. Here, PBPK models can be leveraged to predict the Culations ,63. Specmax when administered with a liquid feed in comparison to the semi-solid/solid feed. This observation further supports that solid foods are associated with a slower gastric emptying than aqueous solutions. Furthermore, the authors suggest that a better understanding of the fluid volume dynamics in the gastrointestinal tract would help explain the lower fed to fasted fraction absorbed ratio of ketoconazole observed in the pediatric age group when compared to adults [Previously, Johnson et al.  integrato adults . This stA shift away from allometric power models to PBPK models to describe food effects in the pediatric population will be an asset to drug development. This will minimize off-label prescription which often leads to a suboptimal efficacy. To build confidence in these models, there needs to be a greater understanding of the gastrointestinal tract’s physiology and biochemistry in each developmental stage. Additionally, barriers to obtaining pediatric pharmacokinetic data need to be overcome for these models to be validated and further optimized. The reiterative optimization of pediatric PBPK models will be proven useful in guiding dose recommendations for all BCS classes while accounting for the prandial state in neonates and infants.Food effect studies inform drug product labeling to include specific instructions regarding food or beverage consumption with drug administration. The characterization of food effects is particularly important for drugs with indications in the critically ill and special populations. Reliance on positive food effects to achieve efficacious exposures for a BCS class II and IV cancer drug may not be ideal for those individuals who have difficulty consuming high-fat meals, which can discourage patient compliance ,64. In cDespite the level of predictability shown in Moreover, some physiological changes following food consumption are not well characterized, such as lymphatic uptake. Under fed conditions, there is an increased lymphatic uptake of the drug, thereby increasing the concentration in systemic circulation. A PBPK model used to describe venetoclax absorption following a high-fat meal was not predictive, and the researchers suggested that lymphatic uptake influences drug absorption to a greater degree than what was previously hypothesized . The exaAdditionally, there remain many unknowns that have yet to be fully characterized. There is a lack of knowledge on how bile–micelle binding, and enzymatic and transporter activity contribute to food effects that needs to be addressed in future studies. Although food has been shown to inhibit various intestinal drug-metabolizing enzymes and transporters , this inIt is also crucial to note that a majority of the food effect studies are explored in adults. In the pediatric population who undergo rapid development changes, physiological processes following food consumption amplify the complexity of characterizing drug absorption. In special populations, there is also sparse data collection, which poses a challenge to validate a PBPK model. Here, sensitivity analyses are useful to determine the value of drug parameters if there is missing or unreliable data.PBPK models are relatively inexpensive and valuable tools used to guide the course of drug development. Despite their advantages, there are many improvements that must be made in order to build confidence in the model’s outputs. The current understanding of biological processes following food consumption limits the accuracy and validity of PBPK models and, consequently, any conclusions drawn from PBPK models need to be accepted with caution.In this review, the application of PBPK models to predict food effects on drug absorption was explored. Various complex physiological processes are initiated upon food consumption, which can enhance or reduce a drug’s dissolution, solubility, and permeability. BCS classes act as a guide to determine whether a food effect exists, although additional studies need to be performed to capture the extent of food effects. In the past few decades, there have been strides in predicting meal-induced changes in pharmacokinetic parameters using PBPK models through reiterative optimization. Although there have been significant strides in understanding food effects, there remains a gap in the knowledge of biological processes following food consumption that needs to be bridged in order to accurately predict food effects on drug absorption. It is hopeful that these mathematical models can streamline the development of novel therapeutic compounds, starting with food effect predictions.


Hospitalists care for a growing population of older patients with unique social needs that can often be addressed by providing caregiver help in the home. The importance of addressing social needs is well-recognized, yet older patients sometimes refuse these services. This refusal of services may result in rehospitalization and increased morbidity for patients. We aimed to overcome this refusal of social support through an innovative workshop training hospitalists in negotiation and dispute resolution. Hospitalists at a tertiary care, urban academic medical center completed a one-hour interactive workshop on negotiation and dispute resolution focused on addressing older patients’ refusal of social services. One month post workshop, participants reported increased confidence in engaging patients and families in conflicts and felt empowered to negotiate in both their clinical practice and personal lives. Training hospitalists to negotiate with older adults needing social services is feasible and positively impacts the ability to provide geriatric care. Older adults constitute a rapidly growing portion of hospitalized patients and have unique social support needs that hospitalists may not be adequately trained to meet—these include support for decrease in both activities of daily living (ADL) and instrumental activities of daily living (IADL) ,2,3. FurNegotiations and dispute resolution (NDR) training is widely used in business, law, communication, and public policy sectors to work through conflicts . The traThe study was conducted at an urban academic medical center in April 2019. An invitation was sent out to hospitalists and advanced practice providers (nurse practitioners and physician assistants) in the Division of Hospital Medicine and were able to attend the in-person workshop, and provided care for older adults age 65 and over. Participants also had to confirm access to the internet and an email address to participate. The study was deemed exempt by the Northwestern University Institutional Review Board.We conducted a needs assessment of hospitalists to determine their current experience in disputes and conflicts in the clinical setting, their baseline knowledge and past experience in negotiations, and their desire to gain skills in negotiations and dispute resolution.Based on the results of the needs assessment, we tailored the NDR workshop, which was originally modelled after Northwestern University Kellogg School of Business negotiations and dispute resolution course, to focus on areas where hospitalists identified deficits in this skillset. We presented a one-hour interactive workshop to physicians and advanced practice providers The workshop included didactics on negotiations and dispute resolution training with specific strategies, including anchoring, determining motivation, building trust, avoiding reaction, and spin. We also included a role-playing session during which participants practiced the strategies they had just learned. One month after the workshop, we emailed participating hospitalists a survey about the workshop asking how they had applied their new knowledge and skills. The survey included the validated Patient-Reported Outcomes Measurement Information System (PROMIS) measure for self-efficacy , the valt-tests were used to analyze the quantitative survey responses. For the open-ended responses, content and constant comparative techniques were used whereby two coders independently assessed participant responses for focal themes before convening to compare and compile their findings to create a preliminary list of categories and major themes [Survey were collected using Qualtrics software with exports into Excel for quantitative analysis. For the quantitative data, descriptive statistics and 2-sided r themes . Discrepr themes .Thirty-two hospitalists attended the workshop with 19 (59.4%) Female, 26 (81.2%) Physician (MD/DO), and 6 (18.8%) Advanced Practice Providers (PA/NP). On average, attendees were 10.8 years post professional education with two also having a Master’s in Business Administration and two having a Master’s in Science. Nine hospitalists completed the pre-workshop and one month post-workshop surveys of which all reported experiencing conflicts with older adult patients at work.p = 0.31).Using the Dutch Test for Conflict Handling (DUTCH), participants self-categorized how they resolved a conflict at work into one of five dimensions: yielding, compromising, forcing, problem-solving, or avoiding . In descp < 0.002).Using the PROMIS General Self-Efficacy short form, we asked participants to rate their confidence and self-efficacy in handling difficult problems and unexpected events . CompariThemes from the post-workshop survey responses are detailed in We asked the participants open-ended questions one month after the workshop to explore the impact of the workshop on both their professional and personal lives. Six out of nine (67%) respondents reported that they had already used the skills learned during NDR training in either their professional and personal lives, and seven out of nine (78%) of respondents indicated interest in undergoing additional training. Our results show that negotiations and dispute resolution workshop can benefit hospitalists in resolving conflicts. Participants in our workshop reported feeling empowered, with more self-efficacy, and confident in handling conflicts with their hospitalized older patients, which may increase the likelihood of patients receiving the social services they need.Results from the one month follow-up revealed that NDR training had an impact on hospitalist clinical practice. Hospitalists reported being able to effectively negotiate with patients and their families by practicing the skills learned during the NDR training. Previous conflicts with older adults would have resulted in an impasse or in acquiescing to patients’ refusal of care. Instead, hospitalists were able to negotiate with patients and families, practicing the strategies learned in the workshop. We recognize that there was no significant difference in conflict behaviors before and after the workshop given the small numbers and short follow-up. However, both the qualitative results and positive trend in reported self-efficacy are encouraging and suggest that with additional training over a longer duration, we will likely see definitive changes in conflict behaviors.This study shows that the skill set of negotiations and dispute resolution is one that is needed in hospitalists’ clinical practice, and they recognize its value in both their personal and professional lives. The benefits of NDR training for workshop participants extended beyond their clinical practice, into their personal lives. Hospitalists reported incorporating the negotiation and dispute resolution strategies into their personal lives and using those skills in negotiating chores at home as well as in completing personal purchases. This study had limitations, including it being conducted at a single site, the low response rate among all the attendees, and lack of understanding on direct effects on patients. These limitations provide areas for further study including the impact on older adult clinical outcomes. Nevertheless, we are encouraged by the findings and look forward to the next steps in the NDR training of clinicians to impact patient care.Negotiation and dispute resolution training can be helpful to hospitalists who experience conflicts while caring for older adult patients. All of the surveyed hospitalists reported experiencing conflicts, with a common conflict occurring when older adults refuse social support assistance at discharge. Older adults have social needs but may not always be receptive to services that would fulfill these needs. Hence, it is imperative that clinicians caring for older adults at this vulnerable time are equipped with the knowledge and skills needed to overcome this refusal of services—knowledge and skills that NDR training provide.


The initial increases in force production with resistance training are thought to be primarily underpinned by neural adaptations. This notion is firmly supported by evidence displaying motor unit adaptations following resistance training; however, the precise locus of neural adaptation remains elusive. The purpose of this review is to clarify and critically discuss the literature concerning the site(s) of putative neural adaptations to short-term resistance training. The proliferation of studies employing non-invasive stimulation techniques to investigate evoked responses have yielded variable results, but generally support the notion that resistance training alters intracortical inhibition. Nevertheless, methodological inconsistencies and the limitations of techniques, e.g. limited relation to behavioural outcomes and the inability to measure volitional muscle activity, preclude firm conclusions. Much of the literature has focused on the corticospinal tract; however, preliminary research in non-human primates suggests reticulospinal tract is a potential substrate for neural adaptations to resistance training, though human data is lacking due to methodological constraints. Recent advances in technology have provided substantial evidence of adaptations within a large motor unit population following resistance training. However, their activity represents the transformation of afferent and efferent inputs, making it challenging to establish the source of adaptation. Whilst much has been learned about the nature of neural adaptations to resistance training, the puzzle remains to be solved. Additional analyses of motoneuron firing during different training regimes or coupling with other methodologies  may facilitate the estimation of the site(s) of neural adaptations to resistance training in the future. Resistance exercise is one of the most common exercise modalities, providing numerous functional and physiological benefits to various populations, from athletes to patients. Following a period of resistance training, the maximal volitional force generating capacity of skeletal muscles is typically increased. Though long-term resistance training is accompanied by modifications of muscle morphology, the initial (< 2–4 weeks) increases in force production are thought to be primarily underpinned by neural adaptations , also known as the final common pathway of neural activation signals  of neural adaptations. Regarding training interventions used throughout the literature, the studies included in the present review used similar training intensities  and volumes . Single-joint, isometric resistance training is the most commonly employed training modality  reflex Fig. a and theThe authors of the aforementioned studies have often inferred that neural adaptations to resistance training are mediated at the ‘spinal’ level. However, the term ‘spinal’ is rather broad, and both H-reflex and V-wave are subject to technical limitations that preclude identification of the precise site of neural adaptation , rather than alterations in neural synaptic input. The uniform increase in discharge rate across the motor pool is also inconsistent with the idea of augmented reticulospinal input following resistance training . Indeed, the literature has predominantly focused on neurophysiological changes in the agonist muscles, with relatively little regard for antagonist and synergists. However, increased force production of the agonist muscle following resistance training may occur due to upregulation of activity within the agonist itself, as well as suppression of the antagonist and/or facilitation of synergist muscles. Early studies investigating interference EMG amplitude suggest reduced antagonist activation following resistance training , coupled with the use of existing methods , as well as indirect probing of reticular formation in humans , have considerable potential to contribute to completing the puzzle regarding the site of neural adaptations to resistance training in the coming decade.


International Journal of Cardiology Heart & Vasculature, and discuss potential factors which may explain this observation.The COVID-19 pandemic has a significant impact on our daily life due to national lockdown restrictions and measures to reduce social contacts to prevent the wider spread of the virus. As one component of these restrictions, most cardiology conferences were canceled or turned into virtual online meetings Following the issued lockdown restriction initiated in mid-March 2020, a transient but substantial increase in submission rate of scientific manuscripts to this journal was noted . DespiteSeveral factors might have contributed to this disproportional transient increase in submission rate. COVID-19 introduced a new research topic, which motivated several groups all over the world to investigate the putative interaction patterns with their respective research topic Although the lockdown restrictions during the COVID-19 pandemic were associated with a substantial increase in submission rate to the journal, it is unclear, whether the increase in submission rate will remain stable and ultimately translate into published manuscripts of better quality. Finally, we hope that this pandemic gets under control very quickly to allow face-to-face meetings and conferences, which created the basis of fruitful networking and productive collaborations for decades.The authors report no relationships that could be construed as a conflict of interest.


Persistent Patent ductus arteriosus (PDA) is a common finding in extremely low gestational age newborn infants and its prevalence is inversely proportional to the gestational age. The presence of a persistent PDA is associated with increased mortality and several significant morbidities including intraventricular hemorrhage, pulmonary hemorrhage, necrotizing enterocolitis, and chronic lung disease or bronchopulmonary dysplasia. However, treating PDA has not been demonstrated to have beneficial impact on the long term outcomes. Currently there is no consensus on whether to treat the PDA or not, and if treat, when to treat and how to treat. The echocardiography is the investigation of choice to diagnose PDA, estimating the magnitude of shunt volume and assessing its hemodynamic significance, and to exclude/diagnose any associated congenital heart defect before any intervention. Various echocardiographic parameters and staging/scoring systems have been described to help the clincians making the clinical decisions and some of theses scoring systems are quite complex to apply in a busy day to day clinical practice. This concised review paper is focused to help the clinicians in making a clinical decision based upon clincial and echocardiography parameters. Hence, only the parameters which are commonly used and helpful in making the clinical decisions in day to day clincial practice have been described in this paper. Patent ductus arteriosus (PDA) is an essential component of the fetal circulation and in most of the term infants it closes soon after birth. However, PDA is known to remain persistent in large proportion of extremely low gestational age newborn (ELGAN) infants and its prevalence is inversely proportional to the gestational age . The incThe important risk factors for persistent PDA include lower gestational age, lack of antenatal steroids, and need for mechanical ventilation. The risk of persistent PDA increases with decreasing gestational age (GA) and lower birth weight 1 4). Cl. Cl4). CThe presence of a persistent PDA is associated with increased mortality and several significant morbidities including intraventricular hemorrhage (IVH), pulmonary hemorrhage, necrotizing enterocolitis (NEC), and chronic lung disease (CLD) or bronchopulmonary dysplasia (BPD) –8. DespiThis review focuses at clinical decision making in managing PDA in the ELGAN infants. The aim of the paper is not to advice on the type of treatment, but primarily looking on the role of echocardiography in hemodynamic evaluation of PDA which can help in making clinical decision on the bedside.The clinical signs of PDA depend upon amount of the shunt volume passing across the ductus arteriosus; which primarily depends upon the systemic and pulmonary vascular resistance, ability of the myocardium to adapt to increased shunt volume and size of the ductus arteriosus –15 Figu.Infants with even a large PDA often have no clinical signs in the first few days after birth because of persistently high pulmonary vascular resistance (PVR) leading to decreased amount of PDA shunt volume. As PVR drops, shunt volume increases and infant develops the signs and symptoms of PDA. Initially, heart murmur may be heard and often the infant is noted to have fleeting desaturations. As PDA persists then further signs such as hyperactive precordium, bounding pulses and widened pulse pressure are recognized and when myocardium fails to adapt to this increased shunt volume the signs of heart failure develop , 16. HowClinical factors and biomarkers can be used both to diagnose PDA and assess its hemodynamic significance In hemodynamically significant PDA (hsPDA), signs and symptoms of pulmonary overcirculation and systemic hypoperfusion are rated by looking at the oxygenation difficulty, number and severity of apnea and desaturations, need and extent of non-invasive or invasive respiratory support, feeding intolerance, radiologic evidence of cardiomegaly and pulmonary edema, presence of oliguria, low mean or diastolic hypotension with or without metabolic acidosis requiring cardiotropic or vassopressor drugs . HoweverMoreover, it is very difficult to diagnose or rule out underlying congenital heart defect on clincial examination alone . Hence, The echocardiography is the gold standard bedside investigation to diagnose PDA. In addition to make a confirmative diagnosis of PDA and exclude/diagnose any associated congenital heart defect (CHD), it can help in estimating the magnitude of shunt volume and assessing its hemodynamic significance—it can be used to assess the hemodynamic impact from pulmonary overcirculation and systemic hypoperfusion due to shunt volume –15. ThisVarious echocardiographic parameters have been described in the research setting and complex staging/scoring systems , 19. ThiThe echocardiography can be used to assess the size of PDA by measuring transductal diameter, interrogate shunt direction, and velocity of blood flow across the ductus arteriosus can be measured by using Doppler technique.Although the PDA can be visualized from many windows, the high left-sided parasternal “ductal” view is the preferred window to obtain a clear 2D image and accurately measure size of the ductus arteriosus. PDA size is measured from the transductal diameter at the site of maximum constriction (narrowest dimension), which is usually at the pulmonary end . Most stThe direction of the ductal shunt depends upon the relationship between the pulmonary and systemic pressures. It is assessed using color Doppler and direction of blood flow across ductus arteriosus is normally left to right, from the aorta (high systemic pressure) to the pulmonary artery (low pulmonary pressure) but it can be right to left or bi-directional when there is high pulmonary vascular resistance or when there is anatomical cause (due to certain CHDs). With conventional setting left to right shunt is seen as red jet while right to left shunt is seen as blue . A rightThe shunt velocity across the PDA during the cardiac cycle can be obtained by applying pulse or continuous wave Doppler in the ductus arteriosus. The maximum velocity during systole and diastole can be measured. Non-restrictive shunts have a low peak systolic velocity with a high systolic to end-diastolic velocity gradient while restrictive shunts have a high peak systolic velocity and a low systolic to diastolic velocity gradient. If the ratio between peak systolic and end-diastolic velocity is >2 then it is considered as a pulsatile flow pattern while a ratio of <2 is described as restrictive shunt suggestive of a closing PDA , 23 Fig.The increased pulmonary blood flow from a significant left-to-right ductal shunt leads to pulmonary blood flow and hence increased pulmonary venous return. This leads to increased volume overload in the left atrium (LA) which gradually gets dilated and if this process of significant left to right shunt persists then it leads to dilatation of left ventricle from increased preload, especially in absence of a large intra-atrial shunt. As aortic valve annulus (Ao) is a relatively fixed structure and it does not get dilated due to left heart overloading. Hence, a ratio of LA/Ao can be used as a surrogate of increased pulmonary venous return , 25. Simz-scores should be used for LVEDD  has been described as a sign of significant left to right shunt through the PDA. Using pulsed wave Doppler in the LPA mean and end-diastolic velocity can be measured and cut-off points of 0.42 and 0.20 m/s, respectively, have been described as indicative of significant ductal shunt  Figure .The mitral valve E/A ratio refers to the ratio of the velocity of the early (E) diastolic phase of ventricular filling vs. the late atrial (A) contraction component. Mitral valve E/A ratio can be obtained from apical 4-chamber view with the pulsed Doppler range gate set slightly below the mitral valve annulus. In preterm infants, mitral valve E/A ratio is usually <1 due to poor compliance of the myocardium leading to moderate impairment of diastolic performance and low early diastolic filling velocity. In the presence of a hsPDA, atrial pressure increases because high pulmonary venous return and this leads to a reversal of the E/A ratio >1. Various other echocardiographic parameters have been studied and described to assess pulmonary circulation such as left ventricular output (LVO) to superior vena cava flow (SVC) ratio, and decreased isovolumic relaxation time (IVRT) using tissue Doppler Imaging (TDI) , 24, 28.In the presence of a large PDA, blood shunts away from the systemic circulation throughout the cardiac cycle, however, this becomes more apparent during diastole and it can be studied using Doppler on echocardiography , 31. RetSimilarly, celiac trunk or superior mesenteric artery can be interrogated using pulsed wave Doppler in the sagittal abdominal view . DopplerBased upon the clinical and echocardiographic criteria various staging systems been described and have been shown to help in decision making for intervention , 19. HowThe above echocardiographic parameters summarized in A large PDA with some or all the signs of hemodynamic significance can be seen in a well infant needing no or minimal ventilatory support, and it may not be clinically significant. There is high rate of spontaneous closure of PDA, even in ELGAN infants, if they are left alone , 36. On In the last few years, there has been move toward conservative “watchful” approach in infants with no significant clinical signs even when there are echocardiographic parameters suggestive of large hsPDA . The pubMost clinicians would agree that ductus arteriosus with echocardiographic parameters suggestive of large PDA associated with pulmonary over-circulation and systemic hypoperfusion should be regarded as hsPDA . InfantsThe treatment intervention varies from no intervention (“wait and watchful” policy) to treating all PDAs diagnosed on echocardiography. “One size may not fit all”—this truly applies on managing PDA in ELGAN infants with huge variation in clinical course and associated co-morbidities. The lack of evidence on how to best evaluate the PDA in these infants probably results in lack of consensus among the scientific bodies, or even among the clinicians within the same unit . The intStudies of prophylactic treatments using indomethacin show reduced rates acute pulmonary hemorrhage, intracranial hemorrhage, and surgical ligation . It doesWith advances in technologies and expertise, PDA can be closed via transcatheter route with faster recovery and avoiding the risk of complications from surgery. This can now be safely done in ELGAN infants weighing over 700 g , 48. A dThe authors recommend a comprehensive assessment of PDA and its hemodynamic significance before making any clinical decision to treat or not and the clinical decision making should be made in clinical context of the individual infant. A simple algorithm to clinical decision making based upon clinical and echocardiographic assessment, whether to treat or follow up, has been summarized in While the best treatment option to treat the PDA in the extremely low gestational age newborn infants remains debatable and lacks consensus at this stage, there has been significant progress in assessing hemodynamic significance of the ductal shunt. Before making a clinical decision to treat a PDA or not, all infants should have a comprehensive structural assessment to rule out any underlying CHD and a meticulous hemodynamic evaluation to assess the impact of PDA shunt on the pulmonary over-circulation and systemic hypoperfusion. In absence of clear evidence, the clinical decision should be individualized based upon clinical concerns and echocardiographic assessment. While in some infants a careful “wait and watchful” strategy may be the best option, other infants may need early intervention to minimize the co-morbidities. There is an urgent need of studying the long term outcomes in the sub-set of infants with hsPDA identified on meticulous echocardiographic assessment.The original contributions presented in the study are included in the article/supplementary materials, further inquiries can be directed to the corresponding author.YS conceptualized the idea and prepared initial manuscript including all images. AF, OE, and BA edited the manuscript and helped in finalizing the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Patients’ choices of providers when undergoing elective surgeries significantly impact both perioperative outcomes and costs. There exist a variety of approaches that are available to patients for evaluating between different hospital choices.This paper aims to compare differences in outcomes and costs between hospitals ranked using popular internet-based consumer ratings, quality stars, reputation rankings, average volumes, average outcomes, and precision machine learning–based rankings for hospital settings performing hip replacements in a large metropolitan area.Retrospective data from 4192 hip replacement surgeries among Medicare beneficiaries in 2018 in a the Chicago metropolitan area were analyzed for variations in outcomes  and costs  between hospitals ranked through multiple approaches: internet-based consumer ratings, quality stars, reputation rankings, average yearly surgical volume, average outcome rates, and machine learning–based rankings. The average rates of outcomes and costs were compared between the patients who underwent surgery at a hospital using each ranking approach in unadjusted and propensity-based adjusted comparisons.Only a minority of patients  were found to be matched to higher-ranked hospitals for each of the different approaches. Of the approaches considered, hip replacements at hospitals that were more highly ranked by consumer ratings, quality stars, and machine learning were all consistently associated with improvements in outcomes and costs in both adjusted and unadjusted analyses. The improvement was greatest across all metrics and analyses for machine learning–based rankings.There may be a substantive opportunity to increase the number of patients matched to appropriate hospitals across a broad variety of ranking approaches. Elective hip replacement surgeries performed at hospitals where patients were matched based on patient-specific machine learning were associated with better outcomes and lower total costs of care. Patients undergoing elective surgeries often seek information at different levels of granularity when choosing providers, ranging from institutions to practices to individual physicians. It is widely established that the choice of provider significantly impacts both perioperative outcomes and costs -4. ThereThis study compares different approaches  and personalized patient-specific rankings using machine learning (referred to as precision navigation) for predicting hospital performance, as measured by postprocedure hospitalization rate, emergency department (ED) visits, and total cost of care. The analyses were performed on data from Medicare fee-for-service (FFS) beneficiaries following elective hip replacement surgery. For each of the different approaches, 90-day outcomes for patients that were treated at highly ranked institutions were measured and compared to the outcomes for patients treated at institutions that were not highly ranked. Outcomes following elective hip replacement surgeries were studied because they are among the most commonly performed surgeries and because there is considerable variation in risk-adjusted performance across hospitals. Postprocedure hospitalization, ED visits, and total cost of care were used as outcome measures because they are quantifiable, meaningful to patients, and available for Medicare FFS populations.The study population comprised Medicare FFS beneficiaries undergoing elective hip replacements between 2013 to 2018 in the Chicago-Naperville-Arlington Heights, Illinois metropolitan area. Hip replacement surgeries were identified among these patients using standard procedure codes available in administrative claims data.All hospitals in the greater Chicago metropolitan area that were visited for hip replacement surgery by at least one Medicare FFS beneficiary who lived in the Chicago-Naperville-Arlington Heights, Illinois area between 2016 and 2018 were included in the analysis . For each patient, up to 10 of the nearest candidate hospitals that were a maximum of 50 miles from their place of surgery were ranked. For each patient, the top-ranked choice was determined for the different approaches, and the average outcomes and costs for patients who had surgeries at a top-ranked hospital were compared with the population averages.For each hospital, online consumer ratings from Yelp , HealthgProcedural volumes were calculated for hip replacement using Medicare FFS data for each hospital between 2013 and 2017. The average postprocedure hospitalization rate and ED admission rate at each hospital following hip replacement procedures were calculated using Medicare FFS data as a measure of quality and were also treated as a rating. For each of these ratings , a single average was computed from 2013 to 2017. For evaluating volume-based ratings, the top hospital was the one with the highest average yearly volume of hip replacement surgeries. For evaluating average outcome–based ratings, the top hospital was the one with the lowest combined average 90-day postprocedure hospitalization rate and ED admission rate for hip replacement surgery.Machine learning–based rankings of orthopedic facilities were generated for each beneficiary undergoing hip replacement in 2018 using a commercially available software system  that uses precision navigation and was trained on data prior to 2018  [The 90-day postprocedure hospitalization rate and rate of ED admission following the surgery were measured as outcomes. In addition, the 90-day total cost of care (TCOC) was also measured for each patient, which included the costs of the surgery and subsequent costs for the patient that occurred over the next 90 days from the day of surgery. The TCOC estimate included reimbursements for inpatient, outpatient, skilled nursing facility, and home health agency care, as these were available for the FFS beneficiaries. All patients included in the analyses had at least 90 days of follow-up .The observed average outcomes  and TCOC were compared between patients who received treatment at the top-ranked hospital for hip replacement surgery in 2018 and the overall population  in an unadjusted analysis. The unadjusted comparisons were also done in subgroups stratified by the Elixhauser comorbidity score. In each comparison, we statistically compared the outcomes of interest between patients who were admitted to a top-ranked hospital and patients who were admitted to a lower-ranked hospital (as determined by each respective method).Pairwise comparisons between patients who visited a top-ranked hospital based on the different approaches were made using an adjusted propensity-based analysis with a one-to-one matching caliper without replacement . PropensP<.001), 4.1% for ED admission rates (P<.001), and US $3315 for TCOC (P<.001) between top hospitals and the overall population. The other ranking methods were associated with smaller variations in outcomes between top hospitals and the overall population. The percentage of patients who underwent surgery at a hospital ranked as a top hospital by each ratings approach varied from 27.6% (1159/4192) for the precision navigation–based rankings to 49.6% (2078/4192) for the average volume–based rankings.The potential impact of using different rating systems under the counterfactual assumption that patients only presented to a top hospital for them was also considered. The precision navigation–based ranking approach resulted in significantly more hospitals being designated as a top hospital for one or more Medicare FFS beneficiary . Out of 69 total hospitals visited by patients in 2018 for hip replacements, 54 were considered top-ranked hospitals for at least one patient when using precision navigation. CMS ratings resulted in 25 hospitals being top ranked. US News and Healthgrades each resulted in 27 hospitals being top ranked. Yelp-based ranking resulted in 22 hospitals being considered top ranked. Average volume and outcome resulted in 26 and 24 hospitals, respectively, being considered top-ranked hospitals for a patient.Prior research on the use of popular ranking and rating approaches, including web-based ratings, consumer guides, and various quality ratings for physicians or hospitals, have resulted in inconsistent findings, and it is unclear which rating approach works best ,21,25-28Overall, several approaches were shown to be associated with better outcomes and lower TCOC when patients presented to a top hospital based on the respective ranking approach. These included CMS quality stars and precision navigation–based rankings, with top-ranked hospitals achieving improved outcomes and TCOC for hip replacement using both propensity-adjusted and nonadjusted analyses. The greatest improvements were observed for precision navigation–based rankings, which were more consistently associated with reductions in 90-day postprocedure hospitalization rate, ED admission rate, and TCOC in each analysis.Prior research has resulted in an inconsistent correlation between outcomes and ratings in top-ranked hospitals. For example, Cram et al  showed nIn this study, hospital performance was measured using the rates of postprocedure hospitalizations and ED visits and the total cost of care among Medicare FFS beneficiaries undergoing elective hip replacements. These metrics, which were available for all hospitals included in this study, are meaningful to patients. Many of the popular consumer-based ranking approaches are based more on patient satisfaction than on objective measures ,25,26,30Typical methods for ranking hospitals for specialty procedures assume that the quality of an institution is the same for all patients. The personalized approach of precision navigation–based ranking predicts outcomes for each hospital-patient pair by learning from the respective hospital’s prior outcomes for patients who resemble the patient being matched. Thus, this study suggests that hospital quality may be a personalized, variable phenomenon rather than a global, uniform value. The overwhelming majority of hospitals considered are not consistently ideal  for all patients but instead lie largely in a “gray zone” of being selectively good or bad for individual patients. More than 85% (80/94) of the hospitals that were included in the Chicago metropolitan area fell in this category. This finding is perhaps not surprising, given the complexity of surgical patients and the variations in case mixes, resources, training, and other organizational characteristics of hospitals that lead to facilities performing well or poorly for specific individuals. Prior research has shown that patient complexity is strongly correlated with outcomes in elective surgeries, such as total knee arthroplasty . Bozic eThe potential policy implications of our study are significant. The paradigm of patients choosing institutions based on crowdsourced online ratings, popular consumer guides, and established metrics, such as high-volume centers, as surrogates for high performance may not be suitable for identifying the preferred centers for patients contemplating elective surgery. Average outcome–based measures are more reliable than online consumer rankings but still far from optimal, and they did not result in lower TCOC. Our results suggest that a personalized approach based on precision navigation that uses readily available data to characterize a patient’s medical complexity in the context of individual hospitals may be associated with substantial improvements in outcomes while also lowering TCOC. An additional policy concern is that any mechanism designed to encourage patients to go to specific hospitals should ideally balance hospital use and capacity. Prioritizing hospital choice based on the typical static rating approaches would lead to a greater concentration of surgeries in a small number of top hospitals, thus overwhelming certain hospitals while underutilizing others. The personalized approach distributed patients over more hospitals  than any of the other approaches . Finally, the low proportion of patients that were matched to top hospitals using the precision navigation–based approach (<30%) presents a substantial opportunity for improving outcomes and costs for many patients by steering them to hospitals that are best suited for them.One of the limitations of this study is the incomplete characterization of each patient’s unique medical needs and medical history, since only CMS administrative claims were available. Ideally, the online ratings would be based on reviews collected before the date of the procedure. However, access to historic ratings for online web-based systems was not available. Furthermore, the use of ED visits and postprocedure hospitalizations as outcomes does not reflect on the quality of life improvement following elective surgery that patients ultimately seek. This study was retrospective in nature and thus only showed associations between outcomes and various ranking and rating methods rather than suggesting causal relationships between ranking methods and patient outcomes. The ranking methods that were evaluated in this study’s experimental design may not have been intended to be used as stand-alone referral services or offer advice on the suitability or choice of particular hospitals. Rather, they may have been intended to be used (where applicable) as additional information that can be factored in with other inputs  in choosing a hospital site for a future surgery. This study only evaluated the association of these ranking methodologies within the experimental framework considered, and the findings here should not be taken as a statement of their suitability for any purpose. Patients’ choices in elective surgeries can be influenced by socioeconomic factors as well as factors beyond their control, such as the availability of surgeons, recommendations from their care providers, and the network limitations of their health insurance plans.The present study was performed using Medicare beneficiary claims data that primarily comprised older patients, and their applicability to younger patients with private health care insurance or Medicaid requires further research. Another limitation of this work was that the analysis was restricted to the greater Chicago metropolitan area. Future work is needed to extend this study to other procedures, non-Medicare populations, and hospitals nationwide. A prospective trial is warranted to further study the impact of hospital-ranking approaches on patient outcomes and total cost of care.


Tumors may consist of billions of cells, which in malignant cases disseminate and form distant metastases. The large number of tumor cells formed by the high number of cell divisions during tumor progression creates a heterogeneous set of genetically diverse tumor cell clones. For cancer therapy this poses unique challenges, as distinct clones have to be targeted in different tissue locations. Recent research has led to the development of specific inhibitors of defined targets in cellular signaling cascades which promise more effective and more tumor-specific therapy approaches. Many of these molecular targeted therapy (MTT) compounds have already been translated into clinics or are currently being tested in clinical studies. However, the outgrowth of tumor cell clones resistant to such inhibitors is a drawback that affects specific inhibitors in a similar way as classical cytotoxic chemotherapeutics, because additionally acquired genetic alterations can enable tumor cells to circumvent the particular regulators of cellular signaling being targeted. Thus, it might be desirable to reduce genetic heterogeneity prior to molecular targeting, which could reduce the statistical chance of tumor relapse initiated by resistant clones. One way to achieve this is employing unspecific methods to remove as much tumor material as possible before MTT, e.g., by tumor debulking (TD). Currently, this is successfully applied in the clinical treatment of ovarian cancer. We believe that TD followed by treatment with a combination of molecular targeted drugs, optimally guided by biomarkers, might advance survival of patients suffering from various cancer types. Cancer is a life-threatening disease and in western populations, about every third person is projected to suffer from cancer between birth and the age of 74 . BetweenTumors in the human body vary strongly in their size, reaching from microscopic lesions to tens of kilograms of tissue. Tumor size has important implications for the genetic heterogeneity within the tumor, as an increase in the amount of neoplastic tissue requires cell divisions. Every new tumor cell, which acquires additional genetic hits and thus becomes genetically distinct from its parental cell, is seen as a new tumor cell clone . As tumoNew genetic alterations in subclones not only drive the metastatic spread, but also can confer drug resistance, e.g., by inhibiting cell death or activating cell signaling downstream of the targeted effectors , 20 . RecentAn important challenge for the clinical use of chemotherapeutics and new targeted drugs is the resistance of tumor cells. Tumor cells can be inherently resistant or acquire resistance. Even after a drug initially caused effective remission, single resistant tumor cell clones can survive and reestablish the tumor which then will be entirely resistant toward repeated treatment with the same drug. This phenomenon was observed recurrently [reviewed in ], especiAs outlined above, clonal heterogeneity is positively linked to tumor burden and increases the chance of drug resistance. This indicates that reduction of tumor volume will elevate the likelihood of successful drug treatment. Clonal heterogeneity also plays an important role in acquired resistance against immunotherapy [reviewed in ]. HoweveBoth treatments are already applied to treat ovarian cancer (OC)  and metaBesides OC and mRCC, there is preclinical data indicating potential for the use of TD with MTT or chemotherapy in other tumor types as well. In a mouse model of malignant mesothelioma, TD was found to support anti-tumor memory when it was combined with chemotherapy and adjuvant immunotherapy , 54. In These examples indicate that TD could support therapy against a variety of cancer types. NSCLC, for example, is a cancer type with many molecular targeted drugs available in clinical practice. MTT for NSCLC includes drugs blocking receptor tyrosine kinases (RTKs) like EGFR, hepatocyte growth factor receptor (HGFR), and anaplastic lymphoma kinase (ALK), as these oncoproteins are frequently aberrantly activated. As described above, resistance against these new approaches in NSCLC therapy is frequently observed –5 and thKRAS oncogene in ctDNA as well as mutations related to the development of resistance toward EGFR blockade in 23 of 24 patients that initially responded but later relapsed. This indicates that liquid biopsy is a sensitive method for analyzing the tumor genome and tailoring MTT to each patient individually. Liquid biopsy might even enable a comparison of the tumor genome before and after TD, so that the impact of TD on clonal heterogeneity could be monitored.As TD represents an unspecific mechanical method, the reduction of genetically distinct tumor cell clones by TD could significantly support all therapy approaches, which are limited in their efficacy by tumor cell resistance mediated by genetic variation within the tumor. If this is true, TD will support MTT regardless of the specific drug's mode-of-action by lowering the chance of resistance. Newer MTT approaches consider the genetics of individual tumor diseases and match molecular targeted drugs to the genetic profile of the tumor . This inBRAF-V600E or -V600K mutations treated with a combination of BRAF and MEK inhibitors after surgery (Of course, the application of TD in order to decrease clonal heterogeneity would make sense especially if promising MTT options can be identified for the particular patient. An example of a highly potent MTT is BRAF-inhibition in melanoma which initially works highly effectively and can eradicate even large tumors, but in most cases induces resistance due to alternative activation of MAPK/Erk signaling or activation of PI3K/Akt signaling [reviewed in ]. Even c surgery .Due to higher tumor volumes and the resulting higher genetic heterogeneity, advanced stage tumor patients might benefit more likely from TD . HoweverPreclinical and clinical studies indicate that TD might cooperate well with MTT approaches. Immunotherapy approaches in particular have been shown to benefit from tumor resection in a large variety of tumor types. The reduction of as many genetically distinct tumor cell clones as possible could be used to reduce the ability of tumors to resist MTT for precision oncology. In order to create synergy effects, unspecific non-mutagenic treatment options like TD should precede genetics-guided combined molecular targeting for a variety of tumor types. Depending on the individual patient's characteristics, tumor type, stage, and genetic profile, oncologists could design a personalized strategy to support specific treatment options like MTT with cytoreductive methods like TD to outsmart the tumor's intrinsic compulsion to resistance. In future, clinical treatment guidelines might be adapted this way to facilitate an effective patient-specific MTT.FO developed the idea and created the design of the article. HS and MG contributed to the idea. All authors participated in writing and editing the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Extraosseous Ewing sarcoma is an uncommon entity in the adult population. Cardiac metastases or local invasion of a tumor into the heart is a known but also infrequent occurrence for most malignancies. We present a case of a patient with a history of extraosseous Ewing sarcoma who presented to the emergency room with chest pain and was found to have an inferior ST-elevation myocardial infarction and systemic emboli and was found to have recurrence of sarcoma invading the left atrium. Ewing sarcoma is an uncommon malignancy in adults that most often presents as an undifferentiated primary bone tumor; less commonly, it arises in soft tissue (extraosseous Ewing sarcoma (EOEWS)). Both are part of a spectrum of neoplastic diseases known as the Ewing sarcoma family of tumors (EFT). Metastases at diagnosis are infrequent, occurring in less than twenty-five percent of patients. However, due to relapse rates with local therapy and tendency to metastasize, EFT is considered to be a systemic disease and usually requires multimodality therapy . We presA 62-year-old male with past medical history significant for extraosseous Ewing sarcoma presented with chest pain and dyspnea to the emergency room. His electrocardiogram revealed inferior ST-elevation myocardial infarction (STEMI) . He was Extraosseous Ewing sarcoma (EOEWS) with invasion of the left atrium occurring simultaneously with systemic emboli is a highly unusual presentation of this disease. EOEWS compromises only fifteen percent of bone sarcomas. The median age of diagnosis is typically around ten to fifteen years old, and less than five percent of cases occur in patients over the age of forty . EOEWS iCardiac metastases in this disease are exceedingly rare and may be either primary or secondary, either from metastases or local invasion. The incidence of primary cardiac tumors is around 0.02%, while secondary tumors are more common, occurring one hundred times more frequently –6. Most