Visceral Adiposity and Progression of ADPKD: A Cohort Study of Patients From the TEMPO 3:4 Trial.

RATIONALE & OBJECTIVE: Body mass index (BMI) is an independent predictor of kidney disease progression in individuals with autosomal dominant polycystic kidney disease (ADPKD). Adipocytes do not simply act as a fat reservoir but are active endocrine organs. We hypothesized that greater visceral abdominal adiposity would associate with more rapid kidney growth in ADPKD and influence the efficacy of tolvaptan. STUDY DESIGN: A retrospective cohort study. SETTING & PARTICIPANTS: 1,053 patients enrolled in the TEMPO 3:4 tolvaptan trial with ADPKD and at high risk of rapid disease progression. PREDICTOR: Estimates of visceral adiposity extracted from coronal plane magnetic resonance imaging (MRI) scans using deep learning. OUTCOME: Annual change in total kidney volume (TKV) and effect of tolvaptan on kidney growth. ANALYTICAL APPROACH: Multinomial logistic regression and linear mixed models. RESULTS: In fully adjusted models, the highest tertile of visceral adiposity was associated with greater odds of annual change in TKV of≥7% versus<5% (odds ratio [OR], 4.78 [95% CI, 3.03-7.47]). The association was stronger in women than men (interaction P<0.01). In linear mixed models with an outcome of percent change in TKV per year, tolvaptan efficacy (% change in TKV) was reduced with higher visceral adiposity (3-way interaction of treatment ∗ time ∗ visceral adiposity, P=0.002). Visceral adiposity significantly improved classification performance of predicting rapid annual percent change in TKV for individuals with a normal BMI (DeLong's test z score: -2.03; P=0.04). Greater visceral adiposity was not associated with estimated glomerular filtration rate (eGFR) slope in the overall cohort; however, visceral adiposity was associated with more rapid decline in eGFR slope (below the median) in women (fully adjusted OR, 1.06 [95% CI, 1.01-1.11] per 10 unit increase in visceral adiposity) but not men (OR, 0.98 [95% CI, 0.95-1.02]). LIMITATIONS: Retrospective; rapid progressors; computational demand of deep learning. CONCLUSIONS: Visceral adiposity that can be quantified by MRI in the coronal plane using a deep learning segmentation model independently associates with more rapid kidney growth and improves classification of rapid progression in individuals with a normal BMI. Tolvaptan efficacy decreases with increasing visceral adiposity. PLAIN-LANGUAGE SUMMARY: We analyzed images from a previous study with the drug tolvaptan conducted in patients with autosomal dominant polycystic kidney disease (ADPKD) to measure the amount of fat tissue surrounding the kidneys (visceral fat). We had previously shown body mass index can predict kidney growth in this population; now we determined whether visceral fat was an important factor associated with kidney growth. Using a machine learning tool to automate measurement of fat in images, we observed that visceral fat was independently associated with kidney growth, that it was a better predictor of faster kidney growth in lean patients than body mass index, and that having more visceral fat made treatment of ADPKD with tolvaptan less effective.

Differentiation of rebound and lymphoid thymic hyperplasia from anterior mediastinal tumors with dual-echo chemical-shift MR imaging in adulthood: reliability of the chemical-shift ratio and signal intensity index.

PURPOSE: To prospectively evaluate (a) effectiveness and limits of dual-echo chemical-shift magnetic resonance (MR) imaging for distinguishing hyperplastic thymus from anterior mediastinal tumors in adulthood by using chemical-shift ratio ( CSR chemical-shift ratio ) and signal intensity index ( SII signal intensity index ), with proposal of optimal threshold value for each, and (b) whether age affects these indexes. MATERIALS AND METHODS: Study was institutional review board approved, with informed consent obtained. Ninety-two subjects (53 men, 39 women; age range, 18-84 years) were divided into a rebound and lymphoid hyperplasia group (group A, 30 patients) and a tumor group (group B, 62 patients). MR images were assessed; interrater reliability was evaluated. Differences in CSR chemical-shift ratio and SII signal intensity index were tested with the Mann-Whitney U test and the Kruskal-Wallis test. Discrimination abilities of CSR chemical-shift ratio and SII signal intensity index were evaluated with logistic regression models, and optimal cutoff points were proposed. Quantitative parameters were correlated with age by using Pearson correlation coefficients. RESULTS: Interreader agreement was excellent (intraclass correlation coefficient: CSR chemical-shift ratio , 0.893; SII signal intensity index , 0.898). Mean CSR chemical-shift ratio and SII signal intensity index ± standard deviation were 0.545 ± 0.162 and 46.29% ± 18.41 for group A and 1.045 ± 0.094 and -0.06% ± 4.89 for group B, respectively, with significant differences for both indexes between groups (P < .0001). No overlap was found for SII signal intensity index between groups; CSR chemical-shift ratio values overlapped in a few younger adults. Distinguishing hyperplastic thymus from tumors was better with SII signal intensity index than CSR chemical-shift ratio . Respective sensitivity, specificity, and cutoff points were 100%, 100%, and 8.92% for SII signal intensity index and 100%, 96.7%, and 0.849 for CSR chemical-shift ratio . Significant correlation was found for CSR chemical-shift ratio (r = -0.761) and SII signal intensity index (r = 0.821) with age in group A (P < .001). For group B, significant correlation with age was seen for CSR chemical-shift ratio (r = 0.702, P < .001) but not SII signal intensity index (r = -0.196, P = .127). All subjects but one in group A and none in group B had signal intensity decrease at chemical-shift MR imaging. CONCLUSION: With dual-echo chemical-shift MR imaging, SII signal intensity index and CSR chemical-shift ratio have high accuracy to distinguish thymic hyperplasia from tumors, although overlapped CSR chemical-shift ratio values can occur in early adulthood.

Dynamic functional connectivity in schizophrenia and bipolar disorder: A review of the evidence and associations with psychopathological features.

Alterations of functional network connectivity have been implicated in the pathophysiology of schizophrenia (SCZ) and bipolar disorder (BD). Recent studies also suggest that the temporal dynamics of functional connectivity (dFC) can be altered in these disorders. Here, we summarized the existing literature on dFC in SCZ and BD, and their association with psychopathological and cognitive features. We systematically searched PubMed, Web of Science, and Scopus for studies investigating dFC in SCZ and BD and identified 77 studies. Our findings support a general model of dysconnectivity of dFC in SCZ, whereas a heterogeneous picture arose in BD. Although dFC alterations are more severe and widespread in SCZ compared to BD, dysfunctions of a triple network system underlying goal-directed behavior and sensory-motor networks were present in both disorders. Furthermore, in SCZ, positive and negative symptoms were associated with abnormal dFC. Implications for understanding the pathophysiology of disorders, the role of neurotransmitters, and treatments on dFC are discussed. The lack of standards for dFC metrics, replication studies, and the use of small samples represent major limitations for the field.

Interpreting permeability as a function of free drug fraction: The case studies of cyclodextrins and liposomes.

In order to solubilize poorly soluble active pharmaceutical ingredients, various strategies have been implemented over the years, including the use of nanocarriers, such as cyclodextrins and liposomes. However, improving a drug's apparent solubility does not always translate to enhanced bioavailability. This work aimed to investigate to which extent complexation with cyclodextrins and incorporation into liposomes influence drug in vitro permeability and to find a mechanistic description of the permeation process. For this purpose, we investigated hydroxypropyl-ß-cyclodextrin (HP-ß-CD) and phosphatidylcholine liposomes formulations of three chemically diverse compounds (atenolol, ketoprofen and hydrocortisone). We studied drug diffusion of the formulations by UV-localized spectroscopy and advanced data fitting to extract parameters such as diffusivity and bound-/free drug fractions. We then correlated this information with in vitro drug permeability obtained with the novel PermeaPadⓇ barrier. The results showed that increased concentration of HP-ß-CD leads to increased solubilization of the poorly soluble unionized ketoprofen, as well as hydrocortisone. However, this net increment of apparent solubility was not proportional to the increased flux measured. On the other hand, normalising the flux over the empirical free drug concentration, i.e., the free fraction, gave a meaningful absolute permeability coefficient. The results achieved for the liposomal formulation were consistent with the finding on cyclodextrins. In conclusion, we proved the adequacy and usefulness of our method for calculating free drug fractions in the examined enabling formulations, supporting the validity of the established drug diffusion/permeation theory that the unbounded drug fraction is the main driver for drug permeation across a membrane.

Modelling drug diffusion through unstirred water layers allows real-time quantification of free/loaded drug fractions and release kinetics from colloidal-based formulations.

The correlation between in vivo and in vitro data is yet not sufficiently optimized to allow a significant reduction and replacement of animal testing in pharmaceutical development. One of the main reasons for this lies in the poor mechanistic understanding and interpretation of the physical mechanisms enabling formulation rely on for deploying the drug. One mechanism that still lacks a proper interpretation is the kinetics of drug release from nanocarriers. In this work, we investigate two different types of classical enabling formulations - i) cyclodextrin solutions and ii) liposomal dispersions - by a combination of an experimental method (i.e. UV-Vis localized spectroscopy) and mathematical modelling/numerical data fitting. With this approach, we are able to discriminate precisely between the amount of drug bound to nanocarriers or freely dissolved at any time point; in addition, we can precisely estimate the binding and diffusivity constants of all chemical species (free drug/bound drug). The results obtained should serve as the first milestone for the further development of reliable in vitro/in silico models for the prediction of in vivo drug bioavailability when enabling formulations are used.

The role of radiology in the evaluation of the immunotherapy efficacy.

In the last years, a great interest has arisen on immunotherapy for the treatment of advanced non-small cell lung cancer (NSCLC). Check-point inhibitor drugs are now considered clinical practice standard in different settings and their use is expected to increase significantly in the near future. As treatment options for lung cancer advance and vary, the different patterns of radiological response increase in number and heterogeneity. To correctly evaluate the radiological findings after and during these treatments is of paramount importance, both in the clinical and sperimental setting. In consideration of their peculiar mechanism, immunotherapies can determine unusual response patterns on imaging, that cannot be correctly evaluated with the traditional response criteria such as World Health Organization (WHO) and Response Evaluation Criteria in Solid Tumours (RECIST). Therefore, during these years, several response criteria [immune-related response criteria (irRC), irRECIST and iRECIST] were proposed and applied in clinical trials on immunotherapies. The aim of this review is to describe the radiological findings after immunotherapy, to critically discuss the different response criteria and the imaging of immune-related adverse events.

Effectiveness of chest radiography, lung ultrasound and thoracic computed tomography in the diagnosis of congestive heart failure.

Hydrostatic pulmonary edema is as an abnormal increase in extravascular water secondary to elevated pressure in the pulmonary circulation, due to congestive heart failure or intravascular volume overload. Diagnosis of hydrostatic pulmonary edema is usually based on clinical signs associated to conventional radiography findings. Interpretation of radiologic signs of cardiogenic pulmonary edema are often questionable and subject. For a bedside prompt evaluation, lung ultrasound (LUS) may assess pulmonary congestion through the evaluation of vertical reverberation artifacts, known as B-lines. These artifacts are related to multiple minimal acoustic interfaces between small water-rich structures and alveolar air, as it happens in case of thickened interlobular septa due to increase of extravascular lung water. The number, diffusion and intensity of B lines correlates with both the radiologic and invasive estimate of extravascular lung water. The integration of conventional chest radiograph with LUS can be very helpful to obtain the correct diagnosis. Computed tomography (CT) is of limited use in the work up of cardiogenic pulmonary edema, due to its high cost, little use in the emergencies and radiation exposure. However, a deep knowledge of CT signs of pulmonary edema is crucial when other similar pulmonary conditions may occasionally be in the differential diagnosis.

Pathophysiology, clinical features and radiological findings of differentiation syndrome/all-trans-retinoic acid syndrome.

In acute promyelocytic leukemia, differentiation therapy based on all-trans-retinoic acid can be complicated by the development of a differentiation syndrome (DS). DS is a life-threatening complication, characterized by respiratory distress, unexplained fever, weight gain, interstitial lung infiltrates, pleural or pericardial effusions, hypotension and acute renal failure. The diagnosis of DS is made on clinical grounds and has proven to be difficult, because none of the symptoms is pathognomonic for the syndrome without any definitive diagnostic criteria. As DS can have subtle signs and symptoms at presentation but progress rapidly, end-stage DS clinical picture resembles the acute respiratory distress syndrome with extremely poor prognosis; so it is of absolute importance to be conscious of these complications and initiate therapy as soon as it was suspected. The radiologic appearance resembles the typical features of cardiogenic pulmonary edema. Diagnosis of DS remains a great skill for radiologists and haematologist but it is of an utmost importance the cooperation in suspect DS, detect the early signs of DS, examine the patients' behaviour and rapidly detect the complications.