Ring-fused 2-pyridones effective against multidrug-resistant Gram-positive pathogens and synergistic with standard-of-care antibiotics.

The alarming rise of multidrug-resistant Gram-positive bacteria has precipitated a healthcare crisis, necessitating the development of new antimicrobial therapies. Here we describe a new class of antibiotics based on a ring-fused 2-pyridone backbone, which are active against vancomycin-resistant enterococci (VRE), a serious threat as classified by the Centers for Disease Control and Prevention, and other multidrug-resistant Gram-positive bacteria. Ring-fused 2-pyridone antibiotics have bacteriostatic activity against actively dividing exponential phase enterococcal cells and bactericidal activity against nondividing stationary phase enterococcal cells. The molecular mechanism of drug-induced killing of stationary phase cells mimics aspects of fratricide observed in enterococcal biofilms, where both are mediated by the Atn autolysin and the GelE protease. In addition, combinations of sublethal concentrations of ring-fused 2-pyridones and standard-of-care antibiotics, such as vancomycin, were found to synergize to kill clinical strains of VRE. Furthermore, a broad range of antibiotic resistant Gram-positive pathogens, including those responsible for the increasing incidence of antibiotic resistant healthcare-associated infections, are susceptible to this new class of 2-pyridone antibiotics. Given the broad antibacterial activities of ring-fused 2-pyridone compounds against Gram-positive (GmP) bacteria we term these compounds GmPcides, which hold promise in combating the rising tide of antibiotic resistant Gram-positive pathogens.

Synthesis of Three-Dimensional Ring Fused Heterocycles by a Selective [4 + 2] Cycloaddition Between Bicyclic Thiazolo 2-Pyridones and Arynes.

A selective [4 + 2] cycloaddition reaction of thiazolo-2-pyridones with arynes has been demonstrated. The developed protocol allows rapid access to highly functionalized, structurally complex thiazolo-fused bridged isoquinolones in high yields, which are susceptible to further late-stage functionalization.

Controlled Noncovalent Synthesis of Secondary Supramolecular Polymers.

Dynamic supramolecular polymers, with their functional similarities to classical covalent polymers and their adaptive and self-repairing nature reminiscent of biological assemblies, have emerged as highly promising systems for the design of smart soft materials. Recent advancements in mechanistic investigations and novel synthetic strategies, such as living supramolecular polymerization, have significantly enhanced our ability to control the primary structure of these supramolecular polymers. However, realizing their full functional potential requires expanding their topological diversity in a manner akin to classical polymers as well as achieving precise molecular organization at higher hierarchical levels of self-assembly. In this paper, we present a remarkable advancement in this field, introducing an unprecedented and controlled synthesis of secondary supramolecular polymers. Our innovative strategy combines chirality-controlled surface-catalyzed secondary nucleation and a bioinspired peptide design, effectively stabilizing higher-order assembly. Furthermore, by harnessing this stereoselective nucleation process, we demonstrate the successful synthesis of racemic supramolecular polymers featuring parallelly stacked conglomerate microstructures─a previously unreported topology in synthetic self-assembled systems. Additionally, we elucidate that the extent of secondary supramolecular polymers can be regulated by modulating the enantiomeric excess of the chiral monomers. Consequently, our study unveils new topologies that exhibit enhanced higher-order structural complexity in the realm of supramolecular polymers.

Strategies to increase primary care provider capacity for hepatitis C care: The California ECHO-PLUS study.

Expanding capacity to screen and treat those infected with the hepatitis C virus (HCV) is an essential element of the global elimination strategy. We evaluated the hub-and-spoke Project ECHO training versus telementoring models to educate, train and support HCV care by primary care providers in 13 targeted counties in northern California. A novel provider engagement strategy was used. Provider engagement and retention, time to readiness to treat HCV, and knowledge and confidence were the outcomes of interest. 94 participants from 60 unique clinics in the target counties participated in the ECHO-PLUS programme; 39.4% were physicians, 48.9% were advanced practice providers, and 11.7% were nurses. The median (range) participation time was 5 (1-49) hours. Confidence scores (minimum score = 13 and maximum score = 65) increased by a mean of 14.0 (SD:8.2) and 11.4 (SD:12.0) points for the hub-and-spoke and telementoring programmes, respectively (p = .53), with the largest changes in confidence seen in treating patients per guidelines, managing side effects and in serving as a consultant for HCV in their clinic. Among 24 participants with data on time to treatment, median time from beginner to experienced was 8 h (IQR:6-12) for hub-and-spoke and 2 h (IQR:1-2.4) for the telementoring programme (p = .01). A 'boots on the ground' approach to recruiting HCV champions was effective within rural communities. Both tele-ECHO hub-and-spoke and telementoring approaches to training primary care providers yielded increase in knowledge and confidence in HCV care and amplified the number of patients who were screened and treated. Telementoring accelerated the timeline of novice providers being 'ready to treat'.

Secondary Nucleation-Triggered Physical Cross-Links and Tunable Stiffness in Seeded Supramolecular Hydrogels.

Mechanistic understanding and the control of molecular self-assembly at all hierarchical levels remain grand challenges in supramolecular chemistry. Functional realization of dynamic supramolecular materials especially requires programmed assembly at higher levels of molecular organization. Herein, we report an unprecedented molecular control on the fibrous network topology of supramolecular hydrogels and their resulting macroscopic properties by biasing assembly pathways of higher-order structures. The surface-catalyzed secondary nucleation process, a well-known mechanism in amyloid fibrilization and chiral crystallization of small molecules, is introduced as a non-covalent strategy to induce physical cross-links and bundling of supramolecular fibers, which influences the microstructure of gel networks and subsequent mechanical properties of hydrogels. In addition, seed-induced instantaneous gelation is realized in the kinetically controlled self-assembled system under this study, and more importantly, the extent of secondary nucleation events and network topology is manipulated by the concentration of seeds.

Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis.

Mycobacterium tuberculosis (Mtb) killed more people in 2017 than any other single infectious agent. This dangerous pathogen is able to withstand stresses imposed by the immune system and tolerate exposure to antibiotics, resulting in persistent infection. The global tuberculosis (TB) epidemic has been exacerbated by the emergence of mutant strains of Mtb that are resistant to frontline antibiotics. Thus, both phenotypic drug tolerance and genetic drug resistance are major obstacles to successful TB therapy. Using a chemical approach to identify compounds that block stress and drug tolerance, as opposed to traditional screens for compounds that kill Mtb, we identified a small molecule, C10, that blocks tolerance to oxidative stress, acid stress, and the frontline antibiotic isoniazid (INH). In addition, we found that C10 prevents the selection for INH-resistant mutants and restores INH sensitivity in otherwise INH-resistant Mtb strains harboring mutations in the katG gene, which encodes the enzyme that converts the prodrug INH to its active form. Through mechanistic studies, we discovered that C10 inhibits Mtb respiration, revealing a link between respiration homeostasis and INH sensitivity. Therefore, by using C10 to dissect Mtb persistence, we discovered that INH resistance is not absolute and can be reversed.

Chiral Arylene Diimide Phosphors: Circularly Polarized Ambient Phosphorescence from Bischromophoric Pyromellitic Diimides.

Chiral organic phosphors with circularly polarized room-temperature phosphorescence (CPP) provide new prospects to the realm of circularly polarized luminescence (CPL) materials, owing to the long-lived triplet states and persistent emission. Although several molecular designs show efficient room-temperature phosphorescence (RTP), realization of ambient organic CPP remains a formidable challenge. Herein, we introduce a chiral bischromophoric phosphor design to realize ambient CPP emission by appending molecular phosphors to a chiral diaminocyclohexane core. Thus, solution-processable polymer films of the trans-1,2-diaminocyclohexane (DAC) chiral cores with heavy-atom substituted pyromellitic diimide phosphors, exhibits one of the most efficient exclusive CPP emissions with high phosphorescence quantum yield (≈18 % in air and ≈46 % under vacuum) and significant luminescence dissymmetry factor (|glum |≈4.0×10-3 ).

Stereoselective Primary and Secondary Nucleation Events in Multicomponent Seeded Supramolecular Polymerization.

Bioinspired, kinetically controlled seeded growth has been recently shown to provide length, dispersity, and sequence control on the primary structure of dynamic supramolecular polymers. However, command over the molecular organization at all hierarchical levels for the modulation of higher order structures of supramolecular polymers remains a formidable task. In this context, a surface-catalyzed secondary nucleation process, which plays an important role in the autocatalytic generation of amyloid fibrils and also during the chiral crystallization of small monomers, offers exciting possibilities for topology control in synthetic macromolecular systems by introducing secondary growth pathways compared to the usual primary nucleation-elongation process. However, mechanistic insights into the molecular determinants and driving forces for the secondary nucleation event in synthetic systems are not yet realized. Herein, we attempt to fill this dearth by showing an unprecedented molecular chirality control on the primary and secondary nucleation events in seed-induced supramolecular polymerization. Comprehensive kinetic experiments using in situ spectroscopic probing of the temporal changes of the monomer organization during the growth process provide a unique study to characterize the primary and secondary nucleation events in a supramolecular polymerization process. Kinetic analyses along with various microscopic studies further reveal the remarkable effect of stereoselective nucleation and seeding events on the (micro)structural aspects of the resulting multicomponent supramolecular polymers.

Dynamic Positron Emission Tomography/Computed Tomography Imaging Correlate of Nonalcoholic Steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease characterized by lobular inflammation and hepatocyte injury and is a key determinant of clinical outcome.1 Liver biopsy remains the gold standard for diagnosis but is limited by risks of the procedure and interobserver variability. Although magnetic resonance imaging (MRI)-based technology may provide novel means to identify NASH,2 there remains a significant need for other modalities to diagnose NASH noninvasively. Glucose transport, an integral tissue process altered in NASH,3 is measurable with 18F-fluorodeoxyglucose positron emission tomography (FDG PET). Because unenhanced computed tomography (CT) scan can detect hepatic steatosis quite reliably,4 and PET combines unenhanced CT for attenuation correction, we hypothesized that measurement of the combination of glucose transport by PET and steatosis by CT could yield a reliable radiologic correlate of NASH.

Willingness to participate in research among black patients with liver disease: A national cross-sectional study.

In the United States, Black people are disproportionately diagnosed with hepatitis C virus (HCV) compared with White people but are under-represented in HCV studies. In this US-based cross-sectional telephone survey study, we assessed willingness to participate (WTP) in health/medical research and attitudes and beliefs that may influence WTP among Black patients with HCV. Two hundred participants who had current or prior HCV diagnosis and self-identified as Black or African American were recruited from a national HCV cohort study and an outpatient hepatology clinic. WTP responses ranged from 1 (not at all willing) to 5 (very willing). Multivariable models were used to identify factors associated with the overall mean WTP score. In addition, an open-ended question solicited strategies to help increase research participation from the Black community. Overall, participants reported moderate WTP in research (Mean [95% Confidence Interval (CI)] = 3.78 [3.68, 3.88]). Of 13 types of research presented, participants reported lowest WTP for randomized controlled trials of medications (Mean [95% CI] = 2.31 [2.11, 2.50]). The initial multivariable model identified higher subjective knowledge of research as positively associated with WTP (Parameter estimate [95% CI] = 0.15 [0.02, 0.27]). Sensitivity analyses also identified higher perceived benefits of research as an additional factor associated with WTP. Qualitative findings indicate that greater community-based outreach efforts would increase accessibility of research opportunities. When given the opportunity to participate, Black participants with HCV reported moderate WTP in health/medical research. Research sponsors and investigators should employ community-based outreach to expand access and awareness of research opportunities.

Patient-reported outcomes 12 months after hepatitis C treatment with direct-acting antivirals: Results from the PROP UP study.

BACKGROUND & AIMS: The long-term impact of hepatitis C virus (HCV) therapy with all-oral direct-acting antivirals (DAAs) on patient-reported outcomes (PROs) has not been well-described. We characterized changes in PROs from pre-treatment to 12 months post-treatment in a real-world cohort. METHODS: PROP UP was a multi-centre observational cohort study of 1601 patients treated with DAAs at 11 US gastroenterology/hepatology practices from 2015 to 2017. PROs were evaluated pre-treatment (T1) and 12 months post-treatment (T5). A minimally important change (MIC) threshold was prespecified as >5% change in PRO scores from T1 to T5. Multivariable analyses identified predictors of change. RESULTS: Three-quarters of patients were 55 or older; 45% were female, 60% were white, 33% were black, nearly half had cirrhosis. The most commonly-prescribed DAA regimens were sofosbuvir-based (83%) and grazoprevir/elbasvir (11%). Study retention was >95%. On average, small improvements were observed at 3 months post-treatment in all PROs and sustained at 12 months post-treatment among patients with sustained virologic response (SVR). Clinically meaningful improvements were achieved in fatigue (mean change score: -3.7 [-4.2, -3.1]), sleep (mean change score: -3.1 [-3.7, -2.5]), abdominal pain (mean change score: -2.6 [-3.3, -1.9]) and functional well-being (mean change score: -7.0 [-6.0, -8.0]). Symptom improvements were generally not sustained with no SVR (n = 52). Patients with cirrhosis and MELD ≥12 had the greatest improvements in functional well-being (-12.9 [-17.6, -8.1]). CONCLUSIONS: The improvements in patient-reported outcomes reported by patients who achieved SVR following HCV DAA therapy were durable at 12 months post-treatment.

Ascites development is associated with worse outcome in patients after kidney transplantation.

BACKGROUND: We provide detailed analysis and outcomes in patients post-kidney transplant (KT) developing ascites, which has never been categorically reported. METHODS: Ascites was identified by ICD9/10 codes and detailed chart review in patients post-KT from 01/2004-06/2019. The incidence of patient death and graft loss were determined per 100-person-years, and the incidence rate ratio was obtained. RESULTS: Of 3329 patients receiving KT, 83 (2.5%) patients had new-onset ascites, of whom 58% were male, 21% blacks, and 29% whites. Seventy-five percentage were on hemodialysis. Patients were maintained primarily on tacrolimus and mycophenolate for immunosuppression. Only 14% of patients with ascites had the appropriate diagnostic workup. There was a trend toward an increased mortality in patients with ascites (incidence rate ratio, IRR [95% CI]: 1.8 [0.92, 3.19], p = .06), and a significantly higher incidence of graft loss (IRR: 5.62 [3.97, 7.76], p < .001), compared with non-ascites patients. When classified by ascites severity, determined by imaging, moderate/severe ascites patients had the worst clinical outcomes, with a mortality of 32% and graft failure in 57%, compared with 9% and 10%, respectively, in those without ascites. CONCLUSION: In this large cohort employing stepwise analysis of ascites post-KT, worse outcomes were noted, dictating the need for optimized management to improve clinical outcomes.

Tandem Ring Opening/Intramolecular [2 + 2] Cycloaddition Reaction for the Synthesis of Cyclobutane Fused Thiazolino-2-Pyridones.

Reaction of thiazoline fused 2-pyridones with alkyl halides in the presence of cesium carbonate opens the thiazoline ring via S-alkylation and generates N-alkenyl functionalized 2-pyridones. In the reaction with propargyl bromide, the thiazoline ring opens and subsequently closes via a [2 + 2] cycloaddition between an in situ generated allene and the α,ß-unsaturated methyl ester. This method enabled the synthesis of a variety of cyclobutane fused thiazolino-2-pyridones, of which a few analogues inhibit amyloid ß1-40 fibril formation. Furthermore, other analogues were able to bind mature α-synuclein and amyloid ß1-40 fibrils. Several thiazoline fused 2-pyridones with biological activity tolerate this transformation, which in addition provides an exocyclic alkene as a potential handle for tuning bioactivity.

Indomethacin impairs mitochondrial dynamics by activating the PKCζ-p38-DRP1 pathway and inducing apoptosis in gastric cancer and normal mucosal cells.

The subcellular mechanism by which nonsteroidal anti-inflammatory drugs (NSAIDs) induce apoptosis in gastric cancer and normal mucosal cells is elusive because of the diverse cyclooxygenase-independent effects of these drugs. Using human gastric carcinoma cells (AGSs) and a rat gastric injury model, here we report that the NSAID indomethacin activates the protein kinase Cζ (PKCζ)-p38 MAPK (p38)-dynamin-related protein 1 (DRP1) pathway and thereby disrupts the physiological balance of mitochondrial dynamics by promoting mitochondrial hyper-fission and dysfunction leading to apoptosis. Notably, DRP1 knockdown or SB203580-induced p38 inhibition reduced indomethacin-induced damage to AGSs. Indomethacin impaired mitochondrial dynamics by promoting fissogenic activation and mitochondrial recruitment of DRP1 and down-regulating fusogenic optic atrophy 1 (OPA1) and mitofusins in rat gastric mucosa. Consistent with OPA1 maintaining cristae architecture, its down-regulation resulted in EM-detectable cristae deformity. Deregulated mitochondrial dynamics resulting in defective mitochondria were evident from enhanced Parkin expression and mitochondrial proteome ubiquitination. Indomethacin ultimately induced mitochondrial metabolic and bioenergetic crises in the rat stomach, indicated by compromised fatty acid oxidation, reduced complex I- associated electron transport chain activity, and ATP depletion. Interestingly, Mdivi-1, a fission-preventing mito-protective drug, reversed indomethacin-induced DRP1 phosphorylation on Ser-616, mitochondrial proteome ubiquitination, and mitochondrial metabolic crisis. Mdivi-1 also prevented indomethacin-induced mitochondrial macromolecular damage, caspase activation, mucosal inflammation, and gastric mucosal injury. Our results identify mitochondrial hyper-fission as a critical and common subcellular event triggered by indomethacin that promotes apoptosis in both gastric cancer and normal mucosal cells, thereby contributing to mucosal injury.

Medication Non-adherence in a Prospective, Multi-center Cohort Treated with Hepatitis C Direct-Acting Antivirals.

BACKGROUND: The prevalence and risk factors for non-adherence to direct-acting antivirals (DAAs) for chronic hepatitis C virus (HCV) in clinical practice settings are under-studied. OBJECTIVES: (1) To quantify DAA non-adherence in the total cohort and among subgroups with and without mental health conditions, alcohol use, and substance use, and (2) to investigate patient- and treatment-level risk factor non-adherence. DESIGN: Prospective, observational cohort study. PARTICIPANTS: A total of 1562 patients receiving DAAs between January 2016 and October 2017 at 11 US medical centers including academic and community practices. MAIN MEASURES: Self-reported medication non-adherence, defined as any missed doses in the past 7 days, surveyed early (T2: at 4 ± 2 weeks) and late in treatment (T3: 2-3 weeks prior to end of treatment). Non-adherence to post-treatment follow-up visits was defined as absence of lab results after DAA therapy completion. KEY RESULTS: Of 1447 patients, 162 (11%) reported non-adherence at T2 or T3. Medical records indicated 262 (17%) of the 1562 participants had not returned for post-treatment visits. At baseline, 37% of patients reported mental health conditions, 15% reported alcohol use, and 23% reported using substances in the previous year. Baseline characteristics associated with DAA non-adherence included alcohol use (OR 1.96), younger age (< 35 years vs. > 55 years: OR 3.40), non-white race (OR > 2.26), and DAA treatment cohort, but not substance use or mental health condition. Non-adherence to follow-up exhibited association with younger age and a higher baseline overall symptom burden. Among 1287 patients with evaluable sustained virologic response (SVR) data, 53 patients (4%) did not achieve SVR. The bivariate correlation between adherence and SVR was negligible (r = 0.01). CONCLUSIONS: DAA non-adherence was low and SVR rates were high. Mental health conditions, substance use, and alcohol use should not disqualify patients from DAA therapy. Patients with alcohol use disorder before DAA therapy initiation may benefit from targeted on-treatment support.

Room-Temperature Synthesis of Isoindolone Spirosuccinimides: Merger of Visible-Light Photocatalysis and Cobalt-Catalyzed C-H Activation.

A room-temperature C-H bond functionalization of benzamides has been developed by merging a photocatalyst with a cobalt catalyst for the synthesis of isoindolone spirosuccinimides. The reaction proceeds in aerobic conditions and does not require any sacrificial external oxidants such as Ag(I) or Mn(III) salts. Visible light activates the photocatalyst, and it acts as an electron-transfer reagent and helps in the fundamental organometallic steps by modulating the oxidation state of the cobalt complex. This C-H bond functionalization and spirocyclization showed wide substrate scope and good functional group tolerance. A possible reaction mechanism was proposed from the experimental outcome, showing that C-H bond activation is irreversible and not the rate-determining step.

Stereoselective Seed-Induced Living Supramolecular Polymerization.

Stereoselective and temporally controlled supramolecular polymerizations are ubiquitous in nature and are desirable attributes for the design of chiral, well-defined functional materials. Kinetically controlled, living supramolecular polymerization (LSP) has emerged recently for the synthesis of supramolecular polymers with controlled length and narrow dispersity. On the other hand, stringent design requirements for chiral-discriminating monomers precludes the stereoselective control of the supramolecular polymer structure. Herein, a synergetic stereo- and structural control of supramolecular polymerization by the realization of an unprecedented stereoselective seed-induced LSP is reported. Homochiral and seeded growth is demonstrated with bischromophoric naphthalene diimide (NDI) enantiomers with a chiral binaphthyl amine core, exhibiting strong self-recognition abilities and pathway complexity.

Macrophage migration inhibitory factor regulates mitochondrial dynamics and cell growth of human cancer cell lines through CD74-NF-κB signaling.

The indispensable role of macrophage migration inhibitory factor (MIF) in cancer cell proliferation is unambiguous, although which specific roles the cytokine plays to block apoptosis by preserving cell growth is still obscure. Using different cancer cell lines (AGS, HepG2, HCT116, and HeLa), here we report that the silencing of MIF severely deregulated mitochondrial structural dynamics by shifting the balance toward excess fission, besides inducing apoptosis with increasing sub-G0 cells. Furthermore, enhanced mitochondrial Bax translocation along with cytochrome c release, down-regulation of Bcl-xL, and Bcl-2 as well as up-regulation of Bad, Bax, and p53 indicated the activation of a mitochondrial pathway of apoptosis upon MIF silencing. The data also indicate a concerted down-regulation of Opa1 and Mfn1 along with a significant elevation of Drp1, cumulatively causing mitochondrial fragmentation upon MIF silencing. Up-regulation of Drp1 was found to be further coupled with fissogenic serine 616 phosphorylation and serine 637 dephosphorylation, thus ensuring enhanced mitochondrial translocation. Interestingly, MIF silencing was found to be associated with decreased NF-κB activation. In fact, NF-κB knockdown in turn increased mitochondrial fission and cell death. In addition, the silencing of CD74, the cognate receptor of MIF, remarkably increased mitochondrial fragmentation in addition to preventing cell proliferation, inducing mitochondrial depolarization, and increasing apoptotic cell death. This indicates the active operation of a MIF-regulated CD74-NF-κB signaling axis for maintaining mitochondrial stability and cell growth. Thus, we propose that MIF, through CD74, constitutively activates NF-κB to control mitochondrial dynamics and stability for promoting carcinogenesis via averting apoptosis.

Patient-reported symptoms during and after direct-acting antiviral therapies for chronic hepatitis C: The PROP UP study.

BACKGROUND & AIMS: A comprehensive analysis of changes in symptoms and functioning during and after direct-acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection has not been conducted for patients treated in real-world clinical settings. Therefore, we evaluated patient-reported outcomes (PROs) in a diverse cohort of patients with HCV treated with commonly prescribed DAAs. METHODS: PROP UP is a US multicenter observational study of 1,601 patients with HCV treated with DAAs in 2016-2017. PRO data were collected at baseline (T1), early on-treatment (T2), late on-treatment (T3) and 3-months post-treatment (T4). PRO mean change scores were calculated from baseline and a minimally important change (MIC) threshold was set at 5%. Regression analyses investigated patient and treatment characteristics independently associated with PRO changes on-treatment and post-treatment. RESULTS: Of 1,564 patients, 55% were male, 39% non-white, 47% had cirrhosis. Sofosbuvir/ledipasvir was prescribed to 63%, sofosbuvir/velpatasvir to 21%, grazoprevir/elbasvir to 11%, and paritaprevir/ombitasvir/ritonavir + dasabuvir to 5%. During DAA therapy, mean PRO scores improved slightly in the overall cohort, but did not reach the 5% MIC threshold. Between 21-53% of patients experienced >5% improved PROs while 23-36% experienced >5% worse symptoms. Of 1,410 patients with evaluable sustained virologic response (SVR) data, 95% achieved SVR. Among those with SVR, all mean PRO scores improved, with the 5% MIC threshold met for fatigue, sleep disturbance, and functioning well-being. Regression analyses identified subgroups, defined by age 35-55, baseline mental health issues and a higher number of health comorbidities as predictors of PRO improvements. CONCLUSIONS: In real-world clinical practices, we observed heterogeneous patient experiences during and after DAA treatment. Symptom improvements were more pronounced in younger patients, those with baseline mental health issues and multiple comorbidities. LAY SUMMARY: Patients who received direct-acting antiviral medications for hepatitis C at several liver centers in the US did not generally experience significant changes in baseline symptoms during treatment. We observed a full range of patient experiences with some patients experiencing substantial symptom improvements, yet others experiencing less improvements and some even experiencing a worsening of symptoms. The 1,346 patients who were cured of hepatitis C experienced improvements in fatigue, sleep disturbance, and functional well-being, and trends for improved pain and depression; whereas the 64 who were not cured experienced minimal improvements. Clinicaltrial.gov: NCT02601820.

Pilot Study to Diagnose Nonalcoholic Steatohepatitis With Dynamic 18F-FDG PET.

OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are major causes of chronic liver disease characterized by steatosis, inflammation, and fibrosis. Diagnosis of inflammation is limited by the need for liver biopsy. Dynamic PET with the widely used radiotracer 18F-FDG provides a novel method for evaluating spatial and temporal changes in liver inflammation. MATERIALS AND METHODS: Patients with NAFLD or NASH underwent dynamic FDG PET and MRI within 6 months of undergoing liver biopsy. Liver time-activity curves were extracted to estimate kinetic parameters representing various rate constants of FDG transport using tracer kinetic modeling. Liver biopsy specimens were scored on the basis of NASH Clinical Research Network criteria. RESULTS: This pilot study included 22 patients, 14 of whom were women. Patient age ranged from 18 to 70 years, and the mean body mass index (weight in kilograms divided by the square of height in meters) was 33.2 (range, 24-43.1). The K1 value, which represents the rate of FDG transport from blood to hepatic tissue, was significantly correlated with inflammation (r = -0.7284; p = 0.0001) and the overall NAFLD activity score (NAS; r = -0.6750; p = 0.0006). K1 values were inversely related to the hepatic inflammation score and NAS. Although heterogeneity in K1 values across eight liver segments was noted, distinct segregation existed among segmental K1 values dependent on the histologic inflammation score (p = 0.022) or NAS (p = 0.0091). K1 had a strong association with both inflammation (ROC AUC value, 0.88) and the NAS (ROC AUC value, 0.89), with K1 = 1.02 (mL/min/mL) corresponding to a sensitivity and specificity of 93% and 88%, respectively, for the NAS. CONCLUSION: Dynamic FDG PET with tracer kinetic modeling has the potential to determine liver inflammation in patients with NAFLD and NASH and can fill an essential gap in diagnosis.