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Purpose: Older patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) may be considered ineligible for curative-intent therapy including high-dose chemotherapy with autologous stem-cell transplantation (HDT-ASCT). Here, we report outcomes of a preplanned subgroup analysis of patients ≥65 years in ZUMA-7. Patients and Methods: Patients with LBCL refractory to or relapsed ≤12 months after first-line chemoimmunotherapy were randomized 1:1 to axicabtagene ciloleucel [axi-cel; autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy] or standard of care (SOC; 2–3 cycles of chemoimmunotherapy followed by HDT-ASCT). The primary endpoint was event-free survival (EFS). Secondary endpoints included safety and patient-reported outcomes (PROs). Results: Fifty-one and 58 patients aged ≥65 years were randomized to axi-cel and SOC, respectively. Median EFS was greater with axi-cel versus SOC (21.5 vs. 2.5 months; median follow-up: 24.3 months; HR, 0.276; descriptive P < 0.0001). Objective response rate was higher with axi-cel versus SOC (88% vs. 52%; OR, 8.81; descriptive P < 0.0001; complete response rate: 75% vs. 33%). Grade ≥3 adverse events occurred in 94% of axi-cel and 82% of SOC patients. No grade 5 cytokine release syndrome or neurologic events occurred. In the quality-of-life analysis, the mean change in PRO scores from baseline at days 100 and 150 favored axi-cel for EORTC QLQ-C30 Global Health, Physical Functioning, and EQ-5D-5L visual analog scale (descriptive P < 0.05). CAR T-cell expansion and baseline serum inflammatory profile were comparable in patients ≥65 and Conclusions: Axi-cel is an effective second-line curative-intent therapy with a manageable safety profile and improved PROs for patients ≥65 years with R/R LBCL.

Humans use socially relevant stimuli to guide perceptual processing of the surrounding environment, with emotional stimuli receiving preferential attention due to their social importance. Predictive coding theory asserts this cognitive process occurs efficiently by combining predictions about what is to be perceived with incoming sensory information, generating prediction errors that are then used to update future predictions. Recent evidence has identified differing neural activity that demonstrates how spatial and feature-based attention may interact with prediction, yet how emotion-guided attention may influence this relationship remains unknown. In the present study, participants viewed a display of two faces in which attention, prediction, and emotion were manipulated, and responded to a face expressing a specific emotion (anger or happiness). The N170 was found to be enhanced by unpredictable as opposed to predictable stimuli, indicating that it indexes general prediction error signalling processes. The N300 amplitudes were also enhanced by unpredictable stimuli, but they were also affected by the attentional status of angry but not happy faces, suggesting that there are differences in prediction error processes indexed by the N170 and N300. Overall, the findings suggest that the N170 and N300 both index violations of expectation for spatial manipulations of stimuli in accordance with prediction error responding processes.

Involvement of the central nervous system (CNS) is a rare complication of mantle cell lymphoma (MCL) with limited treatment options. We report the outcomes of 36 patients with CNS involvement compared to 72 matched control MCL patients without CNS involvement. Four patients (11%) with CNS MCL were diagnosed with CNS involvement at time of MCL diagnosis. Median OS from MCL diagnosis was 50.3 months (95% CI: 22.8-79.6) for the CNS MCL group compared to 97.1 months (95% CI: 82.8-NR

Leukemic involvement in high grade B cell lymphoma (L-HGBL) is rare and has been sparsely described in the literature. We report our experience in a large single institution multicenter academic setting.Medical records of patients with HGBL who received care at Mayo Clinic between 2003 and 2020 were reviewed. L-HGBL was confirmed by peripheral blood smear and flow cytometry with corroboration from tissue and bone marrow biopsy findings.Twenty patients met inclusion criteria. All patients had significant bone marrow involvement by HGBL. Leukemic involvement presented in 11 of 20 (55%) in the de novo and 9 of 20 (45%) in the relapsed setting. Seven of 20 patients had DLBCL, NOS, 6 of 20 had transformation (t-DLBCL), 3 of 20 had transformed double/triple hit lymphoma (t-DHL/THL), 2 of 20 had double hit lymphoma (DHL), and 2 of 20 had HGBL with intermediate features between DLBCL and Burkitt lymphoma. Nine of 15 patients had MYC translocation. Based on Hans criteria, 11 of 20 had germinal center B-cell (GCB) cell of origin (COO) and 9/20 had non-GCB COO. Five of 11 de novo patients experienced CNS relapse/progression. All de novo patients received anthracycline-based chemoimmunotherapy. Eighteen of 20 patients died of progressive disease. Median overall survival was significantly better in the de novo compared to relapsed group (8.9 months vs. 2.8 months, P = .01). COO, MYC status, DHL/THL status, HGBL subtype, or treatment group did not demonstrate a significant effect on overall survival.L-HGBL carries a poor prognosis and is associated with MYC translocation, DHL/THL status, transformation, and high CNS risk. Novel therapeutic approaches are needed for L-HGBL.

CAR T-cell levels in patients ≥65 years

Tabulated data supporting ZUMA-7 elderly analysis Supplementary Table S1. Patient-reported outcomes instruments Supplementary Table S2. Axi-cel delivery and administration time Supplementary Table S3. Summary of efficacy and safety outcomes in patients ≥65 years versus all patients in ZUMA-7 Supplementary Table S4. Serious adverse events in at least 3 patients in patients ≥65 years Supplementary Table S5. Summary of cytopenias present on or after 90 days from initiation of definitive therapy on protocol in patients ≥65 years Supplementary Table S6. Deaths in axi-cel and SOC arms for patients ≥65 years (safety analysis set) Supplementary Table S7. Summary of serum analytes in patients

Purpose:Older patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) may be considered ineligible for curative-intent therapy including high-dose chemotherapy with autologous stem-cell transplantation (HDT-ASCT). Here, we report outcomes of a preplanned subgroup analysis of patients ≥65 years in ZUMA-7.Patients and Methods:Patients with LBCL refractory to or relapsed ≤12 months after first-line chemoimmunotherapy were randomized 1:1 to axicabtagene ciloleucel [axi-cel; autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy] or standard of care (SOC; 2–3 cycles of chemoimmunotherapy followed by HDT-ASCT). The primary endpoint was event-free survival (EFS). Secondary endpoints included safety and patient-reported outcomes (PROs).Results:Fifty-one and 58 patients aged ≥65 years were randomized to axi-cel and SOC, respectively. Median EFS was greater with axi-cel versus SOC (21.5 vs. 2.5 months; median follow-up: 24.3 months; HR, 0.276; descriptive P < 0.0001). Objective response rate was higher with axi-cel versus SOC (88% vs. 52%; OR, 8.81; descriptive P < 0.0001; complete response rate: 75% vs. 33%). Grade ≥3 adverse events occurred in 94% of axi-cel and 82% of SOC patients. No grade 5 cytokine release syndrome or neurologic events occurred. In the quality-of-life analysis, the mean change in PRO scores from baseline at days 100 and 150 favored axi-cel for EORTC QLQ-C30 Global Health, Physical Functioning, and EQ-5D-5L visual analog scale (descriptive P < 0.05). CAR T-cell expansion and baseline serum inflammatory profile were comparable in patients ≥65 and Conclusions:Axi-cel is an effective second-line curative-intent therapy with a manageable safety profile and improved PROs for patients ≥65 years with R/R LBCL.

Chimeric antigen receptor (CAR) T-cell therapy is effective in relapsed/refractory large B-cell lymphoma and results in a unique toxicity profile, namely cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome. The hyper-inflammatory state associated with these toxicities has been suggested to increase the risk of thrombosis. We conducted a retrospective analysis of patients treated with axicabtagene ciloleucel (axi-cel) to assess the rate of thrombosis with axi-cel therapy from the time of CAR T-cell infusion until the end of hospitalization, when performed in the inpatient setting, or up to day +30 when performed in the outpatient setting. Ninety-two (95%) of 97 patients were hospitalized during axi-cel therapy and 85 (88%) developed CRS. Fifty-five patients (57%) received concurrent anticoagulation (53 as prophylaxis). Patients with prior VTE did not have progression or evidence of new VTE. Only 2 (2.1%) patients developed VTE. These results demonstrate a low-risk for thrombosis in axi-cel recipients.

The phase I/II AU-003 study in patients with treatment-naïve (TN) or relapsed/refractory (R/R) chronic lymphocytic leukaemia/small lymphocytic lymphoma demonstrated that zanubrutinib therapy results in clinically meaningful and durable responses with acceptable safety and tolerability. We report updated safety and efficacy data for 123 patients with a median follow-up of 47·2 months. Patients received zanubrutinib 160 mg twice daily (81 patients), 320 mg once daily (40), or 160 mg once daily (two). Discontinuations due to adverse events or disease progression were uncommon. The overall response rate (ORR) was 95·9% (TN, 100%; R/R, 95%) with 18·7% achieving complete response (CR). Ongoing response at 3 years was reported in 85·7%. The ORR in patients with del(17p)/tumour protein p53 mutation was 87·5% (CR 16·7%). The 2- and 3-year progression-free survival estimates were 90% (TN, 90%; R/R, 91%) and 83% (TN, 81%; R/R, 83%) respectively. The most reported Grade ≥3 adverse events were neutropenia (15·4%), pneumonia (9·8%), hypertension (8·9%) and anaemia (6·5%). The annual incidence of atrial fibrillation, major haemorrhage, Grade ≥3 neutropenia and Grade ≥3 infection decreased over time. With a median follow-up of ~4 years, responses remain clinically meaningful and durable and long-term tolerability to zanubrutinib therapy continues.

How does the brain distinguish between the signals it produces and the sensations it registers from the environment? To shed light on this, it was investigated if the human mind could be capable of perceiving an avatar’s body in a third person game as one’s own. To create precise, high-quality motion simulations, we uniquely combined a Virtual Reality-setup (Valve Index) with real-time motion capture (Vicon). In doing so, we systematically explored if (predictions of) self-actions allow the brain to infer self-location and to distinguish the body from the environment including other agents. A full-body illusion paradigm (FBI) was developed in VR with three movement conditions: (A) a standard, passive FBI in which people had no motion control; (B) an active FBI in which they made simple voluntary movements; and (C) an immersive game in which they real-time controlled a full-sized human avatar in third person (i.e., the first third person VR-game). Systematic comparisons between measures (implicit, explicit, exit-interview, and temporal binding) revealed a causal relationship between (i) sense of agency, (ii) self-other identification, and (iii) the ability to locate oneself. A loss in sense of agency was reported when movement was restricted, and a shift in self-location and self-identification towards the virtual body was experienced; which did not happen when healthy volunteers were (to some extent) able to voluntarily move. It is confirmed that motor predictions are salient cues for the brain that not only provide a sense of control in self-actions, but also recognition of the self in time and place. People can recognise their movements in a third-person avatar and psychologically align with it (action observation); but do not seem to lose a sense of place (self-location), time (temporal binding), nor who they are (self vs. other), because voluntary action codes the bodily self to a physical location in space. These results provide further evidence for our hypothesis (de Boer et al., 2020) and may shed light on how bodily self-consciousness is constructed. In the future, immersive game simulations could target and strengthen the brain’s control networks in psychosis, neurodegeneration (e.g., dementia, movement disorders) and old age. In addition, real-time motion simulations could help advance future rehabilitation techniques (e.g., to treat nervous system injury) by fine-tuning and personalising the therapeutic setting on demand.

Purpose To evaluate how the COVID-19 pandemic affected the imaging utilization patterns for non-COVID-19-related illness in a pediatric emergency department (ED). Methods We retrospectively reviewed radiology reports for ultrasound, CT, MRI, and fluoroscopy studies performed at a pediatric ED in April from 2017 to 2021, excluding studies for respiratory symptoms and trauma. Radiology reports and medical records were reviewed to determine if patients had a positive radiology diagnosis, the type of diagnosis, and whether it required hospital admission. Results from during the pandemic were compared to predicted rates based on pre-pandemic years. Results A total of 2198 imaging studies were included. During the COVID-19 pandemic, fewer ED imaging studies were performed compared to predicted. The decrease was greater in April 2020 (RR = 0.56, p

Recent theories suggest that self-consciousness, in its most elementary form, is functionally disconnected from the phenomenal body. Patients with psychosis frequently misattribute their thoughts and actions to external sources; and in certain out-of-body experiences, lucid states, and dreams body-ownership is absent but self-identification is preserved. To explain these unusual experiences, we hypothesized that self-identification depends on inferring self-location at the right angular gyrus (i.e. perspective-taking). This process relates to the discrimination of self-produced signals (endogenous attention) from environmental stimulation (exogenous attention). Therefore, when this mechanism fails, this causes altered sensations and perceptions. We combined a Full-body Illusion paradigm with brain stimulation (HD-tDCS) and found a clear causal association between right angular gyrus activation and alterations in self-location (perspective-taking). Anodal versus sham HD-tDCS resulted in: a more profound out-of-body shift (with reduced sense of agency); and a weakened ability to discriminate self from other perspectives. We conclude that self-identification is mediated in the brain by inferring self-location (i.e. perspective-taking). Self-identification can be decoupled from the bodily self, explaining phenomena associated with disembodiment. These findings present novel insights into the relationship between mind and body, and may offer important future directions for treating psychosis symptoms and rehabilitation programs to aid in the recovery from a nervous system injury. The brain’s ability to locate itself might be the key mechanism for self-identification and distinguishing self from other signals (i.e. perspective-taking)., SCOPUS: ar.j, info:eu-repo/semantics/published

Intravascular lymphoma (IVL) is a rare extranodal non-Hodgkin lymphoma. We performed a retrospective analysis of 55 IVL patients who were treated at our institution 2003-2018. Median age at diagnosis was 68 years, and 64% were males. The most frequent presenting symptoms were skin rash 43% and weight loss 30%. MRI brain on IVL patients with CNS involvement (CNS-IVL) showed multifocal involvement in 76% (13/17). 89% (17/19) of non-CNS-IVL patients with abnormal FDG-PET had biopsy of an avid lesion resulting in definitive diagnosis. The top diagnostic biopsy site was the bone marrow (45%). 56% had multiorgan involvement. Based on CNS involvement, 36.5% (20/55) had CNS-IVL and 63.5% (35/55) had non-CNS-IVL. CNS-IVL group consists of clinically isolated CNS involvement (CNS-only IVL) (22%;12/55) and mixed clinical CNS and peripheral site involvement (M-IVL) (14.5%; 8/55). Non-CNS-IVL group consists of clinically isolated skin involvement (skin-only IVL) (9%; 5/55) and peripheral IVL with or without skin involvement (P-IVL); (54.5%; 30/55). Skin involvement was predominantly in the lower extremities. Pathologically, 89% (48/54) were B-cell IVL. Rituximab + high-dose methotrexate-based regimen were used in 75% (12/16) of CNS-IVL patients and RCHOP in 60% (17/28) of non-CNS-IVL patients. Estimated 5-year progression free survival (PFS) and overall survival (OS) for the entire cohort were 38.6% and 52%, respectively. Skin-only IVL was associated with excellent survival. Platelet count150x10

Purpose To determine whether diagnostic quality thoracic computed tomography angiography (CTA) studies can be obtained without general anesthesia (GA) in infants and young children using dual-source computed tomography (DSCT) with turbo flash spiral mode (TFSM) and free-breathing technique. Materials and methods All consecutive infants and young children (≤ 6 years old) who underwent thoracic CTA studies from January 2018 to October 2020 for suspected congenital thoracic disorders were categorized into two groups: with GA (Group 1) and without GA (Group 2). All thoracic CTA studies were performed on a DSCT scanner using TFSM and free-breathing technique. Two pediatric thoracic radiologists independently evaluated motion artifact in three lung zones (upper, mid, and lower). Degree of motion artifact was graded 0-3 (0, none; 1, mild; 2, moderate; and 3, severe). Logistic models adjusted for age and gender were used to compare the degree of motion artifact between lung zones. Interobserver agreement between reviewers was evaluated with kappa statistics. Results There were a total of 73 pediatric patients (43 males (59%) and 30 females (41%); mean age, 1.4 years; range, 0-5.9 years). Among these 73 patients, 42 patients (58%) underwent thoracic CTA studies with GA (Group 1) and the remaining 31 patients (42%) underwent thoracic CTA studies without GA (Group 2). Overall, the degree of motion artifact was higher for Group 2 (without GA). However, only a very small minority (1/31, 3%) of Group 2 (without GA) thoracic CTA studies had severe motion artifact. There was no significant difference between the two groups with respect to the presence of severe motion artifact (odds ratio [OR] = 6, p = .222). When two groups were compared with respect to the presence of motion artifact for individual lung zones, motion artifact was significantly higher in the upper lung zone for Group 2 (without GA) (OR = 20, p = .043). Interobserver agreement for motion artifact was high, the average Kappa being 0.81 for Group 1 and 0.95 for Group 2. Conclusion Although the degree of motion artifact was higher in the group without GA, only a small minority (3%) of thoracic CTA studies performed without GA had severe motion artifact, rendering the study nondiagnostic. Therefore, the results of this study support the use of thoracic CTA without GA using DSCT with TFSM and free-breathing in infants and young children. In addition, given that motion artifact was significantly higher in the upper lung zone without GA, increased stabilization in the upper chest and extremities should be considered.

There is a strong need for improvements in motion robust T1-weighted abdominal imaging sequences in children to enable high-quality, free-breathing imaging. To compare imaging time and quality of a radial stack-of-stars, free-breathing T1-weighted gradient echo acquisition (volumetric interpolated breath-hold examination [VIBE]) three-dimensional (3-D) Dixon sequence in sedated pediatric patients undergoing abdominal magnetic resonance imaging (MRI) against conventional Cartesian T1-weighed sequences. This study was approved by the institutional review board with informed consent obtained from all subjects. Study subjects included 31 pediatric patients (19 male, 12 female; median age: 5 years; interquartile range: 5 years) undergoing abdominal MRI at 3 tesla with a free-breathing T1-weighted radial stack-of-stars 3-D VIBE Dixon prototype sequence, StarVIBE Dixon (radial technique), between October 2018 and June 2019 with previous abdominal MR imaging using conventional Cartesian T1-weighed imaging (traditional technique). MRI component times were recorded as well as the total number of non-contrast T1-weighted sequences. Two radiologists independently rated images for quality using a scale from 1 to 5 according to the following metrics: overall image quality, hepatic edge sharpness, hepatic vessel clarity and respiratory motion robustness. Scores were compared between the groups. Mean T1-weighted imaging times for all subjects were 3.63 min for radial exams and 8.01 min for traditional exams (P

To assess the degree of narrowing of the popliteal artery during active ankle plantar flexion in healthy volunteers using a non-contrast quiescent-interval single-shot (QISS) magnetic resonance angiography (MRA) technique. Following IRB approval, 10 healthy volunteers were recruited and following informed consent underwent QISS MRA of the lower extremity at rest and during ankle plantarflexion. Two pediatric musculoskeletal radiologists independently reviewed MR images in random order and recorded a number of subjective and objective anatomic variables including branch pattern, proximity of vessel to bony structures, gastrocnemius bulk, and presence of accessory muscle. Arterial narrowing with plantarflexion was recorded by a subjective assessment of 3D reconstructions (negligible or non-negligible) and objectively by measuring the narrowest diameter during plantarflexion and at rest. Agreement between reader scores was assessed using the concordance correlation coefficient (CCC) for continuous variables, and kappa and the proportion of agreement for categorical variables. Mean reduction in arterial diameter during plantar flexion was 17.1% (min 1.9%, max 64.1%, SD 16.7%) for reader 1 and 17.2% (min 1.7%, max 50.0%, SD 14.3%.) for reader 2 with high agreement between readers: CCC = 0.92 and CI = 0.82, 0.96. Arterial narrowing was described subjectively as “non-negligible” in 7/20 legs by reader 1 and 5/20 legs by reader 2 with proportion of agreement = 0.90, CI (0.77, 1.00). We observed a wide range of popliteal arterial narrowing with plantarflexion in asymptomatic volunteers. Larger studies, for which QISS is well suited, may be invaluable for distinguishing physiologic from pathologic arterial narrowing in patients with suspected popliteal artery entrapment syndrome (PAES).

OBJECTIVE. The purpose of this study was to compare radiology trainees' perceptions of the culture regarding speaking up about patient safety and unprofessional behavior in the clinical environment and to assess the likelihood that they will speak up in the presence of a medical hierarchy. MATERIALS AND METHODS. The study included radiology trainees from nine hospitals who attended a communication workshop. Trainees completed questionnaires assessing their perceptions of the support provided by their clinical environment regarding speaking up about patient safety and unprofessional behavior. We also queried their likelihood of speaking up within a team hierarchy about an error presented in a hypothetical clinical vignette. RESULTS. Of 61 participants, 58 (95%) completed questionnaires. Of these 58 participants, 84% felt encouraged by colleagues to speak up about safety concerns, and 57% felt encouraged to speak up about unprofessional behavior (p < .001). Moreover, 17% and 34% thought speaking up about safety concerns and unprofessional behavior, respectively, was difficult (p < .02). Trainees were less likely to agree that speaking up about unprofessional behavior (compared with speaking up about safety concerns) resulted in meaningful change (66% vs 95%; p < .001). In a vignette describing a sterile technique error, respondents were less likely to speak up to an attending radiologist (48%) versus a nurse, intern, or resident (79%, 84%, and 81%, respectively; p < .001). Significant predictors of the likelihood of trainees speaking up to an attending radiologist included perceived potential for patient harm as a result of the error (odds ratio [OR], 6.7; p < .001), perceptions of safety culture in the clinical environment (OR, 5.0; p = .03), and race or ethnicity (OR, 3.1; p = .03). CONCLUSION. Radiology trainees indicate gaps in workplace cultures regarding speaking up, particularly concerning unprofessional behavior and team hierarchy.

The prospective identification of children likely to develop schizophrenia is a vital tool to support early interventions that can mitigate the risk of progression to clinical psychosis. Electroencephalographic (EEG) patterns from brain activity and deep learning techniques are valuable resources in achieving this identification. We propose automated techniques that can process raw EEG waveforms to identify children who may have an increased risk of schizophrenia compared to typically developing children. We also analyse abnormal features that remain during developmental follow-up over a period of $\sim$ 4 years in children with a vulnerability to schizophrenia initially assessed when aged 9 to 12 years. EEG data from participants were captured during the recording of a passive auditory oddball paradigm. We undertake a holistic study to identify brain abnormalities, first by exploring traditional machine learning algorithms using classification methods applied to hand-engineered features (event-related potential components). Then, we compare the performance of these methods with end-to-end deep learning techniques applied to raw data. We demonstrate via average cross-validation performance measures that recurrent deep convolutional neural networks can outperform traditional machine learning methods for sequence modeling. We illustrate the intuitive salient information of the model with the location of the most relevant attributes of a post-stimulus window. This baseline identification system in the area of mental illness supports the evidence of developmental and disease effects in a pre-prodromal phase of psychosis. These results reinforce the benefits of deep learning to support psychiatric classification and neuroscientific research more broadly.

Individual differences in the ability to habitually regulate emotion may impact the efficacy of fear memory extinction. The aim of this study was to assess the relationship between dispositional cognitive reappraisal and expressive suppression with post-retrieval and standard extinction. Fear memory and extinction were measured with the recovery of skin conductance responses. We also examined the relationship between a temporal feature of electrodermal responding (half-recovery time) and each of the emotion regulation strategies. University students (N = 80) underwent a three-day fear conditioning procedure using a within-subject design consisting of acquisition on day one, post-retrieval extinction and standard extinction on day two, and recovery test on day three. Individual difference data on self-reported levels of cognitive reappraisal, expressive suppression, trait anxiety, and depression were collected. We did not detect a relationship between the two emotion regulation strategies measured in this study and acquisition or extinction. We found, however, that increased dispositional use of cognitive reappraisal was associated with lower spontaneous recovery to both the post-retrieval extinction and standard extinction stimulus after controlling for age, trait anxiety, and depression. There were no associations between expressive suppression and conditioned responses. We also observed patterns of faster dissipation of arousal for reappraisal and slower for suppression to the conditioned stimulus during extinction training, which may represent the unique influence of each emotion strategy on the regulation of fear. We conclude greater daily use of cognitive reappraisal, but not expressive suppression, associates with extinction retention after receiving both standard and post-retrieval extinction.

Background: Poor mental health reduces children’s ability to function at school, which in turn may undermine their mental health. The provision of school-based counselling aims to help schools to support their pupil’s mental health. Most work on the types of difficulties brought to school counsellors has focused on secondary school pupils (aged 11 years or over) and to our knowledge, this is the first study of presenting issues in younger children. Method: Data were systematically collected using a list of 21 potential presenting issues during assessment and formulation of 8,893 children referred for counselling in 291 UK primary schools over 3 years. We explored the number, severity and types of presenting issues recorded by counsellors in the whole sample by gender. Results: The children assessed by counsellors had higher levels of known correlates for poor mental health than their peers in the same schools. Most children had multiple presenting issues, while 55% of children had at least one severe presenting issue. The commonest presenting issues were generalised anxiety, low self-esteem, family tensions and mood swings. Girls were more likely to present with all types of anxiety and family tensions, while attentional problems and mood swings were commoner among boys. Conclusions: Children referred for counselling in primary schools often present with multiple difficulties, which are often severe. This indicates the need for systematic and detailed assessment, adequate training and supervision and good links with external agencies.

In the domain of machine learning, Neural Memory Networks (NMNs) have recently achieved impressive results in a variety of application areas including visual question answering, trajectory prediction, object tracking, and language modelling. However, we observe that the attention based knowledge retrieval mechanisms used in current NMNs restrict them from achieving their full potential as the attention process retrieves information based on a set of static connection weights. This is suboptimal in a setting where there are vast differences among samples in the data domain; such as anomaly detection where there is no consistent criteria for what constitutes an anomaly. In this paper, we propose a plastic neural memory access mechanism which exploits both static and dynamic connection weights in the memory read, write and output generation procedures. We demonstrate the effectiveness and flexibility of the proposed memory model in three challenging anomaly detection tasks in the medical domain: abnormal EEG identification, MRI tumour type classification and schizophrenia risk detection in children. In all settings, the proposed approach outperforms the current state-of-the-art. Furthermore, we perform an in-depth analysis demonstrating the utility of neural plasticity for the knowledge retrieval process and provide evidence on how the proposed memory model generates sparse yet informative memory outputs. Funding acknowledgement: QUT Project ID 2018001348 (ARC Future Fellowship FT170100294)

Hutchinson-Gilford progeria syndrome (termed progeria in this Article) is a rare sporadic genetic disorder. One early clinical manifestation of progeria is abnormal skeletal growth, yet this growth has not been fully characterised. We aimed to characterise the skeletal maturation and long-bone growth patterns of patients with the clinical phenotype of progeria.For this retrospective study, we reviewed skeletal surveys of patients (aged20 years) with progeria obtained over a 9·5-year period. Most surveys included radiographs of the hands and long bones (humeri, radii, ulnas, tibias, and fibulas). Bone ages of these patients were estimated by the standards of Greulich and Pyle. Following the established methods for studying long-bone growth, the study cohort was separated into two overlapping age groups: longitudinal bone length measurements were made between physes for the childhood group (aged 12 years or younger) and from the upper margins of the proximal to the lower margin of the distal ossified epiphyses for the adolescent group (aged 10 years or older). Bone age estimates and bone length measurements were plotted against the chronological age of patients and compared with reference standards. Statistical analyses were based on mixed models.85 patients with progeria and 250 skeletal surveys were included in our study. For both sexes, bone age estimates showed a more advanced skeletal maturation rate throughout all chronological ages than the normal rate of 1 (p0·0001), with the rate of maturation being 1·09 (SE 0·02) for boys and 1·14 (0·02) for girls. Longitudinal long-bone lengths began to deviate from normal standards by age 1-2 years. Growth curves for these long bones plateaued at about half the normal eventual bone length, and the half-life (the time taken to grow to half the eventual bone length) was also about half the time compared with normal standards.Our study established growth curves that might serve as reference standards for skeletal maturation and long-bone growth of patients with the clinical phenotype of progeria.The Progeria Research Foundation, the US National Heart, Lung and Blood Institute, the Dana-Farber Cancer Institute StopShop Pediatric Brain Tumor Program, the US National Center for Research Resources, US National Institutes of Health.

TPS777 Background: Pancreatic ductal adenocarcinoma (PDAC) is 3% of cancers diagnosed in the United States and it is the fourth leading cause of cancer-related deaths. Hence, there is a considerable clinical need to develop innovative strategies for effective drug delivery and treatment. Sonoporation is a novel method that can enhance the therapeutic efficacy of co-administered chemotherapy by localized contrast-enhanced ultrasound imaging (CEUS) of gas-filled microbubbles (ultrasound contrast agent UCA), which temporarily changes tumor vascular microenvironment by increasing angiogenic vessel leakage through microstreaming, shockwaves and the activation of various intracellular signaling responses. Our Phase I clinical trial of sonoporation in 10 PDAC patients treated with Gemcitabine demonstrated no additional toxicity and an increase in median survival compared to 63 historical controls (8.9 vs 17.6 months; p = 0.011). Animal studies investigated 4 commercial UCAs under 2 different acoustic regimes and established the optimal UCA (Sonazoid, GE Healthcare, Oslo, Norway) as well as acoustic settings for sonoporation of PDAC. Methods: This Phase II clinical trial aims to improve standard of care (SoC) chemotherapy treatment by adding sonoporation (i.e., augmenting the SoC treatment with CEUS and microbubbles). Two sites (one in USA and one in Norway) will enroll 120 subjects with PDAC stage III or IIV prior to starting SoC chemotherapy. Exclusion criteria include known allergies to the UCA. The primary objective is to evaluate the safety and therapeutic efficacy of sonoporation on PDAC SoC treatment based on local progression-free and overall survival. Two groups: SoC chemotherapy or SoC chemotherapy followed by sonoporation. The optimal CEUS and microbubble conditions will be applied to a single PDAC tumor imaged by ultrasound. Treatment delivered day of SoC chemotherapeutic treatment for PDAC when the concentration of drugs is maximum. Gehan-Breslow-Wilcoxon test and Log-rank test will be used to compare survival. All clinical variables (e.g., concomitant imaging results, blood tests, etc.) will also be compared between groups with and without sonoporation. Clinical trial information: NCT04821284 .

Identifying the faces of familiar persons requires the ability to assign several different images of a face to a common identity. Previous research showed that the occipito-temporal cortex, including the fusiform and the occipital face areas, is sensitive to personal identity. Still, the viewpoint, facial expression and image-independence of this information are currently under heavy debate. Here we adapted a rapid serial visual stimulation paradigm Johnston et al. (2016, https://doi.org/10.1016/j.cortex.2016.10.002) and presented highly variable ambient-face images of famous persons to measure functional magnetic resonance imaging (fMRI) adaptation. fMRI adaptation is considered as the neuroimaging manifestation of repetition suppression, a neural phenomenon currently explained as a correlate of reduced predictive error responses for expected stimuli. We revisited the question of image-invariant identity-specific encoding mechanisms of the occipito-temporal cortex, using fMRI adaptation with a particular interest in predictive mechanisms. Participants were presented with trials containing eight different images of a famous person, images of eight different famous persons or seven different images of a particular famous person followed by an identity change to violate potential expectation effects about person identity. We found an image-independent adaptation effect of identity for famous faces in the fusiform face area. However, in contrast to previous electrophysiological studies, using similar paradigms, no release of the adaptation effect was observed when identity-specific expectations were violated. Our results support recent multivariate pattern analysis studies, showing image-independent identity encoding in the core face-processing areas of the occipito-temporal cortex. These results are discussed in the frame of recent identity-processing models and predictive mechanisms.

Outcomes for marginal zone lymphoma (MZL) and follicular lymphoma (FL) remain suboptimal, owing to the limited number of approved agents and the incurable nature of the diseases. BGB-3111-AU-003 was a phase 1/2, open-label, multicenter, single-agent study of the selective Bruton’s tyrosine kinase inhibitor zanubrutinib in 385 patients with B-cell malignancies. Here, we present safety and efficacy outcomes for the 53 enrolled patients with relapsed/refractory MZL (n = 20) and relapsed/refractory FL (n = 33), all of whom were enrolled during the part 2 dose expansion, and therefore received zanubrutinib at the recommended phase 2 dose. Treatment with zanubrutinib was generally well tolerated, with most adverse events being ≤ grade 2. Atrial fibrillation/flutter was not reported. Two patients required dose reduction, and 4 patients discontinued treatment because of adverse events. Response was assessed by an independent review committee for MZL and the investigators for FL, per Lugano 2014 classification for non-Hodgkin lymphoma. In patients with MZL, the overall response rate (ORR) was 80%, and the complete response (CR) rate was 20%. With median follow-up of 33.8 months, median progression-free survival (PFS) was not reached. In patients with FL, the ORR was 36.4%, and the CR rate was 18.2%. After a median follow-up of 33.9 months, median PFS was 10.4 months. In conclusion, the results of this study suggest a favorable benefit–risk profile and support zanubrutinib as a potentially meaningful addition to available therapies for patients with relapsed/refractory MZL and FL. This trial was registered at www.clinicaltrials.gov as #NCT02343120.

During visual perception, the brain must combine its predictions about what is to be perceived with incoming relevant information. The present study investigated how this process interacts with attention by using event-related potentials that index these cognitive mechanisms. Specifically, this study focused on examining how the amplitudes of the N170, N2pc, and N300 would be modulated by violations of expectations for spatial and featural attributes of visual stimuli. Participants viewed a series of shape stimuli in which a salient shape moved across a set of circular locations so that the trajectory of the shape implied the final position and shape of the stimulus. The final salient stimuli occurred in one of four possible outcomes: predictable position and shape, predictable position but unpredictable shape, unpredictable position but predictable shape, and unpredictable position and shape. The N170 was enhanced by unpredictable positions and shapes, whereas the N300 was enlarged only by unpredictable positions. The N2pc was not modulated by violations of expectations for shapes or positions. Additionally, it was observed post-hoc that the P1pc amplitude was increased by unpredictable shapes. These findings revealed that incorrect prediction increases neural activity. Furthermore, they suggest that prediction and attention interact differently in different stages of visual perception, depending on the type of attention being engaged: The N170 indexes initial prediction error signalling irrespective of the type of information (spatial or featural) in which error occurs, followed by the N300 as a marker of prediction updating involving reorientation of spatial attention.

Background: Carpal tunnel syndrome (CTS) is one of the most common diagnoses in a hand surgeon’s office, with estimated cost exceeding US $2 billion annually in the United States. Due to this prevalence and cost, patients often turn to the Internet for their medical care. It has been estimated that 72% of Internet users have looked online for health information in the last year. There is concern that patients may be getting misinformation with their Internet medical searches. Methods: An informal survey of the Internet was conducted to evaluate the content available to the public on the Internet and social media platforms regarding the diagnosis and treatment of CTS. The top 20 listings of 3 major search engines and information within 3 major social media sites were included. Results: Information gleaned from the search showed that while most listings were helpful in providing accurate diagnostic information and appropriate treatment modalities, there was also a great number of treatment modalities mentioned that may not be recommended by the treating physician. The guidelines established by the American Academy of Orthopaedic Surgeons both in 2007 and in 2008 and more recently in 2016 were used as a general reference but not directly compared with the informal Internet search for statistical analysis. Conclusions: This search outlines the importance of the information readily available to patients and how this may potentially alter patients’ expectations prior to their arrival in the office.

The classic metaphyseal lesion (CML) is a strong indicator of infant abuse, and the distal tibia is one of the most common sites for this injury. To determine the prevalence of subperiosteal new bone formation accompanying the distal tibial CMLs identified on infant skeletal surveys. Skeletal surveys performed for suspected infant abuse (2005–2017) were reviewed. Inclusion criteria were 1) anteroposterior (AP) and lateral radiographs of a distal tibial CML from the initial survey, 2) AP radiograph from the 2-week follow-up survey, 3) additional fractures, 4) child protection team consults and 5) mandated report filing for suspected abuse. We identified 22 distal tibial CMLs from 16 infants. Radiographs of these lesions were shown on the picture archiving and communication system to two blinded pediatric radiologists. Readers indicated the presence/absence of subperiosteal new bone formation on individual and combinations of images. Inter-reader agreements were fair (kappa=0.47). The prevalence of subperiosteal new bone formation on initial AP radiograph was 34%. Significant increases in the prevalence were found with the addition of follow-up AP radiograph (57%; P

5082 Background: Immunotherapy has limited efficacy in castration-resistant prostate cancer. Androgen deprivation therapy (ADT) has significant immunomodulatory effects and initially induces a complex immune infiltrate before castration-resistance develops. However, ADT also recruits immunosuppressive myeloid cells to the tumor microenvironment by increasing interleukin-8 (IL-8). We conducted a phase Ib/II clinical trial of immunotherapy plus ADT in men with recurrent castration-sensitive prostate cancer (CSPC). We hypothesized that anti-PD-1 (nivolumab) +/- anti-IL-8 (BMS-986253) given at the time of castration could induce anti-tumor immune responses and decrease disease progression. Methods: MAGIC-8 was a multicenter, phase Ib/II study evaluating nivolumab +/- BMS-986253 combined with a short course of degarelix acetate in patients with recurrent CSPC and rapid PSA doubling time (≤ 12 mos). In the Phase Ib portion, patients were treated with nivolumab (480mg Q4W) for 8 wks followed by nivolumab plus degarelix for an additional 16 wks. In the phase II portion, patients were randomized 1:2 to nivolumab + degarelix (Arm A) versus nivolumab + BMS-986253 (2400mg Q2W) + degarelix (Arm B). The primary endpoints were PSA recurrence at 10 mos following randomization and safety. Key secondary endpoints included biochemical recurrence-free survival (bPFS), time to recovery of testosterone (> 150ng/dl), and bPFS after recovery of testosterone. Results: Between October 16, 2019 and March 9, 2021, 59 patients were enrolled. The first 15 patients were treated on Arm A followed by 1:2 randomization to Arm A (N = 15) versus Arm B (N = 29). Median follow up was 11.6 mos at the data cutoff (1/24/22). Patients treated on Arm A had a significantly lower rate of PSA relapse (17.39%) at 10 mos compared to historical controls (p = < 0.001), including a subgroup of patients (6.67%) with recovery of testosterone and no PSA relapse at > 2 years of follow up. Median time-to-recovery of testosterone was 12.7 mos, median bPFS was 14.0 mos and median bPFS after recovery of testosterone was 5.5 mos. In Arm B, there was no difference in PSA relapse at 10 mos (35%, p = 0.09), median time-to-recovery of testosterone, median bPFS and median bPFS after recovery of testosterone compared to historical controls. Treatment in both arms was well tolerated with a lower rate of grade 3-4 treatment-related adverse events in Arm B compared to Arm A (3.5% vs 12.9%). Conclusions: A short course of ADT plus nivolumab may decrease the rate of PSA relapse and lead to durable long-term responses after recovery of testosterone in a subset of patients. These data support further evaluation of combining nivolumab with ADT in CSPC. Although the addition of BMS-986253 did not improve rate of PSA relapse, we observed significantly less toxicity with the addition of IL-8 inhibition. Clinical trial information: NCT03689699.

Face Inversion Effects (FIEs) – differences in response to upside down faces compared to upright faces – occur for both behavioural and electrophysiological responses when people view face stimuli. In EEG, the inversion of a face is often reported to evoke an enhanced amplitude and delayed latency of the N170 event-related potential. This response has historically been attributed to the indexing of specialised face processing mechanisms within the brain. However, inspection of the literature revealed that while the N170 is consistently delayed to photographed, schematic, Mooney and line drawn face stimuli, only naturally photographed faces enhance the amplitude upon inversion. This raises the possibility that the increased N170 amplitudes to inverted faces may have other origins than the inversion of the face’s structural components. In line with previous research establishing the N170 as a prediction error signal, we hypothesise that the unique N170 amplitude response to inverted photographed faces stems from multiple expectation violations, over and above structural inversion. For instance, rotating an image of a face upside down not only violates the expectation that faces appear upright, but also lifelong priors that illumination comes from above and gravity pulls from below. To test this hypothesis, we recorded EEG whilst participants viewed face stimuli (upright versus inverted), where the faces were illuminated from above versus below, and where the models were photographed upright versus hanging upside down. The N170 amplitudes were found to be modulated by a complex interaction between orientation, lighting and gravity factors, with the amplitudes largest when faces consistently violated all three expectations and smallest when all these factors concurred with expectations. These results confirm our hypothesis that FIEs on N170 amplitudes are driven by a violation of the viewer’s expectations across several parameters that characterise faces, rather than a disruption in the configurational disposition of its features.

To assess the degree of narrowing of the popliteal artery during active ankle plantar flexion in healthy volunteers using a non-contrast quiescent-interval single-shot (QISS) magnetic resonance angiography (MRA) technique.Following IRB approval, 10 healthy volunteers were recruited and following informed consent underwent QISS MRA of the lower extremity at rest and during ankle plantarflexion. Two pediatric musculoskeletal radiologists independently reviewed MR images in random order and recorded a number of subjective and objective anatomic variables including branch pattern, proximity of vessel to bony structures, gastrocnemius bulk, and presence of accessory muscle. Arterial narrowing with plantarflexion was recorded by a subjective assessment of 3D reconstructions (negligible or non-negligible) and objectively by measuring the narrowest diameter during plantarflexion and at rest. Agreement between reader scores was assessed using the concordance correlation coefficient (CCC) for continuous variables, and kappa and the proportion of agreement for categorical variables.Mean reduction in arterial diameter during plantar flexion was 17.1% (min 1.9%, max 64.1%, SD 16.7%) for reader 1 and 17.2% (min 1.7%, max 50.0%, SD 14.3%.) for reader 2 with high agreement between readers: CCC = 0.92 and CI = 0.82, 0.96. Arterial narrowing was described subjectively as "non-negligible" in 7/20 legs by reader 1 and 5/20 legs by reader 2 with proportion of agreement = 0.90, CI (0.77, 1.00).We observed a wide range of popliteal arterial narrowing with plantarflexion in asymptomatic volunteers. Larger studies, for which QISS is well suited, may be invaluable for distinguishing physiologic from pathologic arterial narrowing in patients with suspected popliteal artery entrapment syndrome (PAES).