Magnetic resonance imaging features of progressive familial intrahepatic cholestasis type 3.

PURPOSE: Progressive familial intrahepatic cholestasis type 3 (PFIC-3) is a rare autosomal recessive cholestatic liver disorder. This study aimed to present the clinical and magnetic resonance imaging (MRI) features of three patients with PFIC­3. METHODS: The study included three patients with cholestasis and pathogenic variants in the ABCB4 gene identified by next-generation sequencing of a targeted-gene panel or by whole-exome sequencing. The clinical, laboratory, histological, molecular, and MRI features of the patients were collected. RESULTS: Three patients (one male and two females) were enrolled. The age when clinical signs and symptoms were first noted was 21, 14, and 39 years, respectively, and the signs and symptoms included pruritus and splenomegaly (in all three patients). Parenchymatous lace-like fibrosis was associated with periportal hyperintensity and periportal halo sign in three patients. Segmental atrophy was observed in two patients, diffuse atrophy was observed in one patient, and liver surface irregularity caused by regenerating nodules was observed in three patients. Magnetic resonance cholangiopancreatography (MRCP) images showed irregular bile duct changes in three patients, focal hilar bile duct stenosis, and local intrahepatic bile duct dilatation. CONCLUSIONS: Imaging studies using MRI and MRCP can support the clinical and laboratory results in cases of PFIC­3 and can also be used as a noninvasive diagnostic option.

Predictive value of 18F-fluorodeoxyglucose PET/CT in histological grade of incidental colorectal adenoma.

BACKGROUND: 18F-fluorodeoxyglucose (18F-FDG) positron-emission tomography/computed tomography (PET/CT) as an imaging modality for the whole body has shown its value in detecting incidental colorectal adenoma. In clinical practice, adenomatous polyps can be divided into three groups: low-grade intraepithelial neoplasia (LGIN), high-grade intraepithelial neoplasia (HGIN) and cancer, which can lead to different clinical management. However, the relationship between the 18F-FDG PET/CT SUVmax and the histological grade of adenomatous polyps is still not established, which is a challenging but valuable task. METHODS: This retrospective study included 255 patients with colorectal adenoma (CRA) or colorectal adenocarcinomas (AC) who had corresponding 18F-FDG uptake incidentally found on PET/CT. The correlations of SUVmax with pathological characteristics and tumor size were assessed. Neoplasms were divided into LGIN, HGIN, and AC according to histological grade. Receiver operating characteristic (ROC) analysis was applied to evaluate the predictive value of the SUVmax-only model and comprehensive models which were established with imaging and clinical predictors identified by univariate and multivariate analysis. RESULTS: The SUVmax was positively correlated with histological grades (r=0.529, P<0.001). Univariate and multivariate analysis showed that SUVmax was an independent risk factor among all groups except between HGIN and AC. The area under the curves (AUCs) of the comprehensive model for distinguishing between AC and adenoma, LGIN and HIGN, LGIN and AC, and HGIN and AC were 0.886, 0.780, 0.945, 0.733, respectively, which is statistically higher than the AUCs of the SUVmax-only model with 0.812, 0.733, 0.863, and 0.688, respectively. CONCLUSIONS: As an independent risk factor, SUVmax based on 18F-FDG PET/CT is highly associated with the histological grade of CRA. Thus, 18F-FDG PET/CT can serve as a noninvasive tool for precise diagnosis and assist in the preoperative formulation of treatment strategies for patients with incidental CRA.

Association of Daily Mean Temperature and Temperature Variability With Onset Risks of Acute Aortic Dissection.

Background The association between ambient temperature and cardiovascular diseases has been well established, but evidence of temporal changes in the risk of acute aortic dissection (AAD) onset is lacking. Methods and Results We conducted an 8-year time-series study based on data from 2120 patients diagnosed with AAD at Tongji Hospital (Wuhan, China). Daily meteorological parameters were measured in the study area. Spearman's rank correlation analysis was applied to measure the associations between daily meteorological data and air pollution indicators. A distributed lag nonlinear model following quasi-Poisson regression was used to express the nonlinear exposure-response relationships and lag effects of daily mean temperature and temperature variability on the occurrence of AAD. Considering a 25-day lag effect, lower or higher temperatures with reference to 25°C did not alter the onset risk of AAD. The lag effect of daily mean temperature on the incidence of AAD is statistically significant within 2 days, and the impact of daily mean temperature on the risk is most influential on the day. The exposure-response curve between daily mean temperature and onset risks of AAD at lag 0 showed that the extremely cold temperature (2.5th percentile, 0.5°C) significantly increased the AAD risk for the total (relative risk, 1.733; 95% CI, 1.130-2.658) and type A dissection (relative risk, 3.951; 95% CI, 1.657-9.418). Temperature variability within 1 week did not affect the onset risks of AAD for the total. Conclusions We confirmed that extremely cold temperatures significantly increased the AAD risk, which could contribute to early prevention and timely diagnosis of the disease.

The Role of Aspirin in the Management of Intracranial Aneurysms: A Systematic Review and Meta-Analyses.

Objective: To evaluate the association between aspirin use and the risks of unruptured intracranial aneurysm (UIA) growth and aneurysmal subarachnoid hemorrhage (aSAH). Methods: We searched PubMed and Scopus from inception to 1 September 2020. Studies evaluating the associations between aspirin prescription and the risk of UIA growth or the risk of aSAH were included. The study only included patients with intracranial aneurysms. We assessed the quality of included studies using the Newcastle-Ottawa scale. Random-effects meta-analysis was conducted to pool the estimates of effect size quantitatively. Sensitivity analyses using the leave-one-out strategy were performed to identify any potential source of heterogeneity. Results: After a review of 2,226 citations, five cohort studies, two case-control studies, and one nested case-control study involving 8,898 participants were included. Pooled analyses showed that aspirin use, regardless of frequency and duration, was associated with a statistically significantly lower risk of UIA growth (OR 0.25, 95% CI 0.11-0.54; I 2 = 0.0%, p = 0.604) and aSAH (OR, 0.37, 95% CI, 0.23-0.58; I 2 = 79.3%, p = 0.001) in patients presented with intracranial aneurysms. The results did not significantly change in sensitivity analyses. Conclusions: Summarizing available evidence in the literature, our findings indicate that aspirin use, regardless of frequency and duration, was associated with a statistically significantly lower risk of UIA growth and aSAH in patients with UIA. Well-designed and large-scale clinical trials are needed to help define the role of aspirin as a protective pharmaceutical for UIAs.

Radiomics Model for Evaluating the Level of Tumor-Infiltrating Lymphocytes in Breast Cancer Based on Dynamic Contrast-Enhanced MRI.

BACKGROUND: To help identify potential breast cancer (BC) candidates for immunotherapies, we aimed to develop and validate a radiology-based biomarker (radiomic score) to predict the level of tumor-infiltrating lymphocytes (TILs) in patients with BC. PATIENTS AND METHODS: This retrospective study enrolled 172 patients with histopathology-confirmed BC assigned to the training (n = 121) or testing (n = 51) cohorts. Radiomic features were extracted and selected using Analysis-Kit software. The correlation between TIL levels and clinical features and radiomic features was evaluated. The clinical features model, radiomic signature model, and combined prediction model were constructed and compared. Predictive performance was assessed by receiver operating characteristic analysis and clinical utility by implementing a nomogram. RESULTS: Seven radiomic features were selected as the best discriminators to construct the radiomic signature model, the performance of which was good in both the training and validation data sets, with an area under the curve (AUC) of 0.742 (95% confidence interval [CI], 0.642-0.843) and 0.718 (95% CI, 0.558-0.878), respectively. Estrogen receptor status and tumor diameter were confirmed to be significant features for building the clinical feature model, which had an AUC of 0.739 (95% CI, 0.632-0.846) and 0.824 (95% CI, 0.692-0.957), respectively. The combined prediction model had an AUC of 0.800 (95% CI, 0.709-0.892) and 0.842 (95% CI, 0.730-0.954), respectively. CONCLUSION: The radiomic signature could be an important predictor of the TIL level in BC, which, when validated, could be useful in identifying BC patients who can benefit from immunotherapies. The nomogram may help clinicians make decisions.

A radiomic-based model of different contrast-enhanced CT phase for differentiate intrahepatic cholangiocarcinoma from inflammatory mass with hepatolithiasis.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is hard to distinguish from inflammatory mass (IM) complicated with hepatolithiasis in clinical practice preoperatively. This study looked to develop and confirm the radiomics models to make a distinction between ICC with hepatolithiasis from IM and to compare the results of different contrast-enhanced computed tomography (CT) phase. METHODS: The models were developed in a training cohort of 110 patients from January 2005 to June 2020. Radiomics features were extracted from both arterial phase and portal venous phase contrast-enhanced computed tomography (CT) scans. The radiomics scores based on radiomics features, were built by logistic regression after using the least absolute shrinkage and selection operator (LASSO) method. The rad-scores of two contrast -enhanced CT phases and clinical features were incorporated into a novel model. The performance of the models were determined by theirs discrimination, calibration, and clinical usefulness. The models were externally validated in 35 consecutive patients. RESULTS: The radiomics signature comprised two features in arterial phase (training cohort, AUC = 0.809, sensitivity 0.700, specificity 0.848, and accuracy 0.774;validation cohort, AUC = 0.790, sensitivity 0.714, specificity 0.800, and accuracy 0.757) and three related features in portal venous phase (training cohort, AUC = 0.801, sensitivity 0.800, specificity 0.717, and accuracy 0.759; validation cohort, AUC = 0.830, sensitivity 0.700, specificity 0.750, and accuracy 0.775) showed significant association with ICC in both cohorts (P < 0.05).We also developed a model only based on clinical variables (training cohort, AUC = 0.778, sensitivity 0.567, specificity 0.891, and accuracy 0.729; validation cohort, AUC = 0.788, sensitivity 0.571, specificity 0.950, and accuracy 0.761). The radiomics-based model contained rad-score of two phases and two clinical factors (CEA and CA19-9) showed the best performance (training cohort, AUC = 0.864, sensitivity 0.867, specificity 0.804, and accuracy 0.836; validation cohort, AUC = 0.843, sensitivity 0.643, specificity 0.980, and accuracy 0.821). CONCLUSIONS: Our radiomics-based models provided a diagnostic tool for differentiate intrahepatic cholangiocarcinoma (ICC) from inflammatory mass (IM) with hepatolithiasis both in arterial phase and portal venous phase. To go a step further, the diagnostic accuracy will improved by a clinico-radiologic model.

Association between bone marrow fluorodeoxyglucose uptake and recurrence after curative surgical resection in patients with T1-2N0M0 lung adenocarcinoma: a retrospective cohort study.

BACKGROUND: Evidence regarding the relationship between fluorodeoxyglucose (FDG) uptake in the bone marrow of patients with lung adenocarcinoma and prognosis is limited. This study aimed to identify whether bone marrow FDG uptake is a risk factor for recurrence in patients after curative surgical resection of T1-2N0M0 lung adenocarcinoma. METHODS: From January 2012 to December 2016, we retrospectively enrolled 195 pT1-2N0M0 lung adenocarcinoma patients who underwent both preoperative FDG positron emission tomography/computed tomography (PET/CT) and surgical resection from the lung adenocarcinoma database maintained by the PET/CT department at our hospital. After surgical resection, patients were followed up mainly through regular outpatient examinations. The maximum standardized uptake value (SUVmax) of the primary tumor, the mean FDG uptake of bone marrow (BM SUV), bone marrow-liver uptake ratio (BLR), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were measured from the pretreatment FDG PET/CT images. Multi-adjusted Cox proportional hazards models were built to evaluate the independent prognostic value of BLR in predicting recurrence-free survival (RFS). A restricted cubic spline regression model was conducted to provide more precise estimates and examine the shape of the associations between BLR and the risk of recurrence. RESULTS: The follow-up results showed that 30 of the 195 patients (15.4%) had tumor recurrence. Compared with non-recurrent patients, the primary tumor size in recurrent patients was larger, and the SUVmax, TLG, and serum C-reactive protein (CRP) levels were higher. Univariate analysis showed that BLR, tumor size, SUVmax, TLG, and CRP were significantly correlated with postoperative tumor recurrence. After adjustment for conventional confounding factors, the hazard ratio of BLR was 5.01 (95% CI, 1.32, 18.98) for the highest tertile of BLR compared with the lowest tertile. The multi-adjusted spline regression showed that BLR had a linear relationship with log relative risk (RR) for recurrence when BLR was lower than 0.7. Over this level, the effect stabilized, suggesting a saturation effect for BLR at a level of approximately 0.7 at recurrence. CONCLUSIONS: BLR was an independent risk factor for predicting RFS in T1-2N0M0 lung adenocarcinoma patients after curative surgical resection. BLR can be used as a biomarker for evaluating the risk of lung cancer recurrence.

Neuron types in the zebrafish optic tectum labeled by an id2b transgene.

The larval zebrafish optic tectum has emerged as a prominent model for understanding how neural circuits control visually guided behaviors. Further advances in this area will require tools to monitor and manipulate tectal neurons with cell type specificity. Here, we characterize the morphology and neurotransmitter phenotype of tectal neurons labeled by an id2b:gal4 transgene. Whole-brain imaging of stable transgenic id2b:gal4 larvae revealed labeling in a subset of neurons in optic tectum, cerebellum, and hindbrain. Genetic mosaic labeling of single neurons within the id2b:gal4 expression pattern enabled us to characterize three tectal neuron types with distinct morphologies and connectivities. The first is a neuron type previously identified in the optic tectum of other teleost fish: the tectal pyramidal neuron (PyrN). PyrNs are local interneurons that form two stratified dendritic arbors and one stratified axonal arbor in the tectal neuropil. The second tectal neuron type labeled by the id2b:gal4 transgene is a projection neuron that forms a stratified dendritic arbor in the tectal neuropil and an axon that exits tectum to form a topographic projection to torus longitudinalis (TL). A third neuron type labeled is a projection neuron with a nonstratified dendritic arbor and a descending axonal projection to tegmentum. These findings establish the id2b:gal4 transgenic as a useful tool for future studies aimed at elucidating the functional role of tectum, TL, and tegmentum in visually guided behaviors.

Rapid-acting antidepressants.

Conventional antidepressants (biogenic amine mechanisms) are not fully efficacious (e.g., symptoms remain after treatment, not all patients respond), produce effects only after weeks of daily dosing, and do not impact all disease symptoms. In contrast, a new class of antidepressants has been emerging since 2006 that has demonstrated rapid onset, large effect size, activity after only a single or few dose applications, and positive impact in treatment refractory patients and against some treatment-resistant symptoms (e.g., anhedonia). Rapid-acting antidepressant drug action has been demonstrated in controlled clinical studies for ketamine, a few other NMDA receptor antagonists, and scopolamine. Less clinical data are currently available for psychedelic drugs such as psilocybin, lysergic acid diethylamide, and ayahuasca. The mechanisms of action of rapid-acting antidepressants are not fully understood. However, a general triggering mechanism appears to involve the potentiation of AMPA receptor function. Although the durability of antidepressant effects of ketamine and scopolamine is limited, psychedelic drugs have been reported to produce effects for many months. The primary impediment to generating a medicine of this type for depressed patients is side effects and the lack of methods to ensure enduring antidepressant effects. Thus, further exploration of drug possibilities continues. Esketamine ((S)-ketamine) was recently FDA approved. Compounds currently in clinical development include the NMDA receptor antagonist (R)-ketamine, the NMDA receptor modulator, GLYX-13 (Rapastinel), and the AMPA receptor potentiator TAK-653. Additional pharmacological classes have produced effects in the preclinical laboratory to suggest their potential as rapid-acting agents. These include mGlu2/3 receptor antagonists, AMPA receptor potentiators, and negative allosteric modulators of GABAA(α5) receptors. In all cases, molecules exist that could be used to provide clinical proof of concept testing.

Quantitative evaluation of computed and voxelwise computed diffusion-weighted imaging in breast cancer.

OBJECTIVES: To assess the value of computed diffusion-weighted imaging (cDWI) and voxelwise computed diffusion-weighted imaging (vcDWI) in breast cancer. METHODS: This retrospective study involved 130 patients (age range, 25-70 years; mean age ± standard deviation, 48.6 ± 10.5 years) with 130 malignant lesions, who underwent MRI examinations, including a DWI sequence, prior to needle biopsy or surgery. cDWIs with higher b-values of 1500, 2000, 2500, 3000, 3500, and 4000 s/mm2, and vcDWI were generated from measured (m) DWI with two lower b-values of 0/600, 0/800, or 0/1000 s/mm2. The signal-to-noise ratio (SNR) and contrast ratio (CR) of all image sets were computed and compared among different DWIs by two experienced radiologists independently. To better compare the CR with the SNR, the CR value was multiplied by 100 (CR100). RESULTS: The CR of vcDWI, and cDWIs, except for cDWI1000, differed significantly from that of measured diffusion-weighted imaging (mDWI) (cDWI1000: CR = 0.4904, p = 0.394; cDWI1500: CR = 0.5503, p = 0.006; cDWI2000: CR = 0.5889, p < 0.001; cDWI2500: CR = 0.6109, p < 0.001; cDWI3000: mean = 0.6214, p < 0.001; cDWI3500: CR = 0.6245, p < 0.001; cDWI4000: CR = 0.6228, p < 0.001). The vcDWI provided the highest CR, while the CRs of all cDWI image sets improved with increased b-values. The SNR of neither cDWI1000 nor vcDWI differed significantly from that of mDWI, but the mean SNRs of the remaining cDWIs were significantly lower than that of mDWI. The SNRs of cDWIs declined with increasing b-values, and the initial decrease at low b-values was steeper than the gradual attenuation at higher b-values; the CR100 rose gradually, and the two converged on the b-value interval of 1500-2000 s/mm2 . CONCLUSIONS: The highest CR was achieved with vcDWI; this could be a promising approach easier detection of breast cancer. ADVANCES IN KNOWLEDGE: This study comprehensively compared and evaluated the value of the emerging post-processing DWI techniques (including a set of cDWIs and vcDWI) in breast cancer.

Negative allosteric modulation of alpha 5-containing GABAA receptors engenders antidepressant-like effects and selectively prevents age-associated hyperactivity in tau-depositing mice.

RATIONALE: Associated with frank neuropathology, patients with Alzheimer's disease suffer from a host of neuropsychiatric symptoms that include depression, apathy, agitation, and aggression. Negative allosteric modulators (NAMs) of α5-containing GABAA receptors have been suggested to be a novel target for antidepressant action. We hypothesized that pharmacological modulation of this target would engender increased motivation in stressful environments. METHODS: We utilized electrophysiological recordings from Xenopus oocytes and behavioral measures in mice to address this hypothesis. RESULTS: In the forced-swim assay in mice that detects antidepressant drugs, the α5ß3γ2 GABAΑ receptor NAM, RY-080 produced a marked antidepressant phenotype. Another compound, PWZ-029, was characterized as an α5ß3γ2 receptor NAM of lower intrinsic efficacy in electrophysiological studies in Xenopus oocytes. In contrast to RY-080, PWZ-029 was only moderately active in the forced-swim assay and the α5ß3γ2 receptor antagonist, Xli-093, was not active at all. The effects of RY-080 were prevented by the non-selective benzodiazepine receptor antagonist flumazenil as well as by the selective ligands, PWZ-029 and Xli-093. These findings demonstrate that this effect of RY-080 is driven by negative allosteric modulation of α5ßγ2 GABAA receptors. RY-080 was not active in the tail-suspension test. We also demonstrated a reduction in the age-dependent hyperactivity exhibited by transgenic mice that accumulate pathological tau (rTg4510 mice) by RY-080. The decrease in hyperactivity by RY-080 was selective for the hyperactivity of the rTg4510 mice since the locomotion of control strains of mice were not significantly affected by RY-080. CONCLUSIONS: α5ßγ2 GABAA receptor NAMs might function as a pharmacological treatment for mood, amotivational syndromes, and psychomotor agitation in patients with Alzheimer's and other neurodegenerative disorders.