Improving the reactivity of hydrazine-bearing MRI probes for in vivo imaging of lung fibrogenesis.

Pulmonary fibrosis (PF) is the pathologic accumulation of extracellular matrix components in lung tissue that result in scarring following chronic lung injury. PF is typically diagnosed by high resolution computed tomography (HRCT) and/or invasive biopsy. However, HRCT cannot distinguish old injury from active fibrogenesis. We previously demonstrated that allysine residues on oxidized collagen represent an abundant target during lung fibrogenesis, and that magnetic resonance imaging (MRI) with a small-molecule, gadolinium-containing probe, Gd-Hyd, could specifically detect and stage fibrogenesis in a mouse model. In this work, we present an improved probe, Gd-CHyd, featuring an N,N-dialkyl hydrazine which has an order of magnitude both greater reactivity and affinity for aldehydes. In a paired study in mice with bleomycin induced lung injury we show that the improved reactivity and affinity of Gd-CHyd results in significantly higher lung-to-liver contrast, e.g. 77% higher at 45 min post injection, and slower lung clearance than Gd-Hyd. Gd-CHyd enhanced MRI is >60-fold higher in bleomycin injured mouse lungs compared to uninjured mice. Collectively, our data indicate that enhancing hydrazine reactivity and affinity towards allysine is an effective strategy to significantly improve molecular MRI probes for lung fibrogenesis.

Advanced MRI of Liver Fibrosis and Treatment Response in a Rat Model of Nonalcoholic Steatohepatitis.

Background Liver biopsy is the reference standard to diagnose nonalcoholic steatohepatitis (NASH) but is invasive with potential complications. Purpose To evaluate molecular MRI with type 1 collagen-specific probe EP-3533 and allysine-targeted fibrogenesis probe Gd-Hyd, MR elastography, and native T1 to characterize fibrosis and to assess treatment response in a rat model of NASH. Materials and Methods MRI was performed prospectively (June-November 2018) in six groups of male Wistar rats (a) age- and (b) weight-matched animals received standard chow (n = 12 per group); (c) received choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD) for 6 weeks or (d) 9 weeks (n = 8 per group); (e) were fed 6 weeks of CDAHFD and switched to standard chow for 3 weeks (n = 12); (f) were fed CDAHFD for 9 weeks with daily treatment of elafibranor beginning at week 6 (n = 14). Differences in imaging measurements and tissue analyses among groups were tested with one-way analysis of variance. The ability of each imaging measurement to stage fibrosis was quantified by using area under the receiver operating characteristic curve (AUC) with quantitative digital pathology (collagen proportionate area [CPA]) as reference standard. Optimal cutoff values for distinguishing advanced fibrosis were used to assess treatment response. Results AUC for distinguishing fibrotic (CPA >4.8%) from nonfibrotic (CPA ≤4.8%) livers was 0.95 (95% confidence interval [CI]: 0.91, 1.00) for EP-3533, followed by native T1, Gd-Hyd, and MR elastography with AUCs of 0.90 (95% CI: 0.83, 0.98), 0.84 (95% CI: 0.74, 0.95), and 0.65 (95% CI: 0.51, 0.79), respectively. AUCs for discriminating advanced fibrosis (CPA >10.3%) were 0.86 (95% CI: 0.76, 0.97), 0.96 (95% CI: 0.90, 1.01), 0.84 (95% CI: 0.70, 0.98), and 0.74 (95% CI: 0.63, 0.86) for EP-3533, Gd-Hyd, MR elastography, and native T1, respectively. Gd-Hyd MRI had the highest accuracy (24 of 26, 92%; 95% CI: 75%, 99%) in identifying responders and nonresponders in the treated groups compared with MR elastography (23 of 26, 88%; 95% CI: 70%, 98%), EP-3533 (20 of 26, 77%; 95% CI: 56%, 91%), and native T1 (14 of 26, 54%; 95% CI: 33%, 73%). Conclusion Collagen-targeted molecular MRI most accurately detected early onset of fibrosis, whereas the fibrogenesis probe Gd-Hyd proved most accurate for detecting treatment response. © RSNA, 2020 Online supplemental material is available for this article.

Hepatitis C virus infection in Australian psychiatric inpatients: A multicenter study of seroprevalence, risk factors and treatment experience.

Screening and treatment for hepatitis C virus (HCV) infection were not prioritised in psychiatric patients due to adverse neuropsychiatric effects of interferon therapy despite reports of high prevalence. However, with the safe new antiviral drugs, HCV eradication has become a reality in these patients. The aim of this study was to report HCV seroprevalence, risk factors and treatment model in an Australian cohort. This prospective study involved patients admitted to four inpatient psychiatric units, from December 2016 to December 2017. After pretest counselling and consent, HCV testing was done; information on risk factors collected. A total of 260 patients (70% male), median age 44 years (IQR 24), were studied. The HCV seroprevalence was 10.8% (28/260) with 95% CI 7-15. Independent predictors of HCV positivity were injection drug use (P < 0.001, OR 44.05, 95% CI 7.9-245.5), exposure to custodial stay (P = 0.011, OR 7.34, 95% CI 1.6-33.9) and age (P = 0.011, OR 1.09, 95% CI 1.02-1.16). Eight of the 16 HCV RNA-positive patients were treated. Hepatitis nurses liaised with community mental health teams for treatment initiation and follow-up under supervision of hepatologists. Seven patients achieved sustained viral response, one achieved end of treatment response. The remaining eight patients were difficult to engage with. In conclusion, HCV prevalence was high in our cohort of psychiatric inpatients. Although treatment uptake was achieved only in 50% patients, it was successfully completed in all, with innovative models of care. These findings highlight the need to integrate HCV screening with treatment linkage in psychiatry practice.

Treatment resistant somatic delusions in bipolar disorder.

Two patients each developed a single, fixed somatic delusion complicating their existing bipolar disorder. Both failed to respond to a range of antidepressant and antipsychotic medications. They each showed a partial response to clozapine and to electroconvulsive therapy, with resolution of mood symptoms and diminution of their ongoing somatic preoccupation. A review of case reports suggests a possible relationship between somatic delusions and affective disorders.