Key roles for phosphorylation and the Coiled-coil domain in TRIM56-mediated positive regulation of TLR3-TRIF-dependent innate immunity.

Tripartite-motif protein-56 (TRIM56) positively regulates the induction of type I interferon response via the TLR3 pathway by enhancing IRF3 activation and depends on its C-terminal residues 621-750 for interacting with the adaptor TRIF. However, the precise underlying mechanism and detailed TRIM56 determinants remain unclear. Herein, we show ectopic expression of murine TRIM56 also enhances TLR3-dependent interferon-ß promoter activation, suggesting functional conservation. We found that endogenous TRIM56 and TRIF formed a complex early (0.5-2 h) after poly-I:C stimulation and that TRIM56 overexpression also promoted activation of NF-κB by poly-I:C but not that by TNF-α or IL-1ß, consistent with a specific effect on TRIF prior to the bifurcation of NF-κB and IRF3. Using transient transfection and Tet-regulated cell lines expressing various TRIM56 mutants, we demonstrated the Coiled-coil domain and a segment spanning residues ∼434-610, but not the B-box or residues 355-433, were required for TRIM56 augmentation of TLR3 signaling. Moreover, alanine substitution at each putative phosphorylation site, Ser471, Ser475, and Ser710, abrogated TRIM56 function. Concordantly, mutants bearing Ser471Ala, Ser475Ala, or Ser710Ala, or lacking the Coiled-coil domain, all lost the capacity to enhance poly-I:C-induced establishment of an antiviral state. Furthermore, the Ser710Ala mutation disrupted the TRIM56-TRIF association. Using phospho-specific antibodies, we detected biphasic phosphorylation of TRIM56 at Ser471 and Ser475 following TLR3 stimulation, with the early phase occurring at ∼0.5 to 1 h, prior to IRF3 phosphorylation. Together, these data reveal novel molecular details critical for the TRIM56 augmentation of TLR3-dependent antiviral response and highlight important roles for TRIM56 scaffolding and phosphorylation.

Shorter-acting glucagon-like peptide-1 receptor agonists are associated with increased development of gastro-oesophageal reflux disease and its complications in patients with type 2 diabetes mellitus: a population-level retrospective matched cohort study.

BACKGROUND: Shorter half-life glucagon-like peptide-1 receptor agonists (GLP-1 RAs) delay gastric emptying (DGE) more than GLP-1 RAs with longer half-lives. DGE is a known risk factor for gastro-oesophageal reflux disease (GERD) and its complications. AIM: To determine whether short-acting or long-acting GLP-1 RAs are associated with an increased risk of new GERD or GERD-related complications DESIGN: We used the TriNetX global database to identify adult patients with type 2 diabetes mellitus and generated two cohorts totalling 1 543 351 patients on (1) GLP-1 RA or (2) other second-line diabetes medication. Using propensity-score matching, Kaplan-Meier Analysis and Cox-proportional hazards ratio (HR), we analysed outcomes and separately examined outcomes in patients starting short-acting (≤1 day) and long-acting (≥5 days) GLP-1 RAs. RESULTS: 177 666 patients were in each propensity-matched cohort. GLP-1 RA exposure was associated with an increased risk (HR 1.15; 95% CI 1.09 to 1.22) of erosive reflux disease (ERD). However, this was solely due to short-acting (HR 1.215; 95% CI 1.111 to 1.328), but not long-acting (HR 0.994; 95% CI 0.924 to 1.069) GLP-1 RA exposure. Short-acting GLP-1 RAs were also associated with increased risk of oesophageal stricture (HR 1.284; 95% CI 1.135 to 1.453), Barrett's without dysplasia (HR 1.372; 95% CI 1.217 to 1.546) and Barrett's with dysplasia (HR 1.505; 95% CI 1.164 to 1.946) whereas long-acting GLP-1 RAs were not. This association persisted in sensitivity analyses, and when individually examining the short-acting GLP-1 RAs liraglutide, lixisenatide and exenatide. CONCLUSION: Starting shorter-acting GLP-1 RAs is associated with increased risks of GERD and its complications.

Creation of Neuronal Ensembles and Cell-Specific Homeostatic Plasticity through Chronic Sparse Optogenetic Stimulation.

Cortical computations emerge from the dynamics of neurons embedded in complex cortical circuits. Within these circuits, neuronal ensembles, which represent subnetworks with shared functional connectivity, emerge in an experience-dependent manner. Here we induced ensembles in ex vivo cortical circuits from mice of either sex by differentially activating subpopulations through chronic optogenetic stimulation. We observed a decrease in voltage correlation, and importantly a synaptic decoupling between the stimulated and nonstimulated populations. We also observed a decrease in firing rate during Up-states in the stimulated population. These ensemble-specific changes were accompanied by decreases in intrinsic excitability in the stimulated population, and a decrease in connectivity between stimulated and nonstimulated pyramidal neurons. By incorporating the empirically observed changes in intrinsic excitability and connectivity into a spiking neural network model, we were able to demonstrate that changes in both intrinsic excitability and connectivity accounted for the decreased firing rate, but only changes in connectivity accounted for the observed decorrelation. Our findings help ascertain the mechanisms underlying the ability of chronic patterned stimulation to create ensembles within cortical circuits and, importantly, show that while Up-states are a global network-wide phenomenon, functionally distinct ensembles can preserve their identity during Up-states through differential firing rates and correlations.SIGNIFICANCE STATEMENT The connectivity and activity patterns of local cortical circuits are shaped by experience. This experience-dependent reorganization of cortical circuits is driven by complex interactions between different local learning rules, external input, and reciprocal feedback between many distinct brain areas. Here we used an ex vivo approach to demonstrate how simple forms of chronic external stimulation can shape local cortical circuits in terms of their correlated activity and functional connectivity. The absence of feedback between different brain areas and full control of external input allowed for a tractable system to study the underlying mechanisms and development of a computational model. Results show that differential stimulation of subpopulations of neurons significantly reshapes cortical circuits and forms subnetworks referred to as neuronal ensembles.

Laboratory diagnosis of CNS infections in children due to emerging and re-emerging neurotropic viruses.

Recent decades have witnessed the emergence and re-emergence of numerous medically important viruses that cause central nervous system (CNS) infections in children, e.g., Zika, West Nile, and enterovirus/parechovirus. Children with immature immune defenses and blood-brain barrier are more vulnerable to viral CNS infections and meningitis than adults. Viral invasion into the CNS causes meningitis, encephalitis, brain imaging abnormalities, and long-term neurodevelopmental sequelae. Rapid and accurate detection of neurotropic viral infections is essential for diagnosing CNS diseases and setting up an appropriate patient management plan. The addition of new molecular assays and next-generation sequencing has broadened diagnostic capabilities for identifying infectious meningitis/encephalitis. However, the expansion of test menu has led to new challenges in selecting appropriate tests and making accurate interpretation of test results. There are unmet gaps in development of rapid, sensitive and specific molecular assays for a growing list of emerging and re-emerging neurotropic viruses. Herein we will discuss the advances and challenges in the laboratory diagnosis of viral CNS infections in children. This review not only sheds light on selection and interpretation of a suitable diagnostic test for emerging/re-emerging neurotropic viruses, but also calls for more research on development and clinical utility study of novel molecular assays. IMPACT: Children with immature immune defenses and blood-brain barrier, especially neonates and infants, are more vulnerable to viral central nervous system infections and meningitis than adults. The addition of new molecular assays and next-generation sequencing has broadened diagnostic capabilities for identifying infectious meningitis and encephalitis. There are unmet gaps in the development of rapid, sensitive and specific molecular assays for a growing list of emerging and re-emerging neurotropic viruses.

A Comprehensive Global Population-Based Analysis on the Coexistence of Eosinophilic Esophagitis and Inflammatory Bowel Disease.

BACKGROUND: We explored inflammatory bowel disease (IBD) and eosinophilic esophagitis (EoE) coexistence using a global dataset. Investigating their epidemiology, risks, and impact, we aimed to enhance the understanding of concurrent diagnoses and patient outcomes. METHODS: A retrospective population-based cohort study was conducted using deidentified patient data from the TriNetX database (2011-2022). We estimated the incidence and prevalence of EoE in patients with IBD, including both Crohn's disease (CD) and ulcerative colitis (UC), and vice versa. Risks of select immune-mediated conditions and disease complications were compared among patients with EoE, IBD, or concurrent diagnoses. RESULTS: Our results included 174,755 patients with CD; 150,774 patients with UC; and 44,714 patients with EoE. The risk of EoE was significantly higher among patients with CD (prevalence ratio [PR] 11.2) or UC (PR 8.7) compared with individuals without IBD. The risk of IBD was higher in patients with EoE (CD: PR 11.6; UC: PR 9.1) versus those without EoE. A propensity-matched analysis of IBD patients revealed that, when comparing patients with and without EoE, the relative risk of immune-mediated comorbidities was significantly greater for celiac disease, IBD-related inflammatory conditions, eczema and asthma (CD: n = 1896; UC: n = 1231; p < 0.001). Patients with a concurrent diagnosis of EoE and IBD had a higher composite risk of IBD-related complications (CD: adjusted HR (aHR) 1.14, p < 0.005; UC: aHR 1.17, p < 0.01) and lower risk of food bolus impaction (aHR 0.445, p = 0.0011). CONCLUSION: Simultaneous EoE and IBD increased IBD-related complications risk, needing more treatment (glucocorticoids, biologic therapy, abdominal surgery), while reducing EoE-related issues like food bolus impaction.

Comparative Analysis of Outcomes of Unibody Endoprosthesis and Aortobifemoral Bypass for Aortoiliac Occlusive Disease.

BACKGROUND: Aortoiliac occlusive disease (AIOD) has traditionally been treated with aortobifemoral bypass (ABF). Unibody endograft (UBE) for AIOD, however, has been increasingly utilized in selected patients. We report outcomes of patients undergoing ABF or UBE for AIOD. METHODS: Patients (2016-2021) undergoing elective ABF or UBE with a unibody device for AIOD were identified at an academic institution. Chi-square and Kaplan-Meier analysis were used to evaluate outcomes by group. RESULTS: One hundred thirty-one patients undergoing UBE or ABF were screened, with 82 included. Twenty-one patients underwent UBE (25.6%) and 61 (74.4%) underwent ABF. UBE patients were older (63.8 vs. 58.2 years; P = 0.01), with a higher prevalence of diabetes (52.4 vs. 19.7%; P = 0.004). Significant differences were seen between UBE and ABF including a shorter surgery length (214 vs. 360 min; P = 0.0001), less blood loss (300 vs. 620 mls; P = 0.001), larger minimum aortic diameter (14.6 vs. 12.6; P = 0.0006), larger common iliac artery (9.5 vs. 7.9; P = 0.005) and lower postoperative ankle-brachial index (0.8 vs. 0.9; P = 0.04). There were no differences in TASC C/D iliac lesions in the UBE than ABF group (66.6% vs. 63.9%; P < 0.82) or Trans-Atlantic Inter-Society Consensus classification femoropopliteal lesions. Unadjusted analysis revealed no significant differences between UBE and ABF for 30-day mortality (0 vs. 1.6%; P = 1), stroke (0 vs. 3.3%; P = 1), or major adverse cardiac events (4.8 vs. 4.9%; P = 1). There were no significant differences in mid-term surgical outcomes over a mean follow-up period of 23.7 months between UBE and ABF groups; specifically endovascular (0 vs. 8.2%; P = 0.3) or open/hybrid reintervention (9.5 vs. 14.8%; P = 0.7) with similar limb occlusion (4.8 vs. 27.8; P = 0.12). Kaplan-Meier estimated primary, primary-assisted, and secondary patency at 36 months were similar with 94%, 100%, and 94% for UBE and 86%, 95%, and 86% for ABF, respectively. Estimated survival at 36 months was 95% for UBE and 97% for ABF (P = 0.8). CONCLUSIONS: Equivalent outcomes were seen between AIOD treated with UBE or ABF in similar patient populations. Mid-term outcomes such as reintervention and patency are similar for UBE and ABF. We still recommend ABF over UBE as a primary modality of treatment in surgically fit patients with greater complexity aortoiliac lesions and with smaller arterial diameters, especially women.

Repeated blood-brain barrier opening with an implantable ultrasound device for delivery of albumin-bound paclitaxel in patients with recurrent glioblastoma: a phase 1 trial.

BACKGROUND: Low-intensity pulsed ultrasound with concomitant administration of intravenous microbubbles (LIPU-MB) can be used to open the blood-brain barrier. We aimed to assess the safety and pharmacokinetics of LIPU-MB to enhance the delivery of albumin-bound paclitaxel to the peritumoural brain of patients with recurrent glioblastoma. METHODS: We conducted a dose-escalation phase 1 clinical trial in adults (aged ≥18 years) with recurrent glioblastoma, a tumour diameter of 70 mm or smaller, and a Karnofsky performance status of at least 70. A nine-emitter ultrasound device was implanted into a skull window after tumour resection. LIPU-MB with intravenous albumin-bound paclitaxel infusion was done every 3 weeks for up to six cycles. Six dose levels of albumin-bound paclitaxel (40 mg/m2, 80 mg/m2, 135 mg/m2, 175 mg/m2, 215 mg/m2, and 260 mg/m2) were evaluated. The primary endpoint was dose-limiting toxicity occurring during the first cycle of sonication and albumin-bound paclitaxel chemotherapy. Safety was assessed in all treated patients. Analyses were done in the per-protocol population. Blood-brain barrier opening was investigated by MRI before and after sonication. We also did pharmacokinetic analyses of LIPU-MB in a subgroup of patients from the current study and a subgroup of patients who received carboplatin as part of a similar trial (NCT03744026). This study is registered with ClinicalTrials.gov, NCT04528680, and a phase 2 trial is currently open for accrual. FINDINGS: 17 patients (nine men and eight women) were enrolled between Oct 29, 2020, and Feb 21, 2022. As of data cutoff on Sept 6, 2022, median follow-up was 11·89 months (IQR 11·12-12·78). One patient was treated per dose level of albumin-bound paclitaxel for levels 1 to 5 (40-215 mg/m2), and 12 patients were treated at dose level 6 (260 mg/m2). A total of 68 cycles of LIPU-MB-based blood-brain barrier opening were done (median 3 cycles per patient [range 2-6]). At a dose of 260 mg/m2, encephalopathy (grade 3) occurred in one (8%) of 12 patients during the first cycle (considered a dose-limiting toxicity), and in one other patient during the second cycle (grade 2). In both cases, the toxicity resolved and treatment continued at a lower dose of albumin-bound paclitaxel, with a dose of 175 mg/m2 in the case of the grade 3 encephalopathy, and to 215 mg/m2 in the case of the grade 2 encephalopathy. Grade 2 peripheral neuropathy was observed in one patient during the third cycle of 260 mg/m2 albumin-bound paclitaxel. No progressive neurological deficits attributed to LIPU-MB were observed. LIPU-MB-based blood-brain barrier opening was most commonly associated with immediate yet transient grade 1-2 headache (12 [71%] of 17 patients). The most common grade 3-4 treatment-emergent adverse events were neutropenia (eight [47%]), leukopenia (five [29%]), and hypertension (five [29%]). No treatment-related deaths occurred during the study. Imaging analysis showed blood-brain barrier opening in the brain regions targeted by LIPU-MB, which diminished over the first 1 h after sonication. Pharmacokinetic analyses showed that LIPU-MB led to increases in the mean brain parenchymal concentrations of albumin-bound paclitaxel (from 0·037 µM [95% CI 0·022-0·063] in non-sonicated brain to 0·139 µM [0·083-0·232] in sonicated brain [3·7-times increase], p<0·0001) and carboplatin (from 0·991 µM [0·562-1·747] in non-sonicated brain to 5·878 µM [3·462-9·980] µM in sonicated brain [5·9-times increase], p=0·0001). INTERPRETATION: LIPU-MB using a skull-implantable ultrasound device transiently opens the blood-brain barrier allowing for safe, repeated penetration of cytotoxic drugs into the brain. This study has prompted a subsequent phase 2 study combining LIPU-MB with albumin-bound paclitaxel plus carboplatin (NCT04528680), which is ongoing. FUNDING: National Institutes of Health and National Cancer Institute, Moceri Family Foundation, and the Panattoni family.

Disparities in Electronic Screening for Cancer-Related Psychosocial Distress May Promote Systemic Barriers to Quality Oncologic Care.

BACKGROUND: Screening for cancer-related psychosocial distress is an integral yet laborious component of quality oncologic care. Automated preappointment screening through online patient portals (Portal, MyChart) is efficient compared with paper-based screening, but unstudied. We hypothesized that patient access to and engagement with EHR-based screening would positively correlate with factors associated with digital literacy (eg, age, socioeconomic status). METHODS: Screening-eligible oncology patients seen at our Comprehensive Cancer Center from 2014 through 2019 were identified. Patients with active Portals were offered distress screening. Portal and screening participation were analyzed via multivariable logistic regression. Household income in US dollars and educational attainment were estimated utilizing zip code and census data. RESULTS: Of 17,982 patients, 10,279 (57%) had active Portals and were offered distress screening. On multivariable analysis, older age (odds ratio [OR], 0.97/year; P<.001); male gender (OR, 0.89; P<.001); Black (OR, 0.47; P<.001), Hawaiian/Pacific Islander (OR, 1.54; P=.007), and Native American/Alaskan Native race (OR, 0.67; P=.04); Hispanic ethnicity (OR, 0.76; P<.001); and Medicare (OR, 0.59; P<.001), Veteran's Affairs/military (OR, 0.09; P<.01), Medicaid (OR, 0.34; P<.001), or no insurance coverage (OR, 0.57; P<.001) were independently associated with lower odds of being offered distress screening; increasing income (OR, 1.05/$10,000; P<.001) and educational attainment (OR, 1.03/percent likelihood of bachelor's degree or higher; P<.001) were independently associated with higher odds. In patients offered electronic screening, participation rate was 36.6% (n=3,758). Higher educational attainment (OR, 1.01; P=.03) was independently associated with participation, whereas Black race (OR, 0.58; P=.004), Hispanic ethnicity (OR, 0.68; P=.01), non-English primary language (OR, 0.67; P=.03), and Medicaid insurance (OR, 0.78; P<.001) were independently associated with nonparticipation. CONCLUSIONS: Electronic portal-based screening for cancer-related psychosocial distress leads to underscreening of vulnerable populations. At institutions using electronic distress screening workflows, supplemental screening for patients unable or unwilling to engage with electronic screening is recommended to ensure efficient yet equal-opportunity distress screening.

Role of hepatic metastatic lesion size on inter-reader reproducibility of CT-based radiomics features.

OBJECTIVES: To evaluate the effect of hepatic metastatic lesion size on inter-reader reproducibility of CT-based 2D radiomics imaging features. METHODS: Computerized tomography (CT) scans of 59 liver metastases from 34 patients with colorectal cancer were evaluated. Image segmentation was performed manually by three readers blinded to each other's results. For each radiomics feature, we created two datasets by sorting measurements according to size, i.e., (i) from the smallest to the largest lesion and (ii) from the largest to the smallest lesion. The Lin concordance correlation coefficient (CCC) was employed to analyze the reproducibility of radiomics features. In particular, the CCC was computed as a function of a number of elements in the dataset, by gradually adding lesions from each sorted dataset. To evaluate the effect of lesion size, we analyzed the difference between these two functions thus assessing the contribution of small and large lesions into the reproducibility of radiomics features. RESULTS: Inter-reader reproducibility of CT-based 2D radiomics features assessed using Lin's CCC demonstrates tumor-size dependence. For example, the Lin CCC for GLCM contrast equals 0.88 (95% C.I. 0.84 to 0.92, p < 0.003) and could change by an additional + / - 0.06 depending on the presence of large or small lesions. CONCLUSIONS: Groups of "large" and "small" lesions show different inter-reader reproducibility. The inter-reader reproducibility from the mixed group consisting of "large" and "small" lesions depends on the lesion-size distribution and can vary widely. This finding could partially explain variability in reproducibility of radiomics features in the literature. KEY POINTS: • Groups of "large" and "small" lesions show different inter-reader reproducibility. • The inter-reader reproducibility from the mixed group consisting of "large" and "small" lesions depends on the lesion-size distribution.

Multimodal Presurgical Evaluation of Medically Refractory Focal Epilepsy in Adults: An Update for Radiologists.

Surgery is a potentially curative treatment option for patients with medically refractory focal epilepsy. Advanced neuroimaging modalities often improve surgical outcomes by contributing key information during the highly individualized surgical planning process and intraoperative localization. Hence, neuroradiologists play an integral role in the multidisciplinary management team. In this review, we initially present the conceptual background and practical framework of the presurgical evaluation process, including a description of the surgical treatment approaches used for medically refractory focal epilepsy in adults. This background is followed by an overview of the advanced modalities commonly used during the presurgical workup at level IV epilepsy centers, including diffusion imaging techniques, blood oxygenation level-dependent functional MRI (fMRI), PET, SPECT, and subtraction ictal SPECT, and by introductions to 7-T MRI and electrophysiologic techniques including electroencephalography and magnetoencephalography. We also provide illustrative case examples of multimodal neuroimaging including PET/MRI, PET/MRI-diffusion-tensor imaging (DTI), subtraction ictal SPECT, and image-guided stereotactic planning with fMRI-DTI.

Psychosocial distress is dynamic across the spectrum of cancer care and requires longitudinal screening for patient-centered care.

PURPOSE: Screening for cancer-related psychosocial distress is recommended for patients with cancer; however, data on the long-term prevalence of distress and its natural history in survivors are scarce, preventing recommendations for screening frequency and duration. We sought to evaluate longitudinal distress in cancer patients. METHODS: We evaluated longitudinal distress screening data for patients with cancer treated or surveilled at our institution from 2010 to 2018. Anxiety, depression, insurance/financial, family, memory, and strength-related distress were separately assessed and analyzed. Multivariable logistic regression was utilized to evaluate factors associated with distress subtypes. RESULTS: In 5660 patients, distress was the highest at diagnosis for anxiety, depression, financial, and overall distress. On multivariable analysis, factors independently associated with distress at diagnosis included younger age, female gender, disease site/stage, payor, and income, varying by subtype-specific analyses. Severe distress in at least one subtype persisted in over 30% of survivors surveyed through 10 years after diagnosis. Over half of patients with initially severe distress at diagnosis improved within 12 months; however, distress worsened in 20-30% of patients with moderate, low, and no initial distress, regardless of the distress subtype. CONCLUSION: Psychosocial distress in cancer survivors is a long-lasting burden with implications for quality of life and oncologic outcomes. Severe distress remains prevalent through 10 years after diagnosis in survivors receiving continued care at cancer centers and results from both persistent and new sources of distress in a variety of psychosocial domains. Longitudinal distress screening is an invaluable tool for providing comprehensive patient-centered cancer care and is recommended to detect new or recurrent distress in cancer survivors.

Clinical significance of measuring serum cytokine levels as inflammatory biomarkers in adult and pediatric COVID-19 cases: A review.

Coronavirus disease 2019 (COVID-19) is a rapidly evolving infectious/inflammatory disorder which has turned into a global pandemic. With severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as its etiologic agent, severe COVID-19 cases usually develop uncontrolled inflammatory responses and cytokine storm-like syndromes. Measuring serum levels of pro-inflammatory cytokines (e.g., IL-6 and others) as inflammatory biomarkers may have several potential applications in the management of COVID-19, including risk assessment, monitoring of disease progression, determination of prognosis, selection of therapy and prediction of response to treatment.This is especially true for pediatric patients with COVID-19 associated Kawasaki-like disease and similar syndromes. In this report, we review the current knowledge of COVID-19 associated cytokines, their roles in host immune and inflammatory responses, the clinical significance and utility of cytokine immunoassays in adult and pediatric COVID-19 patients, as well as the challenges and pitfalls in implementation and interpretation of cytokine immunoassays. Given that cytokines are implicated in different immunological disorders and diseases, it is challenging to interpret the multiplex cytokine data for COVID-19 patients. Also, it should be taken into consideration that biological and technical variables may affect the commutability of cytokine immunoassays and enhance complexity of cytokine immunoassay interpretation. It is recommended that the same method, platform and laboratory should be used when monitoring differences in cytokine levels between groups of individuals or for the same individual over time. It may be important to correlate cytokine profiling data with the SARS-CoV-2 nucleic acid amplification testing and imaging observations to make an accurate interpretation of the inflammatory status and disease progression in COVID-19 patients.

Clinical Efficacy of Reduced-Dose Gadobutrol Versus Standard-Dose Gadoterate for Contrast-Enhanced MRI of the CNS: An International Multicenter Prospective Crossover Trial (LEADER-75).

BACKGROUND. Gadobutrol and gadoterate are widely used macrocyclic gadolinium-based contrast agents. Given gadobutrol's higher T1 relaxivity, a reduced gadobutrol dose should achieve essentially equivalent diagnostic efficacy as a standard dose of gadoterate. OBJECTIVE. The purpose of our study was to show efficacy of a 25% reduced dose of gadobutrol is noninferior to 100% standard dose of gadoterate for contrast-enhanced MRI of the CNS. METHODS. In this international prospective multicenter open-label crossover trial (LEADER-75 [Lower Administered Dose With Higher Relaxivity: Gadovist vs Dotarem]), adult patients with known or suspected CNS pathology underwent contrast-enhanced brain MRI with standard-dose gadoterate (0.1 mmol/kg); if an enhancing lesion was identified, a second MRI with reduced-dose gadobutrol (0.075 mmol/kg) was performed within 15 days of the first MRI. Three radiologists independently reviewed images to score three primary efficacy measures: subjective lesion enhancement, lesion border delineation, lesion internal morphology. A noninferiority analysis used readers' mean scores of the primary efficacy measures. Noninferiority of reduced-dose gadobutrol to standard-dose gadoterate for primary efficacy measures was defined as the difference in score between reduced-dose gadobutrol images and unenhanced images achieving at least 80% of the difference in score between standard-dose gadoterate images and unenhanced images. A post hoc analysis was performed to directly compare contrast-enhanced images for equivalence. Secondary efficacy variables included the number of lesions detected, reader confidence, diagnostic performance for malignancy, and reader preference in side-by-side comparison. RESULTS. The efficacy analysis included 141 patients (78 men, 63 women; mean age, 58.5 ± 13.5 [SD] years). Improvement of reduced-dose gadobutrol over unenhanced images was noninferior to improvement of standard-dose gadoterate over unenhanced images using a 20% noninferiority margin for all three primary efficacy measures using mean readings (p ≤ .025). In the post hoc analysis, the mean reading for the three primary efficacy measures differed by less than 1% between reduced-dose gadobutrol and standard-dose gadoterate, supporting equivalence of all measures using a narrow ± 5% margin (p ≤ .025). The total number of lesions detected by mean reading was 301 for reduced-dose gadobutrol versus 291 for standard-dose gadoterate. Mean reader confidence was 3.3 ± 0.6 for reduced-dose gadobutrol versus 3.3 ± 0.6 for standard-dose gadoterate. Sensitivity (58.7%), specificity (91.8%), and accuracy (70.2%) for malignancy from majority reading were identical for reduced-dose gadobutrol and standard-dose gadoterate. Reader preference was not different (95% CI, -0.10 to 0.11). CONCLUSION. A 25% reduced dose of gadobutrol is noninferior to standard-dose gadoterate for contrast-enhanced brain MRI. CLINICAL IMPACT. Use of reduced-dose gadobutrol should be considered for brain MRI, particularly in patients undergoing multiple contrast-enhanced examinations. TRIAL REGISTRATION. ClinicalTrials.gov NCT03602339; EU Clinical Trials Register EudraCT 2018-00690-78.

Marginal ulceration following Roux-en-Y gastric bypass: risk factors for ulcer development, recurrence and need for revisional surgery.

BACKGROUND: Marginal ulcer formation is a known complication following RYGB. While most respond to medical therapy, many patients have recurrent or chronic MU. Although non-steroidal anti-inflammatory drug (NSAID) use, smoking and Helicobacter pylori infection are known risk factors of MU, little is known about what increases the likelihood of developing recalcitrant ulcers. The objective of this study is to identify risk factors for marginal ulcer (MU) formation, including recalcitrant ulcers requiring surgical revision, and to define the incidence and outcomes of revisional surgery. METHODS: All patients who underwent RYGB between 2011 and 2017 at a high-volume academic center were included. Patients with a postoperative diagnosis of MU were identified from the institution's bariatric database. Patient characteristics, operative data and surgical outcomes were analyzed using data collected in the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program and the Ontario Bariatric Registry. RESULTS: A total of 2830 RYGB were performed during the study period. The incidence of MU was 6.9% with 1% of patients requiring revisional surgery for a recalcitrant ulcer. Patients with a history of smoking (HR 5.03), immunosuppression (HR 4.60) and preoperative NSAID use (HR 3.11) were significantly more likely to develop a MU requiring surgical revision. Patients undergoing revision reported resolution of their symptoms in only 36% of cases with 57% developing a recurrent ulcer. CONCLUSION: Patients with a history of smoking and use of immunosuppressive medication were at significantly higher risk of developing MU that failed medical therapy. Additional evidence is needed to inform perioperative management of bariatric patients.

The Use of Contrast Agents in Interventional Pain Procedures: A Multispecialty and Multisociety Practice Advisory on Nephrogenic Systemic Fibrosis, Gadolinium Deposition in the Brain, Encephalopathy After Unintentional Intrathecal Gadolinium Injection, and Hypersensitivity Reactions.

This Practice Advisory presents a comprehensive and evidence-based set of position statements and recommendations for the use of contrast media in interventional pain procedures. The advisory was established by an international panel of experts under the auspices of 11 multinational and multispecialty organizations based on a comprehensive review of the literature up to December 31, 2019. The advisory discusses the risks of using gadolinium-based contrast agents. These include nephrogenic systemic fibrosis, gadolinium brain deposition/retention, and encephalopathy and death after an unintentional intrathecal gadolinium injection. The advisory provides recommendations on the selection of a specific gadolinium-based contrast agent in patients with renal insufficiency, those who had multiple gadolinium-enhanced magnetic resonance imaging examinations, and in cases of paraspinal injections. Additionally, recommendations are made for patients who have a history of mild, moderate, or severe hypersensitivity reactions to contrast medium.

Plasticity of the Primary Motor Cortex in Patients with Primary Brain Tumors.

There are two neuron-level mechanisms proposed to underlie neural plasticity: recruiting neurons nearby to support the lost function (ipsilesional plasticity) and uncovering latent pathways that can assume the function that was lost (contralesional plasticity). While both patterns have been demonstrated in patient groups following injury, the specific mechanisms underlying each mode of plasticity are poorly understood. In a retrospective case series of 13 patients, we utilize a novel paradigm that analyzes serial fMRI scans in patients harboring intrinsic brain tumors that vary in location and growth kinetics to better understand the mechanisms underlying these two modes of plasticity in the human primary motor cortex. Twelve patients in our series had some degree of primary motor cortex plasticity, an area previously thought to have limited plasticity. Patients harboring smaller lesions with slower growth kinetics and increasing distance from the primary motor region demonstrated recruitment of ipsilateral motor regions. Conversely, larger, faster-growing lesions in close proximity to the primary motor region were associated with activation of the contralesional primary motor cortex, along with increased activation of the supplementary motor area. These data increase our understanding of the adaptive abilities of the brain and may lead to improved treatment strategies for those suffering from motor loss secondary to brain injuries.

Accelerating invasions and the asymptotics of fat-tailed dispersal.

Integrodifference equations (IDEs) are used in ecology to model the growth and spatial spread of populations. With IDEs, dispersal is specified with a probability density function, called the dispersal kernel, and the shape of the kernel influences how rapidly invasions progress. In this paper, we apply tail additivity, a property of regularly varying probability densities, to model invasions with fat-tailed (power-law decay) dispersal in one dimension. We show that fat-tailed invasions progress geometrically fast, with the rate of spread depending on the degree of fatness of the tails. Our analyses apply to populations with no Allee effect as well as weak Allee effects, and we conduct simulations to show that fat-tailed invasions with weak Allee effects produce accelerating invasions. We analyze point-release and front-release invasions, corresponding to newly-established and well-established populations, and we find that front-release invasions gain a permanent speed-up over point-release invasions, invading at a faster geometric rate that persists for all time. Since accelerating invasions are qualitatively different than constant-speed invasions, we also discuss how measures of invasion must be modified and reconsidered when invasions accelerate.

State Coverage and Reimbursement of Antiobesity Medications in Medicaid.

This study examines state Medicaid coverage policies for antiobesity medications and their trends in Medicaid reimbursement from 2011 to 2022.