Humans’ performance varies due to the mental resources that are available to successfully pursue a task. To monitor users’ current cognitive resources in naturalistic scenarios, it is essential to not only measure demands induced by the task itself but also consider situational and environmental influences. We conducted a multimodal study with 18 participants . In this study, we recorded respiratory, ocular, cardiac, and brain activity using functional near-infrared spectroscopy (fNIRS) while participants performed an adapted version of the warship commander task with concurrent emotional speech distraction. We tested the feasibility of decoding the experienced mental effort with a multimodal machine learning architecture. The architecture comprised feature engineering, model optimisation, and model selection to combine multimodal measurements in a cross-subject classification. Our approach reduces possible overfitting and reliably distinguishes two different levels of mental effort. These findings contribute to the prediction of different states of mental effort and pave the way toward generalised state monitoring across individuals in realistic applications. In everyday life, we constantly face situations demanding high stakes for maximum gains; for instance, to succeed in rapidly acquiring complex cognitive skills or making decisions under high pressure. Thereby, a fit between personal skills and the task’s requirements determines the quality of outcomes. This fit is vital, especially in performance-oriented contexts such as learning and training, safety-critical monitoring, or high-risk decision-making. A person’s performance can be affected by several factors: 1) level of experience and skills, 2) current physical conditions , (3) current psychological conditions , or (4) external circumstances  behavioural , (2) subjective, and 3) neurophysiological measures  neurophy,5. Whileunimodal approach). However, a multimodal approach has several advantages over using only one measure. It can compensate for specific weaknesses and profit from the strengths of the different complementary measurement methods  )For the mental effort prediction based on subjective perception, we performed a subject-wise median split and categorised values above the threshold as “high mental effort” and below as “low mental effort”. Across all subjects, we had a mean median-based threshold of 3.8  quartile is the point below which 75% of the data lies. We introduced this data split to also investigate the prediction and informative features of extremely high perceived mental effort, which may indicate cognitive overload. By performing a quartile split, we had a mean threshold of 6.1  Logistic Regression (LR), (2) Linear Discriminant Analysis (LDA), (3) Gaussian Naïve Bayes Classifier (GNB), (4) K-Nearest Neighbour Classifier (KNN), (5) Random Forest Classifier (RFC), and (6) Support Vector Machine (SVM). They were implemented using the scikit-learn package . FigureFor the cross-subject classification, we used a leave-one-out (LOO) approach where each subject served as a test subject once (leading to 18 “outer” folds). With this 18-fold cross-subject approach, we simulate a scenario where a possible future system can predict an operator’s current mental effort during a task without having seen any data  from this person before. This has the advantage that the model learns to generalise across individuals and allows the exploitation of already collected datasets from a similar context as training sets.Our multidimensional feature space consisted of four modalities: (1) brain activity, (2) physiological activity, (3) ocular measures, and (4) performance measures. All features were z-standardised . This scAfterwards, we combined these classifiers using a voting classifier implemented in the mlxtend package (version 0.19.0 ). The enWith this procedure, we were able to compare the predictions of the single unimodal classifiers to a weighted combination of all classifiers of one modality.1 score and a confusion matrix of the training set and the test subject to evaluate model performance. The F1 score can be interpreted as a weighted average or “harmonic mean” of precision and recall (1—good to 0—bad performance). Precision refers to the number of samples predicted as positive that are positive (true positives). Recall measures how many of the actual positive samples are captured by the positive predictions . The F1 score balances both aspects – identifying all positive, i.e., “high mental effort” cases, but also minimising false positives.For the multimodal approach, the voting predictions of each modality were combined into a final multimodal prediction of mental effort using a second voting classifier. This second voting classifier also assigned weights to the different modality-specific classifiers and was optimised in the same manner as the unimodal approach. We report the average F1 score. The upper CI limit of a dummy classifier represents an empirical chance level estimate  median and (1b) upper quartile split of the Nasa TLX effort scale as well as based on the (2) experimentally induced task load. Further, we compare two sizes of the validation set (one subject and two subjects).MThe performance of the different modalities and classifiers is visualised in 1 scores ranging between 0.7 and 1. However, we also identified several subjects whose subjectively perceived mental effort was hard to predict based on the training data of the other subjects. See Interestingly, for 8 out of 18 participants, we observed high prediction performances with FThe unimodal voting classifiers for brain activity mainly used hard voting (94.4%) and gave the highest weights to the LDA classifier A. HoweveFor classifying subjectively perceived mental effort based on physiological measures such as heart rate, respiration, and body temperature, soft voting was chosen in half of the test subjects. The weighting of the classifiers varied considerably, with the KNN obtaining the highest average weights B. The un1 score of the unimodal voting classifier . The other models  revealed also above-chance level performances but with smaller differences . 27.8% of the test subjects had voting classifiers using soft voting, and 72.2% used hard voting with SVM being weighted highest D. The mop≈ 0.05; . The pered cases E revealsTo identify informative measures for very high perceived mental effort potentially reflecting cognitive overload, we also performed predictions based on the subject-wise split at the upper quartile. Compared with the median-split-based results, we observed decreased classifiers’ performance even below dummy classifier performance . This miWe further fitted models to predict the experimentally induced task load instead of the subjectively perceived mental effort. The prediction of mental effort operationalised by the task load was substantially more successful than the prediction of subjectively perceived mental effort. All modalities, including brain activity and physiological activity, revealed at least one classifier that was able to predict the current task load above the chance level . The unire often .In the final step, we combined the different modalities into a multimodal prediction. In most test subjects (55.6%), soft voting was selected to combine the predictions for the different modalities; 44.4% used hard voting. In line with the results outlined above, the multimodal classifier relied on performance measures to predict subjectively perceived mental effort A, therebed cases C compareIn order to assess the performance of the multimodal classifier without incorporating performance-based information such as speed and accuracy, we constrained the classifier to utilise only (neuro-)physiological and visual measures. This approach is especially relevant for naturalistic applications where obtaining an accurate assessment of behavioural performance is challenging or impossible within the critical time window. For the multimodal prediction without performance, brain activity was weighted highest B. HoweveWith the upper quartile split, we observed a fundamentally different allocation of weights. High weights were assigned to brain and ocular activity B, while Similar to the multimodal voting classifier based on a subject-wise median split of perceived mental effort, classifiers predicted the experimentally induced task load solely using the performance measures. The average prediction performance was exceptionally high , we decA crucial aim of this study was the selection and fusion of informative sources for cross-subject mental effort prediction. We integrated data from different modalities comprising brain activity as assessed with fNIRS, physiological activity , ocular measures (pupil dilation and fixations), as well as behavioural measures of performance (accuracy and speed). However, this selection was naturally not exhaustive. Other measures, such as electroencephalography or electrodermal activity , could pTo combine the data streams obtained from the different measurement methods, we implemented data fusion on two levels: (1) the feature level and (2) the classification level. First, we aggregated our raw data, mainly time series, into informative features. We used standard statistical features like the mean, standard deviation, skewness, and kurtosis. Friedman et al.  exploredOnce the feature space is defined, the research focus shifts towards developing strategies for selecting, merging, combining, and weighting multiple classifier models and modalities at the classification level. These strategies are still the subject of ongoing research and exploration. In this context, it is important to strike a balance between computational power, dataset size, and the benefits of finely tuned combinations of optimally stacked or voted classifiers. The exploration of early and late fusion approaches, as commonly employed in the field of robotics, could provide valuable insights. Early fusion involves the early combination of all data points and the fitting of classifiers to multidimensional data. On the other hand, late fusion involves a more fine-grained pipeline, where several classifiers are fitted to different proportions of the dataset and subsequently combined at a later stage. In this study, we implemented a late-fusion approach where we first combined different classifiers for each modality. In a subsequent step, we combined classifiers to create a unified prediction. Exploring early and late fusion strategies is especially important when one wants to account for temporal dynamics in the different measures or the realisation of real-time mental state monitoring. The review of Debie et al.  providesOur proposed multimodal voting classification approach contributes to the ecologically valid distinction and identification of different states of mental effort. It paves the way toward generalised state monitoring across individuals in realistic applications. Interestingly, the choice of ground truth had a fundamental influence on the classification performance. The prediction of subjectively perceived mental effort operationalised through self-reports, is most effectively achieved by incorporating performance-based measures. On the other hand, the experimentally induced task load can be accurately predicted not only from performance-based measures but also by incorporating neurophysiological, physiological and visual measures. Our findings provide valuable guidance for researchers and practitioners in selecting appropriate methods based on their specific research questions or application scenarios, taking into account limited resources or environmental constraints. The capacity to predict subjectively perceived and experimentally induced mental effort on an individual level makes this architecture an integral part of future research and development of user-centred applications such as adaptive assistance systems.


Heyde's syndrome (HS) is a complex condition characterized by the coexistence of severe aortic stenosis (AS) and gastrointestinal (GI) angiodysplasia. The prevailing belief has been that acquired von-Willebrand factor deficiency (AVWD) is the underlying cause of HS. However, the validity of this theory remains contentious, as there have been reports of bleeding angiodysplasia in the setting of AS despite normal von-Willebrand factor (vWF) activity. Here, we present a compelling case of HS with negative diagnostic testing for AVWD. A 61-year-old female with a history of end-stage renal disease on hemodialysis, AS, and a history of recurrent GI bleeding presented with dyspnea. Prior to arrival, she reported multiple episodes of melena and hematochezia and was found to have a hemoglobin of 6 g/dL. Notable exam findings included melenic stool on digital rectal exam and a grade three systolic crescendo-decrescendo murmur that radiated up to the carotids. A transthoracic echocardiogram demonstrated evidence of severe AS. Considering the recurrent GI bleeding and severe AS, HS was suspected. To investigate this further, a vWF disease panel was sent, revealing a normal multimeric pattern. Given hemodynamic stability, she was discharged but had multiple readmissions soon after with recurrent GI bleeding requiring endoscopic intervention. On her last visit, she underwent transcatheter aortic valve replacement (TAVR) with notable resolution in her GI bleeds thereafter. The prevailing theory regarding the etiology of HS is acquired vWF deficiency. However, the validity of this theory remains a topic of debate, as a growing body of evidence suggests that the absence of AVWD does not necessarily rule out the diagnosis. The absence of AVWD in our patient raises questions about its prevalence in HS and its status as a key feature and highlights the importance of considering HS events without AVWD, given the risk of recurrent life-threatening GI bleeds. Heyde’s syndrome (HS) is a rare condition characterized by aortic stenosis (AS) and gastrointestinal (GI) bleeding often due to angiodysplasia that was first described by Edward Heyde in 1958 . HoweverA 61-year-old woman with a history of end-stage renal disease (ESRD) on hemodialysis (HD), hypertension, type 2 diabetes, atrial fibrillation, coronary artery disease with stent placement, AS, and a history of recurrent GI bleeding, presented with dyspnea and decreased exercise tolerance. Of note, the patient experienced multiple episodes of GI bleeding a year prior to her current presentation. Endoscopic evaluation revealed angioectasia, ultimately requiring her to stop anticoagulation, nonsteroidal anti-inflammatory drugs (NSAIDs), and platelet therapy at the time.Prior to arrival, she reported experiencing multiple episodes of melena at home and was sent to the emergency department from HD after being found to have a hemoglobin of 6 g/dL. On arrival, she was hemodynamically stable with melenic stool noted on the digital rectal exam and a grade three systolic crescendo-decrescendo murmur that radiated up to the carotids. With the exception of an elevated creatinine of 3.35 mg/dL, consistent with her ESRD, the rest of her lab values were within normal limits. She was transfused with two units of packed red blood cells (PRBCs) and admitted to the general medicine floor.The patient experienced multiple episodes of melena throughout her admission, necessitating several blood transfusions. During the course of her evaluation, she underwent an esophagogastroduodenoscopy (EGD), which revealed a non-bleeding gastric clean-based ulcer, which was deemed unlikely to be the source of ongoing bleeding. Subsequently, a video capsule endoscopy (VCE) was performed, uncovering discrete areas of fresh blood in the distal duodenum and an isolated site of fresh blood in the mid small bowel. Despite a subsequent push enteroscopy, the source of bleeding could not be identified.A transthoracic echocardiogram (TTE) demonstrated a mildly decreased left ventricular ejection fraction (LVEF) of 45% and severe AS with an aortic valve area of 0.9 cm2. Considering the recurrent GI bleeding and severe AS, HS was suspected. To investigate this further, a vWF disease panel was conducted, showing normal levels of vWF antigen (153%), ristocetin cofactor activity (101%), and factor VIII coagulation assay (191%). In addition, vWF multimeric analysis revealed a normal multimeric pattern. With the patient being hemodynamically stable, she was discharged with scheduled follow-up appointments with gastroenterology and structural cardiology. A month later, she once again sought medical attention due to recurrent GI bleeding and symptomatic anemia. Repeat VCE revealed several small ulcers oozing blood in the distal small intestine Figure . ColonosHS is a complex condition that is characterized by severe aortic valve stenosis and angiodysplasia in the GI tract. The prevailing theory regarding the etiology of this syndrome is acquired vWF deficiency . AccordiHowever, the validity of this theory remains a topic of debate, as a growing body of evidence suggests that the absence of acquired von Willebrand syndrome does not necessarily rule out the diagnosis . This noSeveral alternative theories have been suggested, one of which suggests increased angiogenesis in the gut as mucosal hypoperfusion can cause decreased cardiac output through a severely stenosed aortic valve . AnotherHS is a complex multisystem disorder that at times can present as a diagnostic challenge. While AVWD has been traditionally considered as the prevailing etiology, the presence of AVWD has not been consistently demonstrated in the literature. This raises questions about the existence of alternative pathways contributing to HS. It also highlights the importance of considering HS even in patients without AVWD, especially given the increased risk of recurrent life-threatening GI bleeding without aortic valve replacement. Further investigation is needed to elucidate these alternative mechanisms, improve diagnostic capabilities, and optimize the management of HS in clinical practice.


A 69-year-old man with persistent atrial fibrillation (AF) experiencing recurrences of suspected paroxysmal atrial tachycardia was referred for repeat ablation. He had previously undergone pulmonary vein isolation in 2016. He was suspected to be experiencing a tachycardia involving the mitral isthmus or left-sided veins initially; however, electroanatomic mapping did not reveal a circuit involving these structures. Instead, a focal arrhythmia with the earliest signal on the anterolateral mitral valve annulus was noted. Catheter manipulation in this region consistently terminated the tachycardia. A tachycardia involving the mitral isthmus or left-sided veins was suspected initially; however, EAM did not reveal a circuit involving these structures. Instead, a focal arrhythmia with the earliest signal on the anterolateral mitral valve annulus was noted . Catheter manipulation in this region consistently terminated the tachycardia. The Advisor™ HD Grid was then placed in the left ventricle just distal to this site, and although left ventricular (LV) pacing resulted in termination, eccentric activation was confirmed. Mapping with the ablation catheter during LV pacing revealed a pathway potential, which was eliminated instantly with ablation, restoring concentric activation .A 69-year-old man with persistent atrial fibrillation (AF) status post-ablation with pulmonary vein isolation in 2016 with recurrences of suspected paroxysmal atrial tachycardia was referred for repeat ablation. Electroanatomic mapping (EAM) in the left atrium spontaneously induced supraventricular tachycardia (SVT). The right pulmonary veins were ostially isolated and the left pulmonary veins had recovered at the anterior carina. The Advisor™ HD Grid Mapping Catheter, Sensor Enabled™  and EnSite Precision™ (Abbott) three-dimensional mapping system were used to map this 1:1 eccentric atrioventricular tachycardia with a cycle length of 430 ms 1 The mechanisms and pathogenesis of AF in patients with APs are poorly understood, complex, and often controversial. Even though therapeutic ablation of APs is associated with AF reduction, older age, male sex, and the presence of APs are independent risk factors for the presence and progression of clinical AF.2 Numerous additional risk factors like hypertension, diastolic heart failure, older age, complexity of coronary artery disease, structural changes in the atrium and ventricle, and the presence of renal disease all contribute to the development of AF in patients with CLAPs.3 Given the presence of these risk factors in our patient, it is likely that APs are only one of the many substrates for the development of AF, which was unlikely related to his AP.3 Additionally, previous studies have documented an AF recurrence rate of 10%–25% following AP ablation, and close monitoring of these patients is necessary for uncovering future recurrences.1 This case serves as a reminder to consider the differential of SVT in cases of redo AF ablations and revealed the likely therapeutic advantage of LV pacing near the pathway site to delineate a clear pathway potential.5AF is noted to occur in up to one-third of patients with accessory pathways (APs). There is a 15 times higher incidence of AF occurring in patients with manifest pathways compared to those with concealed accessory pathways (CLAPs), as the overall prevalence of AF in CLAP patients is thought to be <1%.


Baffle leaks are a frequently encountered and often overlooked complication after the atrial switch procedure for transposition of the great arteries. Baffle leaks are present in up to 50% of non-selected patients, and while they initially may not cause clear symptoms, they can complicate the hemodynamic course and influence the prognosis in this complex patient group. A shunt from the pulmonary venous atrium (PVA) to the systemic venous atrium (SVA) can lead to pulmonary overflow and subpulmonary left ventricular (LV) volume overload, while a shunt from the SVA to the PVA can result in (exercise-associated) cyanosis and paradoxical embolism. We report three cases of baffle leaks in patients with systemic right ventricular (sRV) failure late after the atrial switch procedure. Two symptomatic patients who presented with exercise-associated cyanosis due to SVA to PVA shunting over the baffle leak underwent successful percutaneous baffle leak closure with a septal occluder device. One patient with overt sRV failure and signs of subpulmonary LV volume overload due to PVA to SVA shunting was managed conservatively, as baffle leak closure was expected to lead to an increase in sRV end-diastolic pressure and aggravation of sRV dysfunction. These three cases illustrate the considerations made, challenges faced, and necessity of a patient-tailored approach when addressing baffle leaks. Transposition of the great arteries (TGA) is the second most common cyanotic congenital heart defect after Tetralogy of Fallot and affects 2 to 3 out of every 10,000 live births [The morphological and functional characteristics of the sRV, which are not equipped to chronically sustain the pressure of the systemic circulation, lead to a range of long-term complications. Over 50% of patients with TGA who underwent the atrial switch procedure develop symptomatic heart failure by the age of 45 years, and their 40-year survival rate varies from 82 to 90% . AlthougThe diagnosis of baffle leaks can be challenging due to the low sensitivity of transthoracic echocardiography, and might necessitate contrast echocardiography, cardiac magnetic resonance imaging (MRI), computed tomography (CT), and/or exercise testing ,8. The 2This case series presents three cases of adult TGA patients with reduced systolic sRV function and baffle leaks late after the atrial switch procedure, illustrating the patient-tailored approach to the management of baffle leaks in the modern era. A 53-year-old woman born with TGA who underwent atrial correction according to Mustard at the age of 3 years was reviewed in the outpatient clinic due to sRV failure. She had a rate adaptive atrial (AAI-R) pacemaker implanted at the age of 29 due to sick sinus syndrome, which was upgraded to a primary prevention dual chamber implantable cardioverter-defibrillator (DDD-ICD) at the age of 45. She had a history of an ambulant, uncomplicated COVID-19 infection two years ago and has since been checking her peripheral oxygen saturations (SpO2) at home. The patient now reports that SpO2 drops to 87% at ambient air during daily activities. She was in New York Heart Association (NYHA) functional class III despite pharmacological treatment with a beta-blocker, an angiotensin receptor-neprilysin inhibitor (ARNI), and a sodium-glucose cotransporter 2 inhibitor (SGLT2i). Bicycle exercise ergometry revealed an exercise capacity of 100 watts (95% of what was predicted) with a VO2 max of 19.5 mL/min/kg (66% of what was predicted) with progressive decline in SpO2 to 77% at maximal effort. Her SpO2 in ambient air was 97% at rest, and she was euvolemic. Transthoracic echocardiography (TTE) showed a poor systolic function of the dilated sRV and trivial tricuspid regurgitation. The function of the subpulmonary LV was normal A,B. SubsThe patient underwent a successful baffle leak closure with a 10 mm Amplatzer Septal Occluder . The procedure was performed using left femoral access under local anesthesia with fluoroscopic and intracardiac echocardiography (ICE) guidance D–I. No rA 47-year-old woman with TGA late after the atrial switch procedure according to Senning, was analyzed in the outpatient clinic due to progressive dyspnea and decreased exercise tolerance over the past year. She had a history of concomitant pulmonary valve commissurotomy, resection of an infundibular pulmonary stenosis, and ventricular septal defect (VSD) closure at the age of two years. She had two uncomplicated pregnancies at the ages of 23 and 24, respectively. A third pregnancy at the age of 26 years was terminated during the first semester due to a decline in clinical condition and persistent hypertension. In the following decades, as the sRV progressively deteriorated to a moderately reduced systolic function, she underwent a total of five atrial tachycardia ablation procedures, and a dual chamber (DDD) pacemaker was implanted due to sick sinus syndrome . Upon presentation, she was in NYHA functional class III. Pharmacological treatment included a beta-blocker, an ARNI, a mineralocorticoid receptor antagonist, a loop diuretic, amiodarone, and a vitamin K antagonist. Bicycle exercise ergometry revealed a reduced exercise capacity of 80 watts (61% of what was predicted) and a VO2 max of 12.5 mL/min/kg (48% of what was predicted). SpO2 decreased from 93% at ambient air at rest to 84% at maximal effort. TTE showed a stable, moderately reduced function of the sRV, trivial tricuspid regurgitation, and preserved function of the subpulmonary LV. Suspicion of a baffle leak was raised by the apical four chamber view, which revealed systolic flow from the SVA to the PVA (right-to-left) at rest A,B. SignThe patient underwent a successful baffle leak closure with a 18 mm Occlutech Figulla Flex II Atrial Septal Defect (ASD) Occluder . The procedure was performed using left femoral access under conscious sedation and local anesthesia with fluoroscopic and ICE guidance E,F. No rA 60-year-old woman with TGA with VSD, secundum ASD, mild infundibular pulmonary stenosis, partial anomalous pulmonary venous drainage, and a persistent left superior vena cava was evaluated in the outpatient clinic due to progressive sRV failure. She underwent the atrial switch procedure according to Mustard with VSD closure at 11 years of age, followed by surgical closure of a baffle leak at 30 years of age, and combined tricuspid valve restrictive annuloplasty with a second surgical baffle leak closure at 43 years of age. She had a history of paroxysmal supraventricular tachycardias, for which she had undergone two catheter ablation procedures. A DDD-pacemaker was implanted due to sick sinus syndrome. The system was later upgraded to a transvenous DDD-ICD due to symptomatic episodes of ventricular tachycardia, and she required chronic ventricular pacing due to symptomatic atrioventricular conduction block and bradycardia-induced (non-sustained) polymorphic ventricular tachycardia. At the age of 57 years , the patient was diagnosed with a cardiobacterium hominis endocarditis involving a small, hemodynamically not significant baffle leak and the pacemaker leads A,B. Her She was now in NYHA functional class II-III despite pharmacological treatment with a beta-blocker, an ARNI, a SGLT2i, a loop diuretic, and a vitamin K antagonist. Bicycle exercise ergometry revealed a reduced exercise capacity of 50 watts (51% of what was predicted) and a VO2 max of 8.7 mL/min/kg (36% of what was predicted). SpO2 remained above 95% during exercise. TTE showed a dilated sRV with moderately to severely reduced systolic function, signs of dyssynchrony, and mild tricuspid regurgitation. The subpulmonary LV had preserved systolic function but was dilated. During diastole, there was a septal shift towards the sRV, consistent with volume overload of the subpulmonary LV. TTE also demonstrated the presence of a hemodynamically significant baffle leak with a PVA to SVA (left-to-right) shunt causing volume overload of the subpulmonary LV and contributing to the LV dilatation C. The case was discussed in the heart team. The PVA to SVA flow over the baffle leak was deemed to have an unloading effect due to the elevated sRV end-diastolic pressure. A closure of the leak was therefore expected to increase the sRV pressures and potentially aggravate systolic sRV dysfunction. Combined with the lack of cyanosis, closure of the baffle leak at this point was therefore deferred, and it was decided to first attempt to optimize the systolic sRV function. Given the pacing-induced sRV dyssynchrony observed under chronic subpulmonary LV pacing, the patient was considered to be a good candidate for epicardial sRV lead placement and cardiac resynchronization therapy. In this case series, we describe the clinical considerations and contemporary management strategies for baffle leaks in adult patients with TGA late after the atrial switch procedure. The first two cases suffered from progressive sRV failure and exercise-associated cyanosis due to SVA to PVA shunting upon exertion. The baffle leaks were successfully closed through catheter intervention, eliminating the exercise-associated hypoxemia. The third patient had progressive sRV failure without significant cyanosis, yet with a PVA to SVA shunt that resulted in a volume overload of the subpulmonary LV, while “unloading” the failing sRV. The baffle leak closure was deferred, and the initial management strategy focused on optimizing the sRV function. These three cases illustrate the considerations made and challenges faced when choosing the optimal management strategy for an individual patient with a baffle leak. Baffle leaks are a common complication late after the atrial switch procedure, and they are present in up to 50% of non-selected and asymptomatic patients . As a siThe ESC and American Heart Association (AHA) ACHD guidelines state that baffle leaks can be best diagnosed routinely with (contrast) echocardiography. Transesophageal echocardiography, cardiopulmonary exercise test, and/or cardiac MRI have an additive role in the diagnosis and evaluation of baffle leaks ,8. In a In the first two cases, a clinical suspicion of a baffle leak was present prior to diagnosis. Self-registered desaturation, objectified using an in-hospital bicycle exercise ergometry (exercise-associated cyanosis), played an important role in identifying the hemodynamic consequences of a baffle defect in a group of patients with a high a priori risk. Agitated saline contrast echocardiography and/or CT were used to confirm the diagnosis in our patients. While generally considered a safe procedure, patient B suffered from a transient ischemic attack directly after contrast echocardiography due to cerebral embolization of air bubble contrast. Transient visual disturbances have previously been described after agitated saline contrast echocardiography for baffle leak diagnosis . Cardiac MRI can provide more reliable and robust quantification of the interatrial shunt magnitude than echocardiography, although small shunts can easily be missed ,9. NeverAlthough, to the best of our knowledge, no data has been published on exercise catheterization of TGA patients with baffle defects, exercise hemodynamics have been described as being of incremental value in understanding functional limitations in patients with a Fontan circulation . Right hPatients A and C underwent the atrial switch procedure according to Mustard, and patient B according to Senning. A trend towards fewer baffle leaks after the Mustard compared with the Senning procedure has previously been described . As baffThe current AHA ACHD guidelines are less explicit in giving direct recommendations for the management of baffle leaks than the ESC guidelines ,8. JudgiThe decision was made to manage the baffle leak conservatively in this patient, as we expected closure to lead to further elevation of sRV end-diastolic pressures and aggravation of sRV dysfunction. A potentially positive effect of a baffle leak with “ASD-like physiology” has been described in the literature. By placing a volume load on the subpulmonary LV through the PVA to SVA shunt, the interventricular septum is splinted and might support the sRV function in a manner similar to retraining the LV with a pulmonary artery band or in cases with left ventricular outflow tract obstruction/pulmonary stenosis . NeverthThe ESC guidelines also suggest covered stents as an option for percutaneous baffle leak closure . The useWhile historically baffle complications were managed surgically, perioperative mortality for surgical baffle revision after the atrial switch procedure has been reported in up to 36% of cases . PercutaBaffle leaks are present in up to 50% of non-selected patients late after the atrial switch procedure, and while they initially may not cause clear symptoms, their existence can complicate the hemodynamic course and influence the prognosis in this complex patient group. Inherent to the nature of this case series, no conclusions can be drawn to advise specific treatment strategies for patients with a baffle leak. Nonetheless, this case series demonstrates the clinical considerations in an individual, patient-tailored approach when assessing baffle leak hemodynamics in the context of sRV failure. It illustrates the feasibility of a catheter interventional management strategy using septal occluder devices for successfully alleviating exercise-associated cyanosis. Moreover, it highlights the complexity of choosing a treatment strategy in “relatively” asymptomatic patients with signs of ventricular volume overload due to PVA to SVA shunting. Although intervention should be considered in these patients, this may not always be the best option. A clear evidence-based approach is currently missing to make these challenging treatment decisions. Future research should focus on defining more robust criteria for baffle leak closure and the optimal timing window, especially for seemingly asymptomatic patients.


Minimally invasive treatments for renal carcinoma offer a low rate of complications and quick recovery. One drawback of the use of computed tomography (CT) for needle guidance is the use of iodinated contrast agents, which require an increased X-ray dose and can potentially cause adverse reactions. The purpose of this work is to generalise the problem of synthetic contrast enhancement to allow the generation of multiple phases on non-contrast CT data from a real-world, clinical dataset without training multiple convolutional neural networks.A framework for switching between contrast phases by conditioning the network on the phase information is proposed and compared with separately trained networks. We then examine how the degree of supervision affects the generated contrast by evaluating three established architectures: U-Net (fully supervised), Pix2Pix , and CycleGAN .We demonstrate that there is no performance loss when testing the proposed method against separately trained networks. Of the training paradigms investigated, the fully adversarial CycleGAN performs the worst, while the fully supervised U-Net generates more realistic voxel intensities and performed better than Pix2Pix in generating contrast images for use in a downstream segmentation task. Lastly, two models are shown to generalise to intra-procedural data not seen during the training process, also enhancing features such as needles and ice balls relevant to interventional radiological procedures.The proposed contrast switching framework is a feasible option for generating multiple contrast phases without the overhead of training multiple neural networks, while also being robust towards unseen data and enhancing contrast in features relevant to clinical practice. Minimally invasive, image-guided treatment options for renal cell carcinoma, such as cryoablation, offer a lower complication rate and a faster recovery period than radical or partial nephrectomy  by usingTo reduce usage of RCAs, it is necessary to develop computational techniques that can correctly alter the contrast of the clinically relevant regions of interest (ROIs). Histogram-based methods  modify tCreating synthetic contrast-enhanced (sCE) CT images without RCAs has been proposed , 19, usiTo enforce quantitatively realistic intensities for performing clinically relevant downstream tasks, for instance, augmenting scarce data, enhancing images prior to segmentation, RCA dose reduction or identifying tumours in interventional procedures, the distribution of the sCE images should be as close to the actual CE data distribution as possible. An evaluation framework needs to take into account not only image quality and predicted intensities, but also the bias of a given technique compared to the ground truth.cycle-consistency term, which enforces a consistent forward and backward mapping between the two domains but does not prevent the generator from removing (or adding) features that may (or may not) be present in the target image [Adversarial training has become increasingly popular in the super-resolution and style transfer literature, as supervised learning techniques using the  Pix2Pix  was deveCycleGAN  was intret image . In mediThe aim of this work is twofold. First, as a step towards accurate, clinically useful, multi-phase sCE we propose a framework for contrast phase switching and test it against separately trained networks as a baseline. Second, we comprehensively evaluate the quantitative performance of the aforementioned training paradigms  on contrast transfer between NCE and CE images.Does the proposed multi-contrast sCE framework match the performance of individually trained CNNs?Does a supervisory signal improve performance in sCE compared to unsupervised adversarial training?Are the generated intensities quantitatively realistic and of adequate quality to allow their use in clinically relevant tasks?To answer the above questions, we have made the following contributions: (1) We use deep learning to perform multi-phase sCE on pre-procedural iCT images; (2) We compare three training paradigms on this task, exploring whether supervision improves model accuracy; (3). We use Bland–Altman analysis to quantitatively measure the bias of the proposed methods, showing that they generate more consistent enhancement than real CE, and that a network’s bias can affect its performance on downstream tasks; (4). We examine whether these contributions aid a U-Net [To the best of our knowledge, this is the first study performing sCE on interventional CT data that pose challenges such as organ displacement and needle insertion. While iCT data are scarce, we show significance on a real-world dataset that is the largest we have found so far in the literature. In addition, we believe it is the first attempt to generate synthetic contrast conditioned on phase information, allowing the user to readily switch between phases during inference. As sCE is a new interventional application, we focus on validation and reporting first quantitative results using multiple established neural network architectures in the style transfer domain, leaving the development of new models specific to sCE to future work. The research questions posed are:  a U-Net  in segmet maps a source image The proposed method for allowing contrast phase switching in generated images can be applied to any CNN and is achieved by tiling a scalar quantity representing the required phase , which is then concatenated to the feature maps in a layer. A standard CNN The baseline technique (UNet-Baseline) comprises two 3D U-Nets , trainedThe network used for adversarial training with supervision is based on the Pix2Pix architecture . The genmentclass2pt{minimThe Pix2Pix training objective uses the adversarial binary cross-entropy loss for discriminator and generator  were employed for non-normal distributions. Confidence intervals for non-normal data were generated with the nonparametric bootstrap using 100,000 runs.To assess the bias between the proposed techniques and the ground truth ROI intensities, Bland–Altman analysis  is used.p-values from statistical tests underwent the Bonferroni correction for multiple comparisons as needed to maintain a family-wise error rate , renal cortex (Co), medulla (Md) were segmented, as well as the entire tumour (Tu) except in one subject where the tumour could not be confidently identified. The ROIs are referred to by their abbreviations with the phase as a subscript, e.g. All predicted images were converted back to Hounsfield Units (HU) before evaluation with visual examination, mean squared error (MSE), peak signal-to-noise ratio (pSNR) and structural similarity index measure (SSIM). For quantitative comparisons, five equally spaced slices of aorta  was feasible compared to training one network for each phase (UNet-Baseline). There was no significant difference on H-test between any of the techniques in terms of image quality metrics Table , and no entclass1pt{minimaThis demonstrates that it is possible to achieve phase-switching in most ROIs (with superior performance in kidney), opening up the possibility of generating multiple contrast phases later in the procedure when a lesion can be more conspicuous .The second hypothesis concerned the most suitable training paradigm for contrast enhancement, specifically that a supervisory signal would constrain the network to output realistic intensities.The poorest performance was from CycleGAN (entirely unsupervised) in terms of visual appearance, despite no statistical significance in terms of image quality metrics Table . CycleGAentclass1pt{minimaUNet-Phase and Pix2Pix both over-enhanced tumour in both phases (Pix2Pix was significantly more biased on pairwise ANCOVA intercept comparison). Pix2Pix also over-enhanced medulla in both phases  that were not present in the training dataset. Two examples are shown in Figs. Figure Interestingly, Pix2Pix in-paints the photon starvation artefact from the needle Fig. , while bContrast agents are used to identify clinically relevant features by enhancing the feature (e.g. a tumour) more or less than the surrounding tissue. However, all networks enhanced the tumour and surrounding tissue to a similar degree  generated the most intense ROIs and the fully supervised U-Net was most quantitatively accurate. The proposed techniques generate more consistent enhancement than seen in the ground truth images, while assessing the bias by region and phase can inform usage of models with different characteristics for different tasks—UNet-Phase, with its smaller bias, outperforms Pix2Pix for segmentation, while Pix2Pix generates more vivid vasculature and renal medulla. Lastly, we have shown that UNet-Phase and Pix2Pix can generalise to unseen intra-procedural data, a more challenging task given the addition of needles, hydro-dissection contrast and the movement of organs over time. Crucially, the models also improve needle artefacts and tumour visualisation, indicating potential for multi-task sCE and image quality applications.


Spatial manipulation of excitonic quasiparticles, such as neutral excitons, charged excitons, and interlayer excitons, in two-dimensional semiconductors offers unique capabilities for a broad range of optoelectronic applications, encompassing photovoltaics, exciton-integrated circuits, and quantum light-emitting systems. Nonetheless, their practical implementation is significantly restricted by the absence of electrical controllability for neutral excitons, short lifetime of charged excitons, and low exciton funneling efficiency at room temperature, which remain a challenge in exciton transport. In this comprehensive review, we present the latest advancements in controlling exciton currents by harnessing the advanced techniques and the unique properties of various excitonic quasiparticles. We primarily focus on four distinct control parameters inducing the exciton current: electric fields, strain gradients, surface plasmon polaritons, and photonic cavities. For each approach, the underlying principles are introduced in conjunction with its progression through recent studies, gradually expanding their accessibility, efficiency, and functionality. Finally, we outline the prevailing challenges to fully harness the potential of excitonic quasiparticles and implement practical exciton-based optoelectronic devices. Excitonic quasiparticles play a dominant role in the distinctive optical characteristics of two-dimensional (2D) semiconductors –9. TheseIn this comprehensive review, we present recent advancements for the control of excitonic quasiparticles in 2D semiconductors, as illustrated in Fig. We envision that this review provides a comprehensive understanding of exciton transport in two-dimensional semiconductors. In addition, by presenting various control modalities along with their specific progressions, we hope to assist readers to predict future directions on exciton transport study.Understanding and manipulating exciton transport in TMD monolayers can lead to the progress of the next generation electronic and optoelectronic device , 22–26. VRecently, according to Cheng et al., the diffusion and the drift of negative charged excitons in monolayer WSeentclass1pt{minimaentclass1pt{minimaentclass1pt{minimaentclass1pt{minimaFor the development of charged exciton-based devices, inducing high density of charged excitons is a crucial prerequisite. The study by Uddin et al. presented the generation of charged excitons by adjusting gate voltage on the MoSentclass1pt{minimaentclass1pt{minima}∼10 ns) . In the um wells –36.Whereas intralayer charged excitons in TMD monolayers exhibit short lifetimes (∼100 ns) . IXs in ∼100 ns) , 38. Sucentclass1pt{minima∼100 ns) . The red∼100 ns) . While tentclass1pt{minimaentclass1pt{minimaentclass1pt{minimaentclass1pt{minimap [Ex, y) perpendicular to the crystal plane enables the modulation of IXs energy While IXs do not carry a net electric charge, recent studies demonstrated the spatial control of IXs using out-of-plane electric field –43. In tp . Consequument}E→ . This mokT in the diffusion path, blocking the channel of the transistor, as shown in Fig. Employing this quantum confined Stark effect, the recent study by Unuchek et al. demonstrated an excitonic transistor at room temperature, as illustrated in Fig. d was 0.9 nm and 0.6 nm in each device. The difference between two devices was similar to the size of a monolayer h-BN. Here, the device A exhibited larger energy shift compared to the device B as the slope of the energy shift was proportional to the magnitude of the out-of-plane dipole moment The local application of the electric field enabled the artificial electrostatic traps, achieving the high exciton concentration . Figure While previous studies demonstrated the devices enabling radial IX transport, the recent study by Shanks et al. presented a specialized device facilitating unidirectional IX transport, more suitable for excitonic-circuit applications, as shown in Fig. In this section, we have reviewed recent advancements in the electrical control of exciton transport. Unlike the limited transport observed in neutral excitons in TMD monolayers, negatively charged excitons and IXs can be electrically transported. This capacity for electrical transport enables applications in industrial circuits . By utilTMDs have remarkable sustainability to the applied strain  with excRecently, Lee et al. suggested the tunable device enabling the controlled wrinkle formation of WSnolayers .While previous study presented the one-dimensional (1D) confinement of the photo-generated excitons in WSgeometry . Figure While the bright excitons exhibit the funneling toward the minima of tensile stain, the dark excitons drift away from the minima of tensile strain, showing the anti-funneling effect. This is attributed to the opposite stain-induced bandgap energy variation of dark excitons, as the energy of momentum-dark excitons increases with applying tensile strain , 68. RecWhen the strain gradient scales down to the nanoscale, different characteristics of exciton transport with a new controllability can be driven in TMD monolayers. However, the nanoscale strain gradient induced by sub-diffraction-limited geometry significantly limits the optical investigation with conventional optical microscopy technique. Recently, the development of tip-enhanced photoluminescence (TEPL) spectroscopy enables the investigation of nano-optical phenomena with its sub-diffraction-limited spatial resolution –74.The recent study by Koo et al. presented the applications of nanoscale wrinkles in WSeMore recently, Lee et al. reported the in-depth investigation of exciton funneling effect at the nanoscale strain gradient . They cous study . These fus study  and excius study . The morIn this section, we have reviewed recent progresses to control exciton flow in TMD monolayers with strain gradient geometry. By exploiting the various strain gradient geometry and different optical characteristics of excitonic quasiparticles, the correspondingly modified behaviors of exciton flow can be optimized to the specific applications, such as energy harvesting in the excitonic photovoltaics  and exciThe exciton transport as a coupled form with SPP exhibits the potential for the development of plasmonic optical interconnects and circuits –85. The The long-range exciton transport mediated by the SPP has been facilitated by exploiting cascaded exciton energy transfer within a lateral TMD heterostructure, as shown in Fig. While previous study relied on the directionless propagation of substrate-induced SPP, the directional propagation of exciton emission has been demonstrated through the SPP of the Ag nanowire, as shown in Fig. Exciton-based optical logic operation was performed using the Ag nanowire on the stacked MoSenolayers . In thisIn this section, we have reviewed the exciton transport with the SPP of the plasmonic structures. SPP enables not only the overcoming of the intrinsic exciton transport length through the cascaded exciton–SPP–exciton transfer but also directional exciton propagation by coupling to the plasmonic waveguide. To effectively harness the advantages of plasmonic transport, increasing the coupling and conversion efficiency while minimizing the undesirable losses during the propagation plays an important role. Plasmonic structures possess a large degree of freedom in geometry-dependent optical and electrical properties, providing opportunities to develop new design of SPP-mediated exciton transport platform.Photonic systems are primarily characterized by their optical responses based on key degrees of freedom, which include frequency, wavevector, polarization, and phase. For several decades, ongoing research efforts have been dedicated to facilitating optical systems with predetermined optical attributes through meticulous selection of materials, precise manipulation of structures, and deliberate control of dimensions. By integrating a custom-designed photonic cavity structure considering the exciton resonances of 2D materials, it becomes feasible to couple excitons with specific photonic modes. This capability has various applications in exciton transport, such as extending the propagation distance , 102 andWhen the strong coupling is achieved between excitons and cavity photons, a novel bosonic quasiparticle is generated, known as exciton–polaritons , 110. Thperature , 47. MorValley pseudospin of electrons in hexagonal 2D materials arose from the inequivalent electronic properties at the band edge of +K and −K. By controlling the chirality of incident photons, selective exciton formation from the +K and −K valley became possible . In a reSince the discovery of topological insulators, the topology has become an active area of research in condensed matter systems and has extended into the realm of photonics –131. TheIn this section, we have reviewed recent studies of photonic structures designed to couple with excitons in two-dimensional materials. By harnessing the rich excitonic properties of TMDs, various structures including DBR, dielectric-metal hybrid gap waveguide, and topological photonic crystal have been utilized to achieve outcomes, such as low-loss, long-range transport, unidirectional propagation, and efficient routing. These results serve as essential prerequisites for practical applications of exciton-based devices, such as optoelectronic interconnects and photonic circuit elements. Given the substantial potential and ample room for improvement in two-dimensional exciton transport through the integration of photonic structures, we anticipate the emergence of more innovative and progressive research in this field.In this comprehensive review, we have explored the recent progress in the control of exciton transport in various strategies, with a particular focus on its applications in 2D semiconductors. To overcome the lack of controllability for neutral excitons, the short lifetime of charged excitons, and the low exciton funneling efficiency, we explored how incorporating newly developed control parameters of excitonic quasiparticles and structural advancement have attributed to their progress in the field of exciton-based devices. Throughout the review, we delved into four control parameters for excitonic quasiparticle flow in two-dimensional semiconductors.First, we discussed about manipulation of excitonic quasiparticles driven by electric fields. Adjusting the electric field on two-dimensional semiconductors allowed to control the behavior of charged excitons within the circuit. Our exploration extended to interlayer charged excitons, distinguished by their prolonged lifetimes, which enabled the propagation of excitonic quasiparticles in a longer distance. Furthermore, neutral interlayer exciton flow can be driven by the electric field, by the modulation of interlayer exciton energy through quantum confined Stark effect.Second, we explored the strain control of neutral excitons via strain gradient in two-dimensional semiconductors on the artificial structures. Strain gradient induced the local modification of the exciton density, as the exciton current flowed toward a low bandgap energy, allowing neutral excitons propelled along the shape of artificial structure. Meanwhile, we introduced the anti-funneling effect under the strain gradient by exploiting the opposite strain-induced energy variation of momentum-dark excitons. Furthermore, nanoscale strain gradients were revealed to possess discernable characteristics such as drift-dominant exciton flow for significantly enhancing the exciton funneling efficiency at room temperature.Third, our investigation centered on the examination of long-range exciton transport facilitated by SPP within planar two-dimensional semiconductors. The coupling of excitons to plasmons served to concentrate electromagnetic fields at sub-diffraction-limited scale, thereby amplifying the potential for integration within electronic circuits. Additionally, exciton–SPP complexes can be directionally propagated through coupling with plasmonic waveguides.Lastly, we examined exciton transport coupled with specific photonic modes within photonic cavity structures. By coupling various photonic cavity structures, considering the exciton resonances of two-dimensional semiconductors, it led to excitons coupling with specific photonic modes. This phenomenon facilitated the realization of low-loss and long-range exciton transport. Additionally, it enabled unidirectional propagation via controlling chirality of incident photons, consequently leading to the selective formation of excitons from the +K and −K valleys.In this review, while we have primarily discussed the platforms for controlling exciton transport, it is important to acknowledge that various strategies have been concurrently developed to further improve both the speed and the degree of control over exciton transport. For example, exploiting moiré excitons in twisted heterostructures introduced interesting phenomena originated from modified local atomic configurations and diffusivities , such aserations . While tIn addition to the exciton transport in monolayer and bilayer two-dimensional semiconductors, exciton transport can be applied to the transport of single photon emitters combined with waveguide structure , 138. Fu


The Coronavirus 2019 (COVID-19) pandemic has affected over 700 million people worldwide and caused nearly 7 million deaths. Vaccines currently developed or in development are the most effective tools for curbing the pandemic and mitigating its impacts. In Turkey, inoculation with the Pfizer-BioNTech COVID-19 vaccine  has been approved.We report a 56-year-old female patient with underlying essential hypertension who experienced intracranial hemorrhage after receiving her first dose of tozinameran. The patient underwent immediate surgical evacuation of the hematoma, during which a left middle cerebral artery bifurcation aneurysm was macroscopically identified and clipped. The patient was pronounced deceased on the second postoperative day. This is the second case of intracranial hemorrhage following tozinameran administration caused by a ruptured middle cerebral artery bifurcation aneurysm. Upon analyzing the case, there might be a connection between the vaccine's potential immune-triggering effect on hemodynamic patterns and the rupture of the previously unknown cerebral aneurysm. However, these severe complications do not justify avoiding vaccines; further studies are needed. This study emphasizes the need for increased vigilance in patients with underlying systemic comorbidities who have recently been vaccinated and to share our insights into the potential relationship between tozinameran and intracranial hemorrhage. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has had global effects, causing both acute and chronic complications . MedicalExisting literature suggests that the pathophysiology of COVID-19 may trigger cerebral aneurysm rupture; however, the precise relationship between COVID-19 and intracranial hemorrhage due to cerebral aneurysm rupture remains unclear . To our A 56-year-old Caucasian female patient with underlying essential hypertension and hypothyroidism was admitted to the infectious diseases department for her first dose of the Pfizer-BioNTech mRNA COVID-19 vaccine in March 2023. The patient had no significant family history of chronic illnesses, does not use illicit drugs, and had no history of previous surgeries. The patient was a high-school math teacher. As we learned from her son, she was not using drugs unless she felt extremely discomfortable. Upon admission, her pre-vaccination physical examination revealed 110/70 mm Hg blood pressure, 36°C body temperature, and 129 mg/dL blood glucose level. Her initial physical examination of all systems was intact, and her Glasgow Coma Scale (GCS) score was 15 out of 15 . Immediately after the vaccine injection, she became dizzy, experienced temporary cognitive dissociation, and exhibited decreased verbal responsiveness. The supervising physicians from the infectious diseases department referred the patient to the emergency department. Fifteen minutes after vaccination, the patient lost consciousness and demonstrated neither verbal nor motor responses to painful stimuli, with a GCS score of three out of 15 . There was no motor response to the painful stimuli in both the upper or lower extremities. Her pupils were dilated and unresponsive to light. The patient was intubated, and a non-enhanced cranial CT scan revealed a 6x6 cm hyperdense area in the left temporal lobe extending into the intraventricular space, accompanied by perilesional edema  vaccine have been reported in the literature across four different studies ,6-8. In 2b2 vacciIn all reported cases, a couple of days elapsed before the intracranial hemorrhage occurred; however, in our case, it suddenly happened after the tozinameran injection. Female predominance has been reported in all cases similar to ours. Additionally, two cases were vaccinated for their second doses of tozinameran, while the other two were vaccinated for their first doses ,8. FurthThe reason behind the aneurysm rupture should be discussed to better understand this issue. Inflammatory cascades in the cerebral aneurysm wall, primarily due to T-cells and macrophages, may be responsible for the rupture of cerebral aneurysms . AbnormaIntracerebral hemorrhage may also be caused by vasculitis, as reported in the literature in one case . A recenIn our case, the patient had underlying untreated hypertension, mild hypothyroidism, and a family history of hypertension. She never experienced neurological symptoms requiring admission to the neurology or neurosurgery departments. The patient was admitted to the internal medicine department five months ago, and anti-hypertensive drugs were prescribed. However, she never used them, as we learned from her son and medical records. However, the patient's hemorrhage was located in an atypical position for hypertension-related hemorrhage. Consequently, the differential diagnosis includes amyloid angiopathy, CVST, previously unknown arteriovenous malformations, aneurysms, or neoplasms.In this case, we believe that the reason for the intracranial hemorrhage was a rupture of the left middle cerebral artery bifurcation aneurysm. However, postoperative computed tomography and angiography could not be obtained due to the patient's unstable vitals.In light of scientific data, vaccination remains the most potent and safe protection against COVID-19 disease, and it is not possible to definitively state that there is a direct causative relationship between intracranial hemorrhage and COVID-19 vaccination. While these complications do not hinder administering second or subsequent immunization doses, physicians should be aware of these potentially fatal situations that may arise after vaccination.This privileged case report emphasizes a potentially brutal relationship between the tozinameran and intracranial hemorrhage. We want to warn our colleagues about the potential side effects of COVID-19 (Appendix 1). According to our recommendations, care should be taken while examining the patients before getting vaccinated for COVID-19. If there is an underlying chronic disease, such as an unknown cerebral aneurysm, it may cause crucial events. If a patient shows an unwanted side effect after the vaccine injection, such as loss of consciousness, dizziness, or drowsiness, they should be closely monitored risk of intracerebral hemorrhage should always be kept in mind. Needed imagings have to be done immediately.There are some limitations in our study. Preoperative high-quality CT scans and CT angiography could not be obtained. An intraoperative picture of the aneurysm and the postoperative head CT or CT angiography could not be obtained because of the patient's unstable vitals.This case cannot demonstrate a direct relationship between the COVID-19 Pfizer-BioNTech vaccination and intracerebral hemorrhage. Based on our findings, we highly recommend examining the patients thoroughly before vaccination and paying close attention to those with underlying untreated essential hypertension, especially in the first few hours after vaccination. While examining the patients before the vaccination, the physician should always remember that there might be an unknown underlying disease. Patients who exhibit neurological or cognitive symptoms after vaccination should be closely monitored, and necessary imaging or interventions should be promptly performed to prevent devastating outcomes. Upon analyzing the case, there might be a connection between the vaccine's potential immune-triggering effect on hemodynamic patterns and the rupture of the previously unknown cerebral aneurysm. However, these severe complications do not justify avoiding vaccines; further studies are needed. In order to hypothesize the relationship between intracranial hemorrhage and the anti-COVID-19 vaccines, more studies involving more patients are needed.


Since the successful application of messenger RNA (mRNA) vaccines in preventing COVID-19, researchers have been striving to develop mRNA vaccines for clinical use, including those exploited for anti-tumor therapy. mRNA cancer vaccines have emerged as a promising novel approach to cancer immunotherapy, offering high specificity, better efficacy, and fewer side effects compared to traditional treatments. Multiple therapeutic mRNA cancer vaccines are being evaluated in preclinical and clinical trials, with promising early-phase results. However, the development of these vaccines faces various challenges, such as tumor heterogeneity, an immunosuppressive tumor microenvironment, and practical obstacles like vaccine administration methods and evaluation systems for clinical application. To address these challenges, we highlight recent advances from preclinical studies and clinical trials that provide insight into identifying obstacles associated with mRNA cancer vaccines and discuss potential strategies to overcome them. In the future, it is crucial to approach the development of mRNA cancer vaccines with caution and diligence while promoting innovation to overcome existing barriers. A delicate balance between opportunities and challenges will help guide the progress of this promising field towards its full potential. Based on the most recent statistical report, about 5370 new occurrences, and 1670 deaths each day are expected during 2023 in the United States , 5. ICIsRecently, the successful applications of COVID-19 global pandemic offered a great opportunity for messenger RNA (mRNA)vaccines in antitumor therapy –10. TherIn this review, we evaluate the benefits of therapeutic mRNA cancer vaccines while providing a succinct overview of their classification and mechanism. Particularly, we highlight recent advancements from preclinical studies and clinical trials that identify the obstacles associated with the development of mRNA cancer vaccines and discuss potential strategies to overcome them.2in vivo, leading to the expression of the encoded related protein  technology and is based on messenger RNA . This inA phase 1/2 clinical trial (NCT04382898) is currently underway to evaluate the effectiveness of the cancer vaccine BNT112. This vaccine encodes five different tumour-associated antigens and is being administered alone or in combination with cemiplimab to patients with metastatic castration-resistant prostate cancer. Another trial is a randomised phase 2 study (NCT04534205) evaluating the anti-human papillomavirus (HPV)-16-derived oncoprotein-encoding mRNA BNT113 vaccine in HPV16-positive, PD-L1-positive head and neck squamous cell carcinoma. BNT113 is also being tested in a two-arm phase 1/2 vaccine dose-escalation study (NCT03418480) for patients with previously treated or advanced HPV16-positive head and neck squamous cell carcinoma. Another phase 1 study (NCT04163094) is being conducted to evaluate the BNT115 that encodes ovarian-specific tumour-associated antigens. This vaccine is being administered both before and in combination with adjuvant and neoadjuvant chemotherapies to patients with ovarian cancer. Finally, a fifth clinical trial (NCT05142189) is evaluating the FixVac vaccine BNT116 in combination with cemiplimab or docetaxel in a phase 1 study for patients with advanced or metastatic non-small cell lung cancer.4.3The profound potential of mRNA cancer vaccines stems from their ability to encode a wide range of proteins, including immunostimulants that can modify the tumor immune microenvironment (TME) and enhance the efficacy of immune checkpoint inhibitors . This pr5Numerous clinical trials are currently under development or in progress to assess the safety and efficacy of mRNA cancer vaccines . Despite5.1The complexity of treatment decisions is enhanced by tumour heterogeneity, which can be divided into spatial and temporal heterogeneity . TemporaTo overcome spatial heterogeneity in tumours, one strategy is to use tumour tissue multipoint sampling to identify differences between tumour regions and inform the design of personalised mRNA cancer vaccines. Another approach involves using mRNA cancer vaccines that target multiple antigens expressed across various tumour regions, thereby compensating for spatial heterogeneity. Meanwhile, monitoring disease progression and adjusting treatment plans accordingly may help to address temporal heterogeneity. However, these strategies not only increase the complexity of vaccine design and administration but also raise costs and increase treatment time for patients. Another promising method is the use of artificial intelligence algorithms such as MHC-binding prediction, quantification of mutated transcript expression, and clonality of the mutation to predict neoantigens based on tumour genomic data, then used to prioritize these mutations as vaccine candidates based on their likelihood to elicit a T cell response, which could improve the efficiency and accuracy of vaccine design and overcome the heterogeneity of tumour –64. Howe5.2Tumour initiation, progression and maintenance depend highly on interactions between the tumour and the associated microenvironment . Tumour Combining mRNA cancer vaccines with other anti-cancer treatments, which is being constantly tried in cancer patients, can be an effective strategy for overcoming the immunosuppressive microenvironment. One commonly used combination therapy is to combine mRNA vaccines with immune checkpoint inhibitors, which can “release the brakes” on the immune system, allowing it to attack cancer cells more effectively , 70. Ado5.3in vivo  technology has garnered significant attention as a novel tool in assessing the immunotherapy response of cancer patients . The scRRecently, the circulating tumour DNA (ctDNA) test has the advantages of sensitivity, flexibility, repeatability, and safe gain much attention to help the evaluation of treatment responses, and the application of ctDNA detection in monitoring mRNA cancer vaccine therapeutic response is a worthwhile attempt . Accumul6Altogether, mRNA cancer vaccines present a promising new approach to anticancer therapies with both opportunities and challenges. The highly personalized and specific nature of this technology offers tremendous potential for precision medicine in the fight against cancer. However, further clinical trials are necessary to fully establish the safety and efficacy of mRNA cancer vaccines and additional preclinical studies are warranted to explore the combined use of mRNA cancer vaccine and other anticancer therapies. Additionally, addressing issues such as tumoral heterogeneity, routes of administration and development of methods to assess the efficacy processes will be critical for advancing this technology toward meaningful clinical outcomes. With continued research and investment, mRNA cancer vaccines hold great promise as a transformative therapy for cancer patients.BW and JL collected relevant literature and wrote the manuscript. BW and JY conceptualized the main structure of this review, and revised and validated the final version. JP, SX and BW contributed to the literature analysis and manuscript editing. All authors contributed to the article and approved the submitted version.


The 2018 International Federation of Gynecology and Obstetrics (FIGO) revision to the staging criteria for uterine cervical cancer adopted pathological staging for patients who underwent surgery. We investigated the correlation between clinicopathological factors and prognosis in patients with high-risk factors in accordance with the FIGO 2018 staging criteria by analyzing a real-world database of 6,192 patients who underwent radical hysterectomy at 116 institutions belonging to the Japan Gynecologic Oncology Group. A total of 1,392 patients were categorized into the high-risk group. Non-squamous cell carcinoma histology, regional lymph node metastasis, pT2 classification, and ovarian metastasis were identified as independent risk factors for mortality. Based on pathological findings, 313, 1003, and 76 patients were re-classified into FIGO 2018 stages IIB, IIIC1p, and IIIC2p, respectively. Patients with stage IIIC2p disease showed worse prognoses than those with stage IIB or IIIC1p disease. In patients with stage IIIC1p disease, overall survival was significantly better if their tumors were localized in the uterine cervix, except for single lymph node metastasis, with a 5-year overall survival rate of 91.8%. This study clarified the heterogeneity of the high-risk group and provided insights into the feasibility of upfront radical hysterectomy for a limited number of patients harboring high-risk factors. According to a global database, in 2020, 604,127 patients were newly diagnosed with cervical cancer and 341,831 patients died from this cancer5. In Japan, 2,887 patients died of the disease in 20206. Thus, optimization of therapeutic strategies for advanced cervical cancer remains an important concern for both patients and clinicians.Uterine cervical cancer is a widely prevalent gynecological malignancy. Although most cervical cancers can be prevented through human papilloma virus (HPV) vaccination and appropriate cancer screening, not all individuals have access to these amenities7.In 2018, the International Federation of Gynecology and Obstetrics (FIGO) revised their staging system for uterine cervical cancer. The most important changes in the system are the transition from a clinical to a post-surgical pathological staging system for patients whose primary treatment involved surgery and the integration of lymph node metastasis in the staging criteria reflected in FIGO 2018 stage IIIC10. With the development of Okabayashi’s surgery, radical hysterectomy is more frequently performed in Japan than in other countries14. The National Comprehensive Cancer Network guidelines state that radical hysterectomy is a primary treatment option for patients categorized into FIGO 2018 clinical stages IB1, IB2, and IIA1, in which the tumor diameter is ≤ 40 mm. While radical hysterectomy is also listed as an option for patients in clinical stages IB3 and IIA2, CCRT is recommended with a stronger evidence level than surgery. Radical hysterectomy is not a recommended option for patients in stages IIB, III, or IVA9. In contrast, the latest version of the Japan Society of Gynecologic Oncology (JSGO) guidelines recommends either radical hysterectomy or RT/CCRT as the primary treatment for patients with FIGO 2018 clinical stage IB or IIA cervical cancer regardless of tumor diameter. Although CCRT is recommended, radical hysterectomy has also been proposed as an option under particular conditions for FIGO 2018 clinical stage IIB cases. Furthermore, upfront radical hysterectomy is proposed as a primary therapeutic option to CCRT for patients in FIGO 2018 stage IIIC if their T classification is T1 or T210.Radical hysterectomy and definitive radiotherapy (RT) or concurrent chemoradiotherapy (CCRT) are the fundamental therapeutic options for uterine cervical cancer without distant metastasis16. In contrast to low- and intermediate-risk patients, the clinicopathological features of postsurgical high-risk patients, who are positive for pathologically proven parametrial invasion and/or regional lymph node metastasis, have not been fully described as these patients are more likely to be treated with definitive RT/CCRT globally17. Another concern is that lymph node metastasis detected using clinical imaging modalities such as computed tomography (CT), magnetic resonance imaging, or positron emission tomography-CT had not been officially integrated in the cancer staging system for cervical cancer until the FIGO 2018 staging system was announced18; consequently, literature on therapeutic stratification based on lymph node metastasis in the treatment of cervical cancer is lacking. Considering the current popularity of the FIGO 2018 staging schema, we believe that it is especially important to clarify the clinicopathological features of FIGO 2018 stage IIIC population.Patients who undergo surgery as the primary treatment are classified as showing low, intermediate, or high risk for recurrence based on pathological findings. Adjuvant therapy is considered for patients with intermediate- or high-risk factors. Pathologically proven parametrial invasion and regional lymph node metastasis are considered high-risk factors, and adjuvant CCRT is recommended20. This study aimed to elucidate the association between patient survival and clinicopathologic features and to investigate the potential of treatment optimization in the high-risk group by retrospectively analyzing the relevant JGOG data. Because the FIGO adopted postsurgical findings in the staging criteria for the first time in 20187, this study also aimed to assess the feasibility of the current staging system and clarify the clinicopathological characteristics of each FIGO 2018 stage in the high-risk group.The Japanese Gynecologic Oncology Group (JGOG) has established a nationwide database with data from 6,192 patients who underwent radical hysterectomy. We had reported the clinicopathological features of the low- and intermediate-risk groups in the databaseThe primary data included information on 6,192 patients diagnosed with uterine cervical cancer and treated with radical hysterectomy at 116 institutions under the JGOG between January 2004 and December 2008. Patient information was collected and analyzed after obtaining ethical approval from the institutional review board (IRB) at Tottori University . The need for informed consent was waived due to the nature of the retrospective surveillance under the same approval by the IRB at Tottori University. All methods were performed in accordance with the relevant guidelines and regulations. The information consisted of age, FIGO 2008 clinical stage, clinical outcomes such as disease-free survival (DFS) and overall survival (OS), pathological tumor-node-metastasis (pTNM), histological diagnosis (squamous cell carcinoma [SCC] or non-SCC), tumor diameter, pelvic lymph node metastasis status, parametrial invasion, stromal invasion to the outer half, and lymphovascular space invasion. Peritoneal cytology results were reported, where applicable. If para-aortic lymphadenectomy was performed, the presence or absence of para-aortic lymph node metastasis was also recorded.After excluding patients who received neoadjuvant chemotherapy or had distant metastasis, patients were categorized into the high-risk group if they showed positive results for lymph node metastasis and/or parametrial invasion. Patients without information about neoadjuvant chemotherapy, pTNM staging, or clinical outcomes were excluded. We also excluded cases with conflicting data for pTNM staging and parametrial invasion or lymph node metastasis.Survival curves were determined using the Kaplan–Meier method and statistically compared using the log-rank test. Bonferroni correction was applied for post-hoc multiple comparisons. The chi-squared test was used to compare the distribution of adjuvant therapy. Hazard ratios for the clinical outcome and each parameter were determined using univariate and multivariate Cox regression models. A two-tailed p value that was less than 0.05 was considered significant. Statistical analyses were performed using JMP® Pro 16.0.0. .Based on patient selection criteria, 1,392 patients were included in the analysis. The patient selection scheme is shown in Supplementary Fig. 20, we investigated whether histological differences were statistically associated with the type of adjuvant therapy in the high-risk group. As shown in Supplementary Table p = 0.468).Most patients received adjuvant CCRT, RT, or chemotherapy. More specifically, 87.5%, 93.2%, and 92.1% of the patients who were classified into FIGO 2018 stage IIB, IIIC1p, and IIIC2p, respectively, received either adjuvant CCRT, RT, or chemotherapy. Because adjuvant chemotherapy was administered more frequently to patients with non-SCC histology for intermediate-risk factorsTo assess the feasibility of the FIGO 2018 staging criteria, we determined survival curves according to FIGO 2018 stage Fig. . In termTo further assess the influence of pathological factors on patient mortality, we performed univariate and multivariate Cox regression analyses. The results of univariate analysis indicated that all the pathological factors were associated with OS Table . Since p7. To further elucidate the characteristics of each stage, we evaluated the association of clinicopathological factors and OS in stages IIB, IIIC1p, and IIIC2p independently.Based on the FIGO 2018 staging criteria, the most high-risk patients are classified into stage IIB, IIIC1p, or IIIC2pThe results for each substage are summarized in Tables Among the 76 FIGO 2018 IIIC2p cases, neither pathological factor was significantly associated with patient survival in a multivariate analysis. However, patients treated with adjuvant RT showed significantly worse OS than those treated with adjuvant CCRT or chemotherapy, even though the number of patients who received each adjuvant therapy was relatively small Table .In this study, we investigated the association between patient prognosis and clinicopathological features in surgically treated patients with uterine cervical cancer harboring high-risk factors. Overall, the results indicated that patient prognosis was heterogeneous, even in the high-risk group.22, did not influence OS. These results validate the significance of parametrial invasion and lymph node metastasis in patient prognosis. Simultaneously, non-SCC histology and ovarian metastasis were identified as potential risk factors among the high-risk groups. Because pT2a represents vaginal invasion, pathological vaginal invasion may be another risk factor. Importantly, these factors were also identified as risk factors for mortality in the low- and intermediate-risk groups20. Our findings suggest that, in addition to conventional risk factors, other pathological parameters that are not currently deemed indisputable risk factors should be considered when planning therapeutic strategies in patients with surgically treated cervical cancer.As shown in Table 10, adjuvant chemotherapy was adopted in approximately a quarter of the patients, especially in the non-SCC population. One reason for this may be to avoid radiation-related adverse events24. Indeed, Ikeda et al. reported that an increasing proportion of patients were treated with adjuvant chemotherapy in Japan25. Moreover, radiation has been considered to be less effective for adenocarcinoma in several studies, which may lead physicians to prescribe adjuvant chemotherapy for non-SCC cervical cancer28. Nevertheless, evidence for the feasibility of adjuvant chemotherapy in high-risk groups is currently inadequate. Unfortunately, we estimate that our database had substantial physician and institutional biases, making it difficult to appropriately assess the influence of adjuvant therapy. In the light of the current situation, the JGOG is conducting a prospective study to compare adjuvant CCRT and chemotherapy29. The results of this study will provide a certain indication regarding this concern.Adherence to the guidelines regarding adjuvant therapy for patients primarily treated with radical hysterectomy is an unresolved issue in Japan. Although the current Japanese guidelines recommend adjuvant CCRT for treating high-risk patients30.Another concern is related to surgical radicality and the site of recurrence. A study by Matsuo et al. reported a lower risk of distant metastasis and a higher risk of local recurrence among patients with node-positive FIGO2008 stage IB-IIB cervical cancer who received adjuvant chemotherapy, which indicates that a satisfactory local control rate should be achieved through radical hysterectomy if adjuvant chemotherapy is selectedIn classifications of cervical cancer based on the FIGO 2018 staging criteria, stages IIB, IIIC1p, and IIIC2p corresponded to the most high-risk cases. We believe that the inclusion of cases in which para-aortic lymph nodes were pathologically examined is an advantage of the current investigation of the feasibility of the FIGO 2018 staging criteria. Our analysis supported the feasibility of FIGO 2018 IIB, IIIC1p, and IIIC2p classifications from the perspective of prognosis. Patients categorized into stage IIIC2p showed significantly worse prognosis than those classified into stages IIB and IIIC1p. Interestingly, adjuvant RT was indicated as a risk factor for mortality compared with adjuvant CCRT and CT. Despite the previously mentioned limitations in the assessment of adjuvant therapy, our findings highlight the necessity of intensive adjuvant therapy for surgically treated patients with FIGO 2018 stage IIIC2p disease. Moreover, the prognosis observed in this study raised a concern regarding the feasibility of surgery-based therapeutic strategies in patients presenting with clear para-aortic lymph node metastasis as indicated by clinical imaging.32. On the other hand, the treatment strategies for patients with suspected multiple lymph node metastasis or tumor extension beyond uterine cervix should be optimized for each patient based on performance status, preexisting comorbidities, expected adverse effects, cost-effectiveness, and so on, along with careful preoperative physical evaluation and multiple clinical imaging.Patients with FIGO2018 IIIC1p cervical cancer showed heterogeneous prognoses based on the number of lymph node metastases and status of tumor extension. While definitive CCRT is generally considered if lymph node metastasis is suspected on preoperative clinical imaging, our results indicated that a patient was likely to have a favorable prognosis with the upfront surgery approach if the tumor was estimated to be limited to the uterine cervix except for single lymph node involvement. This finding is concordant with previous retrospective studies that reported the number of lymph node metastases as a risk factor for patients with stage IIIC1p cervical cancer33. On the other hand, a nationwide clinicopathological database containing information on patients with uterine cervical cancer harboring high-risk factors is of significant value because these patients are more likely to be treated with RT/CCRT globally. Our findings and the existing literature highlight the need for larger-scale and more inclusive surveillance to optimize the management of FIGO 2018 stage IIIC1 cases.One limitation of this study is that the current database consisted of information collected only from surgically treated patients. Therefore, direct comparison of treatment outcomes between primary radical hysterectomy with subsequent adjuvant therapy and definitive CCRT was not possible. Not limited to patients treated with upfront surgery, the prognosis of patients with FIGO2018 IIIC1 disease was reported to be heterogeneous depending on local tumor factors in a retrospective cohort studyIn conclusion, this study clarified the heterogeneous outcomes associated with the clinicopathological features of patients presenting high-risk factors who underwent radical hysterectomy. The results reinforce the need for optimizing therapeutic strategies for this population, which should be further investigated in future studies.Supplementary Information.


Sentinel lymph node biopsies are recommended for staging in node-positive breast cancer patients who become clinically node-negative after neoadjuvant therapy. Current guidelines support the omission of an axillary lymph node dissection if 3 negative sentinel nodes are retrieved during surgery. Consequently, the utility of routine clip placement in biopsied nodes prior to neoadjuvant chemotherapy and the necessity of targeted removal of these clipped nodes is in question. There are various methods for retrieving clipped nodes. We describe a case in which an intraoperative radiograph of a mastectomy specimen identified a clipped node that had not been localized with targeted axillary dissection in a patient with breast cancer. Pathology revealed persistent nodal positivity after neoadjuvant therapy, resulting in an escalation in care and a complete axillary dissection. We review the current literature on nodal clipping, and discuss the importance of localizing clipped nodes and the impact it can have on management. The assessment of axillary lymph nodes is critical in the oncologic management of breast cancer patients. Ultrasound is frequently used to evaluate nodal involvement at the time of diagnosis. In cases of abnormal-appearing nodes on imaging, confirmatory percutaneous biopsy is performed with clip placement at the biopsy site. In breast cancer patients with biopsy-proven nodal involvement, neoadjuvant chemotherapy (NAC) is often utilized. Pathologic complete response after neoadjuvant chemotherapy ranges from 13% to 65% depending on the subtype and receptor status of breast cancer .The National Comprehensive Cancer Network (NCCN) recommends performing a sentinel lymph node biopsy (SLNB) for staging in node-positive breast cancer patients who become clinically node-negative after neoadjuvant therapy There are various techniques for retrieving clipped nodes, including radioactive seed localization, radiofrequency identification devices, localization wires, and charcoal tattooing ,9. IntraOur patient is a 43 year-old BRCA1 gene-positive female who presented with a biopsy-proven ER+/PR–/HER2– stage IIB (T2N1M0) multicentric, left breast invasive ductal carcinoma. She initially presented with a left breast mass and axillary lymphadenopathy. A left breast diagnostic mammogram showed heterogeneously dense tissue, prominent left axillary nodes, and an area of developing focal asymmetry in the upper outer quadrant of the left breast at the area of palpable concern that was highly suggestive of malignancy, BI-RADS 5 . On ultrGiven the presence of nodal positivity, the patient underwent neoadjuvant chemotherapy with doxorubicin, cyclophosphamide, and paclitaxel with radiologically proven partial response. Due to her BRCA1+ status, she elected to undergo bilateral total skin-sparing mastectomies via an elliptical incision around the nipple-areola complex along with a left sentinel lymph node biopsy and targeted axillary dissection of the clipped node. The patient declined breast reconstruction. Technetium-99m sulfur colloid was injected the night before surgery and methylene blue dye was injected intraoperatively for localization of the axillary sentinel lymph nodes. The bilateral mastectomies were performed first. Interrogation of the axilla identified 3 sentinel lymph nodes: 2 blue but not radioactively hot lymph nodes, and 1 hot but not blue node. Intra-operative X-ray of the sentinel lymph nodes, however, failed to identify the localizing clip . An intrOn final pathologic assessment, metastatic carcinoma with extranodal extension was identified in 5 out of the 24 total axillary lymph nodes retrieved. In the mastectomy specimen, there was a remnant focus of invasive ductal carcinoma measuring 1.5 cm, indicating partial and incomplete response to neoadjuvant chemotherapy. As a result of her significant residual burden of disease, the patient received comprehensive post-mastectomy radiation therapy to the chest wall, axilla, and supraclavicular fields. Post-operatively, the patient was also placed on adjuvant treatment with goserelin for ovarian suppression, tamoxifen, and olaparib.A variety of techniques are utilized to retrieve axillary lymph nodes, and intra-operative imaging is routinely used to confirm successful removal of clipped nodes. Ultrasound-guided excision of clipped axillary nodes in node-positive breast cancer patients treated with neoadjuvant chemotherapy is safe and accurate The targeted removal of a clipped node during a sentinel lymph node biopsy has been accepted as a means to improve axillary staging. This is based on prior studies indicating that a biopsy-proven clipped node is not a sentinel lymph node in approximately 23%-35% of cases . HoweverRecent research has supported the omission of routine nodal clipping. Bario et al. Nevertheless, current NCCN guidelines recommend that if a positive lymph node is clipped at biopsy, every effort should be made to remove the clipped node at the time of surgery Despite some authors recently challenging the value of nodal clipping, our case report highlights the impact it can have on management. In our patient, localizing the clipped node led to an escalation in care. The finding of residual disease in the clipped node led to the performance of a complete ALND, which revealed 5/24 nodes positive for malignancy. Without retrieval of the clipped node, a large burden of residual disease would have been left behind because the negative SLNB would have precluded an ALND. Identifying residual disease in patients after NAC is necessary for determining adjuvant therapy options ,21. BaseOverall, this case illustrates the utility of intraoperative imaging of a mastectomy specimen to localize a clipped node when it was not identified on SLNB and targeted axillary dissection. Increasingly, the finding of residual disease after NAC results in an escalation in care with demonstrated improvements in survival. Given the multitude of localization options for identifying the clipped node, the authors recommend an attempt at identification and removal. If the clipped node cannot be located and the SLNs had no residual disease, further studies evaluating the oncologic benefit of ALND is warranted.Written informed consent was obtained from the patient for publication of this case.