Efficacy and tolerability of Brivaracetam in people with intellectual disability compared to those without intellectual disability.

INTRODUCTION: In England, nearly a quarter of people with intellectual disability (PwID) have epilepsy. Though 70 % of PwID have pharmaco-resistant seizures only 10 % are prescribed anti-seizure medication (ASMs) licenced for pharmaco-resistance. Brivaracetam (BRV) licenced in 2016 has had nine post-marketing studies involving PwID. These studies are limited either by lack of controls or not looking at outcomes based on differing levels of ID severity. This study looks at evidence comparing effectiveness and side-effects in PwID to those without ID prescribed Brivaracetam (BRV). METHODS: Pooled case note data for patients prescribed BRV (2016-2022) at 12 UK NHS Trusts were analysed. Demographics, starting and maximum dose, side-effects, dropouts and seizure frequency between ID (mild vs. moderate-profound (M/P)) and general population for a 12-month period were compared. Descriptive analysis, Mann-Whitney, Fisher's exact and logistic regression methods were employed. RESULTS: 37 PwID (mild 17 M/P 20) were compared to 102 without ID. Mean start and maximum dose was lower for PwID than non-ID. Mean maximum dose reduced slightly with ID severity. No difference was found between ID and non-ID or between ID groups (Mild vs M/P) in BRV's efficacy i.e. >50 % seizure reduction or tolerability. Mental and behavioural side-effects were more prevalent for PwID (27.0 % ID, 17.6 % no ID) but not significantly higher (P = 0.441) or associated with ID severity (p = 0.255). CONCLUSION: This is the first study on BRV, which compares ID cohorts with differing severity and non-ID. Efficacy, tolerability and side-effects reported are similar across differing ID severity to those with no ID.

Toward Precision Diagnosis: Machine Learning in Identifying Malignant Orbital Tumors With Multiparametric 3 T MRI.

BACKGROUND: Orbital tumors present a diagnostic challenge due to their varied locations and histopathological differences. Although recent advancements in imaging have improved diagnosis, classification remains a challenge. The integration of artificial intelligence in radiology and ophthalmology has demonstrated promising outcomes. PURPOSE: This study aimed to evaluate the performance of machine learning models in accurately distinguishing malignant orbital tumors from benign ones using multiparametric 3 T magnetic resonance imaging (MRI) data. MATERIALS AND METHODS: In this single-center prospective study, patients with orbital masses underwent presurgery 3 T MRI scans between December 2015 and May 2021. The MRI protocol comprised multiparametric imaging including dynamic contrast-enhanced (DCE), diffusion-weighted imaging (DWI), intravoxel incoherent motion (IVIM), as well as morphological imaging acquisitions. A repeated nested cross-validation strategy using random forest classifiers was used for model training and evaluation, considering 8 combinations of explanatory features. Shapley additive explanations (SHAP) values were used to assess feature contributions, and the model performance was evaluated using multiple metrics. RESULTS: One hundred thirteen patients were analyzed (57/113 [50.4%] were women; average age was 51.5 ± 17.5 years, range: 19-88 years). Among the 8 combinations of explanatory features assessed, the performance on predicting malignancy when using the most comprehensive model, which is the most exhaustive one incorporating all 46 explanatory features-including morphology, DWI, DCE, and IVIM, achieved an area under the curve of 0.9 [0.73-0.99]. When using the streamlined "10-feature signature" model, performance reached an area under the curve of 0.88 [0.71-0.99]. Random forest feature importance graphs measured by the mean of SHAP values pinpointed the 10 most impactful features, which comprised 3 quantitative IVIM features, 4 quantitative DCE features, 1 quantitative DWI feature, 1 qualitative DWI feature, and age. CONCLUSIONS: Our findings demonstrate that a machine learning approach, integrating multiparametric MRI data such as DCE, DWI, IVIM, and morphological imaging, offers high-performing models for differentiating malignant from benign orbital tumors. The streamlined 10-feature signature, with a performance close to the comprehensive model, may be more suitable for clinical application.

Diagnostic Performance of Dynamic Contrast-Enhanced 3T MR Imaging for Characterization of Orbital Lesions: Validation in a Large Prospective Study.

BACKGROUND AND PURPOSE: Orbital lesions are rare but serious. Their characterization remains challenging. Diagnosis is based on biopsy or surgery, which implies functional risks. It is necessary to develop noninvasive diagnostic tools. The goal of this study was to evaluate the diagnostic performance of dynamic contrast-enhanced MR imaging at 3T when distinguishing malignant from benign orbital tumors on a large prospective cohort. MATERIALS AND METHODS: This institutional review board-approved prospective single-center study enrolled participants presenting with an orbital lesion undergoing a 3T MR imaging before surgery from December 2015 to May 2021. Morphologic, diffusion-weighted, and dynamic contrast-enhanced MR images were assessed by 2 readers blinded to all data. Univariable and multivariable analyses were performed. To assess diagnostic performance, we used the following metrics: area under the curve, sensitivity, and specificity. Histologic analysis, obtained through biopsy or surgery, served as the criterion standard for determining the benign or malignant status of the tumor. RESULTS: One hundred thirty-one subjects (66/131 [50%] women and 65/131 [50%] men; mean age, 52 [SD, 17.1] years; range, 19-88 years) were enrolled. Ninety of 131 (69%) had a benign lesion, and 41/131 (31%) had a malignant lesion. Univariable analysis showed a higher median of transfer constant from blood plasma to the interstitial environment (K trans) and of transfer constant from the interstitial environment to the blood plasma (minute-1) (Kep) and a higher interquartile range of K trans in malignant-versus-benign lesions (1.1 minute-1 versus 0.65 minute-1, P = .03; 2.1 minute-1 versus 1.1 minute-1, P = .01; 0.81 minute-1 versus 0.65 minute-1, P = .009, respectively). The best-performing multivariable model in distinguishing malignant-versus-benign lesions included parameters from dynamic contrast-enhanced imaging, ADC, and morphology and reached an area under the curve of 0.81 (95% CI, 0.67-0.96), a sensitivity of 0.82 (95% CI, 0.55-1), and a specificity of 0.81 (95% CI, 0.65-0.96). CONCLUSIONS: Dynamic contrast-enhanced MR imaging at 3T appears valuable when characterizing orbital lesions and provides complementary information to morphologic imaging and DWI.

Identification of hippocampal area CA2 in hamster and vole brain.

Prairie voles (Microtus ochrogaster) and Syrian, or golden, hamsters (Mesocricetus auratus) are closely related to mice (Mus musculus) and are commonly used in studies of social behavior including social interaction, social memory, and aggression. Hippocampal area CA2 is known to play a key role in these behaviors in mice and responds to social stimuli in rats, but CA2 has yet to be characterized in hamsters or voles, which are also used in studies of social behaviors. Here, we used immunofluorescence to determine whether CA2 could be molecularly identified in tissue from voles and hamsters. We found that  staining for many CA2 markers was similar in these three species, with labeling seen in neurons at the distal end of the mossy fibers . In contrast, although perineuronal nets (PNNs) surround CA2 cells in mice, PNN staining differed across species. In voles, both CA2 and CA3 were labeled, whereas in hamsters, labeling was seen primarily in CA3. These results demonstrate that CA2 can be molecularly distinguished from neighboring CA1 and CA3 areas in voles and hamsters with several antibodies commonly used in mice. However, PNN staining is not useful for identifying CA2 in voles or hamsters, suggestive of differing roles for either PNNs or for the hippocampal subregions in social behavior. These findings reveal commonalities across species in the molecular profile of CA2 and should facilitate future studies of CA2 in these species.

Identification of hippocampal area CA2 in hamster and vole brain.

Prairie voles (Microtus ochrogaster) and Syrian, or golden, hamsters (Mesocricetus auratus) are closely related to mice (Mus musculus) and rats (Rattus norvegicus, for example) and are commonly used in studies of social behavior including social interaction, social memory, and aggression. The CA2 region of the hippocampus is known to play a key role in social memory and aggression in mice and responds to social stimuli in rats, likely owing to its high expression of oxytocin and vasopressin 1b receptors. However, CA2 has yet to be identified and characterized in hamsters or voles. In this study, we sought to determine whether CA2 could be identified molecularly in vole and hamster. To do this, we used immunofluorescence with primary antibodies raised against known molecular markers of CA2 in mice and rats to stain hippocampal sections from voles and hamsters in parallel with those from mice. Here, we report that, like in mouse and rat, staining for many CA2 proteins in vole and hamster hippocampus reveals a population of neurons that express regulator of G protein signaling 14 (RGS14), Purkinje cell protein 4 (PCP4) and striatal-enriched protein tyrosine phosphatase (STEP), which together delineate the borders with CA3 and CA1. These cells were located at the distal end of the mossy fiber projections, marked by the presence of Zinc Transporter 3 (ZnT-3) and calbindin in all three species. In addition to staining the mossy fibers, calbindin also labeled a layer of CA1 pyramidal cells in mouse and hamster but not in vole. However, Wolframin ER transmembrane glycoprotein (WFS1) immunofluorescence, which marks all CA1 neurons, was present in all three species and abutted the distal end of CA2, marked by RGS14 immunofluorescence. Staining for two stress hormone receptors-the glucocorticoid (GR) and mineralocorticoid (MR) receptors-was also similar in all three species, with GR staining found primarily in CA1 and MR staining enriched in CA2. Interestingly, although perineuronal nets (PNNs) are known to surround CA2 cells in mouse and rat, we found that staining for PNNs differed across species in that both CA2 and CA3 showed staining in voles and primarily CA3 in hamsters with only some neurons in proximal CA2 showing staining. These results demonstrate that, like in mouse, CA2 in voles and hamsters can be molecularly distinguished from neighboring CA1 and CA3 areas, but PNN staining is less useful for identifying CA2 in the latter two species. These findings reveal commonalities across species in molecular profile of CA2, which will facilitate future studies of CA2 in these species. Yet to be determined is how differences in PNNs might relate to differences in social behavior across species.

Sex-dependent regulation of social avoidance by oxytocin signaling in the ventral tegmental area.

It has been hypothesized that oxytocin increases the salience of social stimuli, whether the valence is positive or negative, through its interactions with the ventral tegmental area (VTA). Indeed, oxytocin neurons project to the VTA and activate dopamine neurons that are necessary for social experiences with positive valence. Surprisingly, though, there has not been an investigation of the role of oxytocin in the VTA in mediating social experiences with negative valence (e.g., social stress). Given that there are sex differences in how oxytocin regulates the salience of positively-valenced social interactions, we hypothesized that oxytocin acting in the VTA also alters the salience of social stress in a sex-dependent manner. To test this, female and male Syrian hamsters were site-specifically infused with either saline, oxytocin (9 µM), or oxytocin receptor antagonist (90 µM) into the VTA. Subjects were then exposed to either no defeat or a single, 15 min defeat by one RA. The day following social defeat, subjects underwent a 5 min social avoidance test. There was an interaction between sex and drug treatment, such that the oxytocin antagonist increased social avoidance compared to saline treatment in socially stressed females, while oxytocin decreased social avoidance compared to saline treatment in socially stressed males. Contrary to expectations, these results suggest that oxytocin signaling generally acts to decrease social avoidance, regardless of sex. These sex differences in the efficacy of oxytocin and oxytocin receptor antagonists to alter negatively-valenced social stimuli, however, should be considered when guiding pharmacotherapies for disorders involving social deficits.

Overall survival and treatment modalities in pancreatic adenocarcinoma: a retrospective analysis of a single centre in Western Australia.

Background: Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of approximately 10.7% in Australia. It is becoming an increasingly common cause of cancer mortality. The therapeutic model for PDAC remains limited, especially for those with metastatic disease on presentation. Methods: We completed a retrospective cohort study including all patients with PDAC presenting between April 2008 and October 2021 to St. John of God Subiaco Hospital in Western Australia. Overall survival (OS) was calculated via Kaplan-Meier method. Results: We identified 251 patients treated for PDAC. Of these, 134 patients (53%) had resectable, borderline resectable or locally advanced (LA) disease at diagnosis and 117 patients (47%) had metastatic disease. The median age of all patients was 66 years (range, 25-87 years). OS in PDAC was 26 months [95% confidence interval (CI): 23-30]. In the non-metastatic group OS was 34 months (95% CI: 30-39). In the metastatic group OS was 19 months (95% CI: 14-22). Treatment modalities varied between patients. Overall 123 patients were treated with chemotherapy alone, 55 patients had chemoradiotherapy, 34 patients had chemotherapy and surgery and 37 had tri-modality treatment including chemotherapy, surgery and radiotherapy. Two patients received cyberknife radiation alone. Conclusions: This retrospective study shows a significant prolonged survival for PDAC patients. Further studies are needed to validate second- and third-line regimens in PDAC.

Risk factors for traumatic bonding and associations with PTSD symptoms: A moderated mediation.

BACKGROUND: Traumatic bonding, defined as attachment to a perpetrator of intimate partner violence (IPV), offers one explanation as to why many people with abusive romantic partners do not break off these relationships. But what individual-level risk factors make some victims of IPV more likely than others to develop traumatic bonding toward their partners? What is the nature of the potential association between traumatic bonding and PTSD symptoms? PARTICIPANTS: A path model tested the potential roles of childhood maltreatment and attachment insecurity as risk factors for traumatic bonding, as well as the potential association between traumatic bonding and PTSD symptoms, in a high-risk sample of 354 participants in current abusive relationships. RESULTS: As hypothesized, childhood maltreatment and attachment insecurity significantly predicted traumatic bonding over and above the effects of age, gender, and romantic love. In addition, attachment insecurity moderated the association between childhood maltreatment and traumatic bonding, such that at higher levels of attachment insecurity, the association between childhood maltreatment and traumatic bonding was stronger than at mean or lower levels of attachment insecurity. Traumatic bonding was positively associated with PTSD symptoms. CONCLUSIONS: Overall, the results support the role of childhood maltreatment as a risk factor for both traumatic bonding and PTSD symptoms and highlight the importance of attachment insecurity in these associations. This was the first study to examine a complex model of risk factors for traumatic bonding. Theoretical and clinical implications are discussed.

Perineuronal net degradation rescues CA2 plasticity in a mouse model of Rett syndrome.

Perineuronal nets (PNNs), a specialized form of extracellular matrix, are abnormal in the brains of people with Rett syndrome (RTT). We previously reported that PNNs function to restrict synaptic plasticity in hippocampal area CA2, which is unusually resistant to long-term potentiation (LTP) and has been linked to social learning in mice. Here we report that PNNs appear elevated in area CA2 of the hippocampus of an individual with RTT and that PNNs develop precociously and remain elevated in area CA2 of a mouse model of RTT (Mecp2-null). Further, we provide evidence that LTP could be induced at CA2 synapses prior to PNN maturation (postnatal day 8-11) in wild-type mice and that this window of plasticity was prematurely restricted at CA2 synapses in Mecp2-null mice. Degrading PNNs in Mecp2-null hippocampus was sufficient to rescue the premature disruption of CA2 plasticity. We identified several molecular targets that were altered in the developing Mecp2-null hippocampus that may explain aberrant PNNs and CA2 plasticity, and we discovered that CA2 PNNs are negatively regulated by neuronal activity. Collectively, our findings demonstrate that CA2 PNN development is regulated by Mecp2 and identify a window of hippocampal plasticity that is disrupted in a mouse model of RTT.

Novel role for mineralocorticoid receptors in control of a neuronal phenotype.

Mineralocorticoid receptors (MRs) in the brain play a role in learning and memory, neuronal differentiation, and regulation of the stress response. Within the hippocampus, the highest expression of MRs is in area CA2. CA2 pyramidal neurons have a distinct molecular makeup resulting in a plasticity-resistant phenotype, distinguishing them from neurons in CA1 and CA3. Thus, we asked whether MRs regulate CA2 neuron properties and CA2-related behaviors. Using three conditional knockout methods at different stages of development, we found a striking decrease in multiple molecular markers for CA2, an effect mimicked by chronic antagonism of MRs. Furthermore, embryonic deletion of MRs disrupted afferent inputs to CA2 and enabled synaptic potentiation of the normally LTP-resistant synaptic currents in CA2. We also found that CA2-targeted MR knockout was sufficient to disrupt social behavior and alter behavioral responses to novelty. Altogether, these results demonstrate an unappreciated role for MRs in controlling CA2 pyramidal cell identity and in facilitating CA2-dependent behaviors.

2015 UK software audit of hepatobiliary scintigraphy.

INTRODUCTION: This audit investigated hepatobiliary function imaging in UK hospitals, reviewing protocol differences in acquisition and processing parameters and the effect on calculated gallbladder ejection fraction (GBEF). PARTICIPANTS AND METHODS: Two dynamic data sets were available: one continuous dynamic data set, and the other with a 5-min break to administer the fatty stimulus. Participants used a set of 12 anonymized patient data sets most similar to their standard protocol calculating GBEF using their routine method. RESULTS: Fifty-two UK centres responded. Across all centres for all data sets, there was large variability in GBEF quoted, mostly owing to variations in the calculation method, motion correction and imaging type/times. The largest contributor to GBEF variation was time acquired after stimulus which varied from 20 to 70 min. Only 48.1% centres acquired for 60 min after stimulus, which is the acquisition time stated in normal range references. Overall, 13.5% participating centres administered fatty stimuli that fell below the recommended 10 g. Widespread variations were found in GBEF normal ranges and fatty stimulus administration. Motion correction has a large effect on GBEF; in one data set, motion correction alone changed GBEF from 44 to 9%, but 25% of the participants stated motion correction was not used. CONCLUSION: The authors proposed gold standard is fat content of the stimulus should be at least 10 g; and images should be acquired for 60 min after stimulus. If GBEF is quoted, motion correction should be used, and if compared with a normal range, the stimulus used must fit with the reference.

Discovery Molecular Imaging Digital Ready PET/CT performance evaluation according to the NEMA NU2-2012 standard.

OBJECTIVES: The aim of this study was to evaluate and benchmark the performance characteristics of the General Electric (GE) Discovery Molecular Imaging (MI) Digital Ready (DR) PET/CT. MATERIALS AND METHODS: Performance evaluation against the National Electrical Manufacturers Association (NEMA) 2012 standard was performed on three GE Discovery MI DR PET/CT systems installed across different UK centres. The Discovery MI DR performance was compared with the Siemens Biograph mCT Flow, Phillips Ingenuity TF and GE Discovery 690 fully analogue PET/CT systems. In addition, as the Discovery MI DR is upgradable to the Digital MI with silicon photomultipliers, performance characteristics between analogue and digital were compared with assess potential benefits of a system upgrade. RESULTS: The average NEMA results across three Discovery MI DR scanners were: sensitivity 7.3 cps/kBq, spatial resolution full-width-half-maximum radial 5.5 mm, tangential 4.5 mm and axial 6 mm at 10 cm from the centre of the field-of-view, peak noise equivalent count rate 142 kcps, scatter fraction 37.1%, contrast recovery coefficients from the International Electrotechnical Commission phantom ranged from 52 to 87% for 10-37-mm diameter spheres. CONCLUSION: All three Discovery MI DR systems tested in this study exceeded the manufacturer's NEMA specification, yet variability between scanners was noted. Discovery MI DR showed similar performance to Discovery 690 and Ingenuity TF, but lower sensitivity and spatial resolution than Biograph mCT Flow. The Discovery MI DR showed lower spatial resolution and contrast recovery than the 20-cm field-of-view Digital MI.

Reducing CT dose in myocardial perfusion SPECT/CT.

The aim of this study was to reduce the radiation dose arising from computed tomography (CT) attenuation correction to single photon emission computed tomography myocardial perfusion imaging studies without adversely affecting its accuracy. Using the Perspex CTDI phantom with the Xi detector to measure dose, CT scans were acquired using the Siemens Symbia T over the full range of CT settings available. Using the default setting 'AECmean', the measured dose at the centre of the phantom was 1.68 mGy and the breast dose from the scout view was 0.30 mGy. The lowest dose was achieved using the dose modulation setting in which the doses were reduced to 1.21 mGy and undetectable (<0.01 mGy), respectively. To observe the effect of changing these settings, 30 patients received a stress scan with default CT settings and a rest scan utilizing single photon emission computed tomography-guided CT and the dose modulation CT settings. Results showed a mean effective dose reduction of 23.6%. The dose reduction was greatest for larger patients, with the largest dose reduction for one patient being 72%. There was no apparent difference in attenuation correction between the two sets of resultant images. These new lower-dose settings are now applied to all clinical myocardial perfusion imaging studies.

UK audit of glomerular filtration rate measurement from plasma sampling in 2013.

INTRODUCTION: An audit was carried out into UK glomerular filtration rate (GFR) calculation. The results were compared with an identical 2001 audit. METHODS: Participants used their routine method to calculate GFR for 20 data sets (four plasma samples) in millilitres per minute and also the GFR normalized for body surface area. Some unsound data sets were included to analyse the applied quality control (QC) methods. Variability between centres was assessed for each data set, compared with the national median and a reference value calculated using the method recommended in the British Nuclear Medicine Society guidelines. The influence of the number of samples on variability was studied. Supplementary data were requested on workload and methodology. RESULTS: The 59 returns showed widespread standardization. The applied early exponential clearance correction was the main contributor to the observed variability. These corrections were applied by 97% of centres (50% - 2001) with 80% using the recommended averaged Brochner-Mortenson correction. Approximately 75% applied the recommended Haycock body surface area formula for adults (78% for children). The effect of the number of samples used was not significant. There was wide variability in the applied QC techniques, especially in terms of the use of the volume of distribution. CONCLUSION: The widespread adoption of the guidelines has harmonized national GFR calculation compared with the previous audit. Further standardization could further reduce variability. This audit has highlighted the need to address the national standardization of QC methods. Radionuclide techniques are confirmed as the preferred method for GFR measurement when an unequivocal result is required.

Accurate localization of a fall in pH within the ileocecal region: validation using a dual-scintigraphic technique.

Stereotypical changes in pH occur along the gastrointestinal (GI) tract. Classically, there is an abrupt increase in pH on exit from the stomach, followed later by a sharp fall in pH, attributed to passage through the ileocecal region. However, the precise location of this latter pH change has never been conclusively substantiated. We aimed to determine the site of fall in pH using a dual-scintigraphic technique. On day 1, 13 healthy subjects underwent nasal intubation with a 3-m-long catheter, which was allowed to progress to the distal ileum. On day 2, subjects ingested a pH-sensitive wireless motility capsule labeled with 4 MBq (51)Chromium [EDTA]. The course of this, as it travelled through the GI tract, was assessed with a single-headed γ-camera using static and dynamic scans. Capsule progression was plotted relative to a background of 4 MBq ¹¹¹Indium [diethylenetriamine penta-acetic acid] administered through the catheter. Intraluminal pH, as recorded by the capsule, was monitored continuously, and position of the capsule relative to pH was established. A sharp fall in pH was recorded in all subjects; position of the capsule relative to this was accurately determined anatomically in 9/13 subjects. In these nine subjects, a pH drop of 1.5 ± 0.2 U, from 7.6 ± 0.05 to 6.1 ± 0.1 occurred a median of 7.5 min (1-16) after passage through the ileocecal valve; location was either in the cecum (n = 5), ascending colon (n = 2), or coincident with a move from the cecum to ascending colon (n = 2). This study provides conclusive evidence that the fall in pH seen within the ileocolonic region actually occurs in the proximal colon. This phenomenon can be used as a biomarker of transition between the small and large bowel and validates assessment of regional GI motility using capsule technology that incorporates pH measurement.