Iron is essential for many biological processes. Inadequate or excess amount of body iron can result in various pathological consequences. The pathological roles of iron in cardiovascular disease (CVD) have been intensively studied for decades. Convincing data demonstrated a detrimental effect of iron deficiency in patients with heart failure and pulmonary arterial hypertension, but it remains unclear for the pathological roles of iron in other cardiovascular diseases. Meanwhile, ferroptosis is an iron-dependent cell death that is distinct from apoptosis, necroptosis, and other types of cell death. Ferroptosis has been reported in several CVDs, namely, cardiomyopathy, atherosclerotic cardiovascular disease, and myocardial ischemia/reperfusion injury. Iron chelation therapy seems to be an available strategy to ameliorate iron overload-related disorders. It is still a challenge to accurately clarify the pathological roles of iron in CVD and search for effective medical intervention. In this review, we aim to summarize the pathological roles of iron in CVD, and especially highlight the potential mechanism of ferroptosis in these diseases. The heme can be degraded by heme oxygenase-1 (HO-1) to release ferrous iron (Fe2+), carbon monoxide, and biliverdin. The absorption of inorganic ferric ion (Fe3+) requires two key steps: the conversion of insoluble Fe3+ to absorbable Fe2+ by cytochrome b reductase 1 (DCYTB) and following transportation of Fe2+ by divalent metal transporter protein 1 (DMT-1) across the membrane. Internalized Fe2+ enters the cytosolic labile iron pool (LIP). Extra iron can be stored as ferritin or exported through the basolateral membrane by ferroportin (FPN), the only known iron export protein. The exported Fe2+ is undergone re-oxidation to Fe3+ by membrane-bound hephaestin and binds to transferrin (Tf) for long-distance delivery. Circulating Tf-bound iron can be internalized into the cells of peripheral tissues via binding to its receptor, transferrin receptor 1 (TfR1) (Dietary iron is absorbed by gut mucosa cells  of iron . The hem1 (TfR1) .via promoting FPN internalization and degradation. When hepcidin is transcriptionally downregulated in the condition of enhanced erythropoiesis or iron deficiency, more iron is released into circulation from intestinal epithelial cells, macrophages, and hepatocytes  is mediated by DMT-1 protein ubiquitously present on the surface of cells , 12. In Cellular iron homeostasis is post-transcriptionally regulated by the iron regulatory proteins (IRP1 and IRP2) interacting with iron-responsive elements (IREs) . IREs arThe hepcidin-FPN1 axis also plays a pivotal role in controlling cellular iron flux, particularly in cardiomyocytes. Distinct from systemic iron regulation, hepcidin can be produced locally in the heart, and functions as an autocrine protein to regulate iron levels in cardiomyocytes . Interesvia genetically deleting FPN has been reported to develop morphological and molecular features of ferroptosis in hippocampus neurons -glutathione (GSH) and ferroptosis suppressor protein 1 (FSP1)-coenzyme Q (CoQ) pathways, involved in the regulation of ferroptosis , 27 Fig.ApoE−/− mice overexpressing GPX4 showed decreased oxidized lipids and atherosclerotic lesions in the aorta compared with ApoE−/− control mice , was predicted to induce apoptosis by a caspase-1 independent pathway, due to its biochemical similarities to AIFM1 . HoweverAlthough the physiological action of ferroptosis remains elusive, it has been studied in several cardiomyopathies, namely, diabetic cardiomyopathy and doxorubicin (DOX)-induced cardiotoxicity.db/db mice  carried in eastern Finnish men demonstrated firstly that a high level of stored iron, assessed by increased serum ferritin, is a risk factor for myocardial infarction (MI) . Iron deThe mechanism whereby iron may stimulate atherogenesis has been intensively investigated. Plenty of studies have shown an association between iron overload and atherosclerosis . The patDuring the development of atherosclerosis, lipid oxidative modification and iron deposition are well-observed in plaques. It is reasonable to speculate that ferroptosis may happen in this process. A study revealed the downregulation of GPX4 in heart tissue of MI mice using quantitative proteomic analysis . The exoHFE gene knockout mice subjected to I/R injury showed increased iron deposition, cardiomyocyte apoptosis, and ROS production compared with wild-type mice  injury is an important complication of percutaneous coronary intervention or thrombolysis for acute MI . The recype mice . FurtherR damage .via inhibiting USP19/Beclin1-mediated ferroptosis  have proven that intravenous iron supplementation improves the quality of life, exercise tolerance, and reduces hospitalization risk for aggravated HF –77. OtheVascular and valvular calcification refers to ectopic mineralization in vessel walls and heart valve leaflets. It is an important risk factor for adverse cardiovascular events . AlthougValve calcification mainly occurs in aortic valves. VICs differentiate into the pathological myofibroblasts and osteoblast-like cells which promote inappropriate extracellular matrix remodeling and calcification . Previouvia upregulating interleukin-24  and normal pulmonary capillary wedge pressure ( ≤ 15 mmHg) in the absence of other causes of precapillary pulmonary hypertension . PAH is The underlying pathological mechanisms of iron deficiency to the PAH may involve hypoxia, inflammation, and functional alterations of pulmonary vascular cells. Hypoxia exposure can induce vasoconstriction in pulmonary arteries, resulting in increased pulmonary artery systolic pressure (PASP). Furthermore, hypoxia-induced vasoconstriction and PASP could be augmented by iron chelation with DFO in healthy adults . The pulin vitro increased the metabolic activity and proliferation of human PASMCs, while iron supplementation inhibited this process. The rats fed with an iron-deficient diet developed pulmonary vascular remodeling and hemodynamic changes similar to PAH patients, which can be reversed by iron supplementation  in pulmonary vascular remodeling and hypertension. Chelation of iron entation . Systemientation . In the entation . These rDifferent from pulmonary pressure, systemic blood pressure seems to be positively associated with iron markers. Two cross-sectional studies in Korea reported that serum ferritin was positively associated with the prevalence of hypertension , 112. Moin vivo, including premature ventricular contractions and supraventricular/ventricular tachycardia  cardiac magnetic resonance imaging, is important to identify the pathophysiological roles of iron. Although iron repletion has been employed for the treatment of HF or PAH patients with iron deficiency, future studies are still necessary to pay more attention to the clinical significance of iron status and figure out the exact association between iron homeostasis and CVD .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Model predictions at critical points of trip-related fall risk fell within the variability of the ankle angle and moment targets (Benjamini-Hochberg adjusted p > 0.065). EMG contribution to ankle angle and moment predictions occurred consistently across ambulation conditions and model outputs. EMG signals had the greatest impact on noncyclic regions of gait such as double limb support, transitions between terrains, and around plantarflexion and moment peaks. The use of natural muscle activation patterns to continuously predict variations in normal gait and the model’s predictive capabilities to counteract electromechanical inherent delays suggest that this approach could provide robust and intuitive user-driven real-time control of a wide variety of lower limb robotic devices, including active powered ankle-foot prostheses.A hallmark of human locomotion is that it continuously adapts to changes in the environment and predictively adjusts to changes in the terrain, both of which are major challenges to lower limb amputees due to the limitations in prostheses and control algorithms. Here, the ability of a single-network nonlinear autoregressive model to continuously predict future ankle kinematics and kinetics simultaneously across ambulation conditions using lower limb surface electromyography (EMG) signals was examined. Ankle plantarflexor and dorsiflexor EMG from ten healthy young adults were mapped to normal ranges of ankle angle and ankle moment during level overground walking, stair ascent, and stair descent, including transitions between terrains . Prediction performance was characterized as a function of the time between current EMG/angle/moment inputs and future angle/moment model predictions , the number of past EMG/angle/moment input values over time (sampling window), and the number of units in the network hidden layer that minimized error between experimentally measured values (targets) and model predictions of ankle angle and moment. Ankle angle and moment predictions were robust across ambulation conditions with root mean squared errors less than 1° and 0.04 Nm/kg, respectively, and cross-correlations (R Human locomotion continuously adapts to changes in the environment to maintain balance, reacts to unpredictable perturbations, and predictively adjusts walking patterns to changes in the terrain . Gait adDeveloping control algorithms for lower limb prostheses is challenging and impacts the level of human adaptation to the device . The useAlternate approaches have been developed that would continuously determine the dynamic changes of the joint and would not require division into discrete states. Impedance and stiffness control based on joint moment and angle have an increasingly common approach for actuating active powered  lower limb prostheses . SpecifiFor a seamless and intuitive device actuation, controllers must recognize the user’s locomotive intention given changes in the environment. Even though mechanical intrinsic sensors have high repeatability and reproducibility, they introduce an intrinsic delay and the resulting control must infer human intention through secondary information such as gait events or joint mechanics. Therefore, their actuation is reactive to user’s biomechanical changes. Surface EMG activity enables a direct prediction of intended biomechanics given that muscle activity precedes force generation, and consequently, limb movement, on the order of 10 ms . Still, Classification algorithms have been used together with surface EMG to distinguish among discrete locomotion modes  while otAn EMG-driven nonlinear autoregressive neural network with exogenous inputs (NARX) with predictive future states can address these challenges and provide a robust and intuitive control of active powered ankle-foot prostheses. Previous work has demonstrated the ability of a single-output feedforward (open-loop) NARX model to continuously predict future ankle angle of the prosthesis using within-socket EMG activity from the residual limb of transtibial amputees . The incmultiple-output model that provided simultaneous estimates of future intended state of ankle angle and ankle moment across multiple ambulation conditions using lower limb surface EMG signals as input. Ankle plantarflexor and dorsiflexor EMG signals (antagonistic muscles) from healthy young adults were used to continuously predict normal ranges of ankle angle and moment during level overground walking, stair ascent, and stair descent, including transitions between terrains . Prediction performance was quantified using novel data sets and characterized as a function of the model parameters  to identify optimal subject-specific parameters that minimized error. Models were trained and optimized for each participant to account for individual’s specific variations of EMG activity and limb dynamics. The suitability of the model prediction for prosthetic control was then examined by statistically analyzing the prediction variability at critical performance points  participated in the study. Participants were excluded if they presented neurologic or orthopedic impairments that would affect their ability to walk or follow instructions. The study was approved by the Institutional Review Board at Marquette University , and all participants provided written informed consent.TM wireless surface EMG electrodes  were placed bilaterally over the tibialis anterior (dorsiflexor), and the gastrocnemius medialis (plantarflexor). Anthropometric measures (height and weight) were then taken. The walkway was instrumented with two 3-dimensional 6-channel force plates  embedded in the floor, a modified 4-step  instrumented staircase  and a landing platform (1.22 m × 0.91 m) , stair ascent (AS), and stair descent (DS). Twenty-five reflective markers were placed on the participant’s key anatomical landmarks  to define seven lower body segments  based on a modified Helen Hayes marker set . TrignoT 0.91 m) . To miniSurface EMG activity, kinetic, and kinematic data were collected and synchronized. Surface differential EMG recordings were amplified (909 V/V), sampled at 1,200 Hz, filtered to obtain linear envelopes, and down sampled to 120 Hz. EMG linear envelopes were obtained using a band-pass filter from 20 to 499.5 Hz (4th order zero-phase Butterworth), followed by full-wave rectification, and a low-pass filter with a 5.5 Hz cutoff frequency (4th order zero-phase Butterworth). Kinetic data were sampled at 1,200 Hz, low-pass and notch filtered (4th order zero-phase Butterworth) at 15 Hz and 59–61 Hz, respectively, and down sampled to 120 Hz. Kinematic data were sampled at 120 Hz using an OptiTrack  motion capture system (14 to 16 Flex 13 cameras). Markers were manually identified using AMASS  software and processed in Visual 3D  to extract limb kinematic (ankle angle) and foot kinetic  time series and gait events. Marker trajectories, and kinematic and kinetic time series were subsequently low-pass filtered  and interpolated  in Visual 3D. Ankle angle in the sagittal plane was computed as the motion of the foot segment relative to the shank segment coordinate system using Euler angles. Ankle moment in the sagittal plane was calculated using conventional inverse dynamics and resolved to the shank segment coordinate system .Gait events were defined kinematically as HS for heel strike and TO for toe off on floor, and kinetically as ON for first foot contact on force plate, OFF for last foot contact on force plate (threshold 10 N). All trials were temporally normalized and truncated from 225 ms before the first heel strike on the first force plate to the first heel strike before contralateral toe off on the last force plate . As a result, level walking condition consisted of one gait cycle and each stair ambulation condition consisted of three continuous gait cycles, as of traversing from level walking to stair stepping to level waking . StaircaA model of lower limb state was developed to continuously predict simultaneous ankle kinematics and kinetics across ambulation conditions and terrain transitions. Specifically, a feedforward (open-loop) multiple-input multiple-output NARX model  was crea(t+m), at each time point was calculated as,The feedforward NARX model output, n(t+m)v was the output of nth unit in the hidden layer, N was the total number of hidden units, m was the prediction interval in time steps (τ = mΔt), d was the sampling window length (D = dΔt), i(t-q)x was the input of the ith EMG linear envelope for the prior q time step, j(t-q)y was the past jth desired target value (ankle angle and moment), ani, cnj, and wjn were the weights of EMG inputs, desired target values, and ankle angle and moment outputs, respectively, b1n and b2j were the bias weights at the hidden and output layers, respectively, f1 was a nonlinear hyperbolic tangent sigmoid function, and f2 was a linear function with unit slope. The sampling window specified the number of prior input values over time (exogenous and targets) used to calculate future ankle angle and moment. The prediction interval specified the time between the current inputs (exogenous and targets) and the model output predictions of future ankle angle and moment.where Separate models were trained for each participant. During training, ten randomized trials from each ambulation condition of a single limb were organized as a concurrent set of sequences and divided into contiguous blocks where 80-percent  were used for training and 20-percent  were used for validation. An additional trial of each ambulation condition  was held back and used to separately assess model performance after training using a leave-one-out 10-fold cross-validation. Each model was trained and optimized to minimize the mean squared error (MSE) between the ankle angle and moment targets and the model predictions using a Levenberg-Marquardt backpropagation supervised learning procedure. To fit ankle angle and moment equally, training errors  were normalized to the range of  corresponding to normalizing model predictions and targets between −1 and 1 using a min-max mapping of the k-fold training dataset. For each training dataset, ten networks were trained using different initial weights and biases to improve shallow network generalization and avoid overfitting. The network with the lowest MSE averaged across ambulation conditions was selected as the generalized network for that k-fold dataset. To explore the capabilities of the network, NARX model performance was characterized as a function of the prediction interval , sampling window , and number of hidden units  with error goal bounded to 1-percent of the moment variance of all recorded trials . Subsequently, while the prediction interval was fixed to 58 ms (7 time steps) to counteract electromechanical inherent delays of the Marquette University’s ankle-foot prosthesis , minimumn = 10; AS and DS, n = 8).The number of participants included in the analysis of stair ambulation conditions was reduced to eight because two participants initiated trials with the limb opposite to the one being analyzed. All performance measurements and statistical analysis were averaged across ten novel test trials and then across participants for each ambulation condition  were calculated between the target and model prediction of ankle angle and moment for each test trial to evaluate model performance. The coefficient of determination (R2), obtained from squaring the cross-correlation peak, was used to quantify the ability of the model to reproduce the temporal profiles of angle and moment for each ambulation condition and their transitions.Root mean square error (RMSE) and coefficient of determination (R2), and an ANOVA (p < 0.001) was performed for each model parameter and ambulation condition to determine whether the fitted slope was significantly different from zero.Using the first set of models , simple linear regressions were performed to examine the effects of prediction interval, sampling window, and number of hidden units on model performance. For each model output and ambulation condition, a linear fit (slope and intercept) was performed in MATLAB (R2017a) using the average RMSE collapsed along a single model parameter dimension . Goodness of fit was assessed by the coefficient of determination (Rx = Using the second set of models (optimized subject-specific network structure), RMSE was computed over each trial to characterize maximal model performance across participants. To evaluate the impact of EMG signals on model performance, the instantaneous RMSE over time of NARX model predictions (time-varying EMG) were compared against errors of NARX models having constant EMG inputs. Constant EMG inputs, t-test was used to determine if inter-subject NARX predictions were statistically different from that target. Sign test was performed for non-normally and asymmetric distributed critical points. Statistical analyses were performed using SPSS 22  with a significance level of p < 0.05. The Benjamini-Hochberg (B-H) procedure was used to adjust p values with a false discovery rate of 0.05 to correct for multiple comparisons  are illustrated in p < < < 0.001, R2 > 0.98). Model error for predicting ankle angle and moment was largely unaffected by the size of the sampling window across ambulation conditions  with error saturating after 33 ms . The number of hidden units used in the network showed a small negative correlation with ankle angle and moment RMSE across ambulation conditions  that was significant for ankle angle RMSE during level walking and stair ascent . After 8 hidden units, RMSE saturated for ankle angle and moment across ambulation conditions . There were minimal differences in angle and moment error among ambulation conditions  and errors (RMSE) of the NARX model prediction of ankle angle and moment across participants for all ambulation conditions. The results show high levels of accuracy in all ambulation conditions and model outputs. R2 ranged between 0.989 and 0.999. All peak cross-correlations occurred at zero time lag. Stair descent had the lowest RMSE and the highest correlations for both ankle angle  and moment . The maximum error occurred in the prediction of ankle angle during level ground walking  and in the prediction of ankle moment during stair ascent . Using the Benjamini-Hochberg multiple comparisons procedure, no significant difference across participants was found between targets and NARX model predictions in any of the critical performance points (B-H adjusted p > 0.065). Detailed statistical scores, and mean and standard deviation of ankle angle and moment predictions and targets of all critical points are listed in Joint ankle angle and ankle moment model predictions closely matched the experimentally measured targets in all ambulation conditions and staircase transitions as shown in Comparison of the instantaneous RMSE over time for the NARX models using the participant’s time-varying EMG as inputs against models using average EMG showed larger errors and increased variability for the constant-EMG NARX predictions across all ambulation conditions and staircase transitions for both ankle angle and ankle moment . The patAn approach was presented for continuous predictive mapping of lower limb state that incorporated user intent, vis-à-vis surface EMG of the lower limb, to predict future ankle joint kinematics and kinetics simultaneously across ambulation conditions, including transitions between terrains. The single-network, feedforward NARX model had the ability to characterize normal gait patterns of ankle angle and ankle moment with predictions that fell within the experimentally measured variability of the kinematic and kinetic targets across trials and participants.The autoregressive model presented here continuously models the nonlinear dynamic relationships between muscle activation and ankle dynamics to predict ankle kinematics and kinetics across ambulation conditions and terrain transitions. In contrast, EMG-driven FSMs to control active powered lower limb prostheses typically allow the amputee to select a discrete locomotion mode  or to co2 > 0.989) while reducing the model degrees of freedom needed to predict limb kinematics and kinetics during gait. The use of time-varying EMG signals during gait resulted in less error compared to model predictions without time-varying information  of inputs and outputs allowing for the prediction of future limb state. A crucial advantage of prediction  for the control of active ankle-foot prostheses is the ability to counteract delays from prosthetic actuation, signal processing , and sensor response inherent to electromechanical systems. In this study, the performance of the optimized NARX models was evaluated using a prediction interval of 58 ms to account for microcontroller and motor actuation delays (max. 50 ms) inherent to Marquette University’s active powered ankle prosthesis  of ankle angle varied between 2.44 and 5.29 degrees, and between 0.74 and 0.94, respectively, during level walking at different speeds and with various inputs. Specifically, Gupta et al. reported ankle angle errors, across healthy participants, during level walking , stair ascent , and stair descent  using subject-specific NARX models trained and tested separately for each condition  ankle angle and moment are used to estimate changes in ankle dynamics. Feedback of the model predictions is expected to place greater emphasis on the use of EMG inputs to control for errors in the predicted ankle dynamics and to signal user intent during transitions and noncyclic activities . While previous studies have demonstrated the feasibility of continuously predicting ankle angle  and anklThis study has demonstrated that a single-network nonlinear autoregressive model with exogenous EMG inputs can continuously predict future ankle angle and ankle moment simultaneously during normal walking across ambulation conditions  and transitions between terrains. The natural patterns of muscle activation used to predict variations in normal gait, particularly during transitions, suggests that this approach could be used to create a seamless and intuitive interface for an active powered ankle-foot prosthesis that incorporates user intent and does not require conscious user control. The model’s accuracy, robustness, and predictive capabilities  suggest that the approach could be adapted for real-time closed-loop control of a wide variety of lower limb robotic devices, including actuated orthoses, and exoskeletons. Further research will characterize the ability of within-socket residual EMG activity from amputees to continuously predict limb kinematics and kinetics across a variety of ambulation conditions.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Marquette University Institutional Review Board. The patients/participants provided their written informed consent to participate in this study.EZ-G contributed to conception and design of the study, performed acquisition, analysis and interpretation of data, and drafted the manuscript. LR supported data acquisition and processed motion data. PV, BS-T, SK-M, and SB contributed to conception and design of the study, obtained funding, and supervised the study. All authors contributed to manuscript revision and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Diverticulitis is a common cause of an acute surgical abdomen and computed tomography has become an essential part of work up particularly to identify complications that commonly include intraperitoneal perforation, abscess and fistula formation. We report the case of an 81-year-old male who presented to the emergency department with acute lower abdominal pain and was found to have sigmoid diverticulitis with the rare complications of a diverticular abscess that had formed a sinus tract and perforated into the retroperitoneum and secondary acute appendicitis. Initial management was with intravenous antibiotics, a Hartmann's procedure and appendicectomy. Subsequently the retroperitoneal collection was drained percutaneously. The case was further complicated by the patient's multiple co-morbidities and unfortunately the patient died 6 weeks after admission from sepsis. This case highlights the role of computed tomography in the pre- and post-operative period to identify complications which are often clinically occult and require early surgical and interventional radiology management to optimize outcomes. Diverticulitis and acute appendicitis are among the most common causes of an acute surgical abdomen, with estimated incidences of approximately 110 and 190 per 100,000, respectively An 81-year-old male presented to the emergency department with 4 days of abdominal pain and anorexia followed by a fall and 14 h long lie on the floor. He denied any nausea, vomiting or change in bowel habit. The patient had multiple co-morbidities including stage IV chronic kidney disease secondary to polycystic kidney disease, ischemic heart disease, atrial fibrillation, type 2 diabetes, hypothyroidism, erosive gastritis, obesity and diverticular disease. On examination the patient was peripherally shutdown, had poor bibasal air entry and a peritonitic abdomen with left flank fullness. The patient was tachycardic (125 bpm), hypotensive (100/55 mm Hg), tachypnoeic (36 bpm) and afebrile (37°C), with initial blood results supporting a diagnosis of severe sepsis on a background of chronic kidney disease .Table 1APortal-venous phase contrast-enhanced computed tomography (CT) of the abdomen and pelvis demonstrated an approximately 20 cm long segment of circumferentially thickened sigmoid colon containing numerous diverticula and severe pericolic inflammatory stranding A. A 5 cmThe pre-operative P-POSSUM score was 95.8% mortality and 99.9% morbidity. A second consultant surgical opinion was sought given his high-risk profile and, taking into account the patient's strong wishes, a joint decision was made to proceed with a laparotomy.Intraoperative findings were an inflammatory mass attached to the left lateral sidewall containing a loop of perforated sigmoid colon and adherent appendix, cecum and distal small bowel. A sigmoid colectomy with rectal stump and end colostomy formation (Hartmann's procedure) and appendicectomy were performed. Minimal pus was found in the left lateral sidewall at time of operation and the retroperitoneum was not explored. Intra-abdominal drains were placed in the left paracolic gutter and pelvis. Histology confirmed perforated sigmoid diverticulitis with acute transmural inflammation, pericolic tissue abscess formation and acute suppurative appendicitis.The patient was extubated on day 1 and was managed in intensive care for 8 days requiring high levels of oxygen for a co-existing pneumonia. Following stepdown to the surgical ward the patient developed worsening sepsis and CT imaging, performed on post-operative day 21, demonstrated an enlarged, complex retroperitoneal collection in the left flank. In addition to intravenous antibiotics, 2 percutaneous drains were inserted into the retroperitoneal collection but unfortunately the patient deteriorated with worsening sepsis and died on post-operative day 40.We present the case of an 81-year-old man with perforated sigmoid diverticulitis complicated by acute appendicitis and retroperitoneal abscess formation. Perforation is a common complication of acute diverticulitis. The vast majority are contained perforations but in 1%–2% there is free intra-abdominal gas The retroperitoneum is not routinely entered during laparotomy and retroperitoneal collections often have non-specific symptoms. Mortality of patients with retroperitoneal abscesses was historically as high as 22%-46% Additionally, in this case there was co-existing acute suppurative appendicitis which we hypothesize occurred secondary to transmural bacterial spread from the inflamed sigmoid colon. Part of the sigmoid colon was located in the right iliac fossa and the appendix was fibrosed to the inflamed proximal sigmoid in the midline. Serosal appendicitis can occur with an extra-appendiceal source of inflammation but in this case histology demonstrated full thickness appendiceal ulceration, presumably a result of the delayed presentation facilitating transmural spread This case demonstrates the importance of cross-sectional imaging to diagnose the complications of sigmoid diverticulitis, both pre- and post-operatively, to facilitate appropriate and prompt multi-disciplinary management. Antibiotics, surgical resection, image-guided percutaneous drainage and high-quality supportive care are all important to optimize outcomes. In complicated cases early post-operative imaging is also essential to identify potential complications, particularly when there is a suspicion of retroperitoneal involvement that may not be visualized intra-operatively.


Oxygen-guided radiotherapy is a new modality for cancer irradiation. Spatially Fractionated Radiation Therapy allows the treatment of hypoxic tumor areas with high radiation doses. Radiotherapy enhances immunotherapy effectiveness. Abscopal and bystander effects are important radiobiological issues. The aim of this paper was to analyze the recent development of a particular kind of radiation therapy that is based on high-dose delivery in small areas within large tumor masses. We performed a narrative review of the radiobiological rationale behind a potential benefit by using these techniques combined with immunotherapy and employing personalized target definition according to hypoxic areas.Palliative radiotherapy has a great role in the treatment of large tumor masses. However, treating a bulky disease could be difficult, especially in critical anatomical areas. In daily clinical practice, short course hypofractionated radiotherapy is delivered in order to control the symptomatic disease. Radiation fields generally encompass the entire tumor mass, which is homogeneously irradiated. Recent technological advances enable delivering a higher radiation dose in small areas within a large mass. This goal, previously achieved thanks to the GRID approach, is now achievable using the newest concept of LATTICE radiotherapy (LT-RT). This kind of treatment allows exploiting various radiation effects, such as bystander and abscopal effects. These events may be enhanced by the concomitant use of immunotherapy, with the latter being ever more successfully delivered in cancer patients. Moreover, a critical issue in the treatment of large masses is the inhomogeneous intratumoral distribution of well-oxygenated and hypo-oxygenated areas. It is well known that hypoxic areas are more resistant to the killing effect of radiation, hence the need to target them with higher aggressive doses. This concept introduces the “oxygen-guided radiation therapy” (OGRT), which means looking for suitable hypoxic markers to implement in PET/CT and Magnetic Resonance Imaging. Future treatment strategies are likely to involve combinations of LT-RT, OGRT, and immunotherapy. In this paper, we review the radiobiological rationale behind a potential benefit of LT-RT and OGRT, and we summarize the results reported in the few clinical trials published so far regarding these issues. Lastly, we suggest what future perspectives may emerge by combining immunotherapy with LT-RT/OGRT. The treatment of primary or metastatic bulky non-haematologic tumors can be difficult, and radiation therapy is frequently the only available therapeutic option. Systemic therapies are often unable to effectively penetrate within such large lesions due to an inhomogeneous and inadequate neoangiogenesis that could develop asynchronously compared to the tumor cell growth. On the one hand, this phenomenon delays tumor regression necessary for rapid satisfactory symptom relief with chemotherapy only and, on the other hand, could determine well-oxygenated areas alternating with hypoxic areas that are potentially refractory to damage from ionizing radiation. Furthermore, homogeneous irradiation of such large targets could be unsuitable for nearby healthy tissues, which are likely to be significantly affected by a detrimental dose-volume effect. A workaround used to avoid this effect is to aggressively irradiate only very small partial volumes of bulky tumors while limiting the peripheral target dose within tolerance for the neighboring organs at risk. This approach was recently codified by the LATTICE radiotherapy , a recenHere we present a comprehensive narrative review about LATTICE and Oxygen Guided RadioTherapy (OGRT), focusing on their theoretical mechanisms as inferred by analysis of laboratory findings. We also report related clinical experiences and suggest further implementations in the light of the most recent evidence that shows a synergy between radiotherapy and immunotherapy (IT).Lattice radiotherapy is the tridimensional evolution of the 2D GRID radiotherapy, a technique used since the beginning of the last century to spare overlying organs at risk, especially the skin while treating large deep-seated tumors at the time of kilovoltage (kV) and 2D-imaging-guided radiotherapy. As a matter of fact, bulky masses could be very difficult to adequately treat due to the fact that the larger the irradiated tumor volume, the larger the radiation dose delivered to neighboring organs at risk (dose-volume effect). This effect could be amplified by the use of kV photons, characterized by low tissue penetrance, so that pursuing an adequate energy deposit at the tumor depth entails a high dangerous dose at the skin surface. GRID approach overcame such a critical issue by fragmenting the radiation beam through a multi-perforated screen placed between the X-ray source and the target in the patient. By alternating blocks and holes, this radiation field array generates a two-dimensional dose distribution, characterized by foci of high radiation dose (peaks) separated by low dose areas . Such a planning method allowed to significantly reduce the integral peripheral target dose delivered at the boundary with healthy tissues while delivering a high lethal radiation dose to a large portion of tumor volume. The interest in GRID radiotherapy rapidly decreased with the implementation of the newer linear accelerator (LINAC) equipped with much more clinically versatile megavoltage (MV) photons and supported by more and more performing Treatment Planning Systems (TPS) . The hisThe clinical experiences with Lattice radiotherapy are isolated, mostly collected in recent small case series or even individual case reports. The very first was reported in 2010 by Amendola et al. ; it was The inhomogeneous neoangiogenic sprouting that supports the sprawling cancer cells proliferation could generate hypoxic areas due to a non-uniform and deficient oxygen supply for the entire tumor volume . Such hy2 ≤ 10 torr), they proved that it is possible to double tumor control by a selective boosting (13 Gy) without a significant gain for a homogeneous escalated dose  [2 image-based hypoxic voxels were grouped in radiation boost spheres, resembling vertices of lattice radiotherapy technique [1⁸F-fluoromisonidazole (FMISO), 1⁸F-flortanidazole (1⁸F-HX4), and 1⁸F-fluoroazomycin arabinoside (1⁸F-FAZA), reflect the spatial distribution of intratumoral oxygen and may help to guide hypoxia-based dose escalation [1⁸F-FAZA PET is able to detect hypoxic subvolumes within a 1⁸F-FDG PET-homogeneous NSCLC mass [Oxygen-Guided Radiation Therapy is still a recently introduced concept without a large-scale clinical experience. This is due to the fact that there is a difficulty in tracing hypoxic tumor areas at high spatial resolution by means of currently available methods for routine clinical application. Actually, most of the experiences with the above technical approach are with experimental animal models, more suitable and less cumbersome for preliminary tests. Electron paramagnetic resonance is a preclinical spectroscopic technique that works similarly to nuclear magnetic resonance but is based on the relaxation time of unpaired or photoexcited electrons rather than proton spin. It involves the use of intravenous injection of oxygen-measuring spin probes whose intratumoral spreading is directly correlated with partial pressure of oxygen (pO₂), thus being able to distinguish hypoxic areas from normoxic ones. Such an imaging method has very high accuracy (1 torr pO₂) and spatial resolution (1 mm) that permit modulating dose delivery according to both spatial and temporal variations of intratumoral oxygen landscape. Their feasibility and potential were effectively tested in a mouse fibrosarcoma model by Epel et al. Through the detection and targeting of hypoxic areas (pOregions) . In a prechnique . Furtherechnique . The posechnique . Tumor oechnique . As demoechnique . Such anechnique . Hypoxiaechnique . Two recechnique ,49. The calation ,51,52,53CLC mass . Among pCLC mass ,56,57. ICLC mass . A trialCLC mass . HoweverCLC mass . MR imagCLC mass . Other MCLC mass . MultipaCLC mass . FinallyCLC mass . Indeed,CLC mass . FinallyCLC mass  combinedCLC mass  imaging It is widely acknowledged that high radiation doses can increase the immune response against cancer cells when given with immune checkpoint inhibitors ,69,70. SOn the basis of this background, the need for dose-painting approaches is evident. Targeting specifically hypoxic areas with an extreme hypofractionation of radiation dose, just as in SRT and LT-RT, could overcome not only the related radioresistance but also trigger intercellular signaling pathways arising as bystander effect . In factOn the basis of the above, it is clear the need for defining the more appropriate fraction size of high dose, total one, targeted subvolumes size and shape, time interval between fractions, spatial arrangement of doses, including low ones, radiation beam quality (photons vs. hadrons), and integration with immunotherapy. It is noteworthy to underline that, up to date, there is no clear evidence confirming the advantages of LATTICE radiotherapy over classic irradiation. Indeed, in the absence of comparative analyses, the LATTICE approach should not be considered the standard one. Experimental animal models and preliminary clinical trials are intended to clarify these issues for a standardized therapeutic protocol and to better understand the underlying biological mechanisms.


Clinical phenotyping of primary progressive aphasia has largely focused on speech and language presentations, leaving other cognitive domains under-examined. This study investigated the diagnostic utility of visuospatial profiles and examined their neural basis among the three main primary progressive aphasia variants. We studied the neuropsychological performances of 118 primary progressive aphasia participants and 30 cognitively normal controls, across 11 measures of visuospatial cognition, and investigated their neural correlates via voxel-based morphometry analysis using visuospatial composite scores derived from principal component analysis. The principal component analysis identified three main factors: visuospatial-executive, visuospatial-memory and visuomotor components. Logopenic variant primary progressive aphasia performed significantly worst across all components; nonfluent/agrammatic variant primary progressive aphasia showed deficits in the visuospatial-executive and visuomotor components compared with controls; and the semantic variant primary progressive aphasia scored significantly lower than nonfluent/agrammatic variant primary progressive aphasia and control in the visuospatial-memory component. Grey matter volumes over the right parieto-occipital cortices correlated with visuospatial-executive performance; volumetric changes in the right anterior parahippocampal gyrus and amygdala were associated with visuospatial-memory function, and visuomotor composite scores correlated significantly with the grey matter volume at the right precentral gyrus. Discriminant function analysis identified three visuospatial measures: Visual Object and Space Perception and Benson figure copy and recall test, which classified 79.7% (94/118) of primary progressive aphasia into their specific variant. This study shows that each primary progressive aphasia variant also carries a distinctive visuospatial cognitive profile that corresponds with grey matter volumetric changes and in turn can be largely represented by their performance on the visuomotor, visuospatial-memory and executive functions. et al. demonstrate that the distinct visuospatial cognitive phenotypes are associated with anatomical changes over the right hemisphere, albeit the structural changes of PPA are most evident over the left hemisphere.The three canonical variants of a primary progressive aphasia (PPA) carry different visuospatial cognitive profiles. Tee   Patients with nfvPPA are characterized by agrammatism and/or apraxia of speech with left frontoinsular atrophy. Individuals with lvPPA show impairments in phonology and auditory-verbal short-term memory  and display atrophy in the posterior portion of the left superior/middle temporal gyri into the inferior parietal lobule.2Primary progressive aphasia (PPA) represents a neurodegenerative syndrome that manifests predominantly with speech and language impairments.3–6 These non-language impairments are frequently related to the patients’ difficulties in manipulating verbal information. However, in some cases, these deficits also reflect changes in network-level connectivity and the disease evolution that gradually involves regions outside of the language networks. For instance, svPPA individuals exhibit deficits in verbal memory recall,6 but such findings are believed to be confounded by their verbal semantic functions. On the other hand, the behavioural and appetite changes that are found in svPPA,7 are shown to be related to the spreading of disease into orbitofrontal and right temporal areas.9 Similarly, nfvPPA individuals score lower in executive tasks,6 possibly linked to the prefrontal spread of the disease.10 Numerous studies also indicated that individuals with lvPPA display lower performance on memory recall.11 This finding may be related to deficits in verbal auditory short-term memory that interfere with learning but maybe a product of disease progression that subsequently involve the hippocampal regions or clinical heterogeneity.Previous neurocognitive studies on PPA have largely centred on its typical neurolinguistic features. Although by criteria definition, individuals with PPA typically present with relatively isolated speech and language difficulties, few studies have highlighted the presence of non-language cognitive deficits, particularly when examined with neuropsychological tests.12 suggesting a core impairment in visuospatial processing. Conversely, nfvPPA patients showed deficits only in visuospatial tasks that relied on executive functioning but were spared in visual delayed recall.12 Finally, svPPA showed weaker performance in delayed recall of visual information but otherwise had spared visuospatial cognition.12 While the cognitive mechanisms of visuospatial impairment in PPA have begun to be investigated, the neuroanatomical basis leading to such visuospatial phenotypes remains to be elucidated.Among the various non-language cognitive domains, visuospatial cognition is uniquely suited to examine the cognition patterns of PPA beyond the speech and language functions, as visuospatial tasks are relatively less dependent on verbal information. In a previous study, lvPPA individuals demonstrated worse performance across multiple visuospatial tasks,13 Generally, the ventral pathway, connects the occipitotemporal to the anterior temporal cortices and is commonly implicated in comprehension, learning and long-term memory of verbal (left hemisphere) or visual stimuli (right hemisphere). The dorsal pathway (DP) involves a distributed network connecting the temporo-occipital to frontoparietal regions and is associated with working memory, and the auditory- and visual-motor feedback loops that inform articulation and spatial navigation functions, respectively.14–16 Thus, the ventral pathway is recognized as the ‘what’ pathway17–20 and DP is termed the ‘where/how’ pathway.21 Examining the cognitive and anatomical mechanisms of early visuospatial deficits in PPA should provide useful information regarding the disease vulnerabilities and possibly increase diagnostic accuracy.The network model of visuospatial processing offers an enticing juxtaposition to the ventral and dorsal streams that have also been theorized for speech and language functioning.In this study, we examined the neural correlates of numerous visuospatial tasks among the three main PPA variants and investigated the diagnostic utility of visuospatial profiles. We hypothesized that each PPA variant would show a differential association between MRI-based anatomical damage and impairment in specific visuospatial tasks.22 The PPA participants were further classified into svPPA (n = 45), nfvPPA (n = 39) or lvPPA (n = 34) based on the consensus criteria established in 2011.1 After reviewing the clinical history, neuropsychological data and MRI neuroimaging, diagnoses were established among a multidisciplinary team that consisted of one or two behavioural neurologists, a clinical neuropsychologist, and/or a genetic counsellor and a speech-language pathologist. We excluded participants that had a mini-mental state examination  score < 8 or a Clinical Dementia Rating (CDR) scale > 2 and had not undergone MRI imaging within 6 months of their neuropsychological testing. For participants with longitudinal follow-up, we included data from the initial evaluation that consist of both cognitive and imaging data. Written informed consent for inclusion in this research was obtained from all participants or their medical proxies. This study received ethical approval from the University of California, San Francisco (UCSF) Committee on Human Research and was conducted in accordance with the Declaration of Helsinki.A total of 148 participants were included in this study. All participants were recruited from the Memory and Aging Center at the University of California, San Francisco between the year 2002–16 and underwent comprehensive assessments that consisted of a neurological history and examination, neuropsychological testing and MRI neuroimaging. Among them, 30 participants were diagnosed as cognitively normal, and 118 participants fulfilled the PPA diagnostic criteria.F = 7.44, P = 0.001] and at examination  when compared with the other PPA variants but comparable in the time point of assessment since disease onset . As expected, MMSE was significantly lower and CDR scores higher in the PPA groups when compared with the healthy controls . The lvPPA participants also performed lower on the MMSE score in comparison with the other two PPA variants, and the nfvPPA participants had a lower CDR sum of boxes score  but a comparable proportion of individuals with lower CDR grades compared with lvPPA and svPPA groups (P = 0.115).The demographics, neuropsychological, speech and language data for all groups are reported in et al.24 In particular, the neuropsychological battery consisted of an MMSE for global cognition assessment,23 the short form California Verbal Learning Test (CVLT-SF) for verbal episodic memory evaluation,26 the forward and backward digit span length for working memory, the Stroop colour naming/interference test and category fluency test for executive function assessment,24 and the short version of motor speech,27 repetition28 and syntax comprehension tests30 for speech and language assessment. PPA participants are further evaluated by a detailed speech and language battery. The comprehensive speech and language battery consisted of a fluency rating, sequential commands and repetition tests from the Western Aphasia Battery,28 and motor speech tests as illustrated in Ogar et al.27 with apraxia of speech and a dysarthria severity rating score,31 the 15 items Boston Naming Test (BNT),32 the Peabody Picture Vocabulary Test (PPVT)33 and syntax comprehension tests30 to reflect the motor speech, semantic and syntactic functions.The neuropsychological testing was conducted by neuropsychology fellows or research staff under the supervision of board-certified neuropsychologists, the CDR assessment was completed by registered nurses, and the speech and language assessment data were collected by board-certified speech-language pathologists. All participants completed a neuropsychological battery as illustrated in Kramer 34 to assess visuospatial location; the abbreviated Beery visual-motor integration (VMI) test,12 the Benson figure copy test35 and the Wechsler Memory Scale (WMS) Visual Reproduction I test36 to reflect the visuomotor integration ability; the Benson figure delayed recall35 and the WMS Visual Reproduction II test36 as measures of visuospatial-memory function; the forward and backward spatial span length to represent spatial attention and spatial working memory function, respectively; the Wechsler Adult Intelligence Scale (WAIS) Block Design36 to evaluate visuospatial construction skill; the modified Trails B test37 to characterize visuospatial sequencing and switching function; and the Delis–Kaplan Executive Function System (DKEFS) Design Fluency filled dots38 to indicate spatial fluency ability.For the visuospatial battery, we collected 11 visuospatial measures: the number location test from Visual Object and Space Perception battery1-weighted MRI images were collected via 1.5 T and 3 T MRI scanners with a standard quadrature head coil (eight channels) at UCSF MAC. The T1-weighted images were acquired using an MPRAGE sequence with the following parameters: 160 sagittal slices, repetition time = 2300 ms, echo time = 2.98 ms, inversion time = 900 ms, flip angle 9°, field of view = 256 mm3, matrix size = 256 × 240, voxel in-plane size = 1.0 × 1.0 mm2; slice thickness = 1 mm.Thttp://dbm.neuro.uni-jena.de/cat) within Statistical Parametric Mapping software  running on the Matlab 2018b programme (http://www.mathworks.com). The T1-weighted images were spatially aligned with the Montreal Neurological Institute (MNI) space then segmented into grey matter (GM), white matter (WM) and CSF. The GM and WM tissue were further normalized using DARTEL (http://www.fil.ion.ucl.ac.uk/spm/software/spm12). The normalized and modulated GM segments were smoothed by 8 mm full-width at half-maximum Gaussian Kernel.The neuroimaging data of PPA participants were pre-processed using the Computational Anatomy Toolbox  with Kaiser normalization.39 Based on the eigenvalue, three components were extracted. Each factor with a loading >0.5 was considered to contribute heavily to the particular component. To account for the language influences in our visuospatial imaging and discriminant analysis, a similar PCA method was also applied for language data that was collected in both PPA and control groups  to compute language composite scores. Using general linear model, the visuospatial measures were adjusted with age on examination, MMSE score and language composite scores as covariates. We then adopted stepwise discriminant function analysis to identify the covariate-adjusted visuospatial measures that contribute most in discriminating the three PPA variants and delineate the predictability of visuospatial measures in the classification of PPA variants. Statistical analyses were conducted using IBM SPSS Statistics 26.0 (https://www.ibm.com/support/pages/downloading-ibm-spss-statistics-26).To compute the visuospatial composite scores that best represent the visuospatial performances in this PPA cohort, we applied principal component analysis (PCA) using the visuospatial measures to identify variables measuring similar latent cognitive performance. There were <4.1% missing data for each visuospatial measure, and the missing visuospatial data were replaced by the means for each specific group to facilitate the PCA. The visuospatial measures were first standardized via P < 0.05 and family-wise error (FWE) corrected. The VBM analysis was conducted using Statistical Parametric Mapping software (SPM12) running on the Matlab 2017 programme.To identify the GM atrophy regions that correlate with the visuospatial composite values using the structural MRI images of 118 PPA participants, voxel-based morphometry (VBM) analysis with a multiple linear regression was adopted. Age, handedness, total intracranial volume, gender, language composite scores and PPA diagnosis were included as covariates in each of the regression analyses. For the neural correlate analyses reported in this study, the clusters and voxel threshold were set at The clinical and neuroimaging data used in this study are available from the corresponding author upon reasonable request. Given the sensitive nature of participants’ data, our ethics protocol does not permit open data sharing at this stage.F = 26.42, P < 0.0001] and backwards , Stroop colour naming  and interference tasks   = 36.26, P < 0.0001] and semantic fluency tasks . On the CVLT-SF, svPPA and lvPPA learned and recalled significantly fewer words when compared with the controls and nfvPPA individuals .On neuropsychological testing, lvPPA and nfvPPA performed worse on working memory and executive tasks such as digit span forward [ 0.0001] . For verF  = 55.85, P < 0.0001]. In addition to naming difficulties, svPPA participants also demonstrated significantly lower PPVT scores . The Western Aphasia Battery (WAB) fluency was significantly reduced in the nfvPPA , and they also exhibited significantly higher speech apraxia and dysarthria rating scores . On the WAB sequential command and the WAB repetition test, the scores were significantly decreased in the order of svPPA, nfvPPA and lvPPA . In terms of syntax comprehension and production tests, the nfvPPA group performed poorly for syntax comprehension and the lvPPA group scored lower in both syntax tasks when compared with the svPPA group .The speech and language data showed that the PPA groups scored significant lower on the BNT as compared with the control group, particularly for svPPA and lvPPA groups . In contrast, the nfvPPA and the control group scored significantly higher than the lvPPA and svPPA groups on the visuospatial-memory component . As for the composite score representing the visuospatial motor component, the lvPPA participants were found to score significantly lower in comparison with the svPPA and control groups .The lvPPA and nfvPPA groups performed significantly worse than svPPA and control groups on the visuospatial-executive composite score [Two language components (L-Factor) with eigenvalues of 1.87 and 1.67 were identified via PCA approach using the five language measures that were collected in all PPA and control groups . These fTo investigate the neuroanatomical basis of visuospatial performances in PPA, performances on the three visuospatial composite scores were correlated with the GM regions using VBM analysis . The visχ2(12) = 63.38, F = 5.078, P < 0.0001). With these three visuospatial measures, 94 of 118 PPA participants (79.7%) were accurately classified , higher CDR sum of box score  and CDR global score (P = 0.098) with lower performance in BNT , apraxia of speech severity rating  and syntax comprehension test   .In this study, we describe distinct visuospatial cognitive profiles among the three PPA variants and examined the neural basis of visuospatial processing in PPA using GM volume and visuospatial composite scores derived from the PCA. The predictability of the visuospatial measures was studied via discriminant function analysis to identify visuospatial measures that best discriminate the three PPA variants.12 visuospatial short-term memory,41 visuospatial attention,43 visuospatial working memory44 and visuomotor integration functions.12 Ramanan et al. and Watson et al.’s studies also demonstrated that nfvPPA and lvPPA differ in their visuospatial short-term memory performances. The visuospatial cognitive profiles shown in this study are parallel the visuospatial cognitive profiles found in our PPA cohort. Our findings demonstrate that although the PPA syndrome predominantly affects the speech and language networks, it also impacts the less investigated visuospatial cognitive functions. Interestingly, Weintraub et al.45 previously reported that clinically diagnosed PPA patients scored significantly better than patients with amnestic Alzheimer’s disease and were comparable with controls when tasked to perform the delayed recall of simple geometric designs. Compared with patients with amnestic Alzheimer’s disease, Mesulam et al.46 also found that PPA patients with Alzheimer’s biomarkers or pathology have relatively preserved episodic memory in recalling the picture of common objects. We speculate that the variable interpretations of visuospatial-memory function in PPA could have stemmed from the visuospatial complexity of stimuli used (e.g. simple geometric design versus complex figure), the distributions of PPA variants in the PPA cohort and the nature of stimuli .Analysis of the visuospatial battery that consisted of 11 visuospatial measures supports the hypothesis that each PPA variant carries a distinctive pattern of visuospatial deficits. Specifically, svPPA participants exhibited deficits in visuospatial memory but their other visuospatial functions were intact. Conversely, the nfvPPA participants displayed relative preservation of their visuospatial-memory ability, despite evident impairment in the other executive and motor visuospatial measures. Among the three PPA variants, individuals with lvPPA showed the lowest visuospatial performances across all evaluated visuospatial measures. Previous studies have found that lvPPA individuals have lower performance on any tasks heavily dependent on visuospatial localization,The PCA outcomes underscored the pivotal role of the visuospatial-executive, memory and motor functions in portraying the visuospatial profiles of the PPA individuals. Factor 1 is derived from a collection of visuospatial tasks targeting various aspects of visuospatial-executive functions including visuospatial sequencing and switching function, spatial attention and working memory function, spatial generativity ability and visuospatial construction skill. Based on this, we can infer that these visuospatial functions share common neural networks and/or neuroanatomical regions that are affected by the different disease pathophysiology found in PPA individuals. Factors 2 and 3 comprised of tasks reflecting visuospatial memory and visuomotor integration skills, respectively, with the exception of the visual reproduction I task, which is commonly regarded as an indicator of visuomotor integration function. We speculate that the performance on the visual reproduction I was derived as a component of Factor 2, and not Factor 3, given its strong correlation with the performance on the visual reproduction II task.et al.47 demonstrated presence of clinical heterogeneity in lvPPA patients; thus, we speculate that the variations in visuospatial cognitive profiles may be related to the clinical heterogeneity of lvPPA.The discriminant analysis identified visual object and space perception, Benson figure recall and Benson figure copy scores as the three visuospatial measures most pivotal in classifying PPA variants. Coincidentally, these three visuospatial measures each belong to a different visuospatial PCA component. Thus, instead of collecting all 11 visuospatial measures, administering three non-language dependent visuospatial tasks that target visuomotor, visuospatial memory and executive functions can be a time-efficient alternative approach in representing the visuospatial profile of PPA variants. The predictability of PPA variants with the visuospatial measures reached 79.7%, even without relying on the speech and language measures. Therefore, in addition to idiosyncratic language features, the three PPA variants also carry distinctive visuospatial cognitive profiles that potentially provides reference to the classification of PPA variants. This is especially true for individuals with svPPA, nfvPPA and lvPPA based on the congruency rate between the predicted and criteria diagnosis. Interestingly, lvPPA individuals with milder global cognitive impairments display visuospatial profiles which resembles those of nfvPPA individuals. Leyton 14–16 Right posterior parietal and prefrontal cortices have also been reported to be critical for regulating visuospatial attention, visuospatial working memory and spatial localization.48–51 The visuospatial-executive composite score is a derivational product of the modified Trail B test, spatial span length, WAIS Block Design, visual object and space perception and DKEFS Design Fluency tests, and these tests are primarily dependent on spatial attention, localization and working memory functions. It is thus unsurprising that the visuospatial-executive composite score in PPA individuals showed a correlation with the GM volumes over the right posterior parietal, right visual association and right frontal cortices. On the other hand, the ventral stream network of visuospatial processing is most commonly implicated in the identification, learning and episodic memory of visual stimuli. Based on its projections, it can be divided into six distinct pathways: occipitotemporo-neostriatal, occipitotemporo-amygdaloid, occipitotemporo-ventral striatum, occipitotemporo-medial temporal, occipitotemporo-orbitofrontal and occipitotemporo-ventrolateral prefrontal pathways.52 Our study showed that the visuospatial-memory composite performance in PPA individuals is strongly associated with the ventral stream network that projects towards the anterior and medial temporal cortices, primarily involving the occipitotemporo-amygdaloid and occipitotemporo-medial temporal pathways. Generally, the occipitotemporo-medial temporal supports the formation of short-term and long-term visual memory and the occipitotemporo-amygdaloid pathway is related to the effective processing of visual stimuli.52 Hence, the visuospatial-memory composite score, which is mainly composed of visuospatial measures that heavily depend on visual short-term memory, is associated with the volumetric changes over these regions. Similarly, the visuospatial motor composite score, which is composed of visuospatial tasks measuring visuomotor abilities, exhibited neuroanatomical correlation with the GM volume over the right precentral gyrus in PPA individuals. We believe that this region is critical for the parietal–premotor pathway of the dorsal stream network that is known to support visually guided actions.14–16In general, the neural basis of the visuospatial composite scores corresponds well with the neural framework for visuospatial processing. More specifically, the visuospatial-executive composite score correlates with the GM volumetric changes over the right posterior parietal, right visual association cortices and right middle frontal gyrus. Right posterior parietal and visual association cortices are key regions of the occipito-parietal circuit for visuospatial processing. This circuit is commonly regarded as the anatomical precedent circuit of the three pathways in the dorsal visuospatial processing streams: parieto-prefrontal, parieto-premotor and parieto-medial temporal pathways. The occipito-parietal circuit is responsible for transforming the retinotopic represented visual information into egocentric frame of reference.53 we speculate that visuospatial performance in lvPPA individuals is related to the disease involvement over the right occipital-parietal circuit at the early stage of the disease. The disease pathology eventually spreads towards the anterior and medial temporal cortices and results in visual memory deficits. These findings support the notion that the progressive neural network degeneration reported in PPA variants, although predominantly, does not exclusively involve the speech and language network only. Studying these non-language cognitive deficits may help inform the disease evolution and potentially serve as markers for disease severity.Interestingly, the visuospatial cognitive profile and its neural basis of the three PPA variants displayed mirroring neural signatures to the language pathways, albeit involving the contralateral/right hemisphere. Individuals with svPPA that are recognized for their damage over the anterior temporal lobes and ventral WM tracts showed lower performance in visuospatial measures that associate with the ventral stream of the visuospatial neural framework; whereas nfvPPA that are known for left frontoinsular atrophy and altered connectivity over the frontoparietal WM tracts scored lower on visuospatial measures that rely on the dorsal stream visuospatial network. Based on the longitudinal VBM study on the atrophy pattern of lvPPA individuals,44 In comparison, our neural correlate results showed relatively more right hemispheric involvements. This is probably because PPA is a clinical syndrome that typically shows more left-hemispheric atrophy, the limited right hemispheric volumetric changes may have restricted adequate variance to support strong anatomical correlation findings over the right hemisphere. Thus, in this study, we computed language composite scores to statistically adjust for possible neural correlates contributed by language measures. Finally, the PPA and control groups were not equally matched across all demographic variables. In comparison with the svPPA and lvPPA group, the nfvPPA group displayed a higher mean age of onset and a lower CDR sum of box score. The discrepancy in the CDR score may indicate variability in severity across the PPA variants. Nevertheless, the time point of assessment since disease onset did not vary across the PPA variants and the visuospatial profiles noted in our study were in line with the previous literature, suggesting the limited impact of the heterogeneity in the CDR score.42–44 To minimize any possible confounding effect of age and clinical severity, the GM volumetric analysis in this study was adjusted for age at examination.This study has several limitations that warrant consideration. First, our study showed that based on the visuospatial phenotypes alone, only 79.7% of the PPA participants showed congruent PPA variants diagnosis as the consensus criteria. This level of compatibility is arguably insufficient to serve as sole markers for differentiating PPA variants. This may be attributed to the fact that most visuospatial tasks are dependent on verbal/written instructions and motor production abilities and that there is the lack of optimal measures to statistically account for the disease severity of PPA individuals. Second, previous cortical thickness studies of lvPPA participants showed that the spatial span length was related to the left superior parietal or bilateral temporo-parieto-occipital brain regions.In summary, this study describes the distinctive visuospatial cognitive profile of the three PPA variants, outlines the neural basis underlying these visuospatial deficit patterns and examines the predictability of the visuospatial measures in classifying the PPA variants. Overall, our findings highlight the relevance of non-language presentations in PPA individuals and demonstrate the added benefit of incorporating visuospatial measures in the standard evaluation of PPA presentations.fcac060_Supplementary_DataClick here for additional data file.


Lymph node metastasis is a crucial prognostic parameter in many different types of cancers and a gateway for further dissemination to distant organs. Prior to metastatic dissemination, the primary tumor prepares for the remodeling of the draining (sentinel) lymph node by secreting soluble factors or releasing extracellular vesicles that are transported by lymphatic vessels. These important changes occur before the appearance of the first metastatic cell and create what is known as a pre-metastatic niche giving rise to the subsequent survival and growth of metastatic cells. In this review, the lymph node structure, matrix composition and the emerging heterogeneity of cells forming it are described. Current knowledge of the major cellular and molecular processes associated with nodal pre-metastatic niche formation, including lymphangiogenesis, extracellular matrix remodeling, and immunosuppressive cell enlisting in lymph nodes are additionally summarized. Finally, future directions that research could possibly take and the clinical impact are discussed. Many types of cancer, including melanoma, breast, oral, pancreatic and cervical cancers, disseminate through the lymphatic system –5. In a The concept of a pre-metastatic niche was first formulated by David Lyden and colleagues 15 years ago . This piThe lymphatic system is a unidirectional, blind-ended vascular network, of not only lymphatic capillaries and larger collecting vessels, but also secondary lymphoid organs such as LNs. This vascular system is essential for maintaining fluid homeostasis, absorbing dietary lipids and transporting immune cells and soluble antigens from peripheral tissues towards LNs and the central circulatory system , 31.1β2. This interaction between the two cell types induced an upregulation of adhesion molecules. For instance, vascular cell adhesion molecule 1 (VCAM-1) promoted the retention of hematopoietic cells in forming LNs . Se. Se10]. Together, these immune cells actively contribute to the formation of the pre-metastatic niche, necessary for LN colonization by metastatic cells that can eventually exit from the LN into the blood circulation , 125. ThMacrophages are present throughout the LN but are classified in different subtypes according to their location. A distinction is made between macrophages present in the SCS and MS from those residing in the LN parenchyma . SCS macBeyond the vessel wall lining functions described above, LECs can play a key role in immunosuppression, facilitating metastatic cell survival. LECs express inhibitory ligands such as PD-L1, which allows CD8 lymphocyte suppression or deletion . LN LECsThe most striking TGF-β function is immunosuppression, of paramount importance in the context of cancer. Indeed, TGF-β is able to induce the expression of cell cycle regulators (p21 and p27), which inhibit the proliferation of naïve T lymphocytes . TGF-β iUnder physiological conditions, TGF-β1 is the predominantly expressed isoform in immune cells, including immunosuppressive Tregs. Immunosuppression by the TGF-β1 pathway through Tregs avoids autoimmune reactions but contributes to tumor development . FurtherThe role of TGF-β in immunomodulation in LNs has been less well documented. Huang et al. demonstrated in a mouse model that Tregs secrete TGF-β1 in LNs , which iWhile cancer-associated fibroblasts (CAFs) represent a major cellular component of most primary neoplasms , these c+ and CD8+ T cells were more prevalent in the lung, and immunosuppressive factors were reduced in them compared to levels in wild-type mice [ECM remodeling is a key event that contributes to metastatic organ pre-conditioning and to the formation of an appropriate environment for tumor seeding. ECM modifications in the pre-metastatic niche have already been described, in detail, for the lung, liver and bones but have been poorly documented in the case of LNs. Interestingly, organ specificities have been highlighted in terms of ECM remodeling . Among type mice . POSTN iype mice . CAFs exype mice . Unfortuype mice . Furtherype mice . This waype mice –170. Forype mice . MDSCs rype mice . LOX canype mice . Taken aA pre-metastatic niche is now widely accepted as a specific tumor-induced microenvironment, favorable for disseminating tumor cells and metastasis formation . The elaA large number of questions remain unanswered. What are the dynamics of LN pre-metastatic formation? It is largely unknown how different ECM components interact in the pre-metastatic niche and exert cooperative/synergistic or antagonistic effects on metastatic tumor cells. Which markers or signatures could be used to stratify patients and/or predict their potential to form LN and distant metastases? Understanding how and when the key cross-talk between the primary tumor and LN is established to prime the organ is a prerequisite to identify the best potential molecular target(s). Consequently, it is crucial that basic scientists and clinicians work together to explore all facets of the pre-metastatic LN niche for diagnostic, prognostic and therapeutic purposes.


As the seas of advanced therapies have swelled in the last few decades, multiple myeloma patients have been empowered, encouraged, and sometimes required, to engage in their care. We applied a conversation analysis approach to 12 nurse-led education visits (1011 minutes of audio) containing reference to educational videos. We indexed extracts based on whether the nurse or patient first mention the video. Patients oriented toward the video to demonstrate knowledge  and clarify information . Nurses oriented toward the video either through positive , negative (n=13= 36%), or neutral  assessments. Videos created opportunities for patients to pursue their topics of interest during in-person visits. Also, nurses often oriented toward the videos pre-emptively to achieve their teaching goals either by acknowledging the patients’ exposure to upcoming information or by positively or negatively assessing the videos in ways that enable them to re-orient talk to educational scripts.


Cost-effectiveness acceptability curves showed that the probability of cost-effectiveness was never higher than 0.6 for all possible ceiling ratios. Adding routine third trimester ultrasonography to usual care is not cost-effective in reducing SAPO.Routine third trimester ultrasonography is increasingly used to screen for fetal growth restriction. However, evidence regarding its cost-effectiveness is lacking. We aimed to evaluate the cost-effectiveness of routine third trimester ultrasonography to reduce adverse perinatal outcomes compared to usual care (selective ultrasonography). An economic evaluation alongside a stepped-wedge cluster-randomized trial was conducted. Via 60 midwifery practices 12,974 Dutch women aged ≥16 years with low-risk pregnancies were enrolled at 22.8 (SD = 2.4) weeks’ gestation. All practices provided usual care. At 3, 7, and 10 months a third of the practices were randomized to the intervention strategy providing routine ultrasonography at 28–30 and 34–36 weeks’ gestation and usual care. The primary clinical outcome was a dichotomous composite measure of 12 severe adverse perinatal outcomes (SAPO) up to one week postpartum. Information on perinatal care and societal costs was derived from Netherlands Perinatal Registry, hospital records and a survey. Cost-effectiveness analyses revealed no significant differences in SAPO and healthcare and societal costs between the intervention strategy ( Being s neonate . It was  neonate .n = 3977) showed that routine third trimester ultrasonography approximately tripled the detection rate (sensitivity = 57%) of SGA neonates compared to selective ultrasonography (sensitivity = 20%) [n = 34,980) including 13 randomized trials did not show positive effects of routine third trimester ultrasonography on primary outcomes, including perinatal mortality, preterm birth, and Caesarean section rates [n = 13,046) conducted by our research group also showed that routine third trimester ultrasonography had no effect on severe adverse perinatal outcomes [Timely detection and adequate clinical management of FGR during (late) pregnancy is expected to reduce adverse effects and costs, but is only possible when effective screening procedures and subsequent adequate clinical management are available. Currently, many Western countries, such as the Netherlands, selectively use ultrasonography, i.e., serial fundal height (SFH) measurements and ultrasonography if clinically indicated, to monitor fetal growth. Interestingly, a previous cohort study in the UK (y = 20%) . ContrasAlthough routine third trimester ultrasound screening for FGR has not been proven to be clinically effective so far, ,8 Dutch This economic evaluation was conducted alongside a nationwide stepped-wedge cluster-randomized trial, the IUGR Risk Selection (IRIS) Study . In shorAll practices started with the control strategy offering usual care  . At 3, 7All participating women provided written informed consent. The IRIS study has been approved by The Dutch Institutional Review Board of the VU Medical University (reference number: 2013.409) and has been registered at the Netherlands Trial Register (NTR4367).Costs and clinical data were collected using the following four sources: the database of the Netherlands Perinatal Registry (Perined), sonographic databases, hospital records of mothers and their neonates, and a longitudinal survey embedded in the IRIS study .The primary clinical outcome was a composite measure of 12 severe perinatal outcomes based on information from the Perined database and hospital records . This coPregnancy-related healthcare costs were retrieved from the Perined database, covering information for the period from approximately 22 weeks’ gestation until one week postpartum . Cost itUsing digital standardized case report forms, five trained research assistants collected additional in-depth perinatal clinical data and maternal and neonatal cost data from hospital files ,12. DataMoreover, in-depth cost data based on hospital records of mothers participating in the survey were collected in case of a maternal hospital admission during pregnancy or postpartum, a maternal hospital admission of more than 48 h after a birth without medical intervention or an admission of more than 72 h related to a caesarean section. To ensure an adequate retrieval of data from the hospital records by the research assistants, experts in neonatology, obstetrics and economic evaluation research helped to operationalize the respective measures.Cost data for the period from 22 weeks’ gestation until 6 months postpartum were collected using hospital records. Cost items included medical transports (ambulance), laboratory tests or other diagnostic tests , CTG monitoring, duration of (postpartum) hospital admissions, interventions during admission to the neonatal unit, examinations and interventions and treatment during the perinatal/postpartum period  and the iMTA Productivity Cost Questionnaire (iPCQ), respectively .Healthcare costs were calculated based on standard costs published in Dutch costing guidelines or in previous economic evaluations of perinatal care in the Netherlands ,26,27,28The friction cost approach (friction period 85 days) was used to estimate lost productivity costs using Dutch rates ,29. The The economic evaluation related the difference in costs between pregnant women receiving routine third trimester ultrasonography and those receiving usual care to the differences in clinical effects. We performed both cost-effectiveness and cost-utility analyses, applying various perspectives and time horizons. The statistical analyses were conducted according to the intention-to-treat principle.n = 12,974) included in the current study population were used. Cost and effect differences were estimated using a bivariate regression model. Bias-corrected and accelerated bootstrapping with 5000 replications was performed to estimate statistical uncertainty.Firstly, we conducted a cost-effectiveness analysis for the composite outcome measure of severe adverse perinatal outcome from a healthcare perspective . The time horizon of the first analysis ranged from 22 weeks’ gestation to one week postpartum. For this first analysis, pregnancy-related data obtained from the Perined database of all women . The time horizon of these analyses ranged from 22 weeks’ gestation until, respectively, one week postpartum and 6 months postpartum. Pregnancy-related data obtained from the Perined database of all 12,974 women were also used for these analyses. In addition, detailed cost data from hospital records, and self-reported healthcare utilization and lost productivity data of women were extrapolated to estimate societal costs for the complete study population. To do this, a decision tree was developed that includes all possible outcomes for the two treatment conditions, leading to eight possible pathways and outcome strategies . For eacFinally, we conducted a cost-utility analysis from a societal perspective with a time horizon ranging from 22 weeks’ gestation to 6 months after the estimated date of birth . For this cost-utility analysis, we used available data of the women in the non-selective survey sample. Missing cost and effect data were imputed by applying multiple imputation using the MICE algorithm by Van Buuren et al., (1999) . PredictIncremental Cost-Effectiveness Ratios (ICER) were computed by dividing the difference between the groups in healthcare costs by difference in effects. For severe adverse perinatal outcomes, the difference between groups was multiplied by −1 to ensure that positive differences indicate that routine third trimester ultrasound screening is more effective than usual care and negative differences that routine third trimester ultrasound screening is less effective than usual care. Uncertainty surrounding the ICERs was graphically illustrated for cost-effectiveness planes for all conducted analyses. Cost-effectiveness acceptability curves were estimated to illustrate the probability that routine third trimester ultrasonography to screen for FGR is cost-effective in comparison to usual care for a range of different ceiling ratios, thereby showing decision uncertainty.For 12,974 women , information on pregnancy-related healthcare costs could be retrieved from the Perined database and data on the severe adverse perinatal composite outcome were available. Of the 2339 maternal and/or neonatal cases  included in an additional in-depth data-collection based on hospital records, cost data were available for 1515 cases . Of the 1475 respondents  enrolled for the non-selective survey, societal costs data were available for 1426 women , based on at least one or more waves of data collection.The differences in the prevalence of severe perinatal outcomes and costs between routine third trimester ultrasonography and usual care were not statistically significant. The ICER was 13,404, indicating that to prevent one adverse outcome EUR 13,404 need to be invested in the routine ultrasonography group compared to usual care. The bootstrapped cost-effect pairs were located in all four quadrants of the CE plane, although the majority (69%) were situated in the eastern quadrants of the CE plane a. The CEConcerning the extrapolated analysis with a time horizon until 6 months postpartum, the ICER for adverse outcomes prevented was 497,341 indicating that to prevent one adverse outcome EUR 497,341 needs to be invested in routine ultrasonography compared to usual care. As shown in For QALYs, the ICER was −8924, indicating that routine ultrasonography is dominated by usual care . The CEA curve (figure not shown) shows that at a ceiling ratio of EUR 0 per QALY gained the probability of cost-effectiveness is 0.49, and that this probability decreases to 0.43 at a ceiling ratio of EUR 20,000 per QALY gained. We found that results based on the extrapolated analyses for the composite outcome measure of severe adverse perinatal outcome from a societal perspective, with a time horizon until one week after birth, were comparable to those using the six month time horizon see .n = 1426) only. After 6 months, total societal costs in the routine ultrasonography group were EUR 2497  higher than in the usual care group. However, differences in adverse outcomes and QALYs between groups were small and not statistically significant. The ICER for adverse-outcomes-prevented indicates that on average, EUR 2,236,887 needs to be invested to prevent one adverse outcome in the routine ultrasonography group compared to the usual care group. The CEA curve shows that at a ceiling ratio of EUR 0 per adverse outcome prevented, the probability of routine ultrasonography being cost-effective compared to usual care is 0, and this probability only very slowly increases to 0.10 at a ceiling ratio of EUR 180,000 per adverse outcome prevented (figure not shown). For QALYs, the ICER was −288,558, indicating that routine ultrasonography is dominated by usual care. The probability of cost-effectiveness is 0 at all ceiling ratios for QALYs (figure not shown).This nationwide cluster-randomized stepped-wedge trial evaluated the cost-effectiveness of third trimester routine ultrasonography compared to usual care from both a healthcare and societal perspective until 6 months postpartum. Routine third trimester ultrasonography combined with usual care did not reduce severe adverse perinatal outcome compared to usual care alone. Costs based on the Perined data and hospital records did not differ between the strategies, while societal costs in the non-selective subsample were significantly higher in the intervention group compared to usual care. There were no statistically significant differences in QALYs between the two strategies either. Cost-effectiveness acceptability curves show that the probability of cost-effectiveness is never higher than 0.6 for all possible ceiling ratios. These results show that third trimester routine ultrasonography on top of usual care was not cost-effective compared to usual care alone.n = 9310) showed that one-stage second-trimester ultrasound screening was cost-effective in reducing perinatal mortality as compared to usual care [To the best of our knowledge, only three previous studies investigated the cost-effectiveness of routine ultrasonography during pregnancy and they showed mixed results ,33. The ual care . Howeverual care . Our stuual care ,33, and ual care .Our study has several strengths. The current study is the first multi-center large-scale pragmatic stepped-wedge cluster-randomized trial conducted on a national scale on the cost-effectiveness of routine third trimester ultrasonography in addition to usual care to reduce severe adverse perinatal outcomes in low-risk pregnancies in comparison with usual care alone. The cluster-randomized design reduced the risk of contamination between the treatment strategies, which might introduce bias in individually randomized controlled trials. The stepped-wedge design of the trial reduced confounding resulting from differences between the participating midwifery practices as each practice implemented both treatment strategies for a certain time.Apart from these strengths, our study also has several limitations. The current study did not achieve the predefined sample size of 15,000 women required to observe statistically significant differences in severe adverse perinatal outcomes between the two study strategies . As a coThe current large-scale nationwide stepped-wedge cluster randomized trial with a multidisciplinary protocol for the detection and management of FGR showed that introducing routine third trimester ultrasonography to usual care is not cost-effective in reducing severe adverse perinatal outcomes in low-risk pregnancies compared to usual care alone.